ICU

MANAGEMENT & PRACTICE

INTENSIVE CARE - EMERGENCY MEDICINE - ANAESTHESIOLOGY VOLUME 18 - ISSUE 3 - AUTUMN 2018

SPECIAL SUPPLEMENT

Shock
©For personal and private use only. Reproduction must be permitted by the copyright holder. Email to copyright@[Link].

in collaboration with CSL Behring

PLUS
Xenon limits brain damage The sepsis box, bag and trolley,
following cardiac arrest, M. Maze C. Hancock & A. Hermon
& T. Laitio Humanizing the ICU experience
What’s new in sepsis in children? with enhanced communication,
E. Esteban et al. A. Rocher
Optimising sleep in the ICU, Implementing ECCO2R and
M.C. Reade & D. Liu vv-ECMO in non-academic centres,
Cancer patients in the ICU, K. Kogelmann
Pathophysiology of endotoxic shock, F. Forfori et al.
I. Prieto del Portillo et al. Improving access to safe
Fluids in shock, M. Cecconi et al. anaesthesia, J. Mellin-Olsen
What should we stop doing in the
It is time for improved fluid stewardship, M. Malbrain, T.W. Rice, M. Mythen ICU? F.G. Zampieri
S. Wuyts
Caring for very old patients in the
Vasoactive medication and RCTs, J. Gutteling & A.R.J. Girbes ICU, H. Flaatten
Advances in source control in patients with sepsis and septic shock, J.J.
De Waele & I. Martin-Loeches
Organ cross-talk in shock and critical illness, J.R. Prowle
POCUS and SHOCK, A. Wong & J. Wilkinson

[Link] @ICU_Management
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Sedation practices in the ICU Dr. Robert SHULMAN (London, United Kingdom)

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 EDITORIAL 145

ICU MANAGEMENT & PRACTICE VOLUME 18 - ISSUE 3 – AUTUMN 2018

SHOCK
S hock is an emergency, and if it is not treated, it will mostly be fatal. Early intervention
and admission to the ICU is essential. Our cover story considers several aspects of shock,
including pathophysiology and multi-organ dysfunction syndrome, as well as source
control, fluids, differentiation using point-of-care ultrasound and vasoactive medication.
Liu review how to achieve better sleep, including pharmacological and non-pharmacological
treatments. Non-pharmacological methods to improve sleep are almost always preferable
first-line alternatives in critically ill patients, they emphasise.
To admit or not to admit cancer patients to the ICU has been a dilemma in the past. As
Francesco Forfori, Greta Giuliano and Gabriella Licitra elucidate the pathophysiology cancer treatments become more effective, thus improving prognosis, it is likely that the number
of endotoxic shock and the role of endotoxaemia. They suggest that although there are of cancer patients requiring admission to ICU will continue to increase. Isidro Prieto del Portillo,
conflicting results from clinical studies on techniques to remove endotoxin, selected Ignacio Sáez de la Fuente and Pujol Varela apprise us of key elements for successful patient
subgroups of patients could potentially benefit from their use. management: new anti-tumour therapies, admission criteria, improved support measures in
©For personal and private use only. Reproduction must be permitted by the copyright holder. Email to copyright@[Link].

ICUs and ICU trial stays.

Fluids are a key treatment for shock. Antonio Messina, Massimiliano Greco and Maurizio
Cecconi explain which fluids, when, how much and how often. They emphasise that fluids There is a medical aphorism “Don't just stand there, do nothing!” Do we sometimes do
should be administered after testing preload dependency and with continuous evaluation too much or continue with interventions that no longer benefit? Fernando Zampieri argues
of preload dependency/CO response, together with timely monitoring of clinical and that intensivists should acknowledge that they are prone to several cognitive biases and asks
metabolic signs of shock. Fluid stewardship is also important, and Manu Malbrain, Todd “What should we stop doing in the ICU?” Jean-Louis Vincent
Rice and Monty Mythen introduce a conceptual framework for institutional programmes Editor-in-Chief
Next, Elisabeth Esteban, Anna Solé-Ribalta, Iolanda Jordan expound on the diagnosis and ICU Management & Practice
and guidelines to enhance fluid stewardship, which includes appropriate selection, dosing,
treatment of sepsis in children. Rapid response to sepsis is crucial. But does having pre-prepared
duration, de-escalation, and monitoring of fluid therapy. Professor
components, such as a sepsis box, assist? NHS Wales trialled and evaluated this, as described
Vasoactive medication is a cornerstone in shock treatment. Jon Gutteling and Armand by Chris Hancock and Andrew Hermon. Department of Intensive Care
Erasme Hospital / Free Univer-
R.J. Girbes outline the physiology and pharmacology of vasoactive drugs and explain how
In the multidisciplinary ICU team, increasingly psychologists are employed to work with sity of Brussels
to decide on drug dose, the haemodynamic values to pursue, and how much fluid to infuse, Brussels, Belgium
patients, families and staff. Anne Rocher describes an initiative to train clinicians to break bad
by introducing the concept of “enough” for different cardiovascular parameters.
news and communicate with families about limiting therapy and transitioning to comfort care. JLVincent@icu-management.
In the critical first hour of sepsis treatment, source control receives little attention, org
ECMO is feasible outside large academic hospitals, writes Klaus Kogelmann. Before
according to Jan De Waele and Ignacio Martin-Loeches, but should be considered. They
setting up this service, centres should consider which patients, which therapy and which @ICU_Management
outline the challenges, methods and timing. Next, John Prowle expands on the concept
adverse events could be handled.
of ‘organ cross-talk’, which is often used to explain multi-organ dysfunction syndrome.
Our Interview features Jannicke Mellin-Olsen, President of the World Federation of
Point-of-care ultrasound is a useful tool to differentiate and manage shock. Adrian
Societies of Anaesthesiologists. When 5 out of 7 billion people do not have access to safe,
Wong and Jonathan Wilkinson provide an overview of how the various POCUS modules
timely affordable anaesthesia and surgery, anaesthetists need to lead and create awareness,
could be integrated and utilised in the shocked patient.
advocate, educate and set standards, she says, as well as sharing her thoughts on ketamine,
Our Series on Gases continues with a review by Mervyn Maze and Timo Laitio of the gender equity and airway management.
latest research on xenon, which shows promise in treating acute CNS injury, including
after cardiac arrest. As always, if you would like to get in touch, please
In European ICUs, up to 15% of patients may be aged 80 or over, and this age group is email JLVincent@[Link].
increasing in the general population. Hans Flaatten reviews the outcomes for these patients
and outlines geriatric syndromes that intensivists should be aware of as well as specific ICU
care. Achieving good sleep in the ICU depends on many factors. Michael Reade and David Jean-Louis Vincent
 TABLE OF CONTENTS 146

ICU MANAGEMENT & PRACTICE VOLUME 18 - ISSUE 3 – AUTUMN 2018

IN EVERY COVER STORY

ISSUE 150 Pathophysiology of endotoxic shock: mechanisms
of endotoxin-induced multi-organ damage
(Francesco Forfori, Greta Giuliano, Gabriella Licitra)
Summarises the mechanisms and pathways of multi-organ damage induced
175 Organ cross-talk in shock and critical illness
(John R. Prowle)
In this article the concept of organ cross-talk is reviewed and its real
meaning to the clinical is critically appraised.
by LPS exposure.

145 154 Fluids in shock: fluid management during shock

178 POCUS and SHOCK
©For personal and private use only. Reproduction must be permitted by the copyright holder. Email to copyright@[Link].

from physiology to bedside (Adrian Wong, Jonathan Wilkinson)

(Antonio Messina, Massimiliano Greco, Maurizio An overview of how the various POCUS modules could be integrated
EDITORIAL Cecconi) and utilised in the shocked patient.
In critically ill patients with shock, fluid infusion is an early and common
Shock
intervention to restore the balance between the oxygen delivery provided by
(Jean-Louis Vincent)
the cardiac function, and the systemic oxygen request. A modern approach
in patients with shock includes the evaluation of pharmacodynamics and
pharmacokinetics of the infused fluids (type, dose, modality of administra-
SPECIAL SUPPLEMENT
tion, haemodynamic targets and safety limits). in collaboration with CSL Behring
221 (pp.182-190)
I-I-I Blog 158 It is time for improved fluid stewardship
(Manu LNG Malbrain, Todd W. Rice, Monty
Highlights from our I Expert, I
Question, I Answer Blog
Mythen)
A conceptual framework for developing institutional programmes
I Key decisions in a goal-directed coagulation management
approach
Featuring Jean Baptiste Lascarrou, and guidelines to enhance fluid stewardship in the ICU environment.
(Donat R. Spahn)
Linda Kennemar and Pieter An individualised goal-directed approach to managing coagulopathy is recommended to
treat bleeding trauma patients.
Depuydt.
164 Vasoactive medication and RCTs: an
impossible marriage: a review and introduc-
tion of the concept “enough”
(Jon Gutteling, Armand R.J. Girbes)
IV Evidence for using first-line coagulation factor concen-
trates for trauma-induced coagulopathy
An overview of the important physiology and pharmacology of
(Petra Innerhofer)
Fibrinogen limits coagulopathy and massive bleeding, has less transfusion requirements and

224
vasoactive drugs used in the ICU and a review of publications
thereby decreases the risk of multi-organ failure in trauma patients.
comparing these agents. What drug dose should be administered and
what amount of fluid resuscitation is “enough?”
AGENDA
Upcoming events/ courses/
VII Implementation
(Dietmar Fries)
of a revised trauma management protocol
congresses 171 Advances in source control in patients with
sepsis and septic shock Goal-directed therapy of coagulopathy is recommended for trauma patients.

(Jan J. De Waele, Ignacio Martin-Loeches)

Early detection of sepsis and rapid initiation of fluid administration and
antibiotic therapy have improved outcomes. Discussion remains about
the targets for fluid resuscitation, the optimal type of fluid and many
other aspects of sepsis management.
 39th ISICEM
International Symposium
on Intensive Care and
Emergency Medicine
©For personal and private use only. Reproduction must be permitted by the copyright holder. Email to copyright@[Link].

SQUARE - BRUSSELS MEETING CENTER

MARCH 19-22, 2019

Join us in 2019
CME ACCREDITED Endorsed by:
European Society of Intensive Care Medicine
Plenary Sessions, Mini-Symposia, Workshops,
Society of Critical Care Medicine
Technical Forums, Round Tables, Tutorials, American Thoracic Society
Posters European Society for Emergency Medicine
European Shock Society
The Weil Institute of Critical Care Medicine
Meeting Chairman: JL Vincent The Canadian Critical Care Society
Email: jlvincen@[Link]
Australian and New Zealand Intensive Care Society
Manager: V De Vlaeminck International Pan Arab Critical Care Medicine Society
Email: [Link]@[Link] World Federation of Societies of Intensive and
Critical Care Medicine
Dept of Intensive Care, International Sepsis Forum
Erasme University Hospital

[Link]
Route de Lennik, 808, B-1070 Brussels, Belgium
Phone [Link].15/36.31, Email: sympicu@[Link]
 TABLE OF CONTENTS 148

ICU MANAGEMENT & PRACTICE VOLUME 18 - ISSUE 3 – AUTUMN 2018

Editor-in-Chief
Prof. Jean-Louis Vincent Belgium
Editorial Board
Prof. Antonio Artigas Spain
Prof. Jan Bakker Netherlands
SERIES: GASES
Prof. Richard Beale United Kingdom 211 Caring for very old patients in the ICU
(Hans Flaatten)
Prof. Rinaldo Bellomo Australia 192 Xenon limits brain damage following cardiac
arrest: xenon and brain injury (Mervyn Maze, Describes the epidemiology and outcomes for very old patients and the most
relevant “geriatric syndromes” and discusses where we should increase our
Timo Laitio)
Prof. Todd Dorman United States Xenon is neuroprotective and may benefit the critically ill patient that has
body of knowledge to make a more precise triage in this patient group.

ongoing acute neurological injury. Pivotal trials exploring xenon’s efficacy

Prof. Jan De Waele Belgium
214
and safety on clinical outcomes for post-cardiac arrest syndrome are
The sepsis box, bag and trolley: evaluation of aids
Prof. Bin Du China progressing.
to the delivery of sepsis treatment
©For personal and private use only. Reproduction must be permitted by the copyright holder. Email to copyright@[Link].

Prof. Hans Flaatten Norway

(Chris Hancock, Andrew Hermon)
Describes various methods for increasing the speed and effectiveness of Sepsis 6
Prof. Luciano Gattinoni Italy
MATRIX bundle delivery in NHS Wales that have been trialled with positive outcomes.

Prof. Armand Girbes Netherlands

Prof. Edgar Jimenez United States 196 What’s new in sepsis in children? The latest in
diagnosis and treatment (Elisabeth Esteban, Anna
Prof. John A. Kellum United States Solé-Ribalta, Iolanda Jordan)
Updates on diagnosis and treatment of paediatric sepsis.
MANAGEMENT
Prof. Jeff Lipman Australia
Prof. Flavia Machado Brazil 218 Humanizing the ICU experience with enhanced
communication: Avicenne ICU’s initiative
Prof. John Marini United States 200 Optimising sleep in the ICU
(Michael C. Reade, David Liu)
(Anne Rocher)
Supporting families during the process of shared decision-making from the
Disordered sleep is common in ICU patients. While many of the reasons are
pursuit of cure/recovery to the pursuit of comfort/freedom of pain is a key
Prof. John Marshall Canada impossible to modify and others rely on improvement in the underlying
concern for our ICU. As few physicians had received formal training in how to
condition, actions of the treating team could help ICU patients with disordered
Prof. Paul E. Pepe United States deliver bad news, Avicenne ICU, with the help of a newly appointed psycholo-
sleep.
gist, has developed specific training.
Prof. Paolo Pelosi Italy
Dr. Shirish Prayag India 205 Cancer patients in the intensive care unit: recent
advances and new challenges (Isidro Prieto del Portillo,
220 Implementing ECCO2R and vv-ECMO in
non-academic centres
Prof. Peter Pronovost United States Ignacio Sáez de la Fuente, Ignacio Pujol Varela) (Klaus Kogelmann)
Shares experiences of implementing extracorporeal life support in a
Expanding horizons and new opportunities in the management of critical
Prof. Konrad Reinhart Germany oncologic patients.
non-academic hospital.

Prof. Gordon Rubenfeld Canada

Dr. Francesca Rubulotta United Kingdom 208 What should we stop doing in the ICU?
(Fernando G. Zampieri) INTERVIEW
Prof. Jukka Takala Switzerland The most important thing intensive care physicians should stop doing is

Correspondents
ignoring that they are prone to several cognitive biases.
222 Improving access to safe anaesthesia
Interview with Jannicke Mellin-Olsen, President, World Federation of Societies
of Anaesthesiologists.
Prof. Dr. Dominique Vandijck Belgium
 Polymymix B Hemoperfusion Therapy
Additional therapy for patients with endotoxic septic shock

Neutralization of endotoxin
Restoration of the immune balance
Fast recovery of hemodynamics and organ function
©For personal and private use only. Reproduction must be permitted by the copyright holder. Email to copyright@[Link].

A rational precision therapy for

TORAYMYXIN ®
unresponsive septic shock

Monday 22 October, 18.15-19.15, Room Rome

COMPLEMENTARY THERAPIES IN ENDOTOXIC SHOCK:

THE POLYMYXIN B HEMOPERFUSION
Chairmen: Mira J-P. (Paris, France) and Girardis M. (Modena, Italy)

Polymyxin B Hemoperfusion During Emergency Abdominal Surgery: Rationale and Application

Pugin J. (Geneva, Switzerland)

Targeting a Complementary Therapy for Endotoxic Shock: What we have Learned from Literature
and Clinical Experience
Antonelli, M. (Rome, Italy)

High Dose Vasopressor Refractory Shock and Role of Polymyxin B Hemoperfusion Therapy Monti, G.
(Milan, Italy)

[Link]
 150
COVER STORY: SHOCK

Pathophysiology of endotoxic shock

Mechanisms of endotoxin-induced multi-organ damage
Endotoxin-induced sepsis remains a leading cause of mortality in intensive care units (ICUs) worldwide. Lipopolysaccharide (LPS) identification by
the immune system triggers a cascade of signalling pathways, leading to the release of several cytokines and chemokines, which orchestrate the
antimicrobial and inflammatory response, though causing multiorgan damage as well. Furthermore, endotoxin is involved in the alterations of the
innate and adaptative immune system, which are of utmost important in the development of immune-paralysis in sepsis and may contribute to sepsis
late mortality. Even if clinical studies on techniques aiming to remove endotoxin have yielded conflicting results so far, it seems that selected subgroups
©For personal and private use only. Reproduction must be permitted by the copyright holder. Email to copyright@[Link].

Francesco Forfori of patients could benefit from their use.

S
Associate Professor of Anaesthesia
and Intensive Care
epsis remains a leading cause of mortality in ICUs responsible for the potentially lethal consequence attributed (NFκB), leading mainly to the synthesis of pro-inflammatory
Anaesthesia and Intensive Care ITD
Unit Director worldwide (Vincent et al. 2009) and is considered a to this mediator (Monti et al. 2010). cytokines (TNF-α, IL1B, IL-6, IL12B), or the TRIF (Toll-like
Director of Anaesthesia and global health priority (Reinhart et al. 2017). In 2016, receptor domain adaptor inducing interferon-β), which, on
Intensive Care Resident The innate immune response is the first line of defence
new definitions and criteria of sepsis, underlining the utmost the other hand, is involved in the late phase of transcriptional
Programme against infections and is based on recognition of pathogens
Department of Surgical, Medical importance of the non-homeostatic host response to infection activation (IL-10) and in the development of endotoxin tolerance
structures, termed pathogen-associated molecular patterns
Pathology, and Critical Care in the development of this syndrome, were published (Singer (Biswas and Lopez-Collazo 2009) (Figure 1A).
AOUP-University of Pisa (PAMPs), which are vital for survival of microorganisms
et al. 2016).
Pisa, Italy and have consequently remained immutable over millennia.
Sepsis incidence is rising due to several reasons and When PAMPs, such as LPS, peptidoglycan and lipoteichoic Clinical relevance of LPS
francescoforfori@[Link]
treatment is becoming increasingly difficult because of the acid of Gram-positive bacteria, fungal glucan, (Marshfield The most clear-cut example of the relationship between
spreading of multidrug-resistant bacteria. The number of 2011) bind to the so-called pattern recognition receptors endotoxaemia and outcome is meningococcal disease (Cohen
Gram-negative infections in ICU is progressively increasing. (PRRs), the proinflammatory and antimicrobial response is 2000). Even if this relationship is much more difficult to
In 2007, 62% of the positive isolates in ICU patients were triggered. It is noteworthy that also host fragments altered by demonstrate in a heterogeneous ICU population, several studies
Gram-negative organisms (Vincent et al. 2009); moreover the cellular stress are equally recognised by the PRRs as “danger” have highlighted the role of endotoxaemia on progression
mortality for Gram-negative bacteraemia is higher than that signals, termed damage-associated molecular patterns (DAMPs) and outcome of sepsis and septic shock (Danner et al 1991;
for Gram-positive (Cohen et al. 2004). (Mogensen 2009). Opal et al 1999).
Toll-like receptors (TLRs) are the family of PRRs that have In 2004, the MEDIC study, enrolling 857 ICU patients, was
Endotoxins as PAMPs been studied more thoroughly. Currently, ten TLRs have been the first large observational cohort study to correlate endotoxin
Endotoxin (LPS) is probably the most important trigger of described. TLR-4 interacts with LPS and HSP (Opal 2010; Saha level, measured by endotoxin activity assay (EAA), with mortality.
inflammatory response in Gram-negative infection. It is a three et al. 2010). LPS, through LPS binding protein, binds to the Rates of severe sepsis were 4.9%, 9.2%, and 13.2%, and ICU
Greta Giuliano complex CD14/TLR4/MD2, which is expressed on the cell
Aanesthesia and Intensive Care
domains essential component of the cell wall of Gram-negative mortality was 10.9%, 13.2%, and 16.8% for patients with low,
bacteria and it has a highly conserved structure (Opal and surface on both immune and non-immune cells (Molteni et al intermediate, and high EA levels, respectively (Marshall et al.
Resident
AOUP-University of Pisa Gluck 2003). However, it is the ‘regulated host response’ to 2016). Then, two different pathways of cellular activation can 2004). Similarly, in a prospective study, Monti et al. (2010)
Pisa, Italy
LPS, rather than the intrinsic properties of LPS itself, which is occur through either the MyD88 (myeloid differentiation factor showed that ‘high EA level septic shock patients’ were in need
88), which mediates the early activation of nuclear factor κB
[Link]@[Link]

ICU Management & Practice 3 - 2018

 151
COVER STORY: SHOCK

of a significantly higher vasopressors dose than intermediate 2005), associated with altered muscle compliance (Chagnon et al. and interstitial space, alveolar wall thickening, accumulation
and low EA groups with increased hospital mortality. 2006). Microscopically, reversible and irreversible cytopathologic of proteinaceous oedema and detritus in the alveolar space
basic alterations include apoptosis, focal necrosis, congestion, (Matute-Bello et al. 2011). These alterations are mostly due
Interestingly, EA is not detectable only in patients with
inflammatory infiltrates, and oedema (Chagnon et al. 2006). The to the presence of profound vascular leakage causing not only
Gram-negative infection. More than 50% of patients admitted
impairment of cardiac function during sepsis is due to several movement of fluid and macro-molecules into the interstitium
in ICU have intermediate or high levels of EA as compared to
mechanisms (Flesch et al. 1999), which have not been exactly and airspace, but also transendothelial diapedesis of leukocytes
healthy volunteers; however, only 4% of this population had
clarified yet (Yucel et al. 2017). A controversial hypothesis into lung tissues, further contributing to vascular and alveolar
a documented Gram-negative infection (Monti et al. 2010).
proposed to explain sepsis-induced cardiac dysfunctions dysfunction (Peng et al. 2004). Another important feature of ALI
It has been hypothesised that the reason behind endotoxin
is inadequate coronary blood flow (Chagnon et al. 2006). is the formation of microthrombi (Proudfoot et al. 2011) and
increase in those patients is the gut barrier dysfunction (Esteban
In fact, some studies in animals have showed that coronary alveolar fibrin deposition that, due to the extensive cross-talk
et al. 2013) associated with splanchnic hypoperfusion or gut
blood flow is reduced by infusion of endotoxin. On the other between coagulation and inflammation, may further inflame the
permeability changes (McIntyre et al. 2011; Klein et al. 2007).
©For personal and private use only. Reproduction must be permitted by the copyright holder. Email to copyright@[Link].

Gabriella Licitra hand, others reported a marked coronary vasodilation and lungs (Tuinman et al. 2012). Futhermore, Rodriguez-Gonzalez et
Consultant in Anaesthesia and even higher coronary flow in patients with sepsis (Yucel et al. (2015) showed that inflammatory mediators released during
Intensive Care Pathophysiology of organ damage in Gram- al. 2017). Furthermore, numerous chemical mediators such LPS-induced lung epithelial cell injury might contribute to the
AOUP-University of Pisa negative sepsis as tumour necrosis factor alpha (TNF-α), MIF, interleukin-1, development of septic-associated encephalopathy.
Pisa, Italy
Endothelial dysfunction and the consequential barrier disruption nitric oxide and reactive oxygen species (ROS) have been widely
The pathogenesis of LPS-induced acute kidney injury
gabriellalicitra@[Link]
leading to increased vascular permeability is critical to the implicated in the pathogenesis of sepsis-induced cardiomyopathy
(AKI) in humans is complex and it is not simplistically related
pathogenesis of multi-organ failure in sepsis (Winkler et al. (Chagnon et al. 2006; Yucel et al. 2017). Apoptosis seems to
to hypoperfusion and ischaemia (Morrell et al. 2014a; Nakano
2017). Specifically, stimulation of endothelial cells with LPS leads play an important role as well (Chagnon et al. 2005; Lancel
et al. 2015). In the kidney, as well as in the lung and in the
to the upregulation of several adhesion molecules (E-selectin, et al. 2005). In detail, not only may endotoxin trigger heart
heart, TLR-4 is constitutively expressed on tubular epithelial
P-selectin, intercellular adhesion molecule-1, etc), cytokine multiple caspase activation and cytochrome c release from
(IFN-α, INF-γ, IL-6) and chemokine (CCL2, CCL3, CCL5). the mitochondria causing end-stage apoptosis of myocardial
Α) Β)
Moreover, endotoxin decreases the expression of thrombomodulin, cells, but caspase-3 activation may also directly cause changes Endotoxin Apoptosis
Macrophages Immunosuppression

tissue-type plasminogen activator and heparin, while increasing in calcium myofilament response, in troponin T cleavage, and Recruitment of
immune cells
Monocytes
Neutrophils
Lymphocytes

the expression of tissue factor (TF) and plasminogen activator in sarcomere disorganisation, without inducing myocardial Endothelial cells
Expression of cytokines Ac�va�on of the
and effector molecules coagula�on cascade

inhibitor 1 (PAI-1), thus shifting the haemostatic balance from cell death (Lancel et al. 2005). Also myocardial wall oedema TLR4 Complement ac�va�on

per se can be an underestimated component of this reversible

LBP
MD-2

an anticoagulant to a procoagulant state. Systemic infusion of low

CD14
Mul�-organ dysfunc�on

dose LPS in healthy humans results in an enormous rise in TF dysfunction altering myocardial compliance and elastance Central nervous system
• Confusion/encephalopathy

mRNA levels in mononuclear cells causing thrombin generation (Chagnon et al. 2006). MyD88 TRIF
Lungs
• ARDS
Cardiovascular system

and further haemostatic activation (Levi and Sivapalaratnam The frequent cardiac rhythm alteration in septic patients
• Myocardial dysfunc�on
• Shock
Kidneys

2018). Furthermore, LPS-induced apoptosis of endothelial cells, may be partially explained by the evidence of action potential
NFκB

TNFα
IRF3

IFNβ
• Oliguria/AKI
Gastrointes�nal tract
• Loss of barrier func�on
exposing prothrombotic subendothelial proteins to clotting duration (ADP)-prolongation in human pluripotent stem cell
IL-1B, IL-6
IL-12B
IL-10 • Hypoperfusion
Microcircula�on
• Microvascular thrombosis/dysfunc�on
factors, further tilts the balance towards a procoagulant state treated with LPS (Yucel et al. 2017).
• Thrombocytopenia

(Seeley et al. 2012).

LPS infusion is often used to recreate ALI (acute lung
After an LPS challenge or sepsis insult, the heart may become injury) in different species (Waerhaug et al. 2008). In animal Figure 1. Schematic representation of pathophysiology of endotoxin
sepsis A) After the binding of LPS to CD14 and then TLR-4/MD-2, two
dysfunctional, exhibiting a “stunning”-like profile characterised models, after 1 hour from intratracheal instillation or intravenous not mutually exclusive pathways can be activated. B) The activation
by a diffuse and reversible decrease in ejection fraction with infusion, considerable tissue injury can be observed, and it of the immune system can lead both to multiorgan damage and to
enlargement of ventricular diameter/volumes (Chagnon et al. immunosuppression (see text)
is characterised by neutrophil accumulation in the alveolar

ICU Management & Practice 3 - 2018

 152
COVER STORY: SHOCK

cells (especially within the apical brush border of proximal tubules) ‘endotoxin tolerance’ is very helpful to identify the probable mechanisms Several cartridges for extracorporeal blood purification have been
(Morrell et al. 2014a). Unfortunately, so far, little is known about the beyond sepsis-induced alterations of the immune system and their developed, though Toraymixin® has the highest removal capacities
final downstream mechanisms that produce AKI after TLR-4 activation consequences, although it is not easily adaptable to humans, because it is and is the most studied. Three large randomised controlled trials
and the start of the intracellular signalling cascades (Morrell et al. an oversimplification of the far more complex concept of immunoparalysis (RCT)s have been set up on Polymyxin-B (PMX-B) so far, giving
2014a). In a recent review, Morrell et al. (2014b) have suggested seen in human sepsis. contrasting results. The ABDOMIX trial did not demonstrate any
that the inflammatory pathway can induce renal tubular transport benefit of PMX haemoperfusion in organ failure or mortality in patients
The mechanisms underlining LPS tolerance are still ill-understood,
dysfunction with enhanced NaCl delivery to the macula densa and with peritonitis-induced septic shock (Payen et al. 2015), while the
though recently it has been hypothesised that sepsis-induced monocyte
increased tubule-glomerular feedback, impairing the glomerular Early use of polymyxin B hemoperfusion in abdominal septic shock
epigenetic reprogramming may play a pivotal role in the suppressive
filtration rate (GFR). A study on LPS-induced AKI in mice showed (EUPHAS) trial, reported improvement in organ dysfunction, and
monocyte phenotype (Delano and Ward 2016). Alterated nuclear
LPS selectively accumulated in proximal tubule cells through a TLR-4 reduction of 28-day of mortality (Cruz et al. 2009). Similar results
translocation of transduction molecules, decreased stability of messenger
dependent mechanism, associated initially with a reduction in tubular were demonstrated in the retrospective EUPHAS 2 registry (Cutuli et
©For personal and private use only. Reproduction must be permitted by the copyright holder. Email to copyright@[Link].

RNA for cytokine genes (Opal 2007), and enhanced expression of two
flow rate and then with cells swelling and tubular obstruction (Nakano al. 2016). Finally, Evaluating the Use of Polymyxin B Hemoperfusion
micro-RNAs (miR146 e miR155) (Biswas and Lopez-Collazo 2009) are
et al. 2015). Additionally, apoptosis has been proposed to play a role in in a Randomized Controlled trial of Adults Treated for Endotoxemia and
mechanisms implicated in the genetic reprogramming of immune cells.
the pathogenesis of septic AKI, probably through the TNFR1 (Tumor Septic Shock (EUPHRATES), a placebo-controlled multi-centred blinded
Necrosis Factor Receptor 1), as supported by a study where TNFR1−/− Altogether, after LPS challenge, monocytes produce less levels of trial was concluded in 2016 (Klein et al. 2014). Currently, the only
mice had less apoptosis in renal cells and fewer neutrophils infiltrating pro-inflammatory cytokine such as TNF-α, IL-1, IL-6, IL-12 and more existing report is a press release that states that PMX haemoperfusion
the kidney following LPS administration compared with TNFR1+/+ anti-inflammatory ones. Moreover, the ability of monocytes to present significantly improved 28-day survival outcomes of patients with an
(Cunningham et al. 2002). Nonetheless, a recent study shows that LPS antigens is highly impaired due to reduced expression of MCH II EAA level in the range of 0.6-0.9 and a multiple organ dysfunction
can also directly cause apoptosis of tubular cells through Fas-mediated molecules such as HLA-DR (Biswas and Lopez-Collazo 2009; Delano > 9, based on the results of a subgroup analysis ([Link]/
and caspase-mediated pathways (Cantaluppi et al. 2008). Moreover, and Ward 2016). It is noteworthy that not only monocytes, but also assets/[Link]).
LPS can directly act on kidney-resident cells such as podocytes and dendritic cells, neutrophils, T cells (Elyce 2011), and NK cells, are
As described by De Grooth et al. (2018), substantial between-trial
tubular epithelium, stimulating the synthesis of inflammatory mediators involved in the genesis of immunoparalysis (Delano and Ward 2016).
heterogeneity limits the reproducibility and generalisability of septic
(Zurovsky et al. 1995) (Figure 1B). The widespread apoptosis of specific subsets of immune cells may
shock research and may inhibit the discovery of beneficial therapies
contribute as well (Opal 2007) (Figure 1B)
for specific (sub)-populations.
Endotoxin and the immune system
Therapeutical approach
Due to improvements in intensive care management, early sepsis mortality Conclusion
has gone down during the last decades. However, late mortality is soaring. Since the first attempt of anti-endotoxin treatment by Ziegler, published in
Sepsis and septic shock are still associated with a high mortality risk,
The alterations in innate and adaptive immune system induced by sepsis 1982, several strategies aiming to remove endotoxin have been proposed,
and endotoxin is probably the most important trigger of inflammatory
are thought to be of paramount importance in long-term mortality from agents that inhibit endotoxin synthesis, to anti endotoxin vaccines
response. Although the complex interaction between the immune system
(Delano and Ward 2016). or anti endotoxin antibodies. Unfortunately, all of them have failed the
and endotoxin has not been completely elucidated so far, it is clear that
U.S. Food and Drug Administration (FDA) clinical trials (Romaschin et al.
Experimental models of sepsis have been widely used to study the elevated endotoxaemia is associated with increased mortality and organ
2012). Hence, recently much research on blood purification techniques
so-called endotoxin tolerance, that is the desensitisation to endotoxin- dysfunction in critically ill patients.
able to remove LPS has been carried out, giving contrasting results. In
induced lethality after a priming (small) dose of endotoxin before
the fourth edition of the Surviving Sepsis Campaign Guidelines (Rhodes The clinical efficacy of extracorporeal blood purification techniques
an otherwise lethal challenge dose of endotoxin. It probably occurs
et al. 2017), blood purification was considered for the first time, but in sepsis and septic shock remains uncertain, even though Polymyxin
also in human Gram-negative sepsis (Opal 2007). The concept of
neither recommended in favour nor against (Ilia et al. 2017). B hemoperfusion could be considered as a complementary therapeutic
strategy for unresponsive endotoxin-based septic shock.

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COVER STORY: SHOCK

Conflict of interest
Greta Giuliano and Gabriella Licitra declare that they have no conflicts of interest.
Francesco Forfori received honoraria for lectures from Baxter, Orion, Pfizer, Biotest
and Estor.

Abbreviations

ADP action potential duration LPS lipopolysaccharide

AKI acute kidney injury PAMP pathogen-associated molecular pattern

ALI acute lung injury PRR pattern recognition receptor

Safely reduce
©For personal and private use only. Reproduction must be permitted by the copyright holder. Email to copyright@[Link].

antibiotic exposure
DAMP damage-associated RCT randomised controlled trial

molecular pattern REA reactive oxygen species

EAA endotoxin activity assay TLR toll-like receptor

GFR glomerular filtration rate TRIF toll-like receptor domain adaptor induc- B·R·A·H·M·S PCT: An effective tool for antibiotic stewardship
ing interferon-β
ICU intensive care unit
Thermo Scientific™ B·R·A·H·M·S PCT™ (Procalcitonin) supports responsible use of antibiotics to prolong
their effectiveness. Randomized clinical trials show proven efficacy of 16% to 74% antibiotic exposure
reduction across various clinical settings.1,2
References B·R·A·H·M·S PCT guided antibiotic therapy has the potential to:
Biswas SK, Lopez-Collazo E (2009) Endotoxin tolerance: new mechanisms, molecules and clinical significance.
Trends Immunol, 30(10): 475-87.
• Reduce initial antibiotic prescription rates2
Cantaluppi V, Assenzio B, Pasero D et al. (2008) Polymyxin-B hemoperfusion inactivates circulating proapoptotic
factors. Intensive Care Med, 34(9): 1638-45. • Shorten antibiotic treatment durations3
Chagnon F, Bentourkia M, Lecomte R et al. (2006) Endotoxin-induced heart dysfunction in rats: assessment of • Save overall treatment costs 4
myocardial perfusion and permeability and the role of fluid resuscitation. Crit Care Med, 34(1): 127-33.

Chagnon F, Metz CN, Bucala R et al. (2005) Endotoxin-induced myocardial dysfunction: effects of macrophage
migration inhibitory factor neutralization. Circ Res, 96(10): 1095-102.

Cohen J, Cristofaro P, Carlet J et al. (2004) New method of classifying infections in critically ill patients. Crit Care
Visit us at ESICM, Paris, booth n˚ 2.07
Med, 32(7): 1510-26.

Cohen J (2000) The detection and interpretation of endotoxaemia. Intensive Care Med, 26 Suppl 1: S51-6.
Find out more at [Link]/procalcitonin
Cruz DN, Antonelli M, Fumagalli R et al. (2009) Early use of polymyxin B hemoperfusion in abdominal septic shock:
the EUPHAS randomized controlled trial. JAMA, 301(23): 2445-52.

Cunningham PN, Dyanov HM, Park P et al. (2002) Acute renal failure in endotoxemia is caused by TNF acting directly References: 1. Nobre et al., Am J Respir Crit Care Med 2008; 177: 498-505. 2. Briel et al., Arch Intern Med 2008; 168: 2000-7. 3. de Jong et al., Lancet
on TNF receptor-1 in kidney. J Immunol, 168(11): 5817-23. Infect Dis 2016; 3099: 1-9. 4. Kip et al., J Med Econ 2015; 1-10.

Cutuli SL, Artigas A, Fumagalli R et al. (2016) Polymyxin-B hemoperfusion in septic patients: analysis of a multi- Not all products are FDA cleared. Availability of products is related to the registration status in the countries.
center registry. Ann Intensive Care, 6(1): 77.
© 2018 Thermo Fisher Scientific Inc. All rights reserved. B·R·A·H·M·S PCT and all other trademarks are the property of Thermo Fisher Scientific and its
Danner RL, Elin RJ, Hosseini JM et al. (1991) Endotoxemia in human septic shock. Chest, 99(1): 169-75. subsidiaries unless otherwise specified.
de Grooth HJ, Postema J, Loer SA et al. (2018) Unexplained mortality differences between septic shock trials: a
systematic analysis of population characteristics and control-group mortality rates. Intensive Care Med, 44(3): 311-22.

For full references, please email editorial@[Link] or visit [Link]

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Fluids in shock
Fluid management during shock from physiology to bedside
Antonio Messina
Senior consultant Shock is a common life-threatening, generalised form of acute circulatory failure in critically ill patients, which is usually managed by infusing fluids
Department of Anesthesia and
Intensive Care Medicine to increase cardiac output and supply the systemic oxygen request. International guidelines recommend use of an aggressive fluid resuscitation in the
Humanitas Clinical and Research
Centre early phases of shock. In this context, crystalloids, including balanced solutions, are suggested as first-line fluid therapy. However, a single physiological
Milan, Italy
or biochemical measurement able to adequately assess the balance between cardiac output and perfusion pressure is still not available. Moreover, the
©For personal and private use only. Reproduction must be permitted by the copyright holder. Email to copyright@[Link].

[Link]@[Link]

haemodynamic targets and safety limits indicating whether or not to stop this treatment in already resuscitated patients are still undefined. A fluid should
be considered as a drug and the intensivist should consider its pharmacodynamic and pharmacokinetic properties, and whether or not a patient is resistant
to this therapy—before administration.

Why administer fluids? From physiology to The technique of fluid resuscitation to treat an episode al. 2017), the haemodynamic targets and the safety limits
bedside of shock was first described by Dr. Thomas Latta nearly indicating whether or not to stop this treatment in already
200 years ago in a letter to the editor of The Lancet (Latta resuscitated patients are still undefined (Hjortrup et al.
Shock is a life-threatening, generalised form of acute circulatory
1832). He injected repeated small boluses of a fluid solution 2016; Rhodes et al. 2017). Moreover, a single physiological
failure affecting one-third of intensive care unit (ICU) patients
Massimiliano Greco equivalent to approximately ½ Ringers lactate and observed or biochemical measurement able to adequately assess the
Junior consultant (Sakr et al. 2006; Cecconi et al. 2014). It is associated with
Department of Anesthesia and
the clinical changes of his first patient (an elderly woman). The balance between the changes in heart function and in DO2,
the imbalance between the oxygen delivery (DO2) provided
Intensive Care Medicine first bolus did not have any visible effect, but after multiple peripheral perfusion pressure and O2 request, is not available.
Humanitas Clinical and Research by the cardiac function, and the systemic oxygen request. The
Centre boluses (overall 2.8 litres) “soon the sharpened features, and Surely, giving fluids to increase the cardiac output (CO) and,
Milan, Italy first variable is defined as the product of oxygen content and
sunken eye, and fallen jaw, pale and cold, bearing the manifest as a consequence, DO2, seems reasonable.
[Link]@[Link] the cardiac output (CO), whereas inadequate cellular oxygen
imprint of death's signet, began to glow with returning
utilisation derives from a tissue oxygen request exceeding the CO is the dependent variable of the physiological
animation; the pulse returned to the wrist.” To give fluids
DO2, or to the cellular inability of using O2. This latter condition interaction of cardiac function (described by the observations
during shock and observe the clinical improvement of the
is due to mitochondrial dysfunction (Brealey et al. 2002) and of Otto Frank and Ernest Starling more than 100 years ago)
patient at bedside seemed reasonable in 1831 and still makes
deregulated cell-signalling pathways during sepsis-induced and venous return function (based on Guyton’s relationship
sense! In fact, optimal fluid management is a key component
multiple organ damage (Singer 2017). A large trial regarding between the elastic recoil of venous capacitance vessels, the
to improve the outcome of haemodynamically unstable ICU
dopamine or norepinephrine infusion for shock reversal in volume stretching the veins, the compliance of the veins and
patients, since both hypovolaemia and hypervolaemia are
more than 1600 ICU patients demonstrated that septic shock the resistance of the venous system). In this context, fluids
harmful (Cecconi et al. 2014).
occurred in the vast majority of ICU patients (62%), while should be used to increase CO only if the plateau of cardiac
Maurizio Cecconi cardiogenic shock (16%), hypovolaemic shock (16%) and function is not reached. At this point, in fact, and probably
Head of Department Anaesthesia
and Intensive Care Units other types of distributive (4%) or obstructive (2%) shock When to administer fluids? Triggers and safety even before reaching this point, fluid administration does not
Full Professor of Anaesthesia and
Intensive Care are less frequent. Fluid infusion to correct haemodynamic limits of fluid administration increase CO and can be considered as futile or even harmful.
IRCCS Humanitas, Humanitas
instability is a key, early and common intervention in ICU While consensus exists regarding the need for aggressive
University However, clinical assessment of the Frank-Starling curve
Milan, Italy patients with shock (Myburgh and Mythen 2013; Rhodes fluid resuscitation in the early phases of shock (Rhodes et position of the ventricle is complex and the prediction of
[Link]@[Link] et al. 2017).
@DrMCecconi

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Table 1. Clinical bedside triggers of fluid administration

fluid responsiveness in ICU patients is still challenging (Monnet et al. this therapy—before administration. Unfortunately, the reliability Variable Pros Cons
2016). The fluctuations of arterial waveform caused by the fixed and in predicting fluid responsiveness and guiding fluid therapy of the Mean arterial pressure • Target indicated in the • Difficult to be tailored in
guidelines some categories of patients
constant insufflations in patients undergoing a >8 ml/kg controlled physical bedside examination, chest radiography, central venous • Easy to measure and to (hypertensive, chronic renal
mechanical ventilation have been successfully tested to predict fluid pressure and urine output (specifically in septic patients) is very monitor failure)
Lactate • The reduction is usually • Not specific under certain
responsiveness (Monnet et al. 2016). However, most ICU patients are limited (see Table 1). associated with shock conditions (poisoning, liver
protectively ventilated or retain to some extent spontaneous breathing reversal failure, shivering)
An early fluid resuscitation with 30 ml/kg is suggested as the first- • Easy to measure
activity (McConville and Kress 2012; Esteban et al. 2013; Mahjoub et • Early variation even in
step approach to septic shock (Rhodes et al. 2017). On the one hand, normotensive patients
al. 2014), making the changes in intrathoracic pressure neither fixed
a large initial fluid load seems suitable to revert acute hypovolaemia; Capillary refill time • Easy and costless • Low sensitivity and specific-
nor constant and, in turn, the dynamic indexes unreliable (Monnet • Good correlation with ity in vasculopathic patients
on the other hand a tailored fluid therapy could prevent fluid overload systemic perfusion
et al. 2016).
after shock relapse (Hjortrup et al. 2016). Oliguria • High sensitivity • Difficult to evaluate in
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previous renal failure

In daily practice hypotension is usually indicated as the bedside patients
• Need a few hours
trigger to start fluid administration and the mean arterial pressure
(MAP) is the physiological target indicating whether or not to continue
“fluid infusion to correct haemodynamic •
for defining a trend
Affected by diuretics use

fluid infusion for most ICU physicians (Cecconi et al. 2015). The instability is a key, early and common Mottled skin • High specificity • Not always present or late
sign of hypoperfusion
assumption that hypotension and shock are synonymous is misleading.
In fact, restoring MAP above predetermined targets does not necessarily
intervention in ICU patients with shock”
mean reverting shock, whereas MAP below guidelines’ predefined far from being considered a standard in haemodynamically unstable
A modern approach to guide fluid therapy to revert an episode of ICU patients (Cecconi et al. 2015) (see Table 2). As a consequence, the
thresholds does not necessarily indicate shock (Cecconi et al. 2014).
haemodynamic instability should include a portioned fluid administration outcome of a FC is often ambiguous in terms of haemodynamic response
Unfortunately, the physiological relationship between changes in
and bedside tests, aiming at revealing preload dependence. Repeated (responder/non-responder), leading to adjunctive and often futile fluid
systemic pressures and stroke volume becomes weak in previously
fluid challenges [(FCs); an infusion of small aliquots of 300 to 500 administration (Cecconi et al. 2015). Recently, a few studies evaluated the
resuscitated ICU patients, especially during an episode of septic shock
ml of fluid administered over 20-30 minutes, as indicated by the response to FC by considering the early variation of the stroke volume
(Dufour et al. 2011; Pierrakos et al. 2012; Lakhal et al. 2013). For
guidelines (Rhodes et al. 2017)] to assess fluid responsiveness should or dynamic indexes to a quick infusion of smaller portion of the entire
these reasons, the MAP target should be individualised to each patient,
be preferred to a larger and continuous infusion of any fluid. Recent FC (Marik 2015). On the other hand, the dose (ml/Kg) of a FC can
combining the assessment of blood lactates, mixed venous oxygen
findings on postoperative patients suggest that the minimum volume also affect the percentage of responders to the test (Aya et al. 2015).
saturation and veno-arterial carbon dioxide difference (Cecconi et
required to perform an effective fluid challenge is 4 ml/kg infused In practice there is no standard way of performing a FC (Messina et al.
al. 2014). Finally, during fluid administration, the assessment of the
over 5 minutes (Aya et al. 2015). 2017; Toscani et al. 2017). Studies investigating the different components
changes of both right and left ventricle filling pressures is useful as a
safety limit to guide further infusion. In fact, despite static indexes are In principle, FCs should avoid or reduce ineffective fluid (type of fluids, dose, speed and response) of a FC are largely awaited
not reliable in predicting fluid responsiveness, the increase of filling administration. However, the effect on haemodynamics should be (Aya et al. 2017; Toscani et al. 2017; Bennett et al. 2018).
pressures suggests that the ventricle is operating on the flat part of only assessed by measuring the changes in CO. Recently, RACE (rapid Finally, several haemodynamic tests have been proposed in the
the Frank-Starling’s curve. assessment by cardiac echography) has been suggested as a first-line literature to evaluate the preload dependency of the right ventricle by
tool to evaluate the type of shock if the clinical examination does not increasing venous return before FC administration. Among them is
How to administer fluids? Pharmacodynamic and lead to a clear diagnosis, even when used by a minimally trained the passive leg raising (PLR) test. PLR is performed by simultaneously
pharmacokinetic of fluid administration intensivist (Cecconi et al. 2014; Finfer et al. 2018). lowering the trunk and raising the inferior limbs, changing the patient’s
Despite the increasing number of haemodynamic tools measuring position from semi-recumbent to a position in which the head and the
Fluids should be considered as a drug and, as a consequence, the
CO or its surrogates, continuous monitoring of cardiac function is trunk are horizontal and the legs are elevated at 45°(Monnet and Teboul
ICU physician should assess whether or not a patient is resistant to

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2015). This manoeuvre leads to an auto-transfusion of about 300 ml Table 2. Haemodynamic monitoring during shock
of blood volume recruited from the capacitance veins of the legs and
pushed to the heart; an increase in CO of about 10%-15% reliably Variable Pros Cons
predicts fluid responsiveness. Unfortunately, lower trunk trauma, • Prompt evaluation
• Need learning curve for more precise measurements
• Not invasive
increased intracranial pressure, low level of sedation and abdominal Echocardiography • Suggested as first-line haemodynamic evaluation after clinical
• Not yet available in all intensive care units
• Operator/patient dependent
examination
hypertension might limit PLR reliability. • Rapid differentiation of the cause of shock
• Not useful for continuous monitoring

• Accurate in estimating cardiac output and trending cardiac

• Invasive and time-consuming
Which fluid in critically ill patients with shock? Calibrated pulse
contour methods •
function
Provide dynamic indexes of fluid responsiveness and also
• Not available in all intensive care units
• Limited by cardiac arrhythmias or vascular abnormalities
estimate systemic distribution of fluids
The ideal fluid for patients in shock should have a composition as similar
as possible to the extracellular fluid, to support cellular metabolism
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Uncalibrated • Not or minimally invasive • Questioned accuracy in critically ill patients

and avoid organ dysfunction, and should increase intravascular pulse contour • Prompt measurement • Not available in all intensive care units
methods • Provide dynamic indexes of fluid responsiveness • Limited by cardiac arrhythmias or vascular abnormalities
volume and persist over time, to optimise CO. Unfortunately, no
ideal fluid exists, and the available fluid options are roughly divided
• Contraindicated in those with oesophageal pathology
in three groups: crystalloids, colloids, and blood products. The latter Oesophageal • Minimally invasive
• The acquisition of the optimal acoustic signal may require frequent repositioning
Doppler • Prompt measurement
have few very specific indications including shock in trauma patients • Difficult to use in awake patients

and haemorrhagic shock, and will not be discussed in this review

(Stensballe et al. 2017). solutions were later proposed, such as Ringer lactate (Hartman
Colloids are composed of large molecules designed to remain in “the assumption that hypotension and shock are solution), Ringer acetate and PlasmaLyte. These solutions have normal
chloride concentration, lower osmolarity (between 280 and 294)
the intravascular space for several hours, increasing plasma osmotic
pressure and reducing the need for further fluids. Despite the theoretical
synonymous is misleading” and are buffered with lactate or acetate to maintain fluid neutrality.
advantages of this model, subsequent studies challenged this view Two randomised studies were recently published to assess
critically ill patients (Finfer et al. 2004; Caironi et al. 2014). The use
in sepsis patients, where alterations in glycocalyx and endothelial the effect of balanced solutions vs normal saline. The SPLIT trial,
of albumin was associated with improved mean arterial pressure with
permeability may lead to extravasation of colloid’s large molecules conducted in 4 ICUs, showed no advantage in either group (Young
an infusion of a lower volume, but the relative risk of mortality was
(Brunkhorst et al. 2008), abolishing their primary advantage. Colloids et al. 2015). The SMART trial was a monocentric study (5 ICUs/1
similar to the crystalloid infusion (Caironi et al. 2014). A predefined
are further divided into semi-synthetic colloids and albumin. The academic centre) and yielded similar results, with no difference
subgroup analysis of the SAFE study suggested that the use of albumin
former includes hydroxyethyl starches, dextrans and gelatins and have in mortality or kidney injury using balanced solution vs normal
should be avoided in patients with traumatic brain injury. Debate is still
demonstrated either no effect (Annane et al. 2013) or detrimental saline (Semler et al. 2018). A significant difference in favour of
ongoing, and the safer indication for albumin use in shock patients
consequences in critically ill patients, increasing the risk of kidney PlasmaLyte was found in days free from renal replacement therapy
is liver failure (Salerno et al. 2013).
injury (Myburgh et al. 2012; Perner et al. 2012) Thus, the use of and in a composite outcome of renal complications and mortality
semi-synthetic colloids in shock patients should be abandoned. On the other waterside of fluid therapy, crystalloids are composed in the SMART trial (Semler et al. 2018). Both trials were cluster
of water and electrolytes. randomised, and negative trial results may also reflect the relatively
The role of albumin is still debated. While theoretically promising
for its anti-inflammatory and anti-oxidant proprieties (Vincent 2009), Normal saline was the first crystalloid solution to be used in small quantity of fluid infused in the two groups (median quantity
and for its supposed longer intravascular confinement due to the humans. Its drawbacks are a very high concentration of chloride less than 2 litres). Despite the lack of definitive evidence, balanced
interaction between its surface negative charges and endovascular and high osmolarity, which were associated with nephrotoxicity solutions have theoretical advantages that should be compared with
glycocalyx (Vincent 2009), there is no clear evidence of its efficacy in and hyperchloraemic acidosis (Yunos et al. 2015). Several balanced the risk of hyperchloraemic acidosis after large volume resuscitation

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with normal saline. Consequently, balanced solutions are probably the best choice as
a first-line fluid therapy in patients with shock.

Conclusions
Fluids are a crucial component of the resuscitation of patients in shock. A paradigm
shift is taking place in fluid therapy, changing from the administration of large
volume to a more targeted and personalised approach. Fluids should be considered
as a drug, and should be administered after testing preload dependency and with
continuous evaluation of preload dependency/CO response. Fluid therapy should
©For personal and private use only. Reproduction must be permitted by the copyright holder. Email to copyright@[Link].

be paired with timely monitoring of clinical and metabolic signs of shock. Despite
the lack of definitive evidence, balanced crystalloids are the most promising fluids
in patients in shock, while semi-synthetic colloids should be definitively avoided in
this population.

Conflict of interest
Maurizio Cecconi is a consultant for Edwards Lifesciences, LiDCO and Cheetah Medical.

Abbreviations
CO cardiac output

FC fluid challenge

ICU intensive care unit

MAP mean arterial pressure

References
For full references, please email editorial@[Link] or visit [Link]

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It is time for improved fluid stewardship

A conceptual framework for developing institutional programmes and guidelines to enhance fluid stewardship (especially in the intensive care unit
[ICU] environment), an activity that includes appropriate selection, dosing, duration, de-escalation, and monitoring of fluid therapy.

Manu LNG Malbrain *

T he primary goal of fluid stewardship is to optimise clinical
outcomes while minimising unintended consequences
of intravenous (IV) fluid administration. This article sets
the stage for a conceptual framework for developing institutional
Likewise, prescription of intravenous fluids should proceed
with the same caution, taking into account the compounds,
pharmacodynamic and pharmacokinetic properties of different
fluids. Another way of conceptualising this is considering the "four
longer duration of mechanical ventilation and higher mortality
(Ibrahim et al. 2000; Hoffken and Niederman 2002), (ab)normal
saline as resuscitation fluid should not be administered in large
amounts, as it carries the risk of hypernatraemic hyperchloraemic
©For personal and private use only. Reproduction must be permitted by the copyright holder. Email to copyright@[Link].

ICU Director programmes and guidelines to enhance fluid stewardship (especially Ds" of fluid therapy when treating patients with septic shock: metabolic acidosis, acute kidney injury (AKI) and possible RRT
Intensive Care Unit in the ICU environment), an activity that includes appropriate drug, dosing, duration, and de-escalation (Table 1) (Malbrain (renal replacement therapy), and mortality (Semler et al. 2018).
University Hospital Brussels (UZB)
selection, dosing, duration, de-escalation, and monitoring of fluid et al. 2015). Fluid misuse, like antibiotic misuse, almost certainly
Jette, Belgium 2.1.2. Appropriate therapy
therapy. In patients with septic shock, haemodynamic stabilisation has severe consequences for the patient.
Professor using fluids is a major challenge because clinicians are faced Patient risk factors (prior antibiotic use, duration of mechanical
Faculty of Medicine and Pharmacy 2.1. Drug
Vrije Universiteit Brussel (VUB)
with many unresolved questions. It is clear that clinicians regard ventilation, co-morbidity, hospital length of stay above 5 days,
Brussels, Belgium intravenous fluids like prescription drugs and should take into 2.1.1. Inappropriate therapy corticosteroids, recent hospitalisation, residence in nursing
account the indications and contraindications (Perner et al. 2012; home,…) play important roles in the appropriate choice of
[Link]@[Link] All resuscitation, replacement and even maintenance fluids can
Van Regenmortel et al. 2014; Malbrain et al. 2012; Myburgh et al. empiric antibiotics (Kollef et al. 2006). Similarly, patient risk
contribute to the formation of interstitial oedema, particularly
@Manu_Malbrain 2012; Guidet et al. 2012; Annane et al. 2013), as they may affect factors (fluid balance, fluid overload, capillary leak, acid-base
in patients with systemic inflammation associated with altered
patient-centred outcomes (Myburgh and Mythen 2013). Clinicians status, co-morbidity, kidney function, organ function) also play
endothelial function (Myburgh and Mythen 2013). For each
should also consider not only the risk of administering too little, an important role in empiric fluid therapy.
type of fluid, there are distinct indications: crystalloids vs
but also too much fluid, as the deleterious consequences of fluid
colloids; synthetic vs blood-derived; balanced vs unbalanced; In patients with hypoalbuminaemia and septic shock,
overload become better established (Figure 1).
intravenous vs oral. albumin may be an appropriate resuscitation fluid, especially in
the late phase after the initial resuscitation (Rhodes et al. 2016;
1. Definitions Because of their potential risk, hydroxyethyl starches
Caironi et al. 2014).
are contraindicated in patients with septic shock, burns, acute
It is important to precisely define the various terms commonly or chronic kidney injury, or oliguria not responsive to fluids 2.1.3. Combination therapy
used in the context of fluid management to describe fluid balance, (Rhodes et al. 2017).
fluid overload, different dynamic phases during fluid therapy, Possible benefits of antibiotic combination therapy include:
Todd W. Rice and different types of fluids; these definitions are partially based Glucose water should never be used as resuscitation fluid. broader spectrum, synergy, avoidance of emergence of resistance,
Assistant Professor of Medicine
on published conceptual models (Van Regenmortel et al. 2013; Surprisingly, normal saline, which does not contain potassium, less toxicity,…(Tamma et al. 2012). Possible benefits of fluid
Division of Allergy, Pulmonary and
Critical Care Medicine Myburgh and Mythen 2013; Hoste et al. 2014; Vincent and De will result in higher serum potassium levels in patients with renal combination therapy include: specific fluids for different indications
Vanderbilt University School of Backer 2013; Malbrain et al. 2014; Vincent and Pinsky 2018). impairment compared to a balanced solution (lactated Ringer’s), (replacement vs maintenance vs resuscitation), and less toxicity.
Medicine which contains 5 mmol/L of potassium, due to concomitant
Nashville, TN, USA 2.1.4. Class
metabolic acidosis secondary to a reduced strong ion difference
[Link]@[Link]
2. The four Ds of fluid therapy (SID) (Khajavi et al. 2008; Langer et al. 2015). In an analogy With respect to antibiotic administration, it is important to
Many clinicians consider specific aspects when dealing with to antibiotic treatment, where inappropriate therapy may result consider broad-spectrum vs specific narrower coverage classes.
@toddrice_ICU
antibiotics: different classes, spectrum, toxicity, dose, compounds. in more organ failure, longer ICU and hospital lengths of stay, The choice of the antibiotic has a real impact on efficacy and

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toxicity. Likewise, hypotonic or hypertonic fluids, with high or Table 1. Analogy between the 4 Ds of antibiotic and fluid therapy
Monty Mythen
Smiths Medical Professor low sodium or chloride level, lactate or bicarbonate buffer, glucose
Description Terminology Antibiotics Fluids
of Anaesthesia and Critical Care or not, are all equally important aspects of fluid therapy. This will
University College London
have a direct impact on acid-base equilibrium, cellular hydration
Hospital Drug Inappropriate therapy More organ failure, longer ICU LOS, longer hospital LOS, longer MV Hyperchloraemic metabolic acidosis, more AKI, more RRT, increased mortality
National Institute of Health and electrolyte regulation.
Research Biomedical Research Key factor in empiric AB selection is consideration of patient risk factors (e.g.
Centre 2.1.5. Appropriate timing Appropriate therapy prior AB, duration MV, corticosteroids, recent hospitalisation, residence in nursing
Key factor in empiric fluid therapy is consideration of patient risk factors (e.g. fluid balance, fluid
overload, capillary leak, kidney and other organ function). Don’t use glucose as resuscitation fluid
home)
London, UK
Survival decreases 7% with each hour delay of antibiotic Possible benefits: e.g. broader spectrum, synergy, avoidance of emergence of Possible benefits: e.g. specific fluids for different indications (replacement vs maintenance vs
©For personal and private use only. Reproduction must be permitted by the copyright holder. Email to copyright@[Link].

Combination therapy resistance, less toxicity resuscitation), less toxicity

[Link]@[Link] administration in patients with septic shock (Kumar et al. 2006).
In refractory shock early fluid resuscitation has been proven Broad-spectrum or specific, Beta-lactam or glycopeptide, additional compounds
Hypo- or hypertonic, high or low chloride and sodium level, lactate or bicarbonate buffer, glucose
@montymythen Class as tazobactam. The choice has a real impact on efficacy and toxicity
containing or not. This will impact directly acid-base equilibrium, cellular hydration and electrolyte
beneficial in previous studies (Rivers et al. 2001). The longer regulation

the delay in fluid administration, the more microcirculatory Appropriate timing

Survival decreases with 7% per hour delay. Needs discipline and practical
In refractory shock, the longer the delay the more microcirculatory hypoperfusion
organisation
hypoperfusion and subsequent organ damage (related to ischaemia
Stephanie Wuyts
Clinical Pharmacist reperfusion injury). Murphy et al. compared outcomes related to Dosing Pharmacokinetics
Depends on distribution volume, clearance (kidney and liver function), albumin
level, tissue penetration
Depends on type of fluid: glucose 10%, crystalloids 25%, vs colloids 100% IV after 1 hour, depends on
distribution volume, osmolality, oncoticity, kidney function

UZ Brussels, Belgium early adequate vs early conservative and late conservative vs late
Reflected by the minimal inhibitory concentration. Reflected by “kill” characteris-
Depends on type of fluid and desired location: IV (resuscitation), IS vs IC (cellular dehydration)
liberal fluid administration and found that the combination of Pharmacodynamics tics, time (T>MIC) vs concentration (Cmax/MIC) dependent
[Link]@[Link]
early adequate and late conservative fluid management carried Some AB are toxic to kidneys, advice on dose adjustment needed. However, not Some fluids (HES) are toxic for the kidneys. However, not getting shock under control is not helping
Toxicity
@stephanie_w31 the best prognosis (Murphy et al. 2009). getting infection under control isn’t helping the kidney either the kidney either

2.2. Dosing Duration Appropriate duration

No strong evidence but trend towards shorter duration. Don’t use AB to treat fever, No strong evidence but trend towards shorter duration. Don’t use fluids to treat low CVP, MAP, or
CRP, or chest x-ray infiltrates but use AB to treat infections UO, but use fluids to treat shock

corresponding author
*
2.2.1. Poison
Stop AB when signs and symptoms of active infection resolve. Future role for Fluids can be stopped when shock resolves (normal lactate). Future role for biomarkers (NGAL,
Treat to response biomarkers (PCT) cystatin C, citrullin, L-FABP)
As Paracelsus nicely stated: “All things are poison, and nothing
is without poison; only the dose permits something not to be De-escalation Monitoring
Take cultures first, choose empiric AB and tailor when information becomes
available
After stabilisation with EAFM (normal PPV, normal CO, normal lactate) stop ongoing resuscitation
and move to LCFM and LGFR (=deresuscitation)

poisonous.” It is the dose that makes the antibiotic poisonous,

and the same holds true when it comes to fluid management in Adapted from Malbrain et al. (2014; 2018) with permission

the critically ill. The risk of excessive fluid administration leading AB antibiotic AKI acute kidney injury Cmax maximal peak concentration CO cardiac output CRP C reactive protein CVP central venous pressure EAFM early adequate fluid management EGDT early
goal-directed therapy IC intracellular ICU intensive care unit IS interstitial IV intravascular LCFM late conservative fluid management L-FABP L-type fatty acid binding protein LGFR late goal directed
to an increase in the cumulative fluid balance has been clearly fluid removal LOS length of stay MAP mean arterial pressure MIC mean inhibitory concentration MV mechanical ventilation NGAL neutrophil gelatinase-associated lipocalin PCT procalcitonin PPV
pulse pressure variation RRT renal replacement therapy UO urine output
demonstrated (Malbrain et al. 2014), especially in critically ill
patients with septic shock (Vincent et al. 2006) and/or acute and effect site concentration (Elbers et al. 2015). PK depends
means (enteral or parenteral nutrition, medication solutions,…)
respiratory distress syndrome (Jozwiak et al. 2013). Maintenance on distribution volume, clearance (kidney and liver function),
specific maintenance fluids must be stopped.
fluids should be used cautiously and only to cover daily needs tissue penetration and in some situations also on albumin levels.
when the patient receives no other oral or intravenous fluid 2.2.2. Pharmacokinetics Increased distribution volume is seen with capillary leak, hypo-
intake. Their prescription should take other sources of fluids oncotic states, extracorporeal circuits, surgical drains, large burns
The principle of pharmacokinetics is very well known during
and electrolytes into account. Therefore when a patient already and mechanical ventilation. Pharmacokinetics of intravenous
antibiotic administration. Pharmacokinetics (PK) describes
receives daily needs of water, glucose and electrolytes via other fluids depends on distribution volume, osmolality, tonicity,
how the body affects a drug, resulting in a particular plasma

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Respiratory Central nervous system

Pulmonary oedema Cerebral oedema, impaired
Pleural effusion cognition, delirium
Altered pulmonary and ICP CPP IOP
oncoticity and kidney function. Eventually, the half time depends on chest wall elastance (cfr IAP ) ICH, ICS, OCS
the type of fluid, but also on the patient’s condition and the clinical paO2 paCO2 paO2/FiO2
Extra vascular lung water
context. Volume kinetics is an adaptation of pharmacokinetic theory Lung volumes (cfr IAP )
that makes it possible to analyse and simulate the distribution and Prolonged ventilation
Difficult weaning Cardiovascular
elimination of intravenous fluids (Hahn 2010). The context-sensitive Work of breathing Myocardial oedema
Conduction disturbance
half-time of crystalloids and colloids may change and vary over time Impaired contractility
Hepatic Fluid Diastolic dysfunction
depending on the patient’s condition. As long as crystalloids or colloids Hepatic congestion overload CVP and PAOP
Impaired synthetic function
are infused they will exert a similar volume expansion effect and their Cholestatis
Venous return
SV and CO
distribution and/or elimination and excretion will be slowed in Cytochrome P 450 activity
Myocardial depression
Hepatic compartment syndrome
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cases of shock, renal failure, sedation, or general anaesthesia (Hahn Periocardial effusion
Gastrointestinal/visceral GEF GEDVI CARS
2010; 2014). This may explain why crystalloids have a much better
Ascites formation Gut oedema
short-term effect on the plasma volume than previously believed. Their Malabsorption Ileus Abdominal wall
Bowel contractility Tissue oedema Renal
efficiency (i.e. the plasma volume expansion divided by the infused Poor wound healing Renal interstitial oedema
IAP and APP (=MAP-IAP)
volume) is 50-80% as long as infusion continues, and even increases Success enteral feeding Wound infection Renal venous pressure
Intestinal permeability Pressure ulcers Renal blood flow
to 100% when the arterial pressure has dropped. Elimination is very Bacterial translocation Abdominal compliance Interstitial pressure
Salt + water retention
slow during surgery, and amounts to only 10% of that recorded in Splanchnic microcirculatory flow
Uraemia GFR RVR
ICG-PDR , pHi
conscious volunteers. Renal CS

2.2.3. Pharmacodynamics APP: abdominal perfusion pressure IAP: intra-abdominal pressure IAH: intra-abdominal hypertension ACS: abdominal compartment syndrome CARS: cardio-abdominal-renal syndrome CO: cardiac output CPP: cerebral perfusion
pressure CS: compartment syndrome CVP: central venous pressure GEDVI: global end diastolic volume index GEF: global ejection fraction GFR: glomerular filtration rate ICG-PDR: indocyanine green plasma disappearance rate ICH:
intracranial hypertension ICP: intracranial pressure ICS: intracranial compartment syndrome IOP: intra-ocular pressure MAP: mean arterial pressure OCS: ocular compartment syndrome PAOP: pulmonary artery occlusion pressure
Pharmacodynamics (PD) relates plasma concentrations to a specific pHi: gastric tonometry RVR: renal vascular resistance SV: stroke volume

effect, i.e. how the antibiotic affects the body and the bacteria. As
previously described, antibiotic plasma concentrations are determined
from shorter duration of IV fluids (Hjortrup et al. 2016). Clinicians established. After the very initial fluid administration, only one half of
by dosing strategy, volume of distribution (Vd) and clearance (CL)
should not use fluids to treat low central venous pressure, mean patients with circulatory failure respond to continued intravenous fluid
(Elbers et al. 2015). Volume dynamics depends on the type of fluid
arterial pressure, or urine output per se, but to treat shock instead. administration with an increase in cardiac output (Bentzer et al. 2016).
used and desired location: intravascular (resuscitation), interstitial vs
For fluids, the Frank-Starling relationship between cardiac output and
intracellular (cellular dehydration). Volume kinetics and dynamics 2.4 De-escalation
cardiac preload is the equivalent of the dose effect curve for standard
depend on underlying conditions.
medications. Because of the shape of the Frank-Starling relationship, [Link] or withdrawing
2.3. Duration the response of cardiac output to the fluid-induced increase in cardiac
The final step in fluid therapy is to consider withholding or withdrawing
preload is not constant (Monnet et al. 2017).
2.3.1. Appropriate duration resuscitation fluids when they are no longer required (Malbrain et al.
2.3.2. Treat to response 2014; Benes et al. 2015; O’Connor and Prowle 2015). Along with
The duration of fluid therapy is equally important and the volume
conditioning fluid administration on the presence of fluid responsiveness,
must be tapered when shock is resolved. However, many clinicians Clinicians should stop antibiotics when signs and symptoms of active
this contributes to reducing overall cumulative fluid balance. A positive
use certain triggers to start, but are less aware of triggers to stop fluid infection resolve. Likewise, fluids should be stopped when shock is resolved
cumulative fluid balance should be avoided by all means as studies have
resuscitation, hence carrying the potential of fluid overload and all its (e.g. normal lactate). As with antibiotics (e.g. CRP or procalcitonin), the
shown that fluid overload is an independent predictor for increased
detriments (Malbrain et al. 2014; Benes et al. 2015). As with duration future role for biomarkers (e.g. neutrophil gelatinase-associated lipocalin,
morbidity and mortality (Malbrain et al. 2014; Silversides et al. 2017).
of antibiotics, there is no strong evidence but a trend towards benefit cystatin C, citrullin, or liver-type fatty acid binding protein) needs to be
Eventually, active fluid removal may be indicated in some patients with

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global increased permeability syndrome (GIPS) and volume overload, Table 2. The ROSE concept avoiding fluid overload
and this is referred to as de-resuscitation. As for antibiotics (Table 1), the
Resuscitation Optimisation Stabilisation Evacuation
duration of fluid therapy must be as short as possible, and the volume
(i.e. dose) must be the lowest amount effective in treating shock. Hit sequence First hit Second hit Second hit Third hit

2.4.2. Monitoring Time frame Minutes Hours Days Days to weeks

While antibiotic de-escalation may not help individual patients, it

Underlying mechanism Inflammatory insult Ischaemia and reperfusion Ischaemia and reperfusion Global Increased Permeability Syndrome
could benefit the ICU as a whole by reducing the selection pressure
for resistance. Similarly, after stabilisation (normal pulse pressure Clinical presentation Severe shock Unstable shock Absence of shock or threat of shock
Recovery from shock, possible Global Increased Permeability
Syndrome
variation, normal cardiac output, normal lactate) clinicians need to Early adequate goal-directed fluid Focus on organ support and maintaining tissue
Goal Late conservative fluid management Late goal-directed fluid removal (de-resuscitation)
stop ongoing (futile) fluid resuscitation and move to de-escalation management perfusion
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(late conservative fluid management) and de-resuscitation (late Fluid therapy

Early administration with fluid
boluses, guided by indices of fluid
Fluid boluses guided by fluid responsiveness indices
Only for normal maintenance and replacement
Reversal of the positive fluid balance, either spontaneous
and indices of the risk of fluid administration or active
responsiveness
goal-directed fluid removal)(see Table 2 for explanation). However,
too aggressive de-resuscitation may result in new hypoperfusion Fluid balance Positive Neutral Neutral to negative Negative

and increase in end-organ damage. Primary result of

Salvage or patient rescue Organ rescue Organ support (homeostasis) Organ recovery
treatment

Insufficient Insufficient resuscitation and fluid overload (e.g. Fluid overload (e.g. pulmonary oedema, intra- Excessive fluid removal, possibly inducing hypotension,
Main risk
3. The four phases of fluid therapy resuscitation pulmonary oedema, intra-abdominal hypertension) abdominal hypertension) hypoperfusion, and a "fourth hit"

Adapted from Malbrain et al. (2014; 2018) with permission

Recently a conceptual model of septic shock was proposed with four
distinct dynamic phases of fluid therapy (Cordemans et al. 2012;
Malbrain et al. 2018): Resuscitation, Optimisation, Stabilisation, and The specific IV fluid need depends on the indication: whether it is purpose is threefold. First, the most appropriate, individualised therapy
Evacuation (de-resuscitation) (R.O.S.E.) (Table 2). Specifics of the intended to replace lost fluids, maintain basic metabolic needs or restore has to be chosen. It is crucial that the right fluid is prescribed in the
four phases are: “When to start intravenous fluids?”, “When to stop circulating volume (Malbrain et al. 2018). To determine the right type of right dose and duration and that there is a timely evaluation to start
intravenous fluids?”, “When to start de-resuscitation or active fluid fluid therapy for the individual patient, the clinician must choose based on de-escalating fluid therapy (Malbrain et al. 2018). Second, early detection
removal?” and finally “When to stop de-resuscitation?” the clinical exam, laboratory results and the characteristics of the available and prevention of inappropriate fluid administration is necessary to avoid
IV fluids. Though commonly prescribed, intravenous fluids are not always adverse events (Bates et al. 1995). Finally, cost containment should be
appropriate (Gao et al. 2015). Prescription of intravenous fluids is often achieved through implementation of preventive quality improvement
4. Fluid stewardship done by junior doctors using either an experience-based approach, or by measures (Etchells et al. 2012).
4.1. Conceptual framework habit, with limited input from senior colleagues (McCrory et al. 2017;
4.2. Assessment
Lobo et al. 2001; Lewis et al. 2014). A multidisciplinary collaboration is
The multifaceted nature of fluid stewardship will need collaboration
an alternative approach, as has been described for antibiotic stewardship First, measure baseline fluid dosing, duration, costs and use patterns;
between different disciplines such as emergency medicine, critical
(MacDougall and Polk 2005; Paterson 2006; Doron and Davidson 2011; second, study indications for fluid administration (resuscitation,
care, anaesthesiology, nephrology, as well as general medicine, surgery
Schuts et al. 2016). maintenance, replacement, nutrition); and finally, identify clinician
and clinical pharmacy (Malbrain et al. 2018; Dellit et al. 2007). If the
indications for prescriptions.
primary goal of fluid stewardship is to optimise clinical outcomes A comparable strategy could be used for IV fluids, by implementing
while minimising unintended consequences as detailed above, then the ‘fluid stewardship’. There is no clear definition yet, but one preliminary 4.3. Goals of desirable fluid use
bedside clinician needs to understand fluid physiology. The combination example could be “a series of coordinated interventions, introduced to
Goals need to be formulated and ‘appropriate’, and rational IV fluid
of effective fluid stewardship with a comprehensive fluid bundle and select the optimal fluid, dose and duration of therapy that results in the
use needs to be defined for the institution and individual patients.
organ function monitoring programme should limit the deleterious best clinical outcome, prevention of adverse events and cost reduction”
Empiric versus goal-directed IV fluid treatment needs to be defined for
effects of inappropriate fluid prescription. (Dellit et al. 2007; Goff 2011). Similar to antibiotic stewardship, the

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the four indications (resuscitation, maintenance, replacement, 4.6 Implement Fluid Stewardship
Table 3. Four stages of evaluation of IV fluid therapy nutrition). Treatment guidelines for clinical syndromes need to
Analagous to antibiotic practice in critically ill patients, it is time
be established. The appropriateness of IV fluid therapy should
Stage of evaluation Audit standard to introduce fluid stewardship in the ICU, through a few simple
be assessed during the audit process. Therefore, the process of
steps. Start with a snapshot: First, check what intravenous fluids are
1. Assessment • Patient fluid balance is assessed on admission in the hospital an IV fluid treatment is divided into four stages (Table 3), based
• Patient's fluid and electrolyte needs are assessed as part of every commonly used and for what indications. Next, perform a survey
ward review on an audit framework developed by the UK National Institute
• Assessment includes the use of an appropriate clinical parameter for of knowledge (of the nurses, doctors, pharmacists, etc). Finally,
evaluation of the fluid balance
for Health and Care Excellence (NICE) (Sansom and Duggleby
perform a clinical audit of patient records (surgical vs medical).
• Recent lab result with urea and electrolytes (within 24 hours of fluid 2014; Padhi et al. 2013).
prescription) This should be followed by a Plan-Do-Check-Act (PDCA) cycle:
2. Indication A) RESUSCITATION First, the physician has to assess the patient’s IV fluid needs set up guidance (introduce fluid bundle); perform education
• For patients in need of fluid resuscitation:
o the cause of the fluid deficit is identified
and decide on the right treatment (indication). Only the three (including tailored lectures to all junior doctors) and ward-based
o an assessment of shock or hypoperfusion is made major indications need to be examined thoroughly for the purpose opportunistic teaching; and regularly re-evaluate the situation
o a fluid bolus of 500mL of crystalloids is given
of a clinical audit: resuscitation, maintenance and replacement and keep increased awareness (with flyers, screen-savers, etc.).
©For personal and private use only. Reproduction must be permitted by the copyright holder. Email to copyright@[Link].

• Patients who have received initial fluid resuscitation are reassessed

• Care is upgraded in patients who have already been given >2000mL of
crystalloids and still need fluid resuscitation after reassessment or redistribution. Second, every IV fluid prescription has to be
• Patients who have not had >2000mL of crystalloids and who still need detailed in order to ensure a proper administration and a fluid
fluid resuscitation after reassessment receive 250–500 mL of crystal- Conclusions
loids and have a further reassessment management plan is available to enable continuity of care. Third,
B) MAINTENANCE the information in the hospital’s fluid guideline or bundle is There are only four major indications for fluid administration
• Patients should be assessed for maintenance IV fluids needs at least
daily used to create different quality standards. Finally, these standards in the critically ill: resuscitation, maintenance, replacement and
• If patients need IV fluids for routine maintenance alone, the initial represent the necessary elements to do a full and qualitative check nutrition (enteral or parenteral).
prescription is restricted to:
o 25–30 mL/kg/day (1 mL/kg/hr) of water and of appropriateness (see Table 3). If all standards are met, the
o approximately 1 mmol/kg/day of potassium (K+) and In this review, a conceptual framework is presented looking at
o approximately 1-1.5 mmol/kg/day of sodium (Na+) and therapy will be classified as appropriate for that patient.
o approximately 1 mmol/kg/day of chloride and
fluids as drugs by taking into account the four Ds (drug selection,
o approximately 50–100 g/day (1-1.5 g/kg/day) of glucose to limit 4.4. Interventions on IV fluid prescribing dose, duration and de-escalation) and the four phases of fluid
starvation ketosis
• Definition of inappropriateness in case of electrolyte disturbances therapy within the ROSE concept (resuscitation, optimisation,
o Solutions not containing adequate amount of sodium in case of IV fluid prescribing consists of numerous elements. The day-to-day
hyponatraemia (Na < 135 mmol/L) stabilisation, evacuation). This framework will provide answers to
o Solutions not containing adequate amount of potassium in case of work of the core fluid stewardship members is to screen patients’
hypokalaemia K < 3.5 mmol/L)
the four basic questions surrounding fluid therapy: 1) when to
medical records for appropriateness of IV fluid administration.
o Solutions containing too much sodium in case of hypernatraemia start IV fluids?; 2) when to stop fluid administration?; 3) when
(Na > 145 mmol/L)
o Solutions containing too much potassium in case of hyperkalaemia Further tasks may lie in the automatic review of the medical to start fluid removal and finally 4) when to stop fluid removal?
(K > 5 mmol/L)
record after empiric use, fluid balance results, other laboratory Answering these questions for each patient can provide the basis
C) REPLACEMENT AND REDISTRIBUTION for fluid stewardship (like antibiotic stewardship) in the ICU. This
• If patients have ongoing abnormal losses or a complex redistribution
data (urea and electrolytes, kidney function, albumin levels,…),
problem, the fluid therapy is adjusted for all other sources of fluid and and to provide advice on appropriate duration of fluid therapy. fluid stewardship can be promulgated through a three-pronged
electrolyte losses (e.g. normal saline may be indicated in patients with
metabolic alkalosis due to gastro-intestinal losses) Finally, the fluid stewardship team could write an annual report attack for fluid safety: namely educating, changing prescribing
3. Prescription • The following information is included in the IV fluid prescription: to the hospital administration with calculation of clinical benefits habits, and increasing awareness. Good luck!
o the type of fluid
and cost savings, if any.
o the rate of fluid infusion For conflict of interest statement and full references see
o the volume of fluid
• The IV fluid prescription is adapted to current electrolyte disorders 4.5. Provide feedback, continuing education [Link]
and other sources of fluid administration
4. Management • Patients have an IV fluid management plan, including a fluid and The fluid stewardship team should organise a survey to test the
electrolyte prescription plan over the next 24 hours
• The prescription for a maintenance IV fluid is evaluated at least every
prescriber’s knowledge about composition of fluids, indications Abbreviations
24 hours and changes after a clinical exam, a change in dietary intake and monitoring of fluid status. The team can provide targeted ICU intensive care unit
or evaluation of laboratory results
education about particular fluid composition, or one specific IV intravenous
fluid at a time, as well as empiric versus goal-directed treatment.

ICU Management & Practice 3 - 2018

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Vasoactive medication and RCTs: an impossible marriage

A review and introduction of the concept “enough”
We provide a brief overview of important physiology and the pharmacology of vasoactive drugs that are currently used in the ICU as well as newer agents,
along with a concise review of recent publications comparing these agents. We attempt to answer the question what drug dose should be administered as
well as what haemodynamic values to pursue, and how much fluids must be infused by introducing the concept of “enough”.

V asoactive medication is one of the cornerstones in the and importantly, mechanical ventilation. Another issue is the enough for a particular patient, knowledge and understanding
©For personal and private use only. Reproduction must be permitted by the copyright holder. Email to copyright@[Link].

Jon Gutteling treatment of critically ill patients in shock. Shock can be significant inter-individual variation in terms of desirable of basic physiology and pharmacology is required.
Registrar in Anesthesiology defined as a failure of the circulatory system to provide cardiovascular parameters, which can also change for one
Department of Critical Care and
Department of Anesthesiology adequate tissue perfusion resulting in cellular injury and organ individual over the short and long term. In general in published Basic issues
Amsterdam University Medical failure. The definitive treatment of any type of shock is treatment studies haemodynamic goals are given in terms of specific
Centres The pump generating the circulation of blood is placed in
Location VUmc
of the underlying disease and in the case of sepsis achieving figures. Now where a specific figure of blood pressure at one
Amsterdam, The Netherlands source control. This means that during treatment of critically moment may be good in one patient, it might be too low for the thorax, where pressures vary according to the respiratory
ill patients, use of vasoactive drugs is part of a multi-approach another patient (e.g. in case of pre-existent hypertension) and cycle, and the pump, a pressure chamber, is therefore placed
[Link]@[Link]
and complicated but coherent and concerted treatment plan. higher than needed (for good organ function) for another in another pressure chamber. In normal conditions with
The most important contribution of vasoactive medication is patient. And since all vasoactive drugs have side-effects that spontaneous ventilation the intrathoracic pressure will lower
the help for immediate restoration of sufficient cardiovascular are generally dose-dependent, if a patient receives a higher during inspiration and return to normal pressure, which is
circulation to buy time for further treatment. This means that dose than required, the patient is more exposed to side-effects slightly less than the atmospheric pressure. However, during
even if you give the best possible vasoactive drug, the patient than the benefit of the given drug would justify. Therefore we mechanical ventilation the intrathoracic pressure, referring to
will still die if the rest of the treatment is insufficient. Part of introduce the goal of “enough” for different cardiovascular the intrapleural pressure, is increased during inspiration and
the other treatment in critically ill patients consists generally parameters. Enough is defined as: not too low and not too lowers, but remains above zero depending on the amount of
speaking of fluid resuscitation, giving the right antibiotic at high for a specific patient. For example, the best cardiac output PEEP (positive end-expiratory pressure) during expiration.
the right dose, mechanical ventilation, and specific underlying for a patient is “enough,” the best blood pressure and heart Since blood flow is from areas with a higher pressure to a
Armand R.J. Girbes* disease-related treatment that can be medical and/or surgical. rate is also “enough.” The only missing link is then to define lower pressure, the intrathoracic pressure determines the
Professor of Intensive Care Other issues such as specific nursing care, decubitus prevention, “enough” for each particular patient. Thinking this way would pressure gradient for blood streaming towards the heart. It is
Medicine of note that the most important task of the heart is to pump
Chair, Department of
feeding, early start of activity, timely weaning of the ventilator, avoid designing a study where a mean blood pressure of 70
Critical Care prevention of errors and complications, doing all the things mmHg would be compared with 80 mmHg, or a study where and transfer the amount of blood that is presented at the right
Amsterdam UMC right, etc. play an undeniable role in patient survival. different doses of a vasoactive drug are given to establish side of the heart. Therefore, cardiac output is determined by
Amsterdam, The Netherlands
prefixed haemodynamic parameters to patients in order to the flow that is presented at the heart, and the venous flow
Vasoactive medication is generally discussed and studied that enters the heart equals the cardiac output. Similarly, the
ICU Management & Practice compare the vasoactive drugs (DeBacker et al. 2010; Russell et
Editorial Board Member apart from other elements of treatment and the effect on the amount of volume expelled by the right side of the heart—
al. 2008; Asfar et al. 2014). As will be explained this approach
cardiovascular circulation is considered pivotal. This is in fact through the pulmonary circulation—equals the volume that
[Link]@[Link] will also hold for the desirable amount of fluid resuscitation:
odd, since the (short-term) cardiovascular circulatory status is presented to the left side of the heart and is subsequently
enough. In order to be able to estimate at the bedside what is
@ArmandGirbes will depend on many other factors, such as fluid resuscitation expelled by the left ventricle. Because of this it is important
corresponding author
*

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for the practising intensivist to acknowledge that—as put forward by

Guyton—the venous return is determined by the pressure gradient 50% remain fluid responsive after the initial resuscitation (Bentzer
between the peripheral veins and the right heart, i.e. the right atrium et al. 2016). Predictors for a positive fluid response are the passive
or CVP. In a formula, including the venous resistance: leg raise test and pulse pressure variation (Bentzer et al. 2016). In
terms of clinical parameters this has been translated in pulmonary
VR = (Pms-Pra)/venous resistance and peripheral oedema, abdominal compartment syndrome, kidney
Where VR = venous return, Pms = mean systemic pressure, Pra = right injury and longer mechanical ventilation (Malbrain et al. 2014).
atrial pressure (Figure 1). Not surprisingly, there is an increasing focus on potential adverse
effects caused by (too much) intravenous fluid resuscitation and
The venous system can be filled until the intravascular pressure this underscores that one should give just enough to a patient. This
starts to increase: this volume capacitance is called “unstressed volume.” perception has contributed to a shift of earlier use of vasoactive drugs
©For personal and private use only. Reproduction must be permitted by the copyright holder. Email to copyright@[Link].

With further filling the veins will be stretched and the intravascular to obtain haemodynamic goals in patients and to use less fluids.
pressure will increase: the capacitance of this further filling volume
is called “stressed volume.” This theoretical model is depicted in From the previous it may become clear that execution of
Figure 2. When a fluid bolus increases the stressed volume, the Figure 1. Relation between venous return and right atrial pressure
mechanical ventilation and fluid resuscitation, timely treatment of
driving force to the right atrium, right arterial pressure (RAP), can underlying disease as well as the intrinsic properties of the heart at
be increased, provided that the RAP will not increase accordingly. a particular moment will influence the effect of any vasoactive drug.
It is of note that with large volume resuscitation RAP may increase Stressed volume It is therefore extremely surprising that trials evaluating vasoactive

Pressue
Unstressed Stressed
Right atrial volume volume

more than Pms, related to the reduced diastolic compliance of the

pressure
drugs do not take mechanical ventilation and specific properties that
Unstressed volume

heart and pericardium, resulting in a reduction of pressure difference are known to be of importance, into account.
Volume

Pms-Pra (Applegate et al. 1992).

Figure 2. Theoretical model of stressed and unstressed (venous) volume,
making clear that an unstressed volume is required first after which additional Markers of “enough”
Increasing intrathoracic pressure as seen in mechanical ventilation volume loading will increase right atrial pressure
will reduce VR. On the other hand increased intrathoracic pressure Although many studies, including randomised clinical trials (RCTs),
will reduce afterload for the left ventricle. The effect of mechanical focus on a single parameter (e.g. plasma lactate levels, SvO2, cardiac
ventilation and lung volume on right ventricle afterload may vary particular in case of previous coronary or hypertensive disease, with output), clinicians use several parameters simultaneously to assess
according to the balance of stretching the extra-alveolar and intra- a huge spectrum of changes and severity. the situation and possible improvement of the condition of a patient.
alveolar blood vessels: therefore increasing lung volume by e.g. PEEP In this context fluid responsiveness is frequently mentioned and These parameters include signs of adequate organ function and
may both lead to an increase and decrease of pulmonary vascular an increase in stroke volume (SV) of 10-15% after a fluid challenge is perfusion: mental state, peripheral skin perfusion as determined by
resistance (PVR) (Canada et al. 1982). Hyperinflation of the lung will considered as fluid responsiveness. The increase of myocardial contraction nose or knee temperature and mottled skin, capillary refill, diuresis,
result in overstretching of the alveolar vessels, thereby increasing PVR as a result of the stretching of actin and myosin muscular filaments SvO2, lactate levels, oxygenation, blood pressure, ECG abnormalities,
which can induce (acute) right ventricular failure. Hyperinflation can (mostly indicated as according to the Frank-Starling principle) is in venous curves on the monitor, cardiac output if measured. The
be the result of increased respiratory rate, larger tidal volumes (Vt) terms of energy consumption and demands a very favourable response experienced clinician will very much focus on pattern recognition
and insufficient expiratory time. Other heart-lung interactions, such of the heart. However, if the heart does not respond with an increase of all these simultaneously assessed parameters. The response to any
as mechanical effects on the heart, and specific effects of sepsis on of SV to a fluid load, the latter might be harmful due to induction intervention will help to estimate whether the chosen therapy is
the heart and circulation are beyond the scope of this paper and can of oedema, which in turn may cause all kind of unfavourable effects favourable or not. The experienced clinician will furthermore use all
be read elsewhere (Marik and Bellomo 2016; Pinsky 2016; Fessler for diverse organ functions (Hilton and Bellomo 2012). A recent available data and will not be guided by one single parameter alone,
1997). The situation and properties of the heart may even be more meta-analysis of haemodynamically unstable patients showed that e.g. focus only on cardiac output. Errors as made in the past, such

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as striving for “supranormal” oxygen delivery (DO2) with excessive comparing different figures of blood pressure, lack sufficient there is not such a drug that 100% specifically stimulates only one
fluid administration and very high doses of inotropes or very strict acknowledgement of physiological facts. The recommendations of type of receptor. And most adrenergic drugs have a combined effect on
regulation of serum glucose levels with very high doses of insulin the Surviving Sepsis Campaign to maintain a mean arterial pressure both α- and β-adrenergic receptors. To increase arterial blood pressure
and at the price of causing hypoglycaemia, should now turn the (MAP) of 65 mmHg in septic shock may be of use for paramedics an adrenergic drug that has a predominant α1-adrenergic effect is
intensivist into a physician who realises that just enough is enough and inexperienced physicians, but as follows from the previous text required, or a drug that stimulates another receptor or pathway such
and better is the enemy of good (Voltaire). Translated in an example: should not be used by experienced intensivists who are aware of the as angiotensin II or vasopressin. In cardiogenic shock, low cardiac
if a patient is hypotensive, anuric and confused, and responds to two cardiovascular physiology and heart-lung interactions. output state or other types of impaired cardiac function (where
times 250 mL of Ringers lactate intravenously with an increase in cardiac output is “not enough”), an agent may be required that has
blood pressure, a lowering of heart rate and improved mental state affinity for β1-adrenergic receptors to increase inotropy, chronotropy
and diuresis, the amount of given fluid was enough for this moment. “RCTs on vasoactive drugs, aiming at or dromotropy. There are also other cellular pathways to increase the
specific figures, or even comparing different
©For personal and private use only. Reproduction must be permitted by the copyright holder. Email to copyright@[Link].

Blood lactate levels may also be helpful to assess clinical deterioration cardiac contractility via other routes, such as increasing intracellular
or improvement of a patient over time, but one should realise that calcium or affinity of cardiac myocytes for calcium. It is good to realise
lactate can be increased as a result of anaerobic glycolysis due to figures of blood pressure, lack sufficient that any drug has potential adverse effects. Vasopressor therapy can
systemic or regional hypoperfusion, but also due to stress-related acknowledgement of physiological facts” result in decreased stroke volume and thus cardiac output because
adrenergic-induced aerobic glycolysis, impaired hepatic clearance of the increased afterload.
as well as mitochondrial dysfunction limiting pyruvate metabolism.
However, things are not that simple. The blood pressure that is During inotrope use arrhythmias might occur, and cardiac oxygen
One should therefore never focus on a single parameter such as
enough for the brain might not be enough for the kidneys or vice demand might be increased because of increased heart rate. Inotropes
lactate alone to assess the effect of treatment and there is insufficient
versa. Some organs such as the brain, heart and kidney are known to can also cause vasodilatation requiring additional vasopressors to
convincing evidence that decreasing lactate levels alone is a useful
have some ability to auto-regulate blood flow resulting in a constant maintain adequate blood pressure. In general, short-acting vasoactive
target of therapy in critically ill patients (Bakker 2014).
blood flow across a specific MAP range (Hollenberg 2011). But this can drugs should be titrated to effect to achieve specific haemodynamic
be deranged in different situations, such as brain injury, pre-existing goals while minimising potential harmful effects.
Goal for blood pressure: enough hypertension or abdominal compartment syndrome. Therefore it
We provide a brief overview of the pharmacotherapy with
For the treatment of shock, blood pressure has been and is a pivotal is of utmost importance to evaluate clinical signs and markers of
vasoactive drugs in critical care medicine in an attempt to summarise
marker of severity of shock and effectivity of treatment. As outlined tissue perfusion continuously. Measurement of cardiac output can be
cellular effects, indications, common adverse effects as well as recent
before, we argue that blood pressure should be just enough. Now it complementary to understand the present (circulatory) physiology
scientific evidence, for both proven drugs and newer agents.
is clear that “enough” is different and a higher value in a patient with of the patient, either done by thermodilution with a pulmonary
shock and a history of insufficiently treated hypertension compared artery catheter, or combined with continuous pulse contour analysis
Adrenaline (Epinephrine)
to a person who is used to a blood pressure of 105/70 mmHg and through an arterial cannula, or noninvasive using cardiac ultrasound
has a blank medical history. Furthermore, since all treatments involved or pulse contour analysis. Cardiac output should not be aimed at a Adrenaline is an endogenous hormone and neurotransmitter produced by
such as fluid resuscitation and the administration of vasoactive drugs specific target, but again should be “enough” and certainly not too and stored in the adrenal glands. It has a main effect on the β1 receptor,
are known to produce important side-effects such as oedema and high, as has been previously advised for supra-normal goals of therapy. with additional affinity for β2- and α1- adrenergic receptors, resulting
arrhythmias, which are also dose-dependent, it becomes clear that in both increased cardiac output and mean arterial pressure. The main
the lowest possible dose/quantity should be given: the definition Use of vasoactive drugs difference beween adrenaline and noradrenaline (norepinephrine)
of “enough”. Only in this way will the advantages outweigh the is the increased affinity of adrenaline for β2-receptors compared to
In clinical practice, to determine which vasoactive drug to administer, noradrenaline. Low doses of adrenaline result in an increase of cardiac
disadvantages for the patient. We have therefore reasons to believe
the desired effect has to be determined as well as knowledge about the output and variable effects on mean arterial pressure, depending on
that RCTs on vasoactive drugs, aiming at specific figures, or even
required receptors or other cellular pathways involved. Unfortunately, the balance of effects of β1, β2 and α1 adrenergic receptors stimulation.

ICU Management & Practice 3 - 2018

TRACHEOSTOMY –
Advancing Patient Safety
and improving Quality of Life
in Adult Critical Care
Monday 22 October 2018
18.15-19.15
Symposium
supported by
Chair person: Prof. Marco Ranieri – Rome – Italy an unrestricted
Co-chair person: Prof. Samir Jaber – Montpellier – France
educational grant
Patient Safety – Enhancing VAP prevention in ICU – Prof. Marco Ranieri, Rome from Smiths Medical
Patient Quality of Life – Strategies to improve communication in mechanically
ventilated patients – Dr. Brendan McGrath, Manchester FIND US AT
BOOTH 2.42 Visit to register.

You are invited to a post-lecture cocktail close to the

Room Glasgow 19:15 - 19:45

Room Glasgow – Level 2 LIVES 2018

Palais des congrès Paris, France Space is limited.
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COVER STORY: SHOCK

It is short acting and mostly metabolised in the liver by catechol-O- septic shock seemed more favourable towards noradrenaline looking Dobutamine is an agent widely used in cardiogenic shock, and
methyltransferase (COMT) and monoamine oxidases (MAO). Excretion at clinical trials (De Backer et al. 2012) gained popularity as an agent used in septic shock since the original
of metabolites is renal. Because of strong β1 effect, arrhythmias are early goal-directed therapy (EGDT) trial where it was used to achieve
common during use. Lactic acidosis is often reported, which is a direct Dopamine central venous oxygen saturation goals (Rivers et al. 2001). It was
β2 adrenergic effect. only realised later by intensivists that the Rivers study population was
Dopamine is the endogenous precursor of (nor)adrenaline and has a
not a representative population of patients with sepsis. Many other
Current indications for the use of adrenaline in critically ill patients complicated action on the cardiovascular, renal and neurohumoural
large studies proved no benefit for the use of dobutamine as deemed
are during cardiac arrest, anaphylactic shock and as an adjunctive systems. Metabolism is fast, elimination half-life is 1-2 minutes with
indicated according to the EGDT guidelines (Mouncey et al. 2015).
antihypotensive agent. There are few trials that compare adrenaline metabolism in the liver, kidneys and plasma by MAO and COMT
to other agents, of which two larger studies can be mentioned. One into inactive metabolites and noradrenaline. Metabolites are excreted
Vasopressin and analogues
randomised controlled trial (RCT) (n=280) compared adrenaline by the kidneys. The circulatory effect depends on the predominant
©For personal and private use only. Reproduction must be permitted by the copyright holder. Email to copyright@[Link].

to noradrenaline in septic shock and found no difference in survival effect of the different receptors that are stimulated by dopamine: Antidiuretic hormone, also named arginine vasopressin (AVP), is
but a higher incidence of tachyarrhythmia and lactic acidosis in the dopaminergic receptors (DA1, DA2), β1- and α1-adrenergic receptors an endogenous hormone secreted by the anterior pituitary gland
adrenaline group (Myburgh et al. 2008). Another RCT (n=330) (Girbes et al. 2000). Some authors wrongly still write that dopamine in response to stress or shock. There are three major vasopressin
compared adrenaline and a noradrenaline/dobutamine combination stimulates different receptors at different doses, distinguishing 1-4 receptors and for conditions of circulatory shock the vasoconstrictor
and concluded there was no difference in safety and efficacy (Annane µg/kg/min, 4-10 and >10 µg/kg/min. This is simply not true. At effect of smooth muscle caused by activation of the V1 receptor is
et al. 2007). every dose dopamine stimulates DA1, DA2, β1- (β2), and α1-adrenergic most relevant. AVP is given intravenously and has a half-life of 10-35
receptors. Additionally, dopamine inhibits uptake-1. In the past the minutes with V1, V2 and V3-receptor affinity. It is rapidly metabolised
In cardiopulmonary resuscitation adrenaline appears to increase
positive effects of dopamine were overrated, mainly related to its by the liver and kidney.
the chances for return of spontaneous circulation, but does not increase
effects on renal blood flow (Girbes and Smit, 1997). Dopamine was
favourable neurological outcome. A very recent placebo-controlled Terlipressin is a non-selective vasopressin analogue that also
given at “a renal dose”, i.e. a dose up to 4 µg/kg/min to preserve
RCT confirmed these findings, with adrenaline improving 30-day is a prodrug of lysine vasopressin, which is similar to AVP. The
renal function, but later studies indicated no beneficial effects in the
survival, but no difference in proportion of patients surviving hospital elimination half-life is 50 minutes, with active metabolites for up
long-term (Marik 2002). And since the RCTs comparing noradrenaline
discharge with a favourable neurological outcome (Perkins et al. 2018). to 6 hours. Vasoconstriction caused by V1 receptor stimulation could
and dopamine, the use of dopamine is significantly reduced, due to
lead to additional cardiac ischaemia and is possibly more pronounced
its reported side-effects, mainly dysrhythmias.
Noradrenaline in the mesenterial region resulting in gastrointestinal ischaemia.
Reflex bradycardia may lead to decreased cardiac output. V2-receptor
Noradrenaline is also an endogenous hormone and neurotransmitter. Dobutamine
activation causes endothelial von Willebrand factor release, causing
Its main affinity is for α1-adrenergic receptors, with some β1 and
Dobutamine is a mixture of two isomers with mainly β1, but also enhanced platelet aggregation with increased risk for thrombosis.
minor β2 effects. Noradrenaline has a short half-life; it is active for
β2 and mild α1-adrenergic receptor effects. Elimination half-life is 2 (Saad and Maybauer 2017).
about 1-2 minutes. Metabolism is hepatic and in nerve endings and
minutes, metabolism is mostly by COMT in the liver and tissues into
inactive metabolites are excreted renally. Noradrenaline is used mainly Selepressin is a novel, short-acting selective V1 agonist that appears
inactive metabolites that are excreted by the kidney. The main effect of
as a vasopressor in vasodilatory shock, but also cardiogenic shock and promising in initial studies, but a critical appraisal of new data must
dobutamine is as an inotrope through β1-receptor effects: an increase
during general anaesthesia for anaesthesia-induced hypotension. Adverse be awaited. In animal sepsis models, improved survival compared to
in cardiac output by increasing stroke volume and heart rate. Effects
effects are mainly related to severe vasoconstriction, such as limb or noradrenaline is reported. And importantly, a decrease in pulmonary
on blood pressure vary and are unpredictable (Hollenberg 2011).
gastrointestinal ischaemia. A widespread misunderstanding is that capillary leak (Saad 2017).
Because of the positive chronotropic and inotropic effect on the heart,
noradrenaline decreases coronary blood flow (Mueller et al. 1970).
dobutamine causes an increase in myocardial oxygen demand, with a There is no convincing evidence that vasopressin or its analogues
The comparison of noradrenaline versus dopamine in the treatment of
risk of myocardial ischaemia. Ventricular arrhythmia may also occur. are superior to catecholamines in the treatment of sepsis or during

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cardiopulmonary resuscitation. Vasopressin can however be considered trials have been disappointing and at this moment there is no place for muscle cells as a result of opening ATP-sensitive potassium channels.
as a second-line vasopressor therapy. The vasopressin analogue the use of NO-inhibitors in the treatment of septic critically ill patients. The biological half-life is about 1 hour and active metabolites after
terlipressin is commonly used in hepatorenal syndrome and portal conjugation with glutathione, the metabolites are pharmacologically
hypertension but there is no convincing evidence supporting its use in Phosphodiesterase inhibitors: milrinone and enoximone inactive and excreted in urine and faeces. Some metabolites, 4-7%
septic shock. The clinical relevance of studies showing that vasopressin of the levosimendan dose, are formed slowly and the elimation
Frequently used phosphodiesterase inhibitors (PDEi) in the ICU are
reduces the use of noradrenaline are in our view questionable. half-life has been up to 70-80 hours in patients with congestive
enoximone and milrinone. Both inhibit phosphodiesterase type III,
heart failure. A single day of infusion is adequate for several days of
resulting in an increased amount of intracellular cAMP, which leads
Angiotensin 2 treatment. It is therefore not surprising that the use of levosimendan
to an activation of cardiac calcium channels and increased calcium
has been associated with higher incidence of tachyarrhythmia and
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Synthetic (or bovine) angiotensin II is a novel drug that is postulated as influx during systole increasing cardiac contraction force. During
prolonged hypotension (Antila et al. 2007). Initial enthusiasm about
a third type of vasopressor, after adrenergic vasopressors and vasopressin. diastole, there is an increased efflux of calcium increasing relaxation
the application of levosimendan for either low cardiac output states
Angiotensin II is converted from angiotensin I by angiotensin-converting (lusitropy). Because of the inotropic and vasodilatory effects, PDEi
or sepsis has been denied by later and larger studies.
enzyme (ACE) and a product of the renin-angiotensin-aldosterone are also called inodilators. Excretion is mostly renal, and half-life
system (RAAS), which is activated by decreased renal perfusion in depends greatly on kidney function, with the risk of accumulation.
Other agents
hypovolaemia. Angiotensin II has a vasoconstrictor effect by increasing Known adverse events include tachyarrhythmia, thrombocytopaenia
intracellular calcium levels in smooth muscle cells that results in and hypotension. Although many studies found an improvement of Phenylephrine is mainly an α1-agonist, that is used mainly in theatre
vascular contraction after activating several cell-signaling pathways. circulatory parameters in patients with (severe) heart failure in the for perioperative hypotension. Because of the increase in systemic
There is however, little evidence supporting the use of angiotensin short term, later studies showed that this was not translated into a vascular resistance (SVR) and subsequent baroreceptor-induced
II in shocked critically ill patients. The recent Angiotensin II for better long-term outcome. For patients after cardiac surgery that decrease in heart rate, its net effect is a decrease in cardiac output.
the Treatment of High-Output Shock (ATHOS-3) trial investigating require inotropic support, there is also a possible trend towards Ephedrine is an indirect agent that stimulates the release of endogenous
the addition of angiotensin II to noradrenaline in the treatment of greater mortality compared to dobutamine (Nielsen et al. 2018). noradrenaline. Repeated doses show decreased effect known as
“refractory” vasodilatory shock in 344 patients showed a significant tachyphylaxis, caused by a depletion of cellular noradrenaline stores.
increase in blood pressure and decrease of noradrenaline dose in Data on patients in the ICU are scarce and there are no data to justify
the study group. However, there is a lack of data on serum lactate “it is of utmost importance to evaluate prolonged administration in the ICU. Isoprenaline is a short-acting
or central venous oxygen saturation and, most importantly, none of
the patients was in fact treated with high-doses vasopressor therapy
clinical signs and markers nonselective beta agonist that is mostly used in treatment of extreme
bradycardia and atrioventricular block.
at the beginning of the study. There were no significant differences of tissue perfusion continuously”
in mortality or adverse events (Khanna et al. 2017). Special considerations
Levosimendan
Nitric Oxide (NO) inhibitors Pulmonary arterial hypertension
Levosimendan is a calcium sensitiser: it increases the susceptibility of
Systemic inflammation can cause the overexpression of “inducible nitric cardiac myocytes to calcium by binding on troponin C, resulting in Pulmonary arterial hypertension (PAH) has obtained more attention in
oxide synthetase” (iNOS), which is stimulated by pro-inflammatory increased cardiac contraction without increasing calcium levels. There the ICU with a focus on right ventricular (RV) function. In critically ill
cytokines, resulting in excess nitric oxide and vasodilatation. Attempts is no change in diastolic relaxation or increase in myocardial oxygen patients with pulmonary hypertension and (imminent) RV failure, the
have been made to counteract this overexpression. However, clinical demand. Another effect is vasodilatation by opening vascular smooth goal of treatment is to reduce pulmonary vascular resistance, improve

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right ventricular contractility, optimising right ventricular preload After volume resuscitation, noradrenaline is usually recommended Furthermore, one should realise that if such trials compare different
while also maintaining adequate systemic perfusion. Fluid management because of its less outspoken constrictor effect on the splanchnic strategies of the use of vasoactive drugs, the outcome applies only for
requires special attention since in the case of increased RV afterload, circulation. Vasopressin or terlipressin can be added to potentiate that specific strategy with those defined haemodynamic goals. In other
volume loading will result in RV dilatation and displacement of the noradrenaline. There is insufficient reason to believe that terlipressin words, if a trial says that noradrenaline is “better” than dopamine,
interventricular septum toward the left ventricle (LV) with impaired is superior to other vasoactive drugs in case of hepatorenal syndrome it is only applicable if you use the specific haemodynamic goals in
LV diastolic filling as well as decreased right coronary perfusion. (Israelsen et al. 2017). a similar population. And the result might be different if you use a
Failure to take this into account will thus result in deterioration of slightly different haemodynamic goal for dopamine or noradrenaline.
Trumatic brain injury
the circulation with deleterious consequences. The most important We also foresee that the answer on which is the best vasoactive
factor is to establish the diagnosis as soon as possible in order to be In physiological conditions, the brain has the ability to auto-regulate medication for my patient, or groups of patients, will never come
able to provide adjusted precision therapy. Cautious fluid resuscitation cerebral blood flow. After TBI, cerebral autoregulation could be from large RCTs. Recommendations with fixed figures such as in the
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(including no extra fluid administration) is an important factor for impaired, and therefore a pivotal treatment goal in the critical care Surviving Sepsis Campaign are perhaps of use for non-intensivists,
that and the reader is referred to a recent review (Jentzer and Mathier setting is to maintain adequate cerebral perfusion. A commonly used but are potentially dangerous and ignore the complexity of disease
2016). The goals for vasoactive medication include reduction of PVR, parameter to guide treatment is cerebral perfusion pressure, which in individual critically ill patients. Therefore, understanding the
maintenance of SVR and increased cardiac output. PDEi inhibitors have is the function of mean arterial pressure minus intracranial pressure pathophysiology, watching carefully and continuously the effect of
favourable effects compared to dopamine and dobutamine as a result measured by an intraventricular or intraparenchymal probe. The the given therapy, doing all (simple) things right will for the coming
of increased right ventricle contractility and pulmonary vasodilatation recommended cerebral perfusion pressure is between 60-70 mmHg decades remain the cornerstone of therapy with vasoactive medication,
with less tachycardia and additional oxygen consumption. The decrease (Carney et al. 2016). There are no high-quality studies indicating but it will be called precision medicine.
of SVR and concomitant decrease of systemic blood pressure may which vasoactive drug is best used to increase arterial pressure in TBI
Conflict of interest
be treated with a vasopressor such as noradrenaline. However, all patients. Noradrenaline has the most predictable effects.
α-1 agonists are reported to increase PVR, with a possible increase Jon Gutteling declares that he has no conflict of interest. Armand R.J.
in right ventricular afterload. Vasopressin has a moderate additional Discussion Girbes declares that he has no conflict of interest.
and considered favourable effect of endothelin-dependent pulmonary
vasodilation, thereby producing less increase of PVR compared to the Treatment of critically ill patients is micromanagement of all vital
increase of SVR. Intravenous prostanoids are indicated for patients functions. The use of vasoactive medication is only a part of the
with critical PAH, with a preference for prostanoids with a short treatment of a complex pathophysiology. Because of the immense Abbreviations
half-life e.g. epoprostenol. heterogeneity amongst patients, the increasing choice between different MAP mean arterial pressure SVR systemic vascular resistance
agents and the supportive nature of treatment with vasoactive drugs, PVR pulmonary vascular resistance VR venous return
Hepatic failure comparing treatments is challenging and prone to error. Although
SvO2 mixed venous blood oxygen saturation
Patients with hepatic failure are often volume depleted as a result we acknowledge the huge efforts and organisational skills to perform
of low systemic vascular resistance (vasodilation), together with a RCTs with vasoactive drugs, we question the value in terms of external
high cardiac output, and it mimics vasodilatory shock. Few studies validation and applicability, especially in view of individual precision
have been conducted comparing different vasoactive drugs in the medicine, for the reasons mentioned above. The value of such trials is References
critically ill with hepatic failure, and most have very few patients. therefore in our opinion merely on the collection of data of side-effects. For full references, please email editorial@[Link] or visit [Link]

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Advances in source control in patients with

sepsis and septic shock
In the past decades there have been significant advances in the diagnosis and management of patients with sepsis and septic shock, and overall
awareness has increased significantly (Angus and van der Poll 2013). Emphasis is currently on the early detection of sepsis and rapid initiation of fluid
administration and antibiotic therapy, all of which have improved outcomes (Rhodes et al. 2017). Nevertheless, discussion remains about the targets
for fluid resuscitation, the optimal type of fluid and many other aspects of sepsis management, and this directs scientific research in the field (Perner
©For personal and private use only. Reproduction must be permitted by the copyright holder. Email to copyright@[Link].

et al. 2017).

W hile there is consensus that antibiotic therapy and (De Waele 2016) but source control should be considered in appropriate source control should be part of the systematic
Jan J. De Waele
Department of Critical Care source control are the major therapies for severe every patient with sepsis or septic shock. In fact, up to 45% checklist we have to keep in mind in setting up the therapeutic
Medicine
infections, source control has been consistently of patients with sepsis and septic shock require some form strategy in sepsis (Marshall et al. 2004).
Ghent University Hospital
ignored by many studies, and its exact role, particularly the of source control (Bloos et al. 2017). Not every patient of
Ghent, Belgium A practical approach to define source control is rather
timing and methodology used, remains uncertain. Source course may require a surgical procedure, but also in patients
ambiguous in some guidelines. For instance, in the recent
ICU Management & Practice
control is receiving only limited attention in the first hour of with presumed non-surgical infections source control may
Editorial Board Member Surviving Sepsis Campaign (SSC) guidelines from 2016 the
sepsis treatment, disproportional to its impact on outcome. be considered e.g. in patients with bloodstream, urinary tract
[Link]@[Link] recommendation was:
It has proved hard to accurately define source control, and or respiratory infections.
@criticcaredoc
quantifying it is even more difficult. But insights into the role We recommend that a specific anatomic diagnosis of
of source control are evolving, and both the epidemiology “source control has infection requiring emergent source control be identified
or excluded as rapidly as possible in patients with sepsis
and methodology will surely receive more consideration in
the next years. Currently, exact data on the impact of source
been consistently ignored by many studies or septic shock, and that any required source control
control, or data that provide adequate guidance on the timing and its exact role remains uncertain” intervention be implemented as soon as medically and
and preferred method for source control remain scarce. logistically practical after the diagnosis is made (Rhodes
et al. 2017).
Most of the time the focus is on the first two goals of
1. Defining source control source control, namely eliminating the source of infection Interestingly the recommendation was acknowledged as
and controlling ongoing contamination. Source control can a “Best Practice Statement”.
The definition of source control has not changed over the years, involve a surgical procedure, percutaneous drainage using a
yet this definition is more a conceptual approach, focusing on catheter (that either remains in place or not), incision of an
the goal of source control rather than the exact method to 2. Source control in critically ill patients
Ignacio Martin-Loeches abscess, removal of necrotic tissue or removal of an infected
Multidisciplinary Intensive Care reach these goals. Source control is defined as the different device e.g. central venous catheter or external ventricular drain. Applying source control and its principles in critically
Research Organization (MICRO)
measures that are used to eliminate the source of an infection, ill patients poses specific challenges. First, the patient is
Department of Intensive Care
Medicine control ongoing contamination and restore premorbid Historically, the evidence came from non-randomised more severely ill, with less room for compensating for the
St James's University Hospital, anatomy and function (Schein and Marshall 2002). It is true controlled trials, mainly in necrotising fasciitis, with multiple consequences or complications of a procedure; second, the
Dublin, Ireland
that source control is most often thought of in patients with case series conducted in the 1990s (Elliott et al. 1996). The urgency of the need for source control is equally different.
drmartinloeches@[Link] abdominal infections because of the ongoing contamination data were in favour of an aggressive operative approach. An Leaving a patient exposed to an untreated infection can have
expert opinion roundtable in the mid 2000s highlighted that more severe consequences compared to patients who present
@imloeches

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Table 1. Different source control measures and matching clinical scenarios Source control has long been synonymous with a surgical Strategies for source control are improving continuously and
Source control measure Clinical scenario
procedure, mostly a laparotomy or other open intervention, but this no doubt will do so in the future. The trend towards minimally
is changing significantly. Firstly, laparoscopy and minimally invasive invasive procedures will continue, with more advanced endoscopic
Excision Appendicitis, cholecystitis
procedures have replaced open surgical procedures, although in (ultrasound-guided) procedures as the most important development.
Repair Perforated ulcer, early iatrogenic injury
critically ill patients laparoscopy may be less tolerated. The main As an example, transgastric endoscopic drainage and necrosectomy
Diversion +/- excision Leaking anastomosis
evolution regarding source control has been the rise of percutaneous for infected pancreatitis (van Brunschot et al. 2018) is a promising
Drainage Abscesses or infected fluid collections
drainage of abscesses in many locations, either ultrasound or CT-guided technique that obviates the need for open surgery, often fraught
Debridement Necrotic infected tissue
(Soop et al. 2017). Table 2 provides an overview of the different with complications.
interventions and how effective they are in regard to the different
Table 2. Different interventions and their effectiveness on source control principles It remains to be demonstrated that patient condition makes no
source control principles.
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difference in selecting the best source control procedure, and in studies

Intervention Drainage Debridement
Restoration of • Open or endoscopic surgery is still the most controlled method reporting on new techniques severity of illness should definitely be
anatomy and function
Open surgery +++ +++ +++
of source control. It is very effective in completely draining considered to make sure that the most vulnerable patient benefits
collections or abscesses and debriding necrotic tissue. Also, from the most optimal procedure.
Percutaneous drainage ++ + 0
restoration of anatomy and function is straightforward.
Device removal + 0 0
Desobstruction ++ 0 ++ • Percutaneous drainage (PCD) is effective in draining a large 4. Importance of source control
Open abdomen management ++ 0 0 part of most collections, although mostly a small residual Data supporting the role of source control are limited although
amount will remain. This is often managed by rinsing the several studies have recently focused on this important issue. From
without sepsis, even if antibiotic therapy and fluid resuscitation catheter and collection in order to remove the last remainders these data, two relevant aspects are consistently reported: source
have been initiated. of the infection. For multiloculated infections multiple catheters control adequacy and timing of the intervention.
may be needed, and also more residual infection may have to
The proportion of patients with sepsis that requires source The impact of source control seems to be unrelated to the
be tolerated. Implicitly the residual infection may continue to
control clearly depends on the type of infection that is causing sepsis. administration of appropriate antibiotics. Several studies found that
produce signs and symptoms of infection and the response
In the multicentre study by Bloos et al. (2014), 42% of patients with both are independent predictors of mortality (Bloos et al. 2015; Tellor
to the treatment may be more difficult to monitor. Debriding
septic shock required source control. In this study, the majority of et al. 2015), but there is consensus that without adequate source
necrotic tissue is even more difficult and again a considerable
these procedures was surgical (85%), but this may vary according control, antibiotic therapy may have little if any effect (Figure 1).
amount of necrosis may need to be tolerated. Repairing
to the source of the infection, presence of ongoing contamination,
anatomical lesions is not possible using PCD. a) Adequacy of source control
surgical history and general condition as well as co-morbidities of
the patient. • But also simple interventions such as device removal can Inadequate source control seems to be a relatively frequent problem,
be considered for source control. Removing an obstruction but source control has been inconsistently defined in the literature,
3. Available methods for source control such as a urinary tract lithiasis or choledocholithiasis can be and often there is even no definition or description provided. Source
effective in draining the infection, but again no meaningful control adequacy is determined by source of infection, source control
Based on the aspect that source control consists of those definitive debridement is possible. Anatomy and function are mostly intervention, patient type, definition used, methodology applied
measures to control a source of ongoing microbial contamination adequately restored after such a procedure. Open abdomen among other factors.
and to restore anatomy and function, definition of source control management can also be part of a source control procedure,
can be integrated in five categories (Table 1). effective mostly for draining the abdominal cavity. Restoration Logically, not controlling the source of infection should be
of anatomy and function will only follow later. included in a definition of inadequate source control, but there is

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the infection as soon as medically and logistically practical after the

Table 3. Elements of damage control surgery in abdominal sepsis
diagnosis is made (with the suggestion to do so within a 6-12-hour
Resuscitation
window after diagnosis) (Rhodes et al. 2017), whereas the English

© Jan J. de Waele & Ignacio Martin-Loeches

Resection without re-anastomosis or ostomy formation Royal College of Surgeons recommends controlling the source of the
Temporary drainage infection within 6 hours in patients with sepsis and immediately
Antibiotics in patients with septic shock (Royal College of Surgeons of England
Abdominal packing if needed
Appropriate, early and 2011). The latest update of the Surgical Infection Society guideline
dosed adequately Temporary abdominal closure on intra-abdominal infections cites 24 hours as the window in which
the source needs to be controlled, unless when patients have sepsis
or septic shock, when the intervention needs to be undertaken in
Source control
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source control is not feasible from the start (Leppäniemi et al. 2015). a more urgent manner (Mazuski et al. 2017).
Timely and adequate
This concept has been advocated based on experience of damage Timing is a critical aspect of source control. A UK study found
control laparotomy patients with severe abdominal trauma and it that in general surgery patients, the median time to surgical source
Figure 1. Relation of different interventions for sepsis and septic shock is a limited procedure to control the infection with four practical control was 19.8 hours, with no difference in patients with sepsis
strategies (Table 3). This approach has also been named rapid source and septic shock compared to patient without sepsis (as per current
control laparotomy (Becher et al. 2016). definitions) (UK National Surgical Research Collaborative 2017).
no consistency in other elements of source control adequacy. Some In a study on patients with complicated diverticulitis of different
The antibiotic strategy differs depending on the success in
definitions include both timing (e.g. within 24h) as well as pure degrees of severity, one third of source control procedures was
achieving source control. Whilst in patients with adequate source
technical considerations (did the surgical procedure result in control delayed for more than 24h (Coccolini et al. 2015). In another
control, antibiotics can be used as an adjunct to source control, to
of the ongoing infectious process?) (Tellor et al. 2015), whereas large-scale observational study including more than 4500 patients,
prevent dissemination of pathogenic microorganisms during source
others fail to have a clear definition of source control (Bloos et al. delay of source control beyond 24h was present in almost half
control procedures and to eradicate residual pathogens after those
2014; Coccolini et al. 2015; Martínez et al. 2017). of the survivors, and more than 80% of non-survivors (Sartelli
procedures, in patients with incomplete source control, antibiotics
Data on the extent of the problem in critically ill patients is remain as the primary modality for the treatment of the infection. et al. 2015).
unclear. In patients with complicated diverticulitis, source control In a Korean study on emergency department (ED) patients
b) Timing of source control
adequacy was reported to be as high as 91% (Coccolini et al. 2017). with septic shock, the majority of patients received source control
Bloos et al. (2014) reported 86.7% source control adequacy although Delayed source control can be caused by a delay in diagnosis or in within 12 hours after ED arrival; in this study the timing of source
no clear definition was provided (“unsuccessful procedure”). In intervention after a correct diagnosis has been made; evidently both control did not impact outcome (Shin et al. 2017). A Spanish
some studies source control adequacy is evaluated by a panel of require different interventions. An accurate and rapid diagnostic multicentre study also could not link source control timing
surgeons (Tellor et al. 2015), whereas in other studies this is not process in patients with sepsis or septic shock, which runs in parallel (interval between sepsis or septic shock diagnosis to intervention)
specified (Coccolini et al. 2015; Bloos et al. 2014). with the resuscitation and other interventions is key for the former; to worse outcome (Martínez et al. 2017). Again, the majority of
for the latter, often organisational issues such as operating room the patients’ time to source control was short: median time to
Given the importance of source control, a clear definition
or interventional radiology availability may be the primary reason. source control was 4.6 hours, with 76% of patients receiving
of source control adequacy and methodology used is essential in
order to better understand the role and develop the best approach The rationale for rapid source control is straightforward (Figure source control within 12 hours.
to patients requiring source control interventions. 2), yet few guidelines provide clear and evidence-based guidance Bloos et al. (2014) found that the median time from onset of
on the timing of source control in patients with sepsis or septic severe sepsis or septic shock to source control in a large sample of
A final comment would be related to the integration of the new
shock. The SSC guidelines recommend controlling the source of German ICU patients was 2 hours in survivors and 5.7 hours in
concepts in surgery such as damage control, as on many occasions
non-survivors. Time to source control of more than 6 hours was

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independently associated with increased mortality (as were age and with mortality, but the adjusted odds ratio for inadequate source
disease severity) in patients who required source control (Bloos control was twice as high as for inappropriate antibiotics (Tellor
et al. 2014). Time to interventional source control was twice that et al. 2015).
of surgical source control (6 hours vs. 3 hours).
Coccolini et al. found delayed source control (>24h) as
Bloos et al. (2017) found that source control was significantly the sole factor associated with worse outcome in patients with
related to 28-day mortality and reported a 1% increase in mortality complicated diverticulitis (Coccolini et al. 2017).
per hour delay of surgical source control. In patients with abdominal
Based on the available evidence it could be concluded that
©For personal and private use only. Reproduction must be permitted by the copyright holder. Email to copyright@[Link].

sepsis and associated bacteraemia, inadequate and delayed source

the biggest gain in improving outcome is in patients in whom
control was more frequent in non-survivors; inadequate source
source control is delayed beyond 12-24 hours. It would be very
control and inappropriate antibiotics were independently associated References
challenging to reduce the timing to source control further in many
Angus DC, van der Poll T (2013) Severe sepsis and septic shock. N Engl J Med, 369: 840-51.
situations, as also the delay in source control may be explained by
Becher RD, Peitzman AB, Sperry JL et al. (2016) Damage control operations in non-trauma
other patient factors rather than institutional factors alone. patients: defining criteria for the staged rapid source control laparotomy in emergency general
surgery. World J Emerg Surg, 11: 10.

Bloos F, Rüddel H, Thomas-Rüddel D et al. (2017). Effect of a multifaceted educational inter-

6. Where are we going from here? vention for anti-infectious measures on sepsis mortality: a cluster randomized trial. Intensive
© Jan J. de Waele & Ignacio Martin-Loeches

Care Med, 43(11): 1602-12.

Immediate goals
Prevent further contamination It is clear that source control is an important determinant of Bloos F, Thomas-Rüddel D, Rüddel H et al. (2014) Impact of compliance with infection manage-
Eliminate as much of the bacterial inoculum outcome, but its exact role in critically ill patients, and the relevance ment guidelines on outcome in patients with severe sepsis: a prospective observational multi-
center study. Crit Care, 18: R42.
as feasible
of aspects such as timing and methodology of source control
Restore anatomic and physiological integrity Coccolini F, Sartelli M, Catena F et al. (2015) Antibiotic resistance pattern and clinical outcomes
requires more attention. This will help us to provide evidence- in acute cholecystitis: 567 consecutive worldwide patients in a prospective cohort study. Int J
Surg, 21: 32-7.
based recommendations and may also inform targeted randomised
Coccolini F, Trevisan M, Montori G et al. (2017) Mortality rate and antibiotic resistance in compli-
studies on this topic. In the context of severely ill patients, not cated diverticulitis: report of 272 consecutive patients worldwide: a prospective cohort study.
But... only the factors related to the intervention but also the patient Surg Infect (Larchmt), Jul 21. doi: 10.1089/sur.2016.283. [Epub ahead of print]
Avoid undue compromise of the patient’s
physiological status
condition, site of infection and relevant co-morbidities may be De Waele JJ. Abdominal Sepsis. Curr Infect Dis Rep. 2016;18:23.

Diagnostic approach to confirm highly significant in determining outcomes. Elliott DC, Kufera JA, Myers RA (1996) Necrotizing soft tissue infections. Risk factors for mortality
abdominal infection source in septic and strategies for management. Ann Surg, 224: 672-83.
patients depends on the haemodynamic Based on the complexity of severe illness, the range of Leppäniemi A, Kimball EJ, De Laet I et al. (2015) Management of abdominal sepsis--a paradigm
stability of the patient infections where source control is relevant and the choice of source shift. Anaesthesiol Intensive Ther, 47: 400-8.

control interventions at our disposal, it is clear that a generalised Marshall JC, Maier RV, Jimenez M et al. (2004) Source control in the management of severe
sepsis and septic shock: an evidence-based review. Crit Care Med, 32(11 Suppl): S513-26.
Figure 2. Rationale for rapid source control approach will be inadequate and a highly personalised, carefully
For full references, please email editorial@[Link] or visit [Link]
timed approach is the best path to follow.

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Organ cross-talk in shock and critical illness

Organ cross-talk is a popular mechanism invoked to explain the progression of multi-organ dysfunction syndrome; however this term is often ill-
defined and may encompass many differing mechanisms of organ interaction. In this article the concept of cross-talk is reviewed and its real meaning
to the clinical is critically appraised.

M ulti-organ failure, better termed multi-organ

dysfunction syndrome (MODS)— reflecting
a graduation in severity of organ injuries, is
cross-talk” is becoming a widely used term, it is often
employed with little detailed understanding. It could mean
many things in differing circumstances. Clearly, ‘cross-talk’
MODS can arise or progress. MODS can arise in parallel
with a systemic insult such as septic or haemorrhagic shock
affecting many organs simultaneously. In this case such
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one of the defining features of critical illness. MODS is between organs is part of the normal physiology of a large mechanisms affect supply/demand imbalance of organ
a frequent consequence of presentation with circulatory multicellular organism, with physiological mechanisms perfusion and the inflammatory response to circulation
or septic shock, or as a serious complication of organ responsible for maintenance of whole organism homeostasis. damage or pathogen-associated molecular patterns are
hypoperfusion and systemic inflammatory responses during Examples of such mechanisms include neurological and ‘talking’ to multiple organs simultaneously (Figure 1a).
major surgery. Even when the reason for ICU admission is endocrine signalling between organs and the direct effects of Conversely in cases where organ dysfunction arises in series
only to support a single organ system there is invariably physiological parameters such as blood pressure or arterial as the effect of severe injury to one organ goes on to cause
potential for dysfunction of other organ systems, either oxygen content on the function of distant organs. It is the dysfunction in a number of other organ systems in a form of
directly, due to the primary disease, or indirectly from the breakdown of such homeostatic mechanisms that is another predominantly unidirectional cross-talk, an example is the
John R. Prowle distant effects of the primary organ failure or of organ defining feature of critical illness. Furthermore, coordinated systemic effects of cardiogenic shock (Figure 1b). However,
Adult Critical Care Unit
The Royal London Hospital
support therapies such as sedation or invasive mechanical responses to inflammation across many organ systems are irrespective of whether MODS arises in series or parallel,
Barts Health NHS Trust ventilation. Managing the conflicting demands of multi-organ part of the physiological responses to injury, but represent a bidirectional effects of organ injuries and dysfunction on
William Harvey Research Institute support is the bread and butter of modern critical care and form of communication between biological systems. While other organ systems is a key aspect of the progression of
Queen Mary University of London
Department of Renal Medicine and
intensivists are very familiar with the concept of escalating it is pathological forms of cross-talk, where responses in MODS, eventually culminating in refractory shock and
Transplantation increase in risk of death with the presence or acquisition one organ are deleterious to the function of another that death (Figure 2). In addition to acute organ dysfunction
The Royal London Hospital of additional ‘organ failures’ (Ferreira et al. 2001). There have been the focus of most interest, we should not forget chronic organ disease may play an important modifying
Barts Health NHS Trust
London, UK
has been a longstanding appreciation of the importance of that loss of normal physiological cross-talk between organs role in the development of MODS, in critical illness (Figure
providing effective early treatment of primary conditions may play an equally important role in the progression of 3), firstly by increasing risk of developing organ failure
[Link]@[Link] while avoiding secondary injury to prevent a spiral toward multiple organ dysfunction. in response to distant injury, both in decompensation of
progressive organ dysfunction and death. More recently, there the chronically diseased organ (i.e. decompensation of
@johnprowle
has been an interest in the bi-directional impact of organ chronic liver disease in sepsis) and in acquisition of acute
dysfunction and its treatment on the function of other organ “while “organ cross-talk” is becoming a injury in other organs (i.e. predisposition to acute kidney
systems, a process termed “organ cross-talk.” Behind this widely used term, it is often employed with injury in the context of chronic liver or cardiac disease).
concept lie two important observations: firstly that organ Finally, we cannot neglect the effects of treatment for organ
injuries may potentiate, resulting in a far greater burden of little detailed understanding” dysfunction on other organ systems: interventions such as
illness than if the effects of dysfunction of different organs mechanical ventilation, sedation, renal replacement therapy
were merely added, and, secondly, that there may be specific For the bedside clinician what then distinguishes
and extracorporeal membrane oxygenation may be necessary
pathophysiological pathways of organ cross-talk that could pathological organ cross-talk from MODS in general?
for the treatment of one organ system, but have unintended
be targets for specific intervention. However, while “organ Pathological organ cross-talk is one mechanism by which
deleterious effects elsewhere, while the presence of other

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COVER STORY: SHOCK

vicious cycle of organ injury (Figure 2). In addition to the lung

and the kidney the gastrointestinal tract may play a key role in
the development of MODS, primary or secondary gastrointestinal
injury from ischaemia, venous congestion or inflammation, as
well as chronic effects of portal hypertension or uraemia, and may
predispose to bacterial translocation and the systemic release of
potent pathogen associated molecular patterns (Ko et al. 2009).
In contrast, more physiological mechanisms of pathological
organ cross-talk have been best described in the various forms
of cardio-renal syndromes (Ronco et al. 2008), which reflect the
©For personal and private use only. Reproduction must be permitted by the copyright holder. Email to copyright@[Link].

effects of acute or chronic effects of cardiac dysfunction on the

kidney and vice versa. These embrace forward and backward effects
of cardiac dysfunction on the renal circulation, neuroendocrine
abnormalities in acute and chronic cardiac and renal failure
and, in particular, the deleterious effects of fluid overload on
both organ systems. Inflammatory mechanisms also play a role
in renal-cardiac interactions, for instance the pro-inflammatory
milieu of chronic kidney disease. More recently, the cardio-renal
Figure 1. Examples of models of multi-organ dysfunction syndrome (MODS) in shock Figure 2. Organ cross-talk potentiates the severity of organ dysfunction after
systemic multi-organ insult model has been extended to reflect the interdependence of the
MODS may arise primarily in parallel from a major systemic insult (1a) or in series from the effects of a
major primary organ dysfunction (1b) and be mediated primarily by circulating mediators (1a) or by distant
heart, lungs and kidneys in cardio-renal-pulmonary syndromes
Both circulating mediators (damage and pathogen associated molecular patterns, cytokines
physiological effects of organ injury (1b). and other mediators) and physiological effects as well as effects of organ support may mediate (Husain-Syed et al. 2015). However, while these syndromes are
DAMPs damage pathogen associated molecular patterns PAMPs pathogen associated molecular patterns this process
very useful constructs for classifying mechanisms of illness, it
remains questionable if forcing individual patients with complex
organ dysfunctions can complicate the application and use of such or indirectly, via pathophysiological neuro/endocrine effects. and evolving illness into complex categorisations of acute and
methods of organ support, a process of so-called artificial organ Concepts of cross-talk in MODS first gained a high level of interest chronic multi-organ syndromes is useful to the treatment of the
cross-talk (Husain-Syed et al. 2018). Of course, in most cases of in the setting of lung injury, where the generation of circulating individual at the bedside.
critical illness many or all of the above mechanisms co-exist, so inflammatory mediators from the large surface area of injured
An alternative to the development of complex classification
that MODS typically arises in part in series and in part in parallel pulmonary epithelium was described as causing multi-organ
of constellations of organ dysfunctions has been a focus on the
on a background of some chronic co-morbid disease, potentiated dysfunction in distant organs, such as the kidney, cardiovascular
role of individual organs as orchestrators of cross-talk. In the
by bidirectional effects of organ injuries and modified by the system and gastrointestinal tract mediating the high mortality
literature the kidney has been best described in this role due to its
positive and negative effects of organ support therapies. associated with adult respiratory distress syndromes (Imai et al.
function in regulating fluid status, electrolytes and acid base and
2003). Importantly, in this context mediators might arise both as a
Given the diversity of pathological organ cross-talk it’s as a clearing house for many circulating low molecular weight
consequence of the primary lung injury or secondary to effects of
not surprising that multiple mechanisms have been invoked to inflammatory mediators, or conversely as a rich source of such
mechanical ventilation necessary to treat the primary respiratory
explain it. Broadly these could be considered as the distant effects mediators in injury (Doi and Rabb 2016; Grams and Rabb 2012).
failure (Husain-Syed et al. 2016). Similarly, isolated acute kidney
of inflammatory mediators released into the circulation and the Furthermore the distant organ effects of chronic kidney disease
injury caused by ischaemia reperfusion has been shown to mediate
distant effects of the disordered physiology of one organ on others, are well recognised as leading to multi-system chronic disease.
an inflammatory response that can result in secondary lung injury
mediated either directly (i.e. hypoperfusion in cardiac failure) However, in the right context almost any organ system plays a
(Klein et al. 2008; Rabb et al. 2009), potentially setting up a
central role in the development of MODS and, to some extent,

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intervention directed at any organ to adversely affect others. Early Conflict of interest
recognition of the deteriorating patient, particularly in the context
John R. Prowle has consultancy agreements with Medibeacon Inc,
of established chronic organ disease is essential to preventing
Quark Pharmaceuticals Inc, GE Healthcare and Nikkiso Europe
secondary organ injury and progressive organ dysfunction. Secondly,
GmbH. Dr. Prowle has received speakers’ fees and/or hospitality
while multiple interdependent mechanisms of organ cross-talk
from Baxter Inc, Nikksio Europe GmbH and Fresenius Medical
are difficult to dissect there may be some key mediators of organ
Care AG.
interaction that could be amenable to intervention or prevention,
such as the systemic effects of fluid overload. Rather than trying to
classify primary and secondary organ dysfunctions it may be better
to identify the presence of unifying mechanisms of cross-talk that
©For personal and private use only. Reproduction must be permitted by the copyright holder. Email to copyright@[Link].

could be targeted for intervention. Finally we must not neglect

the adverse effects of our therapies. If any lessons can be drawn
from the last 30 years of critical care research, it is that targeting a References
specific physiological parameter in a single organ system is rarely
Doi K, Rabb H, (2016) Impact of acute kidney injury on distant organ function: recent findings and
beneficial, and more often harmful, and that in the treatment of potential therapeutic targets. Kidney Int, 89: 555-64.
the critically ill most often “less is more.” As mechanisms of organ Ferreira FL, Bota DP, Bross A et al. (2001) Serial evaluation of the SOFA score to predict outcome in
critically ill patients. JAMA, 286: 1754-8.
Figure 3. Example of the modifying effect of chronic organ dysfunction on increas-
dysfunction in critical illness are complex and we are unlikely to
Grams ME, Rabb H, (2012) The distant organ effects of acute kidney injury. Kidney Int, 81: 942-8.
ing severity of primary and secondary organ injury fully understand any patient’s illness at a given moment in time,
we should resist the temptation to invoke rigid classifications of Husain-Syed F, McCullough PA, Birk HW et al. (2015) Cardio-pulmonary-renal interactions: a
In this case of chronic liver disease multiple mechanisms will be involved including portal hypertension, multidisciplinary approach. J Am Coll Cardiol, 65: 2433-48.
gut translocation, circulating inflammatory mediators and pathophysiological activation of neuroendocrine
responses. illness, but instead serially evaluate the clinical condition and
Husain-Syed F, Slutsky AS, Ronco C (2016) Lung-kidney cross-talk in the critically ill patient. Am J
response to treatment, seeking opportunities to assess the effects Respir Crit Care Med. 194: 402-14.

of interventions that may break cycles of organ dysfunction. The Husain-Syed F, Ricci Z, Brodie D et al. (2018) Extracorporeal organ support (ECOS) in critical illness
the emphasis on a single organ is against the concept of organ and acute kidney injury: from native to artificial organ crosstalk. Intensive Care Med, 44: 1447-59.
nature of such interventions will be crucially dependent on the
cross-talk as a term encompassing the inter-dependent effects of clinical context. For instance, at one stage of illness appropriate Imai Y, Parodo J, Kajikawa O et al. (2003) Injurious mechanical ventilation and end-organ epithelial cell
apoptosis and organ dysfunction in an experimental model of acute respiratory distress syndrome.
many organs injuries. fluid management could constitute resuscitation and, at another, JAMA, 289: 2104-12.

How then does the clinician get through the diverse and fluid removal. Similar considerations of timing and context are Klein CL, Hoke TS, Fang WF et al. (2008) Interleukin-6 mediates lung injury following ischemic acute
kidney injury or bilateral nephrectomy. Kidney Int, 74: 901-9.
complex process that comes under the umbrella of organ cross-talk likely to apply to anti- and pro-inflammatory interventions targeting
Ko GJ, Rabb H, Hassoun HT, (2009) Kidney-lung crosstalk in the critically ill patient. Blood Purif, 28: 75-83.
to develop insights that are useful at the bedside? Firstly, active humoral mechanisms of cross-talk. While targeted intervention
Rabb H, Wang Z, Nemoto T, Hotchkiss J, Yokota N, Soleimani M, (2003) Acute renal failure leads to
intervention to alter the course of established MODS with multiple to lessen pathological organ cross-talk holds great promise, in dysregulation of lung salt and water channels. Kidney Int, 63: 600-6.

mechanisms of cross-talk is likely to be very difficult due to the practice it is likely to be very challenging and will require careful Ronco C, Haapio M, House AA et al. (2008) Cardiorenal syndrome. J Am Coll Cardiol, 52: 1527-39.

diversity of pathways driving this process and the potential for patient characterisation. For full references, please email editorial@[Link] or visit https://
[Link]/o21

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POCUS and SHOCK

Point-of-care ultrasound (POCUS) is an invaluable tool to differentiate the various types of shock which may co-exist in the critically unwell patient. It
is beyond the remit of this article to teach the skill of POCUS. Rather, it provides an overview of how the various POCUS modules could be integrated
and utilised in the shocked patient.
"A fool with a tool is still a fool"
Grady Brooch
©For personal and private use only. Reproduction must be permitted by the copyright holder. Email to copyright@[Link].

What is point-of-care ultrasound? POCUS in shock - an integrated approach • Is the left ventricle (LV) dilated or impaired?
Adrian Wong
Consultant Intensive Care Point-of-care ultrasound (POCUS) describes the use of ultrasound Encountering the shocked patient is a common occurrence in • Is the right ventricle (RV) dilated or impaired?
Medicine and Anaesthesia
to extend the physical examination of patients at the bedside, the ED and the intensive care unit (ICU). Other articles in this
Kings College Hospital • Is the inferior vena cava (IVC) collapsing?
London, UK guiding diagnosis and management. POCUS covers an array issue have already covered the definition and types of shock. It
of ultrasound modules, including echocardiography, lung must be emphasised that different types of shock may co-exist • Is there a pericardial effusion?
avkwong@[Link]
ultrasound, abdominal ultrasound etc. in the same patient e.g. the septic patient may be shocked due to
@avkwong
• Is/are there pleural effusion(s)?
distributive/vasodilatatory shock or cardiogenic shock. POCUS
The use of ultrasound has undeniably extended far beyond
allows the clinician to more accurately identify the type and/ The complexity of the examination and the techniques
the walls of the radiology department, being utilised in more
or coexistence of the different types of shock and hence target used are obviously operator-dependent. However, there is broad
acute medical specialties such as emergency medicine and
management strategies accordingly. consensus that basic transthoracic echocardiography should be
critical care. POCUS scans are different from those performed
a core competency for every critical care clinician.
by radiologists or sonographers. These scans tend to be take
place at the bedside in non-acute situations and are requested “enhances the clinician’s ability to Despite being a relatively new module, lung ultrasound
has expanded exponentially since the work of Lichtenstein and
to answer very specific, detailed questions. POCUS scans are
performed in order to answer questions, usually in a binary way diagnose and manage critically ill patients” colleagues (Lichtenstein and Mezière 2008). Once used only
i.e. yes or no. For an overview of POCUS and critical care, there to assess for pleural effusions, superior to chest radiographs,
has been a recent review in a previous edition of this journal A perceived weakness of comprehensive radiology or our understanding and hence utilisation of this module has
(Zaidi and Koenig 2018). echocardiography scans is that they are often performed in expanded to include a much broader range of diagnoses. A
isolation. As mentioned above, POCUS is performed by the bed recent systematic review and meta-analysis concluded that
There are numerous training resources available to clinicians,
space and the key to making these diagnoses is the ability to lung ultrasound was superior to chest radiographs in terms
Jonathan Wilkinson but crucially, the number of nationally-recognised accreditation
examine clinically, followed closely by ultrasound. of sensitivity, with similar specificity, hence challenging it as a
Consultant Intensive Care programmes remains small. It is important to emphasise that
Medicine and Anaesthesia first-line diagnostic tool (Winkler et al. 2018).
Northampton General Hospital
clinicians must operate within their own competencies. The The key modules in the diagnosis and management of
Northampton, UK use of POCUS does not replace the need for thorough history shock are the examination of the cardiovascular and respiratory The Rapid Ultrasound for Shock and Hypotension (RUSH)
taking, clinical examination and acumen. Instead, it enhances the system i.e. heart and lungs. protocol (Perera 2010) was designed so that emergency
wilkinsonjonny@[Link]
clinician’s ability to diagnose and manage critically ill patients. physicians could carry out a structured, easy-to-perform
Focused echocardiography is probably the most established
@wilkinsonjonny There is ongoing debate on whether POCUS will replace the ultrasound examination (under two minutes). It requires an
POCUS module. The key questions to be answered are:
stethoscope (Wittenberg 2014). examination of the heart, intravascular filling status and large
[Link]
arteries/veins or simply Pump, Tank and Pipes respectively.

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Table 1. Summary of findings of RUSH examination in types of shock Table 1 summarises the ultrasonographic findings for the various types unit (HDU) beds, workload and ready access to a suitable ultrasound
of shock using RUSH. As mentioned, it must be remembered that the machine. There is unlikely to be a single best method and the most
Obstructive
Hypovolaemic shock Cardiogenic shock Distributive shock various types can co-exist in the same patient. practical and realistic way of incorporating POCUS into the working
shock
Hyperdynamic heart Pericardial culture, training and patient care on the ICU is probably a combination
(early sepsis) tamponade The RUSH protocol is by no means the only integrated POCUS-
Pump Hyperdynamic heart Poor contractility
Poor contractility (late RV strain of all three.
sepsis) Poor contractility based protocol; others include the SESAME (abbreviated from
Large, non-collapsing IVC Large, non-
collapsing IVC
SESAMOOSIC Sequential Echographic Scanning Assessing Mechanism
Tank
Small, collapsing IVC
B-line profile in lungs
Normal/small IVC
Absent lung or Origin of Shock of Indistinct Cause) (Figure 1, Lichtenstein and What the future may hold
Peritoneal or pleural fluid Pleural or peritoneal fluid
sliding
Pleural effusion Malbrain 2015) and the Abdominal and Cardiothoracic Evaluation with There is broad consensus that basic POCUS should be part of core
Pipes
Ruptured Abdominal
Normal Normal DVT Sonography in Shock (ACES) protocols. Such integrated approaches competencies for intensivists. Consensus and expert statements published
Aneurysm or Dissection
form a significant part of most POCUS curricula and courses in in 2011 (Expert Round Table on Ultrasound in ICU 2011) have led
©For personal and private use only. Reproduction must be permitted by the copyright holder. Email to copyright@[Link].

Daniel Lichtenstein, Manu L.N.G. Malbrain, SESAME-protocol in cardiac arrest

emergency medicine and critical care. to the development of national accreditation programmes to support
In addition to its diagnostic prowess, POCUS can also be used colleagues in developing and maintaining this skillset. Comparisons
to assess response to therapy such as fluid administration in the of these programmes highlight a degree of variability between them
context of the shocked patient. Dynamic measures such as the and consensus is needed to better define these competencies to ensure
velocity-time integral measured in the aortic outflow tract have high-quality training and ultimately improve patient care.
been shown to be a useful measure of fluid responsiveness (Miller Supporting improved access to training, technology continues to
and Mandeville 2016). advance in order to make POCUS machines more accessible and portable.
Earlier ultrasound machines were often bulky, not very portable and
Integrating POCUS into daily practice were considered cumbersome to use. The newer machines of several
manufacturers can now fit into the palm of your hand e.g. Philips
POCUS, like any other monitoring device, has not been shown to
LumifyTM and Sonosite IVIZTM. Some of these probes are plugged into
improve patient outcomes without being coupled with an appropriate
the clinician’s smartphone and utilise the screen of the device. Early
management strategy. The recently published SHoC-ED trial (Atkinson
versions of such portable ultrasound machines had variable image
et al. 2018) failed to show any mortality benefit when shocked patients
quality and functionality as a trade-off to size but again, more modern
were managed using a POCUS-centric approach compared to standard
devices have closed this gap.
care. The reasons are probably multifactorial, but this should act as a
word of caution to the enthusiastic practitioner. Image acquisition is only one part of the ability to make the
diagnosis and formulate a management plan. Image interpretation is
The best time to perform a POCUS examination is when the
an integral part of the training process and competency assessment.
patient requires it. The convenience does come at the cost of taking
Artificial intelligence (AI), as seen in other industries has also started
up clinician time and interrupting the workflow of the day and ward
to ‘invade’ healthcare. Several manuscripts on the use of AI to interpret
round; this interruption is particularly relevant since not all clinicians
scans for signs of malignancies have been published. Extrapolating from
are currently competent in POCUS. With clinicians’ time increasingly
this example, machines such as the GE VenueTM have built-in software
being stretched, a way of balancing the inherent benefits of POCUS
in order to facilitate measurements of cardiac output and interpret lung
Figure 1. SESAME protocol and drawbacks is crucial. Ultimately, different ICUs adopt different
Figure 1. The SESAME-protocol ultrasound findings (Figure 2 and 3). These AI systems are meant to
This apparently complex figure just shows, from left to right, simple features. On the far left, the five areas of investigation are shown. Next the type
Reprinted with permission from Lichtenstein D, Malbrain ML (2015) Critical care ultrasound techniques based on staffing, working shift patterns, experience and
of probe used is listed, i.e., only one probe. Then the depth used, i.e., a standard distance (85 mm) in most steps. Then the timing for ruling out,
in cardiac arrest. Technological requirements forfluids
performing the SESAME-protocol--a
fluid), followed by pericardialholistic
aid and not replace the human clinician.
sequentially,
approach.
the
tension
heart comes under
pneumothorax,
Anaesthesiol
lower femoral
analysis, mostIntensive
DVT, free abdominal
Ther,
reversible cases have 47(5): 471-81.
already been
(or massive GI tract
[Link]
assessed. Adapted with permission from Lichtenstein [15]
tamponade. When availability of POCUS practitioners, number of ICU/ high dependency
ogy_intensivetherapy/article/view/43559
ARDS — acute respiratory distress syndrome; DVT — deep venous thrombosis

and thus not indicated in a cardiac arrest situation). Each into the ICU, machines were lacking mainly because of
ICU Management & Practice 3 - 2018
additional button increases the risk for confusion. cost-related issues. However, if doctors had used holistic
A cost-effective machine has one major advantage, ultrasound as soon as it was technically accessible, i.e.
namely its availability. Nowadays, although it is common 1982, they would have found cost-effective machines at
practice to see many ultrasound machines in the hospi- a time where cardiac machines were really expensive and,
 180
COVER STORY: SHOCK
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References
Atkinson PR, Milne J, Diegelmann L et al. (2018) Does point-of-care ultrasonography improve
Figure 2. clinical outcomes in emergency department patients with undifferentiated hypotension? An
international randomized controlled trial from the SHoC-ED investigators. Ann Emerg Med, 2
Jun. pii: S0196-0644(18)30325-1. doi: 10.1016/[Link].2018.04.002.
Figure 3.
Expert Round Table on Ultrasound in ICU (2011) International expert statement on training
Conclusion standards for critical care ultrasonography. Intensive Care Med, 37(7): 1077–83.

Lichtenstein D, Malbrain ML (2015) Critical care ultrasound in cardiac arrest. Technological

Shock is a common, complex clinical condition with several classical requirements for performing the SESAME-protocol--a holistic approach. Anaesthesiol Intensive
types that may co-exist. POCUS techniques offer a powerful diagnostic a portable ultrasound device for his own personal use in his clinical Ther, 47(5): 471-81.

and management tool which is within the skillset of intensivists after work. AW and JW declare that they have no financial conflict of interest. Lichtenstein D, Meziere G (2008) Relevance of lung ultrasound in the diagnosis of acute respira-
tory failure – the BLUE protocol. Chest, 134: 117-25.
appropriate training. Liechtenstein DA. (2014) How can the use of lung ultrasound in cardiac arrest make ultrasound
a holistic discipline. The example of the SESAME-protocol. Med Ultrason 2014; 16(3): 252-255.
Abbreviations Miller A, Mandeville J. (2016) Predicting and measuring fluid responsiveness with echocar-
Conflict of interest diography. Echo Res Pract, 3(2): G1–G12.
ICU intensive care unit
Adrian Wong and Jonathan Wilkinson have both trialled various POCUS point-of-care ultrasound
Perera P, Mailhot T, Riley D et al. (2010) The RUSH Exam: Rapid Ultrasound in SHock in the
evaluation of the critically ill. Emerg Med Clin N Am, 28: 29–56.
ultrasound devices from different manufacturers. JW has self-funded
For full references, please email editorial@[Link] or visit https://
[Link]/o22

ICU Management & Practice 3 - 2018

 How design and usability can reduce use
errors and improve patient transport?
Prof. Erwan L’HER (Brest, France)
Big data and Analytics as support tools to
capitalize on practice?
Dr. Erik KOOMEN (Utrecht, Netherlands)
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Speed-up clinical decisions using

Ultrasound and Artificial Intelligence.
Prof. Heinrich GROESDONK (Homburg,
Germany)

Chairman:
Prof. Erwan L’HER

Co-chairman:
Dr. Marius TERBLANCHE

MONDAY
OCTOBER 22
LUNCH SYMPOSIUM
12:30 - 14:00 Optimizing ICU workflows and
ROOM ROME outcomes through innovative
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LEVEL 2

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Key decisions in a goal-directed coagulation

management approach
An individualised goal-directed approach to managing coagulopathy is recommended to treat bleeding trauma patients.

S evere trauma is a great burden to society, with millions

of victims worldwide.
Fibrinogen replacement
Fresh frozen plasma
Pathogen inactivation reduces fibrinogen concentration
further and consistently to a concentration below 2g/L. If
©For personal and private use only. Reproduction must be permitted by the copyright holder. Email to copyright@[Link].

several units of FFP are transfused at a time a vicious cycle

If trauma patients are hazardly bleeding, surgical
A systematic review of randomised controlled trials using fresh starts (Table 1).
bleeding requires the surgeon to fix the problem, while
coagulopathy requires management with an algorithm that frozen plasma (FFP) concluded that for most clinical situations
includes monitoring and specific treatment. About 30% of the evidence for clinical efficacy is limited (Stanworth et al. Fbrinogen replacement therapy
all major trauma patients have a significant coagulopathy at 2004). FFP is an important source of factor V in demonstrable
multi-factor deficiency with severe bleeding (Stanworth et There is guidance on how to use fibrinogen replacement
hospital admission (Maegele 2010).
al. 2004), but there is limited data on use in liver bleeding. therapy in acquired bleeding (Levy and Goodnough 2015;
In most trauma patients low fibrinogen concentration is Guidelines state that whether and how much FFP to use to Theusinger et al. 2017; Garrigue et al. 2018).
a key element of their coagulopathy. Fibrinogen is central to treat a patient with massive blood loss should be guided Fibrinogen concentration measurement
Donat R. Spahn the coagulation system as it is vital for platelet aggregation by timely tests of coagulation, including near-patient tests.
Professor and a key substrate of plasmatic coagulation (Spahn et al. Formulae to guide replacement strategies should not be used In a goal-directed approach to coagulation management, it is
Institute of Anaesthesiology
University and University Hospital 2013). Fibrinogen is the coagulation ‘element’ that becomes (Stanworth et al. 2004). essential to measure and monitor fibrinogen concentration.
Zurich critically reduced first in many clinical situations, including However, laboratory measurement of fibrinogen concentration
Zurich, Switzerland
trauma. The critical level of fibrinogen may be < 1.5-2.0g/L FFP transfusions are associated with major adverse is difficult. Solomon et al. (2014) showed that six laboratories
[Link]@[Link] or a maximum clot firmness (MCF) in FIBTEM of < 7mm, outcomes, including increased mortality (Welsby et al. 2010), had differences of fibrinogen concentration measurements
or even < 10mm, as measured by a point-of-care rotational increased multi-organ failure (Watson et al. 2009), increased of 80% between them for 30 patient samples, before, during
thromboelastometry (ROTEM) device. infection (Sarani et al. 2008), increased transfusion-associated and after cardiopulmonary bypass. The first international
lung injury (TRALI) (Silliman et al. 2005; Rana et al. 2006;
Unlike red blood cells (RBCs) and platelets there are Eder et al. 2007; Chaiwat et al. 2009), transfusion-associated
no fibrinogen stores in the body that might be mobilised. circulatory overload (TACO) (Rana et al. 2006) and, most Table 1. Clinical consequences of fresh frozen plasma
When bleeding lasts a long time and lost volume is replaced importantly, inefficacy in treating coagulopathy (Weber et al. administration
with crystalloids and/or colloids, haemoglobin goes down 2012; Innerhofer et al. 2017; Stein et al. 2017a).
exponentially. At a certain stage it does not go down anymore Fibrinogen concentration or
despite ongoing blood loss, because RBCs are mobilised. The more bleeding there is, the more likely the need to
Haemoglobin concentration and platelet count
Platelets can also go down, but they can be stabilised or replace fibrinogen from other sources to achieve a minimum
coagulopathy
increased at a later stage since also platelets can be mobilised. fibrinogen concentration of 1.5 to 2 g/L. Sources of fibrinogen RBC transfusion
This is not the case for fibrinogen. The more bleeding is are FFP, fibrinogen concentrate and cryoprecipitate. The range Coagulation potential
ongoing the more likely the need to replace fibrinogen with of fibrinogen concentration in FFP is 1 to 3 g/L, and is highly Further FFP administration - triggers a vicious cycle
exogenous fibrinogen. variable between units (Levy and Goodnough 2015).

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SUPPLEMENT

Tranexamic acid
The European guideline recommends that tranexamic acid be
administered as early as possible to the trauma patient who is
bleeding or at risk of significant haemorrhage at a loading dose of
1g infused over 10 minutes, followed by an IV infusion of 1g over
7 hours (Rossaint et al. 2016).
In a prospective, multicentre observational study (TXA in the
EMS on the Helicopter and the Ambulance, NCT 02354885), our
group gave 1g of tranexamic acid intravenously early on scene to
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70 trauma patients (Stein et al. 2018). The control group (n=38)

Figure 2. Mortality of patient cohorts managed traditionally (2005-2007) and with did not receive tranexamic acid. The coagulation of these control
Figure 1. Outcome of patient cohorts managed traditionally (2005-2007) and with coagulation
algorithm (2012-2014) (Stein et al. 2017a) coagulation algorithm (2012-2014) (Stein et al. 2017a) patients deteriorated until hospital admission. In contrast, patients
who received tranexamic acid on scene had clot stabilisation on
arrival at the emergency department(ED). There were four cases
standard established by the World Health Organization for fibrinogen platelets were about the same, fibrinogen usage was the same, there with documented hyperfibrinolysis on-scene in the tranexamic
concentrate is 10.4 g/L (National Institute for Biological Standards was no rFVIIa anymore and the cost of haemotherapy (including acid group; in all these cases there was no sign of hyperfibrinolysis
and Control 2008); the results in this study varied from 2-12 g/L. cost of monitoring, blood products and factor concentrate) was detectable at hospital admission.
In addition, the laboratory value takes at least 30 to 60 minutes to about half. The patients in the ROTEM group had better survival at
Therefore, 90 minutes after the initial dose of 1g tranexamic
reach the doctor ordering the test. 6-months (Weber et al. 2012).
acid re-dosing is required with an individualised goal-directed
Therefore, it is best to base the coagulation algorithm on Some have suggested that practice in trauma patients should strategy to keep the fibrinogen level to a minimum of 1.5 to 2.0 g/L.
a ROTEM or thrombelastography (TEG) monitoring device. In be based on the Pragmatic, Randomized Optimal Platelet and
In a recent prospective multicentre observational study in
10 minutes there is a clear answer if there is something wrong Plasma Ratios (PROPPR) study, believing that it proved that 1:1:1
major trauma patients receiving tranexamic acid on scene, plasma
with the coagulation and what is wrong. There are concerns that (platelets:FFP:RBC) is better than 1:1:2 (Holcomb et al. 2015).
concentration was measured at hospital admission (Grassin-Delyle
this technology is expensive. However, the UK National Health However, the primary outcome, 24h-30 day mortality, was similar
et al. 2018). The study authors propose a dosing scheme to maintain
Service found consistent cost savings in viscoelastic point-of-care between the two formulae. Nascimento et al. (2013) showed
a specific target blood concentration.
testing compared with standard lab tests to assist with diagnosis, that a 1:1:1 ratio is inferior to a control group treated based on a
management and monitoring of haemostasis in cardiac surgery and laboratory-based algorithm. The European guidelines recommend treatment with fibrinogen
particularly trauma (Whiting et al. 2015). Their systematic review and cryoprecipitate if significant bleeding is accompanied by viscoelastic
The European guideline on management of major bleeding and
of 31 trials (11 in cardiac surgery with 1089 patients) showed signs of a functional fibrinogen deficit or a plasma fibrinogen level
coagulopathy following trauma recommends that routine practice
reduction in blood product use [RBC RR 0.88 (0.80-0.96); FFP of less than 1.5-2.0 g/L (Rossaint et al. 2016).
includes early and repeated monitoring of coagulation, using either
RR 0.47 (0.35-0.65)] and platelets RR 0.72 (0.58-0.89). And it
a traditional laboratory determination of fibrinogen concentration Some express caution over giving fibrinogen to patients as
is efficacious. A prospective study that randomised patients after
[prothrombin time (PT), activated partial thromboplastin time it may induce higher than normal plasma fibrinogen levels after
heparin reversal following cardiopulmonary bypass compared
(APTT) platelet counts and fibrinogen] and/or a viscoelastic method major trauma. However, in their study of the time course of plasma
coagulation management based on conventional laboratory analyses
(ROTEM or TEG) (Rossaint et al. 2016). Measurement is required fibrinogen, Schlimp and colleagues (2016) showed that fibrinogen
with two algorithms, intra- and postoperative, based on ROTEM.
after each treatment to ensure that fibrinogen remains. concentrate treatment at admission does not lead to higher fibrinogen,
The ROTEM group received fewer RBCs and did not receive FFP;

ICU Management & Practice 3 - 2018

 III
SUPPLEMENT

Table 2. Coagulation algorithm concentration levels post-trauma beyond that occurring naturally due
to the acute phase response. Abbreviations
FFP fresh frozen plasma RBC red blood cells
Detect low fibrinogen MCF maximum clot firmness ROTEM rotational thromboelastometry
MCF in FIBTEM ≤ 7mm Fibrinogen 2-4 g IV (after 6 g of fibrinogen,
Prothrombin complex concentrate
PCC prothrombin complex concentrate TEG thromboelastography
administer Factor XIII 15 U/kg IV)
The European guidelines recommend early use of prothrombin
complex concentrate (PCC) for the emergency reversal of vitamin
Detect fibrinolysis K-dependent oral anticoagulants (Rossaint et al. 2016).
EXTEM/INTEM: Clot lysis after Tranexamic acid Key Points
MCF and APTEM: normal = • Bolus: 15 mg/kg IV (consider empiric One study showed that using four-factor PCC compared to
hyperfibrinolysis use) plasma had much faster vitamin K antagonist reversal in patients • Fibrinogen is the coagulation element that becomes critically reduced
©For personal and private use only. Reproduction must be permitted by the copyright holder. Email to copyright@[Link].

• Consider continuous infusion 1-2 mg/ first in many instances

kg/h
needing urgent surgical or invasive interventions (Goldstein et al.
2015), which is key in traumatised patients. PCCs are also indicated • In trauma and cardiac surgery patients, the critical level is 1.5 to 2.0
Ongoing bleeding g/L
according to the European guidelines, if there is evidence of delayed
Factor XIII < 60% Factor XIII 15 U/kg IV • Immediate viscoelastic coagulation monitoring is key for individualised
initiation of coagulation using viscoelastic monitoring (CT in EXTEM),
goal-directed coagulation algorithms
Platelet count/function Platelet concentrate but the condition is that fibrinogen has been normalised. Therefore,
• EXTEM/INTEM MCF < we normalise fibrinogen first and give PCCs only if the CT remains • Coagulation algorithms should be available in every hospital
40mm • Compliance with the European trauma treatment guidelines improves
elevated after fibrinogen administration.
• Platelet count ≤ 50,000/µl survival
(≤ 100,000/ µl in cardiac Consider desmopressin 0.3 µg/kg (max 16 µg)
surgery or traumatic in case of aspirin (like) platelet dysfunction
brain injury) Four-factor prothrombin complex concentrate
Coagulation algorithm
• Platelet function (imped- (slow continuous infusion of small repeated References
ance aggregometry) doses - e.g. 500 IU)
Traditional management of coagulopathy was compared with an
Chaiwat O, Lang JD, Vavilala MS et al. (2009) Early packed red blood cell transfusion and acute
individualised goal-directed coagulation and transfusion protocol respiratory distress syndrome after trauma. Anesthesiology, 110(2): 351-60.
• INR > 2.3 (Quick’s value FFP (2-4 units) during two time periods (Stein et al. 2017a). During the first period Eder AF, Herron R, Strupp A et al. (2007) Transfusion-related acute lung injury surveillance (2003-
< 30%) 2005) and the potential impact of the selective use of plasma from male donors in the American Red
(2005-2007) we used traditional management and in the second Cross. Transfusion, 47(4): 599-607.
period (2012-2014) a protocol that included primary whole-body Garrigue D, Godier A, Glacet A et al. (2018) French lyophilized plasma versus fresh frozen plasma for
CT, tranexamic acid, restrictive fluid therapy (preferably crystalloids), the initial management of trauma-induced coagulopathy: a randomized open-label trial. J Thromb
• Factor V < 20%) Haemost, 16(3): 481-9.
permissive hypovolaemia/hypotension and damage control surgery,
Goldstein JN, Refaai MA, Milling TJ Jr et al. (2015) Four-factor prothrombin complex concentrate
according to the European guidelines. The outcome was the comparison versus plasma for rapid vitamin K antagonist reversal in patients needing urgent surgical or invasive
between the observed and the Trauma Associated Severe Haemorrhage interventions: a phase 3b, open-label, non-inferiority, randomised trial. Lancet, 385(9982): 2077-87.

(TASH)-predicted massive transfusion rate to ICU admission. The Grassin-Delyle S, Theusinger OM, Albrecht R et al. (2018) Optimisation of the dosage of tranexamic
Detect heparin acid in trauma patients with population pharmacokinetic analysis. Anaesthesia, 73(6): 719-29.
simple coagulation algorithm is shown in Table 2 (Stein et al. 2017b).
INTEM (CT/CFT) or ACT Protamine (1:1) to antagonise heparin Holcomb JB, Tilley BC, Baraniuk S et al.; PROPPR Study Group (2015) Transfusion of plasma, platelets,
and red blood cells in a 1:1:1 vs a 1:1:2 ratio and mortality in patients with severe trauma: the PROPPR
prolonged and HEPTEM or In the second period the goal-directed protocol resulted in half randomized clinical trial. JAMA, 313(5): 471-82.
heparinase-ACT normal
the expected massive transfusion rate predicted, the same platelet Innerhofer P, Fries D, Mittermayr M et al. (2017) Reversal of trauma-induced coagulopathy using first-
Source: Stein et al. 2017b count and fibrinogen, more tranexamic acid and no rFVIIa (Stein et al. line coagulation factor concentrates or fresh frozen plasma (RETIC): a single-centre, parallel-group,
open-label, randomised trial. Lancet Haematol, 4(6): e258-e271.
2017a). ICU length of stay (LOS) was reduced by 3 days, ventilatory
Levy JH, Goodnough LT (2015) How I use fibrinogen replacement therapy in acquired bleeding. Blood,
support reduced by 4 days (Figure 1). Also mortality was reduced 125(9): 1387-93.
(Figure 2). For full references, please email editorial@[Link] or visit https://
[Link]/o23

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 IV
SUPPLEMENT

Evidence for using first-line coagulation factor

concentrates for trauma - induced coagulopathy
Fibrinogen limits coagulopathy and massive bleeding, has less transfusion requirements and thereby decreases the risk of multi-organ failure in trauma patients.
What stops the bleeding? Coagulation factor substitutes Fibrinogen concentrate
Haemostatic therapy aims to stop the bleeding, but is it a Plasma There are several concentrates on the market:
concentration of coagulation factors, mainly assessed by
Plasma refers to 6-8% protein solution and 92-94% water. 1. Fibrinogen concentrate
international normalised ratio (INR) readings that works,
©For personal and private use only. Reproduction must be permitted by the copyright holder. Email to copyright@[Link].

It was introduced in clinical practice mainly for volume

or is it fibrinogen/fibrin, which are the precondition for 2. FXIII concentrate
substitution but later to treat coagulation disorders. It
stable clot formation? We conducted a study in patients with
contains all procoagulants and also anticoagulants. It’s easy to 3. PCC (FII, VII, IX, X)
polytrauma and those with isolated brain injury (Tauber et al.
use, is considered safe regarding thrombosis, and relatively
2011) to find out what the most predominant pathology was 4. vWF concentrate
low-cost. However, plasma transfusion is time-consuming
(Figure 1). The red bars refer to polytrauma patients. There is
and requires planning. 5. rVIIa, PCCa
significant increase in the frequency of low fibrinogen, low
Petra Innerhofer fibrinpolymerization and consequently low clot firmness, The concentration of coagulation factors and especially 6. FVIII, IX, X, XI concentrate
Professor in 20-30%, while a significant and prolonged INR of about fibrinogen are rather low in plasma and vary depending on the
Department of Anaesthesia and No factor V concentrate is available.
1.5 was found in only about 14%. Clot firmness and fibrin individual donor and the type of processing. Plasma efficacy
Intensive Medicine
Medical University Innsbruck polymerization were independently associated with mortality can be questioned and partial requirements correction is not Concentrates are immediately ready to use, contain defined
Innsbruck, Austria and also with blood loss as measured by early transfusion possible. It may also induce transfusion-associated circulatory and high concentration of the factor, no volume expansion
[Link]@[Link] requirements. In addition patients had tremendously increased overload (TACO), transfusion-associated lung injury (TRALI), is needed, so there will be an effective rise in concentration,
molecular markers of thrombin generation, regardless of the transfusion-associated immunomodulation (TRIM), multi- making targeted therapy possible. There will be no TACO,
INR readings. It’s not the main interest to increase it more by organ failure (MOF), immunosuppression, lung injury. TRALI or TRIM and the concentrates are virus-inactivated.
substituting plasma, because very huge thrombin levels do
The main problem is cost; they are more expensive
not benefit trauma patients. It may cause endothelial injury
than plasma. Some may be concerned about the risk of
and also activate other receptors and inflammation and so on.
thromboembolism, and this may occur if thrombin formation is
Further results confirm these findings, e.g. in a study ExMCF mortality increased by use of PCC and activated PCC and rFVIIa. It is not
that included more than 4,000 patients, with injury severity OR 0.94 (0.9-0.99)
a problem with fibrinogen, which is also called antithrombin
scores (ISS) considerably lower than in our patient population, FibMCF RBC 6h I, as fibrinogen and fibrin are able to capture free-flowing
OR 0.92 (0.87-0.98)
fibrinogen deficiency occurred frequently and fibrinogen thrombin, and thrombin is the one that initiates thrombosis.
levels < 1.5g/L were associated with increased mortality Authors of reviews and meta-analyses also criticise the fact
(McQuilten et al. 2017). Hagemo et al.’s study investigating that currently there are only a few high-quality studies in
1,133 patients in a multicentre trial, found that increased trauma patients showing a benefit with coagulation factor
Isolated TBI n=60
mortality was associated with fibrinogen levels < 2.29 g/L, Polytrauma n=274 concentrates.
ISS 34 (24,45)
which is barely below normal (Hagemo et al. 2014). The INR Figure 1
The European guideline (Rossaint et al. 2016) recommends
was not independently associated with mortality. Source: Tauber et al. (2011)

the use of standard coagulation tests and/or viscoelastic tests

ICU Management & Practice 3 - 2018

 V
SUPPLEMENT

was terminated early following interim analysis after inclusion

Table 1. Are CFCs useful in trauma patients? Table 3. Mortality in trauma - 1:1:1(2) vs POCT-directed individualised therapy of 100 patients, because predefined stopping was met, showing
Author Design n/ISS Products Main result Country Author Mortality ISS disadvantages with use of plasma. Correction of coagulopathy was
Schöchl 2010 Retrospective 131 FC (128) Mortality lower than predicted
38 ± 15 PCC (98) USA Holcomb 2013 21.4-25.0% 25-26 feasible in 96% of patients in the CFC group; only 2 patients had
FFP (12)
Schöchl 2011 Retrospective 681 CFC n=80 Fewer RBC and PC with CFC USA Nascimento 2013 24% 35 ± 13
treatment failure and also received plasma (Table 4).
35 ± 11 FFP n=601

Nienaber 2011 Retrospective 311 CFC n=18 Fewer RBC, lower MOF USA Holcomb 2015 24.3% 25 In the plasma group more than 50% of patients had no stop of
matched pair 44 FFP n=293 with CFC
(38,50) USA Gonzalez 2016 27% 33
bleeding and no correction of coagulation. These patients received
(25;43)
Schlimp 2013 Retrospective 157
29
FC n=85
FC+PCC n=63
Fibrinogen maintained, within
normal range at 24h ICU
additionally fibrinogen concentrate, some also PCC and factor XIII.
UK Khan 2014 35% 34 (25;41)
(23,41) FC+PCC+FFP n=9 Transfusion requirements were increased and patients received
Innerhofer 2013 Observational 144 CFC n=66 Fewer RBC and PC with CFC
37 CFC +FFP n=78 alone, lower MOF
Austria Tauber 2011 12.8% 35
(25;50)
more frequently platelet concentrates. Importantly, the rate of
(29,50)
Wafaisade 2013 Retrospective 588 FC 294 Reduced 6h mortality and Austria Innerhofer 2013 7.6% 37 (29;50) massive transfusion at comparable ISS was increased tremendously.
matched pair 37 ± 13 no FC 294 MOF with FC Austria Schöchl 2011 7.5-10% 35.5 ± 10.5
Our primary endpoint was difference in MOF. However, to
©For personal and private use only. Reproduction must be permitted by the copyright holder. Email to copyright@[Link].

Austria Innerhofer 2017 7.4% 34 (26;43)

CFC coagulation factor concentrate FC fibrinogen concentrate FFP fresh frozen plasma MOF multi-organ failure PCC
prothrombin complex concentrate RBC red blood cells answer this question, we would have needed to include at least
200 patients. Therefore the difference of 16% between groups
Table 2. Massive transfusion: Fixed ratio RBC: FFP: PC a normal range even if much fibrinogen had been administered. with a higher rate of MOF in the plasma group was not significant.
There were fewer transfusions of red blood cells (RBCs) and platelets. However, ISS and brain injury are confounders, which should be
Pro 1:1 Indifferent Con In the study by Wafaisade and colleagues (2013), early mortality considered when analysing the likelihood of MOF. These confounders
Study Type Study Type Study Type was also reduced. These patients received fibrinogen and also had were used for stratification and considered in regression analysis.
Hirshberg et al. Mathematical Rangarajan Retrospective Scalea et al. 2008 Prospective
2003 model et al. 2011 massive transfusions of plasma. Results showed a significant increased risk of MOF with plasma
Maegele et al. 2008 Retrospective Dirks et al. Retrospective Nienaber et al. Matched pair
2010 2011 analysis
Meta-analyses on plasma efficacy in bleeding patients have (OR 3·13 [1·19–8·88], p=0·025) even in this limited population
Gonzalez et al. 2007 Retrospective Magnotti et Registry - selec- Johnson et al. Prospective
al. 2011 tion bias! 2010 concluded that there is no clear benefit for blood loss, transfusion of 94 patients.
Duchesne et al. Retrospective Snyder et Retrospective - Edens et al. 2010 Prospective
2009 al. 2009 selection bias! and mortality (Stanworth et al. 2004; Casbard et al. 2004; Yang et
Teixeira et al. 2009 Retrospective Holcomb et Only early death Kashuk et al. Prospective
al. 2015 (secondary 2008 al. 2012; Kozek-Langenecker et al. 2011; Desborough et al. 2015). What stops the bleeding–the concentration or the
endpoint)
Mitra et al. 2010 Retrospective Rourke et al. Prospective
However, there are several reports in trauma patients showing clot?
2012 improved survival with early aggressive transfusion without any
Peiniger et al. 2011 Retrospective Chambers et
al. 2011
Before/after
blood measurements. Administration of 1:1 ratios is recommended, In the RETIC study the blue boxes refer to the CFC group that
Holcomb et al. 2013 Prospective Kahn et al. 2014 Prospective
but there are studies that found that mortality did not change and mainly received fibrinogen concentrate. The yellow boxes refer
coagulopathy was not corrected (Table 2). Before massive transfusion to the plasma group (Figure 2). Prothrombin is indexed as a
of plasma, reported mortality in many centres was about 50 percent. percentage of normal, and at baseline they are comparable. After
(level of evidence 1C). Viscoelastic testing gives a timely and more administration of plasma this improved, but decreased further in
Now the rate is between 21% and 35% (Table 3). This mortality
comprehensive picture. The guideline recommends use of plasma the CFC group. The patients in the plasma group received more RBC
is considerably higher than studies using a targeted correction of
together with RBC at least 1:2 or use of fibrinogen concentrate with and platelets concentrates and, despite this, had a dramatic drop
coagulopathy and using coagulation factor concentrates, especially
RBC and PCC and factor XIII in selected cases. in platelet count. Also the haemoglobin levels were lower than in
fibrinogen concentrate.
the CFC group that received fewer RBCS and platelets. Therefore
Evidence for fibrinogen concentrate improved INR or prothrombin time does not limit blood loss.
RETIC trial comparing plasma and coagulation factor What about fibrinogen and clot firmness? Fibrinogen increased
The most frequently cited studies using coagulation factor concentrates concentrates to its normal levels immediately with the factor-based concept,
in trauma patients are summarised in Table 1. All show promising but changed little and marginally and remained below normal in
Our study group conducted the first randomised controlled trial
results: lower mortality than predicted, lower transfusion requirements, the plasma group. Consequently clot strength improved rapidly
comparing the effect of a plasma-based strategy to the use of coagulation
and lower multi-organ failure. Fibrinogen was maintained within with CFC but remained unchanged or decreased in the plasma
factor concentrate in severe trauma (Innerhofer 2017). The study

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Table 4. RETIC trial main findings

factor concentrate in severe trauma (Innerhofer 2017). The study What stops the bleeding–the concentration or the
CFC (n=50) FFP (n=44) OR P value
was terminated early following interim analysis after inclusion clot?
of 100 patients, because predefined stopping was met, showing
In the RETIC study the blue boxes refer to the CFC group that
Treatment 2 (4%) 23 (52.3%) 25.34 <0.001 disadvantages with use of plasma. Correction of coagulopathy was
failure (n) mainly received fibrinogen concentrate. The yellow boxes refer
feasible in 96% of patients in the CFC group; only 2 patients had
to the plasma group (Figure 2). Prothrombin is indexed as a
RBC/24h 4 (2.7) 6 (4,11) .028 treatment failure and also received plasma (Table 4).
percentage of normal, and at baseline they are comparable. After
PC yes 20% 47.7% 3.599 .008
In the plasma group more than 50% of patients had no stop of administration of plasma this improved, but decreased further in
MT% 12% 29.5% 3.038 .042
bleeding and no correction of coagulation. These patients received the CFC group. The patients in the plasma group received more RBC
MOF% 50% 65.9% .1457 additionally fibrinogen concentrate, some also PCC and factor XIII. and platelets concentrates and, despite this, had a dramatic drop
Logistic regression adjusted for confounders ISS/TBI Transfusion requirements were increased and patients received in platelet count. Also the haemoglobin levels were lower than in
Significantly increased risk for MOF with FFP OR 3.1264 (CI 1.1906 - 9.8756), P = .0250
more frequently platelet concentrates. Importantly, the rate of the CFC group that received fewer RBCS and platelets. Therefore
massive transfusion at comparable ISS was increased tremendously. improved INR or prothrombin time does not limit blood loss.
©For personal and private use only. Reproduction must be permitted by the copyright holder. Email to copyright@[Link].

group promising results: lower mortality than predicted, lower What about fibrinogen and clot firmness? Fibrinogen increased to
Our primary endpoint was difference in MOF. However, to
transfusion requirements, and lower multi-organ failure. Fibrinogen its normal levels immediately with the factor-based concept, but
answer this question, we would have needed to include at least
was maintained within a normal range even if much fibrinogen changed little and marginally and remained below normal in the
200 patients. Therefore the difference of 16% between groups
had been administered. There were fewer transfusions of red blood plasma group. Consequently clot strength improved rapidly with
with a higher rate of MOF in the plasma group was not significant.
cells (RBCs) and platelets. In the study by Wafaisade and colleagues CFC but remained unchanged or decreased in the plasma group.
However, ISS and brain injury are confounders, which should be
(2013), early mortality was also reduced. These patients received
considered when analysing the likelihood of MOF. These confounders
fibrinogen and also had massive transfusions of plasma. Abbreviations
were used for stratification and considered in regression analysis. TRALI transfusion-associated lung injury
ISS injury severity score
Meta-analyses on plasma efficacy in bleeding patients have Results showed a significant increased risk of MOF with plasma TRIM transfusion-associated
MOF multi-organ failure
concluded that there is no clear benefit for blood loss, transfusion (OR 3·13 [1·19–8·88], p=0·025) even in this limited population immunomodulation
TACO transfusion-associated circulatory overload
and mortality (Stanworth et al. 2004; Casbard et al. 2004; Yang et of 94 patients.
al. 2012; Kozek-Langenecker et al. 2011; Desborough et al. 2015).
However, there are several reports in trauma patients showing Baseline Single-dose Double-dose Rescue Baseline Single-dose Double-dose Rescue References
Prothrombin Index (%)

improved survival with early aggressive transfusion without any For full references, please email editorial@[Link] or visit https://
[Link]/o24
blood measurements. Administration of 1:1 ratios is recommended,

INR
but there are studies that found that mortality did not change and Conclusion/ Key points
coagulopathy was not corrected (Table 2). Before massive transfusion • Early and effective fibrinogen supplementation is really important to limit
Baseline Single-dose Double-dose Rescue Baseline Single-dose Double-dose Rescue
of plasma, reported mortality in many centres was about 50 percent. blood loss and minimise risk of MOF
Platelet count (x109)

Haemoglobin (g/dL)

Now the rate is between 21% and 35% (Table 3). This mortality • Fibrinogen improves clot strength and also exhibits a platelet-saving effect.
is considerably higher than studies using a targeted correction of This is very important because platelets are one of the transfusion components
coagulopathy and using coagulation factor concentrates, especially that are sometimes dangerous and have many side effects
fibrinogen concentrate. • Fibrinogen limits coagulopathy and massive bleeding and has less transfusion
Baseline Single-dose Double-dose Rescue Baseline Single-dose Double-dose Rescue
requirements especially massive transfusion and thereby it also decreases the
risk of MOF
Fibrinogen (mg/dl)

ExaA10(mm)

RETIC trial comparing plasma and coagulation factor • An effective rise of fibrinogen concentration is not feasible with plasma
concentrates • The lower, better INR after plasma does not reduce the bleeding, therefore we
should not focus on the INR
Our study group conducted the first randomised controlled trial
comparing the effect of a plasma-based strategy to the use of coagulation • Fibrinogen is of interest, should be monitored and should be supplemented
Figure 2 early

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Implementation of a revised trauma management protocol

Goal-directed therapy of coagulopathy is recommended for trauma patients.
Can guidelines direct our strategy? Massive transfusion protocols: fixed ratios A prospective cohort study of 517 trauma patients
(1:1:1) in whom FFP and RBCs were administered in fixed ratios
When presented with bleeding trauma patients, our management
found that fibrinogen was always low at admission, and they
strategy may be directed by guidelines, e.g. the European The evidence for a 1:1:1 (platelets:FFP:red blood cells [RBC])
needed to administer cryoprecipitate to increase fibrinogen
trauma guideline (Rossaint et al. 2016). This recommends ratio in transfusion is that it is not beneficial. Abdel-Wahab
levels (Rourke et al. 2012). In patients with low fibrinogen
treatment with fibrinogen concentrate or cryoprecipitate if and colleagues showed in an audit of patients transfused FFP
©For personal and private use only. Reproduction must be permitted by the copyright holder. Email to copyright@[Link].

at admission mortality was increased, while patients who

Dietmar Fries significant bleeding is accompanied by viscoelastic signs of a for mild coagulation values that prothrombin time (PT) was
received cryoprecipitate had improved survival.
Professor functional fibrinogen deficit or a plasma fibrinogen level of partially normalised in a minority of patients and did not
Department of Surgical and
less than 1.5–2.0 g/L. An initial fibrinogen supplementation correct the PT in 99 percent of patients, regardless of the Frith and colleagues (2015) analysed thrombin generation
General Care Medicine
Medical University Innsbruck of 3–4 g is suggested, and repeat doses must be guided by number of units of FFP transfused (Abdel-Wahab et al. 2006). parameters in 440 trauma patients following FFP transfusion
Innsbruck, Austria Concentration is not increased by transfusing FFP, which has in a RBC:FFP:platelets ratio of 1:1:5. Both patients with and
viscoelastic monitoring and laboratory assessment (Rossaint
[Link]@[Link] et al. 2016). a low concentration of coagulation factor. without acute traumatic coagulopathy had low thrombin
generation after receiving four units. Both groups had a
Guidelines are developed on a scientific empirical basis, Studies on 1:1:1 transfusions have a clear survivor/
further 25% decline in thrombin generation during the next
but in clinical practice it can be hard to define which patient publication bias, as most studies in support came from war
four units, so conventional haemostatic resuscitation failed
will bleed in the next 30 minutes with a clinically substantial situations, when RBCs were available in 20 minutes and
to support the thrombin generation required for fibrinogen
bleed. The U.S. guidelines recommend 1:1:1 massive transfusion plasma within 90 minutes. The result was not that FFP saved
conversion.
packages (American Society of Anesthesiologists Task Force the patient, but that the patients who survived at least the first
on Perioperative Blood Management 2015), which have the 60-90 minutes were able to receive the plasma. For example, Khan and colleagues, in an international prospective
advantage of additional volume effect, but the disadvantages Snyder and colleagues (2009) found an association between cohort study, drew a blood sample when trauma patients
of side effects of fresh frozen plasma (FFP), time delay, higher FFP:packed red blood cells [PRBC] ratios at 24 hours arrived at the hospital, and after 4, 8 and 12 PRBC transfusions
prophylactic transfusion and lower efficacy. The European and improved survival, which after adjustment for survival bias in 160 patients. The percentage of coagulopathic patients
guideline recommends individualised targeted controlled was no longer statistically significant. Manotti and colleagues went up the more transfusions were received (58% after 4
coagulation management and transfusion, which requires (2011) analysed outcomes for trauma patients who received PRBC, 81% after 8) (Khan et al. 2015).
point-of-care monitoring and administration of colloids/ massive blood transfusion. Patients who received a higher
Nascimento and colleagues compared the effect of
crystalloids to give additional volume. The advantages are plasma ratio during the first 24 hours had an improved
a fixed-ratio (1:1:1) transfusion protocol vs laboratory-
that no prophylactic transfusion is required, there are fewer survival rate, but were in less shock. The authors note: “The
results-guided transfusion in 78 patients with severe trauma
side effects of transfusion-related complications and it is proposed survival advantage of a high-ratio may be because
(Nascimento et al. 2013). They concluded that the 1:1:1
efficacious. of selection of those not likely to die in the first place; that
protocol could be exposing patients not only to unnecessary
is, patients die with a low-ratio not because of a low-ratio.”
blood transfusion but also to increased risk of acute respiratory
distress syndrome, sepsis and multiple organ dysfunction.

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SUPPLEMENT

Table 1. Transfusion and coagulation factor requirements during the first 24 h in The Prospective, Observational, Multicenter, Major Trauma transfusion rates and outcome. Table 1 shows the transfusion
trauma patients treated with CF or CF+FFP Transfusion (PROMMTT) Study compared the effectiveness of early requirements in the first 24 hours. Table 2 shows the outcomes.
transfusion of plasma and/or platelets to time-varying plasma:RBC
CF CF + FFP p value
Outcome was worse in the group that received FFP additionally,
and platelet:RBC ratios, with the primary outcome of in-hospital
n=66 n=78 and there was more ARDS, more MOF, more sepsis, and by day
mortality. Higher plasma and platelet ratios early in resuscitation
RBC (U) 2 (0, 4) 9 (5, 12) < 0.001 30 increased mortality. The use of CF alone effectively corrected
were associated with decreased mortality in patients who received
FFP (U) 0 (0, 0) 10 (5, 13) < 0.009 coagulopathy in patients with severe blunt trauma.
PC (U) 0 (0, 0) 1 (0, 2) < 0.001
at least three units of blood products over the first 24 hours after
admission. In patients who survived 24 hours, the subsequent In the RETIC single-centre open label parallel-group crossover
Fibrinogen concentrate (g) 4 (2, 4) 4 (2, 7) 0.0007
risk of death by day 30 was not associated with plasma or platelet study (Innerhofer et al. 2017), patients who were coagulopathic in
©For personal and private use only. Reproduction must be permitted by the copyright holder. Email to copyright@[Link].

Patients treated (n) 66 (100) 70 (89.7) 0.1252

PCC (IE) 0 (0, 1000) 750 (0, 1800) 0.0006 ratios, however (Holcomb et al. 2013). the ER were randomised to receive FFP or CFC and were monitored
Patients treated (n) 23 (34.8) 40 (51.3) 0.064
for incidence of MOF. Patients who received initially coagulation
The Pragmatic, Randomized Optimal Platelet and Plasma
factors had 50% less massive transfusions. Bleeding was increased
RBC red blood cell concentrate FFP fresh frozen plasma PC aphaeresis platelet concentrate PCC prothrombin complex
Ratios (PROPPR) trial compared transfusion of plasma, platelets and
concentrate (factors II, VII; IX, X) NT not tested. in coagulation factor-treated patients, especially those patients
Source: Innerhofer et al. 2013 red blood cells in a 1:1:1 vs 1:1:2 ratio and found no difference
who received some kind of rescue therapy. The group treated with
in mortality at 24 hours or at 30 days (Holcomb et al. 2015).
plasma and then with coagulation factor had a higher MOF score.
Table 2. Outcome parameters of the full unmatched trauma population More patients in the 1:1:1 group achieved haemostasis and fewer
experienced death due to exsanguination by 24 hours. Therefore a 1:1:1 transfusion protocol is ineffective, but FFP
CF Group FFP Group p-Value initially and then coagulation factor concentrates also result in higher
(n = 66) (n = 78) Formula-driven protocols are not effective to reverse coagulopathy,
mortality and higher numbers of massively transfused patients.
paO2/FiO2 24 h 317 (250, 377) 241 (201, 325) 0.002 and result in high complications. FFP transfusion increases the
Ventilator-free days 18 (8, 25) 16 (4, 23) 0.139
risk of hospital-acquired infection by three (Sarani et al. 2008).
Dara and colleagues (2005) found no difference in new bleeding Gol-directed treatment of trauma-induced
Sepsis (n) 11 (16.9) 28 (35.9) 0.014
episodes, but new-onset acute lung injury was more frequent in the coagulopathy
MOF (n) 12 (18.2) 29 (37.2) 0.015 transfused group (18% vs 4%, p = 0.21). The more plasma used, Gonzalez and colleagues (2016) found that using a goal-directed,
ICU stay (days) 12 (6, 24) 14 (7, 30) 0.217
the more complications. Watson and colleagues (2009) showed thromboelastography-guided massive transfusion protocol (MTP)
that each unit of FFP transfused was associated with a 2.1% higher to resuscitate severely injured patients improved survival and
LOS (days) 24 (12, 35) 29 (16, 50) 0.074
risk of multi-organ failure (MOF) and 2.5% higher risk of ARDS. used less plasma and platelet transfusions during the early phase
30-day mortality (n) 5 (7.6) 6 (7.7) 0.979 of resuscitation, compared with an MTP guided by conventional
Thromboembolism (n) 6 (10.0) 6 (7.7) 0.772 Masive transfusion protocols: plasma first followed coagulation assays. Kaserer and colleagues (2018) compared two
by factor concentrates different coagulation algorithms (a target haematocrit range vs
a lower haematocrit limit only and goal-directed coagulation
Data are given as median (interquartile range) or numbers (%).
The alternative to 1:1:1 transfusion is to give plasma first in
ICU intensive care unit LOS length of hospital stay MOF multi-organ failure algorithm vs blind coagulation package) and effect on use of
Source: Innerhofer et al. 2013 hypovolaemic situations and then on top factor concentrates.
allogenic blood products and coagulation factors in a retrospective
Innerhofer and colleagues investigated exclusive use of CFCs in
multicentre observational study of severely injured trauma patients
144 trauma patients with similar ISS (37-38). One group received
(Kaserer et al. 2018). Factor XIII substitution was considered early.
coagulation factor (CF) only and the other group was treated with
They found that a goal-directed coagulation algorithm led to less
CF+FFP in the emergency room (ER). The primary outcome was
transfusion of RBC.
the response profile for coagulation parameters and secondary

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28- or 30-day mortality

Conclusion/ Key points
50 • Trauma is never standardised, patients are never standardised so a
standard regime is not possible
45
• Do not start with massive transfusion algorithms for bleeding trauma
patients
40
• Goal-directed therapy of coagulopathy is recommended for trauma
patients
35
Mortality (%)

30
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25
References
20 Abdel-Wahab OI, Healy B, Dzik WH (2006) Effect of fresh-frozen plasma transfusion on prothrombin
time and bleeding in patients with mild coagulation abnormalities. Transfusion, 46(8): 1279-85.

American Society of Anesthesiologists Task Force on Perioperative Blood Management (2015) Prac-
15 tice guidelines for perioperative blood management: an updated report by the American Society of
Anesthesiologists Task Force on Perioperative Blood Management. Anesthesiology, 122(2): 241-75.

10 Dara SI, Rana R, Afessa B et al. (2005) Fresh frozen plasma transfusion in critically ill medical patients
with coagulopathy. Crit Care Med, 33(11): 2667-71.

5 Fries D, Innerhofer P, Spahn DR (2017) Transfusion approaches and mortality in trauma patients: a
narrative review. Semin Thromb Hemost, 43(7): 759-71.

0 Frith D, Wall J, Baptista M et al. (2015) HEM-4 Thrombin generation potential declines during trauma
haemorrhage despite haemostatic resucitation. Shock, 44 Suppl 2: 1-2.
O 5 10 15 20 25 30 35 40 45
A
Gonzalez E, Moore EE, Moore HB et al. (2016) Goal-directed hemostatic resuscitation of trauma-induced
coagulopathy: a pragmatic randomized clinical trial comparing a viscoelastic assay to conventional
Injury Severity Score coagulation assays. Ann Surg, 263(6): 1051-9.

Holcomb JB, del Junco DJ, Fox EE et al.; PROMMTT Study Group (2013) The prospective, observational,
multicenter, major trauma transfusion (PROMMTT) study: comparative effectiveness of a time-varying
Figure 1 treatment with competing risks. JAMA Surg, 148(2): 127-36.
Source: Fries et al. 2017
Holcomb JB, Tilley BC, Baraniuk S et al.; PROPPR Study Group (2015) Transfusion of plasma, platelets,
and red blood cells in a 1:1:1 vs a 1:1:2 ratio and mortality in patients with severe trauma: the PROPPR
randomized clinical trial. JAMA, 313(5): 471-82.

Stein and colleagues evaluated the results of changing the Innerhofer P, Westermann I, Tauber H et al. (2013) The exclusive use of coagulation factor concen-
trates enables reversal of coagulopathy and decreases transfusion rates in patients with major blunt
transfusion algorithm from 2007 when they introduced a coagulation Abbreviations trauma. Injury, 44(2): 209-16.
trauma algorithm. They reduced ventilator days, mortality, FFP and ARDS acute respiratory distress syndrome PRBC packed red blood cells Innerhofer P, Fries D, Mittermayr M et al. (2017) Reversal of trauma-induced coagulopathy using first-
line coagulation factor concentrates or fresh frozen plasma (RETIC): a single-centre, parallel-group,
RBC transfusion (Stein et al. 2017). ER emergency room PT prothrombin time open-label, randomised trial. Lancet Haematol, 4(6): e258-e271.

Figure 1 summarises the evidence for goal-directed therapy’s FFP fresh frozen plasma RBC red blood cells Kaserer A, Casutt M, Sprengel K et al. (2018) Comparison of two different coagulation algorithms
on the use of allogenic blood products and coagulation factors in severely injured trauma patients: a
effect on 28- or 30-day mortality. ISS injury severity score retrospective, multicentre, observational study. Scand J Trauma Resusc Emerg Med, 26(1): 4.

MOF multi-organ failure For full references, please email editorial@[Link] or visit https://
The white spheres are larger as the number of patients included [Link]/o25
was larger, and mortality was higher (Fries et al. 2017).

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CONGRESS
THE EUROPEAN
ANAESTHESIOLOGY
 192
SERIES: GASES

Xenon limits brain damage following cardiac arrest

Xenon and brain injury
Xenon, a chemically inert but biologically active monatomic gas, has been applied in patients for anaesthesia/sedation, and most recently in the critical care
of patients with acute ongoing neurological damage.
Following preclinical evidence that xenon has ameliorative activity in several pathobiologic pathways that are involved in central nervous system injury,
xenon was shown to be effective at improving both morphology and function in a series of models of hypoxic/ischaemic injury that simulate stroke (both
©For personal and private use only. Reproduction must be permitted by the copyright holder. Email to copyright@[Link].

haemorrhagic and ischaemic), neonatal asphyxia, as well as the ischaemic-reperfusion injury that occurs in the post-cardiac arrest syndrome (PCAS).
Mervyn Maze These promising findings prompted a Phase 2 RCT that revealed that a 24-hour xenon administration during targeted temperature management (TTM)
Distinguished Professor of
Anesthesia resulted in significantly less brain damage than TTM alone in PCAS. A pivotal, multicentre, Phase 3 RCT is now underway to establish the efficacy (primary
Department of Anesthesia and
Perioperative Care endpoint is survival with good functional outcome) and safety of xenon in PCAS.

A
University of California San
Francisco naesthetic and sedative agents are typically administered Similar, but not identical, pathophysiologic mechanisms The haemorrhagic form of stroke is mainly caused by
San Francisco, USA
in perioperative settings to facilitate surgical and propagate ongoing damage whether the acute neurological subarachnoid and intracerebral haemorrhage. The former
[Link]@[Link] discomfort-inducing procedures. Because of the injury is initiated by a stroke (i.e. ischaemic and haemorrhagic), type accounts for 5 % to 10% of all strokes and is mostly
pleiotropic effects of these powerful drugs, investigators cardiac arrest, or traumatic brain injury. attributed to rupture of an aneurysm. Apart from the
have trialled these agents for other indications including the decreased perfusion and ischaemia in the territory of the
Stroke
use of ketamine for refractory depression (McCloud et al. ruptured blood vessel engendering excitotoxicity, additional
2015), dexmedetomidine to facilitate detoxification from Ischaemia is the cause in ~85% of adult stroke victims. pathophysiologic processes supervene due to the collection of
alcohol and substance abuse disorders (Wong et al. 2015), Dirnagl and colleagues (2014; 1999) have offered important extravascular blood (cytotoxic effect) (Budohoski et al. 2014).
and propofol for nausea and vomiting (Griffiths et al. 2012). insights into the potentially-modifiable processes that Because of perturbed cerebrospinal fluid hydrodynamics,
obtain in ischaemic stroke (Figure 1). Sudden interruption the intracranial pressure may rise resulting in failure to
Following the market authorisation for general anaesthesia
of perfusion to discrete brain regions heralds a phase of adequately perfuse other brain regions. Together with
in 2007, xenon’s use has extended to organ protection
excitotoxicity due to ischaemia-induced depolarisation of vasospasm, disruption of the blood-brain barrier and the
because of its multifaceted cytoprotective actions (Maze
glutamatergic neurons causing release of the excitatory supervention of inflammation, delayed cerebral ischaemia
2016). In this report, we focus on the neuroprotective
neurotransmitter, glutamate. Activation by glutamate of exacerbates the patient’s neurologic deficits. However, the
properties of xenon.
Timo Laitio its cognate receptor subtypes results in a massive influx contribution of vasospasm to delayed cerebral injury following
Senior Consultant Neurorotective targets in acute ongoing of calcium cations that produces neuronal death through subarachnoid haemorrhage (SAH) has been challenged
in Anesthesiology and neurologic injury necrosis. In the subacute phase of ischaemic stroke, cell (Budohoski et al. 2014). It is notable that SAH remains
Intensive Care
Division of Perioperative Services, death occurs through apoptotic processes. In the later phases an unmet treatment challenge, and novel interventions,
Prior to considering the possible clinical applications of
Intensive Care Medicine and Pain brain damage can be produced by inflammatory processes including xenon, are worthy of consideration.
Management xenon, we reflect on the pathophysiologic processes that
Turku University Hospital
initiated by engagement of the innate immune response
characterise the clinical conditions for which xenon’s
University of Turku (Dirnagl et al. 1999).
Turku, Finland neuroprotective properties may be exploited.
[Link]@[Link]

ICU Management & Practice 3 - 2018

 193
SERIES: GASES

Excitotoxicity
Inflammation as apolipoprotein E 4 (Lawrence et al. 2015), mitochondrial DNA downstream protective effectors (namely, erythropoietin) within
and
apoptosis
haplotype (Bulstrode et al. 2014) and brain-derived neurotrophic the brain under normoxic conditions (Ma et al. 2009).
factor (Failla et al. 2016). Physiologic monitoring has yielded
The neuroprotective properties of xenon have been corroborated
damage

IL-1 information on dysregulation of intracranial pressure, autoregulation

Glutamate COX-2 in preclinical models of hypoxic ischemic encephalopathy (Wilhelm
of brain perfusion, brain oxygenation and metabolism, inflammation
Contribution to:

Ca2+ MMPs
OFR Caspases et al. 2002; Ma et al. 2006; Dingley 2006; Rajakumaraswamy et
etc. etc. and cortical electrical activity. Macroscopically several types of
al. 2006; Dingley et al. 2008; Cattano et al. 2008; Valleggi et al.
lesions can be distinguished including shearing of white matter
2008; Luo et al. 2008; Bantel et al. 2009,) stroke (Homi et al.
Minutes Hours Days Weeks tracts, contusions, haematomas and oedema. A secondary wave
GABA IL-10 Scar formation 2003; David et al. 2003; Limatola et al. 2010; David et al. 2010;
protection

Adenosine Bd-proteins Vasculogenesis of damage occurs hours to days after the traumatic event that is
KATP activation EPO Neurogenesis Sheng et al. 2012), traumatic brain injury (Coburn et al. 2008;
etc. etc. BM-derived cells characterised by excitotoxicty, free radical generation, mitochondrial
Sprouting Harris et al. 2013; Campos-Pires et al. 2015,Campos-Pires et al.
©For personal and private use only. Reproduction must be permitted by the copyright holder. Email to copyright@[Link].

Anti-
etc. dysfunction, mass effect, ischaemia and inflammatory responses
2018) anaesthetic-induced developmental neurotoxicity (Ma et al.
Anti- inflammation Repair (Maas et al. 2008). Especially in the setting of repetitive trauma,
excitotoxicity and anti-apoptosis Regeneration
2007; Cattano et al. 2008a; Shu et al. 2010; Cattano et al. 2011;
processes are initiated that result in long-term consequences such
Sabir et al. 2013), and cardiac arrest (Schmidt et al. 2005; Fries
as dementia, Parkinsonism, and epilepsy.
Figure 1. Pathobiologic changes following ischaemic stroke et al. 2008; Fries et al. 2012). Preclinical studies have also shown
that xenon and targeted temperature management (TTM; currently,
In this schematic diagram the major damage-inducing changes following ischaemic stroke are
depicted over time following the acute ictus. Also depicted are the mechanisms that can protect
Neurpotective properties of xenon the standard of care for post-cardiac arrest syndrome) can be
against the damage at the various epochs during stroke evolution (Modified from Dirnagl et al.
Xenon is an antagonist of the N-methyl-D-aspartate (NMDA) combined to protect in an additive or super-additive (synergistic)
2014). Reproduced with permission.
subtype of the glutamate receptor (Franks et al. 1998), a pivotal manner. Data, published in eight peer-reviewed manuscripts from
mediator of the excitotoxicity that is ubiquitously present in acute four different laboratories involving four preclinical injury models,
Cardiac arrest demonstrate that xenon’s neuroprotective action is most effective
ongoing neurological injury from a variety of causes. NMDA-
Cardiac arrest is the classical example of ischaemic-reperfusion receptor antagonists are neuroprotective in in vitro and in vivo when body temperature is reduced (Ma et al. 2005; Martin et al.
injury in which the absence of any perfusion to the brain provokes brain injury models (Choi et al. 1988). Interventions, such as 2007; Hobbs et al. 2008; Thoresen et al. 2009; Chakkarapani et
excitotoxicity (Neumar et al. 2008). Successful resuscitation and ketamine, that produce NMDA antagonism through ion pore al. 2010; Faulkner et al. 2011; Fries et al. 2012; Sabir et al. 2014).
restoration of spontaneous circulation causes a new pathophysiologic blockade, result in the development of “Olney’s lesions” with Unlike other neuroprotective strategies, including a different
process characterised by apoptosis and neuroinflammation. psychotomimetic effects (Olney et al. 1991). Xenon produces its NMDA-receptor antagonist (gavestinel), xenon alone exhibits this
NMDA antagonism by competing with glycine at the co-activation enhanced efficacy when temperature is reduced.

Tramatic brain injury site (Dickinson et al. 2007); hence xenon does not induce the
Olney’s lesions or behavioural changes that characterise the direct Clinical evidence for the neuroprotective properties
Traumatic brain injury encompasses heterogeneous conditions ion pore blockers. In fact, xenon ameliorates the injury produced of xenon
from diverse types of trauma of varying severity; as such, different by other NMDA-receptor antagonists (Nagata et al. 2001). Xenon
pathophysiological pathways may be involved and major international The Xe-hypotheca trial (NCT 00879892 - [Link]/ct2/
protects against injury induced by NMDA, glutamate or oxygen-
efforts are more precisely characterising the evolution of injury show/NCT00879892) studied the Effect of Inhaled Xenon on
glucose deprivation (Wilhelm et al. 2002). Other complementary
(International Initiative for Traumatic Brain Injury Research Cerebral White Matter Damage in Comatose Survivors following
neuroprotective properties of xenon include interruption of
[InTBIR - [Link]]; Transforming Research and Clinical an Out-of-Hospital Cardiac Arrest (Laitio et al. 2016). The trial,
apoptosis (Ma et al. 2005), activation of species of ion channels
Knowledge in Traumatic Brain Injury [TRACKTBI - [Link]. which was undertaken at the medical centres of Turku and Helsinki
that result in membrane hyperpolarisation (Bantel et al. 2010;
edu]). From these efforts, much has been learned about genetic Universities in Finland, enrolled 110 successfully resuscitated
Gruss et al. 2004) and a generalised cytoprotective action initiated
factors that modulate the host-response to injury by proteins such (restoration of spontaneous circulation [ROSC] within 45 minutes
by upregulation of hypoxia-inducible factor-1α (HIF-1α) and its
of a witnessed cardiac arrest with an initial shockable rhythm)

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SERIES: GASES

Red: statistically less damage in Xenon + SOC vs SOC alone group

Green: no difference observed in Xenon + SOC vs SOC alone group Future applications of xenon for critical care
Apart from the potential use of xenon for postoperative sedation
(Bedi et al. 2003), and for selected intraoperative settings, e.g., for
neurosurgical procedures (Rylova and Maze 2018) it is unlikely
that xenon will be considered for routine use in perioperative
settings both because of the availability of cheaper alternatives
and because of the need for recirculating systems to minimise
consumption of xenon.

“subarachnoid haemorrhage remains an unmet

©For personal and private use only. Reproduction must be permitted by the copyright holder. Email to copyright@[Link].

Inferior Superior
Figure 2. Differences in white matter tract injury between standard of care (SOC) vs Xenon + SOC groups in patients with post-cardiac arrest syndrome treatment challenge and novel interventions,
Saggital plane sections of the overlaid white matter tracts (inferior to superior) are illustrated in which red indicates tracts with statistically less damage (higher fractional anisotropy) in the xenon + SOC
group vs. SOC alone group. In green are tracts that are no different between the two groups either because no injury occurred or because xenon did not reverse injury in these tracts. In no tracts was injury
including xenon, are worthy of consideration”
significantly less severe in the control group. (Modified from Laitio et al. 2016). Reproduced with permission.
Nonetheless, in critical care settings where there is an unmet
medical need, e.g., Post-Cardiac Arrest Syndrome, xenon’s
but still comatose patients. The trial compared xenon (up to 50% A predefined secondary objective of the XeHypotheCA Trial was to cytoprotective effects may be further appreciated for its physico-
by inhalation) plus the standard of care (SOC) versus SOC alone assess the effect of inhaled xenon on myocardial ischaemic damage. chemical properties that result in a near instantaneous onset
for the primary endpoint of white matter brain damage (global Troponin-T (TnT) levels were measured at hospital admission, and of action together with a low potential for toxicity through its
fractional anisotropy [GFA] derived from a diffusion tensor imaging at 24h, 48h and 72h post-cardiac arrest (Arola et al. 2017). The chemical non-reactivity. A pivotal 1436-patient Phase 3 Trial
sequence); both arms were inclusive of TTM administered for baseline characteristics did not differ significantly between the (Xenon for Neuroprotection During Post-Cardiac Arrest Syndrome
24 hrs. Assessment of the GFA revealed significantly (P=0.006) groups. Results are tabulated (Table 1). After adjustments for age, in Comatose Survivors of an Out of Hospital Cardiac Arrest
reduced brain damage in the subjects randomised to receive xenon. gender, study site, primary coronary percutaneous intervention (XePOHCAS - NCT03176186 - [Link]/ct2/show/
There was 41.7% less damage to white matter tracts (from the (PCI), and norepinephrine dose, the mean standard deviation NCT03176186]) has been launched to determine the efficacy
approximately 115,000 voxels assessed in each patient) in the post-arrival incremental change of the ln-transformed troponin-T and safety of 24h inhalation of xenon to improve survival with
Xenon + SOC vs SOC. alone group. The relative damage to the at 72 hours was 0.79 (1.54) in the xenon group and 1.56 (1.38) good functional outcome in successfully resuscitated (ROSC ≤
major white matter tracts in the two groups is depicted (Figure 2). in the control group (adjusted mean difference, -0.66 [95% CI, 30 min), but still comatose, victims of a witnessed cardiac arrest.
-1.16 ― -0.16], P=0.01). The decline of TnT from the peak value
Xe-HYPOTHECA was not powered to detect differences in
at 24h to 72h was significantly greater in the xenon group than
functional endpoints; reduction in 6-month mortality rate - 27% Production and availability of xenon
in the control group (p =0.0008). The effect of xenon on the
in the xenon group and 35% in the SOC group (adjusted hazard
change in the troponin-T values did not differ in patients with or Xenon is an extremely rare element present in the atmosphere
ratio, 0.49 [95% CI, 0.23-1.01]) - did not achieve statistical
without PCI or in those with a diagnosis of ST-elevation myocardial at approximately 88 parts/billion. Xenon is produced by a
significance (P = 0.053). The degree of white matter injury was
infarction (group by PCI or STEMI interaction effect, P=0.86 and process of cryogenic distillation in which air is fractionated
the strongest predictor of mortality at 6 months.
P=0.71, respectively). In comparison with hypothermia alone, into its primary components by cooling at high pressure until it
inhaled xenon combined with hypothermia resulted in less severe liquefies; the different components are then separated according
Clinical evidence for the myocardial protective myocardial injury as demonstrated by the significantly reduced to physical characteristics, including boiling points and density,
properties of xenon release of troponin-T. within specialised cryogenic columns. The process consumes large

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SERIES: GASES

Table 1. Troponin-T change from baseline to 72 h after OHCA

Xenon Group Control Group Mean Difference (95% CI) p Value

(n = 54) (n = 54)
the recirculation and recycling of xenon can further improve the
Unadjusted Adjusteda Unadjusted Adjusteda
availability of this scarce resource.
Absolute values, µg/l
Conflict of interest
Baseline (hospital
0.09 (0.03-0.30) 0.08 (0.04-0.23) – – – –
admission) Mervyn Maze is a co-founder, and shareholder of equity in NPXe Ltd,
24 h after OHCA 0.38 (0.15-1.27) 0.47 (0.12-1.74) – – – – a company that seeks to commercialise neuroprotective applications
48 h after OHCA 0.25 (0.09-0.85) 0.41 (0.10-1.48) – – – – of xenon. TL is a member of the Trial Executive Committee for
XePOHCAS, a phase 3 RCT designed to test the efficacy and safety
©For personal and private use only. Reproduction must be permitted by the copyright holder. Email to copyright@[Link].

72 h after OHCA 0.22 (0.05-0.69) b

0.40 (0.14-1.87) c
– – – –
of patients with post-cardiac arrest syndrome. The XePOHCAS trial
ln-transformed change from baseline
is sponsored by NeuroproteXeon.
–0.26 –0.16
ln ΔTnT 24 h 1.40 ± 1.39 1.65 ± 1.38 0.33 0.49
(-0.79 to 0.27) (–0.62 to 0.30)
–0.28 –0.18
ln ΔTnT 48 h 1.00 ± 1.37 1.28 ± 1.38 0.29 0.43
(-0.80 to 0.25) (–0.63 to 0.27)
–0.76 –0.66
ln ΔTnT 72 h 0.79 ± 1.54b 1.56 ± 1.38c 0.009 0.01 Abbreviations
(–1.33 to –0.20) (–1.16 to –0.16)
PCAS post-cardiac arrest syndrome TnT Troponin-T
Source: Adapted from Arola et al. 2017, Table 3.
Δ change from the baseline CI confidence interval ln natural logarithm OHCA out-of-hospital cardiac arrest TnT troponin-T ROSC return of spontaneous circulation TTM targeted temperature
Note 1: Values are median (interquartile range) or mean ± standard deviation, unless otherwise indicated. management
SOC standard of care
Note 2: Natural logarithmic transformation for troponin-T values was used in the statistical analysis due to skewness of the data.
a Data are adjusted for age, sex, study site, percutaneous coronary intervention, and dose of noradrenalin during the first 24 h after intensive care admission.
b Data are for 52 patients due to missing data of 2 patients at 72 h.
c Data are for 53 patients due to missing data of 1 patient at 72 h.

amounts of energy and those fractions which are found in low Conclusions
concentrations (i.e., xenon) require multiple distillations, and are
Xenon, the noble elemental gas, may benefit the critically ill patient
therefore extremely expensive to produce to medical grade purity
that has ongoing acute neurological injury because it reduces the
of 99.999%. The estimated total supply of xenon is thought to be
activity in several of the pathobiologic pathways that obtain in these
14 million litres, of which 50% could theoretically be delivered
conditions. A definitive, pivotal, multicentre, trial to establish xenon’s
in medical grade. Approximately 50L of xenon is required for
safety and efficacy in the setting of post-cardiac arrest syndrome
a 24-hour intervention; under these conditions approximately
is now being prosecuted. If successful, the next challenge will be
140,000 patients could be treated annually. References
to increase the production of medical grade xenon through the
retrofitting of oxygen-purification plants. Further refinements in For full references, please email editorial@[Link] or visit https://
[Link]/o26

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What’s new in sepsis in children?

The latest in diagnosis and treatment
Sepsis is a life-threatening condition in children. Current paediatric definitions are based on systemic inflammatory response syndrome. Since the publication
of the third international consensus definitions for sepsis and septic shock for adults, efforts in paediatrics are focused on finding a definition that involves a
premature diagnosis with prognostic implications based on the organic dysfunction as in the adult patient. The latest clinical guidelines on haemodynamic
support are by the American College of Critical Care Medicine. Initial resuscitation and fluid response is guided by minimal invasive monitoring. In PICU
©For personal and private use only. Reproduction must be permitted by the copyright holder. Email to copyright@[Link].

monitoring should be intensified and goals should be appropriate perfusion pressure ScvO2 ≥70% and CI ≥3.3 ≤ 6.0 L/min/m2. In fluid-resistant shock
adrenaline is the initial inotrope (peripheral infusion is possible), except in consistent warm shock when noradrenaline may be the first drug. Then the shock
Elisabeth Esteban
Physician pattern will determine the additional drugs.

S
Paediatric Intensive Care Unit
Chief of the Paediatric and
epsis is a life-threatening condition in children. The lack The third international consensus definitions for sepsis has not been designed for use in children, a population that
Neonatal Transport Team
Hospital Sant Joan de Déu of a clear definition leads to a heterogeneous diagnosis for adults (Sepsis-3) (Singer et al. 2016) agreed on new has different vital signs according to age. At present, attempts
Barcelona, Spain that prevents obtaining fully reliable epidemiological criteria based on organ dysfunction. Sepsis is now defined as are being made to adapt the definitions established for adults
eesteban@[Link]
data. In the study conducted by Weiss et al. (2015) the the organ dysfunction that appears due to the inflammatory through a paediatric score.
Paediatric Intensive Care Unit (PICU) prevalence worldwide host response to an infection (10% death risk). The Sepsis-3
The use of Sepsis-3 definitions in children was feasible and
was 8.2% (Europe 6.2%), and mortality was 25%, and did definitions aim to simplify the diagnosis and allow premature
showed promising results. Schlapbach and colleagues (2017)
not differ by age or between developed and resource-limited detection of patients with organ failure, at a higher risk of
demonstrated that the two SIRS variables-based sepsis criteria
countries. For community-acquired sepsis in European PICUs, death. Organ dysfunction is measured as an acute increase
had poor specificity to discriminate children with infection
mortality was 6%, increasing to 10% in the presence of septic of two points in the Sequential Organ Failure Assessment
at substantially higher mortality risk. Moreover, age-adapted
shock. Of the survivors, 31% were discharged with disability Scale (SOFA) due to an infection. Blood tests are necessary
SOFA and Paediatric Logistic Organ Dysfunction-2 score
(Boeddha et al. 2018). to define SOFA, so it can be a non-optimal tool outside the
(PELOD-2) had significantly greater prognostic accuracy for
ICU. For this reason the use of quick SOFA (qSOFA) has
In 2005, the Barcelona Consensus Conference constituted in-hospital mortality. Their findings indicate that age-specific
been proposed.
by paediatric experts published the paediatric definitions, translation of Sepsis-3 definitions to critically ill children
which were based on systemic inflammatory response As far as the paediatric patient is concerned, what influence using validated measures of organ dysfunction should be
syndrome (SIRS) criteria (Goldstein et al. 2005), approaching can the Sepsis-3 definitions have? A consensus has not been considered in the next revision of paediatric sepsis definitions.
the adult definitions of 1991 and 2001. To date, these criteria published since 2005, and the latest paediatric Surviving Sepsis In contrast, the performance of qSOFA to identify patients
Anna Solé-Ribalta
Physician have been the most widely used to define and classify septic Campaign (SSC) guidelines have not yet been published; the with organ dysfunction at risk for worse outcomes was poor,
Paediatric Intensive Care Unit patients in children. last update was published in 2013. Presumably, the inclusion and may not be of sufficient clinical value to be recommended
Hospital Sant Joan de Déu
Barcelona, Spain
of the concept of organ dysfunction in the definition of sepsis as a screening tool for paediatric age groups within the ICU.
Use of the SIRS criteria has been criticised in recent years
will be shared by the community of paediatricians. Efforts Leclerc and colleagues (2017) concluded that in children
because of their non-specificity. On the other hand, there are
are focused on finding a definition that involves a premature admitted to PICU with suspected infection, PELOD-2 score
patients who may not have two or more SIRS criteria and
diagnosis with prognostic implications based on the organ on day 1 was highly predictive of PICU mortality, suggesting
suffer an infection with organ failure (Weiss et al. 2015;
dysfunction as well as in the adult patient. The SOFA score its use to standardise definitions and diagnostic criteria of
Brown et al 2015).

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MATRIX

paediatric sepsis. The SOFA score was adapted and validated guidelines recommend that each institution implements its central venous catheter during the initial resuscitation should
with age-adjusted cutoffs in critically ill children: paediatric own adopted or home-grown bundles resuscitation and not delay or compromise the resuscitation efforts. Ultrasound
SOFA (pSOFA). Sepsis-3 definitions were assessed in children stabilisation bundle to drive adherence to consensus best guidance may facilitate placement of central catheters.
with confirmed or suspected infection (Matics et al. 2017). practice.
Extract sample for blood analysis and culture when a
All these scores might be more useful for prognosis than for vascular access is accomplished. Initiate antibiotic therapy as
diagnosis of sepsis. The first hour of resuscitation
soon as possible after obtaining cultures and always during
Regarding biomarkers, values of C-reactive protein and The goals of the first hour should be to maintain the airway, the first hour of clinical suspicion.
procalcitonin have been included in the usual management oxygenation, and ventilation; Maintain or restore circulation,
Fluid resuscitation should start immediately unless
although their sensitivity and specificity is lower than desired. capillary refill, normal pulses, urine output ≥ 1 mL/kg/hr,
hepatomegaly, rales, or a cardiac gallop are present. If these
Lactate continues to be valid because its elevation is related normal mental status, normal blood pressure for age; and
signs are present, the patient may not require fluid boluses and
to organ dysfunction and worse prognosis; monitoring restore appropriate heart rate (HR).
©For personal and private use only. Reproduction must be permitted by the copyright holder. Email to copyright@[Link].

instead, inotropic support is recommended. The harm of fluid

Iolanda Jordan its levels can also assess the therapeutic response. New During initial resuscitation the achievement of objectives is
Physician
boluses at the initial haemodynamic resuscitation is a concern
hopes are focused on other biological markers, such as evaluated by minimal invasive monitoring. Echocardiography (Frazier et al. 2015). Fluid infusion (crystalloids or colloids)
Paediatric Intensive Care Unit
Hospital Sant Joan de Déu adrenomoduline (Jordan et al. 2014) or pro-inflammatory is considered an appropriate noninvasive tool to evaluate is best initiated with boluses of 20 mL/kg, titrated to assuring
Barcelona, Spain and anti-inflammatory cytokines (Polic et al. 2017), to help myocardial contractility and intravascular volume, to direct signs of restored circulation and normal HR as commented
us in diagnosis, prognosis, and follow-up. We do not have a resuscitation goals and therapeutic endpoints. above. Initial (first hour) volume resuscitation requirements
perfect biomarker to date; perhaps in the future a panel of commonly are 40–60 mL/kg. Specific evaluation after each
different biomarkers may be the key (Lamping et al. 2018). Supplemental high-flow oxygen should be provided.
bolus for signs of fluid overload and simple algorithms are
Children with persistent or worsening shock should be
needed to support healthcare providers to choose which
“new studies in children to diagnose and intubated and receive mechanical ventilation to eliminate
patients could be harmed and which will benefit from fluid
breathing effort and improve oxygenation and organ perfusion.
classify sepsis according to organ failure- In most cases, there is time for fluid resuscitation and starting
boluses (Ford et al. 2012; Parker et al. 2016).

based scores are promising” a peripheral inotropic infusion before airway management Patients who do not respond rapidly to initial fluid boluses
is needed. Patients with these characteristics are vulnerable should be considered for invasive haemodynamic monitoring.
to the haemodynamic effects of sedatives (Li et al. 2016), In the fluid refractory patient, begin a peripheral epinephrine,
Treatment
emphasising the importance of initial resuscitation prior to while establishing a central venous catheter. Dopamine,
The latest SSC guidelines that include paediatric management airway instrumentation. The use of ketamine with atropine is epinephrine, or norepinephrine can be administered as a
date from 2012 (Dellinger et al. 2013). The American College considered to be the induction regimen which best promotes first-line drug as indicated by haemodynamic state when a
of Critical Care Medicine (ACCM) published in 2017 the cardiovascular integrity. The use of etomidate is discouraged central line is available.
guide for haemodynamic support in neonates and children given its effects on adrenal function. Other options to
with septic shock (Davis et al. 2017). consider are fentanyl and remifentanil or benzodiazepines Beyod the first hour (PICU haemodynamic
titrated with small doses. Barbiturates, inhalational agents support)
Despite the dissemination of the previous guidelines, some
or propofol are not appropriate. Neuromuscular blocking
studies demonstrated incomplete adherence to recommendations Monitoring should be intensified by adding invasive instruments
agents may facilitate intubation.
(Moresco et al. 2018). Consequently quality improvement to the clinical objectives: central venous access, arterial pressure
studies were designed, in order to trigger rapid clinician Vascular access should be rapidly accomplished. Portable monitoring and a modality to assess cardiac output (CO) are
evaluation and implementation of appropriate resuscitation near-infrared imaging devices may assist in peripheral vascular recommended.
efforts (Esteban et al. 2017; Cruz et al 2011). The new ACCM access. Establish intraosseous access if peripheral intravenous
line access cannot be attained in 5-10 minutes. Establishing a

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MATRIX

Table 1. Haemodynamic support algorithm, based on American College of Critical should be monitored carefully to evaluate bolus response. Crystalloid individualized”. Therapeutic plasma exchange could be considered
Care Medicine Clinical Practice Parameters for Hemodynamic Support of Paediatric is the fluid of choice in patients with haemoglobin greater than 10 as a strategy to reverse multi-organ dysfunction syndrome especially
and Neonatal Septic Shock. Crit Care Med. 2017;45:1061-93. g/dL. Red blood cells transfusion can be given to children with in patients with significant coagulopathy.
haemoglobin less than 10 g/dL. Fresh frozen plasma is recommended Conclusion
Low CI, Normal BP, Low CI, Low BP, High CI, low BP,
High SVR Low SVR Low SVR for patients with prolonged INR (infusion, not bolus). Following
shock resuscitation, diuretics/peritoneal dialysis/high flux continuous New studies in children to diagnose and classify sepsis according
Epinephrine, mid dosage Epinephrine Dopamine, epinephrine or
dopamine or dobutamine norepinephrine renal replacement therapy can be used to remove fluid in patients to organ failure-based scores are promising, and probably a
(tends to lower SVR)
who are fluid overloaded and unable to maintain fluid balance. new consensus will approach adult definitions. Adrenaline and
1. Milrinone (to recruit 1. Norepinephrine (to 1. Titrate norepinephrine and noradrenaline will play a major role in shock treatment in children,
microcirculation) increase diastolic blood fluid (if consistent warm Septic shock represents a dynamic process so haemodynamic dopamine being less recommended. We expect the publication
2. Nitroprusside or pressure and SVR) shock)
nitroglycerin (second- 2. Dobutamine, milrinone, 2. Low-dose vasopresine, drugs selected and their infusion dose may need to be changed of the new paediatric SSC guidelines and new consensus in the
line vasodilators) enoximone, levosimen- angiotensin or terlipresin
over time. Frequent re-evaluation of haemodynamic parameters is following months.
©For personal and private use only. Reproduction must be permitted by the copyright holder. Email to copyright@[Link].

3. Levosimendan/ dan (once adequate blood (to restore BP)

enoximone (if no pressure is achieved, to 3. Invasodilator (excessive recommended as haemodynamic support can be required for days.
response to previous) improve CI and SvO2) vasoconstriction compro-
mise microcirculation,
Discontinue if arrhythmia or can reduce CO and distal For children with “fluid-resistant shock” adrenaline is the initial
hypotension necrosis can occur) inotrope (dopamine loses prominence), except in a clear pattern
of low resistance and hypotension when noradrenaline may be the
BP blood pressure CI cardiac index CO cardiac output SVR systemic vascular first drug. Catecholamine-resistant shock can present with low CO/ Abbreviations
resistance PELOD-2 Paediatric Logistic Organ
high SVR, high CO/low SVR, or low CO/low SVR shock (Table 1), ACCM American College of Critical Care
Dysfunction-2 score
Medicine
which will determine following treatment.
BP blood pressure PICU Paediatric Intensive Care Unit

Angiotensin II has been recently reported as an effective CI cardiac index pSOFA paediatric Sequential Organ
Goal-directed therapy to achieve: Failure Assessment scale
treatment in patients with refractory vasodilatory shock (Khanna CO cardiac output
et al. 2017). Due to the lack of specific paediatric trials, its use in qSOFA quick Sequential Organ Failure
1. Perfusion pressure (mean arterial pressure (MAP)-central CRRT continuous renal replacement therapy Assessment scale
venous pressure (CVP) or MAP- intra-abdominal pressure children remains prudent despite exceptional experiences (Yunge CVP central venous pressure RBC red blood cells
(IAP)) appropriate for age. It is considered necessary for organ et al. 2000).
ECMO extracorporeal membrane ScvO2 Venous oxygen saturation
perfusion. oxygenation
Consider hydrocortisone in refractory shock in children at risk SIRS Systemic Inflammatory Response
HR heart rate
2. Venous oxygen saturation (ScvO2) greater than 70% is associated of adrenal insufficiency. Extracorporeal membrane oxygenation Syndrome

with improved outcome. ScvO2 saturation can be used as an (ECMO) is a viable therapy for refractory septic shock in neonates IAP intra-abdominal pressure SOFA Sequential Organ Failure
Assessment scale
indirect indicator of whether CO is adequate to meet tissue and children (Solé et al. 2018). Paediatric and adult patients with ICU intensive care unit
SSC Surviving Sepsis Campaign
metabolic demand. sepsis have lower survival (historically ≤ 50%) than neonates (80% + INR international normalised ratio

survival), but experienced ECMO centres are now reporting survival SVR systemic vascular resistance
MAP mean arterial pressure
3. Cardiac index (CI) greater than 3.3 and less than 6.0 L/min/
rates approaching 75% (MacLaren et al. 2011).
m2 may result in improved survival. Contrary to the adult
experience, low CO, not low systemic vascular resistance (SVR), Outcome benefits of CRRT (management of fluid overload, acute
is associated with mortality in paediatric septic shock. kidney injury, clearance of lactate or inflammatory, etc.), either alone
or in tandem with ECMO, should be considered in paediatric sepsis.
Normal INR, anion gap, and lactate are also objectives at this point.
Regarding blood purification, in 2010 the American Society of
Fluid losses and persistent hypovolaemia secondary to diffuse
Apheresis gave a category III recommendation, which is “Optimum References
capillary leak can continue for days. Ongoing fluid replacement
role of apheresis therapy is not established. Decision-making should be For full references, please email editorial@[Link] or visit [Link]

ICU Management & Practice 3 - 2018

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 200
MATRIX

Optimising sleep in the ICU

Disordered sleep is common in ICU patients. While many of the reasons for this are impossible to modify, and others rely on improvement in the
underlying condition, many directly depend on the actions of the treating team: for example, exposure to noise, timing of therapeutic procedures,
tapering of sedating drug doses, and daytime mobilisation. Some patients might benefit from nocturnal sedation, but there is reasonable evidence that
benzodiazepines and propofol are not the best options. Although unproven in large clinical trials, options including dexmedetomidine, melatonin (and
ramelteon), amitriptyline and mirtazapine are all reasonable, especially as their effect is usually able to be assessed over 1-2 nights, facilitating an “n of
1” trial approach to individualised therapy.
Michael C. Reade
©For personal and private use only. Reproduction must be permitted by the copyright holder. Email to copyright@[Link].

Intensivist & Australian

Defence Force Critical illness reduces normal sleep causing psychological distress. It is much better to make a the most restorative) sleep (Achermann and Borbely 1987;
Professor of Military Medicine diagnosis, address underlying causes, and use symptomatic Borbely et al. 1985), as does propofol (Herregods et al. 1989).
and Surgery Most critically ill ICU patients report, recall, or are observed to
Faculty of Medicine
temporising treatments that do not create adverse effects Similarly, opioids also reduce N3 and REM sleep (Kamdar et
have disordered sleep. Specifically, the number of awakenings
University of Queensland and worse than the problem they are designed to treat. al. 2012). Benzodiazepines in particular have been associated
per hour is higher than in health (Elliott et al. 2013; Roche-
Joint Health Command with delirium in the ICU (Pandharipande et al. 2006; 2008),
Australian Defence Force Campo et al. 2013, Drouot et al. 2014), daytime somnolence Sleep is a physiological state of cognitive and sensory
and delirium itself is an independent risk for disordered sleep
is increased to as much as 50% of total sleep (White et al. disengagement from the environment (Kamdar et al. 2012)
[Link]@[Link] (Devlin et al. 2018). Therefore, commencing or increasing
1983; Cordoba-Izquierdo et al. 2013), and patients report required in some form by all mammals. Various cardiovascular,
the rate of a sedative infusion is not a rational strategy to treat
sleep quality as worse than baseline (Elliott et al. 2013; respiratory, gastrointestinal and thermoregulatory effects are
insomnia in most ICU patients. Rather, specific treatments such
Freedman et al. 1999; Little et al. 2012). EEG recordings show observed, the importance of which is not fully understood.
as those listed below should be tried first. The pain, agitation/
a higher than normal proportion of light to deep sleep and However, acute sleep deprivation experiments are simple to
sedation, delirium, immobility, and sleep (PADIS) guidelines
that sedating drugs are primarily responsible for an “atypical conduct, revealing perceptual distortions within 24-48 hours,
recommend against propofol as a strategy to improve the
sleep” pattern characterised by disorganised delta waves and followed by delusions then hallucinations and psychosis
sleep of critically ill patients, and against benzodiazepines in
the absence of k complexes and sleep spindles [summarised (Waters et al. 2018). Physical performance (Kirschen et al.
general (Devlin et al. 2018). Of course, there remain many
in Devlin et al. (2018)]. There are many possible reasons for 2018) and immune function (Mullington et al. 2010) are
specific indications for opioids or GABA-ergic sedatives in
disordered sleep, and as the importance of each will vary in also degraded by inadequate sleep.
the ICU other than sleep.
different patients (Figure 1), so will the optimal approach

David Liu
to management.
“commencing or increasing the Measuring sleep
Postdoctoral Research Fellow
Burns, Trauma & Critical Care Sedation is a poor substitute for sleep rate of a sedative infusion is not a If specific treatments for sleep are to be used, it would be
Research Centre
University of Queensland Virtually every ICU clinician has at some stage asked: “My rational strategy to treat insomnia logical to measure their effect using a validated instrument.
Regrettably, sleep is more difficult to identify than most other
Registrar
patient didn’t sleep, could we give a sedative?” The single most in most ICU patients” physiological variables, and current tools are so imperfect that
Department of Intensive Care important goal of this paper is to explain why this question is
recent consensus guidelines (Devlin et al. 2018) recommend
Medicine analogous to the request “My patient keeps coughing, could
Royal Brisbane and Women’s Despite their ability to produce the outward appearance of against routine clinical use. Nonetheless, technology is advancing
we give a muscle relaxant?” Cough is distressing to patients
Hospital sleep, GABA-ergic sedatives used to facilitate tolerance of an rapidly in this area. Polysomnography (electroencephalogram,
Brisbane, Australia and staff, but a muscle relaxant is a temporary solution that
endotracheal tube can have the opposite effect. Benzodiazepines electromyogram and electrooculogram), the gold standard,
would make many underlying problems worse, while also
d.liu3@[Link] increase N2 (light) but reduce N3 (deep—thought to be is too complex to acquire and interpret for anything but

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17/09/2018 Word Art

research use. Actigraphy, using motion-sensors on the wrist, while

sufficiently accurate in routine sleep studies, over-estimates sleep in
critically ill patients who can be immobile for reasons other than
sleep (Kamdar et al. 2012). Compressed EEG signals (primarily
Bispectral Index, BIS) can estimate sleep depth, but poorly define
different stages in sleep architecture and are difficult to use over
many hours. Subjective assessment using the Richards-Campbell
Sleep Questionnaire (RCSQ) has been validated in ICU patients
and correlates well with polysomnography (Richards et al. 2000),
and appears better than any technological device at present. An
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observational study formally comparing all of these measurement 17/09/2018 Word Art

approaches is in progress (Delaney et al. 2018).

Non-pharmacological methods to improve sleep

Ventilator mode 1/1

The 2018 PADIS guidelines recommended assist-control ventilation

over pressure-support ventilation, based on three comparative studies
in which sleep had been measured as an outcome (Devlin et al. 2018).
All three trials (which together comprised only 61 patients) found
a significant benefit in sleep efficiency (proportion of time meant
to be asleep actually spent asleep)(18.3% greater, 95% CI 7.9%-
28.8%), and also a small but significant increase in the proportion Figure 1. Word clouds illustrating the relative importance of combinations of factors that might contribute to Figure 2. The contribution of each noise category
of total sleep time spent in REM sleep. Whether this would also be disturbed sleep in two different ICU patients. Clearly the correct response to each will be different. for (A) the acoustic energy and (B) the number of
predicted loudness peaks.
true for synchronised intermittent mandatory ventilation + pressure
Reproduced from (Simons et al. 2014) under the terms of the Creative
support ventilation (SIMV+PSV) (in countries and ICUs where it is Commons Attribution License.
the default mode in preference to assist control) was not studied. 1/1

No recommendation was made on whether adaptive modes of respiratory rate, and spent significantly longer in stage N3 sleep
ventilation are beneficial. It is likely that this question is suitable for and had significantly better subjective sleep scores. etc. was shown by a 2014 Dutch observational study (Simons et al.
an “n of 1” trial design—that is, in a patient with insomnia, trial 2014) that found the loudness peaks (part B of Figure 2) were 60%
of a night on assist control or SIMV+PSV seems likely to lose little. Reduction of ambient noise due to staff activity and 32% due to staff speech. Only 6% were due
to equipment alarms.
Ambient noise levels in the ICU are approximately double that
Music recommended by the World Health Organization (Darbyshire and
Earplugs
One small randomised trial has tested the effect of music on sleep Young, 2013). However, background noise is probably less important
(Su et al. 2013). Participants listened to 45 minutes of classical- for sleep disruption than the frequency and magnitude of peak levels, If encouraging clinical staff to be quiet is impossible, another approach
type music written specifically for the purpose, or no music. Those which were above 85dBA up to 16 times an hour. That this is not the could be to use patient earplugs. This is surprisingly effective, as shown
played music had significantly lower heart rate, blood pressure, inevitable consequence of electronic devices, mechanical ventilators, by a 2017 meta-analysis of nine studies/1,455 patients (Litton et al.

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Table 2. Drugs to improve sleep

et al. 2003; Tamburri et al. 2004) really should be questioned. Often
Table 1. Non-pharmacological strategies to improve sleep
these activities are not done for staff convenience but because of the Drug Suggested Effect on sleep Known effects
Strategy realities of staff rostering; taking this into account at a departmental dose on other
level might alleviate this major problem. outcomes
Ventilator mode (assist-control in preference to pressure support)
Melatonin 3-10mg In normal people and No other benefit
Music at sleep time people with primary has been observed
Tapering of drugs with sedative effects insomnia, reduces time to in ICU patients
Reduction of ambient noise
fall asleep, but no clinically (Devlin et al. 2018)
Earplugs Many drugs used in critical care have sedating effects, and abrupt significant effect on time

Reduction of ambient light at night

withdrawal after a period of habituation leads to a withdrawal state spent asleep. In patients
unable to sleep due to a
characterised by hyper-alertness and insomnia. Unless there is a good medical cause (“secondary”
Scheduling of patient care activities during daytime
reason, it is usually better to slowly reduce doses of opioids and other insomnia), moderate to
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Tapering of drugs with sedative effects high quality studies show

sedating medications over several days (Brown et al. 2000) Doing so
Daytime mobilisation melatonin has little or no
can avoid the need to simply replace one type of sedative with another. beneficial effect on sleep
(Buscemi et al. 2004)
Ramelteon 8mg Shortens time to fall Lower incidence
2016) that found an overall relative risk of delirium of 0.59 (95% CI
0.44-0.78), although not all of the included studies measured sleep. Of
“early mobilisation asleep and increases
total duration of sleep
and duration of
delirium, and

those that did, two found earplugs did indeed improve self-reported is to date the non-pharmacological (Neubauer 2008) fewer night-time
awakenings
sleep quality, while one did not observe any significant difference.
intervention associated with the greatest (Nishikimi et al.
2018)

Light observed reduction in delirium” Dexmedetomidine 0.1mcg/kg/hr Increases total sleep

time and proportion of
Reduced
postoperative
time spent in N2 (deeper) delirium, reduced
Five studies (summarised in Bion et al. 2018) have assessed the effect Mobilisation to restore day-night rhythm stage of sleep; reduces reported pain,
of reducing environmental light at night. However, each has done this proportion of time spent improved reported
Early mobilisation is to date the non-pharmacological intervention in N1 (lighter) sleep. No sleep (Su et al.
as part of a multi-component intervention that also reduced noise
associated with the greatest observed reduction in delirium (Schweickert change in REM sleep (Wu 2016)
and other disruptions to patient sleep, and all used subjective sleep et al. 2016)
et al. 2009). While there are many possible mechanisms for this effect,
assessments. The reviewers concluded that this, combined with the Amitriptyline 10-50mg Shortens time to fall asleep No benefit has
one must be the likelihood that patients were less likely to be able to
different patient populations studied (from non-ventilated neuro ICU and increases overall been proven in
sleep during the day, and hence re-established their day-night circadian sleep time, but reduces ICU patients when
patients to mechanically ventilated ICU patients), made it difficult
rhythm earlier than might otherwise have been the case. The cognitive REM sleep (Wilson and used for this
to reach any conclusion about the utility of this intervention alone. Argyropoulos 2005) indication
and sleep effects of enhancing other daytime activities are yet to be
Nonetheless, it is difficult to argue against such a low-cost, low risk Mirtazapine 15-30mg Increases total slow wave No benefit has
assessed in critically ill patients.
intervention as turning down the intensity of the lighting at night. sleep and REM sleep, as been proven in
well as improving insomnia ICU patients when
scores (Shen et al. 2006) used for this
Scheduling of patient care activities Drugs to improve sleep indication

Noting the adverse effects of GABA-ergic drugs when used as sedatives Trazodone 50mg Increases total slow wave No benefit has
When asked, patients reported that having their vital signs assessed sleep but reduces REM been proven in
and having blood taken were more disruptive to sleep than any in critical illness, it would seem unwise to choose benzodiazepines as sleep. Improves subjective ICU patients when
noise (Freedman et al. 1999). Critical care is a 24-hour activity, but nocturnal sedatives in patients with or recovering from critical illness. insomnia. No effect on total used for this
sleep duration or time to indication
whether medication administration, radiographs, wound care, and While all of the non-pharmacological measures listed above should fall asleep (Montgomery et
bathing need to interrupt sleep up to 40-60 times per night (Gabor be considered first, some patients are so distressed by insomnia or so al. 1983)

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MATRIX

refractory to non-pharmacological treatment that treatment with medication should

be at least attempted. FOR MEDICINE
Melatonin
The 2018 PADIS guidelines make no recommendation regarding melatonin and sleep, Leading International Trade Fair
based on three identified trials they class of low quality that enrolled a total of only 60
patients (Devlin et al. 2018). At least three more trials are planned or already recruiting DÜSSELDORF, GERMANY
in ICU populations (Prevention of Delirium in Intensive Care by Melatonin (DEMEL)
[[Link]/ct2/show/NCT03524937], Melatonin Use in the Intensive Care 12–15 NOVEMBER 2018
Elderly Population (MICE) [[Link]/ct2/show/NCT03013790], and Melatonin
for Prevention of Delirium in Critically Ill Patients (MELLOW-1) [[Link]/ [Link] Member of
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ct2/show/NCT02615340].

Ramelteon • The medical world on its

One small randomised controlled trial of the melatonin-receptor agonist ramelteon was way into the digital future
published in 2018, and two larger trials (Melatonin for Prevention of Delirium in Critically
Ill Patients (MELLOW-1) [[Link]/ct2/show/NCT02615340] and Pro-phylactic • Worldwide overview:
administration of Melatonin for the prevention of Delirium in Intensive Care units – a
Only at MEDICA 2018
randomized placebo controlled trial (Pro-MEDIC study) ACTRN12616000436471 [anzctr.
[Link]/Trial/Registration/[Link]?id=369434] are currently underway. In
the published single-centre study of 88 patients, the 45 who received 8mg/d ramelteon BE PART OF THE NO.1!
had nearly half the incidence of delirium (24.4% vs. 46.5%, p=0.04) of nearly half the
duration (0.78 vs 1.40 days, p=0.048), and the nonintubated patients had fewer night-
time awakenings (Nishikimi et al. 2018), all suggesting this is a promising intervention,
apparently without substantial CNS or other adverse effects. Lack of availability in some
countries currently limits utility.

Dexmedetomidine
Dexmedetomidine, an alpha-2 agonist, produces sedation in critically ill patients by
a mechanism distinct from propofol and benzodiazepines. Unlike these drugs, it
increases the proportion of N3 sleep (Akeju et al. 2018). In a study of 76 postoperative
non-ventilated non-cardiac surgery high dependency unit (HDU) patients aged ≥ 65
years, very low dose dexmedetomidine (0.1 mcg/kg/hr) increased the proportion
of N2 sleep from 15.8% (IQR 1.3-62.8%) with placebo to 43.5% (16.6%-80.2%),
prolonged total sleep time, and improved subjective sleep quality (Wu et al. 2016).
In a larger subsequent trial, the same investigators found the same protocol associated
with significantly improved subjective sleep quality, along with less than half the

Messe Düsseldorf GmbH

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P.O. Box 10 10 06 _ 40001 Düsseldorf _ Germany
Tel. +49 211 4560-01 _ Fax +49 211 4560-668

[Link]
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incidence of postoperative delirium (9% vs. 23%; odds ratio 0.35, syndrome. Use … to promote sleep has been discouraged by an NIH although there are no trials in this context (Borthwick et al. 2006).
95% CI 0.22-0.54; p<0.0001) (Su et al. 2016). Survival rates were consensus panel on chronic insomnia” (Kamdar et al. 2012). However,
higher initially with dexmedetomidine at six months, one year, chronic insomnia is quite different to brief treatment in ICU, and the Antihistamines (diphenhydramine, doxylamine)
and 2 years (rate difference 5.2%, 5.3%, and 6.7%, respectively; doses usually prescribed (10-50mg nocte) are most unlikely to cause
Diphenhydramine (25-50mg nocte) and doxylamine (25mg nocte)
p<0.05), but after three years the difference was not significant the listed complications, especially when patient weight and metabolic
both reduce sleep latency and increase total sleep time (Koski 2011).
(32.6% vs. 34.9% mortality; hazard ratio 0.87, 95% CI 0.68-1.13; function are considered. Amitriptyline, the tricyclic antidepressant
However, a quoted 70% increased risk of cognitive decline in a cohort
p=0.303) (Zhang et al. 2018). In contrast, a study of 100 initially most commonly used as a nocturnal sedative, is generally recognised
study comparing hospitalised patients receiving diphenhydramine
delirium-free critically-ill patients randomised to 0.2-0.7 mcg/kg/ to reduce REM sleep, but to reduce sleep latency and to increase
to those not receiving it, along with more behavioural disturbances
hr dexmedetomidine at night vs. placebo found dexmedetomidine overall sleep time (Wilson and Argyropoulos 2005). Whether this
(Agostini et al. 2001), have led to recommendations against the
associated with less delirium (relative risk, 0.44; 95% CI, 0.23- provides benefit in an individual patient is readily appreciated after
use of sedating antihistamines as nocturnal sedatives in hospitalised
0.82; p=0.006), but no observable difference in sleep quality on only 1-2 nights’ treatment. While non-pharmacological treatments
©For personal and private use only. Reproduction must be permitted by the copyright holder. Email to copyright@[Link].

patients. While this is not trial evidence and these adverse effects
a subjective sleep questionnaire (Skrobik et al. 2018). This led the are always better first-line options, given the known adverse effects
could be the result of many cofounding influences, availability of
PADIS guideline authors to be circumspect in their recommendation, of benzodiazepines and the absence of other good options, some
the alternatives listed above argue against using antihistamines as
stopping short of recommending dexmedetomidine for sleep alone argue that amitriptyline is a reasonable alternative.
first-line options in adults.
but noting its potential benefit on sleep could be considered when
choosing a sedative if one was indicated (Devlin et al. 2018). Mirtazapine
Conclusion
Mirtazapine, an atypical antidepressant with a mechanism that
Zolpidem, zopiclone, zaleplon, eszopiclone Facilitating sleep at night is likely to have outcome benefit in
includes presynaptic alpha-2 negative feedback blockade, postsynaptic
Conveniently grouped as “z-drugs”, zolpidem (an imidazopyridine), serotonergic (5HT2 and 5HT3) blockade, and enhanced noradrenergic many patients, and is also likely to address the insomnia that many
zopiclone and eszopiclone (cyclopyrrolones) and zaleplon (a and 5HT1 neurotransmission, also causes somnolence as a side effect commonly recall as a particularly distressing memory of their ICU
pyrazolopyrimidine) are non-benzodiazepine agonists of the that has been used as a primary indication in some patients. Its effect stay. The non-pharmacological approaches to insomnia are almost
GABAA receptor. They are claimed to have fewer adverse effects than on sleep in patients with major depression is more encouraging than always preferable first-line alternatives in critically ill patients. There
the commonly-used sedative-hypnotic benzodiazepines (typically what is known of amitriptyline: it increases total slow wave sleep is evidence that achieving the outward manifestations of sleep
temazepam, diazepam and lorazepam), although there is little evidence and REM sleep, as well as improving insomnia scores (Shen et al. through use of benzodiazepines or other GABA-ergic drugs has a
for this. Perhaps for this reason, there has been almost no research 2006). As for amitriptyline, its use in critical illness is essentially not net detrimental effect. There are several non-GABA-ergic alternatives
on these drugs as ICU sedatives, and they rarely appear in critical studied, but doses of 15-30mg should be safe, and n-of-1 trials in that show promise, but none has convincingly shown benefit in
care guidelines, including the 2018 PADIS guidelines (Devlin et al. individual patients would appear to be a reasonable strategy in the randomised controlled trials. In part, this is due to the practical
2018). Perhaps their only indication is to continue chronic use (in absence of large randomised trials. difficulties of objectively measuring sleep in critically ill patients. “N
preference to abrupt withdrawal) in a patient planned to stay only of 1” trials of certain agents until the optimal approach is found for
briefly in the ICU. Trazodone each individual might be the best strategy, in anticipation of future
definitive trials.
Trazodone, a tetracyclic antidepressant, is commonly prescribed
Amitriptyline
to outpatients as a treatment for insomnia as an alternative to
Amitriptyline is not covered in the 2018 PADIS guideline (Devlin et al. benzodiazepines. This practice was recently supported by a systematic
2018) and is recommended against by some authors on the grounds that review of 45 studies (Jaffer et al. 2017). Its off-label use (at 50mg
it has “not been studied for use in insomnia and has important potential nocte for at most 7 days) was recommended in a 2006 guideline from References
side effects including hypotension, arrhythmias, and anticholinergic the UK Intensive Care Society as an alternative to benzodiazepines, For full references, please email editorial@[Link] or visit [Link]

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Cancer patients in the intensive care unit

Recent advances and new challenges
It has been thought for years that cancer patients have not benefitted from intensive care unit (ICU) admission when they suffer from severe and poten-
tially reversible acute illnesses. Fortunately, numerous studies have shown that this is not the case. Today, the number of cancer patients in ICUs around
the world is increasing every year, and both survival and quality of life are improving in the same manner. This progress is due to multiple factors, from
progress in anti-tumour treatments to better management of patients in the ICU.

W e are moving towards an individualised and especially in haematological patients. Old age, poor functional also led to the appearance of new complications associated with
©For personal and private use only. Reproduction must be permitted by the copyright holder. Email to copyright@[Link].

dynamic treatment that will be adapted to the type status prior to admission to the ICU, and a higher degree the treatment that the intensivist must know about and treat,
Isidro Prieto del of tumour and the patient's immune response. of multi-organ failure during the ICU stay are independent such as cytokine-release syndrome, which can simulate sepsis
Portillo The prognosis of the critical cancer patient is time-dependent predictors of poorer quality of life. or anaphylaxis and whose treatment can be very different.
Consultant Intensivist
and therefore ICU intensivists must face the challenge of
Residents Tutor In our area, we now have available a recent study series that Laparoscopic (keyhole) surgery has decreased the time and
Department of Intensive Care making a good selection of patients with early admission
includes a mixed population of onco-haematological patients postoperative complications of many tumours. Even the most
Hospital Universitario 12 de Octubre and effective diagnosis and treatment.
Madrid, Spain admitted to ICU, with 36% mortality and 40% dependence on aggressive techniques such as cytoreductive surgery and heated
Oncological and haematological disease is one of the discharge (Díaz-Díaz et al. 2018). A study conducted in France intraperitoneal chemotherapy require a short stay in ICU when
[Link]@[Link]
leading causes of morbidity and mortality in the world showed similar clinical outcomes, with hospital mortality rates, performed by experienced teams.
(Azoulay et al. 2013). The percentage of cancer patients in ICU 3-month mortality and one-year mortality of 39%, 47% and
varies between 6% and 20% (Bos et al. 2015; Shimalbukuro- 57% respectively (Azoulay et al. 2013). These results are far 2) Criteria for admission to ICU
Vornhagen et al. 2016), in many cases lower than that of removed from the classical studies, which presented unacceptably
other less prevalent pathologies. Approximately 50% of these high mortalities that did not justify aggressive management We are getting a better selection of patients who can benefit
admissions are due to surgical procedures, while the other 50% of these populations (Hauser et al. 1982). from admission to the ICU. This is due to, among other reasons,
is related to medical causes, with only 3.3% corresponding greater collaboration by oncologists, haematologists and
The improvement in the prognosis of cancer patients in intensivists, with the development of management protocols
to specific causes of oncological disease (Puxty et al. 2015).
ICU is undoubtedly multifactorial. Knowledge of these factors is and agreements on admission criteria (Carmona-Bayonas et
Considering that cancer treatments have increased their fundamental to patient management and a challenge for future al. 2018).
efficacy, associated with better prognosis and increased life improvement. We can highlight five key elements:
expectancy, it is foreseeable that the number of cancer patients The decision whether or not to admit a cancer patient to
requiring admission to ICU will continue to increase in the the ICU is a difficult one, and both the potential benefit and
1) New anti-tumour therapies
Ignacio Sáez de la coming years, constituting a field of compulsory continuous the possibility of the treatment being unsuccessful should
Fuente The medical and surgical treatment of cancer patients has changed be taken into account. The admission of an oncology patient
Staff Physician
training for intensivists.
Department of Intensive Care considerably. Chemotherapy in ICU, unthinkable until relatively to ICU should be based on three principles:
Hospital Universitario 12 de Octubre
Observational studies have shown an improvement, not recently, may be a therapeutic option in selected critical patients.
Madrid, Spain only in terms of mortality, but also in terms of the quality of • The reason for admission must be reversible
Treatment increasingly targeted at tumour cells as evidenced by
life of cancer patients who have required admission to the ICU. immunotherapy (monoclonal and bispecific antibodies (BABs), • The patient shows an adequate quality of life and the
nachetesaez@[Link]
However, this is still noticeably worse than that of the general chimeric antigen receptor (CAR) T cells, and checkpoint inhibitors) prognosis of the oncological disease and its therapeutic
population, both at 3 and 12 months after hospital discharge, is, in general, effective and well tolerated. These therapies have possibilities justify the use of aggressive measures

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• The patient or his/her family members do not refuse is admitted to the ICU with sepsis or acute respiratory failure has been considered the main risk factor for short-term
admission. (Hanzelka et al. 2013; Mokart et al. 2013). In high-risk mortality in onco-haematological patients admitted to the ICU.
patients we should consider the risk/benefit of preventative Despite the improvement in survival due to the application
The prognosis of cancer patients in the ICU, as well
admission to ICU. of protective mechanical ventilation, and based on different
as those with non-oncological conditions, depends on the
clinical studies (Squadrone et al. 2010; Lemiale et al. 2015),
performance status, the severity of the acute illness and the The speed with which the appropriate treatment is put
NIMV has been recommended as the initial treatment for
number of organ systems that fail. Oncological diagnosis, the in place will have a significant influence on prognosis. The
respiratory failure in these patients, since it significantly
stage of the tumour, neutropaenia, aplasia or the presence creation of extra-ICU rapid response teams, extra-ICU patient
reduces the need for tracheal intubation and IMV, avoiding
of metastasis have little or no relevance to the short-term assessment teams or specific projects for certain pathologies
its associated complications and improving prognosis.
prognosis of a cancer patient in ICU. In general, cancer (sepsis code) has led to progress in this area.
patients have a worse prognosis than non-cancerous patients However, a new multicentre study (Lemiale et al. 2015)
In a large number of critical cancer patients we do not have
in ICU, especially those with haematologic malignancies. This was published in 2015, including the largest number of
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a reliable diagnosis and these patients have a worse prognosis.

Ignacio Pujol Varela is probably due to being an immunocompromised patient patients to date, which sought to demonstrate the possible
Noninvasive or minimally invasive diagnostic techniques such
Chief Physician and not having cancer “per se.” If we could determine the beneficial effects of NIMV on this population of patients.
as computed tomography (CT), lung and heart ultrasound,
Department of Intensive Care. immunosuppression status of critical patients in routine Despite the criticism received (less severe acute respiratory
MD Anderson Cancer Center haemodynamic monitoring by thermodilution and/or
Madrid, Spain
clinical practice, we would see a good correlation between failure based on lower respiratory rate, low mortality of the
pulse wave analysis and early analysis of samples taken by
that status and the prognosis. Over the next few years, the sample, few hours of NIMV) the study found no significant
bronchoscopy (bronchoalveolar lavage and tracheal aspirate)
ipujol@[Link] increased knowledge of the immune response in critical cancer clinical differences when using NIMV as a first therapeutic
should be the cornerstone of early diagnosis.
patients, the possibility of obtaining real-time data and the possibility. In both branches of this study, HFNC was used
possibility of therapeutically modulating this response will in nearly 40% of the cases, which allows us to hypothesise
represent an unprecedented advance in improving survival.
“why not a code cancer if we have to whether the best approach for these patients is a joint use
of both systems.
Traditional prognostic scores have very limited value in
cancer patients and only scores that assess organic function
be especially precise and quick in our In recent retrospective trials (Mokart et al. 2015), this
(sequential organ failure assessment [SOFA], Logistic Organ diagnostic and therapeutic response to approach has been associated with a reduction in mortality,
Dysfunction Score [LODS]), better predict mortality and
are useful in making decisions. The short-term prognosis is
cancer patients?” although it is necessary to wait for the results of new clinical
studies before drawing definitive conclusions. In any case,
mainly associated with the number of dysfunctional organs and as the study by Kangelaris et al. (2016) highlights,
In the group of acute time-dependent pathologies in
(especially if more than 3), the need for invasive mechanical it is important to remember that in patients who choose
which an improvement in prognosis has been demonstrated
ventilation (IMV) and the need for renal replacement therapy. a noninvasive ventilatory strategy, and who subsequently
with rapid action protocols: code myocardial infarction, code
require tracheal intubation, mortality is significantly higher
stroke or code sepsis, there are also complicated oncology
3) Speed and precision in both the short and long term; therefore, we should not
patients. Why not a code cancer if we have to be especially
delay invasive support in the case that it is required.
Cancer patients have varying degrees of immunosuppression, precise and quick in our diagnostic and therapeutic response
making them more likely to have conditions, not just infectious to cancer patients?
5) ICU trial
ones, during their illness and to respond negatively to these
complications. Even minor organ dysfunctions have been 4) Improving support measures in ICUs In the group of patients about whom we have questions as
associated with an increase in mortality, thus making early to the attitude to be taken, it would be advisable to carry
This is especially true for respiratory support, both noninvasive
admission to the ICU a better prognostic determinant (Legrand out an ICU trial, this being understood as admission to the
mechanical ventilation (NIMV) and high-flow nasal cannula
et al. 2012). It is especially relevant when the oncology patient ICU without therapeutic restrictions for at least 72 hours,
oxygen (HFNC). The need for tracheal intubation and IMV

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according to its evolution. We can enter for haemodynamic or renal

The critical oncology patient in almost ten phrases Abbreviations
support and limit IMV. We can even check in to optimise comfort
measures or reduce dyspnoea with high-flow nasal goggles or HFNC high-flow nasal cannula oxygen
Adapt to our environment
IMV for patients with poor prognosis. Here, too, decisions must IMV invasive mechanical ventilation
Teamwork and multidisciplinary work
be made in a multidisciplinary manner (intensivists, oncologists NIMV noninvasive mechanical ventilation

New therapies and better prospects. New complications and haematologists) and in agreement with the patient and family
members.
Early or advance admission. Code cancer
All therapeutic options can be considered and individualised,
Rapid diagnosis and treatment including those that have traditionally been considered limiting
Individualised and dynamic decisions
factors, such as chemotherapy in ICU or extracorporeal membrane References
oxygenation (ECMO) in patients with severe refractory respiratory
©For personal and private use only. Reproduction must be permitted by the copyright holder. Email to copyright@[Link].

Azoulay E, Mokart D, Pène F et al. (2013) Outcomes of critically ill patients with hematologic malignancies:
ICU Trial. Avoid “all or nothing” criteria and measures failure. Subgroups with poorer prognosis, such as patients with prospective multicenter data from France and Belgium -a groupe de recherche respiratoire en
réanimation onco-hématologique study. J Clin Oncol, 31(22): 2810–8.
severe allogenic bone marrow transplant and graft versus host disease
Humanization
(GVHD) or patients with lung neoplasms requiring mechanical Bos MMEM, Verburg IWM, Dumaij I et al. (2015) Intensive care admission of cancer patients: a
comparative analysis. Cancer Med, 4: 966-976.
Quality of life and quality of death ventilation for respiratory failure and who may require chemotherapy
in ICU, may also benefit from admission to ICU. Carmona-Bayonas A et al. (2018) Intensive care in cancer patients in the age of immunotherapy and
molecular therapies: Commitment of the SEOM-SEMICYUC. Med Intensiva, Mar 5. DOI: 10.1016/j.
with frequent and periodic re-evaluations, with the intention of not medin.2018.01.008. [Epub ahead of print]

perpetuating unnecessary treatments and prolonging the suffering Conclusions Díaz-Díaz D, Villanova Martínez M, Palencia Herrejón E (2018) Oncological patients admitted to an
of the patients and their families. intensive care unit. Analysis of predictors of in-hospital mortality. Med Intensiva. 2018, Mar 18. DOI:
For many years ICUs have focused on the treatment of acute illness 10.1016/[Link].2018.02.001. [Epub ahead of print]

The ICU trial is based on a study published by Lecuyer et al. and neglected the emotional side of patients and families. This is Hanzelka KM, Yeung SC, Chisholm G et al. (2013) Implementation of modified early-goal directed
(2007), in which they found no statistically significant variables at most evident in cancer patients. We must humanize ICUs, make them therapy for sepsis in the emergency center of a comprehensive cancer center. Support Care Cancer,
21: 727–34.
the time of admission to the ICU that differentiated between survivors open to family members, minimise noise, integrate psychologists
and non-survivors. However, after 72 hours none of the patients Hauser MJ, Tabak J, Baier H (1982) Survival of patients with cancer in a medical critical care unit.
into our work teams, respect the circadian rhythm of patients and Arch Intern Med, 142(3): 527–9.
who required increased organ support measures survived. Thus, if make the environment less inhospitable and more hospitable.
Kangelaris KN, Ware LB, Wang CY et al. (2016) Timing of intubation and clinical outcomes in adults
after that time, the patient experiences failure of 3 or more organs with acute respiratory distress syndrome. Crit Care Med, 44: 120-9.
or worsening of the previous multi-organ failure, vital expectations We are moving towards individualised treatment for cancer
are minimal and it would be advisable to establish measures to limit patients and this also requires us to adopt individualised and dynamic Lecuyer L, Chevret S, Thiery G et al. (2007) The ICU trial: a new admission policy for cancer patients
requiring mechanical ventilation. Crit Care Med, 35: 808–14.
the therapeutic effort (Prieto del Portillo et al. 2014). support measures. Admission criteria and therapeutic measures in
ICUs should no longer be “all or nothing” and should be adapted to Legrand M, Max A, Peigne V et al. (2012) Survival in neutropenic patients with severe sepsis or septic
shock. Crit Care Med, 40: 43–9.
Thus, not only do we avoid unnecessary treatment or suffering each patient and their wishes. The ICU must also be able to provide
of family members, but we will also participate in the prevention of quality at the end of life. Undoubtedly, the human and technical Lemiale V, Mokart D, Resche-Rigon M et al. (2015) Effect of noninvasive ventilation vs oxygen therapy
on mortality among immunocompromised patients with acute respiratory failure: a randomized
conflicts between ICU staff members and the emergence of burnout resources available to us vary greatly between centres and countries, clinical trial. JAMA, 314: 1711-9.
syndrome (Piers et al. 2011). so we must also adapt to our working environment. Mokart D, Geay C, Chow-Chine L et al. (2015) High-flow oxygen therapy in cancer patients with acute
respiratory failure. Intensive Care Med, 41(11): 2008-10.
Admission to ICU does not necessarily imply taking all necessary
measures for as long as possible. We must take into account a wide Conflict of interest Mokart D, Lambert J, Schnell D et al. (2013) Delayed intensive care unit admission is associated with
increased mortality in patients with cancer with acute respiratory failure. Leuk Lymphoma, 54:1 724–9.
range of possibilities. We can admit patients with the intention of Isidro Prieto del Portillo declares that he has no conflict of interest. For full references, please email editorial@[Link] or visit https://
giving unrestricted treatment for at least five days and reassess it Ignacio Sáez de la Fuente declares that he has no conflict of interest. [Link]/o29

Ignacio Pujol Varela declares that he has no conflict of interest.

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What should we stop doing in the ICU?

In this article, I highlight that the most important thing intensive care physicians should stop doing is ignoring that they are prone to several cognitive
biases. I will first support my statement by looking for conceptual caveats and cognitive bias in routine intensive care unit (ICU) care, and then move to
specific patient and structural problems.

I ntensive care is an interesting specialty. From all the early

excitement in the 1970s, passing through two decades of
intensive physiological use at the bedside, intensive care
for critically ill patients, worsening
the performance of important acute
decisions and making physicians less
Elevation in routine
CRP levels Attentional bias
“We should always be
suspicious for infection”
Tracheal aspirate
negative
“Well, it is not 100%
sensitive”
Anchoring
Conservatism bias
©For personal and private use only. Reproduction must be permitted by the copyright holder. Email to copyright@[Link].

“There must be an
Default
landed on the rough ground of modern randomised controlled prone to notice their own mistakes. infection somewhere”
Confirmation bias 14-day course of
antibiotics
effect
“There must be
trials (RCTs) in the late 1990s and early 2000s. The increasing Biased x-ray interpretation: infection somewhere” “It is our local
practice. I wrote the
As the heart might be responsible “Something is different in
number of critically ill patients coupled with new monitoring right lower lobe. Can't find Information anxiety
VAP protocol myself!” IKEA
effect
for generating its own afterload, yesterday´s x-ray on EMR, “Why can´t I find the
devices and important funding both from governmental but I am pretty sure” x-ray? I need to know
there is something!”
if

intensivists are also partially responsible

and private agencies (including pharmaceutical companies) Nurse/RT
Antibiotics suspended
for generating their own information “If the question was
on day 3 by other
fostered research. In the early 2000s, the panorama looked Asks nurse/RT:
posed that way, some-
physician aſter
discussion with
overload. Examples include excessive thing must be wrong. Fundamental infection control
promising, with positive trials coming out on a frenetic basis “Secretions are more
abundant today, right?”
Indeed, there was a attribution error
use of haemodynamic monitoring in little more sputum

(Bernard 2001; Rivers 2001). Regrettably, the initial enthusiasm today”

Patient worsens
otherwise stable patients, pleiads of three days latter
Fernando G. Zampieri was followed by a wave of negative results (Ranieri 2012; Outcome
routine laboratory and imaging tests Increase in CRP bias
Research Institute PRISM Investigators 2017). Many interventions that seemed Positive x-ray
More secretions “Glad I acted fast!” Self-serving bias
HCor-Hospital do Coração and inputs from several colleagues and VAP!
promising in the early 2000s were sequentially disproved Collect culture
“I told them not to do
it. Seen this happen so
Negativity
São Paulo, Brazil healthcare workers (Manor-Shulman Gives antibiotics many times!”
bias
or proved to be harmful, which has been the basis for the
2008). In the eagerness of having
fgzampieri@[Link] rationale of limiting excesses of interventions and treatments CRP the day before
drops
Illusory
a quick diagnosis and treatment, correlation
in the critically ill, the so-called “doing less” (Singer 2006). Figure 1. Spurious elevation in CRP levels in a stable patient on mechanical ventilation
@f_g_zampieri intensivists generate data that will only
CRP C-reactive protein EMR electronic medical record RT respiratory therapist VAP ventilator-associated pneumonia
aggravate the problem. Coupled with
What are the conceptual caveats in routine ICU the increasing difficulty in accessing
care we should stop doing? laboratory finding and somehow slack his fear of negligence.
patient´s data due to poorly designed electronic health records,
Secure physicians would probably ignore (or would not even
This section could be summarised in one sentence: Obtain less this creates an intensivist that has both information overload
have ordered) CRP levels and would choose a “wait-and-see”
(not more) data and reduce treatment exposure considering and information anxiety; that is, an individual exposed to too
approach (Hranjec 2012). However, some physicians would
it part of the disease and not of the healing process. Do so much data and that has trouble trying to access it (even the
embark on a destructive cycle of cognitive bias aiming at
because we are all prone to cognitive bias. parts that indeed matter!). This results in a nightmare that is
confirming their hypothesis. A similar scenario is conceivable
well known by most of us. A vignette is shown in Figure 1.
The first part of the sentence brings a concept that is well- for an apparently stable patient, who presents with an elevated
known to experts in behavioural science: information overload In the left part of this example, a series of types of lactate level, low central venous oxygen saturation etc. The
(Bawden 2008). Excessive information is known to reduce cognitive bias occurred, triggered by a spurious elevation in problem, therefore, is the attempt to contextualise excessive
accuracy and increase confidence in the decision-making process C-reactive protein (CRP) levels that were routinely collected. information inside an otherwise unremarkable situation.
(Hall 2007). This association can have disastrous consequences Due to concerns of an untreated infection, the physician tries
It may be stated that simply collecting less data is a childish
to find something that suits his/her keenness to explain the

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Table 1

Practice Comment Cognitive bias involved Suggestion Reference

ICU STRUCTURE
New ICUs should be designed to improve patients and staff wellbeing. This
ICUs built in improvised spaces with old-fashioned There is no place for old-fashioned windowless ballroom ICUs
Conservatism; default effect. includes windows, places to interact with staff (cafeterias), proper resting rooms, Caruso 2014; Mroczek 2005
architecture in modern practice. Natural light deprivation is a real issue.
family meeting rooms, etc.
Keep families outside the ICU Family engagement may reduce delirium and improve outcomes. Conservatism; default effect; hostile attribution bias. Adopt liberal visitation policy while coping with staff´s own demand for privacy. Soares 2017

There are few plausible reasons to keep pets outside the ICU.
Keep pets outside the ICU Conservatism; default effect; “not invented here” bias. Adopt a more liberal pet visitation policy in ICUs. Hosey 2018
There are many potential benefits for patients and staff.

Burnout is endemic in practitioners. Ignoring staff burnout can Recognise the problem. Attempt to treat burnout as an organisational problem
Ignore staff´s own health Identifiable victim effect; Ostrich effect. Ricou 2018
harm staff and patients. and not an individual issue.
DAILY CARE
©For personal and private use only. Reproduction must be permitted by the copyright holder. Email to copyright@[Link].

Increases radiation exposure. May worsen several biases due Switch to on-demand methods such as ultrasound (if available) or more selec-
Daily chest x-rays Conservatism; default effect. Resnick 2017
to poor method sensitivity/specificity. tive x-ray prescription.

May produce noise without clear benefit. May increase need

Daily full set of exams Conservatism; default effect; bandwagon effect. Adopt a minimal daily set of tests; add tests as indicated. Zimmerman 1997
for transfusions.
May be useful for Gram-positive bacteria but data lacking for
Widespread contact precautions multidrug-resistant Gram-negative. Widespread use can increase Conservatism; default effect; continued influence effect. Join randomised controlled trials on contact precautions. Consider local study. Furuya 2018
adverse events at patient level.
Aggressive antibiotic use after infection suspicions For stable ICU patients, a wait-and-see approach may result Conservatism; default effect; continued influence effect;
Adopt more conservative triggers to start antibiotics in stable patients. Melsen 2013
in stable patients in better outcomes than an aggressive strategy. Semmelweis reflex.

Shorter courses of antibiotics are probably safe, reduce costs Conservatism; default effect; Bandwagon effect; Semmel-
Long pre-established courses of antibiotics Consider strategies to reduce length of antibiotic courses. Klompas 2017; Sawyer 2015
and antibiotic exposure. weis reflex.

Alveolar recruitment for ARDS Increased mortality in large RCT. “Not invented here” bias; Semmelweis reflex. Apply evidence as it stands. Cavalcanti 2017

Aggressive hypothermia protocols Failed to improve outcomes in most scenarios. Semmelweis reflex. Consider switching to normothermia protocols. Shaefi 2016

Associated with more adverse events, no benefit for clear

Aggressive glycaemic control protocols Semmelweis reflex. Adopt more liberal glycaemic control. Finfer 2009
majority of patients.

While no clear harm can be attributed, it may derive attention

Early aggressive nutrition protocols Semmelweis reflex. Adopt timely introduction of nutrition to the most severely ill patients. Casaer 2011
from more pressing problems.

Proton pump inhibitors prophylaxis for upper

May not be useful and may increase complications. Conservatism; Semmelweis reflex. Probably not necessary. Large RCT recently completed. Krag 2016
gastrointestinal bleeding

Large bulk of evidence suggesting it may increase costs due to Focus on early diagnosis and source control in septic patients (preferably
Early goal therapy for sepsis Semmelweis reflex. PRISM Investigators 2017
more ICU admissions without clear mortality benefit. outside the ICU).
Use fluid bolus to treat every conceivable abnormal- Law of the instrument (“Give a small boy a hammer, and
Fluid creep is a major issue. Fluids should be considered drugs Reduce fluid creep starting with maintenance fluids and reducing unnecessary
ity (oliguria, hypotension, tachycardia, reduction he will find that everything he encounters needs pound- Van Regenmortel 2018
with very low therapeutic range. dilutions. Adopt early negative fluid balance whenever possible.
in consciousness levels, etc.) ing”, Maslow 1966); conservatism; Semmelweis reflex.
Physiology can be bent to fit one´s desire for adequacy. There is no
Attempt to correct physiological abnormalities Conservatism; default effect; continued influence effect. Aim for physiological targets only in the absence of hard evidence. Reade 2009; 2013
single or correct physiological parameter in critically ill patients.

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suggestion and that all efforts should be made to use more data to The right side of the figure continues with a well-known sequence Paul Kriwaczek stated, ancient Eridu habitants were impatient with
improve treatment. I beg to disagree. A probabilistic interpretation of cognitive biases that preclude proper patient management. The what was old and receptive to the new (Kriwaczek 2012). Intensive
of data is well suited in complex scenarios when we are accustomed physician becomes emotionally tied to the diagnosis, knotted to care should remember its roots but allow the new to be built upon
to information (this applies to most Bayesian inference done in the VAP protocol he wrote for the ICU (the “IKEA effect”, Norton its ground.
medicine); however, when data is new, time is short, and a decision 2012) and will fail to see evidence contrary to his hypothesis. If
is crucial, approaches that minimise choices based on less data may antibiotics are withdrawn in the next days by other physician and the
outperform complex models (Hardman 2003). This applies to many patient eventually worsens, this will only further close the book on
busy strained ICUs around the world. cognitive bias. While I used VAP for this example, the reader might
find it suitable for many haemodynamic interventions (including the
Now let´s move to the right part of Figure 1. Damage has been
fluid bolus-diuretics conundrum, cardiac output measurements, etc).
done and our patient with a spurious irrelevant CRP elevation now has Abbreviations
©For personal and private use only. Reproduction must be permitted by the copyright holder. Email to copyright@[Link].

a ventilator-associated pneumonia (VAP) diagnosis. VAP has a doubtful CRP C-reactive protein

attributable mortality but appears to be associated with prolonged Moving to the patient level ICU intensive care unit
mechanical ventilation and, obviously, higher costs (Melsen 2013). After the vignette, I hope that the reader considers that a more VAP ventilator-associated pneumonia
A VAP diagnosis leads to serious developments, such as antibiotic pragmatic approach to intensive care may be desirable. The cornerstone
exposure, family distress (“Now, above all, he has a pneumonia!”) and is transposing one of the Orwellian rules of writing to the ICU: “If
even administrative issues (billing and benchmarking). Cognitive bias it is possible to cut a word out, always cut it out” (Orwell 2013).
will not stop there. Despite evidence that guiding antibiotic time using Let´s replace “word” for “treatment” or “practice” and see what we References
CRP and/or procalcitonin levels are appropriate (de Jong 2016), the can do. Examples are shown in Table 1. Bawden D, Robinson L (2008) The dark side of information: overload, anxiety and other paradoxes
physician may now choose to embrace a conservative approach and and pathologies. J Inf Sci, 35(2): 180-91.

apply a whole two-week course of antibiotics (the default effect). For each intervention, procedure and treatment shown in Bernard GR, Vincent JL, Laterre PF et al; Recombinant human protein C Worldwide Evaluation in
Table 1, one cognitive bias will have to be overthrown. This is not Severe Sepsis (PROWESS) study group (2001) Efficacy and safety of recombinant human activated
The same physician that relied on CRP to diagnose VAP is now shaky protein C for severe sepsis. N Engl J Med, 344(10): 699-709.
to stop antibiotics when CRP drops. However, if CRP dares to rise an easy process, since most of the teaching in medicine is indeed
Caruso P, Guardian L, Tiengo T et al. (2014) ICU architectural design affects the delirium prevalence:
again in the following 48 hours, it is inevitable that concerns about based on passing bias and abstract concepts from generation to a comparison between single-bed and multibed rooms. Crit Care Med, 42(10): 2204-10.

“treatment failure” will arise and the circle of overtreatment will generation. It is commonplace to hear that we should aim to keep a Casaer MP, Mesotten D, Hermans G et al. (2011) Early versus late parenteral nutrition in critically ill
adults. N Engl J Med, 365(6): 506-17.
prevail. If physicians would consider that treatment is part of the patient “normovolaemic”, “well-nourished”, etc., while it remains
de Jong E, van Oers JA, Beishuizen A et al. (2016) Efficacy and safety of procalcitonin guidance in
disease and not an indissociable part of recovery, maybe the pros and underappreciated that these terms are closer to a linguistic trick reducing the duration of antibiotic treatment in critically ill patients: a randomised, controlled, open-
cons would favour the first. In fact, using our infection vignette as than to a medical practice. The first step to embrace a modern ICU label trial. Lancet Infect Dis, 16(7): 819-27.

an example, it is estimated that up to 20% of all patients receiving is understanding that much of what we did and believed was part Furuya EY, Cohen B, Jia H et al. (2018) Long-term impact of universal contact precautions on rates
of multidrug-resistant organisms in ICUs: a comparative effectiveness study. Infect Control Hosp
antibiotics will develop a serious adverse reaction (Tamma 2017). of habit and not science. This is the very reason why conservatism, Epidemiol, 39(5): 534-40.

Maybe net benefit would be negative in our vignette? Semmelweis reflex (Leary and Wilson 1991) and default effect are Hall CC, Ariss L, Todorov A (2007) The illusion of knowledge: when more information reduces accu-
racy and increases confidence. Organ Behav Hum Decis Process, 103(2): 277-90.
the most frequent cognitive bias shown in Table 1.
“in the eagerness of having a quick diagnosis In the dawn of civilization in ancient Eridu, architects were
Hosey MM, Jaskulski J, Wegener ST et al. (2018) Animal-assisted intervention in the ICU: a tool for
humanization. Crit Care, 22(1): 22.

and treatment, intensivists generate data more interested in rebuilding structures from scratch than preserving For full references, please email editorial@[Link] or visit [Link]

previous buildings. The Eridu fortress was rebuilt eleven times. As

that will only aggravate the problem”

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Caring for very old patients in the ICU

Describes the epidemiology and outcomes for very old patients as known in 2018, along with a short introduction to the most relevant “geriatric syn-
dromes” important also for intensivists, and discusses where we should increase our body of knowledge to make a more precise triage in this patient
group.

T he very old ICU patient is a term often used for

those patients aged ≥ 80 years. This group of patients
constitutes 10-15% of today’s ICU patients in Europe,
elderly population is increasing in European countries as
well as in the rest of the world, but very few studies adjust
the increase in elderly ICU admission to the increase in
syndromes, particularly frailty, have also been used to
describe ICU cohorts.
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and is expected to rise in absolute and relative terms in the general population. This was recently done in Scotland Frailty
parallel with the increase of life span in our countries. If where they in fact found the admission rates among the
we continue to have the same policy towards treatment of elderly (≥80) to decrease over time from around 37/105 With frailty, we understand the gradual decline in various
the critically ill very old for the coming 25 years, we may in 2005 to 29/105 in 2009, a reduction of 22%! (Docherty body functions that occurs with age, and manifests itself
well see a doubling of this patient group. Even today there et al. 2016) They speculate whether this reduction can be as diminished reserves during stress. It is important to
is an ongoing discussion about who to treat, when and rationing based on chronological age, selecting less morbid underline two important facts with frailty:
where to treat these patients, and arguments span from elderly patients, but no data was revealed to support this
1. Frailty does not always parallel chronological age;
Hans Flaatten not to consider age at all, to question the admittance of the assumption.
hence we can find frailty in ICU patients not considered
Professor very old in general. Most researchers and clinicians argue
to be aged, and we can find patients with a high
Faculty of Medicine there must be a middle way, allowing for active treatment Outcomes
University of Bergen chronological age without being frail.
Bergen, Norway
in selected patients, while on the other hand reducing the
treatment intensity, maybe to comfort and care, in others. Several studies about short- and long-term mortality in 2. Frailty is not a disease, and must be separated from
ICU Management & Practice very old ICU patients have been published over the last such, although the border between frailty and disease
Editorial Board Member The problem is obvious: how to select those that will 15 years. Lately also some large prospective multicentre is sometimes difficult to define.
profit from intensive care from those that most certainly studies have been performed, mainly to determine survival,
[Link]@[Link]
will not? This is of course a generic challenge intensive care but also quality of life (QOL). Table 1 summarises results Typical frailty symptoms may include (but are not
has had for decades, and we hoped the traditional severity from three such recent studies showing that 25-35% of the restricted to):
scoring systems could offer us help. However, these systems very old die within a month. In the Canadian study, also
have not been found accurate enough to guide decisions at • Slow walking speed
QOL of one-year survivors was studied, indicating that
the individual patient level, although they may perform well approximately 50% of the patients that survived to one • Reduced activity level
on a group level. They have also been found to perform less year (≈50%) had significantly reduced QOL.
well in ICU-subpopulations, like in the very old (Minne • Exhaustion
et al. 2011).
Geriatric syndromes • Decreased muscle mass and strength

Epidemiology Geriatric medicine has for decades used a “battery” of • Unintentional weight loss
age-related assessments found to be very relevant with There are several methods to identify frailty. Such
We are not sure if the absolute increase of patients ≥ 80 advancing age. For some time, many of these assessments
years we observe in many ICUs really is parallel with the also have found use outside traditional geriatric medicine, assessment is usually based on one of two different assessment
increase in the elderly population per se. We know the in particular for surgical procedures. Lately some of these methods: Fried criteria and Rockwood methods. The former

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is often called frailty phenotype, and the latter frailty index. The In intensive care these methods to document sarcopaenia are MCI) or other thinking skills, known as “non-amnestic MCI”. A
phenotype is based on a pre-defined set of criteria (categorical difficult, since both gait speed and handgrip strength require awake detailed mapping of cognitive function takes time and requires
variables), while the frailty index is a result of a clinical evaluation and cooperative patients. However, it may have a role at discharge a cooperative patient. There are quick methods like mini-mental
using continuous variables and a more unspecified set of criteria and post-ICU follow-up. Since sarcopaenia at admission adds to state examinations that are often used to screen for dementia, but
(Cessari et al. 2014). Since both methods have clinical disadvantages, ICU-acquired loss of muscle mass (inactivity and stress-mediated these also require awake patients. However, a simple questionnaire
particularly in the acute care setting, a new clinical frailty scale catabolism) the net result may be detrimental for the very old designed to ask close relatives about their next-of-kin’s mental
(CFS) was developed in Canada in the second part of the large with regards to post-ICU rehabilitation. Hence methods to prevent state is available and can be used also in emergency settings. It is
Canadian study of health and ageing (Rockwood et al. 2005). further muscle mass in critically ill sarcopaenia patients are vital. called IQCODE: the informant questionnaire on cognitive decline
The last version of CFS includes a 9-scale partly visual and partly in the elderly (Jorm et al. 1989). Here an informant who knows
descriptive scale and has gained popularity in situations where the patient well is asked a series of questions about mental state,
patients are unable to participate. Several large prospective studies “frailty was found to be an important and and compares present status (before the illness) with 10 years ago.
©For personal and private use only. Reproduction must be permitted by the copyright holder. Email to copyright@[Link].

have been conducted in recent years using the CFS, showing very independent factor for 30-day mortality” Although not as sensitive as direct examination of the patient, it is
good correlation between frailty and outcomes in the very old a quick screening tool and may have relevance for rehabilitation
population of critically ill patients. In the large Very Old Intensive and cooperation with the patients while in the ICU.
Recently, studies using ultrasound measurement to diagnose
Care Patient: A Multinational Prospective Observation Study (VIP1)
sarcopaenia have been published and may provide a fast, noninvasive
study of more than 5000 elderly ICU patients in Europe, frailty Immunosenescence
method to document muscle mass at admission that can find its
was found to be an important and independent factor for 30-day
way into initial assessment of elderly ICU patients. Our immune system is affected by age. Immune cells are continuously
mortality, with a near linear relation between increasing frailty
and mortality (Flaatten et al. 2017). renewed from stem cells. Both the proliferative capacity and the
Cognitive decline number of these immune cells are decreased due to progressive
telomere shortening, resulting in an immune dysfunction over
Sarcopaenia Age-related cognitive decline is understood as a normal (non-disease
the years, which is called immunosenescence. This may explain
related) ageing of cognitive functions. It does not affect all elderly
Sarcopaenia is the specific name for muscle wasting in the elderly. the increased susceptibility in elderly people to acquire infections,
people, but mild cognitive impairment (MCI) is a frequent
It is an important cause of functional decline and is interwoven clearly demonstrated with the markedly increased incidence of
finding in the elderly and has been found in 15-20% of people
with frailty. Occurrence of sarcopaenia is very common. It is found sepsis in the elderly population. Unfortunately, tests for immune
aged 65 and above. It may affect primarily memory (amnestic
in 11-50% of elderly people > 80 years and is associated with a function are at present not fully developed, and we lack a quick
negative outcome in a variety of studies. There are multiple causes and reliable method to identify patients at risk.
of sarcopaenia, and inactivity is probably the most important one, Table 1. Results of three large prospective multicentre studies in the very old ≥80 years
although malnutrition and inflammation also may play a role.
Commonly it can be diagnosed using imaging techniques like Years Number Number countries ICU One-month 6-month
MRI, CT and ultrasound, but more often simpler methods like gait Author
conducted pts (ICUs) mortality mortality mortality
speed and muscle strength in the arms are used as screening tools.
The European Working Group on Sarcopenia in Older People has Heyland et al. 2015 2009-13 1671 1 (24) 22 % 35 %
published clinical guidelines and consensus criteria for age-related
sarcopaenia (Cruz-Jentoft et al. 2010). Here gait speed < 1 m/s Flaatten et al. 2017 2016-17 5021 21 (311) 22.1% 32.6%
in a 6-metre course and handgrip strength < 30 kg in men and
< 20 in women may indicate sarcopaenia. Guidet et al. 2017 2012-15 3037 1 (24) 25.6% 41.9

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Specific ICU care for the elderly What more do we need to know?
Studies have repeatedly shown that the elderly patient is given less There are more questions than answers with regards to very old Abbreviations
active treatments compared with their younger counterparts. The ICU patients. First and foremost, we need better prediction ability CFS clinical frailty scale
reasons for this are not clear, but may imply therapeutic nihilism. to identify elderly patients that most probably will profit from ICU intensive care unit
This is of course unfortunate, since when admitted, all patients ICU admittance, and those that probably will not. We know the MCI mild cognitive impairment
should be given appropriate care until a decision of limitation one-month mortality after intensive care is about 40% after acute QOL quality of life
eventually is chosen. The potential to involve a geriatrician in the admissions, and to identify most of them before ICU admittance
ICU team is also attractive. Elderly patients usually come with a should be given high priority. Not only is this important for our
lot of “baggage”: co-morbidity and associated drug therapies. A societies with an increasing shortage of ICU beds, but primarily
study from nursing homes (Barber et al. 2009) revealed that on for the patients and caregivers. An ICU admission is a burden for
©For personal and private use only. Reproduction must be permitted by the copyright holder. Email to copyright@[Link].

average the residents used 8 different medications daily. Not all all, and should probably not be offered if most lights alert red.
of them are necessary, and some may be potentially harmful in The search for prediction systems with a very high sensitivity and
the ICU setting. To help sort this out a geriatrician can be of help. specificity may prove to be impossible. Still, we must continue to
Geriatric competence may also be helpful in working out the best investigate this in depth, and in particular to include information
plan for rehabilitation in very old ICU survivors. from “geriatric” syndromes as specified above. The message from
using frailty assessment at admission is promising. Again, in the References
“the potential to involve a geriatrician VIP1 study we found frailty to be the best individual predictor of Barber ND, Alldred DP, Raynor DK et al. (2009) Care homes’ use of medicines study: prevalence,
causes and potential harm of medication errors in care homes for older people. Qual Saf Health
30-day mortality, even better than the Sequential Organ Failure Care, 18(5): 341–6.
in the ICU team is also attractive” Assessment (SOFA) score at admission (Flaatten et al. 2017). It is Cesari M, Gambassi G, van Kan GA et al. (2014)The frailty phenotype and the frailty index: different
instruments for different purposes. Age Ageing, 43: 10–12.
possible that a combination of the geriatric syndromes alone or
The response to ICU therapy is important and should be Cruz-Jentoft A, Baeyens JP, Bauer JM et al. (2010) Sarcopenia: European consensus on defini-
with other selected markers can give us a useful prognostic score, tion and diagnosis. Report of the European Working Group on Sarcopenia in Older People. Age
evaluated as soon as possible after admission. For this daily organ Ageing, 39(4): 412–23.
to be helpful in the pre-ICU triage process. The only way to find
failure assessment is important, and responders should show Docherty AB, Anderson NH, Walsh TS et al. (2016) Equity of access to critical care among elderly
out is through large prospective studies testing the power of these
improved function within some days. If this does not occur or patients in Scotland: a national cohort study. Crit Care Med, 44: 3–13.
new markers to predict outcomes.
failure increases, most would then consider further ICU treatment Flaatten H, de Lange DW, Morandi A et al. (2017) The impact of frailty on ICU and 30-day mortality
and the level of care in very elderly patients (≥ 80 years). Intensive Care Med, 43: 1820–8.
questionable. Withholding or withdrawal of care should be considered Today we have simple and robust methods to map frailty,
Guidet B, Leblanc G, Simon T et al. (2017) Effect of systematic intensive care unit triage on long-
and discussed with caregivers or family. Many of the patients sarcopaenia and cognition before ICU admission. Hopefully also term mortality among critically ill elderly patients in France: a randomized clinical trial. JAMA,
318: 1450–9.
would then be offered comfort and care instead of intensive care. immunosenescence will be possible to assess in a simple way in
Heyland DK, Garland A, Bagshaw SM et al. (2015) Recovery after critical illness in patients aged
the near future. 80 years or older: a multi-center prospective observational cohort study. Intensive Care Med, 41:
Delirium is frequent in the very old, and is the rule more often 1911–20.
than not. Hence the ICU should be prepared, and avoid known Conflict of interest Jorm A, Jacomb PA (1989) The Informant Questionnaire on Cognitive Decline in the Elderly
factors that increase delirium: heavy sedation, particularly use (IQCODE): socio-demographic correlates, reliability, validity and some norms Psychol Med, 19:

of benzodiazepines; ensuring sleep at night and that patients are Hans Flaatten declares that he has no conflict of interest. 1015-22.

Minne L, Ludikhuize J, de Jonge E et al. Prognostic models for predicting mortality in elderly ICU
awake and mobilised at daytime, even if still on a ventilator, are patients: a systematic review. Intensive Care Med, 37: 1258–68.
also important factors. Further muscle wasting and malnutrition Rockwood K, Song X, MacKnight Cet al. A global clinical measure of fitness and frailty in elderly
should also be focused on. people. (2005) CMAJ, 173, 489–95.

Ticinesi A, Meschi T, Narici MV et al. (2017) Muscle ultrasound and sarcopenia in older indi-
viduals: a clinical perspective. J Am Med Dir Assoc, 18(4): 290-300.

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The sepsis box, bag and trolley

Evaluation of aids to the delivery of sepsis treatment
In NHS Wales the Sepsis 6 bundle, delivered within one hour of sepsis recognition, has been standard treatment in acute hospital settings since 2013. We
describe various methods for increasing the speed and effectiveness of Sepsis 6 bundle delivery that have been trialled with positive outcomes.

S epsis is defined as a “life-threatening organ dysfunction

caused by a dysregulated host response to infection” (Singer
An important component in this achievement has been
enabling clinicians to rapidly recognise sepsis and treat using
In NHS Wales the Sepsis 6 bundle, delivered within one
hour of sepsis recognition, has been the accepted and standard
©For personal and private use only. Reproduction must be permitted by the copyright holder. Email to copyright@[Link].

et al. 2016) and is estimated by the UK Sepsis Trust to the ‘Sepsis 6’ care bundle. treatment for sepsis in all acute hospital settings since 2013.
cause the deaths of at least 44,000 people in the UK annually. Percentage compliance with delivery of the bundle is measured
The Sepsis 6 bundle within all Health Boards as a key quality improvement metric.
Scaling the findings of a large meta-analysis (Fleischmann
Chris Hancock
Acute Deterioration et al. 2016) for relative population size gives an incidence in The original Surviving Sepsis Campaign Guidelines (Dellinger An important function of the RRAILS programme has been
Programme Lead Wales of between 8000-13,000 cases of sepsis per annum with 2008) and subsequent revisions have focused on the delivery to support clinicians in testing various methods for increasing
Public Health Wales
Cardiff, UK
an associated mortality of between 2200-2300. of evidence-based, time-limited ‘care bundles’ at various the speed and effectiveness of Sepsis 6 bundle delivery. These
points in the patient pathway, including within 1-, 3-, 6- and have included the sepsis bag, sepsis box and sepsis trolley.
Christopher.Hancock2@wales. These estimates accord with both extrapolation from an
[Link]
inspection of UK critical care data (Daniels 2011a) and a 24-hour time frames. Description and evaluation of such tools is not well developed
retrospective review of mortality within one Welsh hospital UK healthcare has generally chosen to adopt the ‘Sepsis 6’ in the literature. One large-scale literature review of the crash cart
(Robinson 2013). The latter study estimated sepsis to be care bundle, which was first devised by Ron Daniels of the /resuscitation trolley reported little information or uniformity
responsible for approximately 15% of hospital deaths. UK Sepsis Trust and the delivery of which, within a one-hour in the range of equipment, instructions for use or evaluation
timeframe, has been shown to be associated with improved of effectiveness (Jacquet et al 2018).
The size of sepsis in Wales study (Szakmany et al. 2016)
found a prevalence of sepsis and severe sepsis in Welsh acute patient outcomes (Daniels et al. 2011b; NCEPOD 2015) Kafle and Nath (2014) report improvements in outcomes for
hospitals of 5.5% with associated mortality at 90 days of 31%. The six elements of the bundle are: patients treated with a range of sepsis interventions including
a sepsis box but in the context of a small sample size (n=30).
In NHS Wales the aim to reduce avoidable harm and mortality 1. Give O2 to keep sats above 94%
caused by sepsis has been a tier one Welsh Government target
since 2013, and all Health Boards and Trusts have participated 2. Take blood cultures The sepsis bag
in the national Rapid Response to Acute Illness (RRAILS) Working with 1000 Lives Improvement Service, the Critical
3. Give IV antibiotics
Andrew Hermon programme since 2011. Care Outreach Team (CCOT) at the Royal Glamorgan Hospital,
Senior Nurse for Critical Care 4. Give a fluid challenge Cwm Taf University Health Board, introduced a sepsis response
Cwm Taf University Health Board During the time that this programme has enabled clinicians
TOWN to identify and treat sepsis more quickly there has been a 5. Measure lactate bag in 2012. The bag contained the six elements of the Sepsis
reduction in the numbers of deaths associated with two sepsis 6 care bundle with the exception of antibiotics.
[Link]@[Link]
ICD10 codes. NHS Wales was the winner of a Global Sepsis 6. Measure urine output
The bag was evaluated by analysis of the National Early
Award in 2015 (Hancock and Watkins 2017). Warning Scores (NEWS) of eighty patients pre- and post

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12

Service and Cwm Taf University Health Board approached an industry The staff survey revealed that the single-use sepsis box was generally
10 partner to collaborate in developing and testing a solution. positively regarded and was favourably associated with the delivery
of the Sepsis 6 care bundle by ward staff.
8
The sepsis box study
Outcomes
6
The disposable single-use box that was collaboratively developed as
a result contained all the elements to deliver the Sepsis 6 apart from Quantitatively, positive patient outcomes were associated with use
4
antibiotics. Each element was contained within a separate, sealed of the single-use sepsis box. The results from the trial indicated a
2 compartment with a perforated cardboard ‘door’ modelled on the significant drop in average NEWS score at 24 hours and an inferred
idea of the advent calendar. better patient outcome from use of the box (Figure 2). Of the 114
0
patients, the mean NEWS score at the point of Sepsis recognition was
©For personal and private use only. Reproduction must be permitted by the copyright holder. Email to copyright@[Link].

NEWS at initiation of Sepsis Six NEWS 24 hours after Sepsis Six

The box also contained all the documentation necessary for recording 7.66 indicating a high acuity and a strong mortality prediction whilst
Figure 1. National Early Warning Scores (NEWS) pre- and post receiving treatment using the sepsis bag (n=80) delivery of the Sepsis 6 bundle as well as a copy of the Health Board the mean NEWS score at 24 hours post treatment was 3.89.
antibiotic formulary.
Of the 114 patients who received treatment in total with the
receiving treatment using the bag. This analysis showed a statistically The study took place between May 2016 and April 2017 with a box, at 24 hours:
significant reduction of NEWS at 24 hours of treatment using the box being placed in all clinical areas, excluding the intensive care
unit (ICU) and emergency department (ED), at two district general • 10 (9%) patients were admitted to Critical Care, of which
sepsis bag with the largest reduction being -8 (Figure 1).
hospitals within Cwm Taf University Health Board. As boxes were • 1 (1%) patient died
The sepsis response bags were found to be favourably associated used they were replaced by the Critical Care Outreach Team who also
with the delivery of the Sepsis 6 and the reduction in NEWS was performed the role of data collectors. A data entry clerk transferred data • 104 (91%) remained on the ward and improved.
accepted as inferring a better patient outcome. to a purpose-built database and the results were analysed by both the
1000 Lives Improvement Service and Cwm Taf University Health Board. Use of the box by ward nursing staff
However, evaluation of the sepsis bags highlighted several difficulties:
In addition to the outcomes associated with use of the sepsis bag During the trial, ward staff rather than the CCOT initiated treatment
• Infection prevention and control advice in the Welsh Government using the sepsis box on 28 (25%) occasions and of these 1 patient
this study also had the aims to:
was that the bags would be impossible to clean effectively was transferred to critical care with a NEWS of 12, and survived. Of
between patients. • Improve Sepsis 6 bundle compliance these 28 patients treated:
• The bags were not sealed and equipment could be and • Engage ward staff to initiate the Sepsis 6 care bundle • 1 patient had a NEWS of 12
was removed. This obviously had serious implications for
completeness of the kit when the bag came to be used again. • Prevent admissions to critical care. • 2 patients had a NEWS of 11; and

• Once the bag had been used it was difficult to get it replenished A staff survey was carried out concurrently to evaluate attitudes • 25 patients had a NEWS of 9.
immediately. to use of the sepsis box.

• The majority of the bags had been used by the CCOT and Results Discussion
not by medical or nursing staff in the ward areas, potentially The trial showed that initiation of the Sepsis 6 care bundle through
resulting in a delay in delivery of the Sepsis 6 bundle. Data was recorded for 114 patients who had been treated using the
use of the single-use Sepsis Box was linked to a significant drop in
sepsis box. Members of the Critical Care Outreach Team (CCOT), partly
In order to address these issues whilst maintaining the concept of average NEWS at 24 hours, and with significantly fewer patients being
due to an issue with the distribution of blood culture bottles to wards
the single adjunct for delivery of treatment the 1000 Lives Improvement referred to critical care than would normally be expected with such
during the trial period, initiated the majority of boxes.
high NEWS scores.
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MATRIX

NEWS at Screening and at 24 hours

16
The 25% of patients whose treatment was initiated by ward nursing also be aware of the dangers of confirmation bias and potential for
staff were all very sick with a NEWS of 9 or greater, which would inappropriate overtreatment with unnecessary antibiotics in patients 14

ordinarily be associated with an admission to critical care. Only one who do not have sepsis. 12

of these patients was admitted to critical care and survived. 10

Decision support
As the trial was not randomised, compared to a control group, and 8

had a small sample size, it is not possible to infer whether the positive The first consensus statement on medical emergency teams (METs) 6

outcomes are directly attributable to the unique features of the single (Devita et al. 2006) identifies the afferent and efferent arms of the
4
use sepsis box, or are simply associated with the utilisation of any rapid response system. The afferent part consists of the recognition
tool that drives the delivery of sepsis treatment in the clinical area. of acute deterioration and a trigger to action whilst the efferent part 2

consists of the response, usually by a team or individual with critical

©For personal and private use only. Reproduction must be permitted by the copyright holder. Email to copyright@[Link].

0
If the latter then it is possible that the use of a bag, box or trolley NEWS at Screening NEWS at 24 hours
care expertise.
influences a number of factors including reliability, error proofing, Figure 2. National Early Warning Score pre- and post- use of sepsis box (n=114)

decision support and ‘nudging’ behavioural change. Note: the horizontal line shows the Median rather than the Mean

“the use of a piece of equipment to focus

Reliability
delivery of sepsis treatment can have response but that the landscape of patient acuity is more nuanced.
Reliability of healthcare delivery is poor. McGlynn et al. (2003) found
the ‘defect rate’ in the delivery of healthcare to be 45% whilst Burnett positive outcomes for patients” In short, it is apparent that there is a considerable amount of decision-
et al. (2012) demonstrated reliability of care delivery at 80-90%, making taking place between the points of recognition and response to
This binary approach continues to be used to describe the rapid
noting that these rates would not be tolerated by any other industry. sepsis and that this process involves achieving reliable communication of
response system and is undoubtedly useful. However, it is possible
that it may be too simple a model to use when describing the actions a shared mental model and establishing situational awareness amongst
In promoting the idea of ‘Safety 2’ Hollnagel et al (2015) state that:
around the treatment of an acutely, although not critically ill person, teams of nursing and medical staff in the acute setting.
“Safety management should .... move from ensuring that ‘as few such as some with sepsis. It was evident during the study that the use of the sepsis box,
things as possible go wrong’ to ensuring that ‘as many things as
The National Confidential Enquiry into Patient Outcome and alongside a standardised care bundle and screening tool, enhanced
possible go right’”
Death (NCEPOD) report Time to Intervene (2012) identifies system decision-making and promoted escalation of care to appropriate levels.
In seeking to ensure that as many things as possible do go right, in failures not only in the recognition and response to the sick patient This can be seen from the large number of patients with a NEWS that
recent years clinicians have sought to learn lessons from other ‘safety but also in the escalation process of their care. The UK Department of would normally indicate an ICU admission, remaining on the ward
critical’ high-reliability organisations (HROs) (Weick and Sutcliffe Health publication Competencies for Recognising and Responding with a lower NEWS at 24 hours.
2007; Health Foundation 2011). to Acutely Ill Patients in Hospital (2009) identifies six possible roles
in the recognition, escalation and response process, only the last of Behavioural change
An important lesson is how to mitigate for human error, by utilising
a range of human factors principles, including ‘error proofing’ the which necessitates the possession of critical care skills on the part of The Health Foundation paper Behavioural Insights in Healthcare
system. Error proofing, or Poka Yoke as developed by the Toyota the responder. (Perry et al. 2015) identifies the provision of prompts and cues as
Production System, is intended to make it more difficult and to require The recent publication of a competency framework for caring for well as using default options such as care bundles, as important tools
more effort to do the ‘wrong’ thing and easier to do the correct action. Level 1 patients (National Outreach Forum and Critical Care Networks in delivering behaviour change. The Behavioural Insights team (BIT)
2018) is an acknowledgement of the fact that the hospital does not (Service et al. 2014) identify the acronym EAST™ (Easy Attractive,
The sepsis box, containing all required items and instructions
contain only the relatively well and those in need of a critical care Social and Timely) as descriptive of successful behavioural change.
to perform the task, fulfils these criteria well. However, we should

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MATRIX

The use of a focused prompt such as the sepsis box or trolley within Daniels R (2011b) Surviving the first hours in sepsis: getting the basics right (an [Link]/c/icu/issuearticle/reducing-avoidable-harm-and-death-
the context of a rapid response system satisfies the requirements for intensivist’s perspective). J Antimicrob Chemother, 66(Suppl. 2): ii11-23. from-sepsis-and-acute-kidney-injury

an easy, attractive, social and timely approach to behaviour change. Devita MA, Bellomo R, Hillman K et al. (2006). Findings of the first consensus Health Foundation (2011) Evidence scan: high reliability organisations. London: Health
conference on medical emergency teams. Crit Care Med, 34(9): 2463–78. Foundation. [Accessed: 25 June 2018] Available from [Link]/publication/
high-reliability-organisations
Conclusion Dellinger RP, Levy MM, Carlet JM et al. (2008) urviving Sepsis Campaign: International
guidelines for management of severe sepsis and septic shock: 2008. Intensive Hollnagel E, Wears RL, Braithwaite J et al. (2015) From safety-I to safety-II: a white
Whilst limited in both sample size and evaluative rigour this study Care Med, 34: 17-60. paper. The Resilient Health Care Net. Published simultaneously by the University of
does, nevertheless, appear to indicate that the use of a piece of Southern Denmark, University of Florida, USA, and Macquarie University, Australia.
equipment to focus delivery of sepsis treatment can have positive Fleischmann C, Scherag A, Adhikari NK et al. (2016) Assessment of global incidence [Accessed: 2 October 2017] Available from psnet. [Link]/resources/resource/29228
and mortality of hospital-treated sepsis. current estimates and limitations. Am J
outcomes for patients for a number of reasons. These may include
Respir Crit Care Med, 193(3): 259-72. For full references, please email editorial@[Link] or visit
design, effect on improving reliability, error proofing of the system, [Link]
©For personal and private use only. Reproduction must be permitted by the copyright holder. Email to copyright@[Link].

supporting decision-making in the sub-critical patient and in nudging Hancock C, Watkins A. (2017) Reducing avoidable harm and death from sepsis and
acute kidney injury. ICU Management and Practice, 17(4): 246-9. Available from
a change in clinical behaviour.

Since the completion of the sepsis box study, the decision has
been made by the commercial company on economic grounds, to
cease production. Whilst this is disappointing it is nevertheless worth
noting that a by-product of the trial and the interest shown in it is
that all hospitals in Wales now aspire to situate a sepsis bag, box or
trolley in all clinical areas.

Acknowledgements
We would like to acknowledge the hard work, ingenuity and
perseverance of Anne Evans and her colleagues at Rocialle and the
dedication of the CCOT teams and clinicians in Cwm Taf University
Health Board.

Conflict of interest
Chris Hancock declares that he has no conflict of interest. Andrew
Hermon declares that he has no conflict of interest.

References
Burnett S, Franklin BD, Moorthy K et al. (2012) How reliable are clinical systems
in the UK NHS? A study of seven NHS organisations. BMJ Qual Saf, 21: 466-72.

Daniels R, Nutbeam T, McNamara G et al. (2011a) The sepsis six and the severe
sepsis resuscitation bundle: a prospective observational cohort study. Emerg Med
J, 28: 507-12.

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MANAGEMENT

Humanizing the ICU experience with enhanced

communication
Avicenne ICU’s initiative
Decisions to limit therapy (DTLT) are routine for ICU physicians. Although breaking bad news is one of the most difficult tasks clinicians face, ongoing
communication is even more crucial as families (not necessary following a legal or genetic definition) of critically ill patients have heightened communication
©For personal and private use only. Reproduction must be permitted by the copyright holder. Email to copyright@[Link].

needs. Supporting families during the process of shared decision-making from the pursuit of cure/recovery to the pursuit of comfort/freedom of pain
is a key concern for our ICU. Communication, including announcements, but also listening to families requires time and training. As few physicians had
received formal training in how to deliver bad news, Avicenne ICU, with the help of a newly appointed psychologist, has developed specific training.

T he early years of critical care medicine were defined

by remarkable diagnosis and innovation, but were also
associated with substantial suffering for patients and
families, who were kept out of the units with strict visiting
policies. Professionals expressed major concerns that clinical
depression, and post-traumatic stress symptoms.
Intensive care is the ultimate symbol of state-of-the-art
medicine. Despite efforts and innovation, death remains an
outcome for 1 patient out of 4. About half of the deaths occur
•

•
Weakened families go through emotional roller coasters
because of anticipating the separation. Denial, psychic
sideration (freeze response) are frequently observed.
Breaking bad news is one of the most difficult tasks
after a decision to limit or withdraw life-sustaining treatment. that physicians face. They sometimes feel a sense of
care might be impeded and that family members might become
failure in their mission, prompting them to use various
too emotional and out of control, exacerbated by a lack of Being ethical is at the centre of all discussions, and in
coping methods such as avoidance, distancing or
availability of nurses to assist them. Communication was not France decisions are also regulated by law (Claeys-Leonetti law,
intellectualisation, keeping their distance to block their
a priority at that time, as physicians and nurses were focusing February 2016). Withdrawing life support is a shared decision-
own feelings.
on technical skills (remember that in the 1940s, polio patients making process that highlights the switch from a curative
Anne Rocher were ventilated by hand!) strategy to palliative care. Between distressed physicians and confused families, the
Psychologist whole tragic situation can become a source of conflict, especially
Avicenne ICU Meanwhile, ICUs still remain synonymous with hope. Withdrawing life support in ICUs may sound paradoxical
with a lack of or inadequate communication.
Hôpital Avicenne “Resuscitation” as a word feeds immortality fantasies and for clinicians who traditionally have seen their goals as curing
Bobigny, France
sometimes leads families to request unreasonable CPR or invasive disease and restoring health and function. These goals must When DTLT are made, technical skills become less essential,
[Link]@[Link] organ support for their loved ones. expand, when necessary, to also include assuring patients of but there is a risk of losing sight of the humanistic skills of
a ”good death.” medicine. It becomes even more important to stay with the
For some years, the presence of family members has been
patient, and to enhance communication with relatives. Listening
discussed. There is an increasing recognition of their important
role in the ICU, and high family-centred care should now be When the decision is made, the announcement is and explaining are keys to alleviate their anxiety and help them
a critical time for all actors enter the mourning phase.
considered a basic skill for ICU clinicians. Recommendations
include a more open visiting policy, and family conferences to The announcement of a decision to limit therapy crystallises
promote ongoing communication and trust between family communication issues and puts a strain on each protagonist’s Enhance communication to improve relationships:
members and clinicians and thus lower the risks of anxiety, coping mechanism: our programme

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MANAGEMENT

The appointment of a new psychologist in our ICU has been an occasion Although it is endless work, the “hospitality label” of our unit will In the ICU, the psychologist is a bridge between worlds, his/her
to step back and focus even more on high family-centred care with the ultimately highlight the human and highly emotional work, realised in role is to facilitate the work of all actors and help each one find his/
objective of humanizing the ICU experience for all. the shadows every day by our physicians, care assistants and nurses who her role when facing end of life.
address the needs of families with bereavement counselling.
We noticed that communication could be improved with benefits Taking care of the soul as we take care of the body requires taking
both for families and doctors. Taking into account that few physicians into account the psychological and relational dimension as well as the
had received formal training on this matter, despite its crucial role Psychologist in intensive care medical technique. Speech and oxygen are both essential to life.
today, we decided to develop our own training sessions focusing on As a non-medical third party, the psychologist can help to foster another
breaking bad news. References
type of speech, around patients. He/she can be in turn a partner of the
Gerritsen RT, Hartog CS, Curtis JR (2017) New developments in the provision of family-centered care
The programme has been developed jointly by a doctor (Guillaume announcement, a facilitator, an interpreter between different psychic in the intensive care unit. Intensive Care Med, 43(4): 550-3.

Van der Meersch) and the psychologist (Anne Rocher) with real cases. realities, and even sometimes a mediator.
©For personal and private use only. Reproduction must be permitted by the copyright holder. Email to copyright@[Link].

Scheunemann LP, McDevitt M, Carson SS et al. (2011) Randomized, controlled trials of interventions
to improve communication in intensive care: a systematic review. Chest, 139(3): 543-54.
All medical residents and students who work in our unit attend a
training session. The objective is to raise awareness and understanding
of psychological ways of coping, and also to experiment in a secure
and benevolent environment.
There is no good way of breaking bad news, but some can be less
devastating than others. We talk about feeling and showing empathy,
using the right words when appropriate and limiting jargon. We insist
on the importance of body language and on making eye contact, and
overall we focus on opening up to their own feelings, to also be open
to families’ feelings. We also take time to discuss how some situations
impact our young doctors. Giving them the opportunity to experiment,
to share and discuss these subjects is greatly appreciated. We also have
noticed that families remain satisfied with the care they receive even
once a decision to withdraw life support has been made.
Showing empathy, actively listening, learning how to demonstrate
compassion, while delivering accurate and consistent messages helps
to develop positive interactions and contributes to improving family-
centred care.
Studies in different ICUs have shown that improving
communication has a significant impact on lowering what has been
termed “post-intensive care syndrome family” PICS-F (see aftertheicu.
org/what-is-fics), reducing anxiety, depression and post-traumatic
stress symptoms (Scheunemann et al. 2011; Gerritsen et al. 2017).

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Implementing ECCO2R and vv-ECMO in non-academic centres

Shares experiences of implementing extracorporeal life support in a non-academic hospital.

A cute respiratory distress syndrome (ARDS) is a

life-threatening disorder characterised by severe
impairment of gas exchange. The most common causes
are pneumonia, sepsis and acute pancreatitis. It is accurately
need for personnel and technical resources was immense. The
newest improvements for VV-ECMO applications provide the full
spectrum of extrapulmonary lung support, from efficient carbon
dioxide removal to complete oxygenation. The development
clinical decision to start the therapy. In the phase of inserting
the catheters and installing the machine, the ECMO team is
exclusively responsible for these actions. Patients with VV-ECMO
require one nurse per patient all the time.
©For personal and private use only. Reproduction must be permitted by the copyright holder. Email to copyright@[Link].

defined in the Berlin definitions (ARDS Definition Task Force of the acquired techniques and hardware meanwhile allows
As shown in the literature, in centres with 5 or less annual
2012). Progression to ARDS is associated with an increased risk easier handling than before. Nevertheless, these techniques
treatments mortality increases (Barbaro et al. 2015). Position
of in-hospital mortality (46%) (Bellani et al. 2016). Despite should only be used in clearly selected patients e.g. following
papers therefore define required structures (Combes et al.
substantial progress in understanding mechanisms of ARDS the Extracorporeal Life Support Organization (ELSO) guidelines
2014). In our hospital we reach an overall survival rate from
(Blondonnet et al. 2016), there has been little advancement in (Brogan et al. 2017).
> 50% in our ECMO patients, treating 12 patients/year. This is
developing effective treatments. To date, causal therapy means
Implementing ECCO2R/vv-ECMO in non-academic centres quite similar to ELSO data (Brogan et al. 2016) and the ALIVE
treatment of the underlying decompensating factors causing
Klaus Kogelmann therefore is quite possible if one takes care of the depending study data (Brun-Buisson et al. 2004). Guidelines from the
Head of Department
ARDS. Additionally, so called “lung-protective” mechanical
expertise: which patients are we able to handle, which therapy German Society of Anaesthesiology and Intensive Care (DGAI)
Klinikum Emden ventilation can reduce mortality in cases of severe ARDS (Acute
Germany
is realisable and most important: which adverse events are we postulate not less than 20 treatments per year (Adamzik et al.
Respiratory Distress Syndrome Network 2000).
able to cope with? We started to think about this treatment at 2017).
[Link]@[Link] Only two interventions have been shown to increase our clinic, as in the past there had been sporadic difficulties
Concusion
survival in ARDS patients (Tonelli et al. 2014): lung protective to transmit ARDS patients to other centres because they had
ventilation with low tidal volume (Acute Respiratory Distress not the capacity to treat our patients in the required moment. Summing up, the more patients you treat, the more effect for
Syndrome Network 2000) and prone positioning (Guérin your patients you gain. Centres that aim to treat with VV-ECMO
There are several personal and structural specifications
et al. 2013). Each intensive care unit should be able to treat must be able to treat the whole patient with all the problems
needed: qualified intensivists and nurses in 24-hour shifts,
lung protectively like this. In life-threatening cases where and difficulties alongside. That requires clear decisions and
surgical, radiologic and medical support if needed 24/7,
conventional lung-protective ventilation fails, extracorporeal pathways in indication and contraindication for this treatment
including echocardiography, bronchoscopy and CT scans. One
membrane oxygenation (ECMO) can represent a life-saving as well as benchmarking and peer review.
of our most important aims in implementing this therapy was
alternative to treat ARDS and refractory hypoxaemia, to
teaching the staff and team building. In the last 5 years we Conflict of interest
stabilise gas exchange and serve as a temporary replacement
treated 63 patients with ECCO2R/vv-ECMO, selected from our
of pulmonary function and bridge to recovery. Recent evidence Klaus Kogelmann has received lecture honorary and travel fees
ARDS patients. In 2015 we joined the German ARDS Network
from a large multicentric, randomised trial suggested a from Cytosorbents Corp, Xenios AG and Sedana medicalo
group and last year ELSO. Since that time we are following
potential positive effect of the use of veno-venous (VV) ECMO
ELSO guidelines in indicating this therapy. In the ECMO-
in refractory ARDS in terms of mortality and complications
implementing phase within the first two years company support References
(Peek et al. 2009). In the past, extracorporeal lung support
came in house for each patient to teach staff and to stay for For full references, please email editorial@[Link] or visit https://
of ARDS was the domain only of large centres, because the
trouble-shooting. Meanwhile we need about two hours from [Link]/o2e

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I-I-I Blog

Highlights from the I-I-I Blog (I expert, I question, I answer)

Have you got something to say?
A selection from the ICU Management & Practice I-I-I blog. Have you got something to say?
Visit [Link] or contact editorial@[Link]

Jean Baptiste Lascarrou Pieter Depuydt

©For personal and private use only. Reproduction must be permitted by the copyright holder. Email to copyright@[Link].

Medical Intensive Care Unit, Nantes University Hospital,

Head of Clinic - Department of Intensive Care, Ghent University Hospital, Belgium
France
Antibiotic decisions in the ICU: a dragon’s tale
@jblascarrou
See more at: [Link]
Epinephrine for out-of-hospital cardiac arrest
“Epinephrine (or adrenaline for EU physicians) has alpha-
adrenergic action which leads to increased coronary blood
AD” ? AB ?
IL”
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flow but also beta-adrenergic action that can lead to the
TA
recurrence of VF/VT and can also impair cerebral microvascular blood flow. Additionally,
recent data from randomised controlled trials on cardiogenic shock) or meta-analysis
? which AB? Combination? “ RESTRI N
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highlight poor outcome associated with epinephrine use. In this context, clinical trial of LOADING AB? CLINICAL
? Which dose? PICTURE
drug use with only “alpha-adrenergic” action such as norepinephrine deserves attention.” DOSE!
I (biomarker)???
See more at: [Link] CLINICAL
PROBABILITY
CRP
OF INFECTION TRY TO
PICTURE SEVERITY OF IDENTIFY PATHOGEN PCT

Linda Kennemar
II INFECTION PATHOGEN! NF?
PATHOGEN
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CAP-H(C)AP MDR-XDR?
Critical Care Nurse - Nyköping Hospital, Sweden SETTING
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2.’
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PATIENT
How ICU diaries can help patients and families
ALLERGIES/TOX. ANTIBIOTIC STATUS
“CLEARANCE” PRESENT?
?

“The importance of the diaries isdemonstrated when biomarkers ? STEWARDSHIP II

SUSCEPTIBILITY?
PROBABILITY - ALTERNATIVE PATHOGEN
patients have vivid memories and the diaries are able to of infection DIAGNOSIS? NEED FOR ADDITIONAL
I RESPONSE
provide explanations. For example, a patient remembers CULTURES! DIAGNOSTICS?
AL
his throat being cut with a knife; the diary tells the patient
CLINIC
PICTUR
E COMPLICATION? ? AB? TRY TO
DE-ESCALATE!
he had a central venous catheter put in and we can then explain the procedure to
biomarker?
CRP ? Which AB? Combination?
PCT
him. Patients have such wide-ranging comments. It is often a relief for them to tell us TREND! ? Dose? Continuous? III
CLEARANCE TDM ???
stories their relatives don’t believe and sometimes we can help them find some kind of Only PATIENT
? TISSUE PENETRATION
reality in the story or just reassure them that it can be like that after ICU.” SOURCE CONTROL?
TOXICITY
See more at: [Link]
ICU Management & Practice 3 - 2018
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INTERVIEW

Improving access to safe anaesthesia

Interview with Jannicke Mellin-Olsen, President, World Federation of Societies of Anaesthesiologists
Jannicke Mellin-Olsen, MD, DPH is Consultant Anaesthesiologist at the Department of Anaesthesia, Intensive Care and Emergency Medicine,
Bærum Hospital, Norway. She is President of the World Federation of Societies of Anaesthesiologists, and serves as a member of the Patient
Safety and Quality Committee of the European Society of Anaesthesiology. Dr. Mellin-Olsen is on the Patient Safety Movement Foundation’s
Board of Directors and is the Foundation’s Regional Network Chair. Dr. Mellin-Olsen served in the UN Peace Keeping Forces in Lebanon and
©For personal and private use only. Reproduction must be permitted by the copyright holder. Email to copyright@[Link].

for the Red Cross in Pakistan and Serbia, and for 10 years was the medical director for Europe, Middle East, and Africa for MedAire, Inc., which
provides remote medical services to patients in the air and at sea. She is past president of the Norwegian Society in Anaesthesiology and past
President of the European Board of Anaesthesiology. Her Twitter handle is @jmellinolsen.

Eight years on from the Helsinki Declaration on creating awareness of the situation, advocate, set standards the SAFE Courses and all our training centres, we have
Patient Safety in Anaesthesiology what would the and educate. developed the WHO-WFSA Standards for Safe Anaesthesia,
report card say? we work with governments on National Surgical, Obstetric
The WFSA’s global workforce survey highlighted the
and Anaesthesia Plans and more.
It has been a surprise how much it has spread beyond lack of anaesthesia in many parts of the world:
Europe, illustrating that the anaesthesiology world and our What work is being undertaken to define and
How can this gap be closed? It must be a combination of
partners see the need to improve safety for our patients. map non-physician anaesthesia providers as well as
workforce expansion, education, investing in facilities and
The map says it all ([Link] But a signature infrastructure and equipment? Non-physician anaesthesia
equipment, including anaesthesia drugs, and improving
does not mean improvement per se, it must be followed providers are also counted in our Workforce Study, which
the living and working situation to reduce emigration and
up by committed actions. will be repeated during the coming two years.
more. We need to help policy makers and decision makers
understand that they must provide sustainable plans for
What re your priorities as President of the World scale-up. What’s behind the WFSA campaign
Federation of Societies of Anaesthesiologists (WFSA)? #KetamineisMedicine?
How is the WFSA working on the interim goal of at
The WFSA mission is to unite anaesthesiologists around the least 5 specialist physician anaesthesia providers per 100K Where there are limited resources, like when there is
world to improve patient care and access to safe anaesthesia population? The Lancet Commission on Global Surgery no oxygen, no electricity or no equipment and limited
and perioperative medicine. I have noticed that in high-, ([Link]/commissions/global-surgery) estimated training, ketamine is often the only available anaesthetic.
middle- and low-income countries, we are driven by the that there should be at least 20 surgeons + obstetricians + China has called for international scheduling, as Chinese
same goal—we want to help our patients. Five out of seven anaesthesiologists per 100K. We estimated that of those, a ketamine has been used as a recreational drug in
billion people in this world do not have access to safe, bare minimum of 5 must be anaesthesiologists to lead and neighbouring countries. They have been supported by
timely and affordable anaesthesia and surgery. This must be educate in addition to some direct patient care. The WFSA is some other countries where there is illicit use of ketamine.
changed, and we anaesthesiologists cannot expect anyone working on many fronts. We are now developing a Training The morphine experience taught us that when medicines
other than ourselves to drive that change. We must lead by Framework, we do training ourselves—for instance are scheduled, the medical usage is dramatically reduced,

ICU Management & Practice 3 - 2018

 223
INTERVIEW

although countries are supposed to ensure that they are available to reconvene the Guidelines Development Group and expand the European Board of Anaesthesiology and the European Society
for medical purposes. An example is when India enacted the it with more anaesthesiologists. We are also now involved in a of Anaesthesiology have not been supportive of a basic speciality
Narcotic Drugs and Psychotropic Substances Act in November Dutch study looking into the actual practice of perioperative FiO2 in emergency medicine. Yet, “our” emergency medicine represents
1985 (Mohan and Bansal 2005). So many bureaucratic restrictions administration throughout the world. only the critical part—ten percent of what the speciality claims,
were put in place that doctors stopped taking morphine from while 90% of their speciality is totally something else. We argue
the pharmacies, who in turn, stopped stocking it, and the What is holding back gender equity in anaesthesiology and that those most critical patients are better served by a team
manufacturers stopped producing a medicine nobody bought. how can this be improved? approach where we contribute what we are good at, supporting
©For personal and private use only. Reproduction must be permitted by the copyright holder. Email to copyright@[Link].

The use of medicinal morphine dropped by 97%. There is no airways and circulation in those critical patients.
reason to believe that it would be different for ketamine, which The same factors as in other fields of medicine and in society
would be a disaster for patients. in general. It is a multifaceted problem: Medicine should be
Wh should manage the airway in an emergency outside the
gender balanced, to meet the patient mass which is 50/50. Yet,
hospital and inside?
medicine as a profession is being feminised. Hence, we need to
“five out of seven billion people in this investigate factors preventing men to apply to medical school.
But the increased female workforce is not reflected in leadership
Basic airway management—jaw thrust and mask and bag
ventilation should be a basic competence of all health workers.
world do not have access to safe, timely and positions and academics. The reasons are multiple, so the measures Advanced airway management should not be defined by
affordable anaesthesia and surgery” must be multiple: as it is now, there is a positive discrimination
in the way that people have a tendency to select and appoint
designation, but by competence. Health systems are different, so
one cannot transplant one system to another. But in times where
people who resemble themselves. When the “selectors” are white, for instance laryngeal mask is replacing endotracheal intubation,
The WFSA raised concerns about the recommendation on
middle-aged men, they tend to recruit other white middle-aged it should not be spread on too many professions as it will be
FiO2 in the World Health Organization guidelines to prevent
men. Therefore, there must be a mechanism to actively identify difficult to obtain and maintain that competence. Therefore, as a
surgical site infections—has this been amended?
people that “are different” but not sacrificing quality. Quotas have rule inside the hospital it should be that anaesthesia personnel
Our concerns were twofold—one is that even in high-income also been used with success in my country, but it is controversial. are in charge. Outside the hospital, the trend is that intubation
settings, it is very difficult to maintain a level of FiO2 0,8 during Role models and good mentors (not necessarily of your own is being replaced by subglottic airways, and that is probably a
the whole perioperative period, so it does not make sense to gender) are also important. good trend.
recommend it. The other is of course, the effect of a high FiO2
on lungs with atelectasis and other problems. The WHO took What is meant by critical emergency medicine (Böttiger et References
our input seriously but have not been willing to change the al. 2018)? What are the basic principles of CREM? Böttiger BW, Brazzi L, De Robertis E et al. (2018) Reply to: collaboration in emergency
recommendation yet. However, since these discussions started, one medical care in Europe: the ten principles of CRitical Emergency Medicine (CREM). Eur J
Anaesthesiol, 35(3): 238-9.
of the papers by Schietroma has been retracted, so they have now There has been and is some controversy regarding “emergency
European Society of Anaesthesiology (2010) Helsinki Declaration. Available from [Link]/
excluded all his papers previously included in their reviews, and medicine” in Europe and beyond. Anaesthesiologists view patient-safety/patient-safety/helsinki-declaration/full-declaration
the strength of evidence changed. Therefore, they have decided emergency medicine as one of the pillars in our speciality, and Mohan C, Bansal BL (2005) The narcotic drugs and psychotropioc substances act, 1985. New
Delhi: Universal Law Publishing Co. Pvt. Ltd.

ICU Management & Practice 3 - 2018

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