S ECT I O N

SURGICAL BIOLOGY
John A. Stick and Timo Prange
I
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CHAPTER
Shock: Pathophysiology, Diagnosis,
Treatment, and Physiologic
1
Response to Trauma
Katharyn Mitchell and Angelika Schoster

decreased return to the heart. In this situation, although the

DEFINITION OF SHOCK total volume of blood remains unchanged, the effective circulating
In 1872 the trauma surgeon Samuel D. Gross defined shock as volume decreases.
“the rude unhinging of the machinery of life.” Shock represents Myocardial contractility is defined as the rate of cross-bridge
progression of a cascade of events that begins when cells or cycling between actin and myosin filaments within cardiomyo-
tissues are deprived of an adequate energy source because of cytes. Clinically, myocardial contractility assessment is attempted
oxygen deprivation. Shock occurs as a result of inadequate tissue using echocardiographic measures of global systolic function
perfusion; the lack of an adequate energy supply leads to the like left ventricular ejection fraction and fractional shortening,
buildup of waste products and failure of energy-dependent although these variables are load dependent and highly influenced
functions, release of cellular enzymes, and accumulation of by ventricular preload and afterload. Abnormal myocardial
calcium and reactive oxygen species (ROS) resulting in cellular function (both systolic and diastolic) is well described in the
injury and ultimately cellular death. Activation of the inflam- literature following shock, sepsis, endotoxemia, and ischemia/
matory, coagulation, and complement cascades results in further reperfusion injury.1–3 Complex combinations of molecular,
cellular injury and microvascular thrombosis. The amplification metabolic, and structural changes contribute to decreased
of these processes coupled with increased absorption of endotoxin myocardial contractility in these patients.
and bacteria (as a result of liver and gastrointestinal dysfunction) Ventricular afterload (referred to as “afterload”), the third
leads to the systemic inflammatory response syndrome (SIRS) component of SV, is directly affected by vasomotor tone or
(see Chapter 2), multiple organ dysfunction (MOD), and if peripheral vascular resistance. If vascular resistance or tone
uncontrolled, ultimately death. increases (hypertension), afterload also rises with a resultant
fall in CO and tissue perfusion. The opposite extreme is a
severe fall in vascular resistance, which results in pooling of
CLASSIFICATION OF SHOCK blood in capacitance vessels and a drop in blood pressure
Tissue perfusion is dependent on blood flow. The major factors and preload, and it ultimately results in inadequate perfusion
affecting blood flow are the circulating volume, cardiac pump and shock.
function, and the vasomotor tone or peripheral vascular The fundamentals of treatment of shock revolve around restora-
resistance. tion and maintenance of CO through manipulation of preload,
Cardiac output (CO) ultimately determines the blood flow afterload, myocardial contractility, and heart rate.
to tissues and is regulated largely by the stroke volume (SV). SV Shock most commonly occurs because of one of three primary
is the result of ventricular preload (amount of blood returning disturbances and can be classified accordingly. Hypovolemic shock
from the body and entering the heart), the myocardial contractility is the result of a volume deficit, either because of blood loss
(systolic cardiac function), and the ventricular afterload (the force (e.g., resulting from severe hemorrhage), third-space sequestration
the heart must overcome to push blood across the aortic and (e.g., occurring with a large colon volvulus), or severe dehydration.
pulmonic valves into the peripheral or pulmonary vasculature). Cardiogenic shock or pump failure occurs when the cardiac muscle
The interplay between these factors is seen in Figure 1-1. cannot pump out adequate SV to maintain perfusion. Distributive
Ventricular preload (referred to as “preload”) is directly affected shock or microcirculatory failure occurs when vasomotor tone
by the circulating blood volume or amount of blood returning is lost. Loss of vascular tone can result in a dramatic decrease
to the heart. Causes of decreased preload include hypovolemia in both blood pressure and venous return. Although the drop
(e.g., following hemorrhage or dehydration); decreased ventricular in blood pressure will initially decrease afterload (which will
filling time (resulting from tachycardia) or impaired ventricular temporarily improve CO), the pooling of blood and loss of
relaxation; and decreases in vasomotor tone and vasodilation, venous return results in a severe decrease in preload, and con-
which results in pooling of blood in capacitance vessels and sequently, decreased CO and perfusion.

1
 2 SECTION I Surgical Biology

volume is depleted, pressure within the vessels falls. Baroreceptors

and stretch receptors located in the carotid sinus, right atrium,
and aortic arch sense this fall in pressure. These receptor responses
act to decrease inhibition of sympathetic tone while increasing
inhibition of vagal activity and decreasing the release of atrial
natriuretic peptide (ANP) by cardiac myocytes. The increase in
sympathetic tone and fall in ANP results in vasoconstriction,
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which increases total peripheral resistance and thereby increases

blood pressure. Increased sympathetic activity at the heart increases
heart rate and systolic cardiac function, hence increasing SV and
CO. This interplay between the parasympathetic and sympathetic
nervous systems is referred to as autonomic traffic (see Figure
1-1). In addition, peripheral chemoreceptors stimulated by local
hypoxemia respond by enhancing this vasoconstrictive response.
Figure 1-1. Determinants of cardiac output and systemic blood pressure In mild to moderate hypovolemia these responses are sufficient
and the interplay between them. Autonomic traffic refers to inputs from to restore perfusion. Because these compensatory responses result
both the parasympathetic and sympathetic nervous systems (i.e., barorecep-
in tachycardia, increased SV (increased pulse pressure), and
tors, atrial stretch receptors, vagal tone). The text highlighted in bold
indicates those inputs that can be easily monitored and manipulated to
shortened capillary refill time (CRT), the term hyperdynamic is
improve cardiac output. Autonomic traffic and vascular resistance, while often used to describe this stage of shock.
important determinants of cardiac output, are more difficult to quantify The vasoconstrictive response will vary between organ systems,
and influence with therapy. with the greatest response occurring in the viscera, integument,
and kidney. Cerebral and cardiac flow is preferentially maintained
in mild to moderate hypovolemia. Although this response
Common causes of distributive shock include neurogenic improves central blood pressure and flow, it also decreases perfu-
shock, septic shock, and anaphylactic shock. Because distributive sion to individual microvascular beds, worsening local tissue
shock is a consequence of a loss in effective circulating volume, hypoxemia. Consequently, as volume depletion worsens, certain
fluid therapy is indicated to help restore perfusion. In contrast, tissues and organs will become ischemic more rapidly than others.
cardiogenic shock is the result of pump failure, and aggressive A decrease in renal perfusion results in secretion of renin
fluid therapy may actually worsen clinical signs. Less commonly, from juxtaglomerular cells located in the wall of the afferent
shock can develop when increased metabolic demand results in arteriole. Renin stimulates production of angiotensin I, which,
relative perfusion deficits or when oxygen uptake is impaired after conversion to angiotensin II, increases sympathetic tone
because of mitochondrial failure, sometimes termed relative on peripheral vasculature and promotes aldosterone release
hypoxia or dysoxia. from the adrenal cortex. Aldosterone restores circulating volume
It is important to recognize that although the inciting cause by increasing renal tubular sodium and water reabsorption.
may differ, as shock progresses there is often failure of other Arginine vasopressin (AVP, previously known as antidiuretic
organ systems as well. For example, untreated hypovolemic shock hormone, ADH), released from the posterior pituitary gland
can result in microcirculatory failure (loss of vasomotor tone) in response to decreased plasma volume and increased plasma
as oxygen debt causes muscle dysfunction and relaxation. osmolality, is a potent vasoconstrictor and stimulates increased
Alternatively, hypovolemic shock can result in myocardial failure water reabsorption in the renal collecting ducts. Finally, an
as perfusion deficits affect energy supply to the myocardium increase in thirst and a craving for salt is mediated by both the
(coronary artery blood flow), resulting in decreased myocardial renin-angiotensin-aldosterone system (RAAS) and a fall in ANP
contractility. Consequently, as shock progresses, treatment may (Figure 1-2).
require addressing all of these disturbances. With more severe blood loss, compensatory mechanisms
Obstructive shock represents an additional category, with its become insufficient to maintain arterial blood pressure and
underlying mechanism the obstruction of ventilation or of CO. perfusion of vital organs (decompensated shock). Ischemia to
This process is most commonly caused by tension pneumothorax more vital organs including the brain and myocardium begins
(resulting in decreased venous return); pericardial tamponade; to develop. Blood pressure may be maintained, but clinical signs
diaphragmatic hernia or severe abdominal distension causing including resting tachycardia, tachypnea, poor peripheral pulses,
vena cava obstruction, leading to inadequate ventricular filling; and cool extremities are present. Mild anxiety may be apparent
decreased preload; and consequently, decreased SV and CO. Over as well as sweating from increased sympathetic activity. Urine
time as aortic blood pressure falls, coronary artery blood flow output and central venous filling pressure will drop. As blood
is reduced, and myocardial ischemia and finally myocardial failure loss progresses, compensatory mechanisms are no longer capable
may develop. Because obstructive shock is ultimately a combina- of maintaining arterial blood pressure and perfusion to tissues.
tion of the other three categories, it will not be discussed further. Severe vasoconstriction further worsens the ischemia such that
energy supplies are inadequate and cellular functions (includ-
ing the vasoconstriction responses) begin to fail. In addition,
PATHOPHYSIOLOGY OF SHOCK accumulations of waste products of metabolism (lactate and
A blood loss or hypovolemic model of shock will be used to carbon dioxide) cause progressive acidosis and further cellular
describe the pathophysiology of shock. dysfunction.
Shock is usually defined by the stage or its severity. Compensated At the cellular level, the combination of decreased oxygen
shock represents an early or mild shock, during which the body’s delivery and increased accumulation of waste products results
response mechanisms are able to restore homeostasis. As blood in loss of critical energy-dependent functions, including enzymatic
 CHAPTER 1 Shock 3
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Figure 1-2. Physiologic compensatory responses to hypovolemia. ACTH, Adrenocorticotropic hormone.

(Modified from Rudloff E, Kirby R. Hypovolemic shock and resuscitation. Vet Clin North Am Small Anim
Pract. 1994;24:1015–1039.)

activities, membrane pumps, and mitochondrial activity, leading As the situation deteriorates, compensatory mechanisms
to cell swelling and release of intracellular calcium stores. designed to continue to perfuse more vital organs like the heart
Cytotoxic lipids, enzymes, and ROS released from damaged cells and brain will continue to limit flow to other organs. This response
further damage cells, triggering inflammation. Inflammatory cell results in the sparing of one organ with irreversible damage to
and platelet influx into the tissue, the formation of neutrophil another. Consequently, an individual may recover with aggressive
extracellular traps (NETS), and activation of the arachidonic acid intervention only to succumb later because of failure of these
cascade and the complement cascade, cause further cellular injury. “less vital” organs. If blood flow is restored, reperfusion injury
Mitochondrial failure, calcium release, and reperfusion, if present, results from the activated cellular and immunochemical products
further increase production (and decrease scavenging) of ROS. washed into the venous circulation and leads to SIRS, MOD,
Endothelial cell damage, including loss of the endothelial gly- and death (see Chapter 2). Intervention can no longer stop the
cocalyx layer, results in local tissue edema as a result of protein cascade of events because cellular, tissue, and organ damage is
and fluid leakage. Exposure of subendothelial tissue factor further too severe for survival.
activates the coagulation and complement cascades.4 Formation
of microthrombi coupled with coagulopathy impedes blood flow
to the local tissues, worsening the already deteriorating situation. CLINICAL SIGNS OF SHOCK
The lack of energy supplies in combination with accumulation Clinical signs of shock depend on the severity and persistence
of toxic metabolites, microthrombi formation, and the inflam- of blood volume loss or redistribution. The American College
matory injury ultimately result in vascular smooth muscle failure of Surgeons advanced trauma life support guidelines divide shock
and vasodilation. The end results of decompensated shock are into four classes depending on volume of blood loss.5
a pooling of blood in peripheral tissue beds and additional With mild blood loss of less than 15% total blood volume
decreases in blood pressure, venous return, CO, and perfusion, (class I), the body is capable of restoring volume deficits via
ultimately resulting in organ failure (Figure 1-3). Failure of the compensatory responses and there may be little to no change
gastrointestinal tract manifests itself as loss of mucosal barrier in the physical findings other than a drop in urine output. Blood
integrity, resulting in protein and fluid loss, endotoxin absorption, pressure is maintained. Clinical signs typically become apparent
and bacterial translocation. Renal ischemia leads to renal tubular when blood loss exceeds 15%. Class II blood loss (15%–30%)
necrosis, and the inability to reabsorb solutes and water, and is defined as the onset of hyperdynamic shock. Clinical signs
the inability to excrete waste products. At the cardiac level, the include tachycardia, tachypnea, and a bounding pulse (increased
continued drop in blood pressure and venous return decreases CO and peripheral vascular resistance). Mental agitation or anxiety
coronary blood flow. Cardiac muscle ischemia leads to decreased is present, and increased sympathetic output results in pupil
cardiomyocyte contractility and CO and ultimately to further dilation and sweating. Although these compensatory mechanisms
deterioration of coronary artery blood flow. Acidosis and ischemia can normalize blood pressure, perfusion deficits will persist and
accentuate the depression of cardiac muscle function. These can be detected by blood gas analysis (increased lactate and a
changes in combination with decreased venous return (preload) high anion gap metabolic acidosis). If blood loss continues, or
worsen hypotension and tissue perfusion (Figure 1-4). if hypovolemia persists, compensatory mechanisms can become
 4 SECTION I Surgical Biology
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Figure 1-3. Cellular cascade of events that occur as the result of hypovolemia, poor perfusion, and
decreased oxygen delivery. HR, Heart rate; MODS, multiple organ dysfunction syndrome; RAAS, renin-
angiotensin-aldosterone system; SIRS, systemic inflammatory response system.

Figure 1-4. Vicious cycle of cellular and organ failure in shock.

insufficient to restore circulating volume and hypodynamic/ despite increases in heart rate, cardiac contractility, and total
decompensatory shock begins (class III or moderate hypovolemic peripheral resistance. Without intervention, continued cellular
shock). At this time profound tachycardia and tachypnea, anxiety, hypoxia and acidosis result in failure of compensatory mecha-
and agitation are present. Urine output may cease, jugular filling nisms, causing peripheral vasodilation and decreased myocardial
and CRT are prolonged, pulse pressure is weak, and extremity contractility. A vicious cycle ensues with decreased coronary artery
temperatures are decreased. If blood gases are collected, a lactic perfusion causing decreased cardiac function, resulting in
acidosis will be present (Table 1-1). Blood pressure will drop decreased CO and a further drop in perfusion (see Figure 1-4).
 CHAPTER 1 Shock 5

TABLE 1-1. Clinical Assessment of the Different Stages or Progression of Shock

Mild Compensated Moderate Hypotension/ Severe Hypotension/
Variable Shock Class I Shock Class II–III Shock Class III–IV
Extremity temperature May be normal or cool Cool Cool to cold
Mentation Normal to anxious Agitation to lethargy Obtunded
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Urine output Decreased Decreased Anuria possible

CRT Normal to prolonged Prolonged End-stage shock may be shortened
because of blood pooling in
peripheral tissues
Heart rate Normal to tachycardia Tachycardia Severe tachycardia; bradycardia at end
stage
Respiratory rate Normal to tachypnea Tachypnea Tachypnea; bradypnea possible at end
stage
Blood pressure Normal Normal to decreased Decreased
Oxygen extraction ratio May be normal Increased Increased
PvO2 May be normal Decreased Decreased
Blood lactate Mild increase Increased Markedly increased
Arterial pH Normal to acidotic Normal to acidotic Acidotic
Central venous pressure Normal to low Low Low

CRT, Capillary refill time; PvO2, venous partial pressure of oxygen.

If uncontrolled, clinical signs will progress from tachycardia and therapy is the vital first step to restoring oxygen delivery. Extensive
anxiety to bradycardia, obtundation, anuria, profound hypoten- research efforts have addressed the ideal type and volume of
sion, circulatory collapse, and death (class IV, uncompensated fluid for treating hypovolemic shock.9 The ideal resuscitation
life-threatening hemorrhagic shock). fluid should produce a predictable and lasting increase in
A paper published in 2012 described moderate to severe eleva- intravascular volume, with an electrolyte composition as close
tions in cardiac troponin I (cTnI) and the development of as possible to that of extracellular fluid, being metabolized and
potentially life-threatening ventricular arrhythmias in horses excreted without any accumulation in the tissues, without produc-
suffering from severe hemorrhage, with the magnitude of cTnI ing adverse metabolic or systemic effects, and remain cost effective,
elevation and the presence of arrhythmia being association with especially for administration in larger equine patients. Currently,
poor outcomes.6 the ideal resuscitation fluid does not exist.9
Monitoring (via ECG, echocardiography, and serial cTnI In the past, recommendations have been to rapidly infuse
measurements) is indicated in critical patients with arrhythmias large volumes of isotonic crystalloids to replace circulating volume
or unexplained tachycardia.7 Antiarrhythmic therapy is indicated (“aggressive fluid therapy”). Because of their accessibility and
if the arrhythmia becomes hemodynamically relevant.8 low viscosity, crystalloids can be administered fast and quickly
restore the circulating volume. However, approximately 80% of
the volume will rapidly diffuse out of the vascular space into
TREATMENT
the interstitial and intercellular space. Consequently, when using
Fluid Administration crystalloids, replacement volumes must be four to five times
Regardless of the underlying etiology of shock (cardiac failure, greater than the volume lost. In acute blood loss or hypovolemic
blood loss, or sepsis), the greatest need is to restore perfusion states, this approach will result in excess total body water and
and oxygen delivery to the tissues. Delivery of oxygen (DO2) is extreme excesses of sodium and chloride. This movement of
defined by the content of oxygen in the arterial blood (CaO2) fluid out of the vascular space is further exacerbated if the
as well as the amount of blood perfusing the tissue (CO). underlying disease process causes increased microvascular perme-
ability (as a result of lost endothelial glycocalyx and impaired
DO2 = CO × CaO2 endothelial cell function). In addition, if the electrolyte con-
stituents of isotonic crystalloids differ from those in the intracel-
The content of oxygen per volume of blood is determined by lular space, cellular swelling will ensue. Cellular swelling affects
the amount of hemoglobin (Hb) or red cell mass and the satura- the activity of various protein kinases; increases intracellular
tion of that Hb (SaO2). It is important to assess Hb concentration calcium concentrations; alters ion pump activity, membrane
and SaO2 because these variables will affect oxygen delivery. potential, and cytoskeletal structure; and activates phospholipase
Decreased oxygen delivery is most commonly the result of A2.10 Consequently, high volumes of crystalloids can trigger or
decreased perfusion, not decreased oxygen content, but it is potentiate an inflammatory response and have a negative impact
critical to evaluate all contributing factors when planning a in the face of ischemia and reperfusion. Furthermore, large-volume
treatment protocol for an individual in shock. Because hypovo- infusions can result in significant complications including
lemia is the most common cause of shock in adult horses, fluid abdominal compartment syndrome, acute respiratory distress
 6 SECTION I Surgical Biology

syndrome, congestive heart failure, gastrointestinal motility following fluid therapy. Therefore, intravenous crystalloid fluid
disturbances, and dilutional coagulopathy.11,12 therapy should never be withheld, even when the packed cell
Multiple human clinical trials have questioned the need for volume (PCV) and total solids (TS) are reduced. In the treatment
complete and rapid restoration of volume to maximize survival. of severe blood loss, dilutional coagulopathy resulting from
In several hemorrhagic shock models, aggressive fluid therapy thrombocytopenia and dilution of clotting factors can occur,
before hemorrhage was controlled was associated with more leading to further bleeding and deterioration. These patients
severe blood loss, poorer oxygen delivery, and a higher mortality may require subsequent plasma or whole blood transfusions to
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rate compared to more controlled, limited fluid therapy.13,14 Both improve coagulation, oncotic pressure, and oxygen content of
the Advanced Trauma Life Support and the current Surviving blood. Patients with endotoxemia or SIRS often have underlying
Sepsis Campaign guidelines recommend the use of lower-volume coagulopathies as part of their disease process, leaving them at
bolus crystalloid therapy (30 mL/kg within the first 3 hours after particular risk for further problems with aggressive high-volume
presentation) combined with frequent assessment of the hemo- crystalloid therapy.19,20
dynamic status to improve survival of human patients presenting
with signs of hemorrhagic or septic shock.5,15
Clearly there are pros and cons to immediate, large-volume Hypertonic Crystalloids
fluid resuscitation in the treatment of hypovolemic shock. Perfu- Hypertonic saline solution (HSS) is available in several concentra-
sion deficits need to be addressed, but the goal of therapy may tions, with 7.2% being the most commonly used formulation.
need to be considered in light of the potential negative effects At this concentration, HSS has approximately eight times the
of rapidly infusing a large volume of fluids. Large-volume fluid tonicity of plasma. An intravenous infusion of HSS will expand
therapy has also been associated with cardiac and pulmonary the intravascular space by approximately twice the amount infused,
complications in both healthy human patients undergoing elective pulling fluid from the intracellular and interstitial spaces. This
surgery and patients with risk factors for cardiopulmonary expansion is short lived and, similar to the effects of isotonic
disease.16,17 Large-volume fluid therapy in patients with underlying crystalloids, the majority of fluid (and electrolytes) will ultimately
SIRS or patients that have a low colloid oncotic pressure can diffuse into the interstitial space. Because of the variation in
result in significant edema, which can negatively affect intestinal reflection coefficients for sodium, HSS principally pulls volume
motility and barrier function, and can also affect the function from the intracellular space, not the interstitial space. This is
of other organ systems.18 particularly beneficial in the shock state, where endothelial cell
Despite this discrepancy in the literature, the reality is that volume rises with loss of membrane pump function. The decrease
shock is a manifestation of perfusion deficits, and the goal of in endothelial cell volume increases capillary diameter and
therapy should be to restore perfusion and improve oxygen improves perfusion. In addition, HSS appears to blunt neutrophil
delivery. Prompt, goal-directed fluid therapy is indicated in the activation and may alter the balance between inflammatory and
emergency situation to increase the circulating blood volume, antiinflammatory cytokine responses to hemorrhage and ischemia.21
maintain CO and blood pressure, and ultimately provide adequate The recommended dose of HSS is 2 to 4 mL/kg or 1 to 2 L for a
perfusion to the tissues. The amount and type of fluids should 500-kg horse. Hypertonic saline is invaluable in equine surgical
be determined by the individual needs of each patient. Careful, emergencies when rapid increases in blood volume and perfusion
frequent monitoring to assess responses and prevent fluid overload are needed to stabilize a patient before general anesthesia. The
is essential. use of these fluids enables the clinician to quickly improve CO
A “balanced fluid therapy approach” of administering isotonic and perfusion to allow immediate surgical intervention. Additional
crystalloids for hypovolemic shock is currently recommended blood volume expansion will be needed and can be provided
in equine practice.12 Initially a rapid 20 mL/kg (10 L for a 500-kg during and after surgery to further restore homeostasis.
horse) bolus is administered over the first 30 to 60 minutes with
assessment of the cardiovascular system at regular intervals to
monitor the response (for more details, see “Current Recom- Colloids
mendations,” below). Colloids are solutions containing large molecules that, because
of their size and charge, are principally retained within the vascular
space. Because colloid concentrations are higher in the intravas-
Types of Fluids
cular space, they exert an oncotic pressure that opposes the
Isotonic Crystalloids hydrostatic pressure and helps retain water in or draw it into
Commercially available isotonic crystalloids (balanced electrolyte the intravascular space. Normal equine plasma has a colloid
solutions [BES]) for large animal medicine are designed to oncotic pressure (COP) of about 20 mm Hg. Colloids with a
be replacement fluids, not maintenance fluids, meaning that high COP can actually draw additional fluid into the intravascular
the electrolyte composition is designed to closely approximate space. Consequently, infusion of certain synthetic colloids such
the electrolyte composition of the extracellular fluid and not the as hydroxyethyl starch (HES) (COP ~30 mm Hg) will increase
daily replacement needs. The common BES available for horses intravascular volume by an amount that is greater than the infused
include lactated Ringer solution, Plasma-Lyte, and Normosol-R volume. Although this effect is similar to HSS, the benefits of
and are principally composed of sodium and chloride with varying colloids are prolonged.
amounts of calcium, potassium, and magnesium. Physiologic Both synthetic and natural colloids are available. Natural
saline solution (0.9% NaCl) differs in that it contains only sodium colloids include plasma, whole blood, and bovine albumin. The
and chloride but no other electrolytes (see Chapter 3). advantage of natural colloids is that they provide protein such
In cases of moderate to severe blood loss, infusion of large as albumin, antibodies, critical clotting factors, antithrombin 3,
volumes of crystalloids alone can cause dilutional anemia and and other plasma constituents. Because fresh frozen plasma must
hypoproteinemia, although the oxygen-carrying capacity (red be thawed before infusion, it is often not useful in an emergency
blood cell mass) will remain unchanged or become improved situation where immediate fluid therapy may be indicated. In
 CHAPTER 1 Shock 7

addition, hypersensitivity reactions occur in up to 10% of horses

receiving plasma.22 The most common synthetic colloids are Current Recommendations
HES (i.e., hetastarch and tetrastarch) and dextrans. Multiple The debate regarding the use of crystalloids versus colloids is
formulations of HES exist; containing amylopectin molecules extensive. Despite this intense focus, clear benefits of colloids
of sizes ranging from 30 to 2300 kDa (average 480 kDa). or hypertonic solutions over isotonic crystalloids have not been
The elimination of HES occurs via two major mechanisms: renal demonstrated. Rather than always using one or the other, the
excretion and extravasation. Larger molecules are degraded over choice should depend on the situation. In a case of severe blood
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time by α-amylase. The different HES products are differentiated by loss, hypovolemia, and impending circulatory collapse, the rapid
the molecular weight (high, medium, low) and molar substitution expansion of blood volume using hypertonic and isotonic
ratio (number of hydroxyethyl groups per glucose molecule) of crystalloids may be imperative. The addition of colloids, whether
the starch molecules. Recently, a low molecular weight and molar synthetic or natural, and whole blood should depend on the
substitution HES solution (6% HES, 130 kDa/0.4: tetrastarch) severity of shock and the underlying disease process as well as
has replaced the previous higher molecular weight and molar the response to initial treatment.
substitution HES (6% HES, 600 kDa/0.75: hetastarch) because When presented with an adult horse in hypovolemic shock
of concerns identified in human medicine over higher mortality, it is critical to use a large 10- or 12-gauge catheter and large-bore
increased risk of renal replacement therapy, and coagulopathies extension set to maximize flow rate in the initial resuscitation
with the higher molecular weight and molar substitution products. phase. Because crystalloids have the lowest viscosity, they can
The current recommendations from the FDA and Surviving Sepsis be infused more rapidly than colloids or blood. If necessary, a
Campaign are to avoid the use of hydroxyethyl starches for fluid pump can be used to increase the rate of infusion. The
intravascular volume expansion in human patients with sepsis guidelines to determine the fluid deficit (% body weight) present,
and septic shock.15,23 based on the physical examination and clinical laboratory findings,
Currently, there are no published reports of increased risk of are found in Table 3-6 in Chapter 3. In an adult horse, the circulat-
renal complications or increased mortality following administra- ing blood volume is estimated to be 7% to 9% of the total body
tion of HES products in horses, although work in this area is weight or 35 to 45 L for a 500-kg horse. Clinical signs of blood
ongoing. Given the findings in human medicine, HES products loss will occur after the loss of 15% of circulating blood volume
should be used cautiously especially in patients with preexisting or approximately 6 L, during an acute hemorrhage.
renal disease. As mentioned earlier, the fluid deficit should be replaced
In horses, a dose of 10 mL/kg will significantly increase oncotic initially with a 20 mL/kg (10 L for a 500-kg horse) crystalloid
pressure in some patients for longer than 120 hours.24 Though intravenous bolus given over 30 to 60 minutes followed by
evidence of spontaneous bleeding in healthy horses has not reassessment of the hemodynamic situation. If required, an
been documented, an increase in the cutaneous bleeding time additional 10 to 20 mL/kg bolus can be given rapidly with the
was seen with larger doses (20–40 mL/kg) and has been associated remainder of the estimated deficit, including any ongoing losses,
with a decrease in von Willebrand factor antigen (vWf:Ag). and the maintenance requirement can be replaced (2–4 mL/
Consequently, the judicious use of large volumes of HES should kg/h) over the next 12 to 24 hours.12 If the patient fails to respond
be considered in light of the induction of bleeding tendencies with improved hemodynamic indices following the two fluid
in patients.24–27 Measurement of COP must be used to assess the boluses (within 3 hours of commencing therapy), additional
response to HES, because its infusion results in an expanded diagnostic and therapeutic interventions are necessary.
intravascular compartment and consequently a dilution of TS Given the pros and cons of large-volume resuscitation fluid,
or total protein (TP), making estimates of the COP after HES goals should be estimates and not absolutes. Signs of improved
infusion inaccurate. intravascular volume include a decreased heart rate, improved
CRT and jugular filling, skin temperature, and mentation. If
possible, the measurement of urine output is extremely useful
Whole Blood in assessing perfusion, although urine specific gravity is less
Whole blood is the ideal replacement fluid in patients with accurate because it will be affected by the infusion of large
hypovolemic shock as a result of severe blood loss. The use of quantities of crystalloids and will no longer accurately reflect
blood or plasma provides clotting factors and prevents dilutional hydration status. However, high urine specific gravity in the face
coagulopathy. By providing red blood cells (RBCs) and protein, of fluid therapy likely indicates that a fluid deficit still exists.
it helps to retain fluid within the intravascular space and improves The assessment of blood pressure can be useful in monitor-
the oxygen carrying capacity of the blood. However, there are ing trends (i.e., an improvement of pressure toward normal).
several disadvantages. It is unusual for equine referral hospitals In situations where bleeding is uncontrolled, normalization
to store whole blood and it must be collected each time it is of blood pressure should not be the goal because this may
needed. In addition, its viscosity makes it difficult to rapidly promote continued bleeding (permissive hypotension, i.e., mean
infuse large volumes in an emergency situation. Despite these arterial blood pressure [MAP] >65 mm Hg, rather than MAP
drawbacks, the use of blood or blood components can be a >90 mm Hg).
valuable adjunct in preventing some of the potential side effects
of large-volume resuscitation, namely dilutional coagulopathy,
dilutional hypoproteinemia, and anemia. The use of whole blood Vasopressors
is generally unnecessary in patients with mild to moderate Vasopressors are rarely used in standing adult horses in hypo-
hypovolemia because restoration of perfusion often results in volemic shock. Restoration of circulating volume is the primary
adequate oxygen delivery. In more severe cases of hypovolemia treatment goal. However, if the administration of appropriate
or in cases with ongoing bleeding, whole blood may be indicated fluid volumes and types is insufficient to stabilize the patient,
to provide oxygen-carrying capacity, colloid oncotic support, vasopressors may be indicated, particularly as shock progresses
platelets, and coagulation factors. and vasomotor tone and cardiac ischemia cause a further fall in
 8 SECTION I Surgical Biology

perfusion. The most commonly used drug in awake, adult horses seen with endotoxemia or sepsis. In these situations, CRT may
is dobutamine. Dobutamine is a strong β1-adrenoreceptor agonist actually decrease because of vascular congestion and pooling of
with relatively weaker β2- and α-adrenoreceptor affinity. Its primary blood in the periphery. Though CRT at any one time point can
use is to improve oxygen delivery to the tissues via its positive be misleading, if repeatedly assessed over time, it is useful in
inotropic action. Dobutamine has been shown to improve evaluating the progression of shock.
splanchnic perfusion in multiple species, although clinical data
are lacking in the horse. Recommended dosages are 1 to 5 µg/
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kg/min. Higher doses have been reported to cause hypertension, Central Venous Pressure
tachycardia, and arrhythmias in the adult horse.28 Central venous pressure (CVP) assesses cardiac function, blood
Norepinephrine has been reported to be useful in restoring volume, and vascular resistance or tone. Jugular fill is a relatively
adequate organ perfusion in vasodilatory shock in neonatal foals. crude assessment of venous return or CVP. Holding off the jugular
Norepinephrine has strong β1- and α-adrenergic affinity, resulting vein should result in visible filling within 5 seconds in a normally
in vasoconstriction and increased cardiac contractility. It has hydrated horse that is standing with an elevated head. If filling
been successfully used in combination with dobutamine to is delayed, venous return or CVP is decreased. A more accurate
improve arterial pressure and urine output in persistently estimate of CVP can be obtained with a water manometer, attached
hypotensive foals.28 The use of norepinephrine in standing sedated to a large-bore jugular catheter and placed at the level of the
healthy adult horses has been evaluated recently, with norepi- heart base or point of the shoulder. Normal CVP in standing
nephrine counteracting the vasodilatory and hypotensive effects horses ranges from 7 to 12 mm Hg, with pressure measured by
of acepromazine with no arrhythmias or excessive hypertension inserting a catheter into the cranial vena cava/right atrium.32–34
detected.29 Measurement of pressure in the jugular vein using a standard
Vasopressin is released from the pituitary gland following periods IV catheter will result in falsely elevated CVP; however, this
of hypotension and is a powerful vasoconstrictor in addition to measurement can still be a useful estimation to monitor changes
its effects in the kidney. It is administered exogenously as a over time in response to therapy. During an experimental blood
vasopressor when treating vasodilatory shock in humans and loss model, intrathoracic CVP (measured somewhere within the
occasionally in horses under general anesthesia, if hypotension cranial vena cava/right atrium) fell to zero or below with a loss
does not respond to other vasopressors. of 15% to 26% of circulating volume.33 In an experimental
Plasma concentrations of AVP have been shown to increase in hypohydration model, intrathoracic CVP also fell below zero
horses with colic, presumably as a compensatory mechanism for following loss of 4% to 6% body weight.34 Because CVP is a
hypotension, but the use of exogenous AVP in standing horses measure of venous return, it can be used to assess the adequacy
to treat systemic hypotension has not yet been investigated.30 In of fluid resuscitation and prevent fluid overload, especially in
hypotensive anesthetized neonatal foals, the use of AVP resulted in patients at risk for edema (i.e., those with concurrent renal
less splanchnic circulation than norepinephrine or dobutamine.31 disease). If clinical signs are deteriorating despite a normal CVP,
At this time, there is little published information on the use hypovolemia alone is not the cause. Low CVP can occur with
of vasopressors to treat hypovolemic shock in awake adult horses. hypovolemia or a drop in effective circulating volume, as occurs
Consequently, it is difficult to make further recommendations with distributive shock. Cardiogenic shock, fluid overload, or
for their use. Close monitoring of urine output and blood pressure pericardial effusion can result in an elevated CVP, because forward
is recommended when using vasopressor therapy. failure of the cardiac pump results in backup of blood within
the venous side of the system. In this case, jugular veins may
appear distended even with the head held high. Cardiogenic
Monitoring shock is a relatively rare cause of shock in adult horses but
The body’s compensatory responses are designed to restore many should be considered in patients with unexplained tachycardia
of the variables used to assess hypovolemia or perfusion deficits. and other signs of cardiac disease.
Consequently, in the early stages of shock, there is no perfect
measure to assess progression. Despite this, there are several
physical and laboratory variables that can be useful in monitoring Urine Output
the patient’s progression and response to treatment. Urine output is a sensitive indicator of hypovolemia with normal
Repetitive physical exams focusing on assessment of CO and urine production being approximately 1 mL/kg/h or more,
perfusion may be the most sensitive method to assess a patient, depending on how much water an individual is drinking. Produc-
especially during early compensated shock when subtle changes tion of less than 0.5 mL/kg/h suggests significant volume deple-
may indicate impending decompensation. Heart rate, CRT, jugular tion, and fluid therapy is indicated to prevent renal ischemia.
venous fill, extremity temperature, pulse pressure, urine output, Urine output is rarely measured in adult horses, though it is
and mentation are all useful when repeatedly evaluated. Steady relatively simple to perform and commonly done in neonatal
improvement and stabilization of these variables in response to medicine. A sterile urinary catheter (Foley catheter or similar)
treatment would suggest a positive response. Continued tachy- is placed and attached to a closed collection system (e.g., empty
cardia and poor pulse pressure, CRT, jugular fill, and deteriorating resterilized 5-L fluid bag connected to an administration set and
mentation despite treatment suggest that additional blood loss Christmas tree adapter) that is subsequently affixed to the ventral
or decompensation is occurring. aspect of the horse (e.g., using a postoperative colic abdominal
support bandage). Care should be taken to remove the catheter
as soon as adequate urine production is established to reduce
Capillary Refill Time the risk of nosocomial infection. Increased urine production
CRT is usually prolonged in hypovolemic shock. However, CRT coupled with improvement in physical exam abnormalities
can also be affected by changes in vascular permeability such as suggests a positive response to treatment. Though urine specific
 CHAPTER 1 Shock 9

gravity can be used to assess renal concentrating efforts and and clearance capacity. For this reason, trends should be observed
consequently the water balance of the animal, it will be affected over 12 to 24 hours, while caution should be used when interpret-
by intravenous fluid therapy and is not an accurate reflection of ing short-term (1–2 hours) changes in lactate.
dehydration or volume status once bolus intravenous fluids have
been begun.
Oxygen Extraction
The normal response to a decrease in perfusion or CO is to
[Link]

Arterial Blood Pressure increase the oxygen extraction ratio (O2ER) of the blood as it
Arterial blood pressure is a reflection of CO and total vascular moves through the capillaries. By increasing the oxygen extraction,
resistance. Consequently, the measurement of a normal blood the body is able to maintain oxygen delivery to the tissue despite
pressure does not directly correlate with adequate perfusion and a fall in blood flow. Oxygen extraction is determined by the
oxygen delivery to peripheral tissue beds. Because of the com- difference between the oxygen saturation of arterial blood (SaO2)
pensatory increase in peripheral resistance, blood pressure does and oxygen saturation of venous blood (SvO2):
not consistently fall below normal until the blood volume is
profoundly decreased (30% or more). Though a normal blood O2ER = (SaO2 − SvO2 ) ÷ SaO2
pressure does not rule out hypovolemic shock, a low blood
pressure is often an indicator of significant blood loss. Treatment It can be determined by measuring central venous satura-
goals should be to maintain the MAP above 65 mm Hg to ensure tion and arterial oxygen saturation. Alternatively, O2ER can
adequate perfusion of the brain. Blood pressure can be measured be estimated by measuring jugular venous saturation and by
directly via arterial catheterization of the transverse facial artery using a pulse oximeter to assess arterial oxygen saturation. In the
in the adult horse or the transverse facial, metatarsal, radial, normovolemic, healthy individual, DO2 far exceeds oxygen need
and auricular arteries in neonates. Indirect measurement of the or uptake (VO2), and the O2ER ranges from 20% to 30% (one
blood pressure can be achieved using the coccygeal artery in of the four O2 molecules from each Hb is removed). The O2ER
adult horses and the metatarsal artery in foals.35 In healthy can increase with decreased perfusion to a maximum of 50%
individuals, there is good agreement between direct and indirect to 60% (two of the four O2 molecules are removed) at which
measurements.35–38 Direct, invasive blood pressure monitoring point oxygen delivery becomes supply or flow dependent and
is more accurate during states of low flow and significant a further drop in perfusion will result in a decrease in oxygen
vasoconstriction.36–38 Normal MAPs in healthy awake horses delivery. Because of this relationship, the O2ER can be used
obtained using indirect measurement at the coccygeal artery vary to estimate the severity of global perfusion deficits and is a
between 105 and 135 mm Hg.39 Care should be taken to use a useful measurement in evaluating the response to resuscitative
blood pressure monitor validated for use in horses, as some strategies.
devices are inaccurate or unable to calculate blood pressures at
low heart rates and in horses with arrhythmias.
Mixed Venous Partial Pressure of Oxygen
Mixed venous partial pressure of oxygen (PvO2) is a useful
Lactate measure to assess oxygen delivery for the same reasons that
L-lactate is the end product of the anaerobic metabolism of O2ER is. In low-perfusion states, more oxygen is extracted per
glucose. Aerobic metabolism of glucose results in the production volume of blood and, consequently, PvO2 will fall. Mixed venous
of 36 moles of adenosine triphosphate (ATP) per molecule of blood is ideally measured by catheterizing the pulmonary artery,
glucose. In the absence of adequate oxygen to meet energy because a sample from the jugular vein or cranial vena cava
demands, anaerobic metabolism of glucose to lactate results in only assesses venous blood returning from the head. Jugular
production of only 2 moles of ATP. Consequently, inadequate venous pressure of oxygen (PjvO2) is usually greater than PvO2
oxygen delivery to the tissue increases blood lactate concentrations in the shock state, but it still is useful in estimating global tissue
(type A hyperlactatemia). Less commonly, hyperlactatemia can hypoxemia.47,48 Normal PjvO2 ranges from 40 to 50 mm Hg and
develop despite appropriate tissue oxygenation (type B hyper- SjvO2 from 65% to 75%.47,49 Increased venous partial pressure
lactatemia) as a result of hepatic dysfunction (impaired clearance), of oxygen in the presence of significant perfusion or supply
pyruvate dehydrogenase inhibition, catecholamine surges, and deficits (DO2) can signify impaired oxygen consumption caused
sepsis or SIRS. by mitochondrial or cellular dysfunction. This syndrome has
However, the increase in lactate concentrations in type 2 cases been recognized in septic shock or after cardiopulmonary
is generally less than what is seen in horses with hypovolemia. resuscitation.
Because the lactate concentration generally correlates with oxygen
delivery and uptake by the tissues, it is a useful marker for
determining perfusion deficits and response to treatment. Delayed Cardiac Output
lactate clearance is shown to be associated with a poorer prognosis CO monitoring evaluates both volume return to the heart and
in many human and veterinary studies.40–46 A decrease in lactate cardiac function. With prolonged or specific types of shock
following therapy indicates improved oxygen delivery and use, (septic), cardiac function may deteriorate and increasing fluid
suggesting improved perfusion. Conversely, an increased or resuscitation will not resolve the clinical signs of end organ
persistently elevated lactate level indicates continued tissue oxygen perfusion deficits. The gold standard for CO monitoring is the
deficits. In some cases of severely reduced tissue perfusion, pulmonary thermodilution method, which requires catheterization
resuscitation attempts resulting in improved tissue perfusion of the pulmonary artery. This technique is rarely performed in
can result in increased plasma lactate concentrations as the lactate the equine clinical setting. An alternative technique, lithium
is flushed out of the tissues, temporarily exceeding the metabolism dilution, is relatively easy to use once experienced, and it has
 10 SECTION I Surgical Biology

been validated in the equine clinical setting. Injection of

lithium dye into the venous system results in generation of a Hypotensive Resuscitation and
lithium concentration–time curve, which is used to calculate Delayed Resuscitation
CO. Lithium dilution has been used successfully to monitor CO As previously discussed, aggressive large-volume fluid therapy
in adult horses and critically ill foals.50–53 Note that repetitive to restore blood pressure to normal values has potentially nega-
sampling can result in toxic accumulation of lithium.54 tive consequences. In situations of uncontrolled bleeding, this
Transcutaneous 2D echocardiography is becoming a more treatment will result in increased blood loss. Dilution of blood
[Link]

commonly utilized tool for noninvasive assessment and monitor- components (platelets and clotting factors) may additionally
ing of the cardiovascular status in critical patients. Volumetric worsen bleeding. Increasing systolic blood pressure to normal
methods (“four chamber area length,” “Simpson,” and “bullet”) values may dislodge or “blow out” a tenuous clot, leading to
for measuring CO have been shown to have better agreement further bleeding. Hypotensive resuscitation has been advocated
with lithium dilution CO than Doppler-based methods.51,55–57 to prevent or minimize further blood loss until surgical control
Because Doppler measurements require the ultrasound beam to or formation of a stable clot has occurred. In these situations,
be parallel with flow, which is difficult to achieve in an adult resuscitation to a lesser end point is recommended. The ideal
horse, there is large variability in the accuracy of this tech- end point or goal in hypotensive resuscitation is unclear. Strat-
nique.51,56,58 An ultrasound velocity dilution method has been egies include achieving a MAP of 60 to 65 mm Hg, using a
described in foals.59 This technique uses a bolus injection of predetermined, lower fluid infusion rate, or in some situations,
saline and an arteriovenous loop connected to ultrasound velocity completely delaying fluid resuscitation until bleeding is surgically
sensors. Pulse contour analysis or pulse pressure changes that controlled.65 In multiple animal models, controlled resuscita-
are useful for measuring responses to therapy in humans have tion (goal of MAP 40–60 mm Hg, or systolic blood pressure of
not been evaluated in horses but deserve further investigation 80–90 mm Hg) resulted in decreased blood loss; better splanchnic
as noninvasive measures of CO.15 perfusion and tissue oxygenation; less acidemia, hemodilution,
CO measurement has its greatest benefit in cases that fail to thrombocytopenia, and coagulopathy; decreased apoptotic cell
respond as expected to initial resuscitation efforts, cases with death and tissue injury; and increased survival.13,66–73 In cases
complex disease involving multiple organ systems, or those with of severe or ongoing bleeding, resuscitation with blood com-
cardiac disease. Assessment of CO and blood pressure is essential ponents is recommended to minimize the risk of coagulopathy,
when monitoring the response to vasopressor treatment. Because although data with respect to outcome compared to resuscitation
CO does not assess local tissue perfusion, its accuracy in evaluating with crystalloids in horses are currently lacking. This strategy
tissue oxygenation is poor. Many of the standard monitoring of hypotensive resuscitation (with whole blood as part of the
techniques are limited because they principally assess global fluid plan) is indicated in situations such as bleeding of the
function (e.g., CO) and global oxygen debt (e.g., mixed venous uterine artery in a pregnant mare, where ligation of the vessel
lactate), not regional tissue deficiencies. These global measures, is unlikely and of great risk to the mare and fetus. There are
while being helpful, do not assess the perfusion to high-risk currently no specific recommendations for end points of treat-
organs such as the gastrointestinal tract, and may provide a false ment in large animal species. If using blood pressure as the end
sense of security when used to monitor treatment response. With point, direct measurement is currently recommended to ensure
the exception of urine output, none of the above-described Accuracy.
measurements evaluate perfusion to regional vascular beds.
Because of the large variation in perfusion to specific tissues,
such as the gastrointestinal tract and the brain, these global Predicting Outcome
measures have poor sensitivity in determining oxygen delivery In a critical review, high-risk surgical patients were used as a
and uptake to “less important tissues.” model for shock because time relationships could be precisely
documented.74 Nonsurvivors had reduced CO and DO2 in the
intraoperative and immediate postoperative period. Survivors
Regional Perfusion had lower O2ER; higher hematocrits, VO2, and blood volume;
Several techniques have been developed in an effort to more and normal blood gases. In human trials, time is a strong
specifically assess these differences in regional perfusion. Non- predictor of survival, with survivors showing fast improvement
invasive measures of regional tissue perfusion in human patients or normalization of CO, perfusion, oxygen uptake, and clinical
include sublingual capnometry, near-infrared spectroscopy to variables.75 To this end, rapid control of hemorrhage, restoration
monitor muscle tissue oxygen saturation, transcutaneous tissue of perfusion, normalization of blood gas values, and preven-
oxygenation, orthogonal polarization spectral imaging, and tion of dilutional coagulopathy are predictors of survival. In
capnometry.60–62 Slightly more invasive techniques include patients with ongoing blood loss, controlled hypotension has
gastric tonometry, which evaluates CO2 production in the been shown to decrease in-hospital complications and possibly
stomach wall; infrared spectroscopic assessment of splanchnic increase survival rates. Lactate values, particularly lactate clear-
perfusion; and measurement of bladder mucosal pH.63,64 These ance, have been shown to be strongly associated with survival in
alternative techniques are based on the idea that the body pref- both clinical and experimental studies of shock.40–43 Though the
erentially shunts blood away from the skin and gastrointestinal data are not as robust, single lactate measurements and delayed
tract to spare more vital organs. As such, these methods will lactate clearance have been shown to be associated with higher
detect abnormalities in perfusion before many of the more mortality rates in both adult horses and foals.46,76,77 A poor or
established techniques. Although not yet fully evaluated in absent response to resuscitative attempts with continued evidence
the veterinary field, these techniques have been shown to be of perfusion deficits or the development of clinical evidence
sensitive markers of regional perfusion deficits in early shock of organ dysfunction, or both, are associated with a poorer
in humans. outcome.
 CHAPTER 1 Shock 11

hypothalamic-pituitary-adrenal axis (HPA), which increases

On the Horizon
sympathetic output. Because of this effect, modulation of pain
Treatment has been shown to be important in controlling the stress response
Although further research is required, there is strong evidence to trauma, and pain control should be strongly considered in
that a “balanced resuscitation” plan with goal-directed therapy the trauma patient.
in patients with hypovolemic shock provides improved outcomes The sympathoadrenal axis is stimulated through direct input
of survival when compared to the previous “aggressive resuscita- from injured nerves and by hypovolemia, acidosis, shock, and
[Link]

tion” strategies aimed to replace volume deficits in a short period psychologic responses (fear, pain, anxiety). Catecholamines have
of time. The perfect fluid protocol for treatment remains elusive, widespread effects on cardiovascular function (see “Pathophysiol-
and the debate between crystalloids versus colloids continues. ogy of Shock,” earlier in this chapter) and metabolism (see
Liposome encapsulated Hb may offer more benefits than other “Metabolic Response to Injury” in Chapter 6), and they stimulate
fluids because of its oxygen-carrying capacity. The presence of release of other mediators, including cortisol and opioids. The
Hb reduces the need for blood products, thereby lowering the catecholamine response is beneficial; however, prolonged
associated risks to the patient.78,79 In contrast to other synthetic sympathoadrenal stimulation can be detrimental because of its
oxygen carriers, liposome-encapsulated Hb vesicles do not appear effects on general body condition. Catecholamines increase
to cause peripheral vasoconstriction and in a rat model of peripheral vascular resistance, so ongoing stimulation leads to
hemorrhage appear to be as effective in restoring hemodynamic long periods of tissue ischemia.
and blood gas variables.80 Other triggers of cortisol secretion in trauma and shock include
AVP, angiotensin II, norepinephrine, and endotoxin. The degree
of hypercortisolemia correlates with the severity of injury and
Monitoring persists until the anabolic phase of healing begins. Cortisol
The ideal method to assess shock and treatment response would secretion results in sodium and water retention (edema), insulin
enable measurement of oxygen delivery at the tissue level as resistance, gluconeogenesis, lipolysis, and protein catabolism.
well as oxygen uptake and use. The ability to measure end organ Cortisol also affects leukocytes and inflammatory mediator
perfusion in veterinary patients, particularly in “less important” production and, although cortisol is critical for recovery from
organs like the epidermis, has potential implications in assessing acute injury, prolonged cortisol secretion can result in pathologic
the severity of the shock state, developing treatment goals, and suppression of the immune response.
predicting outcomes. The implementation and evaluation of AVP and the RAAS are important mediators of the stress
these techniques in equine critical care medicine is warranted. response. The reader is referred to the section on pathophysiology
of shock for further review of these mediators.
Endogenous opioids released from the pituitary gland as well
Physiologic Response to Trauma as from the adrenal glands in response to sympathetic stimulation
The metabolic response to trauma or injury has classically been are important mediators in the modulation of pain, catecholamine
divided into two phases—the ebb phase, which occurs during release, and insulin secretion. Endogenous opioids modulate
the first several hours after injury, and the flow phase, which lymphocyte and neutrophil function and may act to counter
occurs in the ensuing days to weeks. The ebb phase is characterized cortisol’s effect on immune function.
by hypovolemia and low flow or perfusion to the injured site. Local mediators released in response to injury trigger a
Once perfusion is restored, the flow phase begins. The flow phase multitude of cascades. Tissue factor exposure activates the coagula-
is divided into a catabolic period and an anabolic period. The tion and complement cascades and ultimately stimulates the
catabolic period is triggered by many of the same mediators inflammatory response. Cell membrane injury results in release
discussed in the earlier section on the pathophysiology of shock, and activation of the arachidonic acid cascade and production
and many of the clinical signs will mimic those seen in shock. of various cytokines, including prostaglandins, prostacyclines,
The anabolic period is characterized by the return to homeostasis. thromboxanes, and leukotrienes. These mediators have a multitude
Cortisol levels fall during this final period and normalization of functions including further activating coagulation and platelets;
of physiology occurs. The physiologic response to trauma is altering blood flow via vasoconstriction and vasodilation; and
complex, and the duration and progression will vary depending increasing chemotactic activity mediating the influx and activation
on the injury site, severity, and underlying condition of the patient. of inflammatory cells, with subsequent release of lysosomal
For more specific information regarding trauma of specific organs enzymes and reactive oxygen species (ROS). Microvascular
or body cavities, the reader is referred to chapters dealing with thrombosis at the site of endothelial injury causes further
those specific systems. This section is designed to provide an pathologic changes in perfusion. If perfusion is restored, elevated
overview of the complex pathophysiology of trauma. local concentrations of ROS, coupled with influx of oxygen, can
induce further oxidative stress and production of highly toxic
ROS that result in more tissue damage. Amplification of this
Mediators of the Stress Response: Ebb Phase response coupled with reperfusion can lead to the development
The stress response to trauma is initiated by pain, tissue injury, of SIRS and MOD.
hypovolemia, acidosis, shock, hypothermia, and psychological
responses. Direct tissue injury, ischemia, and inflammation activate
afferent nerve endings, which exert local and systemic effects via Response to Trauma: Catabolic Period
the central nervous system. Hypovolemia, acidosis, and shock Psychological response to trauma and shock is manifested in
exert their effects via baroreceptors and chemoreceptors located changes in behavior, withdrawal, immobilization or reluctance
in the heart and great vessels. Fear and pain have conscious to move, fear, anxiety, aggression, and malaise. These psychological
effects in the cortex, and they stimulate cortisol secretion via the responses can persist for long periods depending on the severity
 12 SECTION I Surgical Biology

of the injury and pain. In people, the psychological effect may levels decrease, a generalized feeling of well-being develops. The
persist long after the injury has resolved. Whether the same length of this period will depend on the severity of the injury,
happens in horses has yet to be determined. the number and type of complications, the patient’s condition
Many of the changes in vital signs will mimic those seen with before injury, and the length of the catabolic period of recovery.
hypovolemic shock. Cardiovascular changes including tachycardia, Healthy individuals that do not develop complications will likely
tachypnea, and other clinical signs of the hyperdynamic response recover more rapidly than debilitated patients that suffer complica-
may be seen. Fever during the early period after injury is typically tions, such as infection, and have a prolonged catabolic phase
[Link]

a response to injury and inflammation itself, particularly in of recovery.

patients with head trauma. Infectious causes of fever should be
suspected if fever persists or is recurrent days after the injury.
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 14 SECTION I Surgical Biology

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xi–xii.

CHAPTER

2 Systemic Inflammatory Response

Michelle Henry Barton and John F. Peroni

The systemic inflammatory response and failure of multiple organ Whether these goals are achieved or defeated, the host relies on
systems are syndromes that result from an inappropriate and a defense and repair response that is appropriate for the insult.
generalized inflammatory response to stimuli, which may or If the host overzealously responds, the same innate components
may not result from an infectious process. Although it appears that are meant for protection and repair may ironically turn out
that the phagocytic activation of the monocyte/macrophage cell to be just as detrimental or even more harmful to the host than
lineage is directly responsible for the development of clinical the initial insult. When the response to infection and injury
signs and symptoms, identifying the bacteria and neutralizing results in an incongruous and exaggerated systemic inflammatory
their toxins has not drastically changed the outcomes of patients reaction, the clinical state is referred to as the systemic inflammatory
affected by these syndromes. As a result, current management response syndrome (SIRS),1 which can be initiated by infection,
strategies and research efforts have been directed at addressing endotoxemia, or noninfectious insults, such as severe trauma,
infectious and noninfectious causes and identifying effective ways ischemia, immune-mediated disease, surgery, hypothermia,
of modulating the associated immune-mediated responses. The hyperthermia, or intense hypoxemia (i.e., hemorrhagic shock).
pathophysiology of these inflammatory-based syndromes has To counteract the proinflammatory response and deter the state
not been clarified in people or lab animal models, and very little of SIRS, the host relies on antiinflammatory opposition that
original work has been produced in the horse. A generally accepted includes production of cytokines, soluble cytokine receptors,
summary of these conditions is that bacteria or their endotoxins, receptor antagonists, prostaglandin E2, and corticosteroids.2 If
or both, induce and sustain a marked inflammatory response there is over-recruitment of the antiinflammatory processes, a
by the host, which eventually overwhelms sensitive organs and state of anergy, increased susceptibility to infection, and inability
often results in a fatal outcome. This chapter reviews the patho- to repair damaged tissues ensues. This scenario is referred to as
physiology of systemic inflammatory response and multiple organ compensatory antiinflammatory response syndrome (CARS).1 In some
failure with the viewpoint that inflammation, not bacterial circumstances, a mixed antiinflammatory response syndrome (MARS)
overgrowth, may directly generate these syndromes in the horse. arises, in which surges of both SIRS and CARS coexist.1 In the
circle of equilibrium, if SIRS and CARS are ultimately appropriately
balanced, then homeostasis resumes. Predominance of SIRS may
SYSTEMIC INFLAMMATORY culminate in adverse pathophysiologic events, such as dissemi-
RESPONSE SYNDROME nated intravascular coagulopathy (DIC), shock, organ failure,
With microbial invasion or any process that results in tissue and death. In this later scenario, dissonance has occurred and
damage, the ultimate goal of the immune system is to contain the patient is defined as having multiple organ dysfunction syndrome
infection, alarm the host to defend, and promote tissue repair. (MODS) or the presence of organ dysfunction associated with