Journal of

Clinical Medicine

Review
Carbon Monoxide Poisoning: From Occupational Health to
Emergency Medicine
Gabriele Savioli 1, * , Nicole Gri 2 , Iride Francesca Ceresa 3 , Andrea Piccioni 4 , Christian Zanza 5 ,
Yaroslava Longhitano 6,7 , Giovanni Ricevuti 8 , Maurizio Daccò 9 , Ciro Esposito 10 and Stefano M. Candura 11,12

1 Emergency Department, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
2 Niguarda Cancer Center, ASST Grande Ospedale Metropolitano Niguarda, Piazza dell’Ospedale Maggiore, 3,
20162 Milano, Italy; nicole.gri93@[Link]
3 Emergency Department and Internal Medicine, Istituti Clinici di Pavia e Vigevano—Gruppo San Donato,
27029 Vigevano, Italy; irideceresa@[Link]
4 Department of Emergency Medicine, Polyclinic Agostino Gemelli/IRCCS, Catholic University of the Sacred
Heart, 00168 Rome, Italy; [Link]@[Link]
5 Geriatric Medicine Residency Program, University of Rome “Tor Vergata”, 00133 Rome, Italy;
[Link]@[Link]
6 Department of Anesthesiology and Perioperative Medicine, University of Pittsburgh Medical Center (UPMC),
Pittsburgh, PA 15260, USA; [Link]@[Link]
7 Department of Emergency Medicine—Emergency Medicine Residency Program, Humanitas
University—Research Hospital, 20089 Rozzano, Italy
8 Emergency Medicine, School of Pharmacy, University of Pavia, 27100 Pavia, Italy; [Link]@[Link]
9 ATS Pavia, Continuità Assistenziale, Via Teodoro Lovati, 45, 27100 Pavia, Italy; maudacc@[Link]
10 Unit of Nephrology and Dialysis, ICS Maugeri, University of Pavia, 27100 Pavia, Italy; [Link]@[Link]
11 Occupational Medicine Unit, Department of Public Health, Experimental and Forensic Sciences, University of
Pavia, 27100 Pavia, Italy
12 Occupational Medicine Unit, Istituti Clinici Scientifici Maugeri IRCCS, 27100 Pavia, Italy
* Correspondence: gabrielesavioli@[Link]

Citation: Savioli, G.; Gri, N.; Ceresa, Abstract: Carbon monoxide poisoning remains a leading cause of accidental poisoning worldwide
I.F.; Piccioni, A.; Zanza, C.;
(both at home and at work), and it is also a cause of suicidal poisoning. Such poisoning can arise
Longhitano, Y.; Ricevuti, G.; Daccò,
following prolonged exposure to low levels of CO or following brief exposure to high concentrations
M.; Esposito, C.; Candura, S.M.
of the gas. In fact, despite exposure limits, high safety standards, and the availability of CO alarms,
Carbon Monoxide Poisoning: From
nearly 50,000 people in the United States visit the emergency department each year due to poison-
Occupational Health to Emergency
Medicine. J. Clin. Med. 2024, 13, 2466.
ing. Additionally, CO poisoning in the United States causes up to 500 deaths each year. Despite
[Link] the widespread nature of this form of poisoning, known about for centuries and whose damage
jcm13092466 mechanisms have been recognized (or rather hypothesized about) since the 1800s, early recognition,
especially of late complications, and treatment remain a medical challenge. A well-designed ther-
Academic Editors: Paolo Aseni,
apeutic diagnostic process is necessary so that indication for hyperbaric or normobaric therapy is
Timothy E. Albertson and Marc
correctly made and so that patients are followed up even after acute exposure to diagnose late com-
B. Sabbe
plications early. Furthermore, it is necessary to consider that in the setting of emergency medicine,
Received: 23 January 2024 CO poisoning can be part of a differential diagnosis along with other more frequent conditions,
Revised: 20 March 2024 making its recognition difficult. The last thirty years have been marked by a significant increase in
Accepted: 9 April 2024
knowledge regarding the toxicity of CO, as well as its functioning and its importance at physiological
Published: 23 April 2024
concentrations in mammalian systems. This review, taking into account the significant progress made
in recent years, aims to reconsider the pathogenicity of CO, which is not trivially just poisonous to
tissues. A revision of the paradigm, especially as regards treatment and sequelae, appears necessary,
Copyright: © 2024 by the authors. and new studies should focus on this new point of view.
Licensee MDPI, Basel, Switzerland.
This article is an open access article Keywords: poison; toxicity; carbon monoxide (CO); emergency department; ED management
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
[Link]/licenses/by/
4.0/).

J. Clin. Med. 2024, 13, 2466. [Link] [Link]

J. Clin. Med. 2024, 13, 2466 2 of 22

1. Introduction
Carbon monoxide (CO) intoxication and its severity in oxygen-dependent organisms
have been known about since ancient times. To understand its importance, we can think
that it has accompanied the history of man since the birth of fire and that of the universe a
long time before that [1–4].
In fact, every time the respiratory tract of a living being comes into contact with smoke
from a flame, the manifestations of monoxide poisoning can occur. All of this might appear
simple and linear, but CO poisoning often represents an insidious event due to its chemical–
physical characteristics and its extraordinary ability to interact with the “queen molecule”
of oxygen transport, earning it the name of “silent killer” and “invisible killer” [5].
However, CO is not only this: in recent decades, new studies have emerged that
would also suggest its therapeutic potential. However, it is obvious that since the Industrial
Revolution, its toxic effects have been the most studied, having dominated for a historically
longer period [1,6].
The objective of our research is to review the literature regarding carbon monoxide,
both in terms of the symptoms related to CO intoxication and the ways to quickly recognize
it in an emergency medicine setting, identifying the signs and symptoms that may arouse
suspicion and therefore making a rapid diagnosis. Furthermore, we also focused on the
immediate and late consequences, to provide concise knowledge of them, identify them,
and, to a certain extent, prevent them.
The ultimate aim of our work is to bring together the pathogenesis, mechanisms of
damage, and symptoms related to CO intoxication with a view to its treatment in emergency
department settings, providing ideas that can lead to the early recognition of intoxication
and its treatment.

2. Materials and Methods

We considered any articles in PubMed and Scopus matching specific keywords such as
carbon monoxide, carbon monoxide toxicity, carbon monoxide intoxication, CO acute intox-
ication, CO workplace intoxication, and CO intoxication management, finding 1378 articles.
After 3 independent authors and 2 senior experts filtered the selected articles based on emer-
gency medicine, anesthesia, basic medicine, pharmacology, and occupational medicine, we
ultimately considered 324 suitable papers.
Finally, 175 papers were analyzed and considered for this review after further screening
led to the exclusion of meeting abstracts, books, unavailable manuscripts, original papers
without abstracts, brief reports, and papers not in English.

3. Results
The results are schematically represented in Figure 1.

3.1. Chemical–Physical Properties and Exposure

Carbon monoxide (CO) is an odorless, colorless, tasteless, non-irritating gas. It is
also a highly reactive molecule, flammable, and miscible with air. It is a highly toxic
gas primarily produced through the incomplete combustion of organic material and of
substances containing carbon (with a lack of oxygen), where it can represent an unwanted
byproduct or be methodically produced to exploit its chemical–physical properties (Table 1).

Table 1. Characteristics of carbon monoxide.

CAS 630-08-0
EC: 006-001-00-2 Molecular formula: CO
Other names: Carbon monoxide, carbonic oxide
Physical state at 25 ◦ C: Gas (odorless and tasteless)
Molecular weight: 28.01 g/mol
Melting point: −205 ◦ C
Vapor pressure: Not applicable
Boiling temperature: −191 ◦ C
J. Clin. Med. 2024, 13, 2466 3 of 22

Table 1. Cont.

Relative vapor density (air = 1): 0.97 Solubility in water: 2.3 mL/100 mL at 20 ◦ C
Conversion factors:
Self-ignition temperature: 605 ◦ C
- 1 mL/m3 = 1.83 mg/m3
Flash point: −101.6 ◦ C
- 1 ppm = 1.14 mg/m3
Explosive limit: 12.5–74.2 vol (%)
- 1 mg/m3 = 0.87 ppm

Figure 1. Infographic of results.

The substances from which CO can be produced include coal, wood, petrol, and diesel.
CO can spread and accumulate very insidiously in confined spaces, passing through walls
and ceilings (Table 2) [5–9].
In working environments, those who carry out their profession in areas with heavy
vehicular traffic, such as train drivers, valets, and garage operators, as well as police,
firefighters, and kitchen workers, are exposed to CO [10,11].
With the identification of its chemical composition at the end of the 19th century, the
first experimental studies began with the aim of identifying its mechanisms of toxicity. At
the same time, the production of so-called illuminating gas or city gas began (containing
4–10% CO, mixed with other elements, including hydrogen, titanium, and other com-
pounds). As its name suggests, it was used for public and domestic lighting, causing
a further increase in cases of poisoning, involuntary or voluntary, such as for suicidal
purposes, before being replaced by methane [4,12,13].
J. Clin. Med. 2024, 13, 2466 4 of 22

Table 2. Main industrial activities with exposure to CO.

Industrial Sector Processing

- Treatment of coke oven gas
- Coke extinguishing
Fuel
- Production and distribution of illuminating gas
- Gasification of solid fuels
Siliceous products - Use of ovens
- Use of ovens
- Production of CO and its mixtures
Chemistry and petrochemistry
- Production of calcium carbide (CaC2 ), acetylene (C2 H2 ),
hydrogen cyanide (HCN), and organic compounds
- Use of ovens
Metallurgy and engineering - Welding and cutting with a blowtorch
- Repair, maintenance, and use of engines

The causes of CO exposure and intoxication present variable percentages between

different states and communities, being in most cases traceable back to environmental,
occupational, or domestic exposure. Causes of home exposure include accidental fires,
defective heating systems, and suicidal exposure to vehicle gas. In the workplace, CO
poisoning and death should be considered in the presence of machinery located in confined
or poorly ventilated spaces [14–18].

3.2. The Environmental Problem

CO is not just a work-related issue, as previously described: its role from an envi-
ronmental point of view is now evident. CO, derived from natural sources (volcanos,
combustion, plant metabolism, photochemical oxidation of organic compounds), repre-
sents a ubiquitous component of the atmosphere (at a concentration lower than 0.2 ppm).
In addition to the CO produced by natural sources, the share produced by anthropogenic
sources (motor vehicle traffic, heating systems, industrial emissions, fires, tobacco smoke)
must be taken into account. It follows that in large urban centers, where there are areas
with high traffic, its concentration reaches considerably higher values (up to 10–20 ppm
or more in particularly polluted areas). High concentrations of CO can be easily reached
in confined and poorly ventilated areas, such as in the passenger compartments of motor
vehicles with malfunctioning exhaust systems, in areas of intense traffic, or in underground
garages or garages isolated from the external environment [7].
Exposure can also occur in the presence of stoves, boilers, water heaters, cookers,
braziers, and devices installed improperly or in poor maintenance conditions [5,19,20].
Furthermore, CO is also a cause of death in the fishing industry; this should conse-
quently lead to greater control of the equipment on fishing vessels, looking for potential
defects. Exposure to CO should also be considered in both commercial and recreational
scuba diving, as the molecule can easily accumulate in hoses and equipment [17,18].
The risk of CO poisoning can also be present in environments intended for recreational
or sporting activities, such as ice skating rinks, where motorized machinery is used for
surface maintenance. CO also contributes to the morbidity and mortality of fire victims due
to its chemical ability to interact synergistically with other combustion compounds, such
as hydrogen cyanide (HCN), nitrogen and sulfur oxides, ammonia, chlorine, phosgene,
halogenated acids, isocyanates, and acrolein, which exert irritating and harmful action in
the respiratory system [21–24].
Tobacco smoke is also a well-known and well-documented source of CO. In smokers,
in fact, there is an increase in COHb levels (which can reach 10–12% in heavy smokers).
It is certainly true that, in confined spaces, the presence of smokers can cause an increase
in the environmental concentration of CO; it is equally true that, however, before the
J. Clin. Med. 2024, 13, 2466 5 of 22

concentration of the gas reaches dangerous levels, irritation due to other components of the
smoke becomes intolerable [25].

3.3. Kinetics and Metabolism

Although it can be assumed that most CO is absorbed from the environment through the
airways, there is a share of CO that is produced through endogenous mechanisms [26–28].
There is a share of endogenous CO produced by various physiological processes,
including heme catabolism and lipid peroxidation. This quota is equal to about 0.42 mL/h
and should not produce CO-Hgb levels in excess of 1%. Endogenous CO performs a
function similar to that of nitric oxide (NO), which is produced from the amino acid L-
arginine. In fact, the two molecules share different biological and chemical properties: the
L-arginine–NO system acts as a transduction system in different cellular functions. CO,
similar to NO, can perform the same function, binding with the iron atom of the porphyrin
group of cytoplasmic guanyl cyclase and with the Fe-S group of various enzymes [7,29–31].
Representing a byproduct of heme degradation, it is clear that endogenous CO produc-
tion increases under pathological conditions that accelerate the metabolism of hemoglobin
and other hemoproteins. These disorders include hemolysis, hemolytic anemia, hematoma
resorption, thalassemia, Gilbert’s syndrome, and sepsis [7,32,33].
The endogenous formation of CO has been measured using different analytical pro-
cedures in different biological systems. In humans, the formation of CO is equal to
0.029 nmol/mg protein/h in the chorionic villi of the term placenta, and it plays a role in its
vascular control. The exact mechanism by which CO is produced in the placenta remains
unknown; however, it has been postulated that it occurs through a combination of lipid
peroxidation and heme degradation on the part of heme oxygenase (HO) [34–36].
Furthermore, CO can also be generated by the hepatic metabolism of methylene chloride
(dichloromethane: CH2 Cl2 ). The main CO transport mechanism is respiratory, i.e., through the
airways, through which environmental CO is rapidly absorbed. It is transported in the blood
in two ways: most of it binds to hemoglobin (its binding to which determines the formation
of COHb), while a small amount is dissolved in the plasma. The plasmatic share diffuses into
tissues, generating toxic intracellular effects. Another portion (equal to 1–10%) is oxidized
into CO2 (mainly by mitochondrial cytochrome oxidase). Like absorption, elimination also
occurs via the respiratory route. The half-life of CO is 4–5 h [37–39].
Due to the endogenous production of CO, normal subjects (non-smokers) have COHb
values around 0.5%. This concentration is higher in inhabitants of urban centers or in
polluted centers (equal to 1–2%). In smokers and heavy smokers (following inhalation
of the CO contained in tobacco smoke), it reaches percentages of up to 8–10% or more.
Cigarette smokers are exposed to an estimated 400 to 500 ppm of CO while actively
smoking [25,40–42].

3.4. Mechanisms of Toxicity

In physiological conditions and concentrations, endogenous CO performs various
functions, functioning as a neurotransmitter, as a modulator of inflammation, as a regulator
of cell proliferation and apoptosis, and as a regulator of mitochondrial function [43–46].
The main biochemical effects and mechanisms of CO toxicity have been studied and
have been known since the 1800s [7,8].
Earlier studies attributed the toxic effects of CO to its strong hemoglobin binding
capacity; today, this sentence must be presented as a historical note. There is now common
agreement that this is its least influential toxic mechanism because tissue toxicity is by far
the most influential [13,47–49].
CO binds to hemoglobin with an affinity up to 200–250 times greater than that of O2 ,
with the consequent formation of COHb, causing a leftward shift in the oxygen–hemoglobin
dissociation curve, resulting in tissue hypoxia. However, this affinity has never been proven
by studies conducted on humans, only in vitro and animal studies [50–54].
 J. Clin. Med. 2024, 13, 2466 6 of 22

However, decreased peripheral O2 release is not the only pathogenetic mechanism; CO

poisoning underlies more complex mechanisms of toxicity that go beyond simple COHb
formation and oxygen displacement [55–57].
Carbon monoxide causes oxidative stress (due to increased levels of cytosolic heme)
and interrupts cellular respiration (through binding to platelet proteins and cytochrome c
oxidase) with the production of reactive oxygen species, which cause apoptosis and neu-
ronal necrosis. The alteration of cellular respiration triggers the mechanisms of response to
stress, with the activation of hypoxia-inducible factors and alterations of genetic expression.
Furthermore, CO exposure is able to induce inflammation through hypoxia-independent
pathways, which also underlie neurological and cardiac damage [58–64].
The toxic mechanism of CO is determined by a combination of hypoxia and ischemia
due to the production of COHb and the direct toxicity that occurs at the cellular level. For
this reason, and because of this combination, the severity of clinical effects and symptoms
does not correlate directly with the amount of COHb [41,65–69].
In fact, in addition to hemoglobin, CO is also able to interact with other protein
structures containing porphyrin groups, including oxidase, catalase, myoglobin (Mb), and
various cytochromes, including cytochrome a3 and cytochrome P450. Binding with cy-
tochrome a3 generates a direct toxic effect on cellular respiration, resulting in the formation
of oxygen free radicals. In the end, the inactivation of mitochondrial enzymes and the
production of free radicals (in particular peroxynitrite) determine the impairment of cellular
respiration, with consequent alteration of the electron transport chain. The action exerted
on cytochrome a3 is the same as that mediated by cyanide ions [7,70–73].
On the other hand, binding with Mb determines a reduction in O2 transport in the
muscles due to the formation of carboxymyoglobin (COMb), with direct effects on the
skeletal muscle, inducing toxicity and rhabdomyolysis.
Myoglobin binding also reduces oxygen availability to the heart muscle, which is
a major target (along with the brain) of CO poisoning, resulting in artemia, abnormal
contraction, and cardiac dysfunction. In some cases, the onset of compartment syndrome
and acute renal failure due to acute tubular necrosis have also been reported [7,25,74–78].
The brain is one of the main targets of the toxic action of CO, representing, together
with the myocardium, one of the tissues with the highest oxygen demand. The toxicity
of CO at the encephalic level is determined by the activation of guanylate cyclase, with
an increase in cyclic guanylyl monophosphate and consequent cerebral vasodilatation.
J. Clin. Med. 2024, 13, x FOR PEER REVIEW
EER REVIEW In animal 7 of 23 has ultimately led to a loss of
J. Clin. Med. 2024,models
13, x FORofPEER
CO REVIEW
poisoning, cerebral vasodilation
EER REVIEW 7 of 23
consciousness (Table 3) [25,79–81].

Table 3. CO toxicity mechanisms.J. Clin.

TableMed.
3.2024, 13, x FOR
CO toxicity Table 3. CO toxicity mechanisms.
PEER REVIEW
mechanisms.
EER REVIEW 7 of 23
Table 3. CO toxicity mechanisms. Table 3. CO toxicity mechanisms.
J. Clin. Med. 2024, 13, x FOR PEER REVIEW
EER REVIEW 7 of 23
EFFECT
EER REVIEWEFFECT J. Clin. Med. 2024, 13,
MECHANISM EFFECT
x FOR PEER REVIEWMECHANISM 7 of 23
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J. Clin. Med. 2024, 13, 2466 7 of 22

a paragraph will be devoted to the delayed neurological syndrome, which must be carefully
suspected in the presence of neurological symptoms and in the presence of a positive history
of CO poisoning [83,84].
Most intoxications occur during the winter period, involving the economically disad-
vantaged strata of the population living in apartments without centralized heating systems.
Often, the symptomatology involves several people belonging to the same family. The
presence of these factors and the presence of collective symptoms must raise suspicion of
CO poisoning [5,19].

3.6. Acute Oxycarbonism

The picture of acute (or subacute) CO intoxication is characterized primarily by neuro-
logical and cardiological symptoms and signs; the severity of intoxication is correlated both
with the environmental concentration of CO and with the duration of exposure. The heart
and the brain are the organs that show the first signs of injury, being the tissues most depen-
dent on an oxygen supply. In the following two paragraphs, the neurological symptoms,
cardiological symptoms, and other symptoms of CO poisoning will be analyzed.

3.6.1. Neurological Symptoms

The initial CO poisoning symptoms include headache, nausea, and dizziness. With
increasing exposure, the symptoms become more severe and characteristic. In healthy subjects,
on average, the first symptoms appear after 4 h of exposure to 200 ppm [5,25,41,85,86].
Headache is the earliest and most common symptom; it has the characteristics of being
frontal and continuous. In the case of neurological symptoms, imaging techniques (CT,
MRI) often document degenerative symmetrical alterations, with the involvement of the
nuclei of the base and of the subcortical white matter. These alterations rarely involve other
areas of the brain. The presence of these alterations has a negative prognostic significance.
Increased exposure results in other neurological symptoms, such as altered mental status,
confusion, syncope, and convulsions, up to acute syndromes that mimic stroke and coma.
Isolated seizures are very common in pediatric patients, with other neurological symptoms
appearing more subtle [25,41,87–91].
Furthermore, the presence of systemic hypotension during CO poisoning is directly
related to the severity of the structural damage at the level of the central nervous system. In
particular, experiments conducted on resus monkeys, which had been exposed for 75–325 min
and had received from 0.1% to 0.3% CO, showed the onset of various effects on the central
nervous system, including severe deficits, paralysis of the limbs, alterations of muscle tone,
deafness, and blindness. The characteristic brain lesion was bilateral destructive leukoen-
cephalopathy, with major involvement of the frontal and posterior parietal regions. Lesions
of the globus pallidus and hippocampus were also noted. The size of the lesions correlated
not only with hypotension but also with the degree of metabolic acidosis. Surprisingly, in-
jury severity was not correlated with the extent of hypoxia, suggesting that it was crucially
determined by other factors, although hypoxia was a preconditioning factor [92–94].

3.6.2. Cardiovascular and Other Symptoms

The primary cardiovascular effect of CO poisoning is hypoxia-induced tachycardia.
Subsequently, more significant exposures determine the onset of hypotension, arrhythmia,
ischemia, infarction, and, in extreme cases, cardiac arrest. Cardiac arrhythmia represents
the main cause of early death after exposure to monoxide. Hypotension is determined by
a combination of direct cardiac damage (due to hypoxia/ischemia), myocardial depressant
activity (due to the action of myoglobin), and peripheral vasodilatation. Furthermore, CO
can exacerbate underlying cardiovascular diseases, making this group of patients particularly
fragile and particularly susceptible to the onset of cardiovascular symptoms [57,62,95–99].
CO poisoning can cause rhabdomyolysis and acute renal failure, as an effect and as
a consequence of direct toxic damage to the skeletal muscle and the ability of CO to bind
myoglobin [64,100,101].
J. Clin. Med. 2024, 13, 2466 8 of 22

Less common symptoms and signs include skin blisters and non-cardiogenic pul-
monary edema. Contrary to popular belief, a “cherry red” skin color, which is considered a
hallmark of CO intoxication, is not commonly observed in clinical practice [102,103].
Then, there are alterations in the acid–base balance, which vary according to the
severity of the intoxication. In grade 3 intoxications (medium-severity), the most com-
mon acid–base disorder is respiratory alkalosis, to compensate for hypoxia; in grade 4
(more severe cases), the most frequent disorder is instead metabolic acidosis (due to the
overproduction of lactates resulting from hypoxia). In the latter case, the skin being a
bright red color (cherry red), induced by vasodilation, and the presence of COHb are often
associated. Possible complications include acute pulmonary edema, aspiration pneumonia,
rhabdomyolysis, compartment syndrome, and renal failure. COHb concentrations >50–70%
are often fatal (Table 4) [5,19,25,104–106].

Table 4. Classification of CO intoxication according to the Italian SIMEU guidelines.

SEVERITY CLASS SIGNS AND SYMPTOMS

ASYMPTOMATIC
Absent (with positive COHb values)
(grade 1)
MILD
Headache, dizziness, nausea, vomiting
(grade 2)
Mental confusion, slow thinking, blurred vision, asthenia,
AVERAGE
ataxia, abnormal behavior, shallow breathing, exertional
(grade 3)
dyspnea, tachypnea, tachycardia, abnormal psychometric test
Drowsiness, sensory blunting, coma, convulsions, syncope,
SERIOUS disorientation, brain CT changes, hypotension, chest pain,
(grade 4) palpitations, arrhythmias, ECG ischemic signs, pulmonary
edema, myonecrosis, skin bullae, lactic acidosis

Pregnant women are particularly fragile to exposure to CO, where intoxication repre-
sents a unique scenario, as CO easily crosses the placenta. Maternal exposure to CO would
result in higher peak fetal COHb levels, with slower elimination of CO than that of maternal
COHb. Severe maternal exposure in humans is linked to an increased risk of miscarriage,
stillbirth, anatomical malformations, and neurological disability. Maternal symptoms do
not correlate directly with the severity of fetal symptoms: even in slightly symptomatic
mothers, the effects on the fetus can be serious, up to fetal death. The fetus being of an
early gestational age is more closely related to anatomical malformations; on the other
hand, functional disturbances and poor neurological development can be evident at any
gestational age. Fetal damage is more evident in the brain, particularly in the basal ganglia
and globus pallidus at autopsy. If the infant reaches full term, it often has a low birth
weight and may develop postnatal neuropsychological developmental delay [41,107–113].
Because of CO’s tighter binding to fetal than adult hemoglobin, infants are more
vulnerable to its effects, making carbon monoxide poisoning potentially lethal in newborns.
Pediatric patients are also more vulnerable to the effects of CO due to a higher oxygen
uptake rate and higher metabolic rate. Despite this, the symptomatological set of pediatric
patients is often non-specific (nausea and vomiting), causing difficulties in differential
diagnosis, as this mimics viral disease [114–117].
COHb levels do not correlate with the severity of the clinical picture; this happens
only for values greater than 40–50%. This depends on several factors. First, the COHb
concentration does not reflect the amount of gas actually inhaled, as it decreases by half
every 4–5 h (more rapidly if oxygen is administered). Second, COHb is not directly
representative of the amount of CO bound to intracellular targets (myoglobin, cytochromes),
which contribute significantly to its toxicity. Third, it is necessary to take into account
factors such as individual sensitivity and the presence of concomitant pathologies. In
intoxicated people who survive to receive assistance in hospital, the mortality is around 3%.
At autopsy, the cherry red color of the blood and hypostasis in the muscles and organs are
J. Clin. Med. 2024, 13, 2466 9 of 22

characteristic; the lungs are distended and edematous, while the brain and myocardium
may show areas of ischemic necrosis [5,19,25,89].

3.7. Presentation and Management in EDs

Patients can therefore arrive in EDs with all these acute symptoms, which must be
placed in differential diagnosis with many other pathologies. Cardiac rhythm disorders
can be caused by other toxicants, metabolic disorders, ischemic disorders, and many
other things. Chest pain can be caused, among other emergencies, by cardiac ischemia,
myocarditis, diseases of the thoracic aorta, pulmonary embolism, pneumothorax, pneumo-
mediastinum, diseases of the pleura and esophagus, and many other things [118].
Neurological symptoms can be an expression of other emergencies, such as cerebral
ischemic pathology, Acute Disseminated Encephalomyelitis (ADEM), cerebral hemorrhage,
neoplastic masses, and metabolic or infectious diseases [118,119].
All these pathologies are part of a differential diagnosis and are emergencies that
require timely exclusion/confirmation diagnoses and immediate treatments. Obviously,
pathologies that do not represent emergencies are also part of the galaxy of differential
diagnosis, as in the case of syncope due to benign causes. Conversely, patients who
experience syncope due to carbon monoxide intoxication may suffer head trauma or other
trauma, with the consequent activation of other therapeutic diagnostic pathways, perhaps
also due to associated therapies that increase the risk of traumatic bleeding and therefore
require their activation [120,121].
The activation of these protocols must not delay the diagnosis of carbon monoxide
poisoning. It should be remembered that a fall at home can cause serious trauma to an
elderly person, resulting in worse outcomes [122].
Patients arriving accompanied by local services may already be suspected to have
monoxide poisoning if a CO detector has alerted the rescuers. However, this may not be
the case because the subject may no longer be in the place, however nearby it is, where
intoxication occurred. Patients who arrive in the ED, however, represent a more complex
diagnostic challenge because it may not be possible to collect a reliable medical history, as
demonstrated in elderly patients or patients with mental disorders or trauma [123–125].
In EDs, a differential diagnosis might be challenging due to the lack of an accurate
medical history and information about the patient’s baseline cognitive function, especially
when caregivers are not available. For example, up to 40% of older adults are unac-
companied, especially when patients arrive by ambulance and/or from long-term care
facilities [126,127].
The difficulties listed herein increase in conditions of ED crowding, a condition that is
increasingly more frequent and related to worse outcomes [128,129].
In conditions of crowding, the doctor–patient and nurse–patient relationships become
unbalanced, making the process more difficult and more susceptible to worse outcomes,
from perceived quality to mortality [130,131].
Since the therapeutic diagnostic process begins at triage, it is necessary to remember
how triage, in real life, is a complex process and how crowding influences the triage
itself [132].
In the opinion of the authors, performing an arterial or venous blood gas analysis in
triage for all neurological disorders, cardiac rhythm disorders, and chest pain is considered
the proper path. In fact, a good blood gas analysis allows you to detect not only the presence
of CO but also hypoglycemia, low hemoglobin values (which could cause, for example,
discrepancy angina), and other alterations and therefore provides elements for better
assessment of a patient. In situations where blood gas analyses cannot be performed in
triage, it is advisable for them to take place at first medical contact. The authors recommend
good collaboration with the relevant anti-poison center, either in each individual case
or with training and refresher courses in selected cases. Depending on the severity of
the symptoms and the characteristics of the patient, hyperbaric chamber therapy may
be necessary, as will be illustrated in detail below in the description of therapy. For this
J. Clin. Med. 2024, 13, 2466 10 of 22

to happen smoothly, the regional hub-and-spoke system must be well defined, and the
dialogue between structures must be constant. Patients, whether they do not require
hyperbaric therapy or are waiting for or returning from hyperbaric therapy, can benefit
from observation and therapy in dedicated areas such as holding areas or observation
areas with a medium–high intensity of care within EDs. These areas can contribute to
improving outcomes and adherence to guidelines and determining a better appropriateness
of treatments and hospitalizations, as already demonstrated in various pathologies and
cases of fragile patients [133–135].

3.8. Chronic Clinical Effects

CO’s chronic clinical effects are less well known due to the inherent difficulties in
quantifying the degree of CO exposure compared to the degree of neurological impairment.
On exposure to low levels of CO, the onset of a neurological syndrome characterized by
headache, dizziness, nausea, cerebellar dysfunction, and cognitive and mood disturbances
has been reported; this symptomatology tends to regress and is revealed once the subject
is removed from a poisonous environment. However, these studies have confounding
factors, as exposure data are lacking. Chronic exposure to CO has also been associated
with decreased physical performance, exacerbation of heart disease, and low birth weight.
Furthermore, chronic hypoxia determines polycythemia and cardiomegaly [136–141].

3.9. Delayed Neurological Syndrome (DNS)

Delayed neurological syndrome (DNS), or delayed encephalopathy, is characterized
by a neurological clinical picture that arises after acute CO intoxication and after a period of
apparent recovery. It generally occurs within 40 days of exposure, although longer latencies,
up to 8 months, have also been reported. The onset of the syndrome is unpredictable. The
true prevalence of DNS is difficult to determine; the estimates range from 1% to 47% of
patients after CO poisoning. The exact incidence rate is also unclear. Studies using rigorous
methodologies, including neuropsychological testing, report the frequency to be as high
as 67%. As for its pathogenesis, it is not clear. In addition to the CO toxicity mechanisms
described in the previous paragraphs, peroxidation of the lipids in the brain with free
radical damage and overstimulation of the excitatory amino acid receptors would also be
implicated. Oxygen therapy may have a preventive role, counteracting these mechanisms
of damage [83,84,142–144].
The risk factors include an age over 40 years, cardiovascular disease, prolonged
exposure to CO (greater than 1 h), electroencephalographic abnormalities, and coma
(especially if prolonged and followed by persistent asthenia and vertigo). It has been
observed that patients with a broader symptomatic clinical picture at onset have a greater
chance of developing long-term neurological sequelae [140,145–147].
The clinical symptoms of DNS overlap with those of any known neurologic clinical
syndrome with neurologic or psychiatric symptoms, possibly including motility disorders
(parkinsonism, choreoathetosis), gait disturbance, autonomic dysfunction resulting in
incontinence (urinary and fecal), seizures, and cortical blindness. Symptoms similar to
those of multiple sclerosis, peripheral neuropathies, Wernicke’s aphasia, and Korsakoff
syndrome, but also agnosia, mutism, dementia, personality changes, psychosis, and bipolar
syndromes, have also been reported. Furthermore, the use of neuropsychological tests
allows us to demonstrate more subtle alterations, which are not evident on neurological
examination. The syndrome can resolve spontaneously, but healing can take more than
two years. In other cases, DNS can result in permanent neurological damage, resulting in
severe impairment of a patient’s quality of life [73,145,146,148].

3.10. Endocrine Disorders

As has been previously reported, the heart and brain represent the organs most affected
by carbon-monoxide-induced hypoxia due to their high metabolism [149–152].
J. Clin. Med. 2024, 13, 2466 11 of 22

The effects of CO on the heart and neurological sequelae are among the main causes
of mortality following CO intoxication. In addition to hypoxia, recent evidence has sug-
gested that CO intoxication can induce inflammatory and immunological reactions in
several organs, resulting in endocrine disorders. These endocrine disorders are induced
at the cerebral level through the alteration of the hypothalamic–pituitary axis by carbon
monoxide intoxication, which has repercussions at the peripheral level for the endocrine
organs subjected to the control of the axis. In particular, we can cite a study conducted
in Taiwan (in 2017), where it was found that the risk of developing diabetes increased by
approximately 2 times after carbon monoxide intoxication due to a combination of damage
to the hypothalamus, brainstem, and pancreas. The risk of diabetes in the presence of CO
intoxication increases in patients <35 years of age and in elderly patients (≥65 years of age),
of the female sex, and with hyperthyroidism, heart failure, or polycystic ovary syndrome.
This risk lasts up to 4 years after exposure [153–155].
CO intoxication also leads to alterations in the adrenal glands, responsible for the
production of three classes of hormones fundamental to the correct functioning of impor-
tant functions in our organism (glucocorticoids, mineralocorticoids, and androgens). In
particular, control of cortisol secretion (the most important glucocorticoid produced by
the adrenal glands) is strictly regulated by the hypothalamic–pituitary–adrenal axis. Any
dysfunction of this important pathway (centrally or peripherally), including that caused by
CO, can contribute to the onset of adrenal insufficiency [151,156,157]. Furthermore, the risk
of developing adrenal insufficiency is greater in patients who experience acute respiratory
failure (ARF), in women and younger populations, and a year after follow-up [152].
Another endocrine disorder caused by CO intoxication is hypothyroidism. Similarly
to adrenal insufficiency, hypoxia and the consequent production of free radicals, resulting
in an inflammatory substrate, can one of the causes that determines the alteration of thyroid
function and then hypothyroidism. Thyroid function and the secretion of thyroid hormones
are regulated by the hypothalamic–pituitary–thyroid (HPT) axis. Hypothyroidism can
therefore be caused both by lesions at the central level (hypothalamus and pituitary gland)
and in the local organ (thyroid gland) [158–160].

3.11. Autoimmune Connective Tissue Disease

Although the evidence and studies on the matter are limited, CO intoxication can lead
to an increased risk of developing autoimmune connective tissue diseases.
Connective tissue diseases include a spectrum of pathologies (systemic lupus ery-
thematosus, rheumatoid arthritis, scleroderma, Sjögren’s syndrome, mixed connective
tissue disease), characterized by spontaneous hyperactivity of the immune system (with
consequent overproduction of antibodies), to which both genetic and environmental factors
contribute. Carbon-monoxide-induced hypoxia, oxidative stress, and inflammation can
increase the risk of autoimmune disease by mediating the production of autoantibodies,
leading to T cell dysfunction and oxidative modification of self-antigens. Oxidative stress,
on the other hand, would be implicated in the pathogenesis and mechanism of damage of
systemic lupus erythematosus. As regards Sjøgren’s syndrome, this would be triggered by
oxidative stress and mitochondrial dysfunction [160–165].
In a recent study, participants with CO poisoning were found to have a higher risk of
autoimmune connective tissue disease than those who had not been poisoned, after adjust-
ing for sex, diabetes mellitus, infectious diseases (H. zoster, HIV, Lyme disease, hepatitis,
mononucleosis), liver disease, malignancy, hypertension, hyperlipidemia, coronary heart
disease, congestive heart failure, chronic obstructive pulmonary disease, and drug abuse.
This increased risk is observed even after 4 years of follow-up; therefore, patients who
experience CO intoxication should undergo a long follow-up, aiming to highlight the onset
of connective tissue diseases and other autoimmune disorders [163–167].
J. Clin. Med. 2024, 13, 2466 12 of 22

3.12. Effects of Prolonged Exposure

Chronic exposure to CO remains a controversial topic, as the possibility of its oc-
currence is very doubtful. In reality, it is believed that the clinical picture that occurs,
defined as chronic oxycarbonism, is more correlated with the sequelae of repeated (and
misunderstood) episodes of subacute intoxication. This syndrome has been described
in workers exposed to CO for years, characterized by a triad of symptoms (asthenia,
headache, dizziness). This symptomatology can also be associated with both neurological
(parkinsonism, epilepsy, otovestibular disorders) and cardiac (arrhythmia, precordial pain)
manifestations [168–171].
A controversial aspect, not yet fully clarified, would concern the possibility of CO
acting as an atherogenic trigger. On the one hand, although many studies tend to exclude
the role of CO in cardiovascular pathology, on the other hand, studies conducted on various
animal species would demonstrate that repeated exposure to relatively low doses (such as
to determine COHb levels of 5–10%) would favor the appearance of aortosclerosis, above
all in the coronary artery. In agreement with the latter observations, several epidemiolog-
ical studies document a higher rate of mortality from ischemic heart disease in subjects
occupationally exposed to CO, including workers exposed to motor vehicle emissions. The
atherogenic mechanism of CO may be related to endothelial hypoxic insult, which would
partially account for the increased cardiovascular risk in smokers [10,11,41,168–172].

3.13. Diagnosis
3.13.1. Clinical Evaluation
Patient evaluation should carefully evaluate the adequacy of ventilation and perfusion,
exposure history, neurologic examination, and cardiac evaluation. The diagnosis of acute
CO poisoning is based, when possible, on anamnesis (recent exposure), the clinical picture
(signs and symptoms), and any evidence of collective symptoms.

3.13.2. Dosage of COHb: The Fundamental Diagnostic Test

The dosage of COHb represents the fundamental diagnostic test: levels > 3–5% (>10%
in smokers) are indicative of intoxication. To evaluate COHb levels, the broad consensus
is to perform a venous blood gas analysis. In fact, given the high diffusibility of CO,
the arterial and venous vascular compartments are in rapid equilibrium, and venous
sampling is therefore sufficient to determine CO. Note that COHb levels are absolutely
not an expression of the severity of intoxication; they are in fact an indicator of exposure,
but over time, they normalize. There are pulse oximeters with CO detection, which
are particularly useful, at least for a first evaluation in children, for whom it could be
difficult or traumatizing to take a blood sample. The diagnosis of CO intoxication includes
several parameters and must be carefully investigated due to its non-specific symptoms.
The basis of the diagnosis is the measurement of the percentage of COHb; this value is
highlighted through blood gas analysis of the arterial blood. An invasive measurement
of carboxyhemoglobin remains the diagnostic standard; on the other hand, the main
disadvantage of this technique is its unavailability in an extra-hospital context. Therefore,
COHb levels remain the only reliable factor for a diagnosis of CO intoxication. Alternatively,
CO oximetry can also be performed in a non-invasive manner.
Already from studies conducted in 1987, it emerged that the main problem in the
diagnosis of CO intoxication is determined by the fact that measuring the peripheral
oxygen saturation using a standard pulse oximeter produces false values. This is due to
the fact that most pulse oximeters only measure two wavelengths of light. Regular pulse
oximeters do not detect the difference between oxyhemoglobin and carboxyhemoglobin
and therefore identify carboxyhemoglobin as oxyhemoglobin. For example, even with
carboxyhemoglobin levels of 70%, a pulse oximeter shows oxygen saturation values of 92%,
demonstrating that the pulse oximeter reads carboxyhemoglobin as if it were composed of
90% oxyhemoglobin and 10% reduced hemoglobin. It therefore appears essential to have
J. Clin. Med. 2024, 13, 2466 13 of 22

a device capable of diagnosing CO poisoning in a non-invasive way, so as to confirm the

presence of carbon monoxide poisoning on site in the presence of suspicion.
The use of a pulse oximeter capable of detecting CO and providing an estimate of these
data is useful in quickly highlighting the presence of intoxication. They, unlike regular pulse
oximeters, use eight wavelengths of light, measuring multiple different types of human
hemoglobin. These devices are therefore able to distinguish between oxyhemoglobin,
carboxyhemoglobin, and methemoglobin. In conclusion, non-invasive COHb analysis
using pulse CO oximetry represents an easy-to-handle method to facilitate the diagnosis of
CO intoxication. It is necessary to remember that this diagnosis, as previously reiterated,
must be supported by further investigations, including objective examination of the patient
and radiological diagnostics.

3.13.3. Arterial Hemogram Analysis: Evaluation of Gas Exchange

Arterial hemogram analysis then provides important information on the adequacy
of gas exchange and on metabolic acidosis, as well as on carboxyhemoglobinemia; it
should therefore be performed when clinically indicated. For severe intoxication and
in intubated patients, it is essential to carry out arterial blood gas analysis, where base
excess can be used as a predictive index for acute mortality and morbidity (especially
post-anoxic encephalopathy).

3.13.4. The Role of Blood Chemistry Tests

There is a broad consensus in the literature that specific blood chemistry tests are
not necessary. Undoubtedly, the anamnesis and clinical state will guide practitioners
in terms of the need to perform myoglobinemia, CPK-MB, and TNI testing, remember-
ing that long exposures to CO and immobility for many hours can lead to very high
myoglobinemia values.

3.13.5. Recommended Cardiological Tests

It is unanimously recommended to perform an ECG before hyperbaric treatment due
to both the arrhythmogenic and ischemic effects of intoxication, regardless of age. Carbon
monoxide poisoning can exacerbate angina and cause heart damage, even in people with
undamaged coronary arteries. Therefore, poisoned patients must undergo a cardiovascular
investigation, including electrocardiography and measurement of cardiac enzymes. If
these detect myocardial damage, cardiological tests should be requested. Additionally,
diagnostic color Doppler echocardiography and coronary angiography are recommended
for patients in whom signs of cardiac ischemia persist. Recent studies support the use of
new biochemical indicators such as B-type natriuretic peptide (BNP) for the identification
of the cardiotoxicity of early CO poisoning. However, studies on this in the literature are
very limited, and the dosage of the enzyme should be considered for research purposes.

3.13.6. Psychometric Tests: Post-Interval Syndrome

Acute psychometric tests are useful, above all to investigate any onset of post-interval
syndrome (a complication of CO poisoning characterized by neuropsychiatric symptoms,
of varying severity, and with a potentially delayed onset after a free interval of 3 weeks).
It is necessary to point out the difficulty of administering these tests to numerous people
in emergency situations, such as in the middle of the night, where medical and nursing
staff are naturally limited. In this regard, other difficulties highlighted are linguistic
barriers, i.e., the need to have tests in multiple languages (Arabic, Romanian, Albanian,
Chinese, etc.) and therefore the possibility of interpreting them. In fact, in Italian case
studies, approximately 35% of patients intoxicated by CO and treated at our center are not
Italian speakers.
J. Clin. Med. 2024, 13, 2466 14 of 22

3.13.7. The Role of Brain Imaging

However, it is not recommended nor is it considered appropriate to perform a brain
CT scan before hyperbaric treatment if the diagnosis is certain, unless the patient shows
clear signs of head trauma following a fall due to intoxication. A chest X-ray is essential if
the patient is subjected to mechanical ventilation, if it is not possible to reconstruct a reliable
medical history, or if data emerge relating to previous episodes of spontaneous pneumoth-
orax. Magnetic resonance imaging (MRI) of the brain is usually performed for research
purposes or, in rare cases, for clinical indications, such as to exclude disorders unrelated
to exposure to carbon monoxide. MRI has been shown to reveal abnormal findings after
carbon monoxide poisoning. In cases of intentional carbon monoxide poisoning, clinical
judgment, psychiatric evaluation, and further toxicological laboratory investigations are
necessary for the detection of alcohol, benzodiazepines, narcotics, amphetamines, or other
such agents. It is clear that in severely intoxicated patients (for example, patients undergo-
ing mechanical ventilation), the possibility of the coexistence of aspiration pneumonia will
extend the range of tests required.

3.13.8. Differential Diagnosis and the Evaluation of Associated Intoxications

Since the symptoms of CO intoxication are highly variable, and since CO is defined as
“the great imitator”, differential diagnosis can be difficult. The clinical picture can easily
be mistaken for manifestations of headache, gastroenteritis or flu syndrome, psychiatric
disorders, hypoglycemia, other intoxications (food, drugs, alcohol, organic solvents), or
with more serious cerebrovascular disease, acute or chronic. In these cases, a correct
diagnosis is not only necessary (obviously) to start the correct therapy but also to avoid
sending an intoxicated person back into a contaminated environment [19,105,169,171,172].
We assert that it is necessary to also evaluate the presence of other combustion compounds,
such as hydrogen cyanide (HCN), nitrogen and sulfur oxides, ammonia, chlorine, phosgene,
halogenated acids, isocyanates, and acrolein.

3.14. Therapy
In cases of acute intoxication, the first measure is represented by the removal of the
patient from the contaminated environment as quickly as possible. If necessary, first aid
resuscitative maneuvers should be applied. Even the rescuers must be minimally exposed
to the risk of intoxication, with them wearing suitable respiratory protective equipment to
avoid chain injuries. The risk of explosions must be mitigated by not introducing lights or
flames into the polluted environment.
The antidote to CO is oxygen, which must be administered in pure form (100%). There
is broad agreement that the first treatment is the administration of normobaric oxygen to
intoxicated patients, either with high-flow oxygen or with 100% oxygen if the carboxyhe-
moglobin values are less than 5% since the administration of normobaric oxygen accelerates
CO elimination. The use of O2 allows for the half-life of COHb to be lowered to about one
hour. It is necessary to mention that this has not been verified by some studies, which have
not shown a significant reduction in neurological sequelae following the administration of
normobaric oxygen. However, its administration is justified by its safety, ready availability,
and low cost. Treatment with high-flow normobaric oxygen therapy, using a one-way valve
device, must be started from the time of first aid and continued until the patient enters a
hyperbaric chamber if this treatment is deemed appropriate [19,41,55,88,89,173–176].
Regarding the rationale of using hyperbaric oxygen therapy (HBOT) for CO poison-
ing, as well as to accelerate the dissociation of CO from hemoglobin, it has other effects.
In experiments conducted on animals poisoned by CO, it was shown that the use of
HBOT not only reduces the binding of CO to hemoglobin but also reduces the binding of
CO to other heme-containing proteins (for example, cytochrome a3) that influence cellu-
lar metabolism. Furthermore, HBOT alters neutrophils’ mechanisms of adhesion to the
endothelium; decreases free-radical-mediated oxidative damage; reduces neurological
deficits and overall mortality when compared with normobaric oxygen therapy (NBO);
J. Clin. Med. 2024, 13, 2466 15 of 22

improves arterial and tissue oxygen tension, facilitating the elimination of CO; increases the
production of adenosine triphosphate; and reduces oxidative stress and inflammation. In
addition, it seems that the use of hyperbaric oxygen reduces the rate of cognitive sequelae at
12 months [41,177–187].
The Undersea and Hyperbaric Medical Society recommends hyperbaric oxygen ther-
apy for patients with severe CO poisoning, exhibiting symptoms such as transient or
prolonged unconsciousness, neurological abnormalities, cardiovascular dysfunction, or se-
vere acidosis. Patients older than 36 or who have been exposed for 24 h or more (including
intermittent exposures) or with carboxyhemoglobin levels of 25% or higher should also
receive hyperbaric oxygen therapy (Table 5) [178–189].

Table 5. Indications for hyperbaric therapy.

INDICATIONS FOR HYPERBARIC THERAPY

Syncope
Coma
Convulsions
Altered mental state
Cerebellar signs
Carboxyhemoglobin > 25%
Fetal distress (in pregnancy)

Children, pregnant women, and adult patients—regardless of their carboxyhemoglobin

values—who have cardiac or neurological toxicity must be transported to specialized cen-
ters equipped with a hyperbaric chamber: in fact, at 2.5 atmospheres absolute, COHb’s
half-life is reduced to 20 min [177–181].
Oxygen therapy must also be accompanied by symptomatic therapy, with possible
correction of the acid–base balance, and intensive supportive care, including airway man-
agement, blood pressure support, and stabilization of cardiovascular status. As far as the
follow-up is concerned, it lasts for six months. Readmission to work is subject to careful
assessment of any neurological and cardiac sequelae [67–69,145,190–192].
Patients with carbon monoxide poisoning should be followed up clinically after
discharge. The extent and rate of recovery after poisoning is variable, and recovery is often
complicated by the development of sequelae, which may persist after exposure or develop
weeks after poisoning and be permanent.
Unfortunately, there is no specific therapy available for the sequelae of carbon monox-
ide poisoning.

4. Conclusions
Carbon monoxide poisoning remains a difficult challenge for emergency doctors due
to its insidious clinical and clinical course. The correct patient assessment, particularly the
administration of cognitive tests, is time-consuming and cannot always be easily performed
today in our increasingly crowded EDs. Effective multi-professional and multidisciplinary
coordination between various emergency medicine figures, such as triage nurses, the
emergency doctor of the receiving hospital, the poison control center, and the doctors of
HUB centers for hyperbaric therapy, is necessary for efficient treatment. This coordination
must be expressed according to a therapeutic diagnostic path that allows patients to
be followed up over time by dedicated centers to diagnose delayed onset sequelae in
good time.

Author Contributions: Conceptualization, G.S.; methodology, G.S., N.G. and S.M.C.; validation,
C.E., G.R. and I.F.C.; investigation, G.S., N.G., S.M.C., C.E., G.R., I.F.C., M.D., Y.L., A.P. and C.Z.;
data curation, G.S., N.G., S.M.C., C.E., G.R., I.F.C., M.D., Y.L., A.P. and C.Z.; writing—original
J. Clin. Med. 2024, 13, 2466 16 of 22

draft preparation, N.G. and G.S.; writing—review and editing, S.M.C. and G.S.; visualization, G.S.,
N.G., S.M.C., C.E., G.R., I.F.C., M.D., Y.L., A.P. and C.Z.; supervision, G.S., N.G. and S.M.C.; project
administration, G.S., N.G. and S.M.C. All authors have read and agreed to the published version of
the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare no conflicts of interest.

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