CLINICAL TOXICOLOGY, 2 7 ( 3 ) , 141-156 (1989)

CARBON MONOXIDE POISONING: A REVIEW

EPIDEMIOLOGY, PATHOPHYSIOLOGY, CLINICAL FINDINGS, AND
TREATMENT OPTIONS INCLUDING HYPERBARIC OXYGEN THERAPY
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Stephen R. Thom, M.D., Ph.D.

Chief, Hyperbaric Medicine
Uni versi ty of Pennsylvania Medical Center
1 John Morgan Building
Philadelphia, Pennsylvania 19104-6068
and
Lon W. Keim, M.D.
Medical Di rector, Baromedi ci ne Uni t
Bi shop C1 arkson Memori a1 Hospital
44th and Dewey Avenue
Omaha, Nebraska 68105-1018
For personal use only.

ABSTRACT
Carbon monoxide (CO) poisoning i s the leading cause of
poisoning deaths (accidental and intentional) in the United States.
While confirmation of CO poisoning is easily obtained via
assessment of carboxyhemoglobin (COHgb) levels, evaluation of the
severity of intoxication is both difficult and inconsistent. Acute
intoxication most commonly results in neurologic dysfunction and/or
myocardial injury. Delayed neurologic sequelae are observed in
approximately 10% of patients. New information from clinical
observations and animal research has prompted a re-evaluation of
the clinical assessment of the severity of CO intoxication and its
resultant pathophysiology. Patients at the extremes of age (the
very young and the elderly), those with pre-existing cardiovascular
and/or pulmonary disease, as well as pregnancy are at increased
risk. Once the diagnosis of CO poisoning has been established,
treatment with 100% 02 is indicated. Based on the body of
clinical , basic and scientific information currently available,
patients who manifest signs of serious intoxication (i .e.,
unconsciousness or altered neurologic function, cardiac or
hemodynamic instabi 1 i ty) should be considered candidates for
hyperbaric oxygen therapy (HBO) in addition to other appropriate
supportive and intensive care. Any patient who has suffered an
interval of unconsciousness, regardless of the patient's el inical
exam on arrival, warrants HBO therapy. Treatment plans based on
any specific COHgb level are not well founded.

141

Copyright 0 1989 by Marcel Dekker, Inc.

 142 THOM AND KEIM

INTRODUCTION

Carbon monoxide (CO) poisoning is the leading cause of

poisoning deaths in the United States (1). Since many nonlethal CO
poisonings go undetected, the true incidence of poisoning is
unknown. Unless health care providers are extremely vigilant, it
is estimated that one-third of all cases of CO poisoning may go
undiagnosed (2). New information from cliniial observations and
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animal research has forced a re-evaluation of not only the problem

of CO poisoning and the corresponding assessment of the severity of
CO intoxication, but also critical review of the treatment
modalities which should be employed to provide an optimum clinical
outcome. The purpose of this review is to emphasize current
information relating to the pathophysiology and treatment of CO
poisoning.
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EPIDEMIOLOGY

Although there are many sources of CO in the environment, smoke

inhalation is the most common recognized source of CO poisoning.
Burn mortality statistics indicate the majority of victims die not
from burns, but rather from smoke associated pu monary injury and
CO poisoning. One estimate suggests smoke inha ation related CO
poisoning may account for 4,800 deaths per year in the United
States (3). An additional 3,800 or more persons die annually
because of accidental or intentional exposure to faulty indoor
heaters or automobi 1 e exhaust (4).
The morbidity estimates of CO poisoning vary widely in the
medical 1 i terature. Several obvious reasons for this include
differences in the methods-used for assessing injury and in
defining the population at risk (i.e., use of clinical
observations, carboxyhemoglobin (COHgb) levels, inpatient vs.
outpatient treatment, and extent of follow-up) (5-11). Neurologic
dysfunction is the most commonly observed result of CO poisoning,
although abnormalities in cardiac, pulmonary, and renal (due to
rhabdomyolysi s) organ systems do occur. The most recent assessment
of morbidity is provided in a report from Denmark, where 14%
 CARBON MONOXIDE POISONING 143

[11/79] of severely poisoned patients were discharged with evidence

of brain damage (11).
A wide array of neurological and psych atric abnormal i ties have
been described as a consequence of numerous forms of ischemic-
hypoxic cerebral insults (12, 5-10). Although any or all of these
abnormalities have been acknowledged as possible sequelae to the
acute intoxication with CO, of particular interest is the risk of
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development of the so-called delayed neurologic sequelae, where the

patient seemingly recovers only to demonstrate some 3-21 days later
manifestations of aphasia, apraxia, apathy, disorientation,
hallucinations, bradykinesia, cogwheel rigidity, gait disturbances,
fecal and urinary incontinence. Coma and seizures have been
reported. Personality changes have included impulsiveness, mood
changes, violence and verbal aggressiveness. Any or all of these
changes may occur despite the absence of gross neurologic or
cognitive deficits. Among patients admitted for CO poisoning in
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two Korean reports from the same institution, 11.6 and 11.8% of
survivors suffered neuropsychiatric sequelae ( 5 , 6 ) .

PATHOPHYSIOLOGY
Carbon monoxide pathophysiology involves compromise of oxygen
transport from the lungs to the tissues and possibly inhibition of
cell ul ar metabol ism by interruption of the electron transport
proteins. Inhaled CO rapidly diffuses across alveolar-capillary
membranes and binds to hemoglobin. A central feature of CO
toxicology to date has been the emphasis on the binding of CO to
hemoglobin (Hgb), with the resultant formation of carboxyhemoglobin
(COHgb). The relative affinity of CO for hemoglobin is
approximately 200-fold greater than that of oxygen (13). CO uptake
depends on the concentration of CO and 02 in the inspired gas, the
ventilatory rate, and the duration of CO exposure (14,15).
Alveolar oxygen tensions (PA02) may be normal to decreased
depending upon the fraction of oxygen in the inspired air (FiO2) as
well as the nature of the inhaled noxious gas. Accordingly,
arterial oxygen tensions (PaOp) may be normal to low, with
 144 THOM AND KEIM

oxyhemoglobin saturations remaining within the normal range, unless

arterial oxygen tensions are severely depressed. As the 02
saturation on a typical set of arterial blood gases is a derived
calculation rather than a direct measurement, it may be falsely
i nterpreted as being normal unl ess a carboxyhemogl obi n saturation
(COHgb) is specifically requested.
Tissue oxygen tensions (PT02) may be decreased directly through
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a reduction in oxygen content by a lowered Pa02 as well as the

presence of COHgb. Tissue hypoxia may be worsened indirectly
through a leftward shift in the oxyhemoglobin dissociation curve.
This shift occurs because of the presence of COHgb in erythrocytes,
and possibly by a hypoxically stimulated hyperventilation
.
respi ratory a1 kal osi s
Whether intrace1,lular CO binding may be a component of CO
toxicity remains unclear. Coburn (16) has estimated 10-15% of the
total body burden of CO is bound to extravascular proteins at any
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given time. At ambient arterial 02 tensions CO can combine with

myoglobin, which will interfere with 02 utilization by muscle
cells. CO binding to other proteins has been assessed, but because
of its relatively low affinity as contrasted to 02, the metabolic
effects of CO are unclear. Animal studies involving respiration
and carbohydrate metabolism have failed to identify any difference
between hypoxemic hypoxia and CO-mediated hypoxia, thus arguing
against a direct cellular component of CO poisoning (17,18).
Under hypoxic conditions CO binding to proteins should
increase, which may profoundly alter CO metabolic effects. In the
case of myoglobin, when Pa02 drops below 40 torr, 20-40% of
intravascular CO may be shifted into muscle (19). Hypoxia will
increase CO binding to cytochrome oxidase, which may adversely
affect oxidative metabolism (20). Because the rate of dissociation
of CO from cytochrome oxidase is slow, concern has been raised that
CO may cause a relatively prolonged adverse effect despite only
transient hypoxia.
Despite the established doubts regarding the physiological
significance of extravascular CO binding, when functions other than
 CARBON MONOXIDE POISONING 145

metabolism and respiration are assayed, animal studies do suggest

the compromise in hemoglobin function caused by CO cannot solely
explain the degree of impairment observed (21-23). These findings,
plus observations in humans on the effects of very low COHgb levels
(approximately 4-5%), which should have only negligible effects on
tissue Pa02, suggest a cellular level of impairment may also occur
(24)-
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As COHgb levels rise cerebral vessels dilate and both coronary

blood flow and capillary perfusion increase. Acutely, these
compensatory reactions are accompanied by tachypnea and a1 veolar
hyperventilation. As CO exposure continues, central respiratory
depression occurs possibly secondary to cerebral hypoxi a (25).
Acute mortality from CO may be mediated through cerebral hypoxia,
either from respiratory depression or from a decreased Pa02 caused
by pulmonary shunting or ventilation/perfusion mismatch. As
related previously, some portion of the hypoxic insult, especially
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in smoke inhalation cases, may be related to 02 consumption by the

fire with a decreased FiO2 (26). The presence of large amounts o f
C02 may also exacerbate CO poisoning (27). Additionally, hydrogen
cyanide gas produced during the pyrolysis of both natural and
synthetic substances, especially plastics and acrylics, may
complicate toxic smoke inhalation (28). Cyanide (CN) poison
accentuate ti ssue hypoxi a and obscure the re1 ati ve contri but
CO and CN to cell/tissue injury or death.
Some animal studies suggest the acute mortality from CO S
caused principal ly by cardiac dysrhythmi as (29). Cram1 et et a1
have indicated myocardial impairment may begin when the COHgb level
approximates 20% (30). Animal and human reports have described
cardiac effects including a myriad of dysrhythmias as well as
pathologic changes including myocardial hemorrhage, leukocyte
infiltration, mural thrombi, degeneration of muscle fibers, and
multifocal myocardial necrosis (31).
Animals that do not die acutely, but instead show neurologic
deterioration hours to days subsequent to CO intoxication, appear
to have a combined hypoxic and ischemic insult during the acute
 146 THOM AND KEIM

exposure (29,32,33). They suffer tissue hypoxia acutely for the

reasons outlined above, and during this hypoxic stress the normal
vascular compensatory mechanisms are thwarted by a transient period
of hypotension which may be, at least in large part, due to CO
cardiac toxicity (29,31). Neurologic deterioration following CO
exposure may occur during treatment when COHgb levels are
decreasing and cerebral 02 delivery is improving. These
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observations, plus knowledge that encephalopathic changes may arise

after a variety of cerebral insults in addition to CO, has led to
the hypothesis that the CO-associated delayed neurologic sequel ae
may be a form of "reperfusion injury" (34,35). Recently, a rat
model of CO poisoning was developed to address this possibility.
Products of lipid peroxidation, used as an index of injury, were
identified only after an interval of air breathing and not
immediately after CO exposure (36 Thom, unpublished observation).
Furthermore, hyperbaric oxygen (HBO), but not 100% 02, at 1.0
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atmosphere absol Ute (ATA) was demonstrated to prevent the CO

effect. On first consideration, this observation would seem
paradoxical as the reperfusion injury is thought to be mediated
through activated oxygen derived free radicals (35). The benefit
o f HBO in diminishing rather than accelerating this reperfusion
injury appears to involve the generation o f small concentrations of
hydrogen peroxide (H202) (37 Thom, unpublished observations).
Antagonism of lipid peroxidation and also oxidative injury to DNA
by H202 has been shown in a number of reports (38-40).

CLINICAL FINDINGS
In day-to-day clinical practice there seems to be an
inappropriate reliance on measurements of COHgb to assess the
severity of CO intoxication. A correlation has been established
between low COHgb levels and relatively nominal symptoms such as
nausea, vomiting, and headaches (41-43). Unfortunately, this
correlation does not hold when assessing patients with more
significant intoxication who have manifested alterations in mental
status (5-7,44). The patient's underlying health status and the
 CARBON MONOXIDE POISONING 147

manner of exposure ( i .e., prolonged exposure t o low CO

concentrations vs. b r i e f exposure t o higher l e v e l s ) a1 so a f f e c t
mortality and morbidity risks. The blood l a c t a t e level may
c o r r e l a t e w i t h the s e v e r i t y of intoxication a1 though i t s prognostic
value has y e t t o be ascertained (45). An elevated amylase level
has been an incidental observation among CO victims i n perhaps 40%
of cases (46). The s a l i v a r y gland has been shown t o be the source
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of these observed serum amylase 1eve1 s , but unfortunately, i t s

documentation provides no additional help i n assessing s e v e r i t y of
intoxication o r prognosis.
Over the p a s t few years e f f o r t s have focused on o b j e c t i v e
methods of assessing neurologic compromise. Myers has reported
abbreviated c o r t i c a l function t e s t s , which take 15-45 minutes, t o
be useful (47). Computerized tomography (CT) of t h e head has been
used, and acute changes i n scans obtained i n one t o six hours
following admission have been noted i n some but not a l l p a t i e n t s
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(48-50). A1 though CT observed abnormalities a r e r e f l e c t i v e of

moderate t o severe poisoning, p a t i e n t s w i t h changes i n the gray
matter (e.g., hypodensity i n the region of the basal ganglia) may
s t i l l have good c l i n i c a l recoveries (48). The presence of lesions
i n t h e white matter, however, more often r e f l e c t s a poor prognosis
(49)
Magnetic resonance imaging (MRI) may prove t o be a more
s e n s i t i v e method t o assess neurological injury, but experience i s
limited (51). To d a t e t h e r e i s no rigorous method f o r predicting a
p a t i e n t ' s outcome following CO poisoning. Clinical observations
do, however, o f f e r useful guidelines and t h u s suggestive parameters
f o r considering treatment. T h e prognostic risk appears t o be
g r e a t e r among p a t i e n t s w i t h pre-exi s t i n g cardiovascular disease,
age g r e a t e r than 60 years, and those who have suf ered an interval
of unconsciousness a s a r e s u l t of the CO exposure e i t h e r a t t h e
scene o r upon a r r i v a l t o a health care f a c i l i t y . The duration of
coma portends a g r e a t e r risk, but any history of oss o f
unconsciousness i s associated w i t h increased morb d i t y (5-8).
 148 THOM AND KEIM

TREATMENT
In addition to supporting vital signs, the imediate inhalation
of supplemental 02 with a hich FiOz, preferably 1.0 via a high flow
system and/or tight fitting mask or via intubation and mechanical
ventilation, is the cornerstone of the emergency treatment of CO
intoxication. Oxygen treatment is recommended because COHgb
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dissociation i s hastened by an elevated arterial partial pressure

(Pa02) (14). Because of variations in reporting methods, and
perhaps unreliable parameters for the assessment of CO
intoxication, it is difficult to determine the impact of aggressive
supportive care as it has evolved in recent years. In a recent
report detailing the use of 100% 02, intensive care using
mechanical ventilation, hypothermia, steroid and diuretic use, the
in-house mortality was 30% (11). Mortality rates of 20-31% have
been described in a number of reports (10,52,53), yet other surveys
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have reported in-hospital mortality rates of only 1-2% (4,7). One

report, especially useful because of its comparative data, noted
the mortality rate with intensive care plus the use of hyperbaric
oxygen therapy (HBO) in a delayed manner (greater than six hours
following patient discovery) to be 30.1% (54). This was contrasted
against a 13.5% mortality rate among similarly poisoned patients
who were treated with HBO within six hours of discovery.
Treatment of severe CO poisoning using methods, in addition to
100% 02 and support of the vital signs as appropriate, has been
under investigation for some years now. To our knowledge,
hypothermia was first reported in 1959 with apparent success (55).
HBO was first employed in the treatment of CO intoxication in 1960
(56). Some authors have argued that treatment should consist only
of supportive measures and the administration of 100% 02 until
controlled prospective studies are carried out on other therapies
(51,518).
In 1972 results of a controlled dog study indicated hypothermia
had no benefit in improving survival after severe CO poisoning,
whereas HBO with or without hypothermia significantly improved
survival (59). Restoration of consciousness and a hastened removal
 CARBON MONOXIDE POISONING 149

of CO from animals by HBO was demonstrated i n t h e c l a s s i c studies

by End and Long i n 1942 (60). A number of c l i n i c a l reports r e l a t e
t h e prompt reversal of CO induced coma in temporal relationship
w i t h the administration of HBO (54,56,61-64). The report of Goulon
e t a1 is, t o our knowledge, the only comparative study t h a t
addresses t h e importance of the prompt administration of HBO (54).
As discussed above, t h e overall mortality r a t e was 30.1% i f HBO was
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delayed f o r more than six hours and 13.5% i f HBO was begun w i t h i n
six hours of p a t i e n t discovery. Additionally, the incidence of
delayed neurologic deterioration was 12.3% [19/155] among p a t i e n t s
who e i t h e r were not t r e a t e d w i t h HBO o r received i t l a t e r than six
hours from discovery. In contrast, the incidence of these delayed
e f f e c t s was 0.7% [1/147] when HBO was administered w i t h i n s i x hours
of discovery.
Grinker was the f i r s t t o identify the delayed neurologic
sequelae i n a report i n 1926 (65). In a large retrospective
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survey, S h i l l i t o e t al reported an incidence of only 0.8% (10).

Meigs and Hughes made similar observations i n 8.6% of 105 cases
(9). More recent studies have used r e l a t i v e l y rigorous
q u a n t i t a t i v e methods f o r evaluating neurologic function, and most
have described the treatment p a t i e n t s received. W i t h the use of
supportive measures and 100% 02 v e n t i l a t i o n , Choi reported l a t e
neurologic sequelae i n 11.6% o f hospitalized p a t i e n t s , the majority
of whom suffered some interval of unconsciousness (5). One
drawback w i t h this paper, however, i s the absence of admission
c r i t e r i a . I n a follow-up report, Min documented an incidence of
11.8% (6). Smith and Brandon reported an alarming incidence of 43%
(8), although t h e r e i s some question whether a l l p a t i e n t s received
100% 02 (66). The recurrent observations of a 12% incidence of
delayed sequelae i n the large Korean reports concurs w i t h the
findings of Goulon e t a1 (54), where p a t i e n t s e i t h e r did not
receive o r were t r e a t e d w i t h HBO more than s i x hours a f t e r
discovery. Myers e t a1 (47) a l s o reported a 12% incidence of
delayed sequelae among p a t i e n t s treated w i t h 100% 02 but a 0%
incidence among p a t i e n t s t r e a t e d w i t h HBO. Further supporting the
 150 THOM AND KEIM

efficacy of HBO in decreasing the incidence of these delayed

neurologic sequelae, Norman et a1 (67) reported an incidence of
1.4% [1/70], a 2% incidence was observed by Norkool et a1 (68)
[3/115] and Lamy and Hanguet (69) [1/50], while Mathieu et a1 (70)
reported a 4% [9/203] incidence. Crocker and Walker (71) reported
no mortality or morbidity among 16 children treated with HBO,
whereas delayed neurological deteriorations occurred in three of 12
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(25%) treated with 100% 02 at ambient pressure.

Whi 1 e these delayed neurologic sequel ae may spontaneously
resolve, improvement may require a convalescent period of two years
(5). The weight of clinical information currently at hand supports
the efficacy and benefits of HBO for CO intoxication. While there
is legitimate concern regarding the transfer of a critically ill,
unstable patient from the initial receiving hospital to a facility
providing hyperbaric oxygen therapy, complications associated with
this practice are rare (72). The potential benefits of HBO in the
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emergent treatment of CO intoxication would appear to offset the

theoretical hazards of transfer to a facility providing HBO
therapy. The data suggest that the benefit of HBO treatment
diminishes when there is a delay of treatment by more than six
hours.

CONCLUSION
Carbon monoxide is the leading cause of death by poisoning in
the United States and the cause of only a crudely estimated number
of morbid consequences (73). It is a sobering testimonial to the
complexity of this poison that studies on its intravascular as well
as extravascul ar (cell ul ar) mechanisms have been pursued for more
than 100 years. Once the diagnosis of CO poisoning and
intoxication has been made, treatment with 100% 02 should be
instituted immediately. Based on the body of clinical, basic, and
scientific information available, patients who manifest signs of
serious poisoning (e.g., unconsciousness or a1 tered neurologic
function, cardiac or hemodynamic instability) should be considered
candidates for HBO therapy in addition to appropriate supportive
 CARBON MONOXIDE POISONING 151

and/or intensive care. The data a l s o support the administration of

HBO t o any p a t i e n t who has suffered an interval of unconsciousness
.
regard1 ess of the p a t i e n t ' s cl i n i cal exam upon a r r i Val Treatment
plans based on any s p e c i f i c COHgb determination a r e not well
founded.

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