Toxicology 334 (2015) 45–58

Contents lists available at ScienceDirect

Toxicology
journal homepage: www.elsevier.com/locate/toxicol

Review

A modern literature review of carbon monoxide poisoning theories,

therapies, and potential targets for therapy advancement.
Joseph D. Roderique a , Christopher S. Josef a, * , Michael J. Feldman b , Bruce D. Spiess a
a
Department of Anesthesiology, VCU School of Medicine Sanger Hall, Rm B1-016, 1101 East Marshall Street, P.O. Box 980695, Richmond, VA 23298,
United States
b
Department of Plastic and Reconstructive Surgery, Critical Care Hospital 8th floor, 1213 East Clay St, Richmond, VA 23298, United States

A R T I C L E I N F O A B S T R A C T

Article history: The first descriptions of carbon monoxide (CO) and its toxic nature appeared in the literature over
Received 21 February 2015 100 years ago in separate publications by Drs. Douglas and Haldane. Both men ascribed the deleterious
Received in revised form 1 May 2015 effects of this newly discovered gas to its strong interaction with hemoglobin. Since then the adverse
Accepted 12 May 2015
sequelae of CO poisoning has been almost universally attributed to hypoxic injury secondary to CO
Available online 18 May 2015
occupation of oxygen binding sites on hemoglobin. Despite a mounting body of literature suggesting
other mechanisms of injury, this pathophysiology and its associated oxygen centric therapies persists.
Keywords:
This review attempts to elucidate the remarkably complex nature of CO as a gasotransmitter. While
Carbon monoxide poisoning
Gasotransmitter
CO’s affinity for hemoglobin remains undisputed, new research suggests that its role in nitric oxide
Nitric oxide release, reactive oxygen species formation, and its direct action on ion channels is much more significant.
Reactive oxygen species In the course of understanding the multifaceted character of this simple molecule it becomes apparent
Cardiac ion channels that current oxygen based therapies meant to displace CO from hemoglobin may be insufficient and
Neuronal ion channels possibly harmful. Approaching CO as a complex gasotransmitter will help guide understanding of the
complex and poorly understood sequelae and illuminate potentials for new treatment modalities.
ã2015 Elsevier Ireland Ltd. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
2. The origins and nature of the carboxyhemoglobin theory of CO poisoning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
3. Flaws with the carboxyhemoglobin (HbCO) theory of CO poisoning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
3.1. Early contradictory experiments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
3.2. Incongruent sequelae . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
3.3. Physiologic reserve . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
3.4. Hypoxemic hypoxia is not enough . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
3.5. The absence of better explanations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
4. The gasotransmitter theory of carbon monoxide poisoning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
4.1. Action sites for carbon monoxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
4.2. Redefining the role of mitochondria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
4.3. Experiments demonstrating extra-hemoglobin activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
4.4. Carbon monoxide signaling dysregulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
5. Current carbon monoxide therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
5.1. Normobaric oxygen (NBO) vs hyperbaric oxygen (HBO) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
5.2. Hyperbaric oxygen (HBO) evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
5.3. The obstacles to HBO therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
5.4. Generation of reactive oxygen species (ROS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
5.5. Hyperoxic hypocapnea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
6. Target sites for CO in the body . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52

* Corresponding author. Tel.: +1 804 828 3213; fax: +1 804 828 6413.
E-mail address: josefcs@vcu.edu (C.S. Josef).

http://dx.doi.org/10.1016/j.tox.2015.05.004
0300-483X/ ã 2015 Elsevier Ireland Ltd. All rights reserved.
46 J.D. Roderique et al. / Toxicology 334 (2015) 45–58

6.1. Carbon monoxide and nitric oxide interplay . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52

6.2. Carbon monoxide and reactive oxygen species (ROS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
6.3. Carbon monoxide and ion channels . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
6.4. Neuronal ion channels . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
6.5. Cardiac ion channels . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
6.6. Other ion channels . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
7. Alternative treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
7.1. NO binding agents . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
7.2. Ion channel therapy . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
7.3. Antioxidants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
7.4. Combination therapies . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
8. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
Reference . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55

1. Introduction vapors” was due to the effect of carbon monoxide (CO) (Bernard
et al., 1857; Cruickshank, 1801a,b). Thirty-eight years later Haldane
It has been almost 100 years since Drs. Douglas and Haldane would demonstrate that the toxic effects of carbon monoxide on
first published their study detailing the hemoglobin dissociation mice and rats could be diminished or even eliminated by
curves for both oxygen and carbon monoxide (CO) adding to the simultaneously (and sufficiently) increasing the partial pressure
discovery of Christian Bohr (Douglas et al., 1912). Those findings, of oxygen at the time of exposure to CO (Haldane, 1895a). During
combined with a series of additional experiments involving the this time Haldane also performed a series of studies on himself,
interplay among oxygen, CO, and hemoglobin (in vitro and in vivo) cataloging the effects of CO that he experienced at rest and with
represented the first truly scientific explanation and evidence exercise while varying both the concentration and duration of
based treatment for CO poisoning (Haldane, 1895a,b, 1919, 1917; exposure (Haldane, 1895b).
Haldane and Smith, 1900, 1897; Smith, 1899). While much of the In 1912 Haldane and Douglas would go on to publish a landmark
work done by Douglas and Haldane still obtains today, a variety of study that elucidated two key facts regarding hemoglobin: (1)
advancements in the past century have helped to develop the oxygenated hemoglobin possessed an intrinsic sigmoid dissocia-
understanding of the in vivo effects of CO. tion curve and (2) this curve is shifted left and downward in the
To date CO poisoning remains a leading cause of unintentional presence of CO (Douglas et al., 1912). This shift indicated not only a
poisoning worldwide (Raub et al., 2000). In the United States it is decreased oxygen carrying capacity for hemoglobin, but also
responsible for approximately 15,000 emergency department indicated that partially saturated carboxyhemoglobin (HbCO)
visits and nearly 500 deaths annually (Braubach et al., 2013; bound the remaining oxygen more tightly. The results of these
Centers for Disease Control and Prevention (CDC), 2009; Raub studies along with observations from his physician colleague
et al., 2000). Both of the aforementioned statistics exclude persons Lorrain Smith, led Haldane to propose that the toxic effects of CO
suffering from smoke inhalation secondary to building fires. were attributable primarily to tissue hypoxia following the
Instances of CO poisoning are more common amongst males, occur disruption of hemoglobin’s oxygen transport mechanism. He
most often during the winter, and often involve gas heating or suspected that injury was secondary to hypoxia caused by a
cooking appliances in the home (Braubach et al., 2013). Despite the combination of reduced oxygen carrying capacity and reduced
widespread nature of this form of poisoning, the therapy for CO oxygen off-loading capacity (Haldane, 1895b, 1919; Smith, 1899).
poisoning has remained virtually unchanged since Haldane’s time These results also led him to propose that oxygen either at high
100 years ago with the mainstay continuing to be the administra- concentration or at high pressure could be used as an antagonist to
tion of oxygen at either normobaric or hyperbaric pressures these toxic effects (Haldane, 1917). Since Haldane’s early work this
(Buckley et al., 2011; Hampson et al., 2012; Weaver, 2009). hemoglobin centric theory of CO poisoning has remained the
The past twenty-five years have been marked by an explosion in officially accepted explanation for both the mechanism of CO
the number and quality of studies regarding the actions of CO in toxicity and the reasoning for the oxygen based therapies used to
mammalian systems. We now know that CO is not simply a tissue treat it; however, this is beginning to change (Guzman, 2012;
poison. CO is a necessary molecule for normal cell signaling and Hampson et al., 2012; Weaver, 2009; Winter and Miller, 1976)
functioning with tremendous therapeutic potential. The recent
developments outlined in this review will (1) identify the flaws in 3. Flaws with the carboxyhemoglobin (HbCO) theory of CO
the current carboxyhemoglobin theory of CO poisoning and its poisoning
associated therapies, (2) continue to expand on the “gasotrans-
mitter” model of carbon monoxide, and (3) Offer targets for new 3.1. Early contradictory experiments
therapeutic interventions.
The effects of CO imbalances in the human body are currently The first to voice dissent with the HbCO theory of poisoning was
and will remain a significant concern to clinicians. It is prudent that ironically J.S. Haldane’s own son, J.B.S Haldane, who was a co-
we now review the current scientific advancements as they pertain author on the original 1912 manuscript. In a simple but elegant set
to CO poisoning and therapies, and re-consider the appropriate- of experiments he demonstrated that CO induced lethargy in
ness of the currently promulgated pathophysiology. moths and inhibited cress (Lepidium sativum) seed germination.
This was intriguing because neither organism possessed hemoglo-
2. The origins and nature of the carboxyhemoglobin theory of bin, leading him to conclude that “cells contain a catalyst of
CO poisoning oxidation which is poisoned by CO” (Haldane, 1927). In a third
experiment in the same manuscript he demonstrated yet another
The structure of CO was first discovered by William Cruikshank example of CO’s effect beyond hemoglobin. The younger Haldane
in 1800; however, in 1857 after a series of blood based studies in recognized that rats could survive on the oxygen dissolved in their
dogs, Claude Bernard proposed that the toxic nature of “fire plasma alone if they were placed in three atmospheres of oxygen.
 J.D. Roderique et al. / Toxicology 334 (2015) 45–58
This would make the hemoglobin delivery mechanism for oxygen
redundant and unnecessary. Once the animals normalized in their
hyperbaric environment he began introducing CO until their
hemoglobin was saturated with 98% CO. Despite this high level of
HbCO, the rats were able to survive.
If CO’s toxicity was due solely to its effects on hemoglobin, as his
father had suggested, then the addition of CO beyond what was
needed to saturate the animal’s hemoglobin should have had no
effect. When the younger J.B.S. Haldane finally added additional CO
it resulted in the prompt death of the animals. From this he
concluded, “rats living on O2 dissolved in their blood in the
presence of sufficient CO to combine with almost all their
hemoglobin are killed by the addition of more CO, which must
affect some substance in their tissues” (Haldane, 1927). Despite
this seemingly plain contradiction of the HbCO theory of
poisoning, the senior Haldane’s explanation persisted and became
the convention.
3.2. Incongruent sequelae
For decades clinicians have noted that the HbCO levels of
patients do not correlate well with their signs/symptoms or their
ultimate clinical outcome (Hampson and Hauff, 2008; Wolf et al.,
2008). If CO poisoning were a simple reduction in available tissue
oxygen and secondary tissue/organ hypoxia, then the relationship
between the HbCO level and symptom severity should be nearly
linear, but this is not the case. Furthermore, a simple hypoxic injury
does not explain the strange cardiac dysrhythmias that often
develop in the face of CO poisoning (Dallas et al., 2012; Gandini
et al., 2001; Kalay et al., 2007). Likewise, it fails to explain the
cognitive dysfunction that patients often develop, not immediate-
ly, but typically between 27 and 270 days post-injury (Choi, 1983;
Piantadosi et al., 1997; Qingsong et al., 2013; Thom et al., 2004a).
Even the loss of consciousness associated with CO poisoning is
often described as an anesthetic-like effect, much like nitric oxide
and other small lipid soluble gaseous compounds (Sampath et al.,
2001; Weaver et al., 2007). Interestingly, unlike the other
mechanisms of hypoxia, CO poisoning can induce neurological
damage without loss of consciousness (Shprecher and Mehta,
2010). CO induced hypoxia of varying degrees likely plays a role in
the overall mechanism of injury for this form of poisoning.
However, its contribution is likely much less than previously
suspected since many of the second order effects described are not
completely explained by hypoxemic hypoxia.
3.3. Physiologic reserve
In recent years, using newly available techniques, a number of
scientists have attempted to study the “carboxyhemoglobin
theory” of CO poisoning directly. Haldane successfully demon-
strated the binding of CO to hemoglobin, and the affinity of this
binding is known to be 200–300 times greater than that of oxygen
for the same substrate (Douglas et al., 1912; Haldane, 1895a). What
has remained unproven for many years was the effect that this
attachment had on oxygen delivery to the various bodily tissues,
and more importantly, what effect this had on oxidative
metabolism and cell viability in those tissues.
One possible explanation for the apparent lack of toxicity at
moderate levels of HbCO may lie in the fact that oxygenated
hemoglobin provides a large functional reserve. In normal humans,
the arterial oxyhemoglobin (HbO2) concentration rarely drops
below 90%, providing an incredible amount of oxygen for high-
demand situations. Adaptive mechanisms that alter oxygen
loading and unloading by both allosteric ligand binding (2,3-
diphosphoglycerate or 2,3-DPG, and CO2) and environmental
47
modifications (pH) allow cells and local environments access to
this vast functional reserve.
A more recent live animal study conducted by Smithline et al.,
attempted to investigate and quantify the effects of CO on whole
body oxygen consumption. The investigation examined critical
oxygen delivery, oxygen utilization, oxygen extraction ratio,
cardiac index, and lactate production during prolonged high-dose
CO exposure in anaesthetized beagle dogs at normobaric
conditions (Smithline et al., 2003). Unlike J.B.S. Haldane’s previous
work with rats in hyperbaric environments, these animals were
exposed to CO in a normal atmospheric environment. They found
that serum lactate levels showed no appreciable rise until shortly
before death when HbCO levels had already exceeded 80%. In
addition, they found that oxygen delivery, and oxygen utilization
were matched quite well, until shortly before death. Contrary to
other recent research, their findings were not suggestive of
mitochondrial dysfunction (Brown and Piantadosi, 1989; Chance
and Williams, 1956). The results of these experiments seem to
suggest that the body was able to maintain critical oxygen delivery
by increasing the cardiac output, regulating local blood flow to
more critical areas, and most importantly by increasing the oxygen
extraction efficiency (i.e., tapping into the reserve). Again, this
compensatory mechanism was not exhausted until HbCO levels
exceeded 80%.
The organ most adept and most studied with respect to vascular
regulation is the brain. Unlike most cells, neurons begin to suffer
irreparable damage in less than 10 min under conditions of hypoxia
or anoxia making oxygen delivery critical to these cell-types (Safar,
1988). Studies using Raman spectroscopy and other methods of
monitoring cerebral oxygen concentration during CO poisoning
have thus far failed to demonstrate the large and global deficit in
oxygen delivery that we would expect based upon the carbox-
yhemoglobin theory of CO poisoning. It is not until extremely high
levels of HbCO are achieved (again exceeding 60–80%) that
measurable decreases in oxygenation become apparent (Koehler
and Traystman, 2002; Langston et al., 1996; Vollmer et al., 2012).
This evidence suggests that the body’s organic mechanisms for
oxygen extraction are flexible enough to sustain adequate cerebral
oxygenation even in the face of a robust CO insult. Taken together,
these studies suggest that tissues may not be as starved for oxygen
in the presence of HbCO as previously taught.
3.4. Hypoxemic hypoxia is not enough
Reductions in available cellular oxygen can be induced by three
different mechanisms: (1) hypoxemic hypoxia (low O2 content in
the blood, but normal blood flow), (2) stagnant hypoxia (inade-
quate supply of oxygenated blood e.g., ischemia), and (3) histotoxic
hypoxia (inability of the tissue to utilize available O2 e.g., cyanide
exposure) (Ellison and Love, 2013). Despite these differences many
discussions and even many neuropathology texts forgo making
this distinction because all three mechanisms seem to share a
common neurologic histopathology, namely that similar lesions
can be found in the CA1 layer of the hippocampus, in laminae 3 and
5 of the cortex, and in the basal ganglia (caudate and putamen)
(Feldman, 1999; Schochet, 1993). While the hypoxemic hypoxia
suggested by the HbCO theory is undoubtedly a component of the
injury mechanism of CO poisoning, it alone is not enough to
account for some of the neuropathological manifestations of CO
poisoning.
The early work of Okeda et al. compared CO poisoning to
nitrogen induced hypoxemic hypoxia in cats and showed that
hypoxemic hypoxia alone was not enough to produce measurable
lesions in the brain (Okeda et al., 1982). They discovered that the
brain was able to overcome the oxygen deficiency through auto
regulation of the vasculature until concomitant hypotension was
48 J.D. Roderique et al. / Toxicology 334 (2015) 45–58
pharmacologically induced. In a subsequent investigation they
confirmed that “for the pathogenesis of the cerebral change in CO-
encephalopathy, both cerebral hypoxia due to elevated CO-
hemoglobin in the blood and cerebral ischemia due to the systemic
blood pressure reduction are necessary” (Okeda et al., 1983). As
discussed later in Section 6.1, CO causes a systemic increases in
nitric oxide which leads to variable reductions in blood pressures.
Pure hypoxia and ischemia have different sequelae, in experimen-
tal models hypoxia without ischemia does not necessarily cause
brain necrosis, but hypoxia exacerbates ischemic necrosis (Ellison
and Love, 2013).
Several different insults including hypoglycemia, heroin
overdose, strangling, anesthetic accidents and CO poisoning can
cause the delayed onset of Parkinson’s like symptoms, akinetic-
mutism, and persistent deficits in executive function commonly
referred to as delayed neurologic sequela (DNS). Unlike the other
mechanisms of hypoxia, DNS secondary to CO poisoning can occur
without loss of consciousness (Shprecher and Mehta, 2010). The
precise mechanisms have not been completely elucidated;
however, the aforementioned lesions found in the hippocampus,
cortex, and basal ganglia are likely joined by a profound
demyelinating process. It is believed that demyelination occurs
secondary to reactive oxygen species (ROS) action on lipid
containing myelin sheaths and cellular membranes, a process
more fully explored in Section 6.2. (Schochet, 1993) When
compared to other mechanism of hypoxia CO poisoning victims
are much more likely to experience DNS, suggesting that ROS
worsen the insult (Crystal and Ginsberg, 2000; Shprecher and
Mehta, 2010). A recent investigation demonstrated the neuro-
protective effects of hydrogen-rich saline, a powerful antioxidant
(Sun et al., 2011). Using rats Sun et al. showed that a number of
biochemical markers of lipid peroxidation and neuronal damage
were reduced, and more importantly, DNS were drastically
reduced, demonstrating the significant role of ROS in the induction
of DNS.
The histopathology and clinical course of CO poisoning is not
fully explained by hypoxemic hypoxia alone, as suggested by the
HbCO theory of poisoning. Severe neurologic injury occurs when
hypoxemic hypoxia is accompanied by hypotension, ROS genera-
tion, and other direct actions of CO discussed later in the
manuscript.
3.5. The absence of better explanations
It is important to note that the evidence supporting Haldane’s
HbCO theory of CO poisoning is indirect. “The argument that CO
toxicity is due only to reaction with Hb is supported only by
negative evidence; i.e., no one has shown that CO binding to
compounds other than Hb occurs in amounts sufficient to cause
deleterious effects” (Coburn and Forman, 2011). Today we now
know that CO has a number of different action sites, many of which
will be discussed later in the manuscript, but the commonly
explained pathophysiology for this process erroneously remains
focused on the interaction of Hb and CO.
Some will point to the common use of oxygen as a therapy for
CO poisoning as convincing evidence that CO poisoning is a
hemoglobin centric process; however, these oxygen treatments,
like the pathophysiology, are based upon deductive reasoning
rather than strong positive scientific evidence. Since the senior
Haldane successfully demonstrated that a sufficient partial
pressure of oxygen during a concomitant exposure with CO could
prevent CO from binding to hemoglobin, it has been logically
assumed that high-flow and/or high-pressure oxygen would
reduce the toxicity of carbon monoxide poisoning in humans. To
date there have been no randomized-controlled trials (RCTs)
examining outcomes of simple treatment with room air as
compared to either normobaric oxygen (NBO) or hyperbaric
oxygen (HBO) therapies (Hampson et al., 2012). The current
evidence only shows that oxygen treatments decrease the half-life
of HbCO an attribute that may not drastically change outcomes in
patients.
4. The gasotransmitter theory of carbon monoxide poisoning
4.1. Action sites for carbon monoxide
The discovery of more sophisticated targets for CO, subse-
quently referred to as “extra-hemoglobin effects,” could not begin
in earnest until scientists discovered that small gaseous com-
pounds could serve a vital role as signaling and regulatory
molecules akin to proteins and lipids. Following the discovery of
nitric oxide (NO) as an endogenously produced gas with regulatory
and cellular transmitter-like properties, scientists began looking
for other “gasotransmitters” (Otterbein et al., 2003; Truss and
Warner, 2011; Verma et al., 1993). Sjöstrand and Tenhunen were
the first to describe the endogenous production of CO via the action
of heme-oxygenase on heme in 1968 (Sjöstrand, 1949, 1952;
Tenhunen et al., 1968). Initially, it was thought that the production
of CO was simply a byproduct of heme degradation, with no
purposeful physiologic action, however, it was quickly discovered
that CO is produced endogenously as a cellular protectant by nearly
every cell in our bodies when they are subjected to situations of
oxidative stress or injury (Applegate et al., 1991; Foresti et al.,
2004; Maines, 1997; Maines et al., 1986; Otterbein, 2002;
Tenhunen et al., 1968). It was then shown that CO (beyond mere
cellular protection) plays a major role in multiple cellular
processes in almost every organ system, and in system-specific
ways. To date researchers have demonstrated CO interaction with
soluble guanylate cyclase, ion channels, nitric oxide and nitric
oxide synthase, mitochondria, cytochromes, NADPH oxidase, and
xanthine oxidase (Dallas et al., 2012; Furchgott and Jothianandan,
1991; Han et al., 2007; Hou et al., 2009; Ignarro, 1989; Peers, 2011;
Thom et al., 2010, 1999b; Wang and Wu, 1997; Wilkinson and
Kemp, 2011).
4.2. Redefining the role of mitochondria
Since the younger J.B.S. Haldane’s early challenge of the
carboxyhemoglobin theory of CO poisoning, a number of
researchers have attempted to uncover and define his proposed
“cellular catalyst.” Early work uncovered a cellular component
within the mitochondria involved in cellular respiration that
would bind CO (Chance and Williams, 1956; Thauer et al., 1974).
This discovery led many to conclude that the mitochondria, and the
heme based cytochromes they contained, were the real targets for
CO and the true source of its toxicity. The thought was that CO, like
cyanide (CN), might bind to the mitochondrial cytochromes and
halt the electron transport chain. In this scenario even if oxygen
delivery to the tissue was adequate the cells would be unable to
utilize that oxygen to produce ATP (Chance et al., 1970; Queiroga
et al., 2012; Zhang and Piantadosi, 1992).
Numerous attempts over the years to conclusively demonstrate
CO’s ability to poison mitochondria have largely failed. While CO
can and does bind to many of the cytochromes, including A, A3, and
C, the conditions under which this occurs are complex. This
binding requires both a low intracellular oxygen tension, and a very
high intracellular CO tension. CO binding also requires the
cytochromes to be in a reduced state (Coburn and Forman,
2011). Whether these conditions occur in vivo and, if they do occur,
whether they are clinically relevant has yet to be demonstrated.
Numerous studies on this subject have failed to show significant
dysfunction of oxidative metabolism under conditions that are
 J.D. Roderique et al. / Toxicology 334 (2015) 45–58 49

expected to mirror those experienced in real life. In fact, several
studies have demonstrated that oxidative metabolism actually
appears to improve in the presence of CO in a concentration
dependent fashion (Almeida et al., 2012; Lavitrano et al., 2004;
Sandouka et al., 2006; Tsui et al., 2005).
While it is unlikely that CO disrupts ATP production in the
mitochondria as conventionally suspected, there is growing
evidence that it plays a pivotal role in the production of reactive
oxygen species (ROS). This attribute of CO gas will be further
elucidated in Section 6.2 in the discussion regarding ROS
formation.
4.3. Experiments demonstrating extra-hemoglobin activity
Leo Goldbaum was one of the first researchers to successfully
demonstrate that the binding of CO to hemoglobin might not be as
detrimental to tissue viability as previously thought (Goldbaum
et al., 1977, 1976, 1975; Hodjati et al., 1976). In a series of creative,

[(Fig._1)TD$IG]

Fig. 1. CO poisoning effects throughout the body: the constellation of symptoms caused by CO poisoning is variable and includes a number of direct effects on separate organ
systems.
50 J.D. Roderique et al. / Toxicology 334 (2015) 45–58
albeit highly controversial, experiments he demonstrated that
inhaled CO was far more toxic than transfused HbCO or CO gas
delivered via intraperitoneal injection. In one set of experiments
Goldbaum et al. connected the vasculature of a pair of dogs in
series so that the two dogs shared a contiguous circulatory system
(Case et al., 1975; Goldbaum et al., 1976). The first dog received
inhaled CO, whereas the second dog only breathed room air but
would receive CO poisoned blood from the first dog. After a period
of time, the HbCO level in both dogs equilibrated at an average level
of 52%. Only the dog directly inhaling the CO died, while the second
dog survived indefinitely without toxic effects despite having an
identical HbCO concentration as the first dog (their total blood
volume was shared). This is surprising since HbCO levels near
40–50% are generally considered fatal in large, unanaesthetized
mammals at normal atmospheric conditions.
In a separate set of experiments, Goldbaum et al. compared the
effects of several different CO poisoning methods in dogs. In the
first arm of the study dogs inhaled 13% CO for 15 min achieving
average HbCO levels of 65%. All of these animals expired by 65 min.
In the second arm dogs were hemorrhaged in a controlled fashion
and had their lost volume replaced with an equal amount of blood
that had been poisoned with CO ex vivo (Goldbaum et al., 1975).
After transfusion the dogs had an average HbCO of 60%; however,
all the animals in this study arm survived indefinitely with little to
no toxic effects. In a third set of experiments Goldbaum
demonstrated that by infusing CO gas into the peritoneal cavity
(instead of the lungs), very high levels of HbCO, in excess of 60–
70%, could be achieved without death and with little or no
evidence of toxicity (Goldbaum et al., 1977, 1976).
Goldbaum’s experiments were significant because he demon-
strated that simple HbCO, even at elevated levels, was not the cause
of toxicity. He concluded that inspired CO creates “a significant CO
tension in the blood (plasma) when it leaves the lungs and when it
reaches the organs, especially the heart and brain” (Goldbaum
et al., 1975). In summary COHb was not directly responsible for the
toxic effects, instead these were the result of the dissolved CO in
the plasma. He speculated, like others at the time, that dissolved
CO was entering cells and blocking oxidative phosphorylation in
much the same fashion as CN.
The previously mentioned studies conducted by the younger J.
B.S. Haldane as well as these studies by Goldbaum make it clear
that the physiologic actions of CO extend far beyond its interplay
with hemoglobin.
4.4. Carbon monoxide signaling dysregulation
If low concentrations of CO play an important regulatory role in
normal physiology then like any medication or biologic an
overdose of CO should result in a dysregulation of these same
pathways. Multiple studies have now validated this line of
reasoning (Arkebauer et al., 2011; Chlopicki et al., 2012; Gorman
et al., 2003; Hampson et al., 2012; Iheagwara et al., 2007; Wang
et al., 2011). These extra-hemoglobin effects have begun to provide
a logical explanation for the extreme variability that is encoun-
tered in patients with this form of poisoning (Fig. 1). They may also
explain why O2 (whether at high pressure or atmospheric
pressure) is such a poor single therapy for this injury. If CO
poisoning was a simple case of hypoxemia leading to tissue
hypoxia, then high-flow, high-pressure O2 would clearly be the
best choice. If on the other hand, as the evidence suggests,
hypoxemia is not the sole or primary problem in CO poisoning then
one could conclude O2 therapy is not the best choice and it is
necessary to look elsewhere to find the right solution.
5. Current carbon monoxide therapies
5.1. Normobaric oxygen (NBO) vs hyperbaric oxygen (HBO)
High flow, normobaric (NBO) oxygen therapy has long been the
mainstay of treatment when there is a clinical suspicion of
hypoxemia. It is not surprising that the current standard of care for
CO poisoning, a condition commonly thought to be exclusively
hypoxic in nature, is oxygen therapy. We currently know that COHb
has an average half-life of 320 min in patients breathing normal
room air which is reduced to an average of 71 min in patients
breathing 100% oxygen on a nonrebreathing mask and an average
of 21 min at 1.5 atm of 100% oxygen (Buckley et al., 2011; Jay and
McKindley, 1997). While there have been no RCTs comparing NBO
or HBO to standard room air, there have been several trials
comparing outcomes of HBO to NBO. These trials provide several
important clues about the efficacy of oxygen as a sole therapy.
The effects of HBO therapy differ from NBO therapy in two
significant ways: (1) HBO further reduces the half-life of HbCO and
(2) HBO increases the PaO2 (partial-pressure of oxygen) in the
plasma. If the toxic effects of CO were the result of reduced oxygen
delivery secondary to elevated HbCO it would be logical to expect
that patient outcomes would correlate well with the speed of
HbCO elimination and PaO2 increase. One could also logically
expect this difference to be prominent. Unfortunately, RCTs
examining the benefits of HBO versus NBO have not consistently
demonstrated a benefit and remain largely inconclusive (Annane
et al., 2011; Buckley et al., 2011; Buckley and Juurlink, 2013;
Juurlink et al., 2005, 2000, 1996; Scheinkestel et al., 1999; Stoller,
2007; Thom et al., 1995; Weaver et al., 2002).
5.2. Hyperbaric oxygen (HBO) evidence
Several cochrane meta-analyses by Juurlink and Buckley et al.
between 2000 and 2011 comparing available trials of HBO vs NBO
have been published. The authors evaluated six studies with a total
of 1361 participants, and have consistently concluded that “there is
insufficient evidence to support the use of hyperbaric oxygen for
treatment of patients with carbon monoxide poisoning” (Buckley
et al., 2011). Furthermore, one of the trials mentioned in the review
(but not included in the final analysis) indicated that HBO may
cause harm to comatose patients under certain treatment
conditions (Annane et al., 2011; Buckley et al., 2011).
The various HBO studies and the conclusions of the cochrane
reviews have been controversial. According to Buckley and Juurlink
(2013) all of the studies were highly heterogeneous, and the quality
of evidence was poor in all but one conducted by Weaver and
colleagues. The cochrane review authors subsequently went on to
suggest that there were numerous sources of bias and error in the
Weaver study and called its highly favorable results into question.
These assertions made by Buckley and Juurlink have also been
vehemently contested by supporters of the Weaver study (Thom,
2005).
It is not the intention of this manuscript to question the
absolute efficacy of HBO therapy. Rather, we question the
magnitude of HBO therapy’s purported benefits, particularly when
the proposed mechanism of injury is considered. If CO toxicity is
simply a problem of HbCO induced hypoxia then an improvement
of outcomes should correlate well with the rapidity of HbCO
conversion to free Hb. There should be a steady upward trend in
positive outcomes when comparing room air (no treatment), NBO,
and HBO. Though there is a paucity of data comparing outcomes of
room air treatments to the other common modalities Weaver et al.
did conduct a follow up analysis of their 2002 HBO trial. This may
offer some insight into the relative efficacy of NBO when compared
to room air.
 J.D. Roderique et al. / Toxicology 334 (2015) 45–58
In their follow up analysis Weaver et al. evaluated the outcomes
of patients who were excluded from their original study because
they had presented to the emergency department greater than
twenty-four hours after exposure. The long delay in presentation to
a definitive care facility meant that this patient group had
essentially received room air as their treatment. When comparing
room air and NBO Weaver et al. discovered no difference in
outcomes between the two treatment groups. In their conclusion
they admit that “clinicians need to be aware that HBO, not
necessarily 100% normobaric oxygen, reduces cognitive sequelae”
(Weaver et al., 2007). If the HbCO theory of poisoning were
accurate then NBO should provide a measurable benefit over room
air, but apparently this is not the case.
5.3. The obstacles to HBO therapy
Even if appropriate evidence of HBO benefit is clearly
demonstrated in the future, there are still some significant hurdles
that must be overcome prior to its widespread use. The first
obstacle will be defining the treatment protocol and population.
Currently there is significant variation with regards to patient
selection, duration of therapy, and the level of pressure to be used
(Brent, 2005). While Weaver et al. (2007) have demonstrated that
certain sub-populations like the elderly and those with extremely
high HbCO concentrations at presentation may benefit from HBO
therapy this assertion has not been confirmed by any other groups
or experimental trials (Brent, 2005).
The second challenge pertains to the availability of the therapy.
HBO is currently available only in select centers, mostly large
tertiary care facilities in first world countries, and there is no strong
consensus on guidelines for its use or requirements for transferring
[(Fig._2)TD$IG]
Fig. 2. Reactive oxygen species formation: a series of cell damaging processes is initiated when CO binds to Cytochrome C (CytC) and when it binds to nitric oxide forming
peroxynitrite (ONOO ).
51
high-risk patients to a facility that possesses HBO capabilities
(Brent, 2005; Roderique et al., 2012).
The only thing that can be said with certainty at this stage is that
HBO is a therapy that lacks sufficient evidence to support its
efficacy, and it should be reserved for selected patients at facilities
familiar with its use until stronger evidence can be made available
and/or HBO chambers become more widely available
(Brent, 2005). A large multi-center RCT will be necessary to
answer the questions surrounding HBO therapy, but at the time of
this writing, a search of clinicaltrials.gov did not reveal any multi-
center RCT’s ongoing or terminated in the past ten years.
5.4. Generation of reactive oxygen species (ROS)
Despite the seemingly innocuous nature of O2 therapies, this
necessary molecule can have untoward effects at high concen-
trations and high pressures. Instances of barotrauma, pulmonary
edema, and seizures have all been reported in the context of HBO
therapy (Buckley et al., 2011). In addition to these familiar risks,
oxygen therapy at all pressures has the potential for significant free
radical generation. These reactive oxygen species (ROS) can
damage DNA, cell membranes, and even affect cellular respiration
(Thom, 1990). Research has previously shown that CO can promote
the formation of ROS throughout the body, possibly playing a
critical role in the mechanism of CO toxicity (Han et al., 2007;
Thom, 1992, 1990; Thom et al., 1997a,b; Thom and Ischiropoulos,
1997; Tofighi et al., 2006; Zhang and Piantadosi, 1992). If CO
promotes ROS generation, then it is likely that the addition of high
concentrations of O2 in a poisoning scenario may further
exacerbate the free radical damage that is occurring in patients
(Thom, 1990). While it may seem like the oxygen therapies have a
52 J.D. Roderique et al. / Toxicology 334 (2015) 45–58
reasonable mechanism of therapeutic action, it is prudent to
wonder if this therapy is actually further exacerbating the injury
caused by CO to some organ systems. This mechanism of ROS
injury may help explain some of the variability seen in clinical
trials of NBO and HBO for CO poisoning, particularly when
considering DNS as an outcome.
5.5. Hyperoxic hypocapnea
Numerous studies completed in the last two decades have
repeatedly shown that administration of high dose oxygen will
precipitate a transient hyperpnea with a secondary reduction in
arterial carbon dioxide (PaCO2) concentrations. While the phe-
nomena is common, the exact mechanism of hyperoxic hyperpnea
is not well understood. Becker et al. (1996) suggested “that the
hyperventilation caused by hyperoxia is caused by hypercapnia in
the central chemoreceptors.” This central effect is thought to be
secondary to the decreased CO2 carrying capacity of the blood in
the face of high PaO2 and HbO2 saturation (the Haldane effect)
(Rangel-Castilla et al., 2010). While understanding the mechanism
of hyperoxic hyperpnea is important, its effects in CO poisoning
scenarios are more relevant.
Increasing the minute ventilation of a CO poisoning victim can
result in a reduction of the HbCO half-life, which by itself seems
desirable. However, this occurs with a concomitant reduction in
PaCO2. Central cerebral and coronary vascular beds are exquisitely
sensitive to O2 and CO2 concentrations. Minor increases in O2 and/
or minor decreases in CO2 concentrations cause a profound
reduction blood flow to these highly metabolic organs eliminating
one of their compensatory mechanisms for preventing hypoxia.
While treatments like HBO therapy will increase the O2 dissolved
in the plasma, it is unlikely that the small increase in PaO2 that
occurs is large enough to compensate for the reduction in blood
flow caused by the resultant hypocapnia; the same is even less
likely for NBO treatments (Case et al., 1975; Kety and Schmidt,
1948; Rucker et al., 2002). Some consideration has been given to
using hyperoxic hyperpnea as a therapeutic modality since it can
reduce the half-life of HbCO. However for this to be effective the
PaCO2 levels of the poisoning victim would need to be held
constant by special ventilatory equipment (Fisher et al., 2011).
6. Target sites for CO in the body
Currently there are over 1000 new articles published annually
concerning carbon monoxide. It is neither possible nor necessary
to cover all of the effects of CO on the body and readers are referred
to several excellent reviews on the subject (Davidge et al., 2009;
Wegiel et al., 2013). In reviewing the extensive literature that is
available, there are three key effects of CO that synchronize well
with the clinical toxidrome: (1) its effects on nitric oxide (NO), (2)
its production of reactive oxygen species (ROS), and (3) its effects
on ion channels. Interestingly all three of these targets may be
amenable to new interventions that are currently available and
could be readily tested.
6.1. Carbon monoxide and nitric oxide interplay
The first component of CO poisoning involves NO, a well-
characterized gasotransmitter with wide-ranging effects at both
the cellular and systemic level (Mustafa et al., 2009). Numerous
studies have now shown that CO results in both the increased
production and release of NO (Fig. 2). (Thom et al., 2004a,b; 1999a,
b; 1997a,b, 1994; Truss and Warner, 2011) CO causes the release of
nitric oxide from the hemeproteins to which it is normally bound
in platelets and possibly other cell types as well. This causes a rapid
rise in free nitric oxide levels both intracellularly and
extracellularly. At the same time, CO has also been shown to be
capable of activating certain forms of nitric oxide synthase,
resulting in an overall increased production of nitric oxide
(Alshehri et al., 2013; Thom et al., 1997b). This dysregulation of
NO homeostasis can lead to profound hypotension that is resistant
to catecholamines (Fischer and Levin, 2010; Ketteler et al., 1998).
NO is also a powerful oxidizing agent and at high levels can lead to
cellular and DNA damage, thereby causing cell death and immune
system activation (Thom et al., 1997a).
6.2. Carbon monoxide and reactive oxygen species (ROS)
The production of ROS is a second major component of CO
poisoning that has been recently demonstrated. Studies have
shown that CO is capable of inducing the formation of ROS
intracellularly (Kim et al., 2008; Queiroga et al., 2012; Thom, 1992,
1990; Thom et al., 1999a,b, 1997b; Zhang and Piantadosi, 1992;
Zuckerbraun et al., 2007). CO appears to do this primarily through
interaction with the mitochondria. CO exposure has also been
shown to directly induce the production of hydrogen peroxide and
superoxide (Thom et al., 1999a,b, 1997b). Production of these ROS
likely occurs through several mechanisms. At least one mechanism
involves the conversion of xanthine dehydrogenase into xanthine
oxidase causing the formation of peroxide (Han et al., 2007). A
second mechanism is through inhibition of the activity of
cytochrome C, leading to a buildup of superoxide within the
mitochondrial matrix (Shibanuma et al., 2011; Zuckerbraun et al.,
2007). As previously mentioned, this binding of CO to cytochrome
C does not significantly reduce the mitochondria’s ability to
produce ATP. Interestingly, while NADPH oxidase is inhibited and
NADPH production of ROS is decreased, xanthine oxidase and
mitochondrial production of ROS are increased. This leads to a net
increase in production of ROS despite NADPH inhibition (Basuroy
et al., 2011; Lamon et al., 2009; Taillé et al., 2005).
The overproduction of ROS such as peroxide and superoxide in
conjunction with elevated levels of NO is hazardous. While the
majority of active NO is released from hemeproteins in platelets,
some of it is produced by the activity of nitric oxide synthase
(NOS). Research has shown that neuronal levels of NO during CO
poisoning are nearly doubled via neuronal-NOS (nNOS) activation
and secondary calcium influx through NMDA channels (Thom
et al., 2004b). The combination of CO and NO can lead to the
conversion of nitric oxide into peroxynitrite (ONOO ) (Thom et al.,
1997b). ONOO is a much more potent free radical than nitric oxide
itself and is resistant to degradation by enzymes like superoxide
dismutase (Ohsawa et al., 2007; Thom et al., 1999a). The effects of
excess levels of ROS are widespread and include DNA/RNA damage,
lipid peroxidation, protein oxidation/nitrosylation, programmed
cell death and immune system activation, among others (Fig. 2)
(Thom, 1992, 1990; Thom et al., 1999a,b, 1997b). These effects have
led some to propose the use of nitrotyrosine residues and other
oxidized/nitrosylated proteins as markers for CO poisoning
severity (Thom, 1992; Thom et al., 2010). Levels of these residues
would afford practitioners a test with a significantly higher
sensitivity for poisoning than current measurements of HbCO
which have been shown to grossly underestimate total body CO
load (Hampson and Hauff, 2008; Varlet et al., 2013).
6.3. Carbon monoxide and ion channels
Ion channels are major regulators of many vital processes
including myocardial rate/rhythm, renal function, muscle contrac-
tion/relaxation, and nerve action potentials. While scientists
continue to sort out the precise mechanisms of how CO interacts
with these channels the implications for clinical medicine are clear.
If CO can act upon these channels directly, then it can hijack control
 J.D. Roderique et al. / Toxicology 334 (2015) 45–58
of hemodynamic parameters. This activity can occur independent
of its effects upon hemoglobin or the mitochondria, ultimately
leading to cardiovascular collapse. Genetic and epigenetic differ-
ences in these channels between individuals may also explain why
some individuals are apparently more susceptible to the effects of
CO.
In some cases, the action of CO upon these ion channels has only
been studied at low or “therapeutic” doses, or through the use of
carbon monoxide releasing molecules (CORM’s) (Peers, 2011;
Wilkinson and Kemp, 2011). In these instances the effect at higher
concentrations is inferred. Of the many channels that are now
known to interact with CO there are several common themes that
stand out as being particularly relevant to the clinical entity of CO
poisoning. The combined actions of CO upon certain channels in
the nervous system, heart, and blood vessels are well characterized
and appear to be the most appropriate targets for therapeutic
intervention at this time.
6.4. Neuronal ion channels
In neurons, there are three ion channels so far identified that
likely play a major role in CO poisoning. CO blocks the actions of
two potassium channels: Kv2.1, and the tandem P domain K+
channel (TREK1: aka K2p2.1) (Dallas et al., 2011, 2008). These
channels are responsible for maintaining and/or returning the cell
to a hyperpolarized state by allowing K+ to diffuse down its
concentration gradient. The Kv2.1 channel is found throughout the
brain with particularly high concentrations in the hippocampus, a
structure that is vital for memory formation and organization
(Misonou et al., 2005). CO inhibits these channels leading to an
increase in intracellular potassium and a movement of the cell
towards the depolarization threshold potential. In addition, CO
[(Fig._3)TD$IG]
Fig. 3. CO poisoning’s direct effect on ion channels: CO has direct effects on ion channels in the lung, brain, and heart.
53
activates a voltage-gated sodium channel, Nav1.5, which is found in
both myocardial and neuronal tissues (Dallas et al., 2012).
Activation of this channel leads to an increase in the intracellular
sodium concentration and a further movement of the cell towards
the depolarization threshold. Taken together, the actions of CO
upon these channels should lead to an increase in excitability. In
the case of neurons, this could explain the wide-ranging CNS and
autonomic deficits that can be seen even at relatively low HbCO
concentrations (Hampson and Hauff, 2008; Kao and Nañagas,
2006; Weaver, 2009; Wolf et al., 2008).
6.5. Cardiac ion channels
It has been suggested that most cases of CO induced fatalities
are primarily a result of cardiac dysfunction (Chamberland et al.,
2004; Gandini et al., 2001; Hancı et al., 2011; Kalay et al., 2007).
Specialists have long recognized that the dysrhythmias induced by
CO poisoning are peculiar, and difficult to attribute simply to
hypoxia alone (Chamberland et al., 2004). In recent years it has
become increasingly clear that CO is capable of regulating many
different types of ion channels which are the primary regulators of
heart rate, rhythm, and vascular tone (Fig. 3) (Peers, 2011;
Wilkinson and Kemp, 2011). This direct effect of CO on ion
channels finally provides a logical explanation for the myocardial
effects of CO, which can be seen even at low concentrations. At
present, the list of CO responsive ion channels includes: the large-
conductance voltage and Ca2+ activated K+ channels (BKCa: MaxiK
and Slo1), the purinergic receptors P2  2, P2  4, the voltage gated
potassium channel Kv2.1, the tandem P domain K+ channel (TREK1:
aka K2p2.1), the epithelial Na+ channel (ENaC), the myocardial
voltage-gated sodium channels (Nav1.5), and the L-type voltage-
activated Ca2+ channel (Althaus et al., 2009; Dallas et al., 2012,
54 J.D. Roderique et al. / Toxicology 334 (2015) 45–58
2011, 2008; Hou et al., 2009, 2008; Jaggar et al., 2005; Lim et al.,
2005; Riesco-Fagundo et al., 2001; Scragg et al., 2008; Telezhkin
et al., 2011; Wang and Wu, 1997; Wang et al., 2009; Wilkinson
et al., 2009; Wilkinson and Kemp, 2011; Williams et al., 2008,
2004). The mechanism of CO’s regulation is not entirely clear in all
cases. Proposed and proven mechanisms include direct effects,
binding to transition-metal containing regulatory proteins, and
production of NO and other ROS (Peers, 2011; Wilkinson and Kemp,
2011).
In the myocardium there are three primary channels that are
consider clinically important in this context. Two channels in
particular, the L-type Ca2+ channels and the myocardial voltage
gated sodium channels (Nav1.5), deserve particular attention in the
context of CO poisoning. The L-type Ca2+ channels are located
primarily in the heart (SA and AV nodes), the blood vessels (carotid
body), and the pancreas (DeWitt and Waksman, 2004). CO inhibits
the L-type Ca2+ channels, reducing Ca2+ influx into the cell.
Inhibition of these channels decreases the heart rate, disrupts AV
node conduction, reduces the contractility of the myocytes, causes
vasodilation, and reduces insulin secretion (DeWitt and Waksman,
2004; Kerns et al., 1994; Shepherd, 2006). If the effect of CO upon
the L-type Ca2+ channels is severe enough, it could cause a
toxidrome similar to a calcium-channel blocker (CCB) overdose
(such as verapamil). Toxic manifestations of CCB overdose include
myocardial depression, hypotension, syncope, lethargy, dizziness,
seizures, altered mental status, and non-cardiogenic pulmonary
edema. Additional symptoms include nausea, vomiting, metabolic
acidosis, and hyperglycemia (due to blockade of insulin release)
(DeWitt and Waksman, 2004; Kerns et al., 1994; Shepherd, 2006).
This toxidrome matches well with the signs and symptoms of CO
poisoning, although the extent to which CO inhibition of these
channels plays a role in vivo has yet to be demonstrated (Guzman,
2012; Hampson et al., 2012).
There is at least one channel that has now been shown in vivo to
have clinically relevant effects. This is the myocardial voltage-
gated sodium channel (Nav1.5). A 2012 study by Dallas et al. (2012)
has shown that CO is capable of inducing the late Na+ current in
myocardial cells (Nav1.5). They demonstrated that induction of this
current is capable of causing QT prolongation, a symptom seen in
CO poisoning and long reported by clinicians (Atescelik et al., 2012;
Gandini et al., 2001; Lippi et al., 2012; Macmillan et al., 2001;
Onvlee-Dekker et al., 2007; Sari et al., 2008). They showed that this
effect was due to the release and production of elevated levels of
NO secondary to CO exposure. QT prolongation predisposes the
heart to development of dangerous arrhythmias including
polymorphic ventricular tachycardia (VT) and ultimately ventric-
ular fibrillation (VF) and death. Often the progression from QT
prolongation to VT to VF requires an additional stimulus that
elevates the heart rate. Dallas and colleagues induced this
transition with the b1 agonist isoproterenol. In a true patient
setting, however, this stimulus could come in the form of stress
from injury. The stimulus could also be the product of CO’s
inhibitory action on the slow-leak K+ channel (TREK-1/ K2p2.1) in
the myocardium, resulting in increased excitability of the heart and
elevated heart rate.
More importantly, Dallas et al. (2012) demonstrated that by
understanding the pathways involved, they could reverse this
dysrhythmia. First they used a nitric oxide synthase (NOS)
inhibitor, L-NAME, and incubated the myocytes in it for thirty
minutes before exposure to CO. This effectively abolished the pro-
arrhythmic effects of CO by blocking CO’s ability to interact with
the Nav1.5 channel (since it requires NO to do so). In another
experiment they showed that they could block dysrhythmias by
interrupting one of the previously mentioned sodium channels.
Ranolazine, a specific inhibitor of the Nav1.5 channels, was used
both in vitro and in vivo to stop the pro-arrhythmic effects of CO.
6.6. Other ion channels
There are several other ion channels affected by CO with
potentially clinically relevant effects. CO inhibits the epithelial
sodium channel (ENaC), found in pulmonary type II alveolar cells
and the kidney (Althaus et al., 2009). This results in impaired
sodium and water reabsorption from the alveolar space (and
natriuresis in the kidneys) and may be a contributor to the
pulmonary edema encountered in many patients with clinically
relevant CO poisoning. Finally, CO’s stimulatory effects on BKCa
channels in blood vessels and the carotid body may be an
additional contributor to the hypotension that is often encoun-
tered in CO poisoning (Jaggar et al., 2005).
7. Alternative treatments
7.1. NO binding agents
As discussed in Section 3.4, hypotension is thought to be a
necessary component of the neurologic injury mechanism seen in
CO poisoning. Blockage of NOS or NO activity may reduce or
prevent hypotension and subsequent neurological insults. Lo et al.
(2014) compared studies that used low doses (1–3 mg) of
methylene blue (MB) as a treatment for cardiovascular collapse
in septic, anaphylactic, and toxin induced shock. MB is proposed to
increase blood pressure in these shock states by interfering with
guanylate cyclase and nitric synthase activity preventing vasodi-
latation and increasing peripheral resistance. At larger doses and in
the presence of cyanide MB induces the formation of methemo-
globin (Wendel, 1935). While the formation of methemoglobin
may be beneficial to victims of pure CN toxicity this action may
exacerbate the reduced oxygen carrying capacity of hemoglobin in
CO poisoned victims (Tor-Agbidy and Spencer, 2000).
Another NO sequestering agent with promise is hydroxocoba-
lamin. This compound is the main constituent of the CyanokitTM,
an FDA approved medication for the treatment of cyanide
poisoning. Hydroxocobalamin has been shown to increase mean
arterial pressures by binding NO, forming a vaso-innactive
compound called nitrosocobalamin (Rajanayagam et al., 1993;
Roderique et al., 2014). Hydroxocobalamin’s low side effect profile
and NO sequestering ability make it an ideal treatment for CO
induced hypotension. Furthermore, there is evidence that reduced
hydroxocobalamin may be able to directly coordinate the
conversion of CO to CO2 (Davidge et al., 2009; Lee and Schrauzer,
1968). The downside of hydroxocobalamin treatment relates to its
effect on blood testing devices that depend on light absorbance.
The dark red, almost violet, color can interfere with CO-oximetry
devices and induce artificially low CO readings (Livshits et al.,
2012).
7.2. Ion channel therapy
The primary cause of mortality in victims of CO poisoning is
cardiac dysrhythmia which is thought to be the result of direct CO
activity on the ion channels as previously mentioned. Future
treatments involving a sodium channel blocker such as Ranolazine,
may be able to attenuate the pro-arrhythmic effects of CO as shown
by Dallas et al. Although it has not been tested, it is also possible
that calcium gluconate and/or insulin might provide some benefit
in these patients by targeting the CCB overdose-like effect of CO on
the L-type calcium channels (Engebretsen et al., 2011; Shepherd,
2006). In contrast, atropine (another CCB-overdose treatment)
might precipitate an arrhythmia due to the concomitant activation
of Nav1.5 channels.
 J.D. Roderique et al. / Toxicology 334 (2015) 45–58
7.3. Antioxidants
As previously explained in Sections 5.2 and 6.2, CO induces
systemic ROS generation. Several groups have investigated
therapies using ROS scavengers with promising results. Already
mentioned is the work of Ohsawa et al. (2007) in which inhaled H2
was used as the scavenger for hydroxyl and ONOO radicals.
Though the injury in this study was induced via ischemia and
reperfusion, it stands to reason that inhaled H2 might be useful in
treating CO victims. Several other studies have examined the use of
hydrogen rich saline in the treatment of CO poisoned rats (Sun
et al., 2011; Wang et al., 2013, 2012). Investigators consistently see
a reduction in markers for lipid peroxidation, such as myelin basic
protein, as well as a preservation of neurological function. While H2
aggressively reduces hydroxyl and ONOO radicals it does not
interact with hydrogen peroxide nor superoxide ions; however this
may be insignificant, as hydroxyl and ONOO seem to have a
greater propensity for injury (Sun et al., 2011).
7.4. Combination therapies
There is a possibility that the concomitant administration of
previously mentioned oxygen therapies with some of these novel
treatments could have a synergistic effect not realized when either
is used alone. However, the aforementioned oxygen therapies have
the undesired consequence of creating a “pro-oxidative” environ-
ment ripe for ROS formation. Further trials would be necessary to
evaluate the benefit of dual treatment.
8. Conclusions
Clinicians and scientists need to appreciate that CO poisoning
pathology is a markedly complex mechanism that involves
extensive disruption of cell signaling and profound oxidative
stress which is sometimes facilitated by hypoxia but is not entirely
dependent upon hypoxia. While current treatments like oxygen
therapy may combat one of the toxic effects of CO (namely CO
binding to hemoglobin), failure to counteract the direct cellular
actions of free CO likely represents a significant missed opportu-
nity. Therefore, it is the opinion of the authors that the medical and
research community investigating CO poisoning should increas-
ingly shift its focus towards interventions that target some of CO’s
extra-hemoglobin effects. It is also our opinion that of the many
extra hemoglobin effects, the most important are the actions of CO
upon nitric oxide, ROS generation, and myocardial ion channels.
Not all patients develop the same set of symptoms when
exposed to equitable amounts of CO gas. While there is, generally
speaking, a dose-response relationship, there are also patient
specific factors that likely contribute to the highly variable clinical
picture. Understanding the pathophysiology of the various signs
and symptoms of CO poisoning and what specific therapies can
counteract each effect (i.e., Ranolazine for QT prolongation, or an
NO binder for hypotension) will allow for more individualized
treatment and better outcomes. It may well be that some
combination of medications (a CO cocktail), targeting the direct
cellular effects of CO and delivered in the field by first-responders,
could significantly improve outcomes in this patient population.
This has yet to be attempted, but the evidence suggests that this
should be investigated with enthusiasm.
The conventional understanding of CO poisoning that has been
passed from thousands of medical professors to their pupils has
remained virtually unchanged for nearly a century. The simple
explanation of HbCO induced hypoxic injury does not sufficiently
explain the cornucopia of adverse effects that CO has on its victims.
The intent of this review is to reinvigorate discussion and
consideration of this extraordinarily complex subject, and to
55
summarize the exciting research that is changing the paradigm of
this injury.
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