Carbon Monoxide Poisoning: Neurologic Aspects by K K Jain MD (Dr

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Carbon monoxide poisoning: neurologic aspects By K K Jain MD (Dr. Jain is a consultant in neurology and has no relevant financial relationships to disclose.) Originally released June 6, 1997; last updated April 5, 2016; expires April 5, 2019

Introduction

This article includes discussion of carbon monoxide poisoning: neurologic aspects and CO poisoning. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

Carbon monoxide can produce several nonspecific symptoms and can mimic several diseases. Most of the signs and symptoms are due to hypoxia, which affects mainly the brain. The most significant neurologic and psychiatric manifestations of carbon monoxide poisoning are seen as subacute or late sequelae, often following a period of complete recovery from an acute episode. There is a possible interaction between nitric oxide, a ubiquitous molecule in the human body, and carbon monoxide. Carbon monoxide exposure initiates processes including oxidative stress that triggers activation of N-methyl-D-aspartate neuronal nitric oxide synthase, and these events are necessary for the progression of carbon monoxide–mediated neuropathology. The most important diagnostic test for carbon monoxide poisoning is the direct spectroscopic measurement of carboxyhemoglobin level in the blood. Brain imaging findings frequently correlate with clinical manifestations. Hyperbaric oxygen plays an important role in the management of carbon monoxide poisoning.

Key points • Carbon monoxide poisoning can produce several nonspecific symptoms and can mimic several diseases. • Most of the effects are due to hypoxia. • Neurologic sequelae are significant and may be delayed in onset. • Hyperbaric oxygen plays an important role in management of carbon monoxide poisoning.

Historical note and terminology

Human beings have been exposed to carbon monoxide ever since they first made fire inside sheltered caves. In 300 BC, Aristotle stated that, "coal fumes lead to heavy head and death." Obviously, this was a reference to carbon monoxide poisoning. In 1857 Claude Bernard showed that carbon monoxide produces hypoxia by reversible combination with hemoglobin (Bernard 1857), and in 1865 Klebs described clinical and pathologic findings in rats exposed to carbon monoxide (Klebs 1865). The classic bilateral lesions of the globus pallidus and diffuse subcortical demyelination were described and correlated with psychic akinesia by Pineas (Pineas 1924) and with parkinsonism by Grinker (Grinker 1925).

In 1895 Haldane showed that rats survived carbon monoxide poisoning when placed in oxygen at a pressure of 2 ATA (Haldane 1895). The effectiveness of hyperbaric oxygen in experimental carbon monoxide poisoning in dogs and guinea pigs was demonstrated in 1942 (End and Long 1942). In 1960 hyperbaric oxygen was first used successfully in treating human cases (Smith and Sharp 1960).

Carbon monoxide is produced in small amounts endogenously during the catabolism of heme, resulting in the coproduction of biliverdin and iron. Carbon monoxide is considered to be a signaling molecule because it shares some chemical and biological properties with nitric oxide. Carbon monoxide is a mediator in the autonomic nervous system. Inhalation of subtoxic concentrations of carbon monoxide may have a cytoprotective effect, which is being investigated currently. Actions of carbon monoxide in the nervous system, thus, range from the physiological to the pathological.

Clinical manifestations

Presentation and course

Carbon monoxide can produce several nonspecific symptoms and can mimic several diseases. Most of the signs and symptoms are due to hypoxia, which affects mainly the brain, but other vital organs (ie, the heart) may also be involved. The onset may be acute or it may be insidious if the cause is chronic, low-grade carbon monoxide poisoning. The severity of symptoms is related to the blood carboxyhemoglobin levels, but frequent disparities exist between these. The most frequent neurologic manifestations of mild acute carbon monoxide poisoning (carboxyhemoglobin 10% to 20%) are headache (90%), dizziness (82%), and visual disturbances. These may be accompanied by impairment of higher cerebral function, nausea, weakness, and abdominal pain. With a moderate degree of poisoning (carboxyhemoglobin 20% to 40%), the patient may present with cardiac disturbances, dyspnea, and vomiting. Loss of consciousness may occur. Severe poisoning (carboxyhemoglobin 40% to 60%) may lead to coma, convulsions, and respiratory impairment. The patient may present in a decerebrate state. A vegetative state, extrapyramidal rigidity and movement disorders, Tourette syndrome, or severe memory deficits may follow recovery from coma. According to a study, the concept of relating specific symptoms to specific carboxyhemoglobin levels is invalid as none of the symptoms of carbon monoxide poisoning can be related to a specific carboxyhemoglobin level (Hampson et al 2012).

The patient may present in a state of delirium associated with neurologic involvement; this may be prolonged in 20% of the cases. Other neurologic manifestations of acute carbon monoxide poisoning are hemiplegia with aphasia, focal epileptiform seizures, hearing loss due to auditory nerve hypoxia, optic neuritis, and peripheral neuropathy. Carbon monoxide toxicity can induce a visual agnosia of apperceptive type, with well-defined characteristics seldom seen with other types of injury and a poor prognosis for recovery. Unilateral involvement of the phrenic nerve may lead to diaphragmatic paralysis.

Various disturbances of cardiac rhythm and conduction are identified by abnormalities on ECG. The patient may suffer from angina pectoris and myocardial ischemia. A combination of cerebral symptoms and a non-Q/non-ST elevation myocardial infarction, with enzyme elevations and electrocardiographic abnormalities, has been described in carbon monoxide poisoning (Johnson 2005). Other manifestations in comatose patients include neurogenic pulmonary edema and acute renal failure due to muscle necrosis or carbon monoxide-induced rhabdomyolysis without pressure necrosis.

Children seem to have a lower threshold for toxicity of carbon monoxide. Lethargy and syncope may occur at a mean carboxyhemoglobin concentration of 25%, whereas these symptoms are seen in adults at a level of about 40% carboxyhemoglobin.

Symptoms of chronic exposure to carbon monoxide are vague. A more subtle form of subacute carbon monoxide poisoning has been termed "occult carbon monoxide poisoning," used when the exposure is initially unknown to the patient and the physician. Chronic occult carbon monoxide poisoning can produce a syndrome of headache, fatigue, dizziness, paresthesias, chest pain, palpitation, and visual disturbances. “Warehouse worker headache” is the term used for carbon monoxide poisoning from industrial exposure to exhausts in unventilated indoor environments. Among patients presenting with the complaint of headache to an emergency department during winter-heating months are those who have raised carboxyhemoglobin levels in blood that could be traced to carbon monoxide exposure. Elevated carboxyhemoglobin levels are found in a small percentage of patients presenting to the emergency department with neurologic complaints of nontraumatic origin other than headache or dizziness and in whom carbon monoxide poisoning is not suspected.

The most significant neurologic and psychiatric manifestations of carbon monoxide poisoning are seen as subacute or late sequelae, often following a period of complete recovery. These are also referred to as "interval form of carbon monoxide poisoning," "secondary syndromes," or "delayed postanoxic encephalopathy," and may develop 1 to 3 weeks after exposure to carbon monoxide. Late sequelae of carbon monoxide poisoning include dementia, parkinsonism, and psychoses. In some instances, there has been repeated exposure to carbon monoxide.

The incidence of secondary syndromes, as described in the older literature, varies from 15% to 40% of the survivors of acute carbon monoxide poisoning. Delayed neurologic sequelae occur several years following the initial exposure. The most frequent neuropsychiatric sequelae of carbon monoxide poisoning are apathy, disorientation, memory impairment, hypokinesia, mutism, irritability, and bizarre behavior. Rare complications include amnesic syndrome, psychic akinesia, akinetic mutism, depression and psychoses, Klüver-Bucy syndrome, perceptual disorders, and cortical blindness.

Several movement disorders occur as late sequelae of carbon monoxide poisoning, mostly in association with neuropsychiatric deficits (Table 1). Delayed movement disorders are the most prominent of these. Of the 242 patients with carbon monoxide poisoning examined between 1986 and 1996 in Korea, parkinsonism was diagnosed in 23 patients (9.5%) and developed within 1 month in the majority of the patients (Choi 2002). A retrospective study of case records of patients with carbon monoxide poisoning found that the Glasgow Coma Scale and MMSE scores and positive findings in brain CT scans were predictors of the development of delayed neuropsychological sequelae but carboxyhemoglobin level was not (Ku et al 2010). Another retrospective study found that predictive risk factors for delayed neuropsychological sequelae after carbon monoxide poisoning that can be assessed in the emergency department include the following: carbon monoxide exposure duration of more than 6 hours, a Glasgow Coma Scale score less than 9, seizures, systolic blood pressure lower than 90 mmHg, elevated creatine phosphokinase concentration, and leukocytosis (Pepe et al 2011).

Table 1. Delayed Neuropsychiatric Sequelae of Carbon Monoxide Poisoning • Akinetic mutism • Apallic syndrome • Apraxia, ideomotor as well as constructional • Ataxia • Convulsive disorders • Cortical blindness • Deafness (neural) • Decreased IQ • Delirium • Dementia • Depression • Dysgraphia • Headaches • Memory disturbances • Movement disorders: parkinsonism, choreoathetosis • Optic neuritis • Peripheral neuropathy • Personality change • Psychoses • Symptoms resembling those of multiple sclerosis • Temporospatial disorientation • Tic disorder (adult onset) • Tourette syndrome • Urinary incontinence • Visual agnosia

Children are subject to the same neuropsychiatric sequelae that are seen in adults. Developmental plasticity of the brain may explain a better prognosis for functional recovery in children with carbon monoxide-induced neuropsychological impairment.

Clinical diagnosis of carbon monoxide poisoning is based more on the history of exposure than on the findings of the clinical examination. The classic cherry-red color of the skin is rarely seen in nonfatal cases. Carbon monoxide is a colorless, odorless, and tasteless gas; the only evidence of exposure to it may be the elevated carboxyhemoglobin levels in the blood, but the severity of signs and symptoms does not always correspond to these. In cases with delayed manifestations, carboxyhemoglobin levels may no longer be elevated.

Carboxyhemoglobin levels of less than 10% are usually considered to be clinically insignificant, but several studies on human volunteers have shown subtle changes on neuropsychological testing. Some of these changes are decreased cognitive and psychomotor ability with carboxyhemoglobin levels of 2% to 5% and impaired ability to discriminate short time intervals with carboxyhemoglobin levels of 4% to 5%.

Prognosis and complications

The mortality of acute carbon monoxide poisoning is about 30% in untreated cases. It is reduced considerably in patients treated by hyperbaric oxygen therapy. Mortality is high in patients who remain in a coma beyond 48 hours, and the survivors have severe neurologic deficits. The prognosis for recovery is usually poor in patients who remain in a "vegetative state" for more than 1 month following carbon monoxide poisoning, but good functional recovery has been reported in exceptional cases after remaining in such a state for a few months. Level of carboxyhemoglobin is not a reliable prognostic index, but pH of the blood may be a significant factor.

There appears to be no biomarkers or constellation of signs or symptoms at presentation that predicts long-term outcome following carbon monoxide poisoning. Interleukin-6 in CSF at the early phase of carbon monoxide poisoning may be a predictive biomarker of delayed encephalopathy (Ide and Kamijo 2009). CT scan has been used as a prognostic index. The prognosis is usually good in most cases with a normal CT, and the chances for recovery diminish in patients with abnormal CT, especially when lesions of both the globus pallidus and the white matter are present.

Patients with severe carbon monoxide poisoning who have abnormalities on CT scan that persist after hyperbaric oxygen treatment are more likely to develop neuropsychiatric sequelae. More than half of patients are diagnosed as suffering from cognitive impairments and other neurologic symptoms after years following carbon monoxide poisoning, with affective disorders in almost three fourths of these patients and personality disorders in more than half (Borras et al 2009).

Biological basis

Etiology and pathogenesis

Traces of carbon monoxide occur in the atmosphere and some carbon monoxide is produced endogenously, but these amounts are ordinarily not significant. Important causes of carbon monoxide poisoning are exposure to automobile exhaust, domestic cooking gas, industrial plant exhausts, fire smoke, and cigarette smoke. Suicide attempts may involve inhalation of cooking gas or automobile exhaust.

Carbon monoxide is the most common killer in fires and in smoke inhalation. Automobile exhaust is the biggest source of atmospheric pollution with carbon monoxide. Smoking is the commonest and the most underestimated cause of nonfatal chronic carbon monoxide intoxication.

Factors that contribute to carbon monoxide poisoning are high carbon monoxide concentration in the air being breathed, prolonged exposure, and high altitude with low oxygen tension.

Pathomechanism. Acute carbon monoxide poisoning is interlaced with multiple factors, including apoptosis, abnormal inflammatory responses, hypoxia, and ischemia/reperfusion-like injury. One of the current hypotheses with regard to the molecular mechanism of carbon monoxide poisoning is the oxidative injury induced by reactive oxygen species, free radicals, and neuronal nitric oxide (Akyol et al 2014).

Inhaled carbon monoxide diffuses readily across the alveolocapillary membrane and binds to hemoglobin to form carboxyhemoglobin. The affinity of carbon monoxide for hemoglobin is 200 times greater than that of oxygen. Deleterious effects of elevated body carbon monoxide stores are usually called carbon monoxide-hypoxia; the term implies that an inhibition of oxygen transport occurs from the blood to the tissues. Carbon monoxide toxicity is the result of a combination of tissue hypoxia-ischemia secondary to carboxyhemoglobin formation and direct carbon monoxide-mediated damage at a cellular level (Guzman 2012). Tissue oxygen tension may be decreased directly through a reduction in oxygen content by a lowered arterial oxygen tension as well as through the presence of carboxyhemoglobin. The oxygen dissociation curve is shifted to the left. The clinical effects of carbon monoxide are usually attributed to tissue hypoxia, but they do not always correlate with carboxyhemoglobin levels.

The neuropathologic sequelae of carbon monoxide poisoning cannot be explained by hypoxia alone. Carbon monoxide combines with extravascular proteins (ie, myoglobin) and, thus, its combination with cytochrome c oxidase and cytochrome P-450 has been considered possibly to cause cellular hypoxia by inhibiting the mitochondrial respiratory chain. Carbon monoxide may alter brain oxidative metabolism independently of carboxyhemoglobin-related decrease in oxygen delivery. Binding of carbon monoxide to cytochrome oxidase in rat brain cortex has been observed by reflectance spectroscopy; this is a possible explanation of a nonhypoxic mechanism of carbon monoxide toxicity. Extended and generalized inhibition of mitochondrial cytochrome c oxidase could explain the persistence of different symptoms after raised levels of acute carboxyhemoglobin levels are normalized. Carbon monoxide-mediated brain injury is a type of postischemic reperfusion phenomenon with involvement of reactive oxygen species. These observations may provide an explanation for a number of poorly understood clinical observations regarding carbon monoxide poisoning, particularly the neuropsychological effects at concentrations below 5%. Delayed amnesia induced by carbon monoxide exposure in mice may result from delayed neuronal death in the hippocampal CA1 subfield and dysfunction of the acetylcholinergic neurons in the frontal cortex. Studies on mice have shown that NMDA receptor or ion channel complex is involved in the mechanism of carbon monoxide-induced neurodegeneration, and that glycine binding site antagonist, as well as NMDA-antagonists, may have neuroprotective properties.

A clinical study on patients with carbon monoxide-related parkinsonism and age- and sex-matched controls used detailed neurologic examinations, diffusion tensor imaging, and PET to assess disturbances in neurotransmitter pathways (Chang et al 2015). Monoaminergic deficits and white matter damage in these patients correlated with severity of parkinsonism and behavior changes. Sparing of substantia nigra and topography of monoaminergic involvement suggest that pathophysiology in carbon monoxide-related parkinsonism is different from the other types.

In spite of various explanations that have been offered, nothing is known with certainty about the pathomechanism of carbon monoxide poisoning. Carbon monoxide may act as a neurotransmitter by interacting with the enzyme guanylyl cyclase, which may provide an important clue to the pathomechanism of carbon monoxide toxicity. Endogenously formed carbon monoxide arises from the enzymatic degradation of heme oxygenase to release a molecule of carbon monoxide, which acts as a neuromodulator. Carbon monoxide, applied at low concentration, has cytoprotective effects mimicking those of heme oxygenase-1HO-1 induction. Many of the effects of carbon monoxide depend on the activation of guanylate cyclase, which generates guanosine 3',5'-monophosphate and the modulation of mitogen- activated protein kinase signaling pathways. In addition to its physiological role, carbon monoxide that arises subsequent to the appearance of heme oxygenase-1 may underlie various pathological states.

Delayed carbon monoxide-mediated neuropathology may be due to an adaptive immunological response to chemically modified myelin basic protein. An allelic variant of rs1784594 single nucleotide polymorphism of PARK2, which is associated with Parkinson disease and other neurodegenerative disorders, is a risk factor for neuropsychological sequelae following acute carbon monoxide poisoning, particularly in females (Liang et al 2013). It is important to investigate the relationship between other PARK2 polymorphisms and clinical outcome following carbon monoxide poisoning.

There is a possible interaction between nitric oxide and carbon monoxide. Nitric oxide, which arises endogenously through the action of nitric oxide synthase enzymes, is a highly reactive molecule that plays important roles in the regulation of various body functions. It is a double-edged sword with beneficial as well as harmful effects. Carbon monoxide exposure initiates processes including oxidative stress that triggers activation of neuronal nitric oxide synthase, which may aggravate carbon monoxide-mediated neuropathology.

Various neurologic manifestations of carbon monoxide poisoning can be correlated with lesions found in the brains of victims. Bilateral necrosis of the globus pallidus is a pathologic hallmark of carbon monoxide intoxication. White matter damage is considered to be significant in the pathogenesis of parkinsonism in patients with carbon monoxide poisoning. Other affected areas include the cerebral cortex, hippocampus, cerebellum, and substantia nigra. Gray matter lesions in the cerebral cortex composed of spongy changes, capillary proliferation, degeneration, and reduction of neurons have been observed on histological examination in a number of patients. The histology of these lesions is similar to those caused by other anoxic conditions. Carbon monoxide is 1 of the classic causes of anoxic leukoencephalopathy (also called "delayed postanoxic demyelination"). Pathological findings in patients with delayed carbon monoxide encephalopathy are atrophy of frontal lobes, diffuse demyelination of the white matter, and softening in the globus pallidus. A study using diffusion tensor imaging found that selective damage to corpus callosum was more profound in patients with delayed encephalopathy after carbon monoxide poisoning as compared to patients without neurologic sequelae (Chen et al 2015). In many cases, globus pallidus lesions do not correlate directly to clinical status and outcome; however, the presence of diffuse white matter disease is a more reliable index of both.

The pathomechanism of brain lesions is not well understood. Factors other than carboxyhemoglobin levels may play a part in this process. Brain white matter edema seen in acute, severe carbon monoxide poisoning may be the result of hypoxia and subsequent acidosis, which increases vascular permeability. Transient disappearance of bilateral low- density lesions of the globus pallidus, similar to the "fogging effect" seen in vascular lesions, supports the hypothesis of necrotic damage of vascular origin following brain edema in patients with carbon monoxide poisoning. It has been postulated, but not proven, that oligodendroglial injury leads to delayed demyelination in carbon monoxide poisoning.

It is also recognized that carbon monoxide exposure can result in brain damage and delayed cognitive impairment in the absence of neuropathological lesions. Epidemiology"

Carbon monoxide is the leading cause of death by poisoning in the United States. More than 4000 persons die annually from carbon monoxide poisoning, and 10,000 receive emergency treatment for exposure to carbon monoxide fumes. In addition to this, carbon monoxide accounts for more than half of the approximately 12,000 annual fire-associated deaths. Approximately 50,000 emergency department visits for carbon monoxide poisoning in the USA occur annually, 3 to 5 times the numbers previously estimated (Hampson and Weaver 2007). In Korea, the incidence of carbon monoxide poisoning in households using charcoal briquettes for heating and cooking was 5.4% to 8.4%, as shown in a survey of 4 major cities (Cho et al 1986). No figures are available for a much larger number of sufferers from occult carbon monoxide poisoning.

Prevention

Physical exercise and restlessness can increase the intake of carbon monoxide at the site of exposure. Carbon monoxide poisoning is aggravated by several preexisting medical conditions such as anemia, myocardial ischemia, cerebrovascular disease, thyrotoxicosis, fever, and diabetes. By increasing availability of glucose, hyperglycemia presumably increases cerebral glycolytic reflux and elevates brain intracellular lactate levels that induce acidosis and edema leading to brain damage. Hyperglycemia following carbon monoxide poisoning is associated with poor outcome.

The average carboxyhemoglobin in chronic, heavy smokers is approximately 5% (Jain 1990). This places the smokers at risk of carbon monoxide poisoning when exposed to low concentrations of environmental carbon monoxide that may not produce symptoms in nonsmokers. Increased incidence of atherosclerotic disease in smokers has been attributed to carbon monoxide content rather than nicotine in cigarettes; however, no convincing evidence is available advancing that chronic carbon monoxide exposure increases the risk of developing clinically significant atherosclerotic disease. Smoking is a recognized risk factor for stroke, but the role of carbon monoxide has not been proven.

The following risk factors have been identified for the development of delayed encephalopathy following carbon monoxide poisoning:

(1) Old age (2) Hypertension (3) Coma lasting 2 to 3 days (4) Persisting dizziness and fatigue after regaining consciousness (5) Excessive mental stimulation during recovery

Prevention is the most important aspect of management of carbon monoxide poisoning. Various measures for this should include control of atmospheric pollution (mainly from automobile exhaust), proper maintenance of household gas appliances, and elimination of indoor charcoal and wood burning without proper exhaust. Industrial hygiene measures should reduce exposure to carbon monoxide at the workplace so that it does not exceed safety standards. Protective equipment should be provided to miners and firefighters who are at risk for exposure to carbon monoxide. Traffic police officers on duty at rush hours in major cities should have carboxyhemoglobin levels checked routinely. If carboxyhemoglobin levels are 10% or higher, the patient should be transferred to a place with less risk of exposure. Finally, smoking cessation measures should be applied to control chronic carbon monoxide poisoning at the individual level.

Differential diagnosis

Approximately one third of nonfatal cases of carbon monoxide poisoning go undetected and undiagnosed. Carbon monoxide poisoning mimics several other diseases and is frequently misdiagnosed as psychiatric illness, migraine headaches, stroke, epilepsy, dementia, alcohol intoxication, flu-like illness, gastroenteritis, pneumonia, and heart disease. Differential diagnosis from psychiatric disorders is sometimes difficult, as the patients who attempt suicide with carbon monoxide may have had psychiatric disorders prior to carbon monoxide poisoning, and some behavioral problems may be late sequelae of carbon monoxide poisoning. Carbon monoxide poisoning may mimic decompression syndrome in divers exposed to air contamination from exhausts of nearby gasoline engines. Another frequent misdiagnosis is food poisoning. Symptoms in other members of the household and pets, recurring at a particular time and place, and related to the use of a gas heater, a vehicle, or any other potential source of carbon monoxide, should suggest the diagnosis. A bit of detective work may be required to locate the source of carbon monoxide poisoning. A simple tool based on the CH2OPD2 mnemonic (Community, Home, Hobbies, Occupation, Personal habits, Diet and Drugs) is helpful in obtaining an environmental exposure history (Abelsohn et al 2002). Diagnosis of carbon monoxide poisoning is particularly difficult in infants in the absence of history of exposure. Convulsions and altered states of consciousness are manifestations of many other illnesses in infants.

Occult carbon monoxide poisoning should be considered in the differential diagnosis of neurologic disorders; if any suspicion exists, carboxyhemoglobin levels should be checked. Response to oxygen or hyperbaric oxygen supports the diagnosis of acute carbon monoxide poisoning, but the lack of response does not exclude it. Characteristic CT lesions are helpful in diagnosis. Akinetic mutism following carbon monoxide poisoning is regarded as a specific condition characterized by injury of the frontal neuronal systems and is different from the locked-in syndrome (Tengvar et al 2004).

Diagnostic workup

The most important diagnostic test for carbon monoxide poisoning is the direct spectroscopic measurement of carboxyhemoglobin level in the blood. An indirect way to estimate is to measure carbon monoxide content of the exhaled breath. Emergency medical technicians, using handheld carbon monoxide meters that detect as little as 1 part per million of carbon monoxide, can effectively screen for elevated carbon monoxide levels during emergency responses. In severely ill patients with suspicion of exposure to carbon monoxide, oxygen therapy is not delayed pending carboxyhemoglobin estimation even though oxygen, by lowering carboxyhemoglobin, may remove the evidence of carbon monoxide exposure. Carboxyhemoglobin levels of greater than 10% have diagnostic significance. It should be taken into consideration that carboxyhemoglobin levels do not necessarily correspond to the severity of the clinical symptoms.

An ideal and objective biochemical serum biomarker could help in the evaluation of carbon monoxide poisoning and determine indication for hyperbaric oxygen therapy. S-100B was elevated in conscious carbon monoxide-poisoned rats left on ambient air or treated with normobaric oxygen, but not in conscious carbon monoxide-poisoned rats treated with hyperbaric oxygen (Brvar et al 2006). S-100B can be measured in the serum of patients by using commercially available ELISA tests. Recurrent myelin basic protein elevation in cerebrospinal fluid is a predictive biomarker of delayed encephalopathy after carbon monoxide poisoning (Kamijo et al 2007). Elevated serum levels of ubiquitin C- terminal hydrolase-L1, a reliable biomarker of neuronal damage after acute neurologic insults, are useful for determining carbon monoxide poisoning severity and outcome (Pang et al 2014).

The blood samples withdrawn should also be used for determining blood gases, blood counts, and basic biochemical investigations. The patient should be screened for other drugs and alcohol intoxication, and in the case of women of childbearing age, a pregnancy test should be done. Various other tests are selected according to the organs affected, the severity of poisoning, and the facilities available. An electrocardiogram is frequently done to detect cardiac arrhythmias, and a chest x-ray is taken to detect pulmonary edema and aspiration pneumonia, particularly in a comatose patient.

Neurologic investigations include neuropsychological testing, EEG, and brain imaging studies. A multifaceted approach combining clinical neuropsychological testing, EEG, and brain imaging is recommended as all of these show abnormalities in a high percentage of patients with carbon monoxide poisoning and because clinicopathological correlations can be established.

Neuropsychological testing. Various psychological tests have been designed for patients with carbon monoxide poisoning. The Carbon Monoxide Neuropsychological Screening Battery consists of 6 tests: (1) general orientation, (2) digit span, (3) trail making, (4) digit symbols, (5) aphasia, and (6) block design. A nonpsychologist can administer these tests in an emergency in 20 minutes. A strong correlation exists between abnormalities detected on psychometric testing and carboxyhemoglobin levels. The former measures actual neurologic disability and is a better index of severity of carbon monoxide poisoning. Neuropsychological impairments in carbon monoxide-poisoned subjects include memory, intellectual, executive, and visuospatial defects (Rahmani et al 2006).

Electrophysiology. Electrophysiological abnormalities are mostly diffuse and include continuous theta and delta activity, rhythmic bisynchronous bursts of slow waves, low-voltage activity with or without periods of silence or spiking, burst suppression pattern, and electrocerebral silence. Topographic quantitative EEG methods may have promise in the study of acute and long-term effects of carbon monoxide poisoning. Quantitative electroencephalography has been used to monitor the efficacy of hyperbaric oxygen treatment of carbon monoxide poisoning, and improvement of occipital alpha activity is considered to be a possible indicator for treatment efficacy (Murata et al 2005).

Brain imaging studies. CT and MRI are valuable in the delineation of disease extent and different patterns of brain injury in the acute and delayed stages of carbon monoxide poisoning (Lo et al 2007).

CT is the most widely used neuroimaging method for patients with carbon monoxide poisoning. Common CT findings are symmetrical low-density basal ganglia abnormalities and diffuse low-density lesions of the white matter. The globus pallidus lucencies may be unilateral, and white matter involvement may show marked asymmetry. Postcontrast CT offers an advantage when noncontrast CT is normal in carbon monoxide poisoning. In the interval form of carbon monoxide poisoning, low-density lesions bilaterally in the frontal regions, centrum semiovale, and pallidum have been correlated with demyelination of white matter of the corresponding parts at autopsy. Hemorrhagic infarction in the white matter has been demonstrated by CT and MRI following acute carbon monoxide poisoning. An initial normal CT scan in a comatose patient does not rule out carbon monoxide poisoning.

Most of the knowledge of MRI findings in carbon monoxide poisoning is based on case studies of patients in the subacute or chronic phase following exposure. With regard to patients in the acute phase of carbon monoxide poisoning, MRI studies show that although the globus pallidus is the commonest site of abnormality in the brain, the effects on the brain are widespread. The white matter hyperintensities seen on MRI do not correlate with carbon monoxide poisoning severity except those in the centrum semiovale, which are significantly associated with cognitive impairments. Diffusion-weighted MRI is useful for early identification of pallidoreticular damage due to acute carbon monoxide poisoning.

Positron emission tomography (PET) studies in acute carbon monoxide poisoning have been reported to show a severe decrease in regional cerebral blood flow and regional cerebral metabolic rate for oxygen in the striatum and the thalamus even in patients treated with hyperbaric oxygen.

SPECT can provide imaging of cerebral perfusion. HMPAO-SPECT has been useful as a guide in determination of responsiveness for hyperbaric oxygen patients with acute as well as delayed sequelae of carbon monoxide poisoning (Harch 2016). In comparison to traditional brain imaging techniques, 99mTc-HMPAO brain imaging with fan-beam SPECT in combination with surface 3-dimensional display is a better tool for early detection of regional cerebral anomalies in acute carbon monoxide poisoning. It is a cheaper and more easily available alternative to PET. Relative values of clinically used imaging methods in carbon monoxide poisoning are shown in Table 2.

Table 2. Value of Brain Imaging Studies in Carbon Monoxide Poisoning CT MRI SPECT/PET Basal ganglia lesions + ++ White matter lesions + +++ Both white and gray matter + ++ +++ Cerebral edema + ++ Cerebral perfusion +++ Predicting late sequelae + +++ ++ Assessing response to + ++ +++ hyperbaric oxygen

Proton magnetic resonance spectroscopy has been used for the interval form of carbon monoxide poisoning. Increase in choline in the frontal lobes indicates progressive demyelination. Appearance of lactate and decrease in N- acetylaspartate reflect the point at which neuron injury becomes irreversible. These findings have been correlated with those of MRI and SPECT or PET. It may be a useful method to determine neuron viability and prognosis in carbon monoxide poisoning. The combination of proton magnetic resonance spectroscopy and diffusion tensor imaging on a 3.0T system is useful for monitoring the changes in brain damage and the clinical symptoms of patients with delayed encephalopathy after carbon monoxide poisoning and response to hyperbaric oxygen treatment (Terajima et al 2008).

Intracranial pressure monitoring. This is required in patients with severe carbon monoxide poisoning with cerebral edema and raised intracranial pressure. Biomarkers in carbon monoxide poisoning. A retrospective study has reported that the level of serum S100B protein was found to be a useful biomarker for evaluating patients with acute carbon monoxide poisoning as well as an independent predictor of the development of delayed neurologic sequelae (Park et al 2012). In another study, the mean S100B levels in the CSF within 24 hours after carbon monoxide exposure were higher (9.25 ng/mL) in those who developed persistent vegetative state than in those who developed delayed encephalopathy (2.03 ng/mL) and those who recovered to a normal state (1.86 ng/mL) whereas the mean serum S100B levels were not elevated (Ide et al 2012).

Fractional anisotropy from diffusion tensor imaging in the centrum semiovale can correlate with myelin basic protein in cerebrospinal fluid to depict demyelination in the central white matter during the subacute phase after carbon monoxide poisoning (Beppu et al 2012).

Management

The objectives of treatment of carbon monoxide poisoning are to hasten the elimination of carbon monoxide from the body and to counteract hypoxia and its sequelae as well as the direct tissue toxicity of carbon monoxide. The mainstay of therapy for carbon monoxide poisoning is supplemental oxygen, ventilatory support, and monitoring for cardiac dysrhythmias. Although immediate oxygen breathing is sometimes an adequate treatment, hyperbaric oxygen therapy is favored.

General measures. The first step is to remove the patient from the site of exposure and administer 100% oxygen by mask immediately. Comatose patients may require endotracheal intubation and resuscitative measures. Other complications should be treated as required by appropriate medications: mannitol and corticosteroids for cerebral edema, diuretics for pulmonary edema, antiarrhythmic drugs for cardiac arrhythmias, antibiotics for pneumonia, and sodium bicarbonate to correct acidosis. Management strategy is influenced by the severity of carbon monoxide poisoning. Mild poisoning (carboxyhemoglobin less than 30%) may be managed symptomatically, and 100% oxygen is administered until carboxyhemoglobin level drops to below 5%. Such patients may be discharged home from the emergency department; admission should be considered if neurologic or cardiac function is impaired. Patients with loss of consciousness should be referred for hyperbaric oxygen therapy. Another accepted indication for this form of treatment is a carboxyhemoglobin level of greater than 30%, regardless of the severity of clinical signs.

Hyperbaric oxygen therapy. This involves administration of 100% oxygen at pressures greater than that at sea level. Physics, physiology, and clinical applications of hyperbaric oxygen are explained in detail in a textbook on this subject (Jain 2016). At 3 ATA, oxygen dissolves in the plasma to the extent of 6 vol% with a partial pressure of oxygen of 2193 mm Hg. This quantity of oxygen is sufficient to sustain life in the complete absence of functional hemoglobin. This is the rationale for use of hyperbaric oxygen in carbon monoxide poisoning. Hyperbaric oxygen counteracts tissue hypoxia in spite of the presence of high levels of carboxyhemoglobin and marked reduction of functional hemoglobin. Additionally, it causes a rapid reduction of carbon monoxide in the blood by mass action of oxygen. The half-life of carbon monoxide when breathing air is 5 hours 20 minutes. It is reduced to 1 hour 20 minutes when breathing 100% oxygen at normal pressure and to 23 minutes during hyperbaric oxygen treatment. Hyperbaric oxygen assists in driving carbon monoxide away from cytochrome oxidase and in restoring its function. Brain lipid peroxidation caused by carbon monoxide is prevented by 100% oxygen at 3 ATA. In an animal model of carbon monoxide poisoning, hyperbaric oxygen was shown to prevent immune-mediated delayed neurologic dysfunction following exposure (Thom et al 2006). Finally, hyperbaric oxygen reduces cerebral edema, which is a serious complication of carbon monoxide poisoning.

Hyperbaric oxygen therapy has been used as a treatment for carbon monoxide poisoning since 1960, but when to use it remained controversial. Earlier conclusions about efficacy were based on clinical experience and uncontrolled studies, but 6 prospective clinical trials have been reported comparing hyperbaric oxygen and normobaric oxygen administration to treat patients with acute carbon monoxide poisoning. Four of these found better clinical outcomes among patients receiving hyperbaric oxygen, whereas 2 showed no treatment effect. The best-designed, randomized, controlled clinical trial supports the efficacy of hyperbaric oxygen in severe acute carbon monoxide poisoning.

Approximately 1500 carbon monoxide-poisoned patients are treated with hyperbaric oxygen in the United States annually, and most treating facilities do not routinely give more than 1 hyperbaric treatment (Hampson and Little 2005). Hyperbaric oxygen has also been used for the prevention as well as the treatment of late sequelae of carbon monoxide poisoning. Visual loss has been reported as a late complication of carbon monoxide poisoning and was successfully treated with hyperbaric oxygen therapy (Ersanli et al 2004).

Early recognition of carbon monoxide poisoning in infants is crucial for the prevention of late sequelae, which include learning and memory difficulties. Many of the signs and symptoms seen in adults with carbon monoxide exposure were difficult to detect in these patients. Hyperbaric oxygen has been used safely and effectively for the treatment of carbon monoxide poisoning in infants.

Various regimens have been used for the treatment of carbon monoxide poisoning. The pressures used vary between 2 ATA and 3 ATA. The most commonly used protocol is an initial 45 minutes of 100% oxygen at 3 ATA followed by further treatment at 2 ATA for 2 hours or until the carboxyhemoglobin is less than 10%. Hyperbaric oxygen is the treatment of choice in patients who lost consciousness during toxic exposure, who are comatose on admission to hospital, and who have persisting neurologic abnormalities. Complications of hyperbaric oxygen in comatose patients include rupture of the eardrum in about 10% of the patients. Seizures may occur in patients with brain injury who are subjected to high hyperbaric oxygen pressures. Although there is some controversy regarding the pressure of hyperbaric oxygen, use of pressures between 2.5 and 3 ATA seems appropriate for carbon monoxide poisoning. A study combining hypothermia with hyperbaric oxygen has shown neurologic deficit-free outcome in several cases of carbon monoxide poisoning (Feldman et al 2013).

There is at least 1 carefully controlled investigation of hyperbaric oxygen for acute carbon monoxide poisoning (Weaver et al 2002). Among the strengths of this trial are its large size, its use of a sham-treatment control group with blinding of both patients and investigators to the treatment-group assignment, its selection of seriously poisoned patients representative of those encountered in emergency departments, its employment of treatment regimens similar to those in common use, its high rates of follow-up evaluation, and its explicit definitions of cognitive sequelae. This trial showed that hyperbaric oxygen treatment significantly reduces the incidence of carbon monoxide-induced delayed neurologic sequelae. The assessment of the primary end point (identification of patients in whom cognitive sequelae developed) took place 6 weeks after poisoning, but evaluations at 6 and 12 months also showed a large benefit of hyperbaric oxygen. Although the results of randomized clinical trials are inconsistent, hyperbaric oxygen therapy is still included in some protocols on the treatment of carbon monoxide poisoning (Domachevsky et al 2005). Although criteria for use of hyperbaric oxygen vary among different organizations, it is strongly recommended that hyperbaric oxygen therapy be considered for patients with carbon monoxide poisoning on the basis of the available data, including biochemical studies, studies in animals, and at least 1 rigorous clinical trial (Weaver 2009).

Randomized controlled trials have shown that hyperbaric oxygen is the only effective therapy for acute carbon monoxide poisoning if delayed neurologic sequelae are to be minimized. Normobaric oxygen should not be used between multiple hyperbaric oxygen treatments, as this can contribute to oxygen toxicity. Hyperbaric oxygen therapy has also been shown to decrease the severity of impairment in patients who have developed delayed neurologic sequelae (Chang et al 2010). A review of clinical trials of hyperbaric oxygen for carbon monoxide has been critical of methodology and not accepting of the benefits, but the review itself is flawed in trying to pool data from trials with different designs on a condition with variable presentation as an emergency in different locations (Buckley et al 2011). A multicenter randomized controlled trial as suggested by the authors of this review is not feasible. A retrospective multi-institutional study in Japan showed that hyperbaric oxygen therapy is an effective form of therapy for carbon monoxide poisoning and prevention of late neurologic sequelae (Kusuba et al 2012).

As of April 2016, only 2 clinical trials of use of hyperbaric oxygen in carbon monoxide poisoning, which were initiated in 2007, were in progress. The first of these is investigating important clinical outcomes of patients with acute carbon monoxide poisoning randomized to receive either 1 or 3 hyperbaric oxygen treatments and is expected to be completed by 2019 (ClinicalTrials.gov). Hyperbaric oxygen will be given 3 ATA for 25 minutes breathing oxygen, 5 minutes air breathing, 25 minutes oxygen breathing, 5 minutes air breathing, pressure reduced to 2 ATA for 30 minutes breathing oxygen, 5 minutes air breathing, and 30 minutes oxygen breathing. For the second and third hyperbaric oxygen sessions, the subject will breathe 100% oxygen delivered at 2 ATA for 90 minutes with two 5- minute air breathing periods. The second clinical study is a retrospective review of the principal investigator's experience using SPECT brain imaging and hyperbaric oxygen therapy in the diagnosis and treatment of nonacute phases of carbon monoxide poisoning (ClinicalTrials.gov). The purpose is to see if the SPECT brain imaging is consistent with the clinical condition and cognitive testing on the patients with neuropsychiatric sequelae. It is expected to be completed by the end of 2016.

Other treatments for sequelae of carbon monoxide poisoning. The following treatments have been tried with various degrees of success: (1) Electroconvulsive therapy has been used for the management of psychiatric sequelae of carbon monoxide poisoning during the recovery phase, but has been shown to cause deterioration of neurologic status. This therapy should be avoided in patients with neurologic complications. (2) L-dopa has not been shown to be useful for carbon monoxide-induced parkinsonism. (3) Bromocriptine has been found to be useful for psychic akinesia and parkinsonism associated with carbon monoxide poisoning. (4) Myoclonus has been treated successfully by intravenous piracetam. (5) Dextroamphetamine has been found to be useful for neuropsychiatric sequelae of carbon monoxide poisoning. (6) Ziprasidone, an atypical antipsychotic, can be used effectively in the treatment of delayed carbon monoxide encephalopathy. (7) Therapeutic red cell exchange may be an alternative method for reducing mortality and morbidity in severe carbon monoxide poisoning (Zengin et al 2013). (8) A randomized, prospective study has shown that early administration of erythropoietin to patients with carbon monoxide poisoning improved neurologic outcomes and reduced the incidence of delayed neurologic sequelae (Pang et al 2013). (9) Hydrogen sulfide (H2S) is a neuroprotective agent by its inhibitory effects on oxidative stress and apoptosis to protect against oxidative damage to the nervous system. Studies in rat models of carbon monoxide poisoning have shown beneficial effect of H2S on delayed encephalopathy after acute carbon monoxide poisoning (Zhang et al 2015).

Special considerations

Pregnancy

Endogenous production of carbon monoxide is doubled in women during the progesterone phase of the menstrual cycle as compared to the level during the estrogen phase or to levels in men. During pregnancy, the rate of endogenous production of carbon monoxide increases even further, but it declines rapidly in the postpartum period. Pregnancy is considered to be a risk factor for carbon monoxide poisoning. Carbon monoxide diffuses readily across the placenta, but its elimination from the fetus lags considerably behind that of the mother, thus, placing the fetus at risk of exposure to exogenous carbon monoxide and the resulting hypoxia. Congenital malformations and fetal death may result if carboxyhemoglobin levels are markedly elevated or if moderately severe maternal toxicity occurs. Carbon monoxide intoxication of the pregnant mother during the first trimester may lead to congenital malformations of the offspring. Severe carbon monoxide poisoning during the latter months of pregnancy can lead to fetal brain lesions similar to those seen in adults. Offspring of rats exposed to carbon monoxide with carboxyhemoglobin levels of 15% have shown retarded behavioral development. Behavioral abnormalities of children of smokers have been attributed to carbon monoxide exposure. Hyperbaric oxygen has been recommended for the treatment of carbon monoxide poisoning during pregnancy. This therapy should be used if the maternal carboxyhemoglobin is above 20% at any time during the exposure, if any neurologic signs are present (regardless of the carboxyhemoglobin level), and if any signs of fetal distress consistent with hypoxia due to exposure are present.

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ICD and OMIM codes

ICD codes

ICD-9: Toxic effect of carbon monoxide: 986

ICD-10: Toxic effect of carbon monoxide: T58

Profile

Age range of presentation

0-01 month 01-23 months 02-05 years 06-12 years 13-18 years 19-44 years 45-64 years 65+ years

Sex preponderance male=female

Family history none

Heredity none

Population groups selectively affected none selectively affected

Occupation groups selectively affected

Warehouse workers

Differential diagnosis list psychiatric illness migraine headaches stroke epilepsy dementia alcohol intoxication flu-like illness gastroenteritis pneumonia heart disease decompression syndrome food poisoning

Associated disorders

Anoxic leukoencephalopathy Carbon monoxide-induced parkinsonism Delayed carbon monoxide encephalopathy Late sequelae of carbon monoxide poisoning Warehouse workers headache