Handbook of Clinical Neurology, Vol. 120 (3rd series) Neurologic Aspects of Systemic Disease Part II Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved
Chapter 64
Neurologic complications of carbon monoxide intoxication KERSTIN BETTERMAN1* AND SURJU PATEL2 Department of Neurology, Penn State College of Medicine, Hershey, PA, USA
1 2
Department of Internal Medicine, Conemaugh Health System, Jonestown, PA, USA
INTRODUCTION French physiologist Claude Bernard was one of the first to describe the pathophysiology of carbon monoxide (CO) poisoning during the mid 19th century (Bernard, 1857). He observed that CO causes tissue hypoxia by interaction with red blood cells requiring him to develop a new method to measure blood-gas transfer. He performed many experiments which showed that CO prevented red blood cells from taking up oxygen and delivering it to the tissues, and described the cherry red appearance of the blood following CO intoxication (Bernard, 1858, 1870). Carbon monoxide poisoning is still the leading cause of poison-related morbidity and mortality worldwide. In the US it results in more than 50 000 emergency visits yearly (Weaver, 2009). Carbon monoxide is an odorless, colorless gas that can be found at toxic levels in homes with gas heating furnaces. It is a product of incomplete combustion of fuels from multiple sources and is found in motor vehicle exhausts or indoor heating units with burning of oil, coal, wood, or kerosene. Frequently chronic intoxication occurs in settings of chimney malfunction or dysfunctional ventilation. Deadly CO poisoning often occurs in the setting of a building fire or from exposure to fuel powered generators and heaters used during natural disasters or with suicide using motor vehicle exhaust gas (Prockop and Chichkova, 2007; Studdert et al., 2010).
PATHOPHYSIOLOGY Endogenous CO production occurs during normal heme metabolism at concentrations not interfering with normal blood- or tissue-oxygen exchange. However, increased CO concentrations following intoxication impact the
transport of oxygen to the tissues. Normally, oxygen diffuses across the alveolar-capillary membrane and binds to hemoglobin. Carbon monoxide interferes with this process by diffusing rapidly through the alveolar-capillary membrane and binding to hemoglobin more than 200 times faster than oxygen. Carboxyhemoglobin (COHb) is formed which causes a left-shift in the oxyhemoglobin dissociation curve (Hardy and Thom, 1994). The tetrameric structure of the hemoglobin molecule goes through a conformational change where the sigmoidal curve is no longer maintained. COHb is unable to transport as much oxygen as normal hemoglobin leading to decreased oxygen delivery to the tissues and subsequent tissue hypoxia. Moreover the allosteric property of hemoglobin induced by CO binding causes other CO molecules to bind more rapidly. Carbon monoxide binds to hemoglobin at such high rate that partial pressures of CO in the capillaries stay relatively low. Carbon monoxide is not perfusion limited meaning it will not be affected by the rate of blood flow or the amount of hemoglobin in the blood. As long as there is hemoglobin, it will bind. Although COHb is a completely reversible complex, the release of oxygen from COHb is relatively slow and depends on the inhaled oxygen concentration. The higher the inhaled oxygen concentration, the faster the CO elimination rate, which is the rationale to treat CO intoxication victims with 100% oxygen or to consider hyperbaric oxygen (HBO) therapy. After COHb levels decrease, tissue oxygenation, mitochondrial function, and cellular energy metabolism are restored, but even transient exposure to high concentrations of CO may cause brain injury acutely or within days to weeks (Okeda et al., 1982; Piantadosi et al., 1997). Carbon monoxide causes tissue hypoxia, ischemia and secondary injury through multiple mechanisms of
*Correspondence to: Kerstin Bettermann, M.D., Ph.D., Department of Neurology, Penn State College of Medicine, 500 University Drive, P.O. Box 850, Hershey, PA 17033, USA. Tel: þ1-717-531-1803, Fax: þ1-717-531-0963, E-mail: [email protected]
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Table 64.1 Summary of the cerebral pathology and pathophysiology associated with CO poisoning Carbon monoxide causes acute cerebral ischemia and hypoxia as well as secondary injury via multiple mechanisms of action Brain pathology Injury of neurons of cortical layers III and V Decreased volume of the hippocampus Globus pallidus injury Demyelination of the white matter Loss of Purkinje cells in the cerebellum Cerebral edema Necrosis and apoptosis Cerebral pathophysiology Interruption of cellular respiration Decreased glucose metabolism Increase in lactid acid Production of reactive oxygen species Endothelial peroxynitrate deposition Decreased dopamine turnover in caudate nucleus Activation of the inflammatory cascade Modification of myelin basic protein and malonyaldehyde Increased intracellular iron deposition Increased nitric oxide levels P450 inhibition Lipid peroxidation Increase of cytosol heme concentration Activation of genes mediating apoptosis
action (Table 64.1). Highly metabolic organs such as the heart and the brain are especially vulnerable. Carbon monoxide binds to platelet heme-protein and cytochrome C oxydase, interrupting cellular respiration in the mitochondria with subsequent tissue acidosis and production of reactive oxygen species (Miro et al., 1998). As a result, the cells shift to anaerobic metabolism and toxic lactic acids and nitrates build up. Oxidative stress results in neuronal necrosis, apoptosis, and activation of hypoxia-induced factors mediating secondary injury. Carbon monoxide also activates the inflammatory
cascade, causes peroxidation of lipids and deposition of peroxynitrate in blood vessel endothelium, causing vascular damage that can potentiate tissue ischemia soon after or even during exposure to CO and at relatively low concentrations (Alonso et al., 2003; Cronje et al., 2004; Thom et al., 2006; Thom, 2008). In the heart CO binds to myoglobin about 60 times faster than oxygen, causing myocardial hypoxia. It causes coronary vasodilation and increased coronary flow which can result in additional hypoxic-ischemic damage to the myocardium and decreased cardiac output. Low cardiac output and hypotension in turn can decrease cerebral perfusion and contribute to hypoxicischemic brain injury (Prockop and Chichkova, 2007). Studies in mice have shown that cerebral flow increases within minutes of CO exposure which is caused by guanylyl cyclase-mediated relaxation of the cerebral arteries (Komuro et al., 2001; Kanu et al., 2006). Cerebral blood flow remains elevated until cardiac compromise causes decrease in blood pressure and cardiac output, at which point cerebral autoregulation fails and asphyxia and apnea start, all contributing to the hypoxic-ischemic brain injury (Thom, 1990; Thom et al., 2006). Carbon monoxide is a naturally occurring signaling molecule in the brain, but following exposure to high CO concentrations during an acute or chronic intoxication CO has detrimental effects on the central nervous system (CNS). Cytosol heme concentrations in the brain increase about tenfold after CO poisoning, adding to its toxicity (Cronje et al., 2004). There are acute as well as delayed neurologic effects following CO intoxication. Acute CO poisoning often causes damage to brain areas with great susceptibility to hypoxic injury, including the second and third cortical layers, watershed areas within the white matter, the basal ganglia and the Purkinje cells of the cerebellum. The nature and distribution of brain lesions depend on the acuteness, the severity, and the duration of exposure to CO. Furthermore CO poisoning causes lipid peroxidation with degradation of unsaturated fatty acids leading to demyelination of CNS lipids and damage to myelin and axons. This process is to some extent reversible and can be observed acutely or with delayed brain injury. Many of the delayed neurologic complications may be mediated by inflammatory and immune responses (Thom et al., 2004). In experimental studies CO causes over-reactivity of neuronal nitric oxide synthase which produces nitrous oxygen (NO). NO is released from platelets and causes changes in cerebral blood flow and aggregation with neutrophils. Neutropohils and platelets interact, producing reactive oxygen species that mediate lipid peroxidation in the brain (Thom et al., 2006). Additionally the peroxidation product malonlylaldehyde (MDA) alters the ionic charge and configuration of myelin basic protein inducing change
NEUROLOGIC COMPLICATIONS OF CARBON MONOXIDE INTOXICATION in its antigenic nature. In experimental studies this causes an increase in macrophages and CD4 lymphocytes with subsequent activation of brain microglia that is associated with learning difficulties, not present in rats without an altered myelin basic protein structure (Thom et al., 2004).
PATHOLOGY The neuropathology of CO intoxication has been well described (Lapresle and Fardeau, 1967; O’Donnell et al., 2000; Chu et al., 2004). Postmortem studies have shown petechial hemorrhages in the white matter, particularly in the corpus callosum, and multifocal necrosis within the globus pallidus, the hippocampus, and the pars reticularis of the substantia nigra. Other findings include laminar necrosis of the cortex and loss of Purkinje cells in the cerebellum. White matter lesions are frequently observed which can be asymmetrical. The typical pallidal lesions are well defined involving the globus pallidus with microscopic infarctions extending anteriorly, superiorly, and into the internal capsules. Often a small linear focus of necrosis is found at the junction of the internal capsule and the internal nucleus of the globus pallidus. The hypothalamus, the thalamus, the third ventricle, and the brainstem are often spared (Lapresle and Fardeau, 1967). In comatose patients who die soon after CO intoxication there is frequently myelin damage with perivascular lesions in the corpus callosum, the internal and external capsules, and the optic tracts. Demyelinating plaques, extensive periventricular demyelination and axonal destruction can be observed in postmortem studies of patients who died from chronic CO intoxication or in comatose patients who survive for longer periods of time after an acute CO intoxication. Demyelination of
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the subcortical and periventricular white matter is often associated with a delayed neuropsychiatric syndrome following CO intoxication which will be described in the following section (O’Donnell et al., 2000). Because of their increased metabolic rate, both brain and myocardium are especially vulnerable to hypoxic injury associated with CO poisoning. Findings related to brain hypoxia include laminar necrosis of the cortex. Here neurons of layers III and V are greatly affected, as is the hippocampus and the Purkinje cells of the cerebellum. Globus pallidus injury is the hallmark of carbon monoxide intoxication (Kumar et al., 2005). The predilection for the globus pallidus remains unclear but may be related to the high iron affinity of CO. The globus pallidus is iron rich, resulting in greater concentration of CO in this area. Additionally the globus pallidus receives blood supply from blood vessels belonging to one of the watershed areas of the brain, making it more susceptible to ischemic injury from cardiac and hypotensive effects which are typically associated with CO poisoning (Lo Ping et al., 2007). If the globus pallidus and basal ganglia are damaged by injury and necrosis, movement disorders such as Parkinsonism can develop. Although globus pallidus lesions are considered to be pathognomonic of CO intoxication, they may not occur even in survivors suffering Parkinsonism (Choi, 1983). In these patients white matter lesions, present on magnetic resonance imaging (MRI), are often responsible for the clinical picture of parkinsonism (Sohn et al., 2000).
CLINICAL FINDINGS Carbon monoxide poisoning can cause acute and delayed signs and symptoms which can be specific (see Table 64.2). However, at times the clinical picture can
Table 64.2 Associations between clinical presentation, carbon monoxide concentration, and exposure times (modified from Struttmann et al., 1998) Carbon monoxide concentration (in parts per million)
COHb level
Symptoms, CO exposure time
35 ppm 100 ppm 200 ppm 400 ppm 800 ppm 1600 ppm
10% 20% 25% 30% 40%
3200 ppm 6400 ppm
50% 60%
12 800 ppm
>70%
Headache and dizziness, within 6–8 h Slight headache, in 2–3 h Slight headache and loss of judgment, within 2–3 h Headache, within 1–2 h Dizziness, nausea, and seizures, within 45 min Headache, tachycardia, dizziness, and nausea within 20 min; death in less than 2h Headache, dizziness, and nausea in 5–10 min; death within 30 min Headache and dizziness in 1–2 min; seizures, respiratory arrest, and death in less than 20 min Death in less than 3 min
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be rather vague and a high level of clinical suspicion is therefore crucial. The CO concentration and the exposure time are associated with specific symptoms which are summarized in Table 64.2. Depending on the duration of CO exposure symptoms are typically first noted with measured blood COHb concentrations of about 10%. Patients with underlying chronic heart and lung disease may present earlier at lower CO concentrations and with more severe symptoms. In a healthy person, the average carboxyhemoglobin levels are approximately 1–2%. In anemic patients the COHb levels are about 5% and in nonsymptomatic smokers the levels are as high as 15%. The most common symptoms of CO poisoning include nausea, vomiting, dizziness, and generalized weakness (Ginsberg, 1985; Prockop, 2005). COHb levels below 40% are not typically associated with coma or death.
Acute intoxication Acute CO poisoning is rarely detected until the patient becomes ill. The so-called classic cherry red discoloration of the skin and cyanosis are very rare. Headache is one of the most common presenting features of CO poisoning, occurring in over 80% of victims. It is typically dull, frontally located, and continuous, or it can mimic migraine headaches (Handa and Tai, 2005). In mild cases only mild flu-like symptoms can be observed. About half of the victims with CO intoxication complain about generalized weakness, nausea, confusion, and shortness of breath. Sometimes abdominal pain, vision changes, chest pain, and other vague symptoms are present (Prockop, 2005). Hypoxia leading to increased intracranial pressure from cytotoxic cerebral edema causes not only headaches, but also confusion, seizures, coma, and death. Transient cerebral edema can develop followed by widespread tissue necrosis and can be diagnosed early by diffusionweighted brain MRI. Other neurologic findings include tinnitus, central hearing loss, nystagmus, and ataxia, visual disturbances, and syncope (Llano and Raffin, 1990; Blumenthal, 2001). Varying degrees of cognitive impairment have been observed following chronic and acute CO intoxication, and are pathognomonic for the delayed neurologic sequelae following CO intoxication. Cardiac symptoms are ischemic in nature and consist of chest pain, myocardial infarct, cardiac dysrhythmias, hypotension, and tachycardia. Frequently ischemic EKG changes are present and cardiac enzymes are elevated. Patients with underlying chronic heart and lung disease are especially at risk of dying from cardiac complications and myocardial infarct. The mortality rate is higher in patients with moderate to severe CO poisoning, which also causes respiratory depression and pulmonary edema (Ginsberg, 1985).
Chronic intoxication Chronic carbon monoxide poisoning occurs when low levels of CO are inhaled over a prolonged period of time, for instance in the setting of an undetected gas leak. This can mimic flu-like symptoms and frequently causes nausea, lethargy, and headaches. Depression, vomiting, gastrointestinal problems, weight loss, short-term memory difficulties, and confusion can develop. A high level of suspicion is essential to make the diagnosis.
Delayed neuropsychiatric syndrome Cognitive deficits develop within 2–240 days following CO intoxication (Tibbles and Perrotta, 1994). Severe dementia, psychosis, anxiety, and other neuropsychological symptoms suddenly start after an initially excellent functional recovery period. Carbon monoxide encephalopathy can also present with alterations in attention, executive function, visuomotor skills, learning, shortterm memory, mood, and social behavior. The delayed neuropsychiatric syndrome occurs in about 3% of CO intoxication cases and personality changes, urinary and fecal incontinence, and parkinsonism may develop (Mimura et al., 1999). The incidence is higher in the elderly and in those being exposed to CO for at least 12–48 hours. After an initial recovery phase, patients rapidly deteriorate, developing some or all of the neuropsychiatric symptoms above (Ernst and Zibrak, 1998). On neurologic examination frontal release and extrapyramidal signs are frequently present. In 57% of cases, the EEG will show delta range slowing and neuroimaging studies are abnormal (Tibbles and Perrotta, 1994). Head CT shows hypodensities in the basal ganglia in half of the patients. MRI usually shows hyperintensities in the globus pallidus and white matter changes in the frontal lobes. Neuropathology often shows extensive lesions in the brain including the globus pallidum, caudate, putamen, substantia nigra, hippocampus, hypothalamus, periventricular white matter, corona radiata, cerebellum, and hippocampus (Brucher, 1967; Lapresle and Fardeau, 1967) (Figs 64.1 and 64.2). About 60–75% of patients with delayed neuropsychiatric syndrome recover within a year. About 15% continue to suffer from dementia and parkinsonism (Bhatia et al., 2007).
DIAGNOSIS The diffuse symptoms and the absence of specific laboratory tests makes it difficult to suspect CO intoxication; especially chronic poisoning. History of exposure to fire, presence of a fireplace, indoor compression appliances, or occupational exposure can be indicative of CO intoxication. Following intoxication, ambient air CO levels at
NEUROLOGIC COMPLICATIONS OF CARBON MONOXIDE INTOXICATION
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Fig. 64.2. Small cystic necrosis in internal pallidal segment and laminary cortical necroses after coal gas poisoning. The patient survived many years in a rigid-akinetic state with severe dementia. (Reproduce from Jellinger, 1986.)
LABORATORY TESTS
Fig. 64.1. Carbon monoxide intoxication. (A) Symmetrical necrosis in oral pallidum and diffuse leukoencephalopathy in intermittent form. (B) Multiple focal necroses in posterior and lateral parts of the globus pallidus and in the reticular zone of the substantia nigra. Heidenhein stain. (Reproduce from Jellinger, 1986.)
the scene of exposure should be measured as soon as possible. The half-life of CO is only 4–5 hours so that blood COHb levels are rather unreliable to determine the severity of an intoxication. Only CO levels measured at the scene of an acute exposure may have potential to assess the degree of intoxication.
The COHb concentration in blood depends on the amount of CO in the inhaled air, the ventilation rate and the exposure time. Often the clinical outcome correlates poorly with measured blood COHb concentrations which may be due to the fact that blood samples are often obtained after a significant amount of time has passed following CO exposure. Another reason for the poor correlation is delayed neurologic injury which can develop independently of measured HbCO levels. Pulse CO oximetry can be used at the bedside to detect increased levels of HbCO in the blood. If it is elevated the value is significant. However, if the value is low carbon monoxide poisoning cannot be completely ruled out as inhalation of low levels of oxygen can also cause low HbCO levels. Pulse oximeters frequently overestimate the arterial oxygenation in patients with severe CO poisoning. Automated spectrophotometers or oximeter devices are now available and are increasingly recommended to assess victims of CO intoxication (Prockop and Chichkova, 2007).
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Lactic acid levels, basic metabolic panels with glucose levels, electrolytes and arterial blood gases should also be closely monitored as patients with CO intoxication frequently develop lactate acidosis. Renal function can be diminished due to myoglobinuria and hypokalemia and hyperglycemia can occur with severe intoxication. Cardiac function must be closely monitored by serial EKGs, echocardiograms and measurements of cardiac enzymes for the development of brady- or tachycardia, atrial or ventricular fibrillation, premature ventricular contractions, conduction abnormalities, or myocardial infarct.
NEUROIMAGING STUDIES One of the most sensitive measures of cerebral injury following CO intoxication is brain MRI, which shows variable findings. Most comatose patients show abnormalities within the globus pallidus, lentiform nucleus, caudate nuclei, thalamus, periventricular and subcortical white matter, especially of the frontal and temporal lobes. Hippocampal and cerebellar lesions can be present. Diffuse high signal abnormalities within the bilateral centrum semiovale are also common (Tuchman et al., 1990). T1-weighted MRI sequences show typically low signal intensity bilaterally in the globus pallidus. This corresponds to high signal intensities on T2-weighted and fluid attenuated inversion recovery (FLAIR) imaging. Pathognomonic pallidal lesions are well visualized by contrast-enhanced MRI (see Fig. 64.1). In the acute intoxication phase contrast enhanced T2-weighted MRI may show patchy or peripheral enhancement of necrotic areas. Diffusion-weighted MRI often shows restriction of water diffusion due to cytotoxic edema within the white matter or diffusely within the brain (Sener, 2003). These changes can develop early after CO exposure. Most acute stages also show restricted water diffusion in the globus pallidus and in the substantia nigra. White matter changes are often reversible. However, following severe CO intoxication persistent changes on MRI can be found for years following the exposure even without clinical deficits (O’Donnell et al., 2000; Durak et al., 2005). T2 and FLAIR sequences often show bilateral symmetric hyperintensities in the white matter of the centrum semiovale with relative sparing of the brainstem (see Fig. 64.2). Clinical status and outcome often correlate with diffuse white matter changes. MR spectroscopy can now be used to help assess prognosis. N-acetylaspartate (NAA) decreases in demyelinated white matter regions representing most likely axonal and neuronal loss (Van Zijl and Barker, 1997). This can often be observed in the basal ganglia or in the white matter. Proton magnetic resonance spectroscopy may show
increased choline peak which indicated progressive demyelination in early CO poisoning cases (Murata et al., 1995). Kamada and coworkers (Kamada et al., 1994) have shown that a marked lowering of the NAA/ Cr ratio and a slight increase in the Cho/Cr ratio with subsequent normalization can parallel clinical improvement. MR spectroscopy is currently mainly investigational but may become useful as prognostic indicator in CO poisoning. Cranial CT typically reveals unilateral or bilateral low attenuation areas in the globus pallidus but is less sensitive than MRI. Hemorrhagic infarctions have been described on both CT and brain MRI. Positron emission tomography (PET) and SPECT can also provide additional information showing decreased glucose metabolism and hypoperfusion that parallel the development of focal and diffuse lesions after CO intoxication.
DIFFERENTIAL DIAGNOSIS Carbon monoxide poisoning can present in a similar way to many other disease states. The symptoms are nonspecific and therefore CO poisoning can easily be mistaken for other conditions such as the flu, gastrointestinal disorders, chronic fatigue syndrome, depression, hypothyroidism, anemia, or chronic migraine headaches. Neurologic and neuropsychiatric signs and symptoms may suggest a neurodegenerative disorder such as dementia, Parkinson disease, other movement disorders, or may mimic psychiatric conditions such as schizoaffective disorder or depression.
TREATMENT Oxygen should be administered to all patients with suspected CO intoxication via face mask with 100% oxygen flow (Elkharrat, 1998). This must be initiated immediately and independently of blood COHb levels as measured COHb levels may underestimate the true intoxication level. The airway needs to be secured and adequate ventilation needs to be maintained. Following inhalation of 100% oxygen at normobaric pressure, the half-life of COHb is reduced from 4–5 hours to 1 hour. Patients should be on strict bed rest and every measure should be taken to decrease oxygen demand and to lower metabolic needs. Patients with respiratory distress and a decreased level of consciousness must be intubated and mechanically ventilated. Chest X-rays and arterial blood gases should be assessed periodically. Cardiac function needs to be closely monitored. Serum pH and lactid acid levels should be closely monitored since aerobic metabolism generates lactate acidosis. Acidosis with pH below levels of 7.15 should be treated with sodium bicarbonate.
NEUROLOGIC COMPLICATIONS OF CARBON MONOXIDE INTOXICATION The use of hyperbaric oxygen therapy remains controversial for the treatment of victims with CO intoxication (Weaver et al., 1995; Juurlink et al., 2000; Stoller, 2007). HBO therapy consists of inhalation of 100% oxygen at higher than normal ambient pressures. It significantly increases the amount of oxygen that is physically dissolved in blood and becomes available for delivery to hypoxic tissues. At pressures of 2.5 atmospheres absolute (ATA) HBO reduces the half-life of COHb from 4 hours to 20 minutes. A single treatment at pressures of 2.5–3.0 ATA given over a duration of 90–120 minutes is commonly considered for treatment of patients with syncope, coma, seizures, and focal neurologic deficits who present with COHb levels of more than 25% (and of more than 15% in pregnant women) (Tibbles and Perotta, 1994; Van Meter et al., 1994; Thom et al., 1995; Weaver et al., 1995; Tibbles and Edelsberg, 1996). However, in clinical practice it is difficult to make a decision on when to use hyperbaric oxygen as COHb levels might underestimate the degree of intoxication and do not necessarily correlate with clinical severity. Hyperbaric oxygen treatment is also sometimes considered for victims of CO intoxication who are at risk of developing the delayed neuropsychological sequelae (Weaver et al., 2007). In one study, patients aged 36 years and older who had been exposed to CO for at least 24 hours and who did not receive HBO treatment had an increased risk of cognitive sequelae at 6 weeks compared with those without these characteristics (Weaver et al., 2007). Pregnant women should probably be treated with hyperbaric oxygen as the fetus is especially vulnerable after CO intoxication, with high rates of fetal mortality and morbidity (Prockop and Chichkova, 2007). The treatment of patients who remain in coma with HBO remains controversial. HBO therapy can increase tissue oxygen concentrations, promoting CO elimination. It increases ATP, and reduces oxidative stress and inflammatory responses. Animal studies suggest that HBO also has additional benefits such as inhibition of neutrophil adherence to the wall of ischemic vessels, decrease in free radical production, vasoconstriction and tissue destruction, but data from clinical trials remain controversial (Juurlink et al., 2000). Subsequently there are no guidelines available which are based on high-level evidence regarding the use of HBO in CO intoxication. Several authors noted that the unselected use of HBO for acute CO poisoning does not reduce the frequency of neurologic symptoms at 1 month, but that further research is necessary to comment on the benefit of HBO use (Juurlink et al., 2000). There are several randomized controlled trials but only one of the trials follows standardization guidelines for the reporting of
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clinical trials (Juurlink et al., 2000). Four of six clinical trials did not find any evidence that HBO reduces neurologic sequelae and two studies showed benefit. However, these studies have methodological limitations, are heterogenous, and have different selection criteria of patients, follow-up protocols, and outcome measures. The methodologies are difficult to compare as different study designs and treatment protocols were used (for details that are beyond the scope of this text see Raphael et al., 1989; Ducasse et al., 1995; Thom et al., 1995; Scheinkestel et al., 1999; Juurlink et al., 2000). One trial showed that cognitive impairment was significantly lower in patients receiving initial treatment with HBO within 24 hours of an intoxication (Weaver et al., 1995). However, the study did not clearly identify subgroups of patients in whom HBO was less beneficial. A Cochrane review of six clinical trials does not support the use of HBO for treatment of patients with CO intoxication (Weaver et al., 2002). It remains currently unknown which patient should receive HBO treatment, if any. Additionally, if HBO is used, the dose, number and duration of treatments remain controversial. Usually a single treatment at 2.5–3 ATA for a duration of 90 minutes has been advocated by some (Prockop and Chichkova, 2007). The effectiveness of different protocols using more frequent treatments or different pressures and treatment durations has not been compared in a systematic fashion. The Undersea and Hyperbaric Medical Society recommends treatment of the following patients with HBO after CO intoxication: patients with transient or prolonged episodes of loss of consciousness, abnormal neurologic signs, cardiovascular dysfunction or severe acidosis, patients who are 36 years or older when exposed for more than 24 hours, or those who have COHb levels of 25% or more, as well as pregnant women (Gesell, 2008). The clinical policy subcommittee of the American College of Emergency Physicians states that the use of HBO therapy is still controversial and advocates randomized controlled trials to assess its effectiveness (Wolf et al., 2008).
PROGNOSIS Clinical outcome in patients after CO exposure is highly variable. Patients with CO poisoning need follow-up after discharge as they may develop the delayed neuropsychological syndrome. There is no specific therapy for this sequela, but usually empirical treatment with various medications, physical, occupational and vocational therapy, and potentially, rehabilitation. The incidence of the delayed neuropsychological syndrome following CO intoxication is not precisely known. In one study 46% of patients had abnormal neuropsychological
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findings and symptoms at 6 weeks (Weaver et al., 2002). Information about neuropsychological outcome beyond the first year after CO intoxication is limited (Weaver et al., 2002, 2007; Jasper et al., 2005). In a cohort study which followed patients for 6 years, 19% had cognitive impairment and 37% had abnormal neurologic findings on examination (Weaver et al., 2008). Patients with white matter lesions or hippocampal atrophy on brain MRI were at higher risk to show delayed cognitive abnormalities (den Heijer et al., 2006; Smith et al., 2008). The initial clinical presentation does not predict the outcome but several factors indicate poor outcomes such as severity and duration of CO exposure. Given the role of inflammation in CO intoxication associated injury, inflammatory biomarkers may help in the future to predict the risk of neuropsychological symptoms. Children are often symptomatic earlier, but can also recover faster than adults (Weaver et al., 2002). The fetus is especially susceptible to the adverse effects of CO poisoning. Fetal mortality exceeds 50% in case of severe CO intoxication (Koren et al., 1991). Patients with underlying cardiopulmonary disease, the elderly, and patients with multiple comorbidities are at increased risk for poor outcome after CO poisoning. Because treatment is often ineffective, emphasis is on prevention by close environmental monitoring.
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Cronje FJ, Carraway MS, Freiberger JJ et al. (2004). Carbon monoxide actuates O(2)-limited heme degradation in the rat brain. Free Radic Biol Med 37: 1802–1812. den Heijer T, Sijens PE, Prins ND et al. (2006). MR spectroscopy of brain white matter in the prediction of dementia. Neurology 66: 540–544. Ducasse JL, Celsis P, Marc-Vergnes JP (1995). Non-comatose patients with acute carbon monoxide poisoning: hyperbaric or normobaric oxygenation? Undersea Hyperb Med 22: 9–15. Durak AC, Coskun A, Yikilmaz A et al. (2005). Magnetic resonance imaging findings in chronic carbon monoxide intoxication. Acta Radiol 46: 322–327. Elkharrat D (1998). Indications of normobaric and hyperbaric oxygen therapy in acute CO intoxication. In: Proceedings satellite meeting IUTOX, VIIIth International Congress of Toxicology, Dijon, France, July 3–4, 1998. Ernst A, Zibrak JD (1998). Carbon monoxide poisoning. N Engl J Med 339: 1603–1608. Gesell LB (Ed.), (2008). Hyperbaric Oxygen 2009: Indications and Results: The Hyperbaric Oxygen Therapy Committee Report. Undersea and Hyperbaric Medical Society, Durham, NC. Ginsberg MD (1985). Carbon monoxide intoxication: clinical features, neuropathology and mechanisms of injury. Clin Toxicol 23: 281–288. Handa PK, Tai DY (2005). Carbon monoxide poisoning: a five year review at Tan Tock Seng Hospital, Singapore. Ann Acad Med Singapore 34: 611–614. Hardy K, Thom S (1994). Pathophysiology and treatment of carbon monoxide poisoning. Clin Toxicol 32: 613–629. Jasper BW, Hopkins RO, Duker HV et al. (2005). Affective outcome following carbon monoxide poisoning: a prospective longitudinal study. Cogn Behav Neurol 18: 127–134. Jellinger K (1986). Exogenous lesions of the pallidum. In: PJ Vinken, GW Bruyn, HL Klawans (Eds.), Handbook of Clinical Neurology, vol. 49. Elsevier Science, Amsterdam, pp. 465–491. Juurlink DN, Stanbrook MB, McGuigan MA (2000). Hyperbaric oxygen for carbon monoxide poisoning. Cochrane Database Syst Rev CD002041. Kamada K, Houkin K, Aoki T et al. (1994). Cerebral metabolic changed in delayed carbon monoxide sequelae studied by proton MR spectroscopy. Neuroradiology 36: 104–106. Kanu A, Whitfield J, Leffler A (2006). Carbon monoixde contributes to hypotension- induced cerebrovascular vasodilation in piglets. Am J Physiol Heart Circ Physiol 291: H2409–H2414. Komuro T, Borsody M, Ono S et al. (2001). The vasorelaxation of cerebral arteries by carbon monoxide. Exp Biol Med 226: 860–865. Koren G, Sharav T, Pastuszak A et al. (1991). A multicenter, prospective study of fetal outcome following accidental carbon monoxide poisoning in pregnancy. Reprod Toxicol 5: 397–403. Kumar V, Abbas A, Fausto N (2005). Robins and Cotran: Pathologic Basis of Disease. 7th edn. Elsevier Saunders, Philadelphia. Lapresle J, Fardeau M (1967). The central nervous system and carbon monoxide poisoning II. Anatomical study of brain lesions following intoxication with carbon
NEUROLOGIC COMPLICATIONS OF CARBON MONOXIDE INTOXICATION monoxide (22 cases). In: H Bour, IM Ledingham (Eds.), Carbon Monoxide Poisoning. Prog Brain Res 24: 31–74. Llano A, Raffin T (1990). Management of carbon monoxide poisoning. Chest 97: 165–169. Lo Ping C, Chen S, Lee K et al. (2007). Brain injury after acute carbon monoxide poisoning early and late complications. Neuroradiology 189: 205–211. Mimura K, Harada M, Sumiyoshi S et al. (1999). Long-terms follow-up study on sequelae of carbon monoxide poisoning: serial investigation 33 years after poisoning. Seishin Shinkeigaku Zasshi 101: 592–618. Miro O, Casademont J, Barrientos A et al. (1998). Mitochondrial cytochrome c oxidase inhibition during acute carbon monoxide poisoning. Pharmacol Toxicol 82: 199–202. Murata T, Itoh S, Koshino Y et al. (1995). Serial proton magnetic resonance spectroscopy in a patient with the interval form of carbon monoxide poisoning. J Neurol Neurosurg Psychiatry 58: 100–103. O’Donnell P, Buxton PJ, Pitkin A et al. (2000). The magnetic resonance imaging appearances of the brain in acute carbon monoxide poisoning. Clin Radiol 55: 273–280. Okeda R, Funata N, Song SJ et al. (1982). Comparative study pathogenesis of selective cerebral lesions in carbon monoxide poisoning and nitrogen hypoxia in cats. Acta Neuropathol (Berl) 56: 265–272. Piantadosi CA, Zhang J, Levin ED et al. (1997). Apoptosis and delayed neuronal damage after carbon monoxide poisoning in the rat. Exp Neurol 147: 103–114. Prockop LD (2005). Carbon monoxide brain toxicity: clinical, magnetic resonance imaging, magnetic resonance spectroscopy, and neuropsychological effects in 9 people. J Neuroimaging 15: 144–149. Prockop LD, Chichkova RI (2007). Carbon monoxide intoxication: an updated review. J Neurol Sci 262: 122–130. Raphael JC, Elkharrat D, Jars-Guincestre MC et al. (1989). Trial of normobaric and hyperbaric oxygen for acute carbon monoxide intoxication. Lancet 2: 414–419. Scheinkestel CD, Bailey M, Myles PS et al. (1999). Hyperbaric or normobaric oxygen for acute carbon monoxide poisoning: a randomized controlled clinical trial. Med J Aust 170: 203–210. Sener RN (2003). Acute carbon monoxide poisoning: diffusion MR imaging findings. AJNR Am J Neuroradiol. 24: 1475–1477. Smith EE, Egorova S, Blacker D et al. (2008). Magnetic resonance imaging white matter hyperintensities and brain volume in the prediction of mild cognitive impairmentand dementia. Arch Neurol 65: 94–100. Sohn YH, Jeong Y, Kim HS et al. (2000). The brain lesion responsible for parkinsonism after carbon monoxide poisoning. Arch Neurol 57: 1214–1218. Stoller KP (2007). Hyperbaric oxygen and carbon monoxide poisoning: a critical review. Neurol Res 29: 147–155. Struttmann T, Scheerer A, Prince S et al. (1998). Unintentional carbon monoxide poisoning from an unlikely source. J Am Board Fam Pract 11: 481–484. Studdert DM, Gurrin LC, Jatkar U et al. (2010). Relationship between vehicle emissions laws and incidence of suicide by motor vehicle exhaust gas in Australia, 2001–06: an ecological analysis. PLoS Med 7: e1000210.
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Thom SR (1990). Carbon monoxide-mediated brain lipid peroxidation in the rat. J Appl Physiol 68: 997–1003. Thom SR (2008). Carbon monoxide pathophysiology and treatment. In: TS Neuman, SR Thom (Eds.), Physiology and Medicine of Hyperbaric Oxygen Therapy. Saunders Elsevier, Philadelphia, pp. 321–347. Thom SR, Taber RI, Mediguren II et al. (1995). Delayed neuropsychological sequelae after carbon monoxide poisoning: prevention by treatment with hyperbaric oxygen. Ann Emerg Med 25: 479–486. Thom S, Bhopale V, Fisher D et al. (2004). Delayed neuropathology after carbon monoxide poisoning is immune-mediated. Proc Natl Acad Sci U S A 101: 13660–13665. Thom SR, Bhopale VM, Fisher D (2006a). Hyperbaric oxygen reduces delayed immune-mediated neuropathology in experimental carbon monoxide toxicity. Toxicol Appl Pharmacol 213: 152–159. Thom SR, Bhopale VM, Han ST et al. (2006b). Intravascular neutrophil activation due to carbon monoxide poisoning. Am J Respir Crit Care Med 174: 1239–1248. Tibbles PM, Edelsberg JS (1996). Hyperbaric-oxygen therapy. N Engl J Med 334: 1642–1648. Tibbles PM, Perrotta PL (1994). Treatment of carbon monoxide poisoning: a critical review of human outcome studies comparing normobaric oxygen with hyperbaric oxygen. Ann Emerg Med 24: 269–276. Tuchman RF, Moser FG, Moshe SL (1990). Carbon monoxide poisoning: bilateral lesions in the thalamus on MR imaging of the brain. Pediatr Radiol 20: 478–479. Van Meter KW, Weiss L, Harch PE et al. (1994). Should the pressure be off or on with use of oxygen in the treatment of carbon monoxide poisoned patients. Ann Emerg Med 24: 283–288. Van Zijl PCM, Barker PB (1997). Magnetic resonance spectroscopy and spectroscopic imaging for the study of brain metabolism. Ann N Y Acad Sci 820: 75–96. Weaver L (2009). Carbon monoxide poisoning. N Engl J Med 360: 1217–1225. Weaver LK, Hopkins RO, Larson-Lorh V et al. (1995). Double blind, controlled, prospective, randomized clinical trial (RCT) in patients with acute carbon monoxide (CO) poisoning: outcome of patients tested with normobaric oxygen or hyperbaric oxygen (HBO2), an interim report. Undersea Hyperb Med 22 (Suppl): 14. Weaver LK, Hopkins RO, Chan KJ et al. (2002). Hyperbaric oxygen for acute carbon monoxide poisoning. N Engl J Med 347: 1057–1067. Weaver LK, Valentine KJ, Hopkins RO (2007). Carbon monoxide poisoning: risk factors for cognitive sequelae and the role of hyperbaric oxygen. Am J Respir Crit Care Med 176: 491–497. Weaver LK, Hopkins RO, Churchill S et al. (2008). Neurological outcomes 6 years after acute carbon monoxide poisoning. Undersea Hyperb Med 35: 258–259. Wolf SJ, Lavonas EJ, Sloan EP et al. (2008). American College of Emergency Physicians. Critical issues in the management of adult patients presenting to the emergency department with acute carbon monoxide poisoning. Ann Emerg Med 51: 138–152.
Chapter 64
Neurologic complications of carbon monoxide intoxication KERSTIN BETTERMAN1* AND SURJU PATEL2 Department of Neurology, Penn State College of Medicine, Hershey, PA, USA
1 2
Department of Internal Medicine, Conemaugh Health System, Jonestown, PA, USA
INTRODUCTION French physiologist Claude Bernard was one of the first to describe the pathophysiology of carbon monoxide (CO) poisoning during the mid 19th century (Bernard, 1857). He observed that CO causes tissue hypoxia by interaction with red blood cells requiring him to develop a new method to measure blood-gas transfer. He performed many experiments which showed that CO prevented red blood cells from taking up oxygen and delivering it to the tissues, and described the cherry red appearance of the blood following CO intoxication (Bernard, 1858, 1870). Carbon monoxide poisoning is still the leading cause of poison-related morbidity and mortality worldwide. In the US it results in more than 50 000 emergency visits yearly (Weaver, 2009). Carbon monoxide is an odorless, colorless gas that can be found at toxic levels in homes with gas heating furnaces. It is a product of incomplete combustion of fuels from multiple sources and is found in motor vehicle exhausts or indoor heating units with burning of oil, coal, wood, or kerosene. Frequently chronic intoxication occurs in settings of chimney malfunction or dysfunctional ventilation. Deadly CO poisoning often occurs in the setting of a building fire or from exposure to fuel powered generators and heaters used during natural disasters or with suicide using motor vehicle exhaust gas (Prockop and Chichkova, 2007; Studdert et al., 2010).
PATHOPHYSIOLOGY Endogenous CO production occurs during normal heme metabolism at concentrations not interfering with normal blood- or tissue-oxygen exchange. However, increased CO concentrations following intoxication impact the
transport of oxygen to the tissues. Normally, oxygen diffuses across the alveolar-capillary membrane and binds to hemoglobin. Carbon monoxide interferes with this process by diffusing rapidly through the alveolar-capillary membrane and binding to hemoglobin more than 200 times faster than oxygen. Carboxyhemoglobin (COHb) is formed which causes a left-shift in the oxyhemoglobin dissociation curve (Hardy and Thom, 1994). The tetrameric structure of the hemoglobin molecule goes through a conformational change where the sigmoidal curve is no longer maintained. COHb is unable to transport as much oxygen as normal hemoglobin leading to decreased oxygen delivery to the tissues and subsequent tissue hypoxia. Moreover the allosteric property of hemoglobin induced by CO binding causes other CO molecules to bind more rapidly. Carbon monoxide binds to hemoglobin at such high rate that partial pressures of CO in the capillaries stay relatively low. Carbon monoxide is not perfusion limited meaning it will not be affected by the rate of blood flow or the amount of hemoglobin in the blood. As long as there is hemoglobin, it will bind. Although COHb is a completely reversible complex, the release of oxygen from COHb is relatively slow and depends on the inhaled oxygen concentration. The higher the inhaled oxygen concentration, the faster the CO elimination rate, which is the rationale to treat CO intoxication victims with 100% oxygen or to consider hyperbaric oxygen (HBO) therapy. After COHb levels decrease, tissue oxygenation, mitochondrial function, and cellular energy metabolism are restored, but even transient exposure to high concentrations of CO may cause brain injury acutely or within days to weeks (Okeda et al., 1982; Piantadosi et al., 1997). Carbon monoxide causes tissue hypoxia, ischemia and secondary injury through multiple mechanisms of
*Correspondence to: Kerstin Bettermann, M.D., Ph.D., Department of Neurology, Penn State College of Medicine, 500 University Drive, P.O. Box 850, Hershey, PA 17033, USA. Tel: þ1-717-531-1803, Fax: þ1-717-531-0963, E-mail: [email protected]
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Table 64.1 Summary of the cerebral pathology and pathophysiology associated with CO poisoning Carbon monoxide causes acute cerebral ischemia and hypoxia as well as secondary injury via multiple mechanisms of action Brain pathology Injury of neurons of cortical layers III and V Decreased volume of the hippocampus Globus pallidus injury Demyelination of the white matter Loss of Purkinje cells in the cerebellum Cerebral edema Necrosis and apoptosis Cerebral pathophysiology Interruption of cellular respiration Decreased glucose metabolism Increase in lactid acid Production of reactive oxygen species Endothelial peroxynitrate deposition Decreased dopamine turnover in caudate nucleus Activation of the inflammatory cascade Modification of myelin basic protein and malonyaldehyde Increased intracellular iron deposition Increased nitric oxide levels P450 inhibition Lipid peroxidation Increase of cytosol heme concentration Activation of genes mediating apoptosis
action (Table 64.1). Highly metabolic organs such as the heart and the brain are especially vulnerable. Carbon monoxide binds to platelet heme-protein and cytochrome C oxydase, interrupting cellular respiration in the mitochondria with subsequent tissue acidosis and production of reactive oxygen species (Miro et al., 1998). As a result, the cells shift to anaerobic metabolism and toxic lactic acids and nitrates build up. Oxidative stress results in neuronal necrosis, apoptosis, and activation of hypoxia-induced factors mediating secondary injury. Carbon monoxide also activates the inflammatory
cascade, causes peroxidation of lipids and deposition of peroxynitrate in blood vessel endothelium, causing vascular damage that can potentiate tissue ischemia soon after or even during exposure to CO and at relatively low concentrations (Alonso et al., 2003; Cronje et al., 2004; Thom et al., 2006; Thom, 2008). In the heart CO binds to myoglobin about 60 times faster than oxygen, causing myocardial hypoxia. It causes coronary vasodilation and increased coronary flow which can result in additional hypoxic-ischemic damage to the myocardium and decreased cardiac output. Low cardiac output and hypotension in turn can decrease cerebral perfusion and contribute to hypoxicischemic brain injury (Prockop and Chichkova, 2007). Studies in mice have shown that cerebral flow increases within minutes of CO exposure which is caused by guanylyl cyclase-mediated relaxation of the cerebral arteries (Komuro et al., 2001; Kanu et al., 2006). Cerebral blood flow remains elevated until cardiac compromise causes decrease in blood pressure and cardiac output, at which point cerebral autoregulation fails and asphyxia and apnea start, all contributing to the hypoxic-ischemic brain injury (Thom, 1990; Thom et al., 2006). Carbon monoxide is a naturally occurring signaling molecule in the brain, but following exposure to high CO concentrations during an acute or chronic intoxication CO has detrimental effects on the central nervous system (CNS). Cytosol heme concentrations in the brain increase about tenfold after CO poisoning, adding to its toxicity (Cronje et al., 2004). There are acute as well as delayed neurologic effects following CO intoxication. Acute CO poisoning often causes damage to brain areas with great susceptibility to hypoxic injury, including the second and third cortical layers, watershed areas within the white matter, the basal ganglia and the Purkinje cells of the cerebellum. The nature and distribution of brain lesions depend on the acuteness, the severity, and the duration of exposure to CO. Furthermore CO poisoning causes lipid peroxidation with degradation of unsaturated fatty acids leading to demyelination of CNS lipids and damage to myelin and axons. This process is to some extent reversible and can be observed acutely or with delayed brain injury. Many of the delayed neurologic complications may be mediated by inflammatory and immune responses (Thom et al., 2004). In experimental studies CO causes over-reactivity of neuronal nitric oxide synthase which produces nitrous oxygen (NO). NO is released from platelets and causes changes in cerebral blood flow and aggregation with neutrophils. Neutropohils and platelets interact, producing reactive oxygen species that mediate lipid peroxidation in the brain (Thom et al., 2006). Additionally the peroxidation product malonlylaldehyde (MDA) alters the ionic charge and configuration of myelin basic protein inducing change
NEUROLOGIC COMPLICATIONS OF CARBON MONOXIDE INTOXICATION in its antigenic nature. In experimental studies this causes an increase in macrophages and CD4 lymphocytes with subsequent activation of brain microglia that is associated with learning difficulties, not present in rats without an altered myelin basic protein structure (Thom et al., 2004).
PATHOLOGY The neuropathology of CO intoxication has been well described (Lapresle and Fardeau, 1967; O’Donnell et al., 2000; Chu et al., 2004). Postmortem studies have shown petechial hemorrhages in the white matter, particularly in the corpus callosum, and multifocal necrosis within the globus pallidus, the hippocampus, and the pars reticularis of the substantia nigra. Other findings include laminar necrosis of the cortex and loss of Purkinje cells in the cerebellum. White matter lesions are frequently observed which can be asymmetrical. The typical pallidal lesions are well defined involving the globus pallidus with microscopic infarctions extending anteriorly, superiorly, and into the internal capsules. Often a small linear focus of necrosis is found at the junction of the internal capsule and the internal nucleus of the globus pallidus. The hypothalamus, the thalamus, the third ventricle, and the brainstem are often spared (Lapresle and Fardeau, 1967). In comatose patients who die soon after CO intoxication there is frequently myelin damage with perivascular lesions in the corpus callosum, the internal and external capsules, and the optic tracts. Demyelinating plaques, extensive periventricular demyelination and axonal destruction can be observed in postmortem studies of patients who died from chronic CO intoxication or in comatose patients who survive for longer periods of time after an acute CO intoxication. Demyelination of
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the subcortical and periventricular white matter is often associated with a delayed neuropsychiatric syndrome following CO intoxication which will be described in the following section (O’Donnell et al., 2000). Because of their increased metabolic rate, both brain and myocardium are especially vulnerable to hypoxic injury associated with CO poisoning. Findings related to brain hypoxia include laminar necrosis of the cortex. Here neurons of layers III and V are greatly affected, as is the hippocampus and the Purkinje cells of the cerebellum. Globus pallidus injury is the hallmark of carbon monoxide intoxication (Kumar et al., 2005). The predilection for the globus pallidus remains unclear but may be related to the high iron affinity of CO. The globus pallidus is iron rich, resulting in greater concentration of CO in this area. Additionally the globus pallidus receives blood supply from blood vessels belonging to one of the watershed areas of the brain, making it more susceptible to ischemic injury from cardiac and hypotensive effects which are typically associated with CO poisoning (Lo Ping et al., 2007). If the globus pallidus and basal ganglia are damaged by injury and necrosis, movement disorders such as Parkinsonism can develop. Although globus pallidus lesions are considered to be pathognomonic of CO intoxication, they may not occur even in survivors suffering Parkinsonism (Choi, 1983). In these patients white matter lesions, present on magnetic resonance imaging (MRI), are often responsible for the clinical picture of parkinsonism (Sohn et al., 2000).
CLINICAL FINDINGS Carbon monoxide poisoning can cause acute and delayed signs and symptoms which can be specific (see Table 64.2). However, at times the clinical picture can
Table 64.2 Associations between clinical presentation, carbon monoxide concentration, and exposure times (modified from Struttmann et al., 1998) Carbon monoxide concentration (in parts per million)
COHb level
Symptoms, CO exposure time
35 ppm 100 ppm 200 ppm 400 ppm 800 ppm 1600 ppm
10% 20% 25% 30% 40%
3200 ppm 6400 ppm
50% 60%
12 800 ppm
>70%
Headache and dizziness, within 6–8 h Slight headache, in 2–3 h Slight headache and loss of judgment, within 2–3 h Headache, within 1–2 h Dizziness, nausea, and seizures, within 45 min Headache, tachycardia, dizziness, and nausea within 20 min; death in less than 2h Headache, dizziness, and nausea in 5–10 min; death within 30 min Headache and dizziness in 1–2 min; seizures, respiratory arrest, and death in less than 20 min Death in less than 3 min
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be rather vague and a high level of clinical suspicion is therefore crucial. The CO concentration and the exposure time are associated with specific symptoms which are summarized in Table 64.2. Depending on the duration of CO exposure symptoms are typically first noted with measured blood COHb concentrations of about 10%. Patients with underlying chronic heart and lung disease may present earlier at lower CO concentrations and with more severe symptoms. In a healthy person, the average carboxyhemoglobin levels are approximately 1–2%. In anemic patients the COHb levels are about 5% and in nonsymptomatic smokers the levels are as high as 15%. The most common symptoms of CO poisoning include nausea, vomiting, dizziness, and generalized weakness (Ginsberg, 1985; Prockop, 2005). COHb levels below 40% are not typically associated with coma or death.
Acute intoxication Acute CO poisoning is rarely detected until the patient becomes ill. The so-called classic cherry red discoloration of the skin and cyanosis are very rare. Headache is one of the most common presenting features of CO poisoning, occurring in over 80% of victims. It is typically dull, frontally located, and continuous, or it can mimic migraine headaches (Handa and Tai, 2005). In mild cases only mild flu-like symptoms can be observed. About half of the victims with CO intoxication complain about generalized weakness, nausea, confusion, and shortness of breath. Sometimes abdominal pain, vision changes, chest pain, and other vague symptoms are present (Prockop, 2005). Hypoxia leading to increased intracranial pressure from cytotoxic cerebral edema causes not only headaches, but also confusion, seizures, coma, and death. Transient cerebral edema can develop followed by widespread tissue necrosis and can be diagnosed early by diffusionweighted brain MRI. Other neurologic findings include tinnitus, central hearing loss, nystagmus, and ataxia, visual disturbances, and syncope (Llano and Raffin, 1990; Blumenthal, 2001). Varying degrees of cognitive impairment have been observed following chronic and acute CO intoxication, and are pathognomonic for the delayed neurologic sequelae following CO intoxication. Cardiac symptoms are ischemic in nature and consist of chest pain, myocardial infarct, cardiac dysrhythmias, hypotension, and tachycardia. Frequently ischemic EKG changes are present and cardiac enzymes are elevated. Patients with underlying chronic heart and lung disease are especially at risk of dying from cardiac complications and myocardial infarct. The mortality rate is higher in patients with moderate to severe CO poisoning, which also causes respiratory depression and pulmonary edema (Ginsberg, 1985).
Chronic intoxication Chronic carbon monoxide poisoning occurs when low levels of CO are inhaled over a prolonged period of time, for instance in the setting of an undetected gas leak. This can mimic flu-like symptoms and frequently causes nausea, lethargy, and headaches. Depression, vomiting, gastrointestinal problems, weight loss, short-term memory difficulties, and confusion can develop. A high level of suspicion is essential to make the diagnosis.
Delayed neuropsychiatric syndrome Cognitive deficits develop within 2–240 days following CO intoxication (Tibbles and Perrotta, 1994). Severe dementia, psychosis, anxiety, and other neuropsychological symptoms suddenly start after an initially excellent functional recovery period. Carbon monoxide encephalopathy can also present with alterations in attention, executive function, visuomotor skills, learning, shortterm memory, mood, and social behavior. The delayed neuropsychiatric syndrome occurs in about 3% of CO intoxication cases and personality changes, urinary and fecal incontinence, and parkinsonism may develop (Mimura et al., 1999). The incidence is higher in the elderly and in those being exposed to CO for at least 12–48 hours. After an initial recovery phase, patients rapidly deteriorate, developing some or all of the neuropsychiatric symptoms above (Ernst and Zibrak, 1998). On neurologic examination frontal release and extrapyramidal signs are frequently present. In 57% of cases, the EEG will show delta range slowing and neuroimaging studies are abnormal (Tibbles and Perrotta, 1994). Head CT shows hypodensities in the basal ganglia in half of the patients. MRI usually shows hyperintensities in the globus pallidus and white matter changes in the frontal lobes. Neuropathology often shows extensive lesions in the brain including the globus pallidum, caudate, putamen, substantia nigra, hippocampus, hypothalamus, periventricular white matter, corona radiata, cerebellum, and hippocampus (Brucher, 1967; Lapresle and Fardeau, 1967) (Figs 64.1 and 64.2). About 60–75% of patients with delayed neuropsychiatric syndrome recover within a year. About 15% continue to suffer from dementia and parkinsonism (Bhatia et al., 2007).
DIAGNOSIS The diffuse symptoms and the absence of specific laboratory tests makes it difficult to suspect CO intoxication; especially chronic poisoning. History of exposure to fire, presence of a fireplace, indoor compression appliances, or occupational exposure can be indicative of CO intoxication. Following intoxication, ambient air CO levels at
NEUROLOGIC COMPLICATIONS OF CARBON MONOXIDE INTOXICATION
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Fig. 64.2. Small cystic necrosis in internal pallidal segment and laminary cortical necroses after coal gas poisoning. The patient survived many years in a rigid-akinetic state with severe dementia. (Reproduce from Jellinger, 1986.)
LABORATORY TESTS
Fig. 64.1. Carbon monoxide intoxication. (A) Symmetrical necrosis in oral pallidum and diffuse leukoencephalopathy in intermittent form. (B) Multiple focal necroses in posterior and lateral parts of the globus pallidus and in the reticular zone of the substantia nigra. Heidenhein stain. (Reproduce from Jellinger, 1986.)
the scene of exposure should be measured as soon as possible. The half-life of CO is only 4–5 hours so that blood COHb levels are rather unreliable to determine the severity of an intoxication. Only CO levels measured at the scene of an acute exposure may have potential to assess the degree of intoxication.
The COHb concentration in blood depends on the amount of CO in the inhaled air, the ventilation rate and the exposure time. Often the clinical outcome correlates poorly with measured blood COHb concentrations which may be due to the fact that blood samples are often obtained after a significant amount of time has passed following CO exposure. Another reason for the poor correlation is delayed neurologic injury which can develop independently of measured HbCO levels. Pulse CO oximetry can be used at the bedside to detect increased levels of HbCO in the blood. If it is elevated the value is significant. However, if the value is low carbon monoxide poisoning cannot be completely ruled out as inhalation of low levels of oxygen can also cause low HbCO levels. Pulse oximeters frequently overestimate the arterial oxygenation in patients with severe CO poisoning. Automated spectrophotometers or oximeter devices are now available and are increasingly recommended to assess victims of CO intoxication (Prockop and Chichkova, 2007).
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Lactic acid levels, basic metabolic panels with glucose levels, electrolytes and arterial blood gases should also be closely monitored as patients with CO intoxication frequently develop lactate acidosis. Renal function can be diminished due to myoglobinuria and hypokalemia and hyperglycemia can occur with severe intoxication. Cardiac function must be closely monitored by serial EKGs, echocardiograms and measurements of cardiac enzymes for the development of brady- or tachycardia, atrial or ventricular fibrillation, premature ventricular contractions, conduction abnormalities, or myocardial infarct.
NEUROIMAGING STUDIES One of the most sensitive measures of cerebral injury following CO intoxication is brain MRI, which shows variable findings. Most comatose patients show abnormalities within the globus pallidus, lentiform nucleus, caudate nuclei, thalamus, periventricular and subcortical white matter, especially of the frontal and temporal lobes. Hippocampal and cerebellar lesions can be present. Diffuse high signal abnormalities within the bilateral centrum semiovale are also common (Tuchman et al., 1990). T1-weighted MRI sequences show typically low signal intensity bilaterally in the globus pallidus. This corresponds to high signal intensities on T2-weighted and fluid attenuated inversion recovery (FLAIR) imaging. Pathognomonic pallidal lesions are well visualized by contrast-enhanced MRI (see Fig. 64.1). In the acute intoxication phase contrast enhanced T2-weighted MRI may show patchy or peripheral enhancement of necrotic areas. Diffusion-weighted MRI often shows restriction of water diffusion due to cytotoxic edema within the white matter or diffusely within the brain (Sener, 2003). These changes can develop early after CO exposure. Most acute stages also show restricted water diffusion in the globus pallidus and in the substantia nigra. White matter changes are often reversible. However, following severe CO intoxication persistent changes on MRI can be found for years following the exposure even without clinical deficits (O’Donnell et al., 2000; Durak et al., 2005). T2 and FLAIR sequences often show bilateral symmetric hyperintensities in the white matter of the centrum semiovale with relative sparing of the brainstem (see Fig. 64.2). Clinical status and outcome often correlate with diffuse white matter changes. MR spectroscopy can now be used to help assess prognosis. N-acetylaspartate (NAA) decreases in demyelinated white matter regions representing most likely axonal and neuronal loss (Van Zijl and Barker, 1997). This can often be observed in the basal ganglia or in the white matter. Proton magnetic resonance spectroscopy may show
increased choline peak which indicated progressive demyelination in early CO poisoning cases (Murata et al., 1995). Kamada and coworkers (Kamada et al., 1994) have shown that a marked lowering of the NAA/ Cr ratio and a slight increase in the Cho/Cr ratio with subsequent normalization can parallel clinical improvement. MR spectroscopy is currently mainly investigational but may become useful as prognostic indicator in CO poisoning. Cranial CT typically reveals unilateral or bilateral low attenuation areas in the globus pallidus but is less sensitive than MRI. Hemorrhagic infarctions have been described on both CT and brain MRI. Positron emission tomography (PET) and SPECT can also provide additional information showing decreased glucose metabolism and hypoperfusion that parallel the development of focal and diffuse lesions after CO intoxication.
DIFFERENTIAL DIAGNOSIS Carbon monoxide poisoning can present in a similar way to many other disease states. The symptoms are nonspecific and therefore CO poisoning can easily be mistaken for other conditions such as the flu, gastrointestinal disorders, chronic fatigue syndrome, depression, hypothyroidism, anemia, or chronic migraine headaches. Neurologic and neuropsychiatric signs and symptoms may suggest a neurodegenerative disorder such as dementia, Parkinson disease, other movement disorders, or may mimic psychiatric conditions such as schizoaffective disorder or depression.
TREATMENT Oxygen should be administered to all patients with suspected CO intoxication via face mask with 100% oxygen flow (Elkharrat, 1998). This must be initiated immediately and independently of blood COHb levels as measured COHb levels may underestimate the true intoxication level. The airway needs to be secured and adequate ventilation needs to be maintained. Following inhalation of 100% oxygen at normobaric pressure, the half-life of COHb is reduced from 4–5 hours to 1 hour. Patients should be on strict bed rest and every measure should be taken to decrease oxygen demand and to lower metabolic needs. Patients with respiratory distress and a decreased level of consciousness must be intubated and mechanically ventilated. Chest X-rays and arterial blood gases should be assessed periodically. Cardiac function needs to be closely monitored. Serum pH and lactid acid levels should be closely monitored since aerobic metabolism generates lactate acidosis. Acidosis with pH below levels of 7.15 should be treated with sodium bicarbonate.
NEUROLOGIC COMPLICATIONS OF CARBON MONOXIDE INTOXICATION The use of hyperbaric oxygen therapy remains controversial for the treatment of victims with CO intoxication (Weaver et al., 1995; Juurlink et al., 2000; Stoller, 2007). HBO therapy consists of inhalation of 100% oxygen at higher than normal ambient pressures. It significantly increases the amount of oxygen that is physically dissolved in blood and becomes available for delivery to hypoxic tissues. At pressures of 2.5 atmospheres absolute (ATA) HBO reduces the half-life of COHb from 4 hours to 20 minutes. A single treatment at pressures of 2.5–3.0 ATA given over a duration of 90–120 minutes is commonly considered for treatment of patients with syncope, coma, seizures, and focal neurologic deficits who present with COHb levels of more than 25% (and of more than 15% in pregnant women) (Tibbles and Perotta, 1994; Van Meter et al., 1994; Thom et al., 1995; Weaver et al., 1995; Tibbles and Edelsberg, 1996). However, in clinical practice it is difficult to make a decision on when to use hyperbaric oxygen as COHb levels might underestimate the degree of intoxication and do not necessarily correlate with clinical severity. Hyperbaric oxygen treatment is also sometimes considered for victims of CO intoxication who are at risk of developing the delayed neuropsychological sequelae (Weaver et al., 2007). In one study, patients aged 36 years and older who had been exposed to CO for at least 24 hours and who did not receive HBO treatment had an increased risk of cognitive sequelae at 6 weeks compared with those without these characteristics (Weaver et al., 2007). Pregnant women should probably be treated with hyperbaric oxygen as the fetus is especially vulnerable after CO intoxication, with high rates of fetal mortality and morbidity (Prockop and Chichkova, 2007). The treatment of patients who remain in coma with HBO remains controversial. HBO therapy can increase tissue oxygen concentrations, promoting CO elimination. It increases ATP, and reduces oxidative stress and inflammatory responses. Animal studies suggest that HBO also has additional benefits such as inhibition of neutrophil adherence to the wall of ischemic vessels, decrease in free radical production, vasoconstriction and tissue destruction, but data from clinical trials remain controversial (Juurlink et al., 2000). Subsequently there are no guidelines available which are based on high-level evidence regarding the use of HBO in CO intoxication. Several authors noted that the unselected use of HBO for acute CO poisoning does not reduce the frequency of neurologic symptoms at 1 month, but that further research is necessary to comment on the benefit of HBO use (Juurlink et al., 2000). There are several randomized controlled trials but only one of the trials follows standardization guidelines for the reporting of
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clinical trials (Juurlink et al., 2000). Four of six clinical trials did not find any evidence that HBO reduces neurologic sequelae and two studies showed benefit. However, these studies have methodological limitations, are heterogenous, and have different selection criteria of patients, follow-up protocols, and outcome measures. The methodologies are difficult to compare as different study designs and treatment protocols were used (for details that are beyond the scope of this text see Raphael et al., 1989; Ducasse et al., 1995; Thom et al., 1995; Scheinkestel et al., 1999; Juurlink et al., 2000). One trial showed that cognitive impairment was significantly lower in patients receiving initial treatment with HBO within 24 hours of an intoxication (Weaver et al., 1995). However, the study did not clearly identify subgroups of patients in whom HBO was less beneficial. A Cochrane review of six clinical trials does not support the use of HBO for treatment of patients with CO intoxication (Weaver et al., 2002). It remains currently unknown which patient should receive HBO treatment, if any. Additionally, if HBO is used, the dose, number and duration of treatments remain controversial. Usually a single treatment at 2.5–3 ATA for a duration of 90 minutes has been advocated by some (Prockop and Chichkova, 2007). The effectiveness of different protocols using more frequent treatments or different pressures and treatment durations has not been compared in a systematic fashion. The Undersea and Hyperbaric Medical Society recommends treatment of the following patients with HBO after CO intoxication: patients with transient or prolonged episodes of loss of consciousness, abnormal neurologic signs, cardiovascular dysfunction or severe acidosis, patients who are 36 years or older when exposed for more than 24 hours, or those who have COHb levels of 25% or more, as well as pregnant women (Gesell, 2008). The clinical policy subcommittee of the American College of Emergency Physicians states that the use of HBO therapy is still controversial and advocates randomized controlled trials to assess its effectiveness (Wolf et al., 2008).
PROGNOSIS Clinical outcome in patients after CO exposure is highly variable. Patients with CO poisoning need follow-up after discharge as they may develop the delayed neuropsychological syndrome. There is no specific therapy for this sequela, but usually empirical treatment with various medications, physical, occupational and vocational therapy, and potentially, rehabilitation. The incidence of the delayed neuropsychological syndrome following CO intoxication is not precisely known. In one study 46% of patients had abnormal neuropsychological
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findings and symptoms at 6 weeks (Weaver et al., 2002). Information about neuropsychological outcome beyond the first year after CO intoxication is limited (Weaver et al., 2002, 2007; Jasper et al., 2005). In a cohort study which followed patients for 6 years, 19% had cognitive impairment and 37% had abnormal neurologic findings on examination (Weaver et al., 2008). Patients with white matter lesions or hippocampal atrophy on brain MRI were at higher risk to show delayed cognitive abnormalities (den Heijer et al., 2006; Smith et al., 2008). The initial clinical presentation does not predict the outcome but several factors indicate poor outcomes such as severity and duration of CO exposure. Given the role of inflammation in CO intoxication associated injury, inflammatory biomarkers may help in the future to predict the risk of neuropsychological symptoms. Children are often symptomatic earlier, but can also recover faster than adults (Weaver et al., 2002). The fetus is especially susceptible to the adverse effects of CO poisoning. Fetal mortality exceeds 50% in case of severe CO intoxication (Koren et al., 1991). Patients with underlying cardiopulmonary disease, the elderly, and patients with multiple comorbidities are at increased risk for poor outcome after CO poisoning. Because treatment is often ineffective, emphasis is on prevention by close environmental monitoring.
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