critical care Management of Carbon Monoxide Poisoning* Aaron L. llano, B.A.; and Thomas A. Raffin, M.D., F.C.C.P.

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1 critical care Management of Carbon Monoxide Poisoning* Aaron L. llano, B.A.; and Thomas A. Raffin, M.D., F.C.C.P. Carbon monoxide poisoning is a major cause of illness and death in the United States. Most cases result from exposure to the internal combustion engine and to stoves burning fossil fuels. Most cases of accidental exposure are preventable if proper precautions are taken; however, when cases arise, their presenting signs and symptoms are nonspeci6c and often lead to a misdiagnosis resembling a Ru-like viral illness. As a result, the incidence of acute CO poisoning is underestimated. The effects of CO poisoning are due to tissue hypoxia, with the CNS and the heart being the most susceptible target organs due to their high oxygen needs. Prolonged hypoxia due to high CO levels may lead to cardiac arrhythmias or arrest (or both) and a variety of neurologic sequelae. Treatment is directed toward the relief of tissue hypoxia and the removal of CO from the body. Severity of poisoning can be divided into three levels based on CO levels in the blood. Administration of normobaric 100 percent oxygen is the therapy of choice for most cases, while hyperbaric oxygen therapy is reserved for severe poisonings. (Chest 1990; 97:16S-69) COBb= carboxyhemoglobin; OSHA= Occupational Safety and Health Administration In the United States, CO poisoning accounts for over 3,800 accidental and suicidal deaths each year, making it the leading cause of death by poisoning in this country today. At least an additional 10,000 individuals miss one or more days of work as a result of sublethal exposure. 2 Although the major environmental source of the gas is the internal combustion engine, fires and associated smoke inhalation are responsible for most of the accidental fatalities associated with CO. Fatalities associated with suicide are more likely to be linked to exposure to automobile exhaust; 3 however, most cases of sublethal exposure can be traced to automobile engines, the use of solid fuels in home heating or cooking, tobacco smoke, or industrial plant exposure. 4 Carbon monoxide exerts its effects by combining with hemoglobin to form the stable compound, COHb, thus reducing the total oxygen-carrying capacity of the blood. Most of the signs and symptoms of CO poisoning can thus be ascribed to the resultant tissue hypoxia. 3 Nonlethal CO exposure is frequently misdiagnosed due to the nonspecific nature of its symptoms. When poisoning is not recognized, its presentation is most commonly described as a flu-like viral illness; however, the persistence of its protean symptoms should lead to its inclusion in the differential *From the Division of Respiratory Medicine, Stanford University Medical Center, Stanford, Calif. Reprint re9uests: Dr. &ffin, C-356 Division of Respiratory Medicine, Stanford University Medical Center, Stanford diagnosis. 5 The goals of therapy in acute CO poisoning are the reduction of blood COHb levels to baseline values by the administration of high concentrations of oxygen and the support of any systems affected by the hypoxia resulting from the exposure;5 however, these steps are of little value unless the offending source is determined and the possibility of subsequent exposure to the gas is eliminated. SouRcEs Enviromental sources of CO are the most important with respect to clinical CO poisoning, yet baseline values of CO levels in the blood are determined by the endogenous production of the gas by the catabolism of hemoglobin and other heme-containing compounds, coupled to its intake as a low level pollutant in the ambient air. For most urban locales, this leads to a normal COHb level ofless than 2 percent of total hemoglobin in nonsmokers. 2 4 This value rises somewhat in pregnant women due to endogenous fetal CO production. 4 For smokers, "normal" values may range from 10 percent to 15 percent immediately after a cigarette to chronic values ranging from 3 percent to 8 percent; thus, a smoking history is of significance in a patient with suspected CO exposure. 2 4 The major environmental source of CO is the incomplete combustion of organic material, either in internal combustion engines or in the burning of fuels such as kerosene, wood, or coal for home or industrial purposes. Automobiles are the most prolific of all CO CHEST I 97 I 1 I JANUARY,

2 sources, producing an estimated 0.37 kg of the gas for each mile travelled. 4 Vehicle exhaust is particularly dangerous in enclosed spaces or areas where there is poor ventilation. In a closed garage, lethal concentrations can be reached in ten minutes or less. 5 Toxic levels of CO have been noted in heavily utilized tunnels, in stationary as well as moving buses, and in ice rinks due to ill-maintained ice-resurfacing machinery.2.4 Malfunctioning equipment has further been responsible for several instances of industrial exposure, as recently highlighted in a garment factory in North Carolina.8 In this occurrence, workers in the cutting room of the plant began complaining of headaches, nausea, faintness, and dizziness. Their symptoms seemed to coincide with the use of a propane-powered forklift used in the area on occasion. Investigators, suspecting CO poisoning, took measurements of CO concentration in the cutting room both before and during operation of the forklift. Finding a basal concentration of 35 ppm, they found that within 30 minutes of forklift start-up, the CO concentration had risen to 250 ppm on continuous monitoring. Spot checks with a different device showed levels of up to 300 ppm. The OSHA guidelines suggest no more than a 50-ppm exposure over an eight-hour time-weighted average. Upon replacement of the forklift with an electric model, no further symptoms were encountered by the workers. Fires of all types and the smoke that they produce are a common source of CO and, as with engine exhaust, rapidly produce hazardous levels of the gas in enclosed environs. The smoke inhalation and CO poisoning resulting from dwelling fires is estimated to be a direct cause of 50 percent of all fire-related fatalities. 4 As alluded to earlier, tobacco smoke contains significant amounts of CO. In particular, secondary smoke to which nonsmokers are exposed contains about two and one-half times the amount of CO as directly inhaled smoke.' Virtually any inadequately vented indoor appliance that relies on combustion of fuels can give rise to toxic levels of CO. Even though natural gas burns quite cleanly, proper oxygenation is required to avoid incomplete combustion; however, what makes natural gas particularly dangerous is that potentially lethal levels of CO may be reached without the warning indicator of irritating fumes.2 Less common causes of CO intoxication are exposure to fumes from Sterno, a type of canned heating fuel, and to solvents containing methylene chloride (which is converted to CO via hepatic metabolism).' PATHOPHYSIOLOGY Carbon monoxide is readily absorbed into the bloodstream through the alveolar capillary network. 188 As with uptake, the main route of excretion is also pulmonary and depends on many factors, one of the most important of which is minute ventilation.' Once in the bloodstream, CO reversibly binds to hemoglobin with an affinity approximately 240 times that of oxygen, leading to a reduction in the total oxygencarrying capacity of the blood, with resultant tissue hypoxia. With affinity of this magnitude, even lowlevel exposure is associated with severe toxicity. Breathing air with CO concentrations of as little as 0.1 percent for only minutes may result in COHb levels of greater than 50 percent.3 While CO concentrations are more significant, an increased minute ventilation will also lead to increased CO uptake. 3 In this case, central respiratory control mechanisms are trying to raise the Pa02 in response to reduced oxygen delivery to the tissues; however, a vicious cycle develops where increasing respiration leads to greater and greater CO intake in a positive feedback loop, further complicating any hypoxia already present. Since the shape of the COHb dissociation curve is very similar to that of oxyhemoglobin, although shifted to the right, thus saturating at much lower levels, even small increases in CO levels in inspired air rapidly lead to dangerous CO levels in the blood;4 however, more important are the effects of any CO present on the oxyhemoglobin dissociation curve and peripheral tissue oxygenation. With increasing concentrations of CO leading to a greater and greater number ofbinding sites unavailable for oxygen, the oxyhemoglobin curve shifts to the left, resulting in lowered Pa0 2 for any given level ofhemoglobin saturation and thus resulting in less oxygen delivery to the periphery. Interference with oxygen delivery to tissues is only partially explained by the competitive inhibition of oxygen uptake of hemoglobin by CO. Binding of CO z ~ a: ~ 0.6 (I) i The presence of CO shifts curve to the left. thus saturating Hb at much lower Po 2 1evels. i! with a concomitant decrease ::c 0.2 in oxygen delivery to the peripheral tissues P0 2 (mm Hg) FIGURE 1. Effect of CO on oxyhemoglobin dissociation curve. Curve is shifted to left, which means oxygen is more tightly bound at lower concentrations. Management of CO~ (limo, Raffln)

3 to hemoglobin causes an allosteric change in the oxyhemoglobin complex and shifts the oxyhemoglobin dissociation curve to the left. This shift increases the affinity of hemoglobin for any bound oxygen, resulting in reduced peripheral hemoglobin desaturation and oxygen release Thus, tissue hypoxia due to CO poisoning is greater than that expected with simple reductions in Pa0 2 In addition to hemoglobin, other heme-containing proteins are affected by CO. Located in the extravascular tissues, these proteins account for approximately 10 to 15 percent of the total body C0.1 These include cytochrome oxidase and myoglobin. Inhibition of cellular respiration by CO binding to cytochrome oxidase has been thought to play a role in tissue damage; however, the fact that this heme protein has an affinity for oxygen nine times greater than for CO has cast doubt on this hypothesis. 1 5 Binding of CO to myoglobin is postulated to reduce available oxygen stores in muscle tissue. In the myocardium, this can be disastrous, leading to arrhythmias and cardiac arrest. Furthermore, cerebral ischemia resulting from decreased cardiac performance, although transient in nature, may underlie some of the neurologic sequelae of CO intoxication. 3 CLINICAL MANIFESTATIONS AND DIAGNOSIS The clinical presentation of acute CO poisoning is variable, but in general, the severity of the observed symptoms correlates roughly with the observed level of COHb ('Iable 1); however, in terms of diagnostic value, the nonspecificity of these presenting symptoms makes definitive diagnosis difficult. Therefore, in circumstances such as these, careful attention to the history of the patient is of great import. The most revealing of facts is in the case where multiple individuals have a common symptomatology and environmental exposure. 4 Another telling fact is the occurrence of illness in household pets concurrent with or just preceding the onset of a patient's own illness. Due to their smaller size and in general higher metabolic rates, pets may be more obviously and more severely affected by CO intoxication than their owners. In cases of individu~ exposure, a history of exposure to known sources of CO should suggest at least the possibility of CO intoxication. A great many of these cases are occupationally related.4 The most important effect of CO is tissue hypoxia. This effect is most significant in areas of high blood flow and oxygen demand. For this reason, it is not surprising that neurologic and cardiovascular manifestations are common and that these are the tissues at greatest risk in CO intoxication. 1-a The most common symptoms include fatigue, headaches, dizziness, difficulty in thinking, nausea, dyspnea, weakness, and confusion. Diarrhea, abdominal pain, visual disturbances, and chest pain are found less frequently. 1 2 u In light of these symptoms, one can see why the diagnosis of viral influenza is often made, particularly when the history also reveals that another member of the family is similarly affected. In addition, the incidence of CO poisoning tends to rise during the winter months due to the increased use of home heating appliances rising in step with the number of cases of true viral influenza. 6 Physical findings, like symptoms, are of little help in establishing a diagnosis. Marked tachycardia and tachypnea are common as the cardiovascular and pulmonary syste~s try to compensate for the reduced peripheral oxygen delivery. Mild hypertension is found in some patients, while others may actually be hypotensive as a result of hypoxic myocardium; however, in otherwise healthy individuals, increases in blood flow due to compensatory dilatation of the coronary vessels are sufficient to meet the increased cardiac needs. Patients with a history of artherosclerotic heart disease may not be able to meet these increased oxygen requirements, and in them, arrhythmias may be noted. 1 4 Neurologic findings include audiovestibular abnormalities. Tmnitus and neurosensory hearing losses may be found. Nystagmus and ataxia are also seen. In extremely severe poisonings, cerebral edema is present. 4 Computer tomographic scans and MRI have shown white matter to be particularly sensitive to cerebral hypoxia brought about by CO intoxication. Although gray matter has greater metabolic oxygen needs, the more restricted vascular supply of the white matter limits its tolerance for reduced oxygen tensions Table 1-Symptoma Commonlg Found with Di./lfn'nt CO Lime& Blood Level ofcohb, percent Symptoms 0-10 Usually none in healthy individuals; reduced exercise tolerance in patients with pulmonary disease; decreased threshold for angina in patients with coronary heart disease Headache; dyspnea on mild exertion; angina in patients with coronary heart disease; dilation of cutaneous vessels Throbbing headache; nausea or vomiti"g (or both); ~ fatigability and irritability; difficulty with concentration Severe headache; dizziness; fatigue and weakness; syncope on exertion; impaired thought processes Tachypnea; tachyclllljia; syncope; confusion Respiratory failure; collapse; intennittent convulsions or seizures; coma Respiratory failure; severe hypotension; coma, frequently fatal >70 Coma, rapidly fatal CHEST I 97 I 1 I JANUARY,

4 and thus increases its susceptibility to damage during hypoxic events Late sequelae in up to 45 percent of the patients may develop gradually from three days to three weeks after initial exposure and therapy for acute poisoning. 1 3 The development of delayed sequelae can be predicted by the appearance of deleterious neurologic changes as observed by cr within the first 24 hours after admission. 3 The resulting neuropsychiatric problems may include intellectual deterioration, memory impairment, and personality changes manifested by increased irritability, aggressiveness, violence, and moodiness. 3 5 The occurrence of these delayed sequelae is more common in patients with decreased levels of consciousness at the time of admission. 1 If the proper therapies are instituted at the time of initial treatment, most, if not all, of these sequelae can be prevented. 7 Those patients not receiving aggressive therapy are more likely to develop permanent neurologic deficits. 8 Cherry-red discoloration of the skin, long thought to be typical in CO poisoning, is rarely found. 1 3 Retinal hemorrhages are not common but, when discovered, may suggest the diagnosis. 1 3 Findings of smoke inhalation such as singed nasal hairs, carbonaceous mucus discharge, or injured mucous membranes should raise concern, since patients in whom these are found are more than likely to have suffered severe CO poisorling. 3 The measurement of COHb levels is, at present, the most useful laboratory method for ascertaining the severity of exposure to C Care must be taken in interpreting the results of these tests, since they may not reftect the initial severity of exposure due to elapsed time or treatment begun since removal of the patient from the vicinity of the source. 3 Additional complicating factors include the smoking history of patients and the fact that individuals with high levels ofcohb may be totally asymptomatic} Arterial blood gas levels are oflittle use, since these values measure oxygenation of the plasma and are not affected by hemoglobin saturation. As such, they are not a very sensitive indicator of tissue oxygenation in the periphery. 3 4 Elevated hemoglobin concentrations and hematocrits due to an absolute elevation in red blood cell mass have been found with chronic exposures to CO. The elevation in red blood cell mass is caused by increased erythrocyte production due to hypoxic stimulation. 4 MANAGEMENT Patients who have been poisoned by CO should be immediately removed from the offending source, and therapy to reverse the tissue hypoxia should be initiated. Removal of CO from the body will be accomplished by the same therapies applied toward relieving tissue hypoxia The mainstay of therapy for CO poisoning is the administration of 100 percent oxygen through a tightfitting nonrebreather mask at a Oow rate of 10 Umin. Comatose patients will require endotracheal intubation and mechanical ventilation. If there are signs of inhalation injury, continuous positive airway pressure should be used. In addition to providing for one-third of the body's total oxygen requirement by simple dissolution in plasma, 100 percent oxygen also reduces the half-life of CO in the body to approximately 40 to 80 minutes from the 240-minute half-life of CO when breathing normal room air. -t The use of hyperbaric oxygen at 2.5 to 3 atm of pressure has been advocated recently. In addition to reducing the half-life of CO to 20 to 25 minutes, oxygen at these pressures dissolves in plasma to concentrations that are sufficient to meet total body oxygen requirements in the absence of functioning hemoglobin Proponents ofhyperbaric oxygen therapy contend that its use reduces morbidity, especially that related to delayed neurologic sequelae, and that hyperbaric oxygen therapy is useful even if treatment is delayed for 20 hours after exposure. 8 In a retrospective review, Norkool and KirkpatrickR found the rate of sequelae in patients treated with hyperbaric oxygen to be one-fourth that of the rate found in a previous study in which patients had not received this therapy. One drawback of hyperbaric oxygen therapy is that it is not readily available. Concern has been expressed regarding the transfer of patients in unstable condition or potentially unstable condition to a hyperbaric oxygen facility that may be quite a distance away. Guidelines put forth by Dolan suggest that comatose patients with high levels of COHb remain at the original hospital of admission until levels fall to below 9 percent; if they remain comatos~ or begin to present with neurologic symptoms, only then should transport to a distant center be considered. In transport, 100 percent oxygen should be continued via mask.3 As a strong proponent ofhyperbaric oxygen therapy, Kirkpatrick advocates the use of this treatment immediately in any patient with COHb levels greater than 40 percent and in any patient exhibiting neurologic problems other than mild headache and nausea. A prior history of unconsciousness and cardiac abnormalities would also be cause for referral. 8 The treatment of CO poisoning can be separated into three categories: treatment for mild poisoning, moderate poisoning, and severe poisoning (Thble 2). In mild poisoning, COHb levels are below 30 percent, and there are no signs or symptoms demonstrating reduced cardiovascular or neurologic function. Patients may complain of headache, nausea, and vomiting, and these may be treated with the appropriate medication. Treatment consists of administration of 100 percent oxygen through a nonrebreathing mask Management of CO l"oiaojwwg (llano, Rtlftln)

5 Table 2-~ of CO Poiaoning Mild poisoning COHb levels <30 percent No signs or symptoms of impaired cardiovascular or neurologic function May complain of headache, nausea, or vomiting Admission of patients with COHb levels >25 percent Symptomatic medication 100 percent oxygen by nonrebreathing mask until COHb remains <5percent Patients with underlying heart disease should be admitted and cardiac function be appropriately monitored regardless of COHblevel. Moderate poisoning COHb levels from 30 to 40 percent No signs or symptoms of impaired cardiovascular or neurologic function Admission Cardiovascular status should be followed closely even in absence of clear cardiac effects, especially in those patients with underlying heart disease. Determination of acid-base status {will be corrected by high-row oxygen) 100 percent oxygen by nonrebreathing mask until COHb remains <5percent Severe poisoning COHb levels >40 percent or Cardiovascular or neurologic functional impairment at any COHb Admission Cardiovascular function monitoring Acid-base status monitoring 100 percent oxygen by nonrebreathing mask Transport to a hyperbaric oxygen facility, immediately if available, or if no improvement in cardiovascular or neurologic function is seen in within 4 h until COHb levels fall below 5 percent. Patients with underlying heart disease should be admitted and cardiac function closely monitored. In moderate poisoning, COHb levels range from 30 percent to 40 percent with no cardiac or neurologic dysfunction; however, cardiovascular status should be closely followed even in the absence of cardiac effects, particularly in those patients with underlying heart disease. Acid-base status should be determined owing to the possible buildup of lactic acid resulting from the lack of oxygen and dependence upon anaerobic metabolism. Administration of 100 percent oxygen is continued until COHb levels fall below 5 percent and all signs and symptoms of poisoning have resolved. In severe poisoning, COHb levels are greater than 40 percent, or cardiovascular or CNS symptoms are evident. If a hyperbaric oxygen chamber is readily available, patients should be immediately transported to the facility. If not, these individuals should be treated the same as the moderately poisoned. If improvement is not seen in four hours with administration of 100 percent oxygen via mask, they should be transported to the nearest hyperbaric oxygen facility regardless of transport time. Supportive therapy more than likely will be required, with cardiac monitoring a must. Whether hyperbaric oxygen is used or not, it is essential to admit all patients with COHb levels greater than 25 percent, those patients with a history of heart disease and COHb levels greater than 15 percent, and any patients presenting with ECG evidence of ischemia, impaired mental function, or neurologic symptoms. 1 Patients not fitting into these groups can be treated with 100 percent normobaric oxygen until their COHb levels fall below 5 percent and any symptoms wane.:j-5 After such treatment is completed, COHb levels may rise again several hours later due to slow release of CO from the tissues. Therefore, conservative therapy for patients treated with 100 percent normobaric oxygen should include prolonged administration of high-how oxygen with serial determinations of COHb levels. CoNCLUSION Carbon monoxide poisoning is currently and has been for many years the leading cause of death by accidental poisoning in the United States. Sublethal exposure is difficult to quantify due to the frequent misdiagnosis of acute poisoning as something other than CO intoxication. The principal sources of this gas are internal combustion engines and appliances burning fossil fuels. Carbon monoxide poisoning exerts its effects by binding to hemoglobin, leading to tissue hypoxia. Diagnosis is often difficult due to the nonspecific nature of presenting signs and symptoms, but a COHb level is often definitive. The severity of exposure can be graded by CO levels found in blood, with different treatment regimens recommended for each; however, hyperbaric oxygen is the best treatment for all cases if it is readily available. REFERENCES 1 Dolan MC. Carbon monoxide poisoning. Can Med Assoc J 1985; 133: Kirlcpatrick JN. Occult carbon monoxide poisoning. West J Med 1987; 146: Olson KR. Carbon monoxide poisoning: mechanisms, presentation, and controversies in management. J Emerg Med 1984; 1: Waftle CM. Carbon monoxide poisoning. In: Brenner BE, ed. Comprehensive management of respiratory emergencies. 1986: Meredith 1J, Vale JA. Carbon monoxide poisoning. Br Med J 1988; 296: Fort L, Griggs P. Carbon monoxide poisoning in North Carolina. NC Med J 1987; 48: Myers RAM, Snyder SK, Emboli" TA. Subacute sequelae of c8fbon monoxide poisoning. Ann Emerg Med 1985; 14: Norkool DM, Kirlcpatrick JN. Treatment of acute carbon monoxide poisoning with hyperbaric oxygen: a review of 115 cases. Ann Emerg Med 1985; 14: CHEST I 97 I 1 I JANUARY,