Hydroxycobalamin is the antidote of choice for cyanide poisoning and early administration may be lifesaving.

Carbon monoxide (CO) is the leading cause of toxin-related morbidity and mortality in North America, with tens of thousands of exposures and thousands of deaths each year in the United States. While most of these deaths represent suicides, the majority of pediatric fatalities result from smoke inhalation or misadventures involving combustion of fossil fuels with inadequate ventilation. In contrast, cyanide is rarely an agent of deliberate harm and is most often encountered in smoke inhalation victims.^1,2 The pathophysiology of smoke inhalation is complex. From a toxicological perspective, carbon monoxide and cyanide poisoning may coexist.^1,2 Critical interventions for the management of both of these poisonings include removal from the source of exposure, meticulous supportive care, and for patients with concomitant cyanide poisoning, timely antidote administration.

CO is an insidious poison. It is an imperceptible gas produced by the incomplete combustion of carbon-based compounds such as wood, charcoal, gasoline, or kerosene. In children, CO poisoning is typically unintentional and most often results from malfunctioning home heating systems or proximity to inadequately ventilated generators, charcoal grills, or motor vehicles.^1,2 Rarely, CO poisoning results from inhalation or ingestion of methylene chloride, a hydrocarbon commonly found in paint stripping products and metabolized to CO by the liver.³

PATHOPHYSIOLOGY

The pathophysiology of CO poisoning is complex and incompletely understood.⁴ It is rapidly absorbed through the alveoli and binds to heme iron with an affinity roughly 240 times that of oxygen, resulting in the formation of carboxyhemoglobin (COHb).^3,5 This produces a functional anemia as well as a conformational change in the structure of the hemoglobin molecule that shifts the oxyhemoglobin dissociation curve to the left. Collectively, these effects reduce the oxygen-carrying capacity of blood and impair the release of oxygen at the tissue level.

In addition, CO produces a host of other cellular effects that contribute to toxicity by interfering with oxygen utilization and promoting inflammation.⁶ Notably, it binds to myoglobin and other heme-containing structures including mitochondrial cytochromes, impairing cellular respiration and adenosine triphosphate (ATP) generation.^7,8 Predictably, the most prominent effects of CO poisoning involve the myocardium and brain, tissues with little ability to tolerate cellular asphyxia.^5,9 The tissue-specific effects of CO are illustrated by the observation that CO-related myocardial dysfunction can occur even when oxygen delivery itself is normal.⁷ A major consequence of CO poisoning is peroxidation of brain lipids, which promotes inflammation and may underlie some of the neurologic sequelae seen in patients with severe CO poisoning.^7,9

The developing fetus is particularly sensitive to CO poisoning. The fetal oxyhemoglobin dissociation curve lies to the left of the adult curve, fetal hemoglobin binds CO more avidly than maternal hemoglobin, and the half-life of COHb is prolonged in utero.

CLINICAL PRESENTATION

The clinical signs and symptoms of CO poisoning are notoriously nonspecific, and correlate poorly with the COHb level at the scene of exposure¹⁰ (Table 128-1). Moreover, symptoms can persist long after COHb is undetectable. The diagnosis can therefore be difficult when a history of exposure is not readily apparent, or when CO poisoning is not considered until long after the patient is removed from the source of exposure. It is important to consider CO poisoning in patients with nonspecific or vague symptoms, particularly when multiple patients present simultaneously from the same environment. Misdiagnosis of carbon monoxide poisoning as a viral illness such as influenza is particularly common in this setting.¹⁰

Headache, nausea, dizziness, and impaired concentration are among the most common presenting symptoms in patients with CO poisoning.¹¹ More severe exposures are characterized by confusion, altered mental status, seizures, and coma. Patients who survive CO poisoning may have long-term neurologic sequelae. Some experts classify these as either persistent neurologic sequelae (PNS) or delayed neurologic sequelae (DNS).¹² The main distinction between the two is that DNS is characterized by a period of neurologic improvement (or even restoration of normalcy) prior to neurologic deterioration. The onset of DNS can be dramatic and accompanied by marked abnormalities on neuroimaging.^12–16 In infants, the only suggestion of CO poisoning may be irritability or difficulty feeding. Children generally exhibit symptoms similar to those of adult patients, but may become symptomatic sooner because of their higher metabolic rates.¹⁷

The physical examination in patients with CO poisoning is of limited utility in making the diagnosis. In many patients, vital signs are either normal or minimally perturbed. A “cherry-red” appearance of the skin is sometimes touted as a clue to the diagnosis. While this is commonly seen in patients who have died from CO poisoning, it is rarely encountered in patients presenting to the emergency department.¹⁸ Neurologic abnormalities are sometimes subtle and may only be appreciated by a detailed neurologic examination that tests comprehension, recall, and attention. More severe cases may be characterized by physical exam findings of delirium, coma, pulmonary edema, arrhythmias, and cardiovascular instability.

LABORATORY STUDIES

It is important for clinicians to recognize that the usual methods of assessing oxygenation not only fail to detect COHb, they produce falsely reassuring measurements. Conventional pulse oximetry does not distinguish COHb from oxyhemoglobin. Because both are reddish pigments, COHb is perceived as oxyhemoglobin and will artificially elevate the estimated percentage of oxyhemoglobin. However, oximeters capable of measuring COHb are available¹³ and have been used for hospital and pre-hospital point-of-care diagnosis. Similarly, because routine arterial blood gas analyzers measure the partial pressure of oxygen dissolved in plasma to estimate hemoglobin saturation, they also produce falsely elevated estimates of hemoglobin saturation. They will, however, provide accurate information about acid–base status and ventilation. Most laboratories use co-oximetry to measure COHb.¹⁸ This can be performed on a venous blood sample, obviating the need for arterial puncture.

The measurement of COHb is subject to several interpretive cautions. While its presence at more than trace percentages is indicative of CO exposure, these values may not correlate well with clinical signs. Although a recent study found that COHb concentrations correlated with severity, as defined by the Poisoning Severity Score,¹⁹ the many limitations of this scoring system have been well described.²⁰ Because COHb concentrations decline once exposure ceases, values obtained in hospital may be significantly lower than peak values. Importantly, severe neurologic toxicity can be present in the absence of measurable COHb, particularly if measurement was delayed or high-flow oxygenation administered prior to COHb measurement.

Significant acidemia is an uncommon manifestation of isolated CO toxicity, but can occur in severely poisoned patients. In victims of structural fires, elevated serum lactate should prompt consideration of concomitant cyanide toxicity (discussed below). Electrocardiography and myocardial enzymes may provide evidence of cardiac injury.²¹ Computed tomography, and in particular, magnetic resonance imaging, may reveal characteristic low-density changes in the globus pallidus and subcortical white matter in cases of CO poisoning.^22–24

TREATMENT

Following removal from exposure, meticulous supportive care is the mainstay of treatment. If the patient has been extricated from a fire, clinicians should maintain a high index of suspicion for concomitant cyanide poisoning, which is often accompanied by mental status abnormalities, lactic acidosis, and hemodynamic instability. Patients with obvious evidence of inhalational injury such as singed nasal hair, soot in the oropharynx, and carbonaceous sputum should be intubated immediately.

High-flow supplemental oxygen is the standard treatment of the CO-poisoned patient (Fig. 128–1). The administration of 100% oxygen (sometimes described as normobaric oxygen [NBO]) significantly hastens the elimination of COHb, with a mean t_1/2 of 74 minutes.²⁵ This is a safe and low-cost intervention that many authorities recommend as standard of care. Typically, 4 to 6 hours of 100% oxygen will suffice, although it is prudent to ensure that COHb is below 5% before supplemental oxygen is discontinued. Extended treatment for pregnant women is sometimes advocated, although there is no strong evidence supporting this practice.