Bronchoscopy
In many centers, bronchoscopy has a role limited to obtaining lavage fluid for culture and assessing the degree of airway injury which may predict outcome [
33]. Severe inhalation injury is in part a mechanical process characterized by pulmonary edema, bronchial edema, and secretions, can occlude the airway leading to atelectasis and pneumonia. Aggressive use of bronchoscopy is highly effective in removing foreign particles and accumulated secretions that worsen the inflammatory response and may impede ventilation [
34,
35]. While it seems intuitive that bronchoscopy could improve pulmonary hygiene and outcomes by removing secretions and epithelial slough in burn patients, only recently has this question been addressed by a review of the National Burn Repository of the
American Burn Association[
33].
Carr and coworkers reviewed the National Burn Repository from 1998 to 2007 to determine outcome differences in burn patients with inhalation injury and pneumonia who did and did not receive bronchoscopy [
33]. Patients with a 30-59% Total Body Surface Area burn and pneumonia who underwent bronchoscopy had a decreased duration of mechanical ventilation compared to patients who did not have bronchoscopy. Patients with larger injuries and pneumonia did not have improved outcomes with bronchoscopy. When patients having at least one bronchoscopy procedure were compared with those who did not undergo bronchoscopy, the patients receiving this test had a shorter length of intensive care unit and hospital stay. Hospital charges were higher in patients who did not undergo bronchoscopy compared with those who received this procedure. When compared with patients who did not undergo bronchoscopy, patients who did have one or more bronchoscopic procedures had a reduced risk of death by 18%. However, while strong trends were present, the mortality benefit associated with bronchoscopy and the reduction in hospital cost represented trends which did not reach statistical significance.
Carbon monoxide toxicity
Morbidity and mortality associated with carbon monoxide toxicity are the result of hypoxic states associated with interference with oxygen transport at the cellular level and compromise of electron transport within cells. Other potential mechanisms include binding to myoglobin or hepatic cytochromes and peroxidation of cerebral lipids. The extent of injury is dependent on the concentration of carbon monoxide, duration of exposure and underlying health status of the exposed individual [
36,
37].
Short- and long-term morbidity of carbon monoxide toxicity involves neurologic and vascular consequences. Neurologic sequelae are divided into two syndromes: 1) persistent neurologic sequelae and 2) delayed neurologic sequelae. Persistent neurologic sequelae involve neurologic deficits occurring after carbon monoxide exposure that may improve over time. Delayed neurologic sequelae is a relapse of neurologic signs and symptoms after a transient period of improvement. Distinguishing between these conditions may be difficult. Symptoms of chronic carbon monoxide toxicity may include fatigue, affective conditions, emotional distress, memory deficits, difficulty working, sleep disturbances, vertigo, neuropathy, paresthesias, recurrent infections, polycythemia, abdominal pain and diarrhea [
37‐
39].
Neuropsychological sequelae are common after carbon monoxide poisoning. In some trials, 40% of involved patients treated with normobaric oxygen had cognitive sequelae when evaluated six weeks after carbon monoxide exposure and a similar number had affective sequelae. Other potential consequences include gait and motor disturbances, peripheral neuropathy, hearing loss and vestibular abnormalities, dementia and psychosis. These changes may be permanent [
37,
40‐
42].
Immediate management of carbon monoxide toxicity is administration of normobaric oxygen by means of a nonrebreather reservoir facemask supplied with high flow oxygen or 100% oxygen by means of an artificial airway. Administration of normobaric oxygen hastens elimination of carbon monoxide but one trial did not show reduction in cognitive sequelae after inhalation of normobaric oxygen as compared with no supplemental oxygen therapy [
36,
37]. Since normobaric oxygen is safe, readily available and inexpensive, however, it should be provided until a carboxyhemoglobin level is less than 5%. Initial support of the exposed patient should emphasize adequate ventilation and perfusion, neurologic examination, exposure history and measurement of arterial blood gases by co-oximetry to assess gas exchange, metabolic status and carboxyhemoglobin level. A carboxyhemoglobin level greater than 3% in nonsmokers or greater than 10% in smokers confirms exposure to carbon monoxide.
The carbon monoxide level does not correlate with the presence or absence of initial symptoms or with later outcomes[
35,
43,
44].
Carbon monoxide exposure can exacerbate angina and cause cardiac injury even in persons with normal coronary arteries. Thus, exposed patients may require cardiovascular investigation including electrocardiogram and measurement of cardiac enzymes. If cardiac injury is present, cardiology consultation should be considered [
37,
45,
46].
The use of hyperbaric oxygen has been advocated to treat carbon monoxide exposure under the hypothesis that rapid displacement of carbon monoxide from hemoglobin at 100% oxygen using hyperbaric pressures will reduce duration of the cellular hypoxic state [
36,
37]. Use of hyperbaric oxygen results in more rapid displacement of carbon monoxide. Absolute indications and outcomes for hyperbaric oxygen remain controversial because of lack of correlation between the only available diagnostic tool, carboxyhemoglobin levels, and the severity of the clinical state and outcomes of the initial insult or therapies [
36]. In addition, there is no standard for duration or intensity of hyperbaric oxygen therapy. Hyperbaric oxygen has potential complications including barotrauma, tympanic membrane disruption, seizures and air embolism [
47‐
50].
Among published clinical trials of hyperbaric oxygen therapy, few satisfy all consolidated standards for the reporting of trials guidelines including double-blinding, enrollment of all eligible patients, a priori definitions of outcomes and high rates of follow-up [
37,
49,
51,
52]. One single center prospective trial showed that the incidence of cognitive sequelae was lower among patients who underwent three hyperbaric oxygen sessions (initial session of 150 minutes, followed by two sessions of 120 minutes each, separated by an interval of 6 to 12 hours) within 24 hours after acute carbon monoxide poisoning than among patients treated with normobaric oxygen (25% versus 46%, p = 0.007 and p = 0.03 after adjustment for cerebellar dysfunction and stratification). Use of hyperbaric oxygen in this trial reduced the rate of cognitive sequelae at 12 months (18% versus 33% with normobaric oxygen; p = 0.04). This trial did not, however, clearly identify subgroups of patients in whom hyperbaric oxygen was more or less beneficial [
37].
A Cochrane review of six trials including two published in abstract form did not support the use of hyperbaric oxygen for patients with carbon monoxide poisoning [
53]. A more recent Cochrane review also failed to demonstrate convincing benefit from hyperbaric oxygen therapy [
54]. However, multiple flaws in the reviewed trials were identified [
36,
37]. The use of hyperbaric oxygen therapy for carbon monoxide victims continues to be guided by standards of the community rather than scientific consensus.
Patients with carbon monoxide poisoning should be followed medically after discharge. Extent and rate of recovery after poisoning are variable and recovery is often complicated by sequelae which can persist after exposure or develop weeks after poisoning and which may be permanent. Specific therapy for sequelae after carbon monoxide exposure is not available. Patients with sequelae should have symptoms addressed through cognitive, psychiatric, vocational, speech, occupational and physical rehabilitation. Data on these interventions in patients with carbon monoxide sequelae are lacking [
37,
40].
An important trial examined long-term outcomes of patients with acute carbon monoxide poisoning [
55]. Over 1,000 patients treated over a 30 year period were examined. Patients studied were treated with hyperbaric oxygen and survived the acute poisoning episode. Long-term mortality was compared to a standard population. Survivors of acute carbon monoxide poisoning experienced excess mortality in comparison to the general population. Excess mortality was highest in the group initially treated for intentional carbon monoxide poisoning. For the entire group, major causes of death were mental and psychiatric disorders, injuries and violence. Other more specific causes of death were alcoholism, motor vehicle crash with pedestrians, motor vehicle crashes of unspecified type, accidental poisoning and intentional self-harm. Consistent with data mentioned above, no difference in survival was observed by measure of carbon monoxide poisoning severity after controlling for age, gender, race and intent of carbon monoxide poisoning.
Cyanide toxicity
Cyanide is produced by combustion of natural or synthetic household materials including synthetic polymers, polyacrylonitrile, paper, polyurethane, melamine, wool, horsehair and silk [
56,
57]. Cyanide can be detected in trace amounts in smoke at house fires and in the blood of smokers and fire victims. Ingestion of cyanide products produces metabolic acidosis which is also seen in burn patients during resuscitation. Cyanide is a normal human metabolite which the body can detoxify. Cyanide can be produced
in vitro by normal human blood and
in situ in certain organs after death. Much of the interest in cyanide as a toxin related to inhalation injury stems from the availability of a cyanide antidote kit.
Barillo recently reviewed the evidence regarding testing of smoke inhalation victims for cyanide [
57,
58]. Unfortunately, a simple and rapid blood assay for cyanide is lacking and may be of limited utility as cyanide is an intracellular toxin. As noted above, cyanide is a normal metabolite in humans and can be produced and degraded in blood samples
in vitro. Erythrocytes convert thiocyanate to cyanide
in vitro and because blood cyanide is mainly bound to erythrocytes, autolysis of red blood cells may elevate blood cyanide levels. In normal individuals, blood cyanide levels range from up to 0.3 mg/L in nonsmokers to 0.5 mg/L in smokers. Firefighters, despite chronic smoke exposure, have relatively normal blood cyanide levels. Cyanide is mildly elevated in both fire survivors and fire fatalities. Survival with blood cyanide levels of 7–9 mg/L has been documented after cyanide ingestion or inhalation. Recommendations for treatment of cyanide intoxication in smoke victims are extrapolated from limited industrial experience or from suicide and homicide victims. Overt cyanide poisoning is uncommon and little human data is available [
57,
59].
A popular cyanide antidote kit utilizes a series of reactions with oxidation of hemoglobin to methemoglobin which binds cyanide forming cyanomethemoglobin [
60,
61]. As cyanomethemoglobin dissociates, free cyanide is converted to thiocyanate by hepatic mitochondrial enzymes using colloidal sulfate or thiosulfate. Thiocyanate is then excreted in the urine. Despite popularity of the cyanide antidote kit, documented effectiveness is limited [
57,
58,
62]. Notably, a methemoglobin level of 20-30% is required to optimally bind cyanide. Additionally, this is contraindicated in patients with concurrent carbon monoxide poisoning as the conversion of carboxyhemoglobin to methemoglobin may exacerbate hypoxia. Another management strategy utilizes sodium thiosulfate as a substrate in conversion of cyanide to thiocyanate and is reported to be an effective antidote when used with or without nitrite. Prospective trials utilizing this strategy are lacking apart from case studies. Administration at recommended doses is without serious side effects while nausea, retching and vomiting have been reported [
57,
63].
European data suggests treatment of cyanide poisoning with chelating agents such as dicobalt edetate or hydroxycobalamin. Dicobalt edetate is associated with anaphylaxis and can produce hypertension, rhythm changes or cobalt poisoning. At present, dicobalt edetate is not available in the United States. It has been used in Great Britain [
57,
64,
65]. Hydroxycobalamin is an effective cyanide antidote at a dose of 100 mg/kg. Unfortunately, in the United States, hydroxycobalamin has been available at 1 mg/mL concentrations which limits usefulness as approximately 10 L of material would be needed to neutralize a fatal cyanide dose [
58,
66]. The European approach to cyanide poisoning is quite aggressive relative to the United States. In Europe, 1 mg/L blood cyanide level is considered significant or fatal. Hydroxycobalamin and dicobalt edetate are used together to manage cyanide exposure in France [
58,
65].
Cyanide antidotes have recently been reviewed by Hall and coworkers. Scattered investigators in the United States and French clinicians continue to study a variety of agents available for management of this problem. A number of agents are available with differing mechanisms of action. Most of the clinical work, originating from firefighters in Paris emphasizes the use of hydroxycobalamin in smoke inhalation victims with high risk smoke exposure. Various antidotes available for cyanide have varied tolerability and safety profiles. For example, dicobalt edetate use is limited by toxicity concerns. Another cyanide antidote used in Germany is 4-dimethylaminophenol. Like sodium nitrate and amyl nitrite, 4-dimethylaminophenol is thought to neutralize cyanide by inducing methemoglobin. Unfortunately, methemoglobin concentrations and toxicity can be significant with this agent. Use of dicobalt edetate is limited by cobalt toxicity. Of studied agents, hydroxycobalamin has the smallest toxicity profile apart from allergic reactions. Because of a favorable side effect profile, this agent has been used in small studies of prehospital and empiric treatment of smoke exposure. Hydroxycobalamin has rapid onset of action and neutralizes cyanide without interfering with cellular oxygen use. At present, multiple investigators suggest that if employed, hydroxycobalamin is the antidote of first resort in cyanide exposure [
67,
68].
Hydroxycobalamin therapy has been used to prevent cyanide toxicity in patients receiving intravenous nitroprusside and to treat toxic amblyopia and optic neuritis caused by cyanide in tobacco smoke. In these applications, hydroxycobalamin is generally well tolerated but may be associated with side effects of headache, allergic reactions, skin and urine discoloration, hypertension or reflex bradycardia [
58,
63,
69]. Hyperbaric oxygen therapy for cyanide has also been advocated. There is little objective data to support this application [
58,
70,
71]. In light of recent experience with hyperbaric oxygen in carbon monoxide toxicity, a role for this modality in cyanide exposure is questionable [
54].
In summary, the need for specific antidotes in cyanide toxicity is unclear. Aggressive supportive therapy directed to restoration of cardiovascular function with provision of supplemental oxygen augments hepatic clearance of cyanide without specific antidotes and should be first line treatment. Even with severe cyanide poisoning (blood levels of 5–9 mg/L), after cyanide ingestion or smoke inhalation, survival has been documented with aggressive supportive therapy provided without cyanide antidotes [
58,
72,
73]. Another critical issue is the lack of a rapid cyanide assay to document actual poisoning before antidote administration is considered. If an accurate and rapid cyanide assay is available, prospective studies can then be designed to address the efficacy of various treatment options.