Cyanide toxicity

Cyanide is produced by the combustion of natural or synthetic household materials such as synthetic polymers, polyacrylonitrile, paper, polyurethane, melamine, wool, and silk [21–26]. In addition, cyanide can be found in small amounts at the scene of a fire and has been detected in the blood of smokers and fire victims [27–32]. Cyanide is a normal metabolite in humans; it is both generated and degraded in blood samples in vitro [33]. Blood cyanide levels range from up to 0.3 mg/L in non smokers to 0.5 mg/L in smokers [34–36]. Cyanide can be produced by brain, liver, kidney, uterus, stomach and intestinal tissue after death, and even putrefaction of organs can result in lethal cyanide levels postmortem [37]. A significant or fatal blood cyanide level is usually defined as 3 mg/L although both lower and higher levels have been cited [38–41].

The need for administration of a specific antidote for cyanide poisoning is controversial, in part due to the problems associated with the lack of a readily available and timely method for laboratory diagnosis of cyanide poisoning [42–43]. Initial treatment should include aggressive supportive therapy aimed at restoring cardiovascular function and improving hepatic clearance of cyanide. Survival of severe poisoning (blood levels of 5.6–9 mg/L) after cyanide ingestion or smoke inhalation has been documented when aggressive supportive therapy has been used without cyanide antidotes [44–47]. The use of antidotes may be used in the event that supportive therapy fails to improve hemodynamic status.

Hydroxycobalamin therapy has been used to prevent cyanide toxicity in patients receiving intravenous nitroprusside and to treat toxic amblyopia and optic neuritis caused by the cyanide present in tobacco smoke [48–50]. The effective dose of hydroxycobalamin as a cyanide antidote is 100 mg/kg. Hydroxycobalamin therapy is usually well tolerated, but has been associated with side effects of headache, allergic reaction, skin and urine discoloration, hypertension or reflex bradycardia [51–54]. Hydroxycobalamin may interfere with the accuracy of cooximetry or autoanalyzer colormetric blood assay (frequently used to assess liver enzymes, electrolytes and minerals) for several days [51, 53–55]. Anaphylactic reactions have also been documented.

In Europe, cyanide toxicity is treated using the chelating agents dicobalt edetate or hydroxycobalamin (vitamin B12a). Dicobalt edetate may cause cobalt poisoning when given in the absence of cyanide and has been associated with anaphylactic reactions, severe hypertension, and cardiac arrhythmias [56, 57]. For these reasons, dicobalt edetate is not available in the United States. These antidotes differ from the oft-mentioned “cyanide antidote kit”, which includes amyl nitrite, 10% sodium nitrite and 25% sodium thiosulfate. The rationale for the use of this kit is the oxidization of hemoglobin to methemoglobin, which then preferentially binds cyanide to generate cyanomethemoglobin [58]. Free cyanide is converted to thiocyanate by liver mitochondrial enzymes (rhodanase), utilizing colloidal sulfate or thiosulfate as a substrate, and thiocyanate is excreted by the kidneys [59]. Intravenous sodium nitrite has several significant side effects, including severe hypotension, cardiovascular instability, and worsening hypoxia [60–62]. Hence, the cornerstone of treatment for cyanide is appropriate resuscitation. Metabolic acidosis in a burn patient must be assumed to be due to under-resuscitation, carbon monoxide toxicity, missed associated traumatic injury or a combination of the three. The use of antidotes for cyanide toxicity should be restricted to patients with a persistent metabolic acidosis after under-resuscitation, carbon monoxide toxicity, and traumatic injury have been ruled out.

Upper airway injury

The second type of inhalation injury does not involve smoke; it is due to thermal injury of the upper airway and oropharynx. During a fire the ambient temperature of inspired room air approaches 150 degrees Centigrade. The heat of the inspired gases is dissipated in the fire victim’s upper airway, resulting in a thermal burn of the posterior pharynx, nasal passages, and mouth. The damage of the oropharynx is, essentially, a type of thermal injury, with the heat resulting in protein degeneration, complement activation, histamine release, and oxygen free radical formation [63–66]. Over time the soft tissue surrounding the airway may become edematous due to increases in microvascular hydrostatic pressure and

interstitial oncotic pressure; or to decreases in interstitial hydrostatic pressure, plasma oncotic pressure, or the reflection coefficient. The result may be airway obstruction and asphyxiation.

Acute airway obstruction occurs in approximately one-fifth to one-third of hospitalized burn patients who have inhalation injury [67]. Upper airway edema may result in the need for an emergent surgical airway if not addressed appropriately. Timely intubation by the most experienced in airway management is preferable to waiting until severe airway obstruction occurs [68]. The edema associated with acute airway obstruction is variable depending on depth of injury, fluid resuscitation, and patient soft tissue anatomy, but generally peaks at 24 hours following injury [68]. In general, endotracheal intubation is indicated to prevent airway obstruction from edema in patients with significant oropharyngeal burn injury. However, endotracheal intubation has a unique set of benefits and risks. Although it establishes airway protection for the prevention of acute airway obstruction, potentially improves oxygenation in respiratory failure, and provides a secure airway for transport, it has several risks. Attempts to gain airway access may be unsuccessful and/or harmful to the patient. Aspiration, airway injury, loss of airway, pneumothorax, or cardiovascular instability may occur during attempts to secure the airway. In addition, endotracheal intubation increases the risk of ventilator associated pneumonia [69, 70]. Hence, accurate assessment of the patient with potential airway compromise due to burn upper airway edema is paramount.

Determining which patients are at risk for upper airway compromise and need intubation is challenging and requires the integration of history, physical findings, and diagnostic modalities. History of heat and fire exposure is a key aspect in determining whether upper airway edema will be a significant factor during patient resuscitation (Table 2). For example, a patient who sustains a brief exposure to flame (“flash burn”) when lighting a barbeque is unlikely to need intubation; however, a person found unconscious in a house fire after 10 minutes is likely to require intubation. History needs to be combined with physical examination, however. The key physical findings suggestive of impending upper airway compromise include hoarseness or stridor, presence of a

Table 2. Diagnostic considerations for inhalation injury

History

Prolonged exposure to heat/flame in an enclosed space

Loss of consciousness

Extensive burns to face and neck

Aspirated or swallowed hot liquid

Physical Exam

Soot covering face

Burns over face and nose

Singed nasal hair

Carbonaceous sputum

Hoarseness, stridor

Drooling

Obstructive breathing pattern

second or third degree face burn, burning of facial hair, and the presence of carbonaceous sputum [11, 71]. It is important to note that patients (especially children) with major burn injury (>50% total body surface area), may be at risk of airway obstruction from edema without the presence of a face burn due to the systemic edema that accompanies massive resuscitation. Diagnostic modalities that may assist in determining whether or not airway compromise is imminent include direct laryngoscopy, bronchoscopy, chest x-ray, blood gases, and measurement of COHb levels. However, a normal chest x-ray and blood gas at admission does NOT exclude the diagnosis of upper airway compromise or lower airway injury.

Patients with evidence of stridor, severe (third degree) face burns, significant hypoxia, ventilation abnormality, and burns > 50% TBSA should be evaluated for immediate endotracheal intubation. In patients without these signs, assessment for airway injury via history, oral examination (evidence of soot, edema of oropharynx), and changes in voice should be performed [11]. If concern exists with respect to potential upper airway edema or injury, laryngoscopy may be advisable. Of note, when performing laryngoscopy, the clinician should be prepared to intubate, as the procedure may result in acute obstruction. If there is evidence of significant edema or injury, intubation is warranted. If the airway is erythematous, close monitoring may be advisable.

Endotracheal intubation of the patient with a significant burn injury can be challenging due to edema, poor visualization of anatomic landmarks, anatomic distortion due to asymmetric burns, and soot in the airway. In general, the most experienced airway provider should be intubating the patient with burns [71]. It is important to select an appropriately sized endotracheal tube when intubating a patient with inhalation injury. Too small a tube may become obstructed by airway debris and make it difficult to maintain airway patency. Since the edema accompanying the initial injury will be present for several days, changing an obstructed or inadequately sized endotracheal tube can result in lethal loss of airway. Endotracheal tubes should be at least 7.0 mm (preferable larger) in adults, and in children the appropriate tube size can be estimated by the equation: (16+age in years)/4. The preferred route of intubation is nasotracheal, as it provides a more stable airway during the edema phase; however, provider experience is more important than route [71]. A provider should choose the route for which he/she is most proficient. Endotracheal tubes should not be secured with tape for patients with significant edema or face burns, as it will not adhere to the moist wounds or edematous surfaces. Endotracheal tubes should be secured with twill ties (also called tracheostomy ties) which are tied to the endotracheal tube, wrapped around the head circumferentially, and tied anteriorly to allow adjustment for edema formation and resolution. The location of the endotracheal tube at the teeth should be documented, since the endotracheal tube can migrate with movement and edema formation. To minimize facial edema and decrease the incidence of ventilator associated pneumonia, the head of the patient’s bed should be elevated 30 degrees [72].

Lower airway injury

Inhalation injury of the lower airway results in several different physiologic effects. First, casts and proteinaceous material accumulate in the airway, leading to bronchoconstriction and airway hyperreactivity. Second, in conjunction with a large cutaneous burn, inhalation injury results in increased capillary permeability, both in the lung and in the distal airway

[73–75]. As such, inhalation injury is actually a form of acute lung injury (ALI), which may progress to the acute respiratory distress syndrome (ARDS). Similar to ALI/ARDS, inhalation injury with associated cutaneous burn injury results in increased mortality compared to burn injury alone [76]. The inflammatory damage to the alveolar-capillary barrier seen in inhalation injury results in the release of proteinaceous fluid into the alveolar space, which impairs gas exchange [77]. The bronchoconstriction accompanying inhalation injury compounds the impairment in gas exchange even further.

The diagnosis of lower airway injury after smoke exposure relies on many of the same clues used to diagnose upper airway injury. History of the injury, physical examination with inspection of the oropharynx for soot, edema, or ulceration, should be performed [11, 71]. Arterial blood gases, COHb levels, and a chest x-ray should be obtained. Elevated levels of COHb are associated with a higher likelihood of lower airway injury, and one author has developed an algorithm to estimate smoke exposure based on COHb levels [21]. Normal arterial blood gases and chest x-ray do not exclude lower airway injury, but provide valuable baseline data for further comparison. Bronchoscopy is frequently used to visualize injury of the lower airway, and can provide valuable information with respect to airway anatomy and obstruction. At times frequent bronchoscopy is necessary to remove debris and facilitate oxygenation. Xenon perfusion scan has also been reported to be a sensitive indicator of lower airway inhalation injury [78]. However, the need for transport of the patient to nuclear medicine and the resources needed to conduct the examination are prohibitive for many centers.

The treatment of lower airway inhalation injury is largely supportive. Mechanical ventilation is used for severe oxygenation or ventilation deficits. Debate exists with respect to the best form of mechanical ventilation to use for the acute lung injury accompanying lower airway inhalation injury. The volumetric diffusive respirator, a time-cycled pressure limited ventilator, was reported in multiple studies to decrease the incidence of pneumonia and improve mortality after inhalation injury [79–81]. However, this mode of ventilation has not been tested against a low tidal volume ventilation strategy or some of the newer forms of mechanical ventilation such as airway pressure re-

lease ventilation or oscillatory ventilation. Recent therapies touted to improve outcomes after inhalation injury include the use of aerosolized heparin, tocopherol, and 2-agonists [82–84]. Nitric oxide has been shown to decrease pulmonary hypertension and improve oxygenation in critically ill patients, but has had limited studies after burn injury [85–87]. However, further randomized prospective trials are needed to validate these therapies.

Diagnosis

It can be difficult to diagnose inhalation injury. Therefore it is imperative to obtain a detailed history of the event, including source of fire, time of exposition and history of loss of consciousness. A history of entrapment in a closed space, burns in facial area, singed nasal hair, hoarseness, stridor and soot in sputum are early findings that should raise suspicion of the presence of inhalation injury. It is important to remember that inhalation injury can be present without cutaneous burns and in the case that both history and clinical findings are suggestive of inhalation injury the patient should be considered to present inhalation injury until otherwise proven.

On arrival, the patient can be disorientated or mentally altered as a result of CO, cyanide, drug and alcohol intoxication and cephalic trauma [5a]. Chest radiography, arterial gases, carboxyhemoglobin and cyanide levels should be determined on arrival at hospital. Arterial gases and chest X-rays are often normal at admission and this situation does not exclude inhalation injury, but they are valuable as baseline. Afterward, as the injury progresses, both are necessary to monitor the evolution of the patient. Carboxyhemoglobin levels are used to identify CO poisoning and cyanide to assess exposure to hydrogen cyanide.

Fiberoptic bronchoscopy is the most useful diagnostic tool for the assessment of the airway and should be performed in every patient with clinical suspicion of inhalation injury it has the advantage that allows for intubation if needed. Typical bronchoscopic findings of inhalation injury include hyperemia, edema and presence of soot and carbonaceous material along the airway [3a, 5a]. Gamelli et al. graded the extend of the injury which should be used to objectively quantify the extend of inhalation injury (Table 3).

Resuscitation after inhalation injury

Inhalation injury without burn is associated with a mortality of approximately 5 %. Mortality after inhalation injury has decreased in the past 20 years due to recognition of the effects of inhalation injury on resuscitation and advances in airway management. Inhalation injury, due to its effects on the pulmonary parenchyma and its blood flow, impacts the volume of fluid required for burn resuscitation. In severe inhalation injury with associated burn injury the volume of fluid required in the first 24 hours can be as much as 30 % higher than the calculated standard Parkland resuscitation formula of 4 ml/ kg/total body surface area burn [88]. In addition, studies in sheep have suggested that under-resus- citation exacerbates the lung injury caused by smoke inhalation due to the increased capillary leak and extravascular lung water [89]. The goal for resuscitation after combined burn/inhalation injury is a urine output of 0.5 ml/kg (30 – 60 ml/hr) in adults and 1 ml/kg/hr in children.

Other treatment issues

The incidence of pneumonia after inhalation injury approaches 30% [90]. This is due to the impaired airway clearance of debris, loss of ciliary function, mu-

Table 3. Bronchoscopic criteria used to grade inhalation injury

Grade 0 (no injury): absence of carbonaceous deposits, erythema, edema, bronchorrhea, or obstruction

Grade 1 (mild injury): minor or patchy areas of erythema, carbonaceous deposits in proximal or distal bronchi (any or combination)

Grade 2 (moderate injury): moderate degree of erythema, carbonaceous deposits, bronchorrhea, with or without compromise of the bronchi (any or combination)

Grade 3 (severe injury): severe inflammation with friability, copious carbonaeous deposits, bronchorrhea, bronchial obstruction (any or combination)

Grade 4 (massive injury): evidence of mucosal sloughting, necrosis, endoluminal obliteration (any or combination)

From Endorf FW, Famelli RL (2007) Inhalation injury, pulmonary pertubations, and fluid resuscitation. J Burn Care and Research 28: 80–83