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Use of Cyanide Antidotes in Burn Patients With Suspected Inhalation Injuries in North America: A Cross-Sectional Survey

Use of Cyanide Antidotes in Burn Patients With Suspected Inhalation Injuries in North America: A... Abstract This study aimed to assess the use of cyanide antidotes and the determine the opinion on empiric administration of hydroxocobalamin in North American burn patients with suspected smoke inhalation injuries. An online cross-sectional survey was sent to directors of 90 major burn centers in North America, which were listed on the American Burn Association Web site. A multiple-choice format was used to determine the percentage of patients tested for cyanide poisoning on admission, the current administration of a cyanide antidote based solely on clinical suspicion of poisoning, and the antidote used. To ascertain views on immediate administration of hydroxocobalamin before confirmation of cyanide poisoning an option was included to expand the response in written format. Twenty-nine of 90 burn directors (32%) completed the survey. For the population of interest, the majority of burn centers (59%) do not test for cyanide poisoning on admission and do not administer an antidote based solely on clinical suspicion of cyanide poisoning (58%). The most commonly available antidote is hydroxocobalamin (50%), followed by the cyanide antidote kit (29%). The opinion regarding instant administration of hydroxocobalamin when inhalation injury is suspected is mixed: 31% support its empiric use, 17% do not, and the remaining 52% have varying degrees of confidence in its utility. In North America, most patients burnt in closed-space fires with inhalation injuries are neither tested for cyanide poisoning in a timely manner nor empirically treated with a cyanide antidote. Although studies have shown the safety and efficacy of empiric and immediate administration of hydroxocobalamin, most centers are not willing to do so. The most common source of cyanide exposure is from inhalation of the smoke of combusted synthetic materials by patients in closed-space fires.1 In these patients, although carbon monoxide poisoning has traditionally been what is considered and treated, cyanide is also frequently present in toxic-to-lethal levels.2,–13 Cyanide causes intracellular hypoxia by reversibly binding to mitochondrial cytochrome oxidase a3.4,14 Signs and symptoms of cyanide poisoning are secondary to profound hypoxia and begin in less than 1 minute after inhalation. They include “almond”-smelling breath, tachycardia, and hypertension quickly followed by bradycardia and hypotension, and neurological symptoms such as headache and confusion. Progression to seizures, decreased levels of consciousness, coma, severe cardiovascular compromise leading to cardiac arrest, and ultimately death, occurs within minutes to hours.1,4,11,12,14,–21 These consequences are avoidable if the poisoning is rapidly recognized and treated with an antidote. Because of the short half-life of cyanide, no investigations can both confirm the poisoning and allow for timely treatment.5,15,17,22 Lactate levels are specific markers of cyanide toxicity, but even these may delay treatment, and are more useful to quantify treatment effects and determine further management plans.23,–25 Therefore, to effectively treat patients with cyanide poisoning, an antidote needs to be administered based on a presumptive diagnosis.1,2,16,17,26,–30 Recent reviews1,2,30 outline current and historic management options for cyanide poisoning. The cyanide antidote kit (CAK: amyl nitrite, sodium nitrite, and sodium thiosulfate) and hydroxocobalamin are the two antidotes currently used in North America.14 The nitrites in the CAK form methemoglobin to bind to and chelate the cyanide. Their side effects include interference with the oxygen-carrying capacity of hemoglobin, and hypotension and vasodilation leading to hemodynamic instability. Concurrent carbon monoxide poisoning is often present in these patients, which compromises their oxygen delivery. The methemoglobin produced by the nitrites further exacerbates this issue, rendering them a less desirable option.2,14,27,31,–34 Sodium thiosulfate avoids these side effects, but its slower onset of action limits its use as the sole antidote for empiric and rapid treatment of cyanide poisoning.14,34,–36 In contrast to the nitrites, hydroxocobalamin directly binds cyanide to form cyanocobalamin, which is renally excreted and nontoxic. It has no effect on the oxygen-carrying capacity, and actually improves hemodynamic status.9,14,20,32,37,–41 Although its efficacy and safety seem to be agreed on, no consensus has been reached on the indications for hydroxocobalamin use in the studied patient subset. This lack of consensus prompted our curiosity as to 1) whether burn centers in North America currently use a cyanide antidote, 2) the antidote of choice, and 3) the reasons for or against the empiric use of hydroxocobalamin in burn patients of closed-space fires, with suspected smoke-inhalation injuries. METHODS An online cross-sectional survey was sent to the directors of the 90 major burn centers in North America listed on the American Burn Association Web site in January 2012. The survey included questions regarding burn patients from closed-space fires with suspected inhalation injuries. A multiple-choice format was used to gather information on 1) the percentage of patients tested for cyanide poisoning on admission, 2) the current administration of a cyanide antidote based solely on clinical suspicion of poisoning, and 3) the antidote of choice. The survey additionally determined the centers' views on the immediate administration of hydroxocobalamin before confirmation of cyanide poisoning, using a multiple-choice format with an option to expand the response and rationale in writing. RESULTS Twenty-nine of 90 burn directors (32%) completed the survey. For the population of interest, the majority of burn centers do not test for cyanide poisoning on admission (59%; Figure 1). Based solely on clinical suspicion of cyanide poisoning, most do not empirically administer an antidote (58%; Figure 2). The most commonly available antidote is hydroxocobalamin (50%), followed by the cyanide antidote kit (29%; Figure 3). The opinion regarding the instant administration of hydroxocobalamin, when inhalation injury is clinically suspected is mixed. Thirty-one percent believe it is unlikely to cause harm, may help significantly, and support its empiric use. Seventeen percent believe it is of no utility and thus do not support its use, whereas the remaining 52% had varying degrees of confidence in its utility (Figure 4). Figure 1. View largeDownload slide Percentage of burn centers that test for cyanide poisoning on admission. Figure 1. View largeDownload slide Percentage of burn centers that test for cyanide poisoning on admission. Figure 2. View largeDownload slide Percentage of burn centers that administer a specific antidote based solely on clinical suspicion of cyanide poisoning. Figure 2. View largeDownload slide Percentage of burn centers that administer a specific antidote based solely on clinical suspicion of cyanide poisoning. Figure 3. View largeDownload slide Cyanide antidote available at burn centers in North America. Figure 3. View largeDownload slide Cyanide antidote available at burn centers in North America. Figure 4. View largeDownload slide The opinion of burn centers regarding the instant administration of hydroxocobalamin when inhalation injury is clinically suspected. Figure 4. View largeDownload slide The opinion of burn centers regarding the instant administration of hydroxocobalamin when inhalation injury is clinically suspected. Of the 15 centers that elaborated on reasons against the empiric administration of hydroxocobalamin, the majority (40%) believe that although unlikely to cause the patient harm, the antidote is also unlikely to help, and is therefore a waste of money. One center that does test cyanide levels on admission when inhalation injuries are suspected, reports that no increased level of cyanide has been observed in 5 years and thus sees no need to treat empirically. Another states that despite receiving a higher-than-average amount of burn patients with inhalation injuries, it has never had a case of cyanide toxicity and sees no reason for antidote use, because they also boast a higher-than-average survival rate. Other centers (27%) are uncomfortable with administering the antidote because of lack of experience and information on its risk/benefit ratio. Two centers (13%) believe the use of hydroxocobalamin should be limited to patients with cardiovascular collapse or with severe metabolic acidosis unresponsive to resuscitation. The remainder of centers (13%) believe that the administration of hydroxocobalamin is of minimal benefit. They believe there are few situations where it will make the difference between life or death, whereas it will create a potential for harm and diagnostic dilemmas. They raise concern of the red coloration of the skin and urine caused by hydroxocobalamin interfering with burn assessment, laboratory tests, urinalysis (impaired assessment of hematuria/myoglobinuria), and dialysis (red coloring may cause the machines to shut down, removing plasmapharesis as a potential therapy). DISCUSSION Recent reviews illustrate evidence supporting hydroxocobalamin as the preferred cyanide antidote.1,2,19,27,28,30,32,36,–38,42 Its effects are ideal for use in the burn population with inhalation injuries, as it does not affect the treatment of carbon monoxide poisoning, does not compromise oxygen delivery, and has the ability to improve hemodynamic status in the hypotensive patient.9,14,20,32,37,–41 When used in healthy volunteers and in smoke inhalation victims, its most common adverse events are chromaturia and reddening of the skin.9,27,28,32,37,38,40,43 These are self-limited and asymptomatic but pose some concern because of potential interference with clinical examination and photometric-dependent investigations.27,44,–46 Other less-frequent adverse events include rash, headache, injection site reaction, decreased lymphocyte count, nausea, pruritis, chest discomfort, dysphagia, and the rare occurrence of an allergic reaction, none of which have been reported as a significant morbidity.27,28,38,39,43 Despite this evidence, our results illustrate that there is still a proportion of centers (29%) using the CAK instead of hydroxocobalamin. Because of the more dangerous safety profile of the CAK,2,14,27,31,–34 we recommend that if the decision to stock a cyanide antidote is made, hydroxocobalamin alone be used. Hydroxocobalamin is typically given in doses of 5 g (70 mg/kg), up to a maximum of 10 g per patient.2 The cost of a 5 g vial is around 800 to 900 USD, with a shelf-life of 30 months, whereas the cost of a CAK is closer to 100 to 200 USD.47 The number needed to treat and the cost/benefit ratio have not yet been determined for either hydroxocobalamin or the CAK in the discussed patient subset. Given this lack of data, it is not surprising that despite the evidence of hydroxocobalamin as a safe and effective cyanide antidote, little consensus exists on its empiric use in patients with inhalation injuries as a result of closed-space fires. The significant difference in price renders it tempting to stock the CAK rather than hydroxocobalamin. However, we believe that the increased morbidity and potential mortality associated with the use of the CAK outweighs its cost–benefit.2,14,27,31,–34 In our opinion, when a cyanide antidote is needed, hydroxocobalamin remains the safer option, despite its higher cost. The abovementioned reviews provide their recommendations for management of patients with suspected cyanide poisoning after closed-space fires.1,2,30 All three deem hydroxocobalamin the most suitable cyanide antidote because of its safety profile and rapid onset of action, and it is agreed that its administration should be based on clinical presentation. The discrepancy between these recommendations arises in the determination of which patients require treatment. In patients with physical signs of smoke inhalation (soot in mouth/nose/larynx, hoarseness, stridor, facial burns, singed nasal hairs, carbonaceous sputum),12,30,48 the European consensus2 and an American recommendation30 advise 100% oxygen and supportive measures regardless of hemodynamic status. If hemodynamically unstable, unremittingly acidotic, in cardiac arrest, and/or with a decreased Glasgow Coma Scale score (<13 and <8, European and American recommendation, respectively), early empiric treatment with 5 g of hydroxocobalamin is advised. If the patient does not meet these criteria, antidote administration is not recommended; however, in a prehospital setting with many patients exposed to inhaled smoke, Anseeuw et al2 advocate for the immediate provision of 2.5 g of hydroxocobalamin to all patients while awaiting a thorough assessment. Labwork (arterial blood gas, lactate, carboxyhemoglobin, and cyanide levels) is recommended for every patient, ideally before treatment with hydroxocobalamin, to assist with further management and to allow for diagnosis and data collection for future studies. The Australian Resuscitation Council1 recognizes the potential benefits of hydroxocobalamin, particularly with neurological impairment, carboxyhemoglobin >10% or plasma lactate >10 mmol/L; however, the council also recommends that hospitals and emergency medical services individually determine whether sufficient patients with inhalation injuries from closed-space fires and suspected cyanide poisoning are encountered to justify stocking hydroxocobalamin. Our study highlights the variability in both the antidote used and the management of these patients in North America. Although limited by the low survey response rate, which leads to voluntary response bias and nonresponse bias, this survey does allow the educated assumptions that in North America, the majority of patients burnt in closed-space fires with inhalation injuries are neither tested for cyanide poisoning in a timely manner nor empirically treated with a cyanide antidote. Despite evidence demonstrating the advantageous side-effect profile of hydroxocobalamin compared with CAK, a significant proportion of the centers (29%) that responded to the survey still supply the latter, perhaps because of cost or inexperience with the use of hydroxocobalamin. The expense of hydroxocobalamin, combined with the lack of data and skepticism regarding its true benefits, results in mixed opinions among burn centers, with the majority not willing to administer the antidote. It is difficult to determine at this point how to provide optimal care in patients with smoke-inhalation injuries after closed-space fires. With the available evidence, we support a similar management plan to the European and American studies described above.2,30 We recommend that all patients involved in a closed-space fire be assessed for signs of smoke inhalation. If positive, 100% oxygen and other standard supportive measures should be initiated while maintaining a high index of suspicion for cyanide poisoning. Hydroxocobalamin should be readily available at the scene of the fire, in all tertiary centers, and in other medical care centers with a high incidence of smoke-inhalation injuries. As a suggestion to decrease the cost associated with the provision of hydroxocobalamin to every ambulance, regardless of the quantity of fires they respond to, fire trucks could keep a store of hydroxocobalamin to be used by EMS services prehospital admission. Empiric use of hydroxocobalamin is most likely beneficial and should be provided to hemodynamically or neurovascularly affected individuals, including those in a comatose state or in cardiac arrest. In those who are initially stable, vitals and neurological status should be closely observed with a low-threshold for the use of hydroxocobalamin should any deterioration occur. We agree that arterial blood gas, lactate levels, carboxyhemoglobin levels, and cyanide levels should be drawn in all patients with suspected smoke inhalation in addition to routine labwork if it does not disrupt acute management, preferably before the administration of the antidote. The need for further evidence to determine the optimal use of hydroxocobalamin is clear. Future studies should focus on the incidence of inhalation injuries and cyanide poisonings from closed-space fires. In addition, evaluating the severity of clinical presentations in these scenarios, determined by hemodynamic and neurological status, acidosis, and lactate and cyanide levels, would be useful. These studies will allow the cost/benefit and risk/benefit ratio of hydroxocobalamin use to be better assessed. The creation and implementation of more cohesive guidelines will then be possible to ultimately provide effective patient care. REFERENCES 1. Reade MC, Davies SR, Morley PT, Dennett J, Jacobs ICAustralian Resuscitation Council. Review article: management of cyanide poisoning. Emerg Med Australas. 2012;24:225–38. 2. Anseeuw K, Delvau N, Burillo-Putze G, et al. Cyanide poisoning by fire smoke inhalation: a European expert consensus. Eur J Emerg Med. 2013;20:2–9. 3. Grabowska T, Skowronek R, Nowicka J, Sybirska H. Prevalence of hydrogen cyanide and carboxyhaemoglobin in victims of smoke inhalation during enclosed-space fires: a combined toxicological risk. Clin Toxicol (Phila). 2012;50:759–63. 4. Alarie Y. Toxicity of fire smoke. Crit Rev Toxicol. 2002;32:259–89. 5. Baud FJ, Barriot P, Toffis V, et al. Elevated blood cyanide concentrations in victims of smoke inhalation. N Engl J Med. 1991;325:1761–6. 6. Jones J, McMullen MJ, Dougherty J. Toxic smoke inhalation: cyanide poisoning in fire victims. Am J Emerg Med. 1987;5:317–21. 7. Silverman SH, Purdue GF, Hunt JL, Bost RO. Cyanide toxicity in burned patients. J Trauma. 1988;28:171–6. 8. Clark CJ, Campbell D, Reid WH. Blood carboxyhaemoglobin and cyanide levels in fire survivors. Lancet. 1981;1:1332–5. 9. Rachinger J, Fellner FA, Stieglbauer K, Trenkler J. MR changes after acute cyanide intoxication. AJNR Am J Neuroradiol. 2002;23:1398–401. 10. Eckstein M, Maniscalco PM. Focus on smoke inhalation–the most common cause of acute cyanide poisoning. Prehosp Disaster Med. 2006;21:s49–55. 11. Kales SN, Christiani DC. Acute chemical emergencies. N Engl J Med. 2004;350:800–8. 12. Shusterman D, Alexeeff G, Hargis C, et al. Predictors of carbon monoxide and hydrogen cyanide exposure in smoke inhalation patients. J Toxicol Clin Toxicol. 1996;34:61–71. 13. Alarie Y. The toxicity of smoke from polymeric materials during thermal decomposition. Annu Rev Pharmacol Toxicol. 1985;25:325–47. 14. Hamel J. A review of acute cyanide poisoning with a treatment update. Crit Care Nurse. 2011;31(1):72–81; quiz 82. 15. DesLauriers CA, Burda AM, Wahl M. Hydroxocobalamin as a cyanide antidote. Am J Ther. 2006;13:161–5. 16. Gracia R, Shepherd G. Cyanide poisoning and its treatment. Pharmacotherapy. 2004;24:1358–65. 17. Lawson-Smith P, Jansen EC, Hyldegaard O. Cyanide intoxication as part of smoke inhalation—a review on diagnosis and treatment from the emergency perspective. Scand J Trauma Resusc Emerg Med. 2011;19:14. 18. Vogel SN, Sultan TR, Ten Eyck RP. Cyanide poisoning. Clin Toxicol. 1981;18:367–83. 19. Mégarbane B, Delahaye A, Goldgran-Tolédano D, Baud FJ. Antidotal treatment of cyanide poisoning. J Chin Med Assoc. 2003;66:193–203. 20. Fortin JL, Desmettre T, Manzon C, et al. Cyanide poisoning and cardiac disorders: 161 cases. J Emerg Med. 2010;38:467–76. 21. Goh SH, Tiah L, Lim HC, Ng EK. Disaster preparedness: Experience from a smoke inhalation mass casualty incident. Eur J Emerg Med. 2006;13:330–4. 22. Kirk MA, Gerace R, Kulig KW. Cyanide and methemoglobin kinetics in smoke inhalation victims treated with the cyanide antidote kit. Ann Emerg Med. 1993;22:1413–8. 23. Baud FJ, Borron SW, Mégarbane B, et al. Value of lactic acidosis in the assessment of the severity of acute cyanide poisoning. Crit Care Med. 2002;30:2044–50. 24. Baud FJ. Cyanide: critical issues in diagnosis and treatment. Hum Exp Toxicol. 2007;26:191–201. 25. Strickland A, Wang RY, Hoffman RS, Goldfrank LR. Blood cyanide concentrations after smoke inhalation. N Engl J Med. 1992;326:1362. 26. Alcorta R. Smoke inhalation & acute cyanide poisoning. Hydrogen cyanide poisoning proves increasingly common in smoke-inhalation victims. JEMS. 2004;29(8):suppl 6–15; quiz suppl 16–17. 27. Borron SW, Baud FJ, Barriot P, Imbert M, Bismuth C. Prospective study of hydroxocobalamin for acute cyanide poisoning in smoke inhalation. Ann Emerg Med. 2007;49(6):794–801 801 e791–2. 28. Borron SW, Baud FJ, Mégarbane B, Bismuth C. Hydroxocobalamin for severe acute cyanide poisoning by ingestion or inhalation. Am J Emerg Med. 2007;25:551–8. 29. Rehberg S, Maybauer MO, Enkhbaatar P, Maybauer DM, Yamamoto Y, Traber DL. Pathophysiology, management and treatment of smoke inhalation injury. Expert Rev Respir Med. 2009;3:283–97. 30. O'Brien DJ, Walsh DW, Terriff CM, Hall AH. Empiric management of cyanide toxicity associated with smoke inhalation. Prehosp Disaster Med. 2011;26:374–82. 31. Lavon O, Bentur Y. Does amyl nitrite have a role in the management of pre-hospital mass casualty cyanide poisoning? Clin Toxicol (Phila). 2010;48:477–84. 32. Becker CE. The role of cyanide in fires. Vet Hum Toxicol. 1985;27:487–90. 33. Hall AH, Kulig KW, Rumack BH. Suspected cyanide poisoning in smoke inhalation: complications of sodium nitrite therapy. J Toxicol Clin Exp. 1989;9:3–9. 34. Hall AH, Saiers J, Baud F. Which cyanide antidote? Crit Rev Toxicol. 2009;39:541–52. 35. Bebarta VS, Pitotti RL, Dixon P, Lairet JR, Bush A, Tanen DA. Hydroxocobalamin versus sodium thiosulfate for the treatment of acute cyanide toxicity in a swine (Sus scrofa) model. Ann Emerg Med. 2012;59:532–9. 36. Hall AH, Dart R, Bogdan G. Sodium thiosulfate or hydroxocobalamin for the empiric treatment of cyanide poisoning? Ann Emerg Med. 2007;49:806–13. 37. Fortin JL, Giocanti JP, Ruttimann M, Kowalski JJ. Prehospital administration of hydroxocobalamin for smoke inhalation-associated cyanide poisoning: 8 years of experience in the Paris Fire Brigade. Clin Toxicol (Phila). 2006;44(Suppl 1):37–44. 38. Uhl W, Nolting A, Golor G, Rost KL, Kovar A. Safety of hydroxocobalamin in healthy volunteers in a randomized, placebo-controlled study. Clin Toxicol (Phila). 2006;44(Suppl 1):17–28. 39. Uhl W, Nolting A, Gallemann D, Hecht S, Kovar A. Changes in blood pressure after administration of hydroxocobalamin: relationship to changes in plasma cobalamins-(III) concentrations in healthy volunteers. Clin Toxicol (Phila). 2008;46(6):551–9 discussion 576–57. 40. Houeto P, Hoffman JR, Imbert M, Levillain P, Baud FJ. Relation of blood cyanide to plasma cyanocobalamin concentration after a fixed dose of hydroxocobalamin in cyanide poisoning. Lancet. 1995;346:605–8. 41. Gerth K, Ehring T, Braendle M, Schelling P. Nitric oxide scavenging by hydroxocobalamin may account for its hemodynamic profile. Clin Toxicol (Phila). 2006;44(Suppl 1):29–36. 42. Shepherd G, Velez LI. Role of hydroxocobalamin in acute cyanide poisoning. Ann Pharmacother. 2008;42:661–9. 43. Forsyth JC, Mueller PD, Becker CE, et al. Hydroxocobalamin as a cyanide antidote: safety, efficacy and pharmacokinetics in heavily smoking normal volunteers. J Toxicol Clin Toxicol. 1993;31:277–94. 44. Livshits Z, Lugassy DM, Shawn LK, Hoffman RS. Falsely low carboxyhemoglobin level after hydroxocobalamin therapy. N Engl J Med. 2012;367:1270–1. 45. Hudson M, Cashin BV, Matlock AG, Kang C, Wills BK. A man with purple urine. Hydroxocobalamin-induced chromaturia. Clin Toxicol (Phila). 2012;50:77. 46. Geraci MJ, McCoy SL, Aquino ME. Woman with red urine: hydroxocobalamin-induced chromaturia. J Emerg Med. 2012;43:e207–9. 47. Dart RC, Borron SW, Caravati EM, et al. Expert consensus guidelines for stocking of antidotes in hospitals that provide emergency care. Ann Emerg Med. 2009;54(3):386–394 e381. 48. Woodson LC. Diagnosis and grading of inhalation injury. J Burn Care Res. 2009;30:143–5. Copyright © 2013 by the American Burn Association http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Burn Care & Research Oxford University Press

Use of Cyanide Antidotes in Burn Patients With Suspected Inhalation Injuries in North America: A Cross-Sectional Survey

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Copyright © 2013 by the American Burn Association
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1559-047X
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1559-0488
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10.1097/BCR.0b013e31829b3868
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Abstract

Abstract This study aimed to assess the use of cyanide antidotes and the determine the opinion on empiric administration of hydroxocobalamin in North American burn patients with suspected smoke inhalation injuries. An online cross-sectional survey was sent to directors of 90 major burn centers in North America, which were listed on the American Burn Association Web site. A multiple-choice format was used to determine the percentage of patients tested for cyanide poisoning on admission, the current administration of a cyanide antidote based solely on clinical suspicion of poisoning, and the antidote used. To ascertain views on immediate administration of hydroxocobalamin before confirmation of cyanide poisoning an option was included to expand the response in written format. Twenty-nine of 90 burn directors (32%) completed the survey. For the population of interest, the majority of burn centers (59%) do not test for cyanide poisoning on admission and do not administer an antidote based solely on clinical suspicion of cyanide poisoning (58%). The most commonly available antidote is hydroxocobalamin (50%), followed by the cyanide antidote kit (29%). The opinion regarding instant administration of hydroxocobalamin when inhalation injury is suspected is mixed: 31% support its empiric use, 17% do not, and the remaining 52% have varying degrees of confidence in its utility. In North America, most patients burnt in closed-space fires with inhalation injuries are neither tested for cyanide poisoning in a timely manner nor empirically treated with a cyanide antidote. Although studies have shown the safety and efficacy of empiric and immediate administration of hydroxocobalamin, most centers are not willing to do so. The most common source of cyanide exposure is from inhalation of the smoke of combusted synthetic materials by patients in closed-space fires.1 In these patients, although carbon monoxide poisoning has traditionally been what is considered and treated, cyanide is also frequently present in toxic-to-lethal levels.2,–13 Cyanide causes intracellular hypoxia by reversibly binding to mitochondrial cytochrome oxidase a3.4,14 Signs and symptoms of cyanide poisoning are secondary to profound hypoxia and begin in less than 1 minute after inhalation. They include “almond”-smelling breath, tachycardia, and hypertension quickly followed by bradycardia and hypotension, and neurological symptoms such as headache and confusion. Progression to seizures, decreased levels of consciousness, coma, severe cardiovascular compromise leading to cardiac arrest, and ultimately death, occurs within minutes to hours.1,4,11,12,14,–21 These consequences are avoidable if the poisoning is rapidly recognized and treated with an antidote. Because of the short half-life of cyanide, no investigations can both confirm the poisoning and allow for timely treatment.5,15,17,22 Lactate levels are specific markers of cyanide toxicity, but even these may delay treatment, and are more useful to quantify treatment effects and determine further management plans.23,–25 Therefore, to effectively treat patients with cyanide poisoning, an antidote needs to be administered based on a presumptive diagnosis.1,2,16,17,26,–30 Recent reviews1,2,30 outline current and historic management options for cyanide poisoning. The cyanide antidote kit (CAK: amyl nitrite, sodium nitrite, and sodium thiosulfate) and hydroxocobalamin are the two antidotes currently used in North America.14 The nitrites in the CAK form methemoglobin to bind to and chelate the cyanide. Their side effects include interference with the oxygen-carrying capacity of hemoglobin, and hypotension and vasodilation leading to hemodynamic instability. Concurrent carbon monoxide poisoning is often present in these patients, which compromises their oxygen delivery. The methemoglobin produced by the nitrites further exacerbates this issue, rendering them a less desirable option.2,14,27,31,–34 Sodium thiosulfate avoids these side effects, but its slower onset of action limits its use as the sole antidote for empiric and rapid treatment of cyanide poisoning.14,34,–36 In contrast to the nitrites, hydroxocobalamin directly binds cyanide to form cyanocobalamin, which is renally excreted and nontoxic. It has no effect on the oxygen-carrying capacity, and actually improves hemodynamic status.9,14,20,32,37,–41 Although its efficacy and safety seem to be agreed on, no consensus has been reached on the indications for hydroxocobalamin use in the studied patient subset. This lack of consensus prompted our curiosity as to 1) whether burn centers in North America currently use a cyanide antidote, 2) the antidote of choice, and 3) the reasons for or against the empiric use of hydroxocobalamin in burn patients of closed-space fires, with suspected smoke-inhalation injuries. METHODS An online cross-sectional survey was sent to the directors of the 90 major burn centers in North America listed on the American Burn Association Web site in January 2012. The survey included questions regarding burn patients from closed-space fires with suspected inhalation injuries. A multiple-choice format was used to gather information on 1) the percentage of patients tested for cyanide poisoning on admission, 2) the current administration of a cyanide antidote based solely on clinical suspicion of poisoning, and 3) the antidote of choice. The survey additionally determined the centers' views on the immediate administration of hydroxocobalamin before confirmation of cyanide poisoning, using a multiple-choice format with an option to expand the response and rationale in writing. RESULTS Twenty-nine of 90 burn directors (32%) completed the survey. For the population of interest, the majority of burn centers do not test for cyanide poisoning on admission (59%; Figure 1). Based solely on clinical suspicion of cyanide poisoning, most do not empirically administer an antidote (58%; Figure 2). The most commonly available antidote is hydroxocobalamin (50%), followed by the cyanide antidote kit (29%; Figure 3). The opinion regarding the instant administration of hydroxocobalamin, when inhalation injury is clinically suspected is mixed. Thirty-one percent believe it is unlikely to cause harm, may help significantly, and support its empiric use. Seventeen percent believe it is of no utility and thus do not support its use, whereas the remaining 52% had varying degrees of confidence in its utility (Figure 4). Figure 1. View largeDownload slide Percentage of burn centers that test for cyanide poisoning on admission. Figure 1. View largeDownload slide Percentage of burn centers that test for cyanide poisoning on admission. Figure 2. View largeDownload slide Percentage of burn centers that administer a specific antidote based solely on clinical suspicion of cyanide poisoning. Figure 2. View largeDownload slide Percentage of burn centers that administer a specific antidote based solely on clinical suspicion of cyanide poisoning. Figure 3. View largeDownload slide Cyanide antidote available at burn centers in North America. Figure 3. View largeDownload slide Cyanide antidote available at burn centers in North America. Figure 4. View largeDownload slide The opinion of burn centers regarding the instant administration of hydroxocobalamin when inhalation injury is clinically suspected. Figure 4. View largeDownload slide The opinion of burn centers regarding the instant administration of hydroxocobalamin when inhalation injury is clinically suspected. Of the 15 centers that elaborated on reasons against the empiric administration of hydroxocobalamin, the majority (40%) believe that although unlikely to cause the patient harm, the antidote is also unlikely to help, and is therefore a waste of money. One center that does test cyanide levels on admission when inhalation injuries are suspected, reports that no increased level of cyanide has been observed in 5 years and thus sees no need to treat empirically. Another states that despite receiving a higher-than-average amount of burn patients with inhalation injuries, it has never had a case of cyanide toxicity and sees no reason for antidote use, because they also boast a higher-than-average survival rate. Other centers (27%) are uncomfortable with administering the antidote because of lack of experience and information on its risk/benefit ratio. Two centers (13%) believe the use of hydroxocobalamin should be limited to patients with cardiovascular collapse or with severe metabolic acidosis unresponsive to resuscitation. The remainder of centers (13%) believe that the administration of hydroxocobalamin is of minimal benefit. They believe there are few situations where it will make the difference between life or death, whereas it will create a potential for harm and diagnostic dilemmas. They raise concern of the red coloration of the skin and urine caused by hydroxocobalamin interfering with burn assessment, laboratory tests, urinalysis (impaired assessment of hematuria/myoglobinuria), and dialysis (red coloring may cause the machines to shut down, removing plasmapharesis as a potential therapy). DISCUSSION Recent reviews illustrate evidence supporting hydroxocobalamin as the preferred cyanide antidote.1,2,19,27,28,30,32,36,–38,42 Its effects are ideal for use in the burn population with inhalation injuries, as it does not affect the treatment of carbon monoxide poisoning, does not compromise oxygen delivery, and has the ability to improve hemodynamic status in the hypotensive patient.9,14,20,32,37,–41 When used in healthy volunteers and in smoke inhalation victims, its most common adverse events are chromaturia and reddening of the skin.9,27,28,32,37,38,40,43 These are self-limited and asymptomatic but pose some concern because of potential interference with clinical examination and photometric-dependent investigations.27,44,–46 Other less-frequent adverse events include rash, headache, injection site reaction, decreased lymphocyte count, nausea, pruritis, chest discomfort, dysphagia, and the rare occurrence of an allergic reaction, none of which have been reported as a significant morbidity.27,28,38,39,43 Despite this evidence, our results illustrate that there is still a proportion of centers (29%) using the CAK instead of hydroxocobalamin. Because of the more dangerous safety profile of the CAK,2,14,27,31,–34 we recommend that if the decision to stock a cyanide antidote is made, hydroxocobalamin alone be used. Hydroxocobalamin is typically given in doses of 5 g (70 mg/kg), up to a maximum of 10 g per patient.2 The cost of a 5 g vial is around 800 to 900 USD, with a shelf-life of 30 months, whereas the cost of a CAK is closer to 100 to 200 USD.47 The number needed to treat and the cost/benefit ratio have not yet been determined for either hydroxocobalamin or the CAK in the discussed patient subset. Given this lack of data, it is not surprising that despite the evidence of hydroxocobalamin as a safe and effective cyanide antidote, little consensus exists on its empiric use in patients with inhalation injuries as a result of closed-space fires. The significant difference in price renders it tempting to stock the CAK rather than hydroxocobalamin. However, we believe that the increased morbidity and potential mortality associated with the use of the CAK outweighs its cost–benefit.2,14,27,31,–34 In our opinion, when a cyanide antidote is needed, hydroxocobalamin remains the safer option, despite its higher cost. The abovementioned reviews provide their recommendations for management of patients with suspected cyanide poisoning after closed-space fires.1,2,30 All three deem hydroxocobalamin the most suitable cyanide antidote because of its safety profile and rapid onset of action, and it is agreed that its administration should be based on clinical presentation. The discrepancy between these recommendations arises in the determination of which patients require treatment. In patients with physical signs of smoke inhalation (soot in mouth/nose/larynx, hoarseness, stridor, facial burns, singed nasal hairs, carbonaceous sputum),12,30,48 the European consensus2 and an American recommendation30 advise 100% oxygen and supportive measures regardless of hemodynamic status. If hemodynamically unstable, unremittingly acidotic, in cardiac arrest, and/or with a decreased Glasgow Coma Scale score (<13 and <8, European and American recommendation, respectively), early empiric treatment with 5 g of hydroxocobalamin is advised. If the patient does not meet these criteria, antidote administration is not recommended; however, in a prehospital setting with many patients exposed to inhaled smoke, Anseeuw et al2 advocate for the immediate provision of 2.5 g of hydroxocobalamin to all patients while awaiting a thorough assessment. Labwork (arterial blood gas, lactate, carboxyhemoglobin, and cyanide levels) is recommended for every patient, ideally before treatment with hydroxocobalamin, to assist with further management and to allow for diagnosis and data collection for future studies. The Australian Resuscitation Council1 recognizes the potential benefits of hydroxocobalamin, particularly with neurological impairment, carboxyhemoglobin >10% or plasma lactate >10 mmol/L; however, the council also recommends that hospitals and emergency medical services individually determine whether sufficient patients with inhalation injuries from closed-space fires and suspected cyanide poisoning are encountered to justify stocking hydroxocobalamin. Our study highlights the variability in both the antidote used and the management of these patients in North America. Although limited by the low survey response rate, which leads to voluntary response bias and nonresponse bias, this survey does allow the educated assumptions that in North America, the majority of patients burnt in closed-space fires with inhalation injuries are neither tested for cyanide poisoning in a timely manner nor empirically treated with a cyanide antidote. Despite evidence demonstrating the advantageous side-effect profile of hydroxocobalamin compared with CAK, a significant proportion of the centers (29%) that responded to the survey still supply the latter, perhaps because of cost or inexperience with the use of hydroxocobalamin. The expense of hydroxocobalamin, combined with the lack of data and skepticism regarding its true benefits, results in mixed opinions among burn centers, with the majority not willing to administer the antidote. It is difficult to determine at this point how to provide optimal care in patients with smoke-inhalation injuries after closed-space fires. With the available evidence, we support a similar management plan to the European and American studies described above.2,30 We recommend that all patients involved in a closed-space fire be assessed for signs of smoke inhalation. If positive, 100% oxygen and other standard supportive measures should be initiated while maintaining a high index of suspicion for cyanide poisoning. Hydroxocobalamin should be readily available at the scene of the fire, in all tertiary centers, and in other medical care centers with a high incidence of smoke-inhalation injuries. As a suggestion to decrease the cost associated with the provision of hydroxocobalamin to every ambulance, regardless of the quantity of fires they respond to, fire trucks could keep a store of hydroxocobalamin to be used by EMS services prehospital admission. Empiric use of hydroxocobalamin is most likely beneficial and should be provided to hemodynamically or neurovascularly affected individuals, including those in a comatose state or in cardiac arrest. In those who are initially stable, vitals and neurological status should be closely observed with a low-threshold for the use of hydroxocobalamin should any deterioration occur. We agree that arterial blood gas, lactate levels, carboxyhemoglobin levels, and cyanide levels should be drawn in all patients with suspected smoke inhalation in addition to routine labwork if it does not disrupt acute management, preferably before the administration of the antidote. The need for further evidence to determine the optimal use of hydroxocobalamin is clear. Future studies should focus on the incidence of inhalation injuries and cyanide poisonings from closed-space fires. 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Journal

Journal of Burn Care & Research – Oxford University Press

Published: Mar 1, 2014

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