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Three Part Question

In patients with suspected [cyanide inhalation or ingestion], does the administration of [hydroxocobalamin] lead to improved [mortality or clinical outcome].

Clinical Scenario

You are confronted with a patient who has been in a house fire. They are unconscious, hypotensive, and have sooty deposits around their mouth. You recognise that an elevated blood lactate of 12mmol/l makes cyanide poisoning as an important consideration. You wonder whether the administration of an antidote (hydroxocobalamin) could reduce mortality or improve clinical outcome.

Search Strategy

Ovid Medline search from 2000 to April week 1 2015.
MeSH Terms: Cyanides, Hydroxocobalamin, Inhalation, Ingestion, Burns, Fires.
Search Strategy: ((Cyanides OR cyanide) AND (Hydroxocobalamin) AND (inhalation OR ingestion OR fires OR burns)).af.

Search Outcome

50 results were retrieved, of which 4 primary studies were directly relevant to the question.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Borron SW et al 2007 France [9]	69 inhalation injury victims (mean age 49.6y).	Prospective Observational Case Series (1987 – 1994).	Survival to discharge.	Survival: 50/69 overall survival; 67% in those with confirmed cyanide poisoning. Haemodynamic Status: 54/69 patients had a spontaneous circulation initially; 15/69 were in cardiac arrest. 2/15 survived cardiac arrest to discharge.	No Control; Deaths confirmed at scene excluded from study; No record of concomitant drugs/ interventions; High number of patients received hyperbaric oxygen (57/69); Descriptive statistics only.
Fortin J et al 2006 France [8]	101 patients administered hydroxocobalamin pre hospital between 1995 and 2003 (median age 48.5).	Retrospective case note review 1995—2003 using Paris Fire Brigade records. Intervention: Median dose 5g hydroxocobalamin IV pre hospital (R1—10g)	Survival and Rate of ROSC.	Survival: 30/101 survived vs. 42/101 died vs. 29/101 lost to follow up. ROSC only: 21/38 arrested patients had ROSC on scene, 2/21 survived (2%).	No control; Retrospective case note review; Missing data;No record of concomitant treatment; Descriptive statistics only.
Borron SW 2007 France [10]	14 cases of ingestion or inhalation of cyanide salts (mean age 35.2 years)	Retrospective case note review 1988--2003. Intervention: Administration of hydroxycobalamin (5—20g) as first line antidote in all cases.	Survival and Adverse Events.	Survival: 10/14 overall survival; 11/14 of patients administered only hydroxocobalamin survived; 10/14 of patients administered hydroxocobalamin in high toxicity group (>100umol/L). Adverse events: Urine discoloration 5/14, Skin discoloration 3/14, Tachycardia 1/14, Hypertension 1/14.	Uncontrolled; Small sample over long time period; Descriptive statistics.
Fortin J 2009 France [11]	161 patients with suspected cyanide poisoning.	Retrospective multi centre case note review focussing on cardiac abnormalities. Intervention: Administration of hydroxocobalamin (4.37—7.50g) .	ROSC and survival	61/161 were in cardiac arrest (58 asystole, 3 VF). ROSC in 31/61, neurologically intact survival 5/51. Resolution of ECG abnormalities : ST changes 12/161, all resolved on ECG taken post hydroxocobalamin, 5/161 exhibited BBB. Resolution in all during HC infusion. Confirmed on second ECG, 56/161 had a tachycardia (mean 120bpm pre administration vs. 92bpm post administration)	Uncontrolled retrospective chart review; Higher doses of Hydroxocobalamin in ROSC and survival groups; Lower doses of adrenaline in ROSC and survival groups.

Comment(s)

Current data supporting hydroxocobalamin use in humans is derived from uncontrolled case series and is of low quality. Potentially significant amounts of data are missing in one series [8]. The effect of additional resuscitative care and supportive management, in addition to the administration of hydroxocobalamin, is not accounted for in any study. There exists considerable variation in the dosage of hydroxocobalamin administered both within and between the studies. Nonetheless, review articles [1-2] and European Expert Consensus [3-4] identified as part of this search all recommend the use of hydroxocobalamin in suspected cyanide poisoning. The rationale behind these recommendations was manually checked, and no additional clinical studies in humans were identified. Whilst available animal data supports the efficacy of hydroxycobalamin in cyanide poisoning [5-6], these study protocols involve the exclusive parenteral administration of cyanide in a controlled laboratory setting. These studies cannot therefore indicate effectiveness in the context of inhalation injury where inhalation superheated fire smoke with multiple consistutents is the norm. Nonetheless, hydroxocobalamin has a favourable safety profile [7]. Owing to the high mortality and morbidity associated with cyanide poisoning, empiric use of hydroxocobalamin in addition to standard care may be warranted where cyanide poisoning is suspected as a part of inhalation injury.

Editor Comment

KMJ

Clinical Bottom Line

There is expert consensus that hydroxocobalamin should be administered in suspected cyanide poisoning. The evidence underpinning current recommendations does not indicate whether hydroxocobalamin is actually beneficial in terms of patient mortality or other outcomes.

Level of Evidence

Level 3 - Small numbers of small studies or great heterogeneity or very different population.

References

1. Borron SW, Baud FJ, Barriot P, Imbert M, Bismuth C. Prospective study of hydroxocobalamin for acute cyanide poisoning in smoke inhalation . Annals of Emergency Medicine. 2007; 49(6):794-801, .e1-2.
2. Fortin J-L, Giocanti J-P, Ruttimann M, Kowalski J-J. Prehospital administration of hydroxocobalamin for smoke inhalation-associated cyanide poisoning: 8 years of experience in the Paris Fire Brigade. Clinical Toxicology: The Official Journal of the American Academy of Clinical Toxicology & European Association of Poisons Centres & Clinical Toxicologists. 2006; 44 Suppl 1:37-44.
3. Borron SW, Baud FJ, Megarbane B, Bismuth C. Hydroxocobalamin for severe acute cyanide poisoning by ingestion or inhalation. American Journal of Emergency Medicine 2007; 25(5):551-8.
4. Fortin J-L, Desmettre T, Manzon C, Judic- Peureux V, Peugeot- Mortier C, Giocanti JP et al Cyanide Poisoning and cardiac disorders: 161 cases. The journal of emergency medicine 2010; 38(4): 467-476
5. Megabarne B, Delahaye A, Goldgran-Tolédano D, Baud F. Antidotal treatment of cyanide poisoning. Journal of the Chinese Medical Assosciation 2003; 66(4):193-203.
6. O’Brien D, Walsh D, Terriff D, Hall C, Alan H. Empiric management of cyanide toxicity associated with smoke inhalation. Prehosp Disaster Med 26(5):374-382.
7. Anseeuw K, Delvau N, Burillo-Putze G, De Iaco F, Geldner G, Holmström P, Lambert Y et al. Cyanide poisoning by smoke inhalation: A european expert consensus. European journal of emergency medicine 2013; 20(1): 2-9.
8. Santiago M, Clerigue N, Vincenzo T, Eduardo P, Davide L, Burillo-Putze G et al. Paediatric cyanide poisoning by fire smoke inhalation: A European Expert Consensus. Paediatric Emergency Care 2013; 29 (11): 1234- 1240
9. Bebarta VS, Tanen DA, Lairet J, Dixon PS, Valtier PS, Bush A. Hydroxocobalamin and sodium thiosulfate versus sodium nitrite and sodium thiosulfate in the treatment of acute cyanide toxicity in a swine (Sus scrofa) model. Ann Emerg Med (55):345–351.
10. Borron SW, Stonerook M, Reid F. Efficacy of hydroxocobalamin for the reatment of acute cyanide poisoning in adult beagle dogs. Clin Toxicol 2006; 44 (Suppl 1):5–15.
11. Uhl W, Nolting A, Golor G, Rost KL, Kovar A. Safety of hydroxocobalamin in healthy volunteers in a randomized, placebo-controlled study. Clin Toxicol 2006; (44): 17–28.