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sodium thiosulfate as a cyanide antidote
ThF-’ Journalof EmergencyMedione Vol 5 pp
1 i5-
121
i 987
Printed I” the USA
??
Ci?pyright
1987 Petgamon rO~irrals Lid
HYDROXYCOBALAMIN/SODlUM THIOSULFATE AS A CYANIDE ANTIDOTE Alan H. Hall, MD,* and Barry H. Rumack, MDt ‘Cllnlcal
Toxicology
DIrector Unwewty Repnnl address
Rocky
of Colorado Barry
Health
H Rumack. 645 Bannock
I? Abstract-Severe, is uncommon
Polson
Sciences
MD. Dlrector Street
of exposure
of smoke inhalation
is unavailable.
may have signifi-
oxide toxicity. The Lilly Cyanide Antidote available
in America
has its own inherent
toxicity.
Kit%
unfortunate11 An efficacious
antidote lacking toxicity is desirable, especially in cases where the diagnosis of cyanide poisoning cannot be made with certainty. balamin/sodium
thiosulfate
Hydroxyco-
has been used in
France since 1970. Both components
have been
shown
in animal
to be safe and efficacious
studies. Case reports
of human
cyanide
poi-
soning treated with hydroxycobalamin/sodium thiosulfate Animal antidotal
have been published only in French.
and human
cobalamin/sodium cyanide antidote 0
data
combination
is an efficacious
with little inherent toxicity.
Keywords-cyanide;
hgdroxycobalamin:
on the use of this
are reviewed. Hydroxy-
thiosulfate
Denver
Rocky
Mountain
General
Hospital
Poison and Drug Center
CO 80204-4507
have survived with supportive measures only.‘-” However, the highest blood level reported in a patient surviving with only supportive measures was 2.9 ,bg/‘mL, whereas survival with levels of 3.2 to 16.3 pg/mL have been reported with administration of the amyl and sodium nitrite/ sodium thiosulfate, Lilly Cyanide Antidote Kita.‘-’ The administration of a cyanide antidote may therefore allow survival after a relatively greater poisoning. The sodium nitrite component of the Lilly Cyanide Antidote Kit” available in the United States is not without inherent toxicity. Rapid administration may cause hypotension owing to excessive peripheral vasodilatation. Sodium nitrite induces methemoglobinemia, which can be lifethreatening when inappropriately large amounts of nitrite are administered.“’ Methemoglobinemia with resultant decreased oxygen-carrying capacity is dangerous in smoke inhalation victims having significant carboxyhemoglobin levels in addition to cyanide poisoning.” II Other cyanide antidotes currently being employed in Europe include dimethylaminophenol (DMAP), another methemoglobin inducer, and dicobalt-EDTA
to diag-
cant cyanide poisoning as well as carbon moncurrently
of Pedlatrlcs.
and Drug Center,
Center,
Denver
acute cyanide poisoning
and can be very difficult
nose if a history Victims
Fellow, and tProfessor Mountain
cyanide poisoning: sodium thiosulfate
Introduction Cyanide poisoning is notoriously difficult to diagnose without a history of exposure.‘.? Patients with significant symptoms
of the most critical and challenging areas confronting the emergency department staff-is coordinated by Kenneth Kulig, .MD, of the Rocky Mountain Poison Center.
Toxicology-one
v B
RECEIVED:28 April
1986; ACCEPTED:24 August 11
1986
0736-4679187
-__ $3 .OO + .OO
116
(Kelocyanor@), which chelates cyanide as cobalticyanide. DMAP has the same disadvantage as sodium nitrite of methemoglobin induction which is dangerous in cases of smoke inhalation with elevated carboxyhemoglobin levels and decreased oxygen transport. Dicobalt-EDTA can cause hypertension or hypotension, cardiac dysrhythmias, and cardiac insufficiency if administered in the absence of cyanide poisoning.lJ In a continuous cyanide infusion dog model, Paulet and Dassonville’” found that sodium nitrite/sodium thiosulfate was efficacious only early in the course of the poisoning. Hydroxycobalamin/sodium thiosulfate and DMAP were equally efficacious if administered later, and dicobalt-EDTA was efficacious even if administered very late.15 A cyanide antidote of low toxicity that does not worsen circulatory shock, does not reduce the oxygen-carrying capacity of hemoglobin, and is devoid of significant side effects, especially when administered in the absence of cyanide poisoning, would be most desirable.
Discussion Cyanide Poisoning Cyanide is an intracellular poison that acts by binding to the Fe+ 3 moiety of mitochondrial cytochrome oxidase, inhibiting cellular oxygen utilization and oxidative phosphorylation. This results in strictly anaerobic metabolism with cellular hypoxia, decreased adenosine triphosphate (ATP) production, and lactic acid accumulation.’ Coma, seizures, apnea, mydriasis, nausea, vomiting, ischemic ECG changes, elevated anion gap metabolic acidosis, bradycardia, and hypotension may be seen. Symptoms are usually extremely rapid in onset after inhalation of hydrogen cyanide gas or ingestion of cyanide salts. Cyanosis is either absent or a late finding occurring after respiratory arrest. I4
Alan H. Hall and Barry H. Rumack
Diagnosis is often difficult in the absence of exposure history. Retinal veins and arteries that have an equally red color have been described on funduscopic examination. There may be a “bitter almonds” smell to the gastric contents or breath, but this cannot be detected by a large percentage of individuals.
Hydroxycobalamin/Sodium
Thiosulfate
Pharmacology Hydroxycobalamin (vitamin B,z,) detoxifies cyanide by giving up its hydroxyl group and binding a cyanyl group, forming cyanocobalamin (vitamin B,,), which is excreted harmlessly in the urine16m1*(Fig 1). Hydroxycobalamin has a greater affinity for cyanide than cytochrome oxidase and thus frees the enzyme to resume its normal function in cellular respiration. Ix The reaction requires one molecule of hydroxycobalamin for each molecule of cyanide detoxified, but with a molecular weight ratio of approximately 50 : 1 of hydroxycobalamin:cyanidelh~“, it therefore requires about 20 g of hydroxycobalamin to detoxify 1 g of absorbed potassium cyanide.lh Hydroxycobalamin crosses the bloodbrain barrier’” and is excreted unchanged in the urine in the absence of cyanide poisoning. I6 Pharmacokinetic data are not available for the standard 4-g antidotal dose. Total serum cobalamin levels in healthy human subjects peak at about 13 ng/mL two hours after intramuscular injection of 0.2 mg of hydroxycobalamin.20 In an in vitro experiment with human blood having a hydroxycobalamin plasma level of 1.33 pg/mL, hydroxycobalamin was approximately 35Yo protein bound.” Body retention and urinary excretion studies in humans have produced somewhat contradictory results. Borochovitz et alZ2 found urinary excretion of radiolabeled hydroxycobalamin to be virtually complete in 24 hours after a I-mg intramuscular dose. Boddy et al,23 however, reported a 42.1% retention at three days
HydroxycobalaminiSodlum
Thlosulfate
117
OH
CN
+
(1) A COBALAMIN
F” Fe’3-
cytochrome
oxidase
-
+
Fees- cytochrome
A COBALAMIN
&tactive)
(Hydroxycobalamin) Vitamin B 12,
oxidass
+
OH-
(Active)
(Cyanocobalamin) Vitamin 812
CN
OH
(II) + A COBALAMIN (Cyanocobalamin)
Sulfur
+
H,O
B
(from Sodium Thiosulfats)
+ A COBALAMIN
SCN
+
H+
Uhiocyanate)
(Hydroxycobalamin)
Figure 1. (I) Proposed mechanism of reactivation of cytochrome oxidase by hydroxycobalamin; (II) A possible mechanism explaining the finding of up to 50% of an administered dose of hydroxycobalamin excreted apparently unchanged in the urine.
and 32.5% retention at 28 days after a lmg radiolabeled hydroxycobalamin intramuscular injection (0.189 mg retained at 28 days). Patients receiving 4 mg of hydroxycobalamin daily by mouth had unchanged urinary excretion of 4.7 pg over the first 24 hours and 8.4 pg over the first 48 hours after starting treatment.24 Urinary clearance was 84 to 97 ml/minute after a 5mg intravenous dose in normal human subjects.” Sodium thiosulfate serves as a sulfur donor for the endogenous cyanide-detoxifying enzyme, rhodanese. The rate-limiting step of rhodanese is dependent upon the availability of sulfur.‘” Antidotal synergy of hydroxycobalamin and sodium thiosulfate has been demonstrated in animals by Mizoulel” and Evans.‘” In a study of the urinary elimination of cyanide in rabbits, Mizoule showed that the primary detoxification product was cyanocobalamin if hydroxycobalamin was administered alone. When hydroxycobalamin was combined with SOdium thiosulfate, the primary urinary detoxification product eliminated in the urine was thiocyanate. Hydroxycobalamin may act in the combination by binding cyanide, which later is given up to rhodanese and eliminated as thiocyanate, regenerating hydroxycobalamin, which is then available to rebind cysnide which is excreted in the urine.‘” Up
to 50% of an administered dose of hydroxycobalamin may be recovered in the urine in animal experiments.lh In acute poisonings the antidotal action of sodium thiosulfate used alone is insufficiently rapid to ensure survival.li~lh.‘X Hydroxycobalamin is rapid acting, allowing survival for a period long enough for sodium thiosulfate to exert its action.‘” In man the combination of hydroxycobalamin with 8 g of sodium thiosulfate produces an antidotal synergy permitting reduction of the hydroxycobalamin dose, which is still efficacious at 4 g.lx Safety Hydroxycobalamin produced no toxicity in Swiss mice in single intravenous injections of 0.4, 0.75, and 1 g/kgJh Rabbits injected intravenously with 50 and 100 mg/kg showed no toxicity.‘” Intravenous injection of 50 mg/kg every other day for ten days produced no toxicity in rabbits.lh Rats given 50 pg subcutaneously three days/week for 82 days showed no signs of toxicity and had no differences from controls in red and white blood cell counts.ih Guinea pigs given 1 g/kg intravenously showed no toxic effects.” In humans, a 4-g dose of hydroxycobalamin produced a transient reddish discoloration of the skin, mucous membranes, and urine.‘? One case of transient facial acne” and one case of urticaria and Quinke’s edema16 have been reported with
Alan H. Hall and Barry H. Rumack
118
administration of the hydroxycobalamin/ sodium thiosulfate antidote kit. Three cases of anaphylaxis and one case of urticaria attributable to hydroxycobalamin have been reported in patients chronically administered either cyanocobalamin or hydroxycobalamin in small doses for vitamin B,>-deficiency states.*‘-‘” Hypotension has been noted in dogs and rabbits rapidly administered 500 to 4,000 mg/kg of sodium thiosulfate intravenously.lh The average adult dose of sodium thiosulfate in the hydroxycobalamin/sodium thiosulfate antidote kit is only about 115 mg/kg. Reports of human toxicity are notably absent, although sodium thiosulfate has been a part of the Lilly Cyanide Antidote Kit@ used since the 1930s.”
Animal Efficacy Studies Mushett et a13? were the first to demonstrate the antidotal efficacy of hydroxycobalamin. This agent is effective in reviving mice poisoned with cyanide even after the cessation of respirations. Hydroxycobalamin has been shown to be efficacious in mice, 19.32 rabbits,lh.lY.33.34 guinea pigs,lh,25 dogs,‘S-37 and baboons.38 The majority of animal experiments have demonstrated a strong antidotal synergy between hydroxycobalamin and sodium thiosulfate,lh*l” although one dog35 and two rabbit experimentslh.ly failed to show this effect.
Hydroxycobalamin
Clinical Trials
Chronic low-level cyanide exposure has been implicated in the development of various neurological conditions, including tobacco amblyopia.3” Vincent et ali4 studied the effect of hydroxycobalamin 45 mg/d for 10 to 15 days in 34 patients with different optic nerve diseases; tobacco abuse was the most common cause. Free and total cyanide “clearly showed a de-
crease” in blood and urine, and 61% of patients had clinical improvement.3J Cottrell et althO using a 1 mg/mL solution of hydroxycobalamin (up to 100 mg) as a concomitant infusion with sodium nitroprusside in patients undergoing deliberate hypotensive anesthesia, showed smaller blood cyanide level increases and the development of less acidosis than in control patients receiving nitroprusside alone.
French Cyanide Poisoning Case Reports Ten patients treated with the hydroxycobalamin/sodium thiosulfate antidote kit (4 g hydroxycobalamin/S g sodium thiosulfate; Trousse Anficyanure, ANPHARROLLAND Laboratories, Chilly-Mazarin, France) and one treated with 200 mg of hydroxycobalamin were reported in the French literature between 1970 and 1984 11.17.2h.Jl~lJ In two cases, hydroxycobalamin/sodiurn thiosulfate was the only antidote utilized.dZ~J”In one case a patient ingested 1.5 g of potassium cyanide, suffered severe poisoning with cardiac arrest, and recovered after supportive measures and administration of the hydroxycobalamin/sodium thiosulfate antidote kit.‘a Another patient ingested 50 mg of potassium cyanide, developed shock, coma, and ECG evidence of myocardial ischemia, but recovered fully after receiving supportive treatment and two doses of hydroxycobalamin/sodium thiosu1fate.Q The remaining reported victims had other antidotes administered in addition to hydroxycobalamin/sodium thiosulfate. A patient who ingested 1 g of potassium cyanide had no response to sodium nitrite/sodium thiosulfate, dicobalt-EDTA, and methylene blue, but recovered after receiving hydroxycobalamin/sodium thiosulfate.” Lutier et al”’ reported a patient who ingested 0.98 to 1 g of potassium cyanide and became comatose and apneic. The administration of hydroxycobala-
HydroxycobalaminEodtum
Thiosulfate
119
minIsodium thiosulfate brought almost immediate improvement .‘I These authors detail two other cases of cyanide poisoning treatment failures (one with sodium nitrite/sodium thiosulfate and dicobaltEDTA, the other with amyl nitrite and dicobalt-EDTA) in which hydroxycobalamin/sodium thiosulfate produced nearly immediate clinical improvement.J’ Yacoub et alZh reported a case of ingestion of 1 g of potassium cyanide. This patient developed severe toxicity and a whole blood cyanide level of 15 pg/mL. After receiving amyl nitrite, dicobalt-EDTA, and hydroxycobalamin/sodium thiosulfate, the patient recovered fully.‘h Urticaria and Quinke’s edema developed after administration of all three agents, but quickly resolved with antihistamine and corticosteroid treatment.Zh Bourrelier and PauletJ3 reported three workers burned with molten sodium cyanide. One died quickly; the other two developed coma and shock. One of these patients recovered with administration of dicobalt-EDTA alone. The second victim received both dicobalt-EDTA and 200 mg of hydroxycobalamin with full recovery.” Bismuth et alI4 reported a series of 25 cases of cyanide poisoning, including three patients treated with both dicobaltEDTA and hydroxycobalamin/sodium thiosulfate. One patient who suffered cardiac arrest prior to the arrival of the paramedics died. A second who suffered cardiac arrest during transport to the hospital was resuscitated but had prolonged coma and died 6 months after the poisoning. A third patient had coma, apnea, shock, pulmonary edema, and a whole blood cyanide level of 6 pg/mL three hours after exposure, but recovered without sequelae. French authors often recommend hydroxycobalamin/sodium thiosulfate in
cases where the diagnosis of cyanide poisoning is in doubt because of this antidote’s lack of toxicity when compared with dicobalt-EDTA, which can produce significant cardiovascular adverse reactions in the absence of cyanide.‘J.“,4Z As the various antidotes all have different mechanisms of action, their effects may be additive or synergistic.‘4,‘7
Current Status of Hydroxycobalamin in America The hydroxycobalamin/sodium thiosulfate cyanide antidote combination was designated an “orphan drug” by the Food and Drug Administration in October 1985. Studies of safety and efficacy are necessary before the antidotal combination can be considered for approval for general use in the United States. These studies are now being organized by the Rocky Mountain Poison and Drug Center.
Conclusion The Lilly Cyanide Antidote KitB currently available in America for cyanide poisoning is efficacious but has inherent toxicity, making its use in cases of diagnostic uncertainty or smoke inhalation with elevated carboxyhemoglobin levels undesirable. The hydroxycobalamin/sodium thiosulfate antidotal combination currently used in France is at least equally efficacious and practically devoid of toxicity. It is a logical agent for development in the United States. Acknowledgmentsof a McNeil
Dr Hall
Fellowship
was the recipient
in Clinical
Toxicology
at the time of this review.
REFERENCES I, Graham
DL, Laman D, Theodore .I, et al: Acute cyanide poisoning complicated by lactic acidosis and pulmonary edema. Arch Intern Med 1977;
137:1051-1055. 2. Vogel SN, Sultan TR, Ten Eyck RP: Cyanide poisoning. C/in ~xicol 1981: 18:367-3X3.
120
3. Brivet F, Delfraissy JF, Duche M, et al: Acute cyanide poisoning: Recovery with non-specific supportive therapy. Infensive Cure Med 1983; 9:33-35. 4. Ortega JA, Creek JE: Acute cyanide poisoning following administration of laetrile enemas. J fediarr 1978; 93: 1059. 5. Moertel CC, Ames MM, Kovack JS, et al: A pharmacological and toxicological study of amyndalin. JAMA 1981: 245:591-594. 6. M&e DL, Boros L, Findley PA: More on cyanide poisoning from laetrile. N Engl J Med 1979; 301:892. 7. Rubino MJ: Cyanide toxicity: Report of a case. Poison Informalion Bulletin, Connecticut Poison Information Cenler 1978; 3: l-5. 8. Litovitz TL, Larkin RF, Myers RAM: Cyanide poisoning treated with hyperbaric oxygen. Am J EtnergMed 1983; 1:94-101. 9. Hall AH, Linden CH, Kulig KW, et al: Cyanide poisoning from laetrile: Role of nitrite therapy (Abstract). Vet Human Toxic01 1985; 28:308309. 10. Berlin CM: The treatment of cyanide poisoning in children. Pediatrics 1970; 46:793-796. 1 1. Symington IS, Anderson RA, Thomson, I, et al: Cyanide exposure in fires. Lance/ 1978; 2:91-92. 12. Clark CJ, Campbell D, Reid WH: Blood carboxyheamoglobin and cyanide levels in fire survivors. Lance/ 1981; 1:1332-1335. 13. Hart GB, Strauss MB, Lennon PA, et al: Treatment of smoke inhalation by hyperbaric oxygen. JEmerg Med 1985; 3:211-215. 14. Bismuth C, Cantineau J-P, Pontal P, et al: Priorite de I’oxygenation dans I’intoxication cyanhydrique: A propos de 25 cas. J Toxicol Med 1984; 4:107-121. 15. Paulet G, Dassonville J: Valeur du dimethylaminophenol (DMAP) dans le traitement de I’intoxication cyanhydrique: Etude experimentale. J Toxicol Clin Exp 1985; 5:105-l 11. 16. Mizoule J: Etude de I’Acfion de I’tlydroxocobalamine a I’Egard de I’lnfoxicaiion Cyanhydrique thesis. Faculte de Pharmacie de I’Universite de Paris, 1966, pp I-178. 17. Motin J, Bouletreau P, Rourioux JM: Intoxication cyanhydrique grave traite avec succes par 1970; hydroxycobalamine. J Med Sfrusbourg 1:717-722. 18. Pronczuk de Garbino J, Bismuth C: Propositions therapeutiques actuelles en cas d’intoxication par les cyanures. Toxicol Eur Res 1981; 3~69-76. 19. Evans CL: Cobalt compounds as antidotes for hydrocyanic acids. B; J Pharmrrcol 1964; 23~455-475. 20. Hall CA, Begley JA, Green-Colligan PD: The availability of therapeutic hydroxocobalamin to cells. Blood 1984; 63:335-341. 21. Shearman DJC, Calvert JA, Ala FA, et al: Renal excretion of hydroxycobalamin in man. Lance/ 1965; 2:1329-1330. 22. Borochovitz D, Stevens K, Metz J: Body retention of a depot preparation of cyanocobalamin compared with hydroxycobalamin. S Afr Med J 1970: 44:532-533.
Alan H. Hall and Barry H. Rumack
23. Boddy K, King P, Mervyn L, et al: Retention of cyanocobalamin, hydroxocobalamin, and coenzyme B12 after parenteral administration. Luncet 1968; 2:710-712. H: Urinary excretion of hydroxoco24. Hed5trand balamine and cyanocobalamine after oral administration of large dose,. At/u Med Scund 1969; 186:535-537. 25. Posner MA, Tobey RE, McElroy H: Hydroxocobalamin therapy of cyanide intoxication in guin1976; 44: I57- 160. ea pigs. Anueslhesiology 26. Yacoub M, Faure J, Morena H, et al: L’intoxication cyanhydrique aigue: Donnees actuelles sur le metabolisme du cyanure et le traitement par I’hydroxocobalamine. J Eur Toxicol 1974; 7:2229. 27. Auzepy P, Veissieres JF, DeParis M: Choc anaphylactique du a I’hydroxocobalamine. Nouv Presse Med 1974; 3:152. 2X. Dally S, Gaultier M: Choc anaphylactique du a I’hydroxycobalamine. Nouv Presse Med 1976; 5:1917. 29. Hovding G: Anaphylactic reaction after injection of vitamin B12. Br Med / 1968; 3:102. 30. James J, Warin RP: Sensitivity to cyanocobalamin and hydroxocobalamin. Br Med J 1971; 21262. 3 1. Chen KK, Rose CL: Nitrite and thiosulfate therapy in cyanide poisoning. JAMA 1952; 149: 1 I3119. 32. Mushett CW, Kelly KL, Boxer GE, et al: Antidotal efficacy of vitamin B12 (hydroxo-cobalamin) in experimental cyanide poisoning. Proc Sot Exp Biol Med 1952; 81~234-237. 33. Faure J, Vincent M, Benabid A-L, et al: Traitement par I’hydroxycobalamine de I’hypercyanemie et de I’hypercyanurie consecutives a la compression du nerf sciatique cher le lapin. CRCSoc Biol 1977; 171:1221-1223. 34. Vincent M, Vincent F, Marka C, et al: Cyanide and its relationship to nervous suffering. Physiopathological aspects of intoxication. C/in Toxicol 1981; l8:1519-1527. 35. Krapez JR, Vesey CJ, Adams L, et al: Effects of cyanide antidotes used with sodium nitropruyside infusions: Sodium thiosulphate and hvdroxocobalamin given prophyla&cally to dogs. Br JAnaesth 1981; 53:793-804. 36. Rose CL, Worth RM, Chen KK: Hydroxo-cobalamine and acute cyanide poisoning in dogs. Ltfe Sci 1965; 4:1785-1789. 37. lvankovich AD, Braverman B, Kanuru RP, et al: Cyanide antidotes and methods of their administration in dogs: A comparative study. Anerthesiology 1980; 52:210-216. 38. Posner MA, Rodkey FL, Tobey RE: Nitroprusside-induced cyanide poisoning: Antidotal effect of hydroxocobalamin. Anaesthesiology 1976; 44: 330-335. 39. Wilson J: Cyanide in human disease: A review of clinical and laboratory evidence. Fundam Apol Toxicoll983; 3~397-399. 40. Cottrell JE, Casthely P, Brodie JD, et al: Prevention of nitroprusside-induced cyanide toxicity with hydroxycobalamin. N Engl J Med 1978; __” ^^^ ^.. LY8:KVY-81
I.
HydroxycobalamlnlSodlum
Thlosulfate
-II. Luricr I., Dusoleil P, de Montgros J: Action dc I’liydro~ocohalan~i~~~ a dose ma55i\e dans I’intoxicarion
aigue au cyanure.
A propo\
121
43
d’un cas.
,31.<./?MuI PIUJ” 1971; 32:6X3-686. 42. Racle JP, Chauswt R, Di\sait F, et al: L’intouication\ cyanhydrique aiguc. Aspects biologiqucs, tosicologique~. cliniqucs. ct therapeutiques. Kev Mcd C’lolllot~c-~~rrurl~l 1976; 51371-382.
Bourrelier J, Paulet G: Intoxication
cyanhydrique
conwutive a des brulures graves par cyanure de sodium fondu. Sur trois cas traites par EDTA cobaltique. 44
PresseMed
1971; 22:1013-1014.
Jouglard J, Nava G, Botta A. ct al: A prop05 d’une intoxication aigue par le cyanure de pota\sium traitce par I’hydroxocobalamine. Marseille Wed 1974; 12:617-624.
1 i5-
121
i 987
Printed I” the USA
??
Ci?pyright
1987 Petgamon rO~irrals Lid
HYDROXYCOBALAMIN/SODlUM THIOSULFATE AS A CYANIDE ANTIDOTE Alan H. Hall, MD,* and Barry H. Rumack, MDt ‘Cllnlcal
Toxicology
DIrector Unwewty Repnnl address
Rocky
of Colorado Barry
Health
H Rumack. 645 Bannock
I? Abstract-Severe, is uncommon
Polson
Sciences
MD. Dlrector Street
of exposure
of smoke inhalation
is unavailable.
may have signifi-
oxide toxicity. The Lilly Cyanide Antidote available
in America
has its own inherent
toxicity.
Kit%
unfortunate11 An efficacious
antidote lacking toxicity is desirable, especially in cases where the diagnosis of cyanide poisoning cannot be made with certainty. balamin/sodium
thiosulfate
Hydroxyco-
has been used in
France since 1970. Both components
have been
shown
in animal
to be safe and efficacious
studies. Case reports
of human
cyanide
poi-
soning treated with hydroxycobalamin/sodium thiosulfate Animal antidotal
have been published only in French.
and human
cobalamin/sodium cyanide antidote 0
data
combination
is an efficacious
with little inherent toxicity.
Keywords-cyanide;
hgdroxycobalamin:
on the use of this
are reviewed. Hydroxy-
thiosulfate
Denver
Rocky
Mountain
General
Hospital
Poison and Drug Center
CO 80204-4507
have survived with supportive measures only.‘-” However, the highest blood level reported in a patient surviving with only supportive measures was 2.9 ,bg/‘mL, whereas survival with levels of 3.2 to 16.3 pg/mL have been reported with administration of the amyl and sodium nitrite/ sodium thiosulfate, Lilly Cyanide Antidote Kita.‘-’ The administration of a cyanide antidote may therefore allow survival after a relatively greater poisoning. The sodium nitrite component of the Lilly Cyanide Antidote Kit” available in the United States is not without inherent toxicity. Rapid administration may cause hypotension owing to excessive peripheral vasodilatation. Sodium nitrite induces methemoglobinemia, which can be lifethreatening when inappropriately large amounts of nitrite are administered.“’ Methemoglobinemia with resultant decreased oxygen-carrying capacity is dangerous in smoke inhalation victims having significant carboxyhemoglobin levels in addition to cyanide poisoning.” II Other cyanide antidotes currently being employed in Europe include dimethylaminophenol (DMAP), another methemoglobin inducer, and dicobalt-EDTA
to diag-
cant cyanide poisoning as well as carbon moncurrently
of Pedlatrlcs.
and Drug Center,
Center,
Denver
acute cyanide poisoning
and can be very difficult
nose if a history Victims
Fellow, and tProfessor Mountain
cyanide poisoning: sodium thiosulfate
Introduction Cyanide poisoning is notoriously difficult to diagnose without a history of exposure.‘.? Patients with significant symptoms
of the most critical and challenging areas confronting the emergency department staff-is coordinated by Kenneth Kulig, .MD, of the Rocky Mountain Poison Center.
Toxicology-one
v B
RECEIVED:28 April
1986; ACCEPTED:24 August 11
1986
0736-4679187
-__ $3 .OO + .OO
116
(Kelocyanor@), which chelates cyanide as cobalticyanide. DMAP has the same disadvantage as sodium nitrite of methemoglobin induction which is dangerous in cases of smoke inhalation with elevated carboxyhemoglobin levels and decreased oxygen transport. Dicobalt-EDTA can cause hypertension or hypotension, cardiac dysrhythmias, and cardiac insufficiency if administered in the absence of cyanide poisoning.lJ In a continuous cyanide infusion dog model, Paulet and Dassonville’” found that sodium nitrite/sodium thiosulfate was efficacious only early in the course of the poisoning. Hydroxycobalamin/sodium thiosulfate and DMAP were equally efficacious if administered later, and dicobalt-EDTA was efficacious even if administered very late.15 A cyanide antidote of low toxicity that does not worsen circulatory shock, does not reduce the oxygen-carrying capacity of hemoglobin, and is devoid of significant side effects, especially when administered in the absence of cyanide poisoning, would be most desirable.
Discussion Cyanide Poisoning Cyanide is an intracellular poison that acts by binding to the Fe+ 3 moiety of mitochondrial cytochrome oxidase, inhibiting cellular oxygen utilization and oxidative phosphorylation. This results in strictly anaerobic metabolism with cellular hypoxia, decreased adenosine triphosphate (ATP) production, and lactic acid accumulation.’ Coma, seizures, apnea, mydriasis, nausea, vomiting, ischemic ECG changes, elevated anion gap metabolic acidosis, bradycardia, and hypotension may be seen. Symptoms are usually extremely rapid in onset after inhalation of hydrogen cyanide gas or ingestion of cyanide salts. Cyanosis is either absent or a late finding occurring after respiratory arrest. I4
Alan H. Hall and Barry H. Rumack
Diagnosis is often difficult in the absence of exposure history. Retinal veins and arteries that have an equally red color have been described on funduscopic examination. There may be a “bitter almonds” smell to the gastric contents or breath, but this cannot be detected by a large percentage of individuals.
Hydroxycobalamin/Sodium
Thiosulfate
Pharmacology Hydroxycobalamin (vitamin B,z,) detoxifies cyanide by giving up its hydroxyl group and binding a cyanyl group, forming cyanocobalamin (vitamin B,,), which is excreted harmlessly in the urine16m1*(Fig 1). Hydroxycobalamin has a greater affinity for cyanide than cytochrome oxidase and thus frees the enzyme to resume its normal function in cellular respiration. Ix The reaction requires one molecule of hydroxycobalamin for each molecule of cyanide detoxified, but with a molecular weight ratio of approximately 50 : 1 of hydroxycobalamin:cyanidelh~“, it therefore requires about 20 g of hydroxycobalamin to detoxify 1 g of absorbed potassium cyanide.lh Hydroxycobalamin crosses the bloodbrain barrier’” and is excreted unchanged in the urine in the absence of cyanide poisoning. I6 Pharmacokinetic data are not available for the standard 4-g antidotal dose. Total serum cobalamin levels in healthy human subjects peak at about 13 ng/mL two hours after intramuscular injection of 0.2 mg of hydroxycobalamin.20 In an in vitro experiment with human blood having a hydroxycobalamin plasma level of 1.33 pg/mL, hydroxycobalamin was approximately 35Yo protein bound.” Body retention and urinary excretion studies in humans have produced somewhat contradictory results. Borochovitz et alZ2 found urinary excretion of radiolabeled hydroxycobalamin to be virtually complete in 24 hours after a I-mg intramuscular dose. Boddy et al,23 however, reported a 42.1% retention at three days
HydroxycobalaminiSodlum
Thlosulfate
117
OH
CN
+
(1) A COBALAMIN
F” Fe’3-
cytochrome
oxidase
-
+
Fees- cytochrome
A COBALAMIN
&tactive)
(Hydroxycobalamin) Vitamin B 12,
oxidass
+
OH-
(Active)
(Cyanocobalamin) Vitamin 812
CN
OH
(II) + A COBALAMIN (Cyanocobalamin)
Sulfur
+
H,O
B
(from Sodium Thiosulfats)
+ A COBALAMIN
SCN
+
H+
Uhiocyanate)
(Hydroxycobalamin)
Figure 1. (I) Proposed mechanism of reactivation of cytochrome oxidase by hydroxycobalamin; (II) A possible mechanism explaining the finding of up to 50% of an administered dose of hydroxycobalamin excreted apparently unchanged in the urine.
and 32.5% retention at 28 days after a lmg radiolabeled hydroxycobalamin intramuscular injection (0.189 mg retained at 28 days). Patients receiving 4 mg of hydroxycobalamin daily by mouth had unchanged urinary excretion of 4.7 pg over the first 24 hours and 8.4 pg over the first 48 hours after starting treatment.24 Urinary clearance was 84 to 97 ml/minute after a 5mg intravenous dose in normal human subjects.” Sodium thiosulfate serves as a sulfur donor for the endogenous cyanide-detoxifying enzyme, rhodanese. The rate-limiting step of rhodanese is dependent upon the availability of sulfur.‘” Antidotal synergy of hydroxycobalamin and sodium thiosulfate has been demonstrated in animals by Mizoulel” and Evans.‘” In a study of the urinary elimination of cyanide in rabbits, Mizoule showed that the primary detoxification product was cyanocobalamin if hydroxycobalamin was administered alone. When hydroxycobalamin was combined with SOdium thiosulfate, the primary urinary detoxification product eliminated in the urine was thiocyanate. Hydroxycobalamin may act in the combination by binding cyanide, which later is given up to rhodanese and eliminated as thiocyanate, regenerating hydroxycobalamin, which is then available to rebind cysnide which is excreted in the urine.‘” Up
to 50% of an administered dose of hydroxycobalamin may be recovered in the urine in animal experiments.lh In acute poisonings the antidotal action of sodium thiosulfate used alone is insufficiently rapid to ensure survival.li~lh.‘X Hydroxycobalamin is rapid acting, allowing survival for a period long enough for sodium thiosulfate to exert its action.‘” In man the combination of hydroxycobalamin with 8 g of sodium thiosulfate produces an antidotal synergy permitting reduction of the hydroxycobalamin dose, which is still efficacious at 4 g.lx Safety Hydroxycobalamin produced no toxicity in Swiss mice in single intravenous injections of 0.4, 0.75, and 1 g/kgJh Rabbits injected intravenously with 50 and 100 mg/kg showed no toxicity.‘” Intravenous injection of 50 mg/kg every other day for ten days produced no toxicity in rabbits.lh Rats given 50 pg subcutaneously three days/week for 82 days showed no signs of toxicity and had no differences from controls in red and white blood cell counts.ih Guinea pigs given 1 g/kg intravenously showed no toxic effects.” In humans, a 4-g dose of hydroxycobalamin produced a transient reddish discoloration of the skin, mucous membranes, and urine.‘? One case of transient facial acne” and one case of urticaria and Quinke’s edema16 have been reported with
Alan H. Hall and Barry H. Rumack
118
administration of the hydroxycobalamin/ sodium thiosulfate antidote kit. Three cases of anaphylaxis and one case of urticaria attributable to hydroxycobalamin have been reported in patients chronically administered either cyanocobalamin or hydroxycobalamin in small doses for vitamin B,>-deficiency states.*‘-‘” Hypotension has been noted in dogs and rabbits rapidly administered 500 to 4,000 mg/kg of sodium thiosulfate intravenously.lh The average adult dose of sodium thiosulfate in the hydroxycobalamin/sodium thiosulfate antidote kit is only about 115 mg/kg. Reports of human toxicity are notably absent, although sodium thiosulfate has been a part of the Lilly Cyanide Antidote Kit@ used since the 1930s.”
Animal Efficacy Studies Mushett et a13? were the first to demonstrate the antidotal efficacy of hydroxycobalamin. This agent is effective in reviving mice poisoned with cyanide even after the cessation of respirations. Hydroxycobalamin has been shown to be efficacious in mice, 19.32 rabbits,lh.lY.33.34 guinea pigs,lh,25 dogs,‘S-37 and baboons.38 The majority of animal experiments have demonstrated a strong antidotal synergy between hydroxycobalamin and sodium thiosulfate,lh*l” although one dog35 and two rabbit experimentslh.ly failed to show this effect.
Hydroxycobalamin
Clinical Trials
Chronic low-level cyanide exposure has been implicated in the development of various neurological conditions, including tobacco amblyopia.3” Vincent et ali4 studied the effect of hydroxycobalamin 45 mg/d for 10 to 15 days in 34 patients with different optic nerve diseases; tobacco abuse was the most common cause. Free and total cyanide “clearly showed a de-
crease” in blood and urine, and 61% of patients had clinical improvement.3J Cottrell et althO using a 1 mg/mL solution of hydroxycobalamin (up to 100 mg) as a concomitant infusion with sodium nitroprusside in patients undergoing deliberate hypotensive anesthesia, showed smaller blood cyanide level increases and the development of less acidosis than in control patients receiving nitroprusside alone.
French Cyanide Poisoning Case Reports Ten patients treated with the hydroxycobalamin/sodium thiosulfate antidote kit (4 g hydroxycobalamin/S g sodium thiosulfate; Trousse Anficyanure, ANPHARROLLAND Laboratories, Chilly-Mazarin, France) and one treated with 200 mg of hydroxycobalamin were reported in the French literature between 1970 and 1984 11.17.2h.Jl~lJ In two cases, hydroxycobalamin/sodiurn thiosulfate was the only antidote utilized.dZ~J”In one case a patient ingested 1.5 g of potassium cyanide, suffered severe poisoning with cardiac arrest, and recovered after supportive measures and administration of the hydroxycobalamin/sodium thiosulfate antidote kit.‘a Another patient ingested 50 mg of potassium cyanide, developed shock, coma, and ECG evidence of myocardial ischemia, but recovered fully after receiving supportive treatment and two doses of hydroxycobalamin/sodium thiosu1fate.Q The remaining reported victims had other antidotes administered in addition to hydroxycobalamin/sodium thiosulfate. A patient who ingested 1 g of potassium cyanide had no response to sodium nitrite/sodium thiosulfate, dicobalt-EDTA, and methylene blue, but recovered after receiving hydroxycobalamin/sodium thiosulfate.” Lutier et al”’ reported a patient who ingested 0.98 to 1 g of potassium cyanide and became comatose and apneic. The administration of hydroxycobala-
HydroxycobalaminEodtum
Thiosulfate
119
minIsodium thiosulfate brought almost immediate improvement .‘I These authors detail two other cases of cyanide poisoning treatment failures (one with sodium nitrite/sodium thiosulfate and dicobaltEDTA, the other with amyl nitrite and dicobalt-EDTA) in which hydroxycobalamin/sodium thiosulfate produced nearly immediate clinical improvement.J’ Yacoub et alZh reported a case of ingestion of 1 g of potassium cyanide. This patient developed severe toxicity and a whole blood cyanide level of 15 pg/mL. After receiving amyl nitrite, dicobalt-EDTA, and hydroxycobalamin/sodium thiosulfate, the patient recovered fully.‘h Urticaria and Quinke’s edema developed after administration of all three agents, but quickly resolved with antihistamine and corticosteroid treatment.Zh Bourrelier and PauletJ3 reported three workers burned with molten sodium cyanide. One died quickly; the other two developed coma and shock. One of these patients recovered with administration of dicobalt-EDTA alone. The second victim received both dicobalt-EDTA and 200 mg of hydroxycobalamin with full recovery.” Bismuth et alI4 reported a series of 25 cases of cyanide poisoning, including three patients treated with both dicobaltEDTA and hydroxycobalamin/sodium thiosulfate. One patient who suffered cardiac arrest prior to the arrival of the paramedics died. A second who suffered cardiac arrest during transport to the hospital was resuscitated but had prolonged coma and died 6 months after the poisoning. A third patient had coma, apnea, shock, pulmonary edema, and a whole blood cyanide level of 6 pg/mL three hours after exposure, but recovered without sequelae. French authors often recommend hydroxycobalamin/sodium thiosulfate in
cases where the diagnosis of cyanide poisoning is in doubt because of this antidote’s lack of toxicity when compared with dicobalt-EDTA, which can produce significant cardiovascular adverse reactions in the absence of cyanide.‘J.“,4Z As the various antidotes all have different mechanisms of action, their effects may be additive or synergistic.‘4,‘7
Current Status of Hydroxycobalamin in America The hydroxycobalamin/sodium thiosulfate cyanide antidote combination was designated an “orphan drug” by the Food and Drug Administration in October 1985. Studies of safety and efficacy are necessary before the antidotal combination can be considered for approval for general use in the United States. These studies are now being organized by the Rocky Mountain Poison and Drug Center.
Conclusion The Lilly Cyanide Antidote KitB currently available in America for cyanide poisoning is efficacious but has inherent toxicity, making its use in cases of diagnostic uncertainty or smoke inhalation with elevated carboxyhemoglobin levels undesirable. The hydroxycobalamin/sodium thiosulfate antidotal combination currently used in France is at least equally efficacious and practically devoid of toxicity. It is a logical agent for development in the United States. Acknowledgmentsof a McNeil
Dr Hall
Fellowship
was the recipient
in Clinical
Toxicology
at the time of this review.
REFERENCES I, Graham
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I.
HydroxycobalamlnlSodlum
Thlosulfate
-II. Luricr I., Dusoleil P, de Montgros J: Action dc I’liydro~ocohalan~i~~~ a dose ma55i\e dans I’intoxicarion
aigue au cyanure.
A propo\
121
43
d’un cas.
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Bourrelier J, Paulet G: Intoxication
cyanhydrique
conwutive a des brulures graves par cyanure de sodium fondu. Sur trois cas traites par EDTA cobaltique. 44
PresseMed
1971; 22:1013-1014.
Jouglard J, Nava G, Botta A. ct al: A prop05 d’une intoxication aigue par le cyanure de pota\sium traitce par I’hydroxocobalamine. Marseille Wed 1974; 12:617-624.