Morocco AP.
Cyanides.
Crit Care Clin. 2005 Oct;21(4):691-705, vi. doi: 10.1016/j.ccc.2005.06.002.
Abstract/Text
Cyanide is a likely weapon for terrorists due to its notoriety, lethality, and availability. Poisoning results in central nervous system and cardiovascular dysfunction due to inhibition of oxidative phosphorylation. Laboratory findings of anion gap metabolic acidosis and hyperlactemia aid in confirming the diagnosis. Treatment for significant poisonings includes aggressive supportive care and administration of antidotes such as sodium nitrite, sodium thiosulfate, and hydroxocobalamin. Survivors of significant poisonings can have long-term neurologic dysfunction.
Christopher P. Holstege, Gary E.Isom ,Kirk MA. Cyanide and hydrogen sulfide. In: Goldfrank LR, Flomenbaum NE,Lewin NA, Howland MA, Hoffman RS, Nelson LS, editors. Goldfrank’s toxicologic emer-gencies. 8th edition. New York: McGraw-Hill, 2006: 1712–1733.
Marx: Rosen’s Emergency Medicine, 7th ed. CYANIDE AND HYDROGEN SULFIDE.
Medical Management Guidelines for Hydrogen Cyanide: Agency for Toxic Substances and Disease.
厚生労働省: 酸素欠乏症・硫化水素中毒による労働災害発生状況（平成23年）について.
Truong DH, Eghbal MA, Hindmarsh W, Roth SH, O'Brien PJ.
Molecular mechanisms of hydrogen sulfide toxicity.
Drug Metab Rev. 2006;38(4):733-44. doi: 10.1080/03602530600959607.
Abstract/Text
RATIONALE: The toxicity of H2S has been attributed to its ability to inhibit cytochrome c oxidase in a similar manner to HCN. However, the successful use of methemoglobin for the treatment of HCN poisoning was not successful for H2S poisonings even though the ferric heme group of methemoglobin scavenges H2S. Thus, we speculated that other mechanisms contribute to H2S induced cytotoxicity. Experimental procedure. Hepatocyte isolation and viability and enzyme activities were measured as described by Moldeus et al. (1978), and Steen et al. (2001).
RESULTS: Incubation of isolated hepatocytes with NaHS solutions (a H2S source) resulted in glutathione (GSH) depletion. Moreover, GSH depletion was also observed in TRIS-HCl buffer (pH 6.0) treated with NaHS. Several ferric chelators (desferoxamime and DETAPAC) and antioxidant enzymes (superoxide dismutase [SOD] and catalase) prevented cell-free and hepatocyte GSH depletion. GSH-depleted hepatocytes were very susceptible to NaHS cytotoxicity, indicating that GSH detoxified NaHS or H2S in cells. Cytotoxicity was also partly prevented by desferoxamine and DETAPC, but it was increased by ferric EDTA or EDTA. Cell-free oxygen consumption experiments in TRIS-HCl buffer showed that NaHS autoxidation formed hydrogen peroxide and was prevented by DETAPC but increased by EDTA. We hypothesize that H2S can reduce intracellular bound ferric iron to form unbound ferrous iron, which activates iron. Additionally, H2S can increase the hepatocyte formation of reactive oxygen species (ROS) (known to occur with electron transport chain). H2S cytotoxicity therefore also involves a reactive sulfur species, which depletes GSH and activates oxygen to form ROS.
Eghbal MA, Pennefather PS, O'Brien PJ.
H2S cytotoxicity mechanism involves reactive oxygen species formation and mitochondrial depolarisation.
Toxicology. 2004 Oct 15;203(1-3):69-76. doi: 10.1016/j.tox.2004.05.020.
Abstract/Text
A number of scavengers of reactive oxygen species (ROS) were found to be protective against cell death induced by hydrogen sulfide (H2S) in isolated hepatocytes. The H2O2 scavengers alpha-ketoglutarate and pyruvate, which also act as energy substrate metabolites, were more protective against H2S toxicity than lactate which is only an energy substrate metabolite. All of these results suggest that H2S toxicity is dependent on ROS production. We measured ROS formation directly in hepatocytes using the fluorogenic dichlorofluorescin method. H2S-induced ROS formation was dose dependent and pyruvate inhibited this ROS production. Non-toxic concentrations of H2S enhanced the cytotoxicity of H2O2 generated by glucose/glucose oxidase, which was inhibited by CYP450 inibitors. Furthermore, hepatocyte ROS formation induced by H2S was decreased by CYP450 inhibitors cimetidine and benzylimidazole. These results suggest that CYP450-dependant metabolism of H2S is responsible for inducing ROS production. H2S-induced cytotoxicity was preceded by mitochondrial depolarization as measured by rhodamine 123 fluorescence. Mitochondrial depolarization induced by H2S was prevented by zinc, methionine and pyruvate all of which decreased H2S-induced cell death. Treatment of H2S poisoning may benefit from interventions aimed at minimizing ROS-induced damage and reducing mitochondrial damage.
O'Brien B, Quigg C, Leong T.
Severe cyanide toxicity from 'vitamin supplements'.
Eur J Emerg Med. 2005 Oct;12(5):257-8. doi: 10.1097/00063110-200510000-00014.
Abstract/Text
The use of alternative medicines is increasing and poorly regulated. We describe a case of severe cyanide poisoning arising from amygdalin, a putative vitamin supplement. A 32-year-old woman arrived in the emergency department by ambulance unresponsive, shocked and with fixed dilated pupils. She was hypothermic and tachycardic but was breathing spontaneously. Despite her age, she had documented breast cancer with hepatic metastases. Conventional treatment having failed, she only took 'vitamin supplements' bought on the Internet, her father said. Over the next 6 h she required mechanical ventilation and increasing doses of inotropes. Diabetes insipidus developed. As the appropriateness of further treatment was considered, a relative arrived with her medications including 'vitamin B 17' or amygdalin. An Internet search identified this as a debunked cancer remedy and cyanogen. Serum thiocyanate level was markedly elevated. She recovered fully over 8 h. While various antidotes to cyanide exist, in this case supportive therapy alone proved effective.
Bromley J, Hughes BG, Leong DC, Buckley NA.
Life-threatening interaction between complementary medicines: cyanide toxicity following ingestion of amygdalin and vitamin C.
Ann Pharmacother. 2005 Sep;39(9):1566-9. doi: 10.1345/aph.1E634. Epub 2005 Jul 12.
Abstract/Text
OBJECTIVE: To describe a case of severe accidental cyanide poisoning following a single ingestion of amygdalin with therapeutic intent.
CASE SUMMARY: A 68-year-old patient with cancer presented to the emergency department shortly after her first dose (3 g) of amygdalin with a reduced Glasgow Coma Score, seizures, and severe lactic acidosis requiring intubation and ventilation. The patient also ingested 4800 mg of vitamin C per day. She responded rapidly to hydroxocobalamin treatment. The adverse drug reaction was rated probable on the Naranjo probability scale.
DISCUSSION: Amygdalin and laetrile (a synthetic form of amygdalin) are commonly used as complementary or alternative medicine (CAM) for the treatment of cancer. Vitamin C is known to increase the in vitro conversion of amygdalin to cyanide and reduce body stores of cysteine, which is used to detoxify cyanide. Amygdalin has been used for decades by patients with cancer who are seeking alternative therapies, and severe reactions have not been reported with this dose. An interaction with vitamin C is a plausible explanation for this life-threatening response.
CONCLUSIONS: This case highlights the fact that CAMs can produce life-threatening toxicity. This case also adds a further note of caution, namely, the potential for serious interactions between CAMs, particularly where there is no tradition of concomitant use.
Van de Louw A, Haouzi P.
Ferric Iron and Cobalt (III) compounds to safely decrease hydrogen sulfide in the body?
Antioxid Redox Signal. 2013 Aug 10;19(5):510-6. doi: 10.1089/ars.2012.4513. Epub 2012 Mar 6.
Abstract/Text
To sort out the putative roles of endogenous hydrogen sulfide (H2S) in clinical conditions wherein systemic inflammation or hypoxia is present, it becomes crucial to develop approaches capable of affecting H2S concentration that can be safely applied in humans. We have investigated a paradigm, which could achieve such a goal, using vitamin B12 (vit.B12), at the dose recommended in cyanide poisoning, and very low levels of methemoglobin (MetHb). Hydroxocobalamin in the plasma, supernatant of kidney, and heart tissue homogenates of rats that had received vit.B12 (140 mg.kg(-1) intravenous) was found in the μM range. Exogenous H2S (100 μM) added to the plasma or supernatants of these rats decreased at a significantly higher rate than in control rats. In the latter however a spontaneous oxidation of exogenous H2S occurred. In vitro, hydroxocobalamin solution (100 μM) decreased, within <2 min, an equimolar concentration of H2S by 80%. Three to five percent MetHb prevented H2S induced hyperventilation in vivo and decreased exogenous H2S in vitro by 25-40 μM within 30 s. Our observations lead to the hypothesis that innocuous levels of MetHb and vit.B12 could be a used as an effective and safe way to test the role of endogenous H2S in vivo.
Moertel CG, Fleming TR, Rubin J, Kvols LK, Sarna G, Koch R, Currie VE, Young CW, Jones SE, Davignon JP.
A clinical trial of amygdalin (Laetrile) in the treatment of human cancer.
N Engl J Med. 1982 Jan 28;306(4):201-6. doi: 10.1056/NEJM198201283060403.
Abstract/Text
One hundred seventy-eight patients with cancer were treated with amygdalin (Laetrile) plus a "metabolic therapy" program consisting of diet, enzymes, and vitamins. The great majority of these patients were in good general condition before treatment. None was totally disabled or in preterminal condition. One third had not received any previous chemotherapy. The pharmaceutical preparations of amygdalin, the dosage, and the schedule were representative of past and present Laetrile practice. No substantive benefit was observed in terms of cure, improvement or stabilization of cancer, improvement of symptoms related to cancer, or extension of life span. The hazards of amygdalin therapy were evidenced in several patients by symptoms of cyanide toxicity or by blood cyanide levels approaching the lethal range. Patients exposed to this agent should be instructed about the danger of cyanide poisoning, and their blood cyanide levels should be carefully monitored. Amygdalin (Laetrile) is a toxic drug that is not effective as a cancer treatment.
Johnson RP, Mellors JW.
Arteriolization of venous blood gases: a clue to the diagnosis of cyanide poisoning.
J Emerg Med. 1988 Sep-Oct;6(5):401-4. doi: 10.1016/0736-4679(88)90014-5.
Abstract/Text
Prompt diagnosis and treatment of cyanide poisoning is essential for a successful therapeutic outcome. We present a patient with acute cyanide poisoning in whom venous blood gases disclosed an abnormally high pO2. Prompt treatment of the patient with the cyanide antidote, sodium nitrite plus sodium thiosulfate, rapidly reversed the cardiovascular and central nervous system manifestations of cyanide toxicity. The pathogenesis of cyanide-induced blood gas abnormalities and their potential value in the recognition of cyanide intoxication are discussed. Current treatment recommendations for cyanide poisoning are also reviewed.
Martín-Bermúdez R, Maestre-Romero A, Goñi-Belzunegui MV, Bautista-Lorite A, Arenas-Cabrera C.
Venous blood arteriolization and multiple organ failure after cyanide poisoning.
Intensive Care Med. 1997 Dec;23(12):1286. doi: 10.1007/s001340050502.
Abstract/Text
Baud FJ, Barriot P, Toffis V, Riou B, Vicaut E, Lecarpentier Y, Bourdon R, Astier A, Bismuth C.
Elevated blood cyanide concentrations in victims of smoke inhalation.
N Engl J Med. 1991 Dec 19;325(25):1761-6. doi: 10.1056/NEJM199112193252502.
Abstract/Text
BACKGROUND: The nature of the toxic gases that cause death from smoke inhalation is not known. In addition to carbon monoxide, hydrogen cyanide may be responsible, but its role is uncertain, because blood cyanide concentrations are often measured only long after exposure.
METHODS: We measured cyanide concentrations in blood samples obtained at the scene of residential fires from 109 fire victims before they received any treatment. We compared the results with those in 114 persons with drug intoxication (40 subjects), carbon monoxide intoxication (29 subjects), or trauma (45 subjects). The metabolic effect of smoke inhalation was assessed by measuring plasma lactate at the time of admission to the hospital in 39 patients who did not have severe burns.
RESULTS: The mean (+/-SD) blood cyanide concentrations in the 66 surviving fire victims (21.6 +/- 36.4 mumol per liter, P less than 0.001) and the 43 victims who died (116.4 +/- 89.6 mumol per liter, P less than 0.001) were significantly higher than those in the 114 control subjects (5.0 +/- 5.5 mumol per liter). Among the 43 victims who died, the blood cyanide concentrations were above 40 mumol per liter in 32 (74 percent), and above 100 mumol per liter in 20 of these (46 percent). There was a significant correlation between blood cyanide and carbon monoxide concentrations in the fire victims (P less than 0.001). Plasma lactate concentrations at the time of hospital admission correlated more closely with blood cyanide concentrations than with blood carbon monoxide concentrations. Plasma lactate concentrations above 10 mmol per liter were a sensitive indicator of cyanide intoxication, as defined by the presence of a blood cyanide concentration above 40 mumol per liter.
CONCLUSIONS: Residential fires may cause cyanide poisoning. At the time of a patient's hospital admission, an elevated plasma lactate concentration is a useful indicator of cyanide toxicity in fire victims who do not have severe burns.
Baud FJ, Borron SW, Mégarbane B, Trout H, Lapostolle F, Vicaut E, Debray M, Bismuth C.
Value of lactic acidosis in the assessment of the severity of acute cyanide poisoning.
Crit Care Med. 2002 Sep;30(9):2044-50. doi: 10.1097/00003246-200209000-00015.
Abstract/Text
OBJECTIVE: To test the hypothesis that plasma lactate concentrations could be of confirmatory value in patients with histories consistent with acute pure cyanide poisoning because immediate laboratory confirmation of suspected cyanide poisoning is rarely possible and because clinicians must rapidly decide whether to administer specific antidotes, which may have severe side effects.
DESIGN: Retrospective clinical study.
SETTING: An intensive care unit in a university-affiliated teaching hospital.
PATIENTS: All acute cyanide-poisoned patients admitted to our intensive care unit, excluding fire victims, from 1988 to 1999.
INTERVENTIONS: None.
MEASUREMENTS AND MAIN RESULTS: Eleven patients were studied. Before antidotal treatment, the median plasma lactate concentration was 168 mg/dL, the median blood cyanide concentration was 4.2 mg/L. Using Spearman's test, there was a significant correlation between plasma lactate and blood cyanide concentrations ( =.74, =.017). Before antidotal treatment, plasma lactate concentration correlated positively with anion gap and inversely with systolic blood pressure, spontaneous respiratory rate, and arterial pH. During the course of cyanide poisonings, a plasma lactate concentration of >or=72 mg/d/L (8 mmol/L) was sensitive (94%) and moderately specific (70%) for a toxic blood cyanide concentration (>or=1.0 mg/L). The specificity was substantially improved in patients not receiving catecholamines (85%).
CONCLUSIONS: The immediate and serial measurement of plasma lactate concentrations is useful in assessing the severity of cyanide poisoning.
Benaissa ML, Mégarbane B, Borron SW, Baud FJ.
Is elevated plasma lactate a useful marker in the evaluation of pure carbon monoxide poisoning?
Intensive Care Med. 2003 Aug;29(8):1372-5. doi: 10.1007/s00134-003-1866-0. Epub 2003 Jul 10.
Abstract/Text
OBJECTIVE: To examine whether CO poisoning induces a significant increase in plasma lactate concentration.
DESIGN AND SETTING: Prospective observational clinical study in the emergency department and intensive care unit in a university-affiliated teaching hospital.
PATIENTS: 146 pure CO poisonings resulting from dysfunction of gas cookers or water heaters.
MEASUREMENTS AND RESULTS: Patients were classified into four neurological impairment groups: 37% were severely, 8% moderately, and 45% mildly intoxicated, while 1% were asymptomatic. We found only very mild increases in plasma lactate concentration (median 2.30 mmol/l) which, however, was significantly correlated with the severity of neurological impairment and blood CO concentration (1.41 mmol/l, Spearman's test r=0.3).
CONCLUSIONS: Plasma lactate is mildly elevated in pure CO-exposed patients. This mild increase and the extensive overlap between the groups of neurological impairment severity do not suggest the usefulness of systematic plasma lactate measurement in pure CO poisoning.
Lambert RJ, Kindler BL, Schaeffer DJ.
The efficacy of superactivated charcoal in treating rats exposed to a lethal oral dose of potassium cyanide.
Ann Emerg Med. 1988 Jun;17(6):595-8. doi: 10.1016/s0196-0644(88)80399-8.
Abstract/Text
Due to the apparent low binding capacity of activated charcoal for potassium cyanide (KCN) in vitro, the use of oral activated charcoal therapy for oral exposure to cyanide compounds is controversial. In our study, rats were given a lethal oral dose of ground granular KCN (35 or 40 mg/kg) in a gelatin capsule followed immediately by either 4 g/kg of superactivated charcoal in a 20% suspension or a similar volume of deionized water. Signs of cyanide toxicosis occurred rapidly, with a mean time to signs of 3.3 and 2.7 minutes in control animals receiving 35 or 40 mg/kg KCN, respectively. All 26 of the control rats showed signs, and all but one in the 35 mg/kg group died within 19 minutes. Only 12 of 26 rats treated with superactivated charcoal showed signs of KCN toxicosis and eight of those animals died. Oral exposure of rats to lethal doses of KCN can be treated effectively by immediate administration of superactivated charcoal.
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 Jun;49(6):794-801, 801.e1-2. doi: 10.1016/j.annemergmed.2007.01.026. Epub 2007 May 4.
Abstract/Text
STUDY OBJECTIVE: To assess outcomes in patients treated with hydroxocobalamin at the fire scene or in the ICU for suspected smoke inhalation-associated cyanide poisoning.
METHODS: Adult smoke inhalation victims with suspected cyanide poisoning as determined by soot in the face, mouth, or nose or expectorations and neurologic impairment received an intravenous infusion of hydroxocobalamin 5 g (maximum 15 g) at the fire scene or in the ICU in this observational case series conducted from 1987 to 1994. Blood cyanide specimens were collected before administration of hydroxocobalamin. The threshold for cyanide toxicity was predefined as greater than or equal to 39 micromol/L.
RESULTS: The sample included 69 patients (mean age 49.6 years; 33 men), of whom 39 were comatose. Out-of-hospital deaths were excluded. Fifty of the 69 patients (72%) admitted to the ICU survived after administration of hydroxocobalamin. In the group in which cyanide poisoning was confirmed a posteriori (n=42), 67% (28/42) survived after administration of hydroxocobalamin. The most common adverse events were chromaturia (n=6), pink or red skin discoloration (n=4), hypertension (n=3), erythema (n=2), and increased blood pressure (n=2). No serious adverse events were attributed to hydroxocobalamin. Laboratory tests revealed transient alterations in renal and hepatic function consistent with the critical condition of the patients and mild anemia consistent with progressive hemodilution.
CONCLUSION: Empiric administration of hydroxocobalamin was associated with survival among 67% of patients confirmed a posteriori to have had cyanide poisoning. Hydroxocobalamin was well tolerated irrespective of the presence of cyanide poisoning. Hydroxocobalamin appears to be safe for the out-of-hospital treatment of presumptive cyanide poisoning from smoke inhalation.
Borron SW, Baud FJ, Mégarbane B, Bismuth C.
Hydroxocobalamin for severe acute cyanide poisoning by ingestion or inhalation.
Am J Emerg Med. 2007 Jun;25(5):551-8. doi: 10.1016/j.ajem.2006.10.010.
Abstract/Text
This chart review was undertaken to assess efficacy and safety of hydroxocobalamin for acute cyanide poisoning. Hospital records of the Fernand Widal and Lariboisière Hospitals were reviewed for intensive care unit admissions with cyanide poisoning for which hydroxocobalamin was used as first-line treatment from 1988 to 2003. Smoke inhalation cases were excluded. Hydroxocobalamin (5-20 g) was administered to 14 consecutive patients beginning a median 2.1 hours after cyanide ingestion or inhalation. Ten patients (71%) survived and were discharged. Of the 11 patients with blood cyanide exceeding the typically lethal threshold of 100 micromol/L, 7 survived. The most common hydroxocobalamin-attributed adverse events were chromaturia and pink skin discoloration. Severe cyanide poisoning of the nature observed in most patients in this study is frequently fatal. That 71% of patients survived after treatment with hydroxocobalamin suggests that hydroxocobalamin as first-line antidotal therapy is effective and safe in acute cyanide poisoning.
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 Jun;59(6):532-9. doi: 10.1016/j.annemergmed.2012.01.022. Epub 2012 Mar 3.
Abstract/Text
STUDY OBJECTIVE: We compare the efficacy of hydroxocobalamin to sodium thiosulfate to reverse the depressive effects on mean arterial pressure in a swine model of acute cyanide toxicity and gain a better understanding of the mechanism of action of the hydroxocobalamin in reversal of the toxicity.
METHODS: Swine were intubated, anesthetized, and instrumented with central arterial and venous lines and a pulmonary artery catheter. Animals (n=36) were randomly assigned to one of 3 groups: hydroxocobalamin alone (150 mg/kg), sodium thiosulfate alone (413 mg/kg), or hydroxocobalamin (150 mg/kg)+sodium thiosulfate (413 mg/kg) and monitored for 60 minutes after the start of antidotal infusion. Cyanide was infused until severe hypotension developed, defined as blood pressure 50% of baseline mean arterial pressure. Repeated-measures ANOVA was used to determine statistically significant changes between groups over time.
RESULTS: Time to hypotension (25, 28, and 33 minutes), cyanide dose at hypotension (4.7, 5.0, and 5.6 mg/kg), and mean cyanide blood levels (3.2, 3.7, and 3.8 μg/mL) and lactate levels (7, 8.2, 8.3 and mmol/L) were similar. All 12 animals in the sodium thiosulfate group died compared with 2 of 12 in the hydroxocobalamin/sodium thiosulfate group and 1 of 12 in hydroxocobalamin group. No statistically significant differences were detected between the hydroxocobalamin and hydroxocobalamin/sodium thiosulfate groups for carbon monoxide, mean arterial pressure, cyanide levels, or mortality at 60 minutes. Lactate level (2.6 versus 2.1 mmol/L), pH (7.44 versus 7.42), and bicarbonate level (25 versus 26 mEq/L) at 60 minutes were also similar between groups.
CONCLUSION: Sodium thiosulfate failed to reverse cyanide-induced shock in our swine model of severe cyanide toxicity. Further, sodium thiosulfate was not found to be effective when added to hydroxocobalamin in the treatment of cyanide-induced shock. Hydroxocobalamin alone was again found to be effective for severe cyanide toxicity.
Copyright © 2012. Published by Mosby, Inc.
Bebarta VS, Tanen DA, Lairet J, Dixon PS, Valtier S, 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. 2010 Apr;55(4):345-51. doi: 10.1016/j.annemergmed.2009.09.020. Epub 2009 Nov 27.
Abstract/Text
STUDY OBJECTIVE: Cyanide can cause severe hypotension with acute toxicity. To our knowledge, no study has directly compared hydroxocobalamin and sodium nitrite with sodium thiosulfate in an acute cyanide toxicity model. Our objective is to compare the return to baseline of mean arterial blood pressure between 2 groups of swine with acute cyanide toxicity and treated with hydroxocobalamin with sodium thiosulfate or sodium nitrite with sodium thiosulfate.
METHODS: Twenty-four swine were intubated, anesthetized, and instrumented (continuous arterial and cardiac output monitoring) and then intoxicated with a continuous cyanide infusion until severe hypotension. The animals were divided into 2 arms of 12 each and then randomly assigned to intravenous hydroxocobalamin (150 mg/kg)+sodium thiosulfate (413 mg/kg) or sodium nitrite (10 mg/kg)+sodium thiosulfate (413 mg/kg) and monitored for 40 minutes after start of antidotal infusion. Twenty animals were needed for 80% power to detect a significant difference in outcomes (alpha 0.05). Repeated measures of analysis of covariance and post hoc t test were used for determining significance.
RESULTS: Baseline mean weights, time to hypotension (31 minutes 3 seconds versus 28 minutes 6 seconds), and cyanide dose at hypotension (5.6 versus 5.9 mg/kg) were similar. One animal in the hydroxocobalamin group and 2 animals in the sodium nitrite group died during antidote infusion and were excluded from analysis. Hydroxocobalamin resulted in a faster return to baseline mean arterial pressure, with improvement beginning at 5 minutes and lasting through the conclusion of the study (P<.05). No statistically significant difference was detected between groups for cardiac output, pulse rate, systemic vascular resistance, or mortality at 40 minutes post intoxication. Mean cyanide blood levels (4.03 versus 4.05 microg/mL) and lactate levels (peak 7.9 versus 8.1 mmol/L) at hypotension were similar. Lactate levels (5.1 versus 4.48 mmol/L), pH (7.40 versus 7.37), and base excess (-0.75 versus 1.27) at 40 minutes were also similar.
CONCLUSION: Hydroxocobalamin with sodium thiosulfate led to a faster return to baseline mean arterial pressure compared with sodium nitrite with sodium thiosulfate; however, there was no difference between the antidote combinations in mortality, serum acidosis, or serum lactate.
Copyright (c) 2009 American College of Emergency Physicians. Published by Mosby, Inc. All rights reserved.
Lee J, Mukai D, Kreuter K, Mahon S, Tromberg B, Brenner M.
Potential interference by hydroxocobalamin on cooximetry hemoglobin measurements during cyanide and smoke inhalation treatments.
Ann Emerg Med. 2007 Jun;49(6):802-5. doi: 10.1016/j.annemergmed.2006.11.016. Epub 2007 Jan 8.
Abstract/Text
STUDY OBJECTIVE: Concentrated aqueous solutions of hydroxocobalamin (OHCob) are administered intravenously for cyanide poisoning victims, many of whom also have concurrent smoke inhalation. Because of its intense light absorbance in visible wavelengths (absorption peak at 532 nm), we investigate potential interference effects of OHCob on total hemoglobin concentration (tHb), carboxyhemoglobin (COHb), methemoglobin (MetHb), and oxyhemoglobin (Hb-O2) cooximetry measurement values in blood.
METHODS: In vivo cooximetry measurements were conducted with 3 specific pathogen-free white New Zealand rabbits (3.80+/-0.21 kg) during the intravenous infusion of OHCob (625 mg during a 100-minute period). Resultant changes in tHb, Hb-O2, COHb, and MetHb values were measured and correlated with respect to estimated in vivo OHCob concentrations. In vitro measurements were conducted with rabbit blood to confirm in vivo measurements.
RESULTS: The introduction of OHCob clearly interfered with the cooximetry measurements of each of the hemoglobin component fractions in whole blood and resulted in altered measurement values from the baseline values. The presence of OHCob in blood interferes with cooximetry measurements of COHb, MetHb, and Hb-O2. The increase in measured COHb fraction with increasing concentrations of OHCob was most notable.
CONCLUSION: The presence of OHCob in blood interferes with cooximetry measurements of COHb, MetHb, and Hb-O2. These effects need to be considered during OHCob treatment of cyanide poisoning, particularly in smoke inhalation victims with potential for concurrent carbon monoxide exposure, because it may lead to potentially erroneous reported COHb levels.
Kirk MA, Gerace R, Kulig KW.
Cyanide and methemoglobin kinetics in smoke inhalation victims treated with the cyanide antidote kit.
Ann Emerg Med. 1993 Sep;22(9):1413-8. doi: 10.1016/s0196-0644(05)81988-2.
Abstract/Text
STUDY OBJECTIVE: To evaluate serial cyanide, methemoglobin, and carbon monoxide levels in smoke inhalation patients.
SETTING: Regional poison center and regional toxicology treatment center.
PARTICIPANTS: Seven critically ill smoke inhalation patients referred to the regional poison center.
INTERVENTIONS: Peak level and half-life were determined by obtaining serial carboxyhemoglobin, cyanide, and methemoglobin levels.
RESULTS: The mean observed half-life of cyanide was 3.0 +/- 0.6 hours. Methemoglobinemia was evaluated in four patients after sodium nitrite administration. The peak measured methemoglobin levels (mean, 10.5% +/- 2%; range, 7.9% to 13.4%) did not occur until a mean of 50 minutes (range, 35 to 70 minutes) following administration of sodium nitrite. The total oxygen-carrying capacity reduced by the combination of carboxyhemoglobin and methemoglobin was never more than 21% (range, 10% to 21%) in this series.
CONCLUSION: The administration of sodium nitrite to smoke inhalation patients in the presence of concomitant carbon monoxide poisoning may be relatively safe.
Johnson WS, Hall AH, Rumack BH.
Cyanide poisoning successfully treated without 'therapeutic methemoglobin levels'.
Am J Emerg Med. 1989 Jul;7(4):437-40. doi: 10.1016/0735-6757(89)90057-0.
Abstract/Text
A 24-year-old woman ingested an unknown amount of potassium cyanide in a suicide attempt. Coma and metabolic acidosis developed. Administration of the Lilly Cyanide Antidote kit (Eli Lilly and Co, Indianapolis) resulted in prompt resolution of symptoms and full recovery. Whole blood cyanide level was 13 micrograms/mL approximately one hour after ingestion. The highest measured methemoglobin level after sodium nitrite administration was 9.2%, demonstrating that attaining a "therapeutic methemoglobin level" of 25% is unnecessary to insure a satisfactory clinical outcome. Because severe hypotension or excessive methemoglobinemia can be caused by the sodium nitrite component of the Lilly kit, only enough to produce an acceptable clinical response should be administered.
Berlin CM Jr.
The treatment of cyanide poisoning in children.
Pediatrics. 1970 Nov;46(5):793-6.
Abstract/Text
Brenner M, Mahon SB, Lee J, Kim J, Mukai D, Goodman S, Kreuter KA, Ahdout R, Mohammad O, Sharma VS, Blackledge W, Boss GR.
Comparison of cobinamide to hydroxocobalamin in reversing cyanide physiologic effects in rabbits using diffuse optical spectroscopy monitoring.
J Biomed Opt. 2010 Jan-Feb;15(1):017001. doi: 10.1117/1.3290816.
Abstract/Text
Our purpose is to compare cobinamide to hydroxocobalamin in reversing cyanide (CN)-induced physiologic effects in an animal model using diffuse optical spectroscopy (DOS). Cyanide poisoning is a major threat worldwide. Cobinamide is a novel molecule that can bind two molecules of cyanide, has a much higher binding affinity than hydroxocobalamin, and is more water soluble. We investigated the ability of equimolar doses of cobinamide and hydroxocobalamin to reverse the effects of cyanide exposure in an animal model monitored continuously by DOS. Cyanide toxicity was induced in 16 New Zealand white rabbits by intravenous infusion. Animals were divided into three groups: controls (n=5) received saline following cyanide, hydroxocobalamin (N=6) following cyanide, and cobinamide (N=5) following cyanide. Cobinamide caused significantly faster and more complete recovery of oxy- and deoxyhemoglobin concentrations in cyanide-exposed animals than hydroxocobalamin- or saline-treated animals, with a recovery time constant of 13.8+/-7.1 min compared to 75.4+/-25.1 and 76.4+/-42.7 min, for hydroxocobalamin- and saline-treated animals, respectively (p<0.0001). This study indicates that cobinamide more rapidly and completely reverses the physiologic effects of cyanide than equimolar doses of cobalamin at the dose used in this study, and CN effects and response can be followed noninvasively using DOS.
Brenner M, Kim JG, Mahon SB, Lee J, Kreuter KA, Blackledge W, Mukai D, Patterson S, Mohammad O, Sharma VS, Boss GR.
Intramuscular cobinamide sulfite in a rabbit model of sublethal cyanide toxicity.
Ann Emerg Med. 2010 Apr;55(4):352-63. doi: 10.1016/j.annemergmed.2009.12.002. Epub 2010 Jan 4.
Abstract/Text
STUDY OBJECTIVE: Exposure to cyanide in fires and industrial exposures and intentional cyanide poisoning by terrorists leading to mass casualties is an ongoing threat. Current treatments for cyanide poisoning must be administered intravenously, and no rapid treatment methods are available for mass casualty cyanide exposures. Cobinamide is a cobalamin (vitamin B(12)) analog with an extraordinarily high affinity for cyanide that is more water-soluble than cobalamin. We investigate the use of intramuscular cobinamide sulfite to reverse cyanide toxicity-induced physiologic changes in a sublethal cyanide exposure animal model and determine the ability of an intramuscular cobinamide sulfite injection to rapidly reverse the physiologic effects of cyanide toxicity.
METHODS: New Zealand white rabbits were given 10 mg sodium cyanide intravenously over 60 minutes. Quantitative diffuse optical spectroscopy and continuous-wave near-infrared spectroscopy monitoring of tissue oxyhemoglobin and deoxyhemoglobin concentrations were performed concurrently with blood cyanide level measurements and cobinamide levels. Immediately after completion of the cyanide infusion, the rabbits were injected intramuscularly with cobinamide sulfite (n=6) or inactive vehicle (controls, n=5).
RESULTS: Intramuscular administration led to rapid mobilization of cobinamide and was extremely effective at reversing the physiologic effects of cyanide on oxyhemoglobin and within deoxyhemoglobin extraction. Recovery time to 63% of their baseline values in the central nervous system occurred within a mean of 1,032 minutes in the control group and 9 minutes in the cobinamide group, with a difference of 1,023 minutes (95% confidence interval 116 to 1,874 minutes). In muscle tissue, recovery times were 76 and 24 minutes, with a difference of 52 minutes (95% confidence interval 7 to 98 minutes). RBC cyanide levels returned toward normal significantly faster in cobinamide sulfite-treated animals than in control animals.
CONCLUSION: Intramuscular cobinamide sulfite rapidly and effectively reverses the physiologic effects of cyanide poisoning, suggesting that a compact cyanide antidote kit can be developed for mass casualty cyanide exposures.
Copyright (c) 2009 American College of Emergency Physicians. Published by Mosby, Inc. All rights reserved.
Chan A, Balasubramanian M, Blackledge W, Mohammad OM, Alvarez L, Boss GR, Bigby TD.
Cobinamide is superior to other treatments in a mouse model of cyanide poisoning.
Clin Toxicol (Phila). 2010 Aug;48(7):709-17. doi: 10.3109/15563650.2010.505197.
Abstract/Text
CONTEXT: Cyanide is a rapidly acting cellular poison, primarily targeting cytochrome c oxidase, and is a common occupational and residential toxin, mostly via smoke inhalation. Cyanide is also a potential weapon of mass destruction, with recent credible threats of attacks focusing the need for better treatments, as current cyanide antidotes are limited and impractical for rapid deployment in mass casualty settings.
OBJECTIVE: We have used mouse models of cyanide poisoning to compare the efficacy of cobinamide (Cbi), the precursor to cobalamin (vitamin B(12)), to currently approved cyanide antidotes. Cbi has extremely high affinity for cyanide and substantial solubility in water.
MATERIALS AND METHODS: We studied Cbi in both an inhaled and intraperitoneal model of cyanide poisoning in mice.
RESULTS: We found Cbi more effective than hydroxocobalamin, sodium thiosulfate, sodium nitrite, and the combination of sodium thiosulfate-sodium nitrite in treating cyanide poisoning. Compared to hydroxocobalamin, Cbi was 3 and 11 times more potent in the intraperitoneal and inhalation models, respectively. Cobinamide sulfite (Cbi-SO(3)) was rapidly absorbed after intramuscular injection, and mice recovered from a lethal dose of cyanide even when given at a time when they had been apneic for over 2 min. In range-finding studies, Cbi-SO(3) at doses up to 2000 mg/kg exhibited no clinical toxicity.
DISCUSSION AND CONCLUSION: These studies demonstrate that Cbi is a highly effective cyanide antidote in mouse models, and suggest it could be used in a mass casualty setting, because it can be given rapidly as an intramuscular injection when administered as Cbi-SO(3). Based on these animal data Cbi-SO(3) appears to be an antidote worthy of further testing as a therapy for mass casualties.
Bebarta VS, Tanen DA, Boudreau S, Castaneda M, Zarzabal LA, Vargas T, Boss GR.
Intravenous cobinamide versus hydroxocobalamin for acute treatment of severe cyanide poisoning in a swine (Sus scrofa) model.
Ann Emerg Med. 2014 Dec;64(6):612-9. doi: 10.1016/j.annemergmed.2014.02.009. Epub 2014 Apr 18.
Abstract/Text
STUDY OBJECTIVE: Hydroxocobalamin is a Food and Drug Administration-approved antidote for cyanide poisoning. Cobinamide is a potential antidote that contains 2 cyanide-binding sites. To our knowledge, no study has directly compared hydroxocobalamin with cobinamide in a severe, cyanide-toxic large-animal model. Our objective is to compare the time to return of spontaneous breathing in swine with acute cyanide-induced apnea treated with intravenous hydroxocobalamin, intravenous cobinamide, or saline solution (control).
METHODS: Thirty-three swine (45 to 55 kg) were intubated, anesthetized, and instrumented (continuous mean arterial pressure and cardiac output monitoring). Anesthesia was adjusted to allow spontaneous breathing with FiO2 of 21% during the experiment. Cyanide was continuously infused intravenously until apnea occurred and lasted for 1 minute (time zero). Animals were then randomly assigned to receive intravenous hydroxocobalamin (65 mg/kg), cobinamide (12.5 mg/kg), or saline solution and monitored for 60 minutes. A sample size of 11 animals per group was selected according to obtaining a power of 80%, an α of .05, and an SD of 0.17 in mean time to detect a 20% difference in time to spontaneous breathing. We assessed differences in time to death among groups, using Kaplan-Meier estimation methods, and compared serum lactate, blood pH, cardiac output, mean arterial pressure, respiratory rate, and minute ventilation time curves with repeated-measures ANOVA.
RESULTS: Baseline weights and vital signs were similar among groups. The time to apnea and cyanide dose required to achieve apnea were similar. At time zero, mean cyanide blood and lactate concentrations and reduction in mean arterial pressure from baseline were similar. In the saline solution group, 2 of 11 animals survived compared with 10 of 11 in the hydroxocobalamin and cobinamide groups (P<.001 between the 2 treated groups and the saline solution group). Time to return of spontaneous breathing after antidote was similar between hydroxocobalamin and cobinamide (1 minute 48 seconds versus 1 minute 49 seconds, respectively). Blood cyanide concentrations became undetectable at the end of the study in both antidote-treated groups, and no statistically significant differences were detected between the 2 groups for mean arterial pressure, cardiac output, respiratory rate, lactate, or pH.
CONCLUSION: Both hydroxocobalamin and cobinamide rescued severely cyanide-poisoned swine from apnea in the absence of assisted ventilation. The dose of cobinamide was one fifth that of hydroxocobalamin.
Copyright © 2014 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.
Fujita Y, Fujino Y, Onodera M, Kikuchi S, Kikkawa T, Inoue Y, Niitsu H, Takahashi K, Endo S.
A fatal case of acute hydrogen sulfide poisoning caused by hydrogen sulfide: hydroxocobalamin therapy for acute hydrogen sulfide poisoning.
J Anal Toxicol. 2011 Mar;35(2):119-23. doi: 10.1093/anatox/35.2.119.
Abstract/Text
A patient committed suicide with hydrogen sulfide (H(2)S) by combining two commercial products. The patient was given hydroxocobalamin as an antidote in addition to treatment with cardiopulmonary resuscitation, but died approximately 42 min after his arrival at the hospital. The patient's cause of death was attributed to acute hydrogen sulfide poisoning. Serum concentrations of sulfide before and after administration of hydroxocobalamin were 0.22 and 0.11 μg/mL, respectively; serum concentrations of thiosulfate before and after hydroxocobalamin administration were 0.34 and 0.04 μmol/mL, respectively. Hydroxocobalamin is believed to form a complex with H(2)S in detoxification pathways of H(2)S. Although H(2)S is rapidly metabolized and excreted, the decreased sulfide concentration may be also associated with this complex formation. The decreased sulfide concentration suggests that hydroxocobalamin therapy may be effective for acute H(2)S poisoning. The decreased thiosulfate concentration seems to be associated with formation of a thiosulfate/hydroxocobalamin complex, because hydroxocobalamin can form a complex with thiosulfate. The thiosulfate concentration decreased to a greater extent than did sulfide, suggesting that hydroxocobalamin has a higher affinity for thiosulfate than for H(2)S. Therefore, prompt administration of hydroxocobalamin after H(2)S exposure may be effective for H(2)S poisoning.
Truong DH, Mihajlovic A, Gunness P, Hindmarsh W, O'Brien PJ.
Prevention of hydrogen sulfide (H2S)-induced mouse lethality and cytotoxicity by hydroxocobalamin (vitamin B(12a)).
Toxicology. 2007 Dec 5;242(1-3):16-22. doi: 10.1016/j.tox.2007.09.009. Epub 2007 Sep 15.
Abstract/Text
Recently, H(2)S (an environmental toxin) was proposed to induce cytotoxicity not only by inhibiting cytochrome oxidase but also by generating reactive oxygen species [Truong, D., Eghbal, M., Hindmarsh, W., Roth, Sh., O'Brien, P., 2006. Molecular mechanisms of hydrogen sulfide toxicity. Drug Metab. Rev. 38, 733-744]. In the following, evidence is presented supporting the use of hydroxocobalamin (vitamin B(12a)) as an antidote against H(2)S poisoning. More than 60% of the mice administered 35 mg/kg (0.63 mmol/kg) of NaSH (LD(90)) survived (at 24 h) when hydroxocobalamin (0.25 mmol/kg) was given after NaSH administration whereas less than 15% of the mice survived without hydroxocobalamin. Hydroxocobalamin (50-100 microM) or cobalt (50-100 microM) also prevented hepatocyte cytotoxicity induced by NaSH (500 microM). Furthermore, adding hydroxocobalamin 60 min later than NaSH still showed some protective activity. Catalytic amounts of hydroxocobalamin or cobalt added to a solution containing NaSH caused the disappearance of NaSH and induced oxygen uptake, indicative of NaSH oxidation and Co reduction, respectively.
Wu N, Du X, Wang D, Hao F.
Myocardial and lung injuries induced by hydrogen sulfide and the effectiveness of oxygen therapy in rats.
Clin Toxicol (Phila). 2011 Mar;49(3):161-6. doi: 10.3109/15563650.2011.565419.
Abstract/Text
OBJECTIVE: To study myocardial and lung injuries initiated by hydrogen sulfide, and evaluate the role and effectiveness of normobaric and hyperbaric oxygen (HBO) treatment in rats.
METHODS: One hundred healthy male Wistar rats were randomly divided into five groups: A: Normal control group (no H2S); B: H2S-exposed group; C: H2S+33% oxygen treatment group; D: H2S+50% oxygen treatment group; E: H2S+HBO group. The rats in groups C, D and E were exposed to H2S in an exposure chamber (1 m3) and were made to inhale 300 ppm hydrogen sulfide for 60 min, and then they were subjected to normobaric or HBO therapy. Normobaric oxygen was at concentrations of 33% or 50%, HBO was for 100 min including compression and decompression; the rats in group A inhaled air under the same conditions. Blood was sampled immediately after the experiment for analysis of arterial blood gases, myocardial enzymes and cardiac troponin I. Lung was rapidly removed to be made into tissue homogenates and then cytochrome c oxidase activity was measured; myocardial and lung ultrastructural changes were observed by electron microscopy.
RESULTS: Arterial blood gases: partial pressure of O2 (mmHg) (Group A, 97.6 ± 8.38; B, 76.5 ± 6.95*; C, 83.2 ± 2.66*; D, 86.20 ± 10.75*; E, 93.50 ± 4.97: *p < 0.01 compared to group A) was significantly lower than that in group in all but HBO rats. For myocardial enzymes and cardiac troponin I every parameter in groups B and C was significantly higher than that in group A (p<0.01),with no difference in D and E. Cytochrome c oxidase activity (u/mg) of lung tissue was reduced compared to group A after all treatments (A, 1.76 ± 0.02; B, 0.36 ± 0.04; C, 0.50 ± 0.12; D, 0.56 ± 0.07; E, 0.68 ± 0.05 (A vs. B p < 0.01; B vs. C,D,E p < 0.05 or p < 0.01), with a graded effect of oxygen dose in C, D and E. Pathological changes: (1) Myocardium - Mitochondrial swelling and autolysis with blurred or broken cristae was observed in the myocardium of H2S-exposed group; in group E, mitochondrial structure was basically normal, and clear cristae were found. (2) Lung tissue - In H2S-exposed group, alveolar epithelial cells disappeared, vacuolization of the organelle occurred, nuclear membrane was irregular and marginal condensation of heterochromatin was present; nucleus showed relatively normal morphology in group E, although some vacuoles still persisted within them.
CONCLUSIONS: HBO therapy can effectively improve arterial oxygen partial pressure, and significantly reduce myocardial damage, as well as potentially relieve lung injury in this model. Further work in humans appears warranted.
Smilkstein MJ, Bronstein AC, Pickett HM, Rumack BH.
Hyperbaric oxygen therapy for severe hydrogen sulfide poisoning.
J Emerg Med. 1985;3(1):27-30. doi: 10.1016/0736-4679(85)90216-1.
Abstract/Text
The optimum therapy for hydrogen sulfide poisoning is unclear. Adjuncts used in the treatment of cyanide poisoning have been advocated because of the shared mechanism of toxicity between hydrogen sulfide and cyanide. Following success in cyanide poisoning, hyperbaric oxygen therapy (HBO) has been suggested for use in treating hydrogen sulfide poisoning. A case of severe hydrogen sulfide poisoning was successfully treated with HBO after standard therapy was apparently ineffective. HBO as a therapeutic adjunct in hydrogen sulfide poisoning and the rationale for its use are discussed.
Haouzi P, Chenuel B, Sonobe T.
High-dose hydroxocobalamin administered after H2S exposure counteracts sulfide-poisoning-induced cardiac depression in sheep.
Clin Toxicol (Phila). 2015 Jan;53(1):28-36. doi: 10.3109/15563650.2014.990976.
Abstract/Text
CONTEXT: Severe H2S poisoning leads to death by rapid respiratory and cardiac arrest, the latter can occur within seconds or minutes in severe forms of intoxication.
OBJECTIVES: To determine the time course and the nature of H2S-induced cardiac arrest and the effects of high-dose hydroxocobalamin administered after the end of sulfide exposure.
MATERIALS AND METHODS: NaHS was infused in 16 sedated mechanically ventilated sheep to reach concentrations of H2S in the blood, which was previously found to lead to cardiac arrest within minutes following the cessation of H2S exposure. High-dose hydroxocobalamin (5 g) or saline solution was administered intravenously, 1 min after the cessation of NaHS infusion.
RESULTS: All animals were still alive at the cessation of H2S exposure. Three animals (18%) presented a cardiac arrest within 90 s and were unable to receive any antidote or vehicle. In the animals that survived long enough to receive either hydroxocobalamin or saline, 71% (5/7) died in the control group by cardiac arrest within 10 min. In all instances, cardiac arrest was the result of a pulseless electrical activity (PEA). In the group that received the antidote, intravenous injection of 5 g of hydroxocobalamin provoked an abrupt increase in blood pressure and blood flow; PEA was prevented in all instances. However, we could not find any evidence for a recovery in oxidative metabolism in the group receiving hydroxocobalamin, as blood lactate remained elevated and even continued to rise after 1 h, despite restored hemodynamics. This, along with an unaltered recovery of H2S kinetics, suggests that hydroxocobalamin did not act through a mechanism of H2S trapping.
CONCLUSION: In this sheep model, there was a high risk for cardiac arrest, by PEA, persisting up to 10 min after H2S exposure. Very high dose of hydroxocobalamin (5 g), injected very early after the cessation of H2S exposure, improved cardiac contractility and prevented PEA.
Sonobe T, Haouzi P.
H2S induced coma and cardiogenic shock in the rat: Effects of phenothiazinium chromophores.
Clin Toxicol (Phila). 2015 Jul;53(6):525-39. doi: 10.3109/15563650.2015.1043440. Epub 2015 May 12.
Abstract/Text
CONTEXT: Hydrogen sulfide (H2S) intoxication produces an acute depression in cardiac contractility-induced circulatory failure, which has been shown to be one of the major contributors to the lethality of H2S intoxication or to the neurological sequelae in surviving animals. Methylene blue (MB), a phenothiazinium dye, can antagonize the effects of the inhibition of mitochondrial electron transport chain, a major effect of H2S toxicity.
OBJECTIVES: We investigated whether MB could affect the immediate outcome of H2S-induced coma in un-anesthetized animals. Second, we sought to characterize the acute cardiovascular effects of MB and two of its demethylated metabolites-azure B and thionine-in anesthetized rats during lethal infusion of H2S.
MATERIALS AND METHODS: First, MB (4 mg/kg, intravenous [IV]) was administered in non-sedated rats during the phase of agonal breathing, following NaHS (20 mg/kg, IP)-induced coma. Second, in 4 groups of urethane-anesthetized rats, NaHS was infused at a rate lethal within 10 min (0.8 mg/min, IV). Whenever cardiac output (CO) reached 40% of its baseline volume, MB, azure B, thionine, or saline were injected, while sulfide infusion was maintained until cardiac arrest occurred.
RESULTS: Seventy-five percent of the comatose rats that received saline (n = 8) died within 7 min, while all the 7 rats that were given MB survived (p = 0.007). In the anesthetized rats, arterial, left ventricular pressures and CO decreased during NaHS infusion, leading to a pulseless electrical activity within 530 s. MB produced a significant increase in CO and dP/dtmax for about 2 min. A similar effect was produced when MB was also injected in the pre-mortem phase of sulfide exposure, significantly increasing survival time. Azure B produced an even larger increase in blood pressure than MB, while thionine had no effect.
CONCLUSION: MB can counteract NaHS-induced acute cardiogenic shock; this effect is also produced by azure B, but not by thionine, suggesting that the presence of methyl groups is a prerequisite for producing this protective effect.
Chenuel B, Sonobe T, Haouzi P.
Effects of infusion of human methemoglobin solution following hydrogen sulfide poisoning.
Clin Toxicol (Phila). 2015 Feb;53(2):93-101. doi: 10.3109/15563650.2014.996570. Epub 2015 Jan 29.
Abstract/Text
RATIONALE: We have recently reported that infusion of a solution containing methemoglobin (MetHb) during exposure to hydrogen sulfide results in a rapid and large decrease in the concentration of the pool of soluble/diffusible H2S in the blood. However, since the pool of dissolved H2S disappears very quickly after H2S exposure, it is unclear if the ability of MetHb to "trap" sulfide in the blood has any clinical interest and relevance in the treatment of sulfide poisoning.
METHODS: In anesthetized rats, repetition of short bouts of high level of H2S infusions was applied to allow the rapid development of an oxygen deficit. A solution containing MetHb (600 mg/kg) or its vehicle was administered 1 min and a half after the end of H2S intoxication.
RESULTS: The injection of MetHb solution increased methemoglobinemia to about 6%, almost instantly, but was unable to affect the blood concentration of soluble H2S, which had already vanished at the time of infusion, or to increase combined H2S. In addition, H2S-induced O2 deficit and lactate production as well as the recovery of carotid blood flow and blood pressure were similar in treated and control animals.
CONCLUSION: Our results do not support the view that administration of MetHb or drugs-induced methemoglobinemia during the recovery phase following severe H2S intoxication in sedated rats can restore cellular oxidative metabolism, as the pool of diffusible sulfide, accessible to MetHb, disappears rapidly from the blood after H2S exposure.
UHMS: Hyperbaric Oxygen Therapy Indications Book. The Undersea and Hyperbaric Medical Society; 2008.
井上治, 久木田一朗, 合志清隆, 山見信夫, 鈴木一雄: 高気圧酸素療法（hyperbaric oxygen therapy, HBO）における 適応疾患の見直しと再編―特に国内の臨床報告と基礎研究 及び国外のランダム化比較試験などからの提案―. 日本高気圧環境・潜水医学会, 2009.
Lawson-Smith P, Olsen NV, Hyldegaard O.
Hyperbaric oxygen therapy or hydroxycobalamin attenuates surges in brain interstitial lactate and glucose; and hyperbaric oxygen improves respiratory status in cyanide-intoxicated rats.
Undersea Hyperb Med. 2011 Jul-Aug;38(4):223-37.
Abstract/Text
Cyanide (CN) intoxication inhibits cellular oxidative metabolism and may result in brain damage. Hydroxycobalamin (OHCob) is one among other antidotes that may be used following intoxication with CN. Hyperbaric oxygen (HBO2) is recommended when supportive measures or antidotes fail. However, the effect of hydroxycobalamin or HBO2 on brain lactate and glucose concentrations during CN intoxication is unknown. We used intracerebral microdialysis to study the in vivo effect of hydroxycobalamin or HBO2 treatment on acute CN-induced deterioration in brain metabolism. Anesthetized rats were allocated to four groups receiving potassium CN (KCN) 5.4 mg/kg or vehicle intra-arterially: 1) vehicle-treated control rats; 2) KCN-poisoned rats; 3) KCN-poisoned rats receiving hydroxycobalamin (25 mg); and 4) KCN-poisoned rats treated with HBO2 (284 kPa for 90 minutes). KCN alone caused a prompt increase in interstitial brain lactate and glucose concentrations peaking at 60 minutes. Both hydroxycobalamin and HBO2 abolished KCN-induced increases in brain lactate and glucose concentration. However, whereas HBO2 treatment increased cerebral PtO2 and reduced respiratory distress and cyanosis, OHCob did not have this beneficial effect. In conclusion, CN intoxication in anesthetized rats produces specific uncoupling of cerebral oxidative metabolism resulting in interstitial lactate and glucose surges that may be ameliorated by treatment with either hydroxycobalamin or HBO2.
Lawson-Smith P, Jansen EC, Hilsted L, Johnsen AH, Hyldegaard O.
Effect of acute and delayed hyperbaric oxygen therapy on cyanide whole blood levels during acute cyanide intoxication.
Undersea Hyperb Med. 2011 Jan-Feb;38(1):17-26.
Abstract/Text
Cyanide and carbon monoxide, which are often found in fire victims, are toxic gases emitted from fires. Cyanide and carbon monoxide have similar molecular structure. Cyanide binds to the enzyme cytochrome oxidase a, a3 similar to carbon monoxide, thus blocking the mitochondrial respiration chain causing depletion of adenosine triphosphate. Hyperbaric oxygen (HBO2) is recommended for treating carbon monoxide poisoning. The therapeutic effect is due to a high oxygen pressure removing carbon monoxide from the cells. We hypothesise that HBO2 induces changes in whole-blood-cyanide by a competitive mechanism forcing cyanide out of cellular tissues. A rat model was developed to study this effect. Female Sprague Dawley rats were anesthetized with a fentanyl + fluanizone combination and midazolam given subcutaneously (s.c.). Rats were poisoned with 5.4 mg/kg KCN injected intra-peritoneally in Group 1 and intra-arterially in Group 2. Blood samples were taken immediately after poisoning, and at one and a half, three and five hours. Blood was drawn from a jugular vein in Group 1 and from a femoral artery in Group 2. Group 1 rats were divided into a control group of 12 rats without HBO2, 10 rats had acute HBO2 immediately after poisoning and a group of 10 rats had HBO2 one and a half hours after poisoning. Group 2 rats were divided into a control group and an acute HBO2 group, with 10 rats in both groups. Whole-blood-cyanide concentrations were measured using the Conway method based on diffusion and the subsequent formation of cyanocobalamin measured by a spectrophotometer. Results showed that whole-blood-cyanide concentration in Group 1 controls and acute HBO2 initially rose and then fell towards zero. In rats treated with delayed HBO2, the reduction in whole-blood-cyanide concentration was significantly less as compared to controls and acute HBO2-treated rats. Group 2 controls whole-blood-cyanide concentration decreased towards zero throughout the observation period. However, in Group 2 acute HBO2-treated rats a secondary rise in whole-blood-cyanide was observed. The study indicates that HBO2 can move cyanide from tissue to blood. These findings may be of clinical importance, as combined HBO2 and antidote treatment, may accelerate detoxification.
Takano T, Miyazaki Y, Nashimoto I, Kobayashi K.
Effect of hyperbaric oxygen on cyanide intoxication: in situ changes in intracellular oxidation reduction.
Undersea Biomed Res. 1980 Sep;7(3):191-7.
Abstract/Text
To evaluate the efficacy of hyperbaric oxygen on cyanide intoxication, changes in the intracellular oxidation-reduction state of the renal cortex were observed in situ in 16 New Zealand white rabbits by detecting the reduced pyridine nucleotide fluorescence that represents the degree of cyanide blockade of the respiratory chain. The data indicated that 100% oxygen at 2 ATA exerted both prophylactic and therapeutic antagonistic effects on the cyanide poisoning. Administration of hyperbaric oxygen could constitute a significant treatment if proper chemical treatment is carried out concomitantly.
Goodhart GL.
Patient treated with antidote kit and hyperbaric oxygen survives cyanide poisoning.
South Med J. 1994 Aug;87(8):814-6. doi: 10.1097/00007611-199408000-00010.
Abstract/Text
A 54-year-old man deliberately drank a potassium-gold cyanide solution that contained approximately 1,650 mg of potassium cyanide. He survived after treatment with the Lilly antidote kit and hyperbaric oxygen.
Scolnick B, Hamel D, Woolf AD.
Successful treatment of life-threatening propionitrile exposure with sodium nitrite/sodium thiosulfate followed by hyperbaric oxygen.
J Occup Med. 1993 Jun;35(6):577-80. doi: 10.1097/00043764-199306000-00014.
Abstract/Text
Propionitrile, a substituted aliphatic nitrile commonly used in the chemical manufacturing industry, is capable of generating cyanide. However, there are few reports of human intoxication involving propionitrile. We report two workers at an organic chemical manufacturing plant who were overcome by fumes while treating a waste slurry into which unreacted propionitrile was discharged by mistake. One victim was comatose, acidotic, and hypotensive; his blood cyanide level was later measured at 5.0 micrograms/ml. He responded to sodium nitrite/sodium thiosulfate therapy by regaining consciousness. Continued symptoms were treated with hyperbaric oxygen at 2 atmospheres for a total of 4 hours. The second victim, who complained only of nausea, dizziness, and headache and who never lost consciousness, was treated with sodium nitrite/sodium thiosulfate. His measured blood cyanide concentration was 3.5 micrograms/ml. The ambient concentration of propionitrile in air samples at the work site shortly after the exposure was 77.5 mg/m3. In occupational situations in which workers exhibit rapidly progressive symptoms of headache, dizziness, collapse, and coma, and where substituted nitriles are known to be on site, acute cyanide poisoning should be strongly considered. Because of continued endogenous generation of cyanide from the metabolism of the parent compound, hyperbaric oxygen may be a valuable adjunctive therapy to consider, in addition to the immediate use of the cyanide antidote kit, in cases of poisoning by propionitrile or other substituted nitrile compounds. We urge the Occupational Safety and Health Administration to adopt workplace standards for the maximum ambient air concentrations for propionitrile.
