CYANIDE TOXICITY FROM SODIUM NITROPRUSSIDE: RISKS AND MANAGEMENT Joseph P. Rindone and Edward P. Sloane
OBJECTIVE: To review the risks, manifestations, and treatment of cyanide toxicity from nitroprusside therapy.
DATA SOURCES: All English case reports identified in Index Medicus (MEDLINE) of cyanide intoxication related to nitroprusside from 1970 to the present were reviewed. In addition, literature regarding the incidence, risks, and treatment of cyanide toxicity from nitroprusside is presented.
Numerous cases of cyanide toxicity associated with nitroprusside have been reported. The overall incidence appears to be infrequent; however, certain patients may be at high risk. Risk factors may include hypoalbuminemia, cardiopulmonary bypass procedures, or the administration of moderate to high doses of nitroprusside. Treatment of cyanide toxicity requires the cessation of nitroprusside and, for severe toxicity, use of the cyanide antidote kit. Cyanide toxicity from nitroprusside may be prevented by concomitant administration of sodium thiosulfate infusions.
CONCLUSIONS:
Ann
Pharmacother 1992;26:515-9.
NITROPRUSSIDE HAS EMERGED as an essential drug in the treatment of common disorders such as hypertensive emergencies and congestive heart failure.'> Its use is limited by the potential accumulation of cyanide which may result in significant morbidity and, at times, mortality. The following literature review focuses on the risks associated with cyanide toxicity following nitroprusside administration and management of this complication.
Nitroprusside Pharmacokinetics
Nitroprusside is a complex molecule containing five separate cyanide groups.' Upon intravenous administration, nitroprusside undergoes rapid degradation which liberates free cyanide. This reaction is thought to be facilitated by sulfhydryl groups of vascular endothelium or erythrocytes.' Cyanide is either metabolized to thiocyanate or combines with endogenous hydroxocobalamin to form cyanocobalamin.' Conversion to thiocyanate is facilitated by the rhodenase enzyme (a transulfurase) which is found in abundant quantities in the mitochondria of most tissues in animals." The rate-limiting step of the conversion of cyaJOSEPH P. RINDONE, Phann.D .• is a Clinical Pharmacist, Department of Veterans Affairs Medical Center (119). Tucson, AZ 85723; and EDWARD P. SLOANE, Phann.D.• is a Clinical Pharmacist, Department of Veterans Affairs Medical Center (lIC), Fort Wayne, IN. Reprints: Joseph P. Rindone, Phann.D.
This article is approved for continuing education credit.
nide to thiocyanate is postulated to be the availability of sulfur-containing compounds such as thiosulfate, cystine, and cysteine.' Thiocyanate formed by the reaction is subsequently eliminted by the kidneys," Scope and Risks ofCyanide Toxicity
The incidence of cyanide toxicity from nitroprusside therapy has been poorly described. A Department of Veterans Affairs cooperative study examined the outcome of 400 patients who received nitroprusside infusions after acute myocardial infarction. In this study no reports of cyanide-related complications were noted. However, small to moderate doses (mean 92.311g/min for 48 hours) were used in this trial." MacRae reported only one incident of cyanide toxicity in 1000 patients who received nitroprusside. The doses of nitroprusside were not specified in this brief report.'? Patel et al. reported that 7 of 292 patients developed cyanide toxicity after receiving nitroprusside following coronary artery bypass surgery." A review of the literature from 1970 to the present reveals 23 cases of documented cyanide intoxication resulting from nitroprusside administration.l':" Seventeen of these cases are well described and the data are presented in Table I. The onset of toxicity in these cases was reported to occur from 50 minutes to 14 days after initiation of nitroprusside. The maximum infusion rates ranged from 2.6 to 120 ug/kg/min. Toxicity was observed in seven patients who received maximum infusion rates between 2.3 and 5 llg/kg/min. In many cases, metabolic acidosis and tachyphylaxis to nitroprusside's hypotensive effect often heralded the onset of serious cyanide toxicity. Changes in mental status were often observed. Death was the [mal outcome in six patients. Identifying patients who are at risk for cyanide intoxication following nitroprusside administration is difficult. Patients with hepatic impairment may be at greater risk because cyanide is primarily metabolized; however, the rate of cyanide elimination after cigarette smoking has been shown to be similar in normal subjects and in patients with cirrhosis." This could be attributable in part to the presence of rhodenase throughout the body (as described in laboratory animals)" and these patients may be able to detoxify cyanide peripherally. Albumin has been postulated to act as a protein carrier for a sulfur substrate that reacts with cyanide to form thiocyanate." Patients who are malnourished may have low serum albumin concentrations,
The Annals ofPharmacotherapy • Downloaded from aop.sagepub.com at City University Library on December 13, 2015
1992 April. Volume 26 • 515
which could impair cyanide detoxification. Tobacco smoking theoretically can predispose patients to cyanide toxicity from nitroprusside as tobacco smoke contains cyanide" and chronic exposure may reduce endogenous stores of thiosulfate and hydroxocobalamin. There are few clinical data to support this speculation." Patients undergoing hypothermic cardiopulmonary bypass procedures may be at risk for cyanide intoxication. Hypothermia has been described as impairing the conversion of cyanide to thiocyanate. 31,32 In addition, plasma thiosulfate concentrations are decreased in patients during and immediately after cardiopulmonary bypass surgery; this may slow the detoxification of cyanide." These factors may explain the relatively high incidence of cyanide toxicity from nitroprusside in patients who have undergone this procedure." Several clinical studies have shown that the degree of cyanide accumulation is proportional to the nitroprusside dosage.30,34-38 Many of these studies dealt with cyanide accumulation during surgery when nitroprusside was used for controlled surgical hypotension. Aitken et al. studied 13 patients undergoing neurosurgery who received varying doses of nitroprusside for controlled hypotension. The mean duration of these procedures was five hours. There was a significant correlation between dose and blood cyanide concentration. At total doses greater than 0.5 mg/kg, blood cyanide concentrations approached or exceeded 38 umol/L (100 llg/dL), a level considered to be moderately toxic (fable 2). A base deficit was noted in patients whose blood cyanide concentration was 38 umol/l, or more, indicating cellular hypoxia induced by cyanide." In a similar study, Pasch et aI. examined 55 patients who received nitroprusside for controlled surgical hypotension. They also noted a correlation between nitroprusside dose and blood cyanide concentration. Erythrocyte cyanide concentrations were consistently below 40 nmol/rnl. for infusion rates less than 4 Ilg/kg/min. In patients who received higher dosage rates, erythrocyte cyanide concentrations accumulated to a
maximum of 113 nmol/ml., a concentration considered potentially toxic by the authors." Vessey and Cole measured plasma cyanide concentrations in 30 patients during or near the end of chronic nitroprusside dosing (range 12-314 h duration). All patients who received less than 2 Ilg/kg/min had plasma cyanide concentrations less than I umol/L. With infusions of 2-41lg/kg/min, 2 of 9 patients had plasma cyanide concentrations greater than I umol/L, a concentration considered to be potentially toxic by the authors. For infusion rates between 4 and 7 Ilg/kg/min, 4 of 8 patients had plasma cyanide concentrations in excess of I umol/l., The authors did not report if clinical toxicity occurred in any of the patients."
Treatment and Prevention ofCyanide Toxicity All patients receiving nitroprusside should be monitored for possible cyanide toxicity. Early signs and symptoms of intoxication can include metabolic acidosis, hyperpnea, giddiness, confusion, palpitations, and headache. Tachyphylaxis to the hypotensive effect of nitroprusside may be noted. Later complications may include vomiting, bradycardia, hypotension, coma, convulsions, and apnea. 39,40 Arterial blood gas results from patients will consist of a normal p02' but a decreased measured O 2 saturation." Measuring blood cyanide concentrations has been suggested in corroborating suspected cyanide toxicity." Monitoring patients with daily blood cyanide concentrations (if available) and/or blood acid-base determinations may be of little value in predicting toxicity as serious intoxication can occur rapidly,13,14,42 before information from these tests is available. Cetnarowski and Conti recommended continuous monitoring of mixed venous oxygen saturation via a pulmonary arterial catheter to detect changes in tissue oxygenation in patients administered nitroprusside." Treatment of cyanide intoxication requires discontinuing nitroprusside and, for severe intoxications, use of the
Table I. Case Reports of Cyanide Toxicity from Nitroprusside INDICATION
AGE
TOTALDOSE
MAXIMUM DOSE
(mg)
(!ig/kg/min)
ONSET
62
Hypertension
721
3.5
80 h
65
NS
157
NS
30h
20 NS 14
Surgical hypotension Surgical hypotension Surgical hypotension
750 750 400
NS NS 120
5h 50 min 80 min
66
Hypertension
238
2.3
38 h
42 66 42 52 14 27
Surgical hypotension Hypertension Hypertension Hypertension Surgical hypotension Hypertension
250 490 13 1093 130 1120
2.8 7 3 NS II 12.5
58 43 NS days
Heart failure Hypertension NS Hypertension
1000 2878 NS NS
2.6 8 4.9 5
72h 14d 14h 30h
53
Hypertension
NS
2.5
7d
90 min 28 h 90 min 34 h 5h 48 h
COMMENTS tachyphylaxis, mental status change, BC CN=22 umol/L. survived acidosis, mental status change, BC CN=14.4 umol/L, died tachyphylaxis, acidosis, died tachyphylaxis, acidosis, died tachyphylaxis, acidosis, BC CN=I40 umol/L, died acidosis, mental status change, BC CN=8 I umol., died tachyphylaxis, acidosis, survived acidosis, mental status change, survived acidosis, hypotension, died acidosis, mental status change, survived acidosis, hypotension, survived acidosis, mental status change, hypotension, survived mental status change, survived coma, BC CN=140 umol/L, cardiac arrest acidosis, mental status change, survived acidosis, mental status change, RBC CN=4oo nmol/L, survived acidosis, mental status change, survived
BC CN = blood concentration of cyanide; NS = not specified; RBC CN = red blood cell cyanide.
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cyanide antidote kit (Table 3). Potential toxicities and high cost of the kit ($110) mandate its use only in severe intoxications. Sodium nitrite will induce methemoglobinemia, which will bind cyanide and prevent further intoxication. Maintaining methemoglobin levels of less than 40 percent has been advocated." Rapid administration of intravenous sodium nitrite may cause hypotension; therefore, blood pressure monitoring should be performed after administration. Sodium thiosulfate should be administered immediately after sodium nitrite. Administration through the same intravenous line is acceptable. Sodium thiosulfate will facilitate the metabolism of cyanide to thiocyanate, which is then renally excreted. A repeat dose of sodium nitrite and thiosulfate at one-half the original dose can be administered if there is insufficient response. Sodium thiosulfate may be useful in preventing cyanide toxicity from nitroprusside. Schulz et al. measured blood cyanide concentrations in 19 patients who received nitroprusside and thiosulfate for hypertension or aortic aneurysm and in 51 patients who received nitroprusside alone for surgical hypotension. Nitroprusside 50 mg was mixed in 50 mL of I % sodium thiosulfate solution. The results showed that cyanide accumulation was minimal in all patients who received nitroprusside with thiosulfate despite infusion rates up to 900 ug/min. Blood cyanide concentrations increased proportionally to the dose of nitroprusside in patients who received nitroprusside alone." In a similar study by Pasch et al., eight patients undergoing controlled surgical hypotension received mixed infusions of nitroprusside 60 mg dissolved in 50 mL of 1% sodium thiosulfate. Nitroprusside alone was administered to 39 other patients. Blood cyanide concentrations were consistently low in all patients receiving nitroprusside and thiosulfate despite doses of up to 9 flg/kg/min of nitroprusside. Patients
Table 2. Whole Blood Cyanide Concentration and Toxicity" CONCENTRATION
b
SYMPTOMS
llg/ mL
0.2-0.5 0.5-1.0 1.0-2.5 2.5-3.0 3.0
8-20 20-38 38-95 95-114 114
none tachycardia. flushing depressed level of consciousness coma death
"Reproduced with permission from Reference 40. "Concentrauons are considered general correlations in essentially untreated patients.
Table 3. Recommendations for Administration of the Cyanide Antidote Kit" I. Crush amyI nitrite pearls into gauze or handkerchief and hold by patient's mouth for 15-30 severy 2-3 min until administration of iv amyl nitrite. 2. Stop inhaled amyl nitrite and administer amyl nitrite 300 mg iv (10 mL of 3% solution) over 2-4 min. Pediatric dose is 6-8 mL/m 2 or 0.2 mL/kg body weight. Do not exceed 10 mL per injection. 3. Immediately thereafter, administer sodium thiosulfate 12.5 g iv. Administration via the same vein or line as for step 2 is acceptable. Pediatric dose is 7 g/rrr'; do not exceed 12.5 g. 4. Repeat steps 2 or 3 at one-half the dose if symptoms reappear. "Available from Eli Lilly.
who received nitroprusside alone had blood cyanide accumulation proportional to the dose of nitroprusside." Sodium thiosulfate is relatively inexpensive with little toxicity. Unfortunately, thiosulfate infusions will not prevent thiocyanate accumulation. Administering infusions at a dose of 10 mg for every 1 mg of nitroprusside infused should be considered in high-risk patients (e.g., malnutrition) or when large doses of nitroprusside are administered (e.g., >3 ug/kg/min). Some authors recommend that all patients receiving nitroprusside receive concomitant thiosulfate infusions." Intravenous boluses of thiosulfate may also be effective, but may require frequent dosing because of its short half-life (17 minutes to three hours ).33.37 Mixing sodium thiosulfate in the same container with nitroprusside has been suggested. Schulz et al. mixed nitroprusside 50 mg with 50 mL of 1% sodium thiosulfate in plastic syringes (protected from light) and found this mixture to have hypotensive effects up to eight days later," In a similar open-label study, nitroprusside plus sodium thiosulfate (same mixture as above) lowered mean systolic blood pressure from 212 to 145 mm Hg in 30 patients. The mean dose of nitroprusside in this study was 2.4 ug/kg/min." There have been no studies that chemically determined the compatability characteristics of nitroprusside and sodium thiosulfate. Hydroxocobalamin may be an ideal agent to prevent metabolite toxicity from nitroprusside. Cyanide displaces the hydroxyl group on the hydroxocobalamin molecule to form cyanocobalamin (vitamin B (2 ) , which is renally eliminated." Because cyanide is bound to hydroxocobalamin, thiocyanate accumulation may also be prevented. Cottrell et al. studied the effect of hydroxocobalamin in a nonrandomized fashion in 14 patients who received nitroprusside for controlled surgical hypotension. Nitroprusside was titrated to a goal mean arterial blood pressure of 70 torr for at least 210 minutes. The patients were divided into two groups: nitroprusside alone and nitroprusside with hydroxocobalamin 25 mg/h for up to four hours. Plasma and erythrocyte cyanide were measured at specified times during the study. The dose of nitroprusside did not statistically differ between both groups (mean total dose of 44.09 and 44.56 mg in nitroprusside and control groups, respectively). The results showed that the patients receiving hydroxocobalamin had statistically lower concentrations of both erythrocyte cyanide and plasma cyanide (p
OBJECTIVE: To review the risks, manifestations, and treatment of cyanide toxicity from nitroprusside therapy.
DATA SOURCES: All English case reports identified in Index Medicus (MEDLINE) of cyanide intoxication related to nitroprusside from 1970 to the present were reviewed. In addition, literature regarding the incidence, risks, and treatment of cyanide toxicity from nitroprusside is presented.
Numerous cases of cyanide toxicity associated with nitroprusside have been reported. The overall incidence appears to be infrequent; however, certain patients may be at high risk. Risk factors may include hypoalbuminemia, cardiopulmonary bypass procedures, or the administration of moderate to high doses of nitroprusside. Treatment of cyanide toxicity requires the cessation of nitroprusside and, for severe toxicity, use of the cyanide antidote kit. Cyanide toxicity from nitroprusside may be prevented by concomitant administration of sodium thiosulfate infusions.
CONCLUSIONS:
Ann
Pharmacother 1992;26:515-9.
NITROPRUSSIDE HAS EMERGED as an essential drug in the treatment of common disorders such as hypertensive emergencies and congestive heart failure.'> Its use is limited by the potential accumulation of cyanide which may result in significant morbidity and, at times, mortality. The following literature review focuses on the risks associated with cyanide toxicity following nitroprusside administration and management of this complication.
Nitroprusside Pharmacokinetics
Nitroprusside is a complex molecule containing five separate cyanide groups.' Upon intravenous administration, nitroprusside undergoes rapid degradation which liberates free cyanide. This reaction is thought to be facilitated by sulfhydryl groups of vascular endothelium or erythrocytes.' Cyanide is either metabolized to thiocyanate or combines with endogenous hydroxocobalamin to form cyanocobalamin.' Conversion to thiocyanate is facilitated by the rhodenase enzyme (a transulfurase) which is found in abundant quantities in the mitochondria of most tissues in animals." The rate-limiting step of the conversion of cyaJOSEPH P. RINDONE, Phann.D .• is a Clinical Pharmacist, Department of Veterans Affairs Medical Center (119). Tucson, AZ 85723; and EDWARD P. SLOANE, Phann.D.• is a Clinical Pharmacist, Department of Veterans Affairs Medical Center (lIC), Fort Wayne, IN. Reprints: Joseph P. Rindone, Phann.D.
This article is approved for continuing education credit.
nide to thiocyanate is postulated to be the availability of sulfur-containing compounds such as thiosulfate, cystine, and cysteine.' Thiocyanate formed by the reaction is subsequently eliminted by the kidneys," Scope and Risks ofCyanide Toxicity
The incidence of cyanide toxicity from nitroprusside therapy has been poorly described. A Department of Veterans Affairs cooperative study examined the outcome of 400 patients who received nitroprusside infusions after acute myocardial infarction. In this study no reports of cyanide-related complications were noted. However, small to moderate doses (mean 92.311g/min for 48 hours) were used in this trial." MacRae reported only one incident of cyanide toxicity in 1000 patients who received nitroprusside. The doses of nitroprusside were not specified in this brief report.'? Patel et al. reported that 7 of 292 patients developed cyanide toxicity after receiving nitroprusside following coronary artery bypass surgery." A review of the literature from 1970 to the present reveals 23 cases of documented cyanide intoxication resulting from nitroprusside administration.l':" Seventeen of these cases are well described and the data are presented in Table I. The onset of toxicity in these cases was reported to occur from 50 minutes to 14 days after initiation of nitroprusside. The maximum infusion rates ranged from 2.6 to 120 ug/kg/min. Toxicity was observed in seven patients who received maximum infusion rates between 2.3 and 5 llg/kg/min. In many cases, metabolic acidosis and tachyphylaxis to nitroprusside's hypotensive effect often heralded the onset of serious cyanide toxicity. Changes in mental status were often observed. Death was the [mal outcome in six patients. Identifying patients who are at risk for cyanide intoxication following nitroprusside administration is difficult. Patients with hepatic impairment may be at greater risk because cyanide is primarily metabolized; however, the rate of cyanide elimination after cigarette smoking has been shown to be similar in normal subjects and in patients with cirrhosis." This could be attributable in part to the presence of rhodenase throughout the body (as described in laboratory animals)" and these patients may be able to detoxify cyanide peripherally. Albumin has been postulated to act as a protein carrier for a sulfur substrate that reacts with cyanide to form thiocyanate." Patients who are malnourished may have low serum albumin concentrations,
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1992 April. Volume 26 • 515
which could impair cyanide detoxification. Tobacco smoking theoretically can predispose patients to cyanide toxicity from nitroprusside as tobacco smoke contains cyanide" and chronic exposure may reduce endogenous stores of thiosulfate and hydroxocobalamin. There are few clinical data to support this speculation." Patients undergoing hypothermic cardiopulmonary bypass procedures may be at risk for cyanide intoxication. Hypothermia has been described as impairing the conversion of cyanide to thiocyanate. 31,32 In addition, plasma thiosulfate concentrations are decreased in patients during and immediately after cardiopulmonary bypass surgery; this may slow the detoxification of cyanide." These factors may explain the relatively high incidence of cyanide toxicity from nitroprusside in patients who have undergone this procedure." Several clinical studies have shown that the degree of cyanide accumulation is proportional to the nitroprusside dosage.30,34-38 Many of these studies dealt with cyanide accumulation during surgery when nitroprusside was used for controlled surgical hypotension. Aitken et al. studied 13 patients undergoing neurosurgery who received varying doses of nitroprusside for controlled hypotension. The mean duration of these procedures was five hours. There was a significant correlation between dose and blood cyanide concentration. At total doses greater than 0.5 mg/kg, blood cyanide concentrations approached or exceeded 38 umol/L (100 llg/dL), a level considered to be moderately toxic (fable 2). A base deficit was noted in patients whose blood cyanide concentration was 38 umol/l, or more, indicating cellular hypoxia induced by cyanide." In a similar study, Pasch et aI. examined 55 patients who received nitroprusside for controlled surgical hypotension. They also noted a correlation between nitroprusside dose and blood cyanide concentration. Erythrocyte cyanide concentrations were consistently below 40 nmol/rnl. for infusion rates less than 4 Ilg/kg/min. In patients who received higher dosage rates, erythrocyte cyanide concentrations accumulated to a
maximum of 113 nmol/ml., a concentration considered potentially toxic by the authors." Vessey and Cole measured plasma cyanide concentrations in 30 patients during or near the end of chronic nitroprusside dosing (range 12-314 h duration). All patients who received less than 2 Ilg/kg/min had plasma cyanide concentrations less than I umol/L. With infusions of 2-41lg/kg/min, 2 of 9 patients had plasma cyanide concentrations greater than I umol/L, a concentration considered to be potentially toxic by the authors. For infusion rates between 4 and 7 Ilg/kg/min, 4 of 8 patients had plasma cyanide concentrations in excess of I umol/l., The authors did not report if clinical toxicity occurred in any of the patients."
Treatment and Prevention ofCyanide Toxicity All patients receiving nitroprusside should be monitored for possible cyanide toxicity. Early signs and symptoms of intoxication can include metabolic acidosis, hyperpnea, giddiness, confusion, palpitations, and headache. Tachyphylaxis to the hypotensive effect of nitroprusside may be noted. Later complications may include vomiting, bradycardia, hypotension, coma, convulsions, and apnea. 39,40 Arterial blood gas results from patients will consist of a normal p02' but a decreased measured O 2 saturation." Measuring blood cyanide concentrations has been suggested in corroborating suspected cyanide toxicity." Monitoring patients with daily blood cyanide concentrations (if available) and/or blood acid-base determinations may be of little value in predicting toxicity as serious intoxication can occur rapidly,13,14,42 before information from these tests is available. Cetnarowski and Conti recommended continuous monitoring of mixed venous oxygen saturation via a pulmonary arterial catheter to detect changes in tissue oxygenation in patients administered nitroprusside." Treatment of cyanide intoxication requires discontinuing nitroprusside and, for severe intoxications, use of the
Table I. Case Reports of Cyanide Toxicity from Nitroprusside INDICATION
AGE
TOTALDOSE
MAXIMUM DOSE
(mg)
(!ig/kg/min)
ONSET
62
Hypertension
721
3.5
80 h
65
NS
157
NS
30h
20 NS 14
Surgical hypotension Surgical hypotension Surgical hypotension
750 750 400
NS NS 120
5h 50 min 80 min
66
Hypertension
238
2.3
38 h
42 66 42 52 14 27
Surgical hypotension Hypertension Hypertension Hypertension Surgical hypotension Hypertension
250 490 13 1093 130 1120
2.8 7 3 NS II 12.5
58 43 NS days
Heart failure Hypertension NS Hypertension
1000 2878 NS NS
2.6 8 4.9 5
72h 14d 14h 30h
53
Hypertension
NS
2.5
7d
90 min 28 h 90 min 34 h 5h 48 h
COMMENTS tachyphylaxis, mental status change, BC CN=22 umol/L. survived acidosis, mental status change, BC CN=14.4 umol/L, died tachyphylaxis, acidosis, died tachyphylaxis, acidosis, died tachyphylaxis, acidosis, BC CN=I40 umol/L, died acidosis, mental status change, BC CN=8 I umol., died tachyphylaxis, acidosis, survived acidosis, mental status change, survived acidosis, hypotension, died acidosis, mental status change, survived acidosis, hypotension, survived acidosis, mental status change, hypotension, survived mental status change, survived coma, BC CN=140 umol/L, cardiac arrest acidosis, mental status change, survived acidosis, mental status change, RBC CN=4oo nmol/L, survived acidosis, mental status change, survived
BC CN = blood concentration of cyanide; NS = not specified; RBC CN = red blood cell cyanide.
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Cyanide Toxicity
cyanide antidote kit (Table 3). Potential toxicities and high cost of the kit ($110) mandate its use only in severe intoxications. Sodium nitrite will induce methemoglobinemia, which will bind cyanide and prevent further intoxication. Maintaining methemoglobin levels of less than 40 percent has been advocated." Rapid administration of intravenous sodium nitrite may cause hypotension; therefore, blood pressure monitoring should be performed after administration. Sodium thiosulfate should be administered immediately after sodium nitrite. Administration through the same intravenous line is acceptable. Sodium thiosulfate will facilitate the metabolism of cyanide to thiocyanate, which is then renally excreted. A repeat dose of sodium nitrite and thiosulfate at one-half the original dose can be administered if there is insufficient response. Sodium thiosulfate may be useful in preventing cyanide toxicity from nitroprusside. Schulz et al. measured blood cyanide concentrations in 19 patients who received nitroprusside and thiosulfate for hypertension or aortic aneurysm and in 51 patients who received nitroprusside alone for surgical hypotension. Nitroprusside 50 mg was mixed in 50 mL of I % sodium thiosulfate solution. The results showed that cyanide accumulation was minimal in all patients who received nitroprusside with thiosulfate despite infusion rates up to 900 ug/min. Blood cyanide concentrations increased proportionally to the dose of nitroprusside in patients who received nitroprusside alone." In a similar study by Pasch et al., eight patients undergoing controlled surgical hypotension received mixed infusions of nitroprusside 60 mg dissolved in 50 mL of 1% sodium thiosulfate. Nitroprusside alone was administered to 39 other patients. Blood cyanide concentrations were consistently low in all patients receiving nitroprusside and thiosulfate despite doses of up to 9 flg/kg/min of nitroprusside. Patients
Table 2. Whole Blood Cyanide Concentration and Toxicity" CONCENTRATION
b
SYMPTOMS
llg/ mL
0.2-0.5 0.5-1.0 1.0-2.5 2.5-3.0 3.0
8-20 20-38 38-95 95-114 114
none tachycardia. flushing depressed level of consciousness coma death
"Reproduced with permission from Reference 40. "Concentrauons are considered general correlations in essentially untreated patients.
Table 3. Recommendations for Administration of the Cyanide Antidote Kit" I. Crush amyI nitrite pearls into gauze or handkerchief and hold by patient's mouth for 15-30 severy 2-3 min until administration of iv amyl nitrite. 2. Stop inhaled amyl nitrite and administer amyl nitrite 300 mg iv (10 mL of 3% solution) over 2-4 min. Pediatric dose is 6-8 mL/m 2 or 0.2 mL/kg body weight. Do not exceed 10 mL per injection. 3. Immediately thereafter, administer sodium thiosulfate 12.5 g iv. Administration via the same vein or line as for step 2 is acceptable. Pediatric dose is 7 g/rrr'; do not exceed 12.5 g. 4. Repeat steps 2 or 3 at one-half the dose if symptoms reappear. "Available from Eli Lilly.
who received nitroprusside alone had blood cyanide accumulation proportional to the dose of nitroprusside." Sodium thiosulfate is relatively inexpensive with little toxicity. Unfortunately, thiosulfate infusions will not prevent thiocyanate accumulation. Administering infusions at a dose of 10 mg for every 1 mg of nitroprusside infused should be considered in high-risk patients (e.g., malnutrition) or when large doses of nitroprusside are administered (e.g., >3 ug/kg/min). Some authors recommend that all patients receiving nitroprusside receive concomitant thiosulfate infusions." Intravenous boluses of thiosulfate may also be effective, but may require frequent dosing because of its short half-life (17 minutes to three hours ).33.37 Mixing sodium thiosulfate in the same container with nitroprusside has been suggested. Schulz et al. mixed nitroprusside 50 mg with 50 mL of 1% sodium thiosulfate in plastic syringes (protected from light) and found this mixture to have hypotensive effects up to eight days later," In a similar open-label study, nitroprusside plus sodium thiosulfate (same mixture as above) lowered mean systolic blood pressure from 212 to 145 mm Hg in 30 patients. The mean dose of nitroprusside in this study was 2.4 ug/kg/min." There have been no studies that chemically determined the compatability characteristics of nitroprusside and sodium thiosulfate. Hydroxocobalamin may be an ideal agent to prevent metabolite toxicity from nitroprusside. Cyanide displaces the hydroxyl group on the hydroxocobalamin molecule to form cyanocobalamin (vitamin B (2 ) , which is renally eliminated." Because cyanide is bound to hydroxocobalamin, thiocyanate accumulation may also be prevented. Cottrell et al. studied the effect of hydroxocobalamin in a nonrandomized fashion in 14 patients who received nitroprusside for controlled surgical hypotension. Nitroprusside was titrated to a goal mean arterial blood pressure of 70 torr for at least 210 minutes. The patients were divided into two groups: nitroprusside alone and nitroprusside with hydroxocobalamin 25 mg/h for up to four hours. Plasma and erythrocyte cyanide were measured at specified times during the study. The dose of nitroprusside did not statistically differ between both groups (mean total dose of 44.09 and 44.56 mg in nitroprusside and control groups, respectively). The results showed that the patients receiving hydroxocobalamin had statistically lower concentrations of both erythrocyte cyanide and plasma cyanide (p
