Sodium Nitroprusside

Almost from its first reported use in humans in 1928 1, sodium nitroprusside (SNP) has been characterized as either villain or hero, depending on the clinician's assessment of the drug's risk-benefit ratio regarding cyanide toxicity. Not until 1955 was the safety of short-term SNP infusion established for treatment of severe hypertension 2. Nevertheless, owing to difficulties with chemical preparation, SNP was not released for clinical use in the United States until 1974. Despite its immediate widespread adoption and apparent safety, concern remained about its potential for toxicity. Recently, the routine use of SNP in doses exceeding 2 micro gram centered dot kg-1 centered dot min-1 or at smaller doses when continued for >24 h has been challenged 3-5. In 1991, the Food and Drug Administration, yielding to outside pressure as outlined by Robin and McCauley 5, approved new labeling for SNP which contained greater detail about the risk of cyanide toxicity, based on knowledge gained from clinical use and limited research since SNP's initial approval 17 yr earlier 6. In addition to renewed warnings about SNP toxicity, several studies have examined whether prophylactic administration of various drugs to patients requiring SNP infusions would ameliorate or eliminate cyanide toxicity 7-11. In short, although beset with controversy, SNP remains a commonly used drug, with total sales in the United States in 1993 (the latest year for which complete data are available) exceeding 2 million (Mr. Mark Sebree, Abbott Laboratories, personal communication, 1995). In this review we discuss the current indications and contraindications to SNP, evaluate its toxicity, and provide a plan for its rational use. Chemical Properties and Mechanism of Action SNP (disodium pentacyanonitrosylferrate (2-) dihydrate, Na2 Fe (CN) (5) NO centered dot 2H2 O) is comprised of a ferrous ion center complexed with five cyanide moieties and a nitrosyl group. The molecule is 44% cyanide by weight and soluble in water. Once infused, SNP can interact with oxyhemoglobin, dissociating immediately and forming methemoglobin while releasing cyanide and nitric oxide 12, 13Figure 1. Most investigators recognize nitric oxide (NO) as endothelium-derived relaxing factor, the active mediator responsible for the direct, vasodilating effect of SNP, although some would argue for a related nitrosothiol instead 14-16. In contrast to the organic nitrates (e. g. , nitroglycerin) which require the presence of highly specific thiol-containing compounds to generate NO, SNP spontaneously generates this product, thus functioning as a prodrug 14. Figure 1: Primary pathways of SNP metabolism. SNP = sodium nitroprusside; CN- = cyanide radical; NO sup. = nitric oxide radical; METHGB = methemoglobin; CYANOHGB = cyanomethemoglobin; OXYHGB = oxyhemoglobin. Once released, NO activates the enzyme guanylate cyclase found within vascular smooth muscle Figure 2, resulting in increased intracellular concentrations of cyclic guanosine monophosphate, which inhibits calcium entry into vascular smooth muscle cells and may increase calcium uptake by the smooth endoplasmic reticulum to produce vasodilation 14. Recent, controversial evidence suggests that NO may possess a direct myocardial effect of unknown clinical significance 14, 17. Figure 2: Mechanism of action of SNP. A decrease in intracellular free calcium concentration leads to relaxation. SNP = sodium nitroprusside; CN- = cyanide radical; NO sup. = nitric oxide radical; Ca2+ = calcium ion; PM = plasma membrane; GC = guanylate cyclase; GTP = guanosine triphosphate; cGMP = cyclic guanosine monophosphate; SER = smooth endoplasmic reticulum circle plus = promotes; circle minus = inhibits. Metabolism and Toxicology SNP's spontaneous breakdown products, NO sup. and CN-, are rapidly cleared by nonenzymatic means, through interaction with sulfhydryl groups on proteins in surrounding tissue and in erythrocytes 2, 12, 13, 18, 19Figure 1. Five cyanide radicals are released by each SNP molecule, which may immediately react with methemoglobin to produce cyanomethemoglobin 13. Normal adult methemoglobin concentrations in blood (approximately 0. 5% of all hemoglobin species) are capable of binding the cyanide released from 18 mg of SNP 8. Cyanomethemoglobin remains in a dynamic equilibrium with free cyanide and is considered nontoxic 12, 20. Adverse effects from methemoglobinemia generated by SNP breakdown are rare, even in patients with congenital inability to convert methemoglobin to hemoglobin (i. e. , methemoglobin reductase deficiency). The total SNP dose typically required to generate 10% methemoglobinemia exceeds 10 mg/kg (i. e. , 10 micro gram centered dot kg-1 centered dot min-1 for more than 16 h) 18. Patients receiving such doses of SNP who present with evidence of impaired oxygenation despite adequate cardiac output (CO) and PaO2 should have methemoglobinemia included in their differential diagnosis and measurement of methemoglobin via co-oximetry may be advisable 20-22. The remaining cyanide radicals enter the "cyanide pool" and are converted to thiocyanate via transulfuration within the liver 8, 12, 23Figure 1. Rhodanase (sometimes referred to as rhodanese, thiosulfate sulfurtransferase), the free cyanide-specific mitochondrial enzyme catalyzing this process, utilizes thiosulfate ions as sulfur donors 12, 20, 23. The transulfuration reaction is theoretically reversible via the enzyme thiocyanate oxidase found in erythrocytes, but the thermodynamics greatly favor thiocyanate production 12, 24. Most normal adults can detoxify approximately 50 mg total of SNP using existing sulfur stores; factors that reduce these stores, e. g. , malnutrition, surgery, and diuretics, decrease this capacity 7, 11. When SNP infusions exceed 2 micro gram centered dot kg-1 centered dot min-1, or when sulfur donors and methemoglobin are exhausted, cyanide radicals may accumulate producing clinical cyanide toxicity 7, 11. Assuming normal rhodanase activity, onset of toxicity may be minutes to hours depending on the above-mentioned sulfur stores. Since any free cyanide radical may bind and inactivate tissue cytochrome oxidase and prevent oxidative phosphorylation, increased cyanide concentrations may precipitate tissue anoxia, anaerobic metabolism, and lactic acidosis 8, 11. Children may be less able to mobilize thiosulfate stores despite increasing cyanide concentrations, leading to accelerated toxicity 7. The cytochrome oxidase-cyanide complex can interact with methemoglobin to form cyanomethemoglobin thus freeing cytochrome oxidase resulting in an apparent dynamic equilibrium between cyanomethemoglobin and cyanide 12Figure 1. Cyanide gradually dissociates from methemoglobin, and is converted to thiocyanate 18. There is considerable controversy regarding the true incidence of clinically significant cyanide toxicity. Thus, impassioned pleas to reduce the use of SNP are found concurrently with studies which demonstrate no evidence of clinical toxicity despite several days of SNP infusion 3-5, 10, 18. Possible cyanide poisoning has been reported over a wide range of SNP infusion rates and total doses; deaths clearly linked to cyanide toxicity involve excessive total doses and infusion rates, i. e. , 30-120 micro gram centered dot kg (-1) centered dot min-118. Blood cyanide concentrations required for clinical toxicity appear to exceed 40 micro Meter 11, 25, 26; deaths have been reported with concentrations exceeding 77 micro Meter 11, 100 micro Meter 22, or 1309 micro Meter 27, 28. Nevertheless, many patients have survived blood cyanide concentrations, not necessarily as a consequence of nitroprusside therapy, which exceed the lethal range 25. There is controversy as to the definitive method for assaying blood cyanide concentrations and the importance of photodecomposition during the assay or the infusion 11, 25, 29. In any case, measurements of cyanide in blood are of limited clinical utility due to the time delay (ranging from several hours to days) before the results will be known 8. Regardless of the SNP infusion rate or total administered dose, any patient receiving SNP who subsequently exhibits central nervous system dysfunction, cardiovascular instability, and increasing metabolic acidosis should be assessed for cyanide toxicity 8, 11, 18Table 1. SNP infusion should be discontinued with further intervention based on the clinical assessment. Some authors believe that metabolic acidosis occurs only as a terminal event in cyanide toxicity and that cerebral dysfunction provides the more valuable diagnostic clue 5. We are aware of no studies with SNP which substantiate this view; we believe that the literature supports a closer association of cyanide toxicity and metabolic acidosis 25, 30, 31. Table 1: Administration of Sodium Nitroprusside (SNP): Recognizing and Treating Its Toxic Side-EffectsWhen SNP infusion overwhelms the cyanide-removing capacity, the arterial base deficit correlates well with increased blood lactate concentration although not necessarily in critically ill patients 30, 31. Thus, base deficit, a readily available diagnostic test, may assist in the decision whether to initiate further therapy. In smoke inhalation, where cyanide toxicity also occurs, plasma lactate concentrations exceeding 10 mM correlate well with blood cyanide concentrations exceeding 40 micro Meter and may also provide an additional guide to interventions 20, 25. When life-threatening tissue hypoxia is present, having the patient breath 100% oxygen, correcting metabolic acidosis with sodium bicarbonate, and administering 3% sodium nitrite (4-6 mg/kg very slowly intravenously IV), and sodium thiosulfate (150-200 mg/kg IV over 15 min) is the usual treatment 8, 11, 12, 18. Sodium nitrite converts hemoglobin to methemoglobin which competes with cytochrome oxidase for cyanide radicals, as previously noted. Some clinicians will withhold sodium nitrite therapy in anemic patients, particularly when oxygen delivery is already compromised while others consider its vasodilating effects to be problematic 9, 11, 12. Some practitioners administer hydroxocobalamin (vitamin B12a) to prevent or treat cyanide toxicity. Hydroxocobalamin binds CN- forming cyanocobalamin which acts as a nontoxic reservoir and can be excreted in the urine. The vitamin can be infused at 25 mg/h to a total of 100 mg or more during and after SNP infusion 9, 12, 18-20, 25, 27, 32. Infusion of vitamin B12 (cyanocobalamin) is considered ineffective in removing CN- due to poor binding, thus is not a substitute for hydroxocobalamin 9. The principal toxic effect of hydroxocobalamin is reddish discoloration of the skin and mucous membranes 33. The evidence that hydroxocobalamin administration is either needed or efficacious is controversial. One study of patients receiving SNP infusion at 2. 5 micro gram centered dot kg-1 centered dot min (-1) for an average of 100 h showed no evidence of either cyanide toxicity or significant vitamin B12 deficiency despite average daily doses of 179 mg SNP 10. Williams et al. , using a dog model, showed hydroxocobalamin loading increased the minimum cyanide dose required to produce evidence of cyanide toxicity 34. Of interest, hydroxocobalamin competitively inhibits SNP's relaxant effects and is quite expensive 35. Perhaps the most commonly advocated prophylaxis for SNP toxicity is concomitant infusion of sodium thiosulfate to provide a continuous source of sulfur donors. Many studies and reviews advocate this method as the one sure way to prevent the accumulation of cyanide radicals regardless of the SNP dose 7, 11, 19, 36. Unfortunately, the thiocyanate formed can itself cause toxicity in patients with impaired renal thiocyanate excretion 8, 11, 12, 18. The normal thiocyanate elimination half-life is 2. 7 days, but it may be prolonged up to 9 days in patients with renal insufficiency 11. Thiocyanate was once evaluated as an antihypertensive drug 2, 11, 31. Although thiocyanate was abandoned as an antihypertensive, these pilot studies provided an understanding of its toxic effects. Once formed, thiocyanate is eliminated intact via renal excretion (elimination half-life of 3-7 days). Clinical thiocyanate toxicity is rare, the drug being 100-fold less toxic than cyanide 8, 11. In patients with normal renal function, 7-14 days of SNP infusion in the 2-5 micro gram centered dot kg-1 centered dot min-1 range may be required to generate thiocyanate levels high enough to produce toxicity. SNP infusions as short as 3-6 days may prove toxic to patients with chronic renal failure not maintained on hemodialysis 8, 11. As might be anticipated, with normal renal function, increased water and chloride intake enhances thiocyanate excretion; hyponatremia and administration of thiosulfate favor thiocyanate accumulation 18. Nonspecific symptoms of thiocyanate toxicity include fatigue, tinnitus, nausea, and vomiting. Clinical signs of thiocyanate neurotoxicity include hyperreflexia, confusion, psychosis, and miosis. Toxicity may progress to seizures and coma when thiocyanate concentrations exceed 60 mg/L. Life-threatening thiocyanate toxicity is of concern when blood thiocyanate concentrations approach 200 micro Although thiocyanate levels are not in cyanide toxicity, can the diagnosis of thiocyanate toxicity 8, 11, 12, 18. concentrations of thiocyanate competitively uptake and binding of in the producing clinical 8, 11, 12, 18. Thiocyanate can be by hemodialysis or SNP direct and arterial vasodilation with of adequate blood to all provided is and arterial is is a and a direct of has an immediate onset and short in In the of SNP vascular vascular and while the effect on is on initial pressure Figure increased is increased with normal may be cardiovascular can a in to or an increase in rate and with adequate Figure of sodium nitroprusside (SNP) with and in with cardiac patients of approximately from et and after sodium nitroprusside (SNP) infusion micro gram centered dot kg-1 centered dot for in patients and oxide for their before SNP for all from et with and nitroprusside during for and In 1991, the Food and Drug Administration the for SNP, the risk of cyanide toxicity and that smaller doses be used 6. The drug remains for immediate of arterial blood pressure in and for during to reduce 6. clinicians to use SNP for a wide range of and Since the SNP has been considered an for after failure of less drugs SNP many that have it the of of of and of its effects after and of the of to the drug's SNP typically acts within its effects min after of infusion SNP has been used to treat all of hypertension and whether by cerebral of or hypertension SNP used as a with by as as and of SNP after myocardial was first reported in patients with SNP infusions to reduce decrease the and increase the studies have from SNP infusion in severe or severe and after myocardial by failure In a new controversy the effects of SNP on after myocardial on in patients with SNP after the diagnosis of myocardial patients with signs of the drugs for myocardial due to concern that SNP might produce which may when in the blood from of The clinical significance of remains have in after treatment with SNP In a study at the use of SNP in patients with dysfunction after myocardial that SNP patient when used within the first h of an myocardial In patients with failure which more than h after myocardial SNP In clinicians have to use in to SNP after myocardial in these patients with dysfunction, particularly in association with SNP can rapidly cardiac and clinical provided adequate is maintained In many studies of chronic regardless of the SNP has of is to to the to to a is by blood in further to When are SNP will with only minimum in despite adequate to during SNP therapy, addition of an is The of SNP with or cardiac is an used in a of arterial of can be maintained in patients apparent The to and the infusion to the SNP an drug Figure surgery, particularly involve considerable blood provides a and regarding SNP toxicity, particularly in has many to reduce their on SNP infusions by with calcium or to within the range well for this but also decrease cardiac and should be in patients with impaired for may also be in may require excessive doses to the in but it may be the more drug for patients with particularly are but have a more prolonged onset to the In patients, and during and in the when of increased pressure during SNP showed that the rate of SNP high concentrations of oxygen, and to eliminate this potential effect in patients with hypertension SNP has been to have to direct effect on cerebral during and cerebral of and the resulting in which is severe enough to produce cerebral SNP, in with has been administered to patients for of within the and to decrease SNP has as the drug of in this due to concern over effects and for A of SNP to a of surgery, has assessment of SNP's effects on blood When used to the SNP may to the has many investigators to advocate a to the the of cerebral to Children and receiving SNP may be more to accelerated toxicity as previously 7. of remains a for and due to the of blood with or over of of typically in patients with in patients with adequate to surgery, and in patients with excessive hypertension occurs during hypertension can be with either IV SNP, or Some clinicians to more on SNP, the effects of which more rapidly than of to the in hypertension is during cardiac surgery, particularly after or of a Although characterized by increased and the responsible for the hypertension have that of the system and increased concentration of are to the increased pressure to and are in detail in a Regardless of the SNP is to reduce this hypertension of blood pressure during include increasing the of either IV or IV calcium and cardiac surgery, hypertension remains with an incidence reported to range between and after from increased and hypertension can function, increase myocardial oxygen patients for and increase the incidence of SNP remains a treatment for hypertension either or in with drugs and its continued use despite drugs and controversy may be a of its and of use no drug has to be to SNP in this As calcium and cause more myocardial with the of which may prove efficacious when are not increased are to and excessive doses to the blood pressure and may decrease The of SNP as a is well SNP has been used to treat hypertension after and may be the drug of for these patients in the of hypertension and increased NO is and may be a in this patient In patients with centered dot min-1 centered dot after despite adequate SNP and with additional in are significant increase in vascular pressure during is a concern for the particularly during and A increase in pressure can produce of to an or of the and SNP arterial hypertension or increasing hypertension doses of micro can be to decrease blood pressure during and contraindications to SNP use are and is that the risk for cyanide toxicity may be increased in with pathways or of rhodanase of SNP reviews have that patients with congenital or should be considered for drugs these have based their on a in the of a who mg of SNP over h after thiocyanate not be in the blood or urine. The authors that the of thiocyanate at an of cyanide since and the only known with this apparent contraindications to SNP use based this on a in in which patients with to have a in cyanide based on increased cyanide concentrations from Of interest, these patients all concentrations of plasma and thiocyanate of as well as adequate rhodanase in liver tissue on to an apparent of an decrease in production resulting in the than a specific enzyme We are aware of no reported of effects related to SNP use in patients with either or no data to knowledge that SNP use in these patients is would of patients with or when SNP is and of therapy. We believe that patients with or renal failure are at greater risk for cyanide toxicity and that this risk is than Patients with hypertension from a vascular e. g. , of the and patients with known cerebral e. g. , increased pressure or are also considered to be for SNP therapy in the use of SNP in patients was due to the of from increased time and SNP to via NO The clinical importance of this effect has been since no in blood or studies in a study of cardiac patients with hypertension with SNP The of the SNP effect is min SNP should be used in patients due to the potential for cyanide toxicity this is not a concern when SNP doses micro gram centered dot kg-1 centered dot are administered for short SNP to be used for when in and Administration The of SNP that therapy be by IV infusion at an initial rate of micro gram centered dot kg-1 centered dot min-1 to a rate of 10 micro gram centered dot kg-1 centered dot min-1, with the rate not to be infused than 10 min arterial for continuous blood pressure is 18. is by infusion with or via system IV of have also been for of blood i. e. , direct SNP should be only in in water is that the be from due to the of SNP to which would readily cause of cyanide in the patient A can eliminate cyanide at a rate to the cyanide production during a SNP infusion of approximately 2 micro gram centered dot kg-1 centered dot SNP administered at rates than 2 micro gram centered dot kg-1 centered dot min-1 results in accumulation of cyanide the concurrently sodium thiosulfate or hydroxocobalamin with SNP infusion at rates exceeding 2 micro gram centered dot kg-1 centered dot min-1, the risk of cyanide toxicity be considered 1. One way of toxicity from SNP is to SNP with drug, e. g. , or a et with a of was with considerable in drug doses to the drugs administered authors also that the dose of required for be further by administration of a to of studies several that the might prevent SNP toxicity by it with drugs as to reduce the total SNP SNP remains an and commonly used drug for the of significant arterial hypertension regardless of the for in the of when blood is normal or and for arterial an initial infusion rate of micro gram centered dot kg-1 centered dot min-1 is with as needed up to micro gram centered dot kg (-1) centered dot rates for of time min) are The use of drugs to reduce the dose or the of infusion should be considered when the micro gram centered dot kg-1 centered dot min-1 range is 1. SNP should not be used by with its and metabolic as the many of to infusion rates, particularly in patients at risk for thiosulfate stores, is and the use of drugs in with or instead of SNP should be As with many SNP administration to patients by a who its Despite its toxicity, SNP is it is the most some the drug in some clinical