| NIPRIDE® |
|Sodium Nitroprusside |
|Action And Clinical Pharmacology: Nitroprusside is a potent, rapid acting i.v. antihypertensive agent. The antihypertensive action of nitroprusside is probably due to the nitroso (NO) group. Its effect is almost immediate and usually ends when the i.v. infusion is stopped. The brief duration of the drug's action is due to its rapid biotransformation. The hypotensive effect is augmented by ganglionic blocking agents. The hypotensive effects of nitroprusside are caused by peripheral vasodilation as a result of a direct action on the blood vessels, independent of autonomic innervation. No relaxation is seen in the smooth muscle of the uterus or duodenum in situ in animals.
Nitroprusside administered i.v. to hypertensive and normotensive patients produced a marked lowering of the arterial blood pressure, a slight increase in heart rate, a mild decrease in cardiac output, and a moderate diminution in calculated total peripheral vascular resistance.
The decrease in calculated total peripheral vascular resistance suggests arteriolar vasodilation. The decreases in cardiac and stroke index noted may be due to the peripheral vascular pooling of blood.
Indications And Clinical Uses: Treatment of acute hypertension refractory to standard therapeutic measures.
Nitroprusside is also indicated for producing controlled hypotension during anesthesia in order to reduce bleeding in surgical procedures where surgeon and anesthesiologist deem it appropriate. In each case, the benefit-risk ratio should be carefully considered on an individual basis.
Contra-Indications: Nitroprusside should not be used in the treatment of compensatory hypertension, e.g., arteriovenous shunt or coarctation of the aorta. It is also contraindicated in physically poor risk patients (ASA Risk 5), in patients with uncorrected anemia or hypovolemia or in those with known inadequate cerebral circulation.
Controlled hypotension during anesthesia induced by nitroprusside is contraindicated in patients with liver disease, severe renal disease, Leber's optic atrophy, tobacco amblyopia and disease states associated with vitamin B12 deficiency.
Manufacturers' Warnings In Clinical States: Nitroprusside is only to be used as an infusion with sterile 5% dextrose in water. Not for direct injection.
Nitroprusside can cause precipitous decreases in blood pressure. In patients not properly monitored, these decreases can lead to irreversible ischemic injuries or death. Nitroprusside should be used only when available equipment and personnel allow blood pressure to be continuously monitored.
Except when used briefly or at low (<2 µg/kg/min) infusion rates, nitroprusside injection gives rise to important quantities of cyanide ion, which can reach toxic, potentially lethal levels. The usual dose rate is 0.5 to 8 µg/kg/min, but infusion at the upper dose rate should never last more than 10 minutes. If blood pressure has not been adequately controlled after 10 minutes of infusion at 8 µg/kg/min, administration of nitroprusside should be terminated immediately. Infusion rates greater than 8 µg/kg/min are virtually never required.
Although acid-base balance and venous oxygen concentration should be monitored and may indicate cyanide toxicity, these laboratory tests provide imperfect guidance.
Fatalities due to cyanide poisoning have occurred following nitroprusside administration. One factor is common to all known cases, namely that large amounts of nitroprusside were infused at high rates. Since detoxification relies upon enzymatic action, the rare possibility of deficient or atypical enzymes occurring in humans should always be considered. Patients most apt to run into difficulty are those who are resistant to the hypotensive effect or those in whom maintenance at the selected blood pressure level is difficult or impossible.
Constant attention to the patient's dose-response characteristics is mandatory. If infusion rates are in excess of 8 µg/kg/min. determine the nature of the response (effective constant response at higher dose; tachyphylactic; resistant - none or less than the expected). As soon as either tachyphylaxis or resistance is determined, the infusion of nitroprusside should be discontinued immediately. In abnormal responders, acid-base balance should be monitored since metabolic acidosis is evidence of cyanide toxicity.
Nitroprusside infusions at rates above 2 µg/kg/min generate cyanide ion (CN faster than the body can normally dispose of it. (When sodium thiosulfate is given, the body's capacity for CNelimination is greatly increased.) Methemoglobin normally present in the body can buffer a certain amount of CN but the capacity of this system is exhausted by the CNproduced from about 500 µg/kg of nitroprusside (see Pharmacology). This amount of nitroprusside is administered in approximately 1 hour when the drug is administered at 8 µg/kg/min.
Nitroprusside is metabolized to cyanide and then to thiocyanate, which in turn is excreted by the kidney (see Pharmacology). If excessive amounts of nitroprusside are used, thiocyanate toxicity (e.g., tinnitus, blurred vision (miosis), delirium hyperreflexia) may occur. Estimating the thiocyanate blood levels will help to determine thiocyanate toxicity but may not reflect cyanide toxicity. Thiocyanate is mildly neurotoxic at serum levels of 60 mg/L (1 mmol/L). Thiocyanate toxicity is life-threatening when levels are 3 or 4 times higher (200 mg/L).
Since thiocyanate inhibits both the uptake and binding of iodine, caution should be exercised in using nitroprusside in patients with hypothyroidism and patients with severe renal impairment.
Blood levels of thiocyanate should be determined if treatment is to be extended. This monitoring is critical in patients with severe renal dysfunction. Although nitroprusside i.v. infusions are not intended for long-term use, as long as blood thiocyanate levels are measured daily and do not exceed 100 mg/L, it is probably safe to continue with the infusion until the patient can be safely treated with oral antihypertensive medications. Peritoneal dialysis can be helpful if too high levels of thiocyanate are found.
Hypertensive patients are more sensitive to the i.v. effect of nitroprusside than are normotensive subjects. Patients who are also receiving concomitant antihypertensive medications (specifically, hydralazine or hexamethonium) are more sensitive to the hypotensive effect of nitroprusside; the dosage of nitroprusside should be adjusted downward accordingly.
Signs of cerebral underperfusion, such as confusion and somnolence, may occur if blood pressure is reduced too rapidly, especially in hypertensive patients with encephalopathy.
There is marked variation in individual sensitivity to the antihypertensive action of nitroprusside.
The following warnings apply to the use of nitroprusside for controlled hypotension during anesthesia: 1. Extreme caution should be exercised in patients who are especially poor surgical risks (ASA class 4 and 4E). 2. Tolerance to blood loss, anemia and hypovolemia may be diminished. If possible, pre-existing anemia and hypovolemia should be corrected prior to employing controlled hypotension. 3. Hypotensive anesthetic techniques may alter pulmonary ventilation perfusion ratio. Patients intolerant of additional dead air space at ordinary oxygen partial pressure may benefit from higher oxygen partial pressure. 4. Resistance and tachyphylaxis occur more frequently in normotensive patients infused with nitroprusside. Induction of deliberate hypotension in healthy young individuals may prove to be more difficult than in other segments of the population. 5. Upon discontinuation of the nitroprusside infusion for the purpose of controlled hypotension during anesthesia a rebound hypertension has been observed on rare occasions.
Pregnancy: The safety of nitroprusside in women who are or who may become pregnant has not been established; hence, it should be given only when the potential benefits have been weighed against possible hazard to mother and child.
Precautions: Adequate facilities, equipment and trained personnel should be available for frequent and vigilant monitoring of blood pressure. The hypotensive effects of nitroprusside occur rapidly, and blood pressure usually begins to rise immediately and returns to pretreatment values within 1 to 10 minutes when the infusion is slowed or stopped. It should be used with caution and initially in low doses in elderly patients, since they may be more sensitive to the drug's hypotensive effects.
Because of the rapid onset of action and potency of nitroprusside, it should be administered with the use of an infusion pump, micro-drip regulator, or any similar device that would allow precise measurement of the flow rate.
If, in the clinical situation, stress, induced by pain or manipulation, is reduced or eliminated during nitroprusside infusion, the patient could experience a greater than expected reduction in blood pressure unless the rate of infusion is adjusted downward as required.
Several authors have reported tachyphylaxis in young male patients during hypotensive anesthesia. However, tachyphylaxis has not been reported to date with nitroprusside in the treatment of hypertensive emergencies.
Once dissolved in solution, nitroprusside tends to deteriorate in the presence of light. It should be protected from light by wrapping the container of the prepared solution with aluminum foil or other opaque materials. Solutions of nitroprusside should not be kept or used longer than 12 hours. Nitroprusside in aqueous solution yields the nitroprusside ion, which reacts with even minute quantities of a wide variety of inorganic and organic substances to form usually highly colored reaction products (blue, green or dark red). If this occurs, the infusion should be replaced as quickly as possible.
Adverse Reactions: Fatalities due to cyanide poisoning have occurred following nitroprusside administration (see Warnings).
Nausea, retching, emesis, diaphoresis, apprehension, headache, restlessness, agitation, muscle twitching, retrosternal discomfort and chest pain, palpitations, dizziness, faintness, weakness, rash, abdominal pain, confusion and somnolence have been noted with too rapid reduction in blood pressure, but these symptoms rapidly disappeared with slowing of the rate of infusion or temporary discontinuation of infusion and did not reappear with continued slower rate of administration.
Irritation of the injection site may occur.
One case of hypothyroidism following prolonged therapy with i.v. nitroprusside has been reported. Thiocyanate blood levels were 95 µg/mL after 21 days of nitroprusside administration to this patient with severe hypertension and renal disease.
Methemoglobinemia has been reported in the literature. Nitroprusside infusions can cause sequestration of hemoglobin as methemoglobin (see Pharmacology). Clinically significant methemoglobinemia (>10%) is seen only rarely in patients receiving nitroprusside. Methemoglobinemia should be suspected in patients who have received >10 mg/kg of nitroprusside and who exhibit signs of impaired oxygen delivery.
Symptoms And Treatment Of Overdose: Symptoms: Overdosage of nitroprusside can be manifested as excessive hypotension or cyanide toxicity or as thiocyanate toxicity. In moderate cases, the signs are dyspnea, headache, vomiting, dizziness, ataxia and loss of consciousness. Massive overdosage produces coma with imperceptible pulse, absent reflexes, widely dilated pupils, pink color, distant heart sounds, hypotension and very shallow breathing. Relief with oxygen alone is not seen. Death may result. High overdosage also results in the occurrence of hyperkalemia and metabolic acidosis which will require appropriate corrective measures.
Treatment of cyanide toxicity: Cyanide levels can be measured by many laboratories, and blood-gas studies that can detect venous hyperoxemia or acidosis are widely available. Acidosis may not appear until more than an hour after the appearance of dangerous cyanide levels, and laboratory tests should not be awaited. Reasonable suspicion of cyanide toxicity is adequate grounds for initiation of treatment.
The treatment of cyanide toxicity consists of: discontinuing the administration of nitroprusside, providing a buffer for cyanide by using sodium nitrite to convert as much hemoglobin into methemoglobin as the patient can safely tolerate; and then infusing sodium thiosulfate in sufficient quantity to convert the cyanide into thiocyanate.
Treatment: (a) Discontinue immediately nitroprusside infusion or any other medication. (b) If the patient is conscious, administer amyl nitrite ampuls immediately by inhalation, 1 for 30 seconds every 2 minutes, unless pressure is below 80 mm Hg. If there is a delay in obtaining 3% sodium nitrite solution, amyl nitrite may be repeated as indicated. (c) Follow as soon as possible (but not together with amyl nitrite) with i.v. injection of 10 mL of 3% sodium nitrite over a 3 minute period (i.v. infusion of noradrenaline may be necessary to maintain blood pressure during this injection). (d) Administer 50 mL of 25% sodium thiosulfate i.v. over a 10 minute period following the sodium nitrite administration. (e) Institute supportive measures as soon as possible, e.g. artificial respiration with 100% oxygen. (f) Administration of sodium nitrite and sodium thiosulfate may have to be repeated if symptoms reappear, with a 50% dosage reduction. (g) Peritoneal dialysis may be helpful in reducing thiocyanate concentrations. (h) Undertake constant monitoring for cyanide and thiocyanate blood levels. (i) If a severe and prolonged hypoxemia results due to excessive methemoglobinemia inhalation of pure oxygen or a blood transfusion may be required. (j) Further treatment should be symptomatic.
A cyanide antidote kit is available from Eli Lilly Canada Inc.
Dosage And Administration: Use of nitroprusside in anesthetized normotensive patients undergoing deliberate hypotensive surgery must be restricted to carefully selected cases. There is a possibility of an abnormal response occurring in normotensive patients. In the event of an abnormal response, the infusion of nitroprusside should be discontinued immediately (see Warnings).
Dissolve the contents of the 50 mg vial in 3 mL of sterile 5% dextrose in water without preservatives. No other diluents should be used. Depending on the desired concentration, dilute all of the prepared stock solution in 500 to 1 000 mL of sterile 5% dextrose in water and promptly wrap container in aluminum foil or other opaque material to protect from light. Both the stock solution and the infusion solution should be freshly prepared and any unused portion discarded. The freshly prepared solution for infusion has a very faint brownish tint. Discard if highly colored (see Precautions).
Once prepared, the solution should not be kept or used longer than 12 hours. Do not employ the infusion fluid used for nitroprusside administration as a vehicle for simultaneous administration of any other drug.
Administer the i.v. infusion by an infusion pump, micro-drip regulator or any similar device that will allow precise measurement of the flow rate (see Table I). Care should be taken to avoid extravasation.
In patients who are not receiving antihypertensive drugs, the average dose of nitroprusside for both adults and children, is 3 µg/kg/minute (range of 0.5 to 8 µg/kg/minute). Usually, at 3 µg/kg/minute, blood pressure can be lowered by about 30 to 40% below the pretreatment diastolic levels and maintained.
In hypertensive patients receiving concomitant antihypertensive medications, smaller doses are required.
In order to avoid excessive thiocyanate levels and to lessen the possibility of a precipitous drop in blood pressure, infusion rates greater than 8 µg/kg/minute should rarely be used. If, at this rate, an adequate blood pressure reduction is not obtained within 10 minutes, administration of nitroprusside should be stopped.
Nitroprusside dosage varies considerably from patient to patient; hence the need for individual titration. Start the infusion at the lower dosage range, 0.5 µg/kg/min. and adjust in increments of 0.2 µg/kg/min., usually every 5 minutes, until the desired blood pressure reduction is obtained. Continuous, careful blood pressure monitoring on a minute to minute basis is necessary. Adjustments in the rate of infusion may be required to keep the blood pressure smoothly controlled and prevent extremes of hypotension and hypertension.
The blood pressure usually starts to drop immediately or at least within a few minutes. It is recommended that the blood pressure should not be allowed to drop at a too rapid rate and that the systolic pressure should not be lowered below 60 mm Hg. Too rapid a reduction in blood pressure may result in retching or vomiting, muscular twitching, diaphoresis and agitation. These symptoms subside promptly when the rate of infusion is slowed or temporarily stopped.
In hypertensive emergencies nitroprusside infusion may be continued until the patient can safely be treated with oral antihypertensive medications alone.
Availability And Storage: Each 5 mL amber colored ampul contains: sodium nitroprusside USP 50 mg. Reconstitute with 3 mL of sterile 5% dextrose in water only and dilute with sterile 5% dextrose in water only. Sodium: <1 mmol (9.2 mg)/ampul. Alcohol-, paraben- and sulfite-free. Packs of 10. Store powder at 15 to 30°C. Protect the reconstituted powder and i.v. infusion fluid from light.