Source: Medicines and Medical Devices Safety Authority (NZ) Revision Year: 2019 Publisher: Pfizer New Zealand Limited, P O Box 3998, Auckland, New Zealand, 1140, Toll Free Number: 0800 736 363
Sodium 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 with known inadequate cerebral circulation or in moribund patients (ASA Risk 5), in patients with uncorrected anaemia or hypovolaemia, severe renal disease or disease states associated with vitamin B12 deficiency.
Patients with congenital (Leber’s) optic atrophy or with tobacco amblyopia have unusually high cyanide/thiocyanate ratios. These rare conditions are probably associated with defective or absent rhodanase, and sodium nitroprusside should be avoided in these patients.
Sodium nitroprusside should not be used for the treatment of acute congestive heart failure associated with reduced peripheral vascular resistance such as high-output heart failure that may be seen in endotoxic sepsis.
SODIUM NITROPRUSSIDE IS ONLY TO BE USED AS AN INFUSION WITH STERILE 5% GLUCOSE IN WATER. IT SHOULD NOT BE ADMINISTERED BY DIRECT INJECTION.
The principal hazards of sodium nitroprusside administration are excessive hypotension and excessive accumulation of cyanide (see section 4.9 and section 4.2).
Sodium nitroprusside can cause precipitous decreases in blood pressure (see section 4.2). In patients not properly monitored, these decreases can lead to irreversible ischemic injuries or death. Sodium nitroprusside should be used only when available equipment and personnel allow blood pressure to be continuously monitored.
Small transient excesses in the infusion rate of sodium nitroprusside can result in excessive hypotension, sometimes to levels so low as to compromise the perfusion of vital organs. These haemodynamic changes may lead to a variety of associated symptoms (see section 4.8). Nitroprusside induced hypotension will be self limited within 1 to 10 minutes after discontinuation of the nitroprusside infusion; during these few minutes, it may be helpful to put the patient into a head down (Trendelenburg) position to maximise venous return. If hypotension persists more than a few minutes after discontinuation of the infusion of sodium nitroprusside, sodium nitroprusside is not the cause, and the true cause must be sought.
Except when used briefly or at low (less than 2 micrograms/kg/min) infusion rates, sodium nitroprusside gives rise to important quantities of cyanide ion, which can reach toxic, potentially lethal levels. (When sodium thiosulfate is given, as described under section 4.2, the body’s capacity for CNelimination is greatly increased.)
The usual dose rate is 0.5 to 10 microgram/kg/min, but infusion at the maximum dose rate should never last more than 10 minutes. If blood pressure has not been adequately controlled after 10 minutes of infusion at the maximum rate, administration of sodium nitroprusside should be terminated immediately.
Methaemoglobin 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 microgram/kg of sodium nitroprusside. This amount of sodium nitroprusside is administered in less than an hour when the medicine is administered at 10 microgram/kg/min (the maximum recommended rate). Thereafter, the toxic effects of CN- may be rapid, serious, and even lethal.
The true rates of clinically important cyanide toxicity cannot be assessed from spontaneous reports or published data. Most patients reported to have experienced such toxicity have received relatively prolonged infusions, and the only patients whose deaths have been unequivocally attributed to nitroprusside induced cyanide toxicity have been patients who had received nitroprusside infusions at rates (30 to 120 microgram/kg/min) much greater than those now recommended. Elevated cyanide levels, metabolic acidosis, and marked clinical deterioration, however, have occasionally been reported in patients who received infusions at recommended rates for only a few hours and even, in one case, for only 35 minutes. In some of these cases, infusion of sodium thiosulfate caused dramatic clinical improvement, supporting the diagnosis of cyanide toxicity.
Cyanide toxicity may manifest itself as venous hyperoxaemia with bright red venous blood, as cells become unable to extract the oxygen delivered to them; metabolic (lactic) acidosis; air hunger; confusion; and death. Cyanide toxicity due to causes other than nitroprusside has been associated with angina pectoris and myocardial infarction; ataxia, seizures, and stroke; and other diffuse ischemic damage.
Hypertensive patients, and patients concomitantly receiving other antihypertensive medications, may be more sensitive to the effects of sodium nitroprusside than normal subjects.
Although acid-base balance and venous oxygen concentration should be monitored and may indicate cyanide toxicity, these laboratory tests provide imperfect guidance.
Like other vasodilators, sodium nitroprusside can cause increases in intracranial pressure. In patients whose intracranial pressure is already elevated, sodium nitroprusside should be used only with extreme caution.
Use caution when administering nitroprusside to patients with hepatic insufficiency.
When sodium nitroprusside (or any other vasodilator) is used for controlled hypotension during anaesthesia, the patient’s capacity to compensate for anaemia and hypovolaemia may be diminished. If possible, pre-existing anaemia and hypovolaemia should be corrected prior to administration of sodium nitroprusside.
Hypotensive anaesthetic techniques may also cause abnormalities of the pulmonary ventilation/perfusion ratio. Patients intolerant of these abnormalities may require a higher fraction of inspired oxygen.
Extreme caution should be exercised in patients who are especially poor surgical risks (ASA Class 4 and 4E).
Direct monitoring of blood pressure is mandatory.
Adequate facilities, equipment and personnel should be available for frequent and vigilant monitoring of blood pressure, since the hypotensive effect of sodium nitroprusside occurs rapidly.
It is recommended that the blood pressure should not be allowed to drop rapidly and the systolic pressure not be lowered below 60 mmHg. Too great a reduction in blood pressure may result in retching or vomiting, muscular twitching, diaphoresis and agitation.
When the infusion is slowed or stopped, blood pressure usually begins to rise immediately and returns to pre-treatment levels within one to ten minutes.
Sodium nitroprusside should be used with caution and initially in low doses in elderly patients, since they may be more sensitive to the hypotensive effect of the medicine.
Young, vigorous males may require somewhat larger than ordinary doses of sodium nitroprusside for hypotensive anaesthesia, however, the infusion rate of 10 micrograms/kg/minute should not be exceeded. Deepening of anaesthesia, if indicated, might permit satisfactory conditions to exist within the recommended dosage range.
Because of the rapid onset of action and potency of sodium 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.
Patients should remain recumbent during the infusion to avoid severe postural hypotensive effects.
The cyanide level assay is technically difficult, and cyanide levels in body fluids other than packed red blood cells are difficult to interpret. Cyanide toxicity will lead to lactic acidosis and venous hyperoxaemia, but these findings may not be present until an hour or more after the cyanide capacity of the body’s red cell mass has been exhausted.
Sodium 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 coloured reaction products (blue, green or dark red). If this occurs, the infusion should be replaced.
Since thiocyanate inhibits both the uptake and binding of iodine, caution should be exercised in using sodium nitroprusside in patients with hypothyroidism and severe renal dysfunction. Thyroid hormone deficiency has been reported following prolonged infusions.
The medicine should be used with extreme caution if the patient is hypothermic.
If in the clinical situation, stress, induced by pain or manipulation is reduced or eliminated during sodium 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 anaesthesia. However, tachyphylaxis has not been reported to date with sodium nitroprusside in the treatment of hypertensive emergencies.
Refer to section 4.2.
Refer to section 4.2.
Ganglion blocking agents and other antihypertensive agents, volatile liquid anaesthetics, inhaled anaesthetics, negative inotropes and most other circulatory depressants potentiate the hypotensive action of sodium nitroprusside.
The transition from sodium nitroprusside to oral antihypertensive therapy may predispose to severe, sudden hypertension.
No data available.
Category C: Drugs which, owing to their pharmacological effects, have caused or may be suspected of causing harmful effects on the human foetus or neonate without causing malformations. These effects may be reversible.
There are no adequate or well controlled studies of sodium nitroprusside in either laboratory animals or pregnant women. It is not known whether sodium nitroprusside can cause foetal harm when administered to a pregnant woman or can affect reproductive capacity. Sodium nitroprusside should be given to a pregnant woman only if clearly needed. There have been no reports on its use in the hypertension of pre-eclampsia.
Sodium nitroprusside is used in high risk situations and there may be additional hazards associated with the drug. It crosses the placenta. Short term use for control of hypertensive crises may be safe provided the maternal pH and cyanide levels are monitored.
In three studies in pregnant ewes, nitroprusside was shown to cross the placental barrier. Foetal cyanide levels were shown to be dose related to maternal levels of nitroprusside. The metabolic transformation of sodium nitroprusside given to pregnant ewes led to fatal levels of cyanide in the foetuses. The infusion of 25 micrograms/kg/minute of sodium nitroprusside for one hour in pregnant ewes resulted in the death of all foetuses. Pregnant ewes infused with 1 microgram/kg/minute of sodium nitroprusside delivered normal lambs.
It is not known whether sodium nitroprusside or its metabolites are excreted into breast milk, nor whether they have a harmful effect on the newborn. Therefore, the drug is not recommended for nursing mothers, unless the expected benefits outweigh any potential risk.
No data available.
The most important adverse reactions to sodium nitroprusside are the avoidable ones of excessive hypotension and cyanide toxicity, described above under Section 4.4. The adverse effects described in this section develop less rapidly and, as it happens, less commonly.
As described in the section 5.2 section, sodium nitroprusside infusions can cause sequestration of haemoglobin as methaemoglobin. The back conversion process is normally rapid, and clinically significant methaemoglobinaemia (>10%) is seen only rarely in patients receiving sodium nitroprusside. Even patients congenitally incapable of back converting methaemoglobin should demonstrate 10% methaemoglobinaemia only after they have received about 10 milligram/kg of sodium nitroprusside, and a patient receiving sodium nitroprusside at the maximum recommended rate (10 microgram/kg/min) would take over 16 hours to reach this total accumulated dose.
Methaemoglobin levels can be measured by most clinical laboratories. The diagnosis should be suspected in patients who have received >10 milligram/kg of sodium nitroprusside and who exhibit signs of impaired oxygen delivery despite adequate cardiac output and adequate arterial pO2. Classically, methaemoglobinaemic blood is described as chocolate brown, without colour change on exposure to air.
When methaemoglobinaemia is diagnosed, the treatment of choice is 1 to 2 milligram/kg of methylene blue, administered intravenously over several minutes. In patients likely to have substantial amounts of cyanide bound to methaemoglobin as cyanmethaemoglobin, treatment of methaemoglobinaemia with methylene blue must be undertaken with extreme caution.
As described in section 5.2, most of the cyanide produced during metabolism of sodium nitroprusside is eliminated in the form of thiocyanate. When cyanide elimination is accelerated by the co-infusion of thiosulfate, thiocyanate production is increased.
Thiocyanate is mildly neurotoxic (tinnitus, miosis, hyperreflexia) at serum levels of 1 millimol/L (60 milligram/L). Thiocyanate toxicity is life threatening when levels are 3 or 4 times higher (200 milligram/L).
The steady-state thiocyanate level after prolonged infusions of sodium nitroprusside is increased with increased infusion rate, and the half time of accumulation is 3 to 4 days. To keep the steady-state thiocyanate level below 1 millimol/L, a prolonged infusion of sodium nitroprusside should not be more rapid than 3 microgram/kg/min; in anuric patients, the corresponding limit is just 1 microgram/kg/min. When prolonged infusions are more rapid than these, thiocyanate levels should be measured daily.
Physiologic manoeuvres (e.g. those that alter the pH of the urine) are not known to increase the elimination of thiocyanate. Thiocyanate clearance rates during dialysis, on the other hand, can approach the blood flow rate of the dialyser.
Thiocyanate interferes with iodine uptake by the thyroid.
Other adverse effects reported are:
General: Too rapid reduction in blood pressure may cause adverse effects. Nausea, retching, diaphoresis, apprehension, headache, restlessness, muscle twitching, retrosternal discomfort, palpitations, dizziness, drowsiness, paraesthesial warmth, and abdominal pain have been reported during use of the drug. These symptoms, however, rapidly disappeared with slowing of the rate of infusion or temporary discontinuation of the infusion and did not reappear with continued slower rate of administration.
Cardiovascular: Tachycardia, postural hypotension, bradycardia, electro-cardiographic changes.
Dermatological: Irritation, rash and flushing, reddening of the skin at the injection site and venous streakinghave been reported. Care should be taken to avoid extravasation.
Endocrine: Since thiocyanate inhibits both uptake and binding of iodine, symptoms of hypothyroidism may occur.
Haematologic: Decreased platelet aggregation.
Neurologic: Raised intracranial pressure.
Gastrointestinal: Ileus.
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are asked to report any suspected adverse reactions https://nzphvc.otago.ac.nz/reporting/.
No data available.
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