Uses and Indications
In 1991, the Food and Drug Administration updated the package insert for SNP, emphasizing the risk of cyanide toxicity and recommending that smaller doses be used . The drug remains indicated for immediate reduction of arterial blood pressure in hypertensive emergencies and for induced hypotension during surgery to reduce operative bleeding . Clearly, clinicians continue to use SNP for a wide range of other medical and surgical indications.
Since the early 1960s, SNP has been considered an option for treating hypertensive emergencies after failure of less potent drugs [31,38]. SNP possesses many favorable characteristics that have made it the mainstay of aggressive management of hypertensive crises . Rapid onset, ease of titration, and rapid dissipation of its effects after discontinuation, and almost universal efficacy (regardless of the etiology of hypertension) contribute to the drug's popularity [18,19]. SNP typically acts within 30 s; its effects persist 2-4 min after cessation of infusion [18,19]. SNP has been used to successfully treat all forms of hypertensive emergencies, including malignant hypertension and hypertensive encephalopathy, whether caused by renovascular disease, pheochromocytoma, cerebral hemorrhage, aortic coarctation, postoperative status, toxemia of pregnancy, or "essential" hypertension [18,19,31,38,39]. Current opinion favors SNP used as a temporary measure with replacement by longer-lasting medications as soon as feasible [5,18].
Acute and Chronic Heart Disease
Use of SNP after acute myocardial infarction was first reported in 1972. These patients were treated with SNP infusions to reduce afterload, decrease the left-ventricular filling pressure, and increase the CO [19,31,40,41]. Subsequent studies have confirmed benefit from SNP infusion in severe mitral or aortic regurgitation, severe congestive heart failure, and after acute myocardial infarction complicated by left-ventricular failure [19,31,40,42-44]. In 1976, a new controversy arose concerning the effects of SNP on ischemic myocardium after acute myocardial infarction [19,40,45]. Increased ST segments on electrocardiogram were noted in patients treated with SNP shortly after the diagnosis of myocardial infarction; other patients treated with nitroglycerin demonstrated reduced ST segment signs of ischemia . Subsequent work comparing the two drugs favored nitroglycerin for myocardial ischemia, due to emerging concern that SNP might produce coronary "steal" [40,46], which may occur when vasodilated small resistance vessels in the myocardium shunt blood away from areas of ischemia . The clinical significance of coronary steal remains unclear; other reports have demonstrated improvement in ST segments after treatment with SNP . In 1982, a study looking at the use of SNP in 812 patients with left-ventricular dysfunction after acute myocardial infarction determined that SNP worsened patient outcome when used within the first 8 h of an acute myocardial infarction. In patients with left-ventricular failure which persisted more than 8 h after myocardial infarction, SNP improved outcome [40,49]. In recent years, clinicians have tended to use nitroglycerin in preference to SNP after acute myocardial infarction; however, in these patients with continuing left-ventricular dysfunction, particularly in association with regurgitant valvular lesions, SNP can rapidly improve cardiac function and clinical stability, provided adequate ventricular filling is maintained [18,40,44].
In many studies of chronic congestive heart failure, regardless of the etiology, SNP has improved CO [18,19,48,50-53]. Enhancement of ventricular function is secondary to reduced impedance to ventricular ejection, permitting the ventricle to eject to a lower end-diastolic volume [18,19,53]. Preload is reduced by blood pooling in venous capacitance vessels, further contributing to decreased ventricular end-diastolic volume [18,19,53]. When filling pressures are increased, SNP will improve CO with only minimum increases in heart rate. If, despite adequate filling pressures, CO fails to improve during SNP therapy, then addition of an inotrope is indicated. The combination of SNP with dopamine, dobutamine, or epinephrine significantly improves cardiac performance [19,43,50,51] Figure 3.
Induced Intraoperative Hypotension
Purposeful hypotension is an anesthetic technique used in a variety of surgical procedures. Mean arterial pressures (MAP) of 50-60 mm Hg can be maintained in healthy patients without apparent complication [54,55]. The ability to rapidly, reversibly, and (somewhat) predictably titrate the infusion to achieve the desired MAP makes SNP nearly an ideal drug Figure 4. Orthopedic surgery, particularly major spinal operations, often involve considerable blood loss. Induced hypotension provides a relatively bloodless field and reduces transfusion requirements [6,18,19,54]. Concern regarding SNP toxicity, particularly in children, has prompted many anesthesiologists to reduce their reliance on SNP infusions by supplementing with beta-adrenergic receptor blockers, calcium channel blockers, nitroglycerin, or volatile anesthetics to maintain MAP within the targeted hypotensive range [19,54]. beta-Adrenergic receptor blockers work well for this purpose, but also decrease cardiac index (CI) and should be avoided in patients with impaired left-ventricular function. Calcium channel blockers, save for nicardipine, may also be inappropriate in reduced left-ventricular function [56,57]. Nitroglycerin may require excessive doses to achieve the target reduction in MAP, but it may be the more appropriate drug for patients with coronary artery disease. Volatile anesthetics, particularly isoflurane, are effective but have a more prolonged onset to achieve the desired MAP .
In neurosurgical patients, induced hypotension facilitates exposure and access during transsphenoidal hypophysectomy and intracranial aneurysm repair [18,19,31,54]. Concern arose in the late 1970s when there were reports of increased intracranial pressure during SNP infusion. However, subsequent reports showed that slowing the rate of SNP infusion, high inspired concentrations of oxygen, and hyperventilation appeared to eliminate this potential side effect in patients with intracranial hypertension . Furthermore, SNP has been shown to have to direct effect on cerebral vasculature during cardiopulmonary bypass and indeed preserves cerebral autoregulation .
Surgical repair of thoracic aortic aneurysms, dissections, and coarctations involves cross-clamping the aorta resulting in immediate, proximal hypertension, which unless treated is severe enough to produce cerebral edema. SNP, in conjunction with beta-adrenergic receptor blockers has been administered to aneurysm patients preoperatively for reduction of shearing forces within the dissecting lumen and intraoperatively to decrease proximal MAP. SNP has largely replaced trimethaphan as the drug of choice in this setting, due to concern over trimethaphan's side effects and tendency for tachyphylaxis. A possible contribution of SNP to spinal cord ischemia, a devastating complication of aortic surgery, has prompted rigorous assessment of SNP's effects on spinal cord blood flow. When used to control proximal (to the aortic clamp) hypertension, SNP may aggravate hypotension distal to the clamp. This has led many investigators to advocate a target MAP (proximal to the clamp) just below the upper limits of cerebral autoregulation to maintain spinal cord perfusion . Children undergoing aortic surgery and receiving SNP may possibly be more prone to accelerated toxicity as previously stated .
Safe resection of pheochromocytomas remains a challenge for surgeons and anesthesiologists, due to the extreme intraoperative lability of blood pressure. Standard preoperative management includes alpha-adrenergic receptor blockade with oral phenoxybenzamine or prazosin over 1-2 wk . Slow initiation of alpha-adrenergic receptor blockade permits restoration of intravascular volume, typically reduced in patients with untreated pheochromocytomas. Occasionally in patients with apparently adequate alpha-blockade prior to surgery, and frequently in patients with untreated pheochromocytomas, excessive hypertension occurs during resection. This hypertension can be controlled with either IV phentolamine, SNP, or both. Some clinicians prefer to rely more heavily on SNP, the effects of which dissipate more rapidly than those of phentolamine, to avoid the postoperative hypotension frequently complicating pheochromocytoma resection .
Uses in Cardiac Surgery
Intraoperative Hypertension Systemic hypertension is frequent during cardiac surgery, particularly after coronary artery bypass grafting or replacement of a stenotic aortic valve [51,62,63]. Although characterized by increased SVR, filling pressures, and heart rate, the mechanisms responsible for the hypertension remain unclear. Various theories have proposed that activation of the renin-angiotensin system and increased concentration of circulating catecholamines are major contributors to the increased pressure . These hormonal responses to cardiopulmonary bypass and surgery are reviewed in detail in a recent text . Regardless of the etiology, SNP is often chosen to reduce this hypertension [51,62,63]. Alternative methods of blood pressure control during coronary artery bypass surgery include increasing the depth of anesthesia (with either volatile anesthetics, IV opioids, or IV sedatives), calcium channel blockers, beta-adrenergic receptor blockers, and nitroglycerin [51,62,63,65].
Postoperative Hypertension After successful cardiac surgery, hypertension remains common, with an incidence variably reported to range between 30% and 60% [66-68]. Early after separation from cardiopulmonary bypass, increased SVR and hypertension can depress left-ventricular function, increase myocardial oxygen consumption, predispose patients for postoperative bleeding, and increase the incidence of arrhythmias [51,66,69]. SNP remains a common treatment for postoperative hypertension either alone or in combination with other drugs and its continued use despite newer drugs and ongoing controversy may be a reflection of its efficacy and ease of use [19,52,66,70-74]. Moreover, no other drug has proven to be superior to SNP in this setting. As noted earlier, calcium channel blockers and beta-adrenergic receptor blockers cause more myocardial depression with the exception of nicardipine which may prove equally efficacious when filling pressures are not increased . Longacting vasodilators are difficult to titrate acutely, and nitroglycerin often requires excessive doses to achieve the desired blood pressure reduction and may decrease CO [62,66,68,71-77].
The efficacy of SNP as a pulmonary vasodilator is well known. SNP has been used to treat postoperative pulmonary hypertension after heart valve replacement, and may be the drug of choice for these patients in the setting of systemic hypertension and increased filling pressures [57,78]. Inhaled NO is currently under investigation and may be a promising replacement in this patient population [79,80].
In pediatric patients with low CI (CI < 2.0 L centered dot min-1 centered dot m-2) after cardiopulmonary bypass, despite adequate filling pressures, SNP increases CI, and if combined with epinephrine additional increases in CI are noted without significant increase in systemic vascular resistance  Figure 3.
Increased intraocular pressure during ophthalmic surgery is a concern for the anesthesiologist, particularly during intubation and extubation. A sudden increase in intraocular pressure can produce permanent loss of vision secondary to hemorrhage, vitreous extrusion (with an "open" eye injury), or prolapse of the iris and lens. SNP effectively controls arterial hypertension without causing or increasing intraocular hypertension . Bolus doses of 1-2 micro gram/kg can be given to decrease blood pressure during laryngoscopy and extubation .
Medical contraindications to SNP use are rare and largely theoretical. It is possible that the risk for cyanide toxicity may be increased in individuals with abnormal cyanide-thiocyanate pathways or decreased availability of hepatic rhodanase enzyme. Generations of SNP reviews have stated that patients with congenital Leber's optic atrophy (LOA) or tobacco amblyopia (TA) should be considered candidates for alternative drugs [18,19,31]. However, these previous publications have based their statements on a case report published in 1975 involving the death of a 14-yr-old male who received 400 mg (10 mg/kg) of SNP over 80 min. At autopsy 20 h after death, thiocyanate could not be detected in the blood or urine. The authors surmised that the absence of thiocyanate at autopsy implied an abnormality of cyanide metabolism and, since LOA and TA were the only known pathologic states with this same apparent abnormality, they declared them contraindications to SNP use [83,84]. They based this suggestion on a report published in 1965 in which patients with LOA were shown to have a possible defect in cyanide metabolism based on increased cyanide concentrations from tobacco smoking. Of interest, these LOA patients all had detectable concentrations of both plasma and urine thiocyanate (>50% of control concentrations), as well as adequate rhodanase activity in liver biopsy tissue . Recent publications on LOA point to an apparent multitude of genetic defects causing an overall decrease in cell energy production resulting in the disease, rather than a specific enzyme defect [86-88]. We are aware of no reported cases of adverse effects related to actual SNP use in patients diagnosed with either LOA or TA. Likewise, no data exists to our knowledge showing that SNP use in these patients is safe. Prudence would dictate close monitoring of patients with LOA or TA when SNP is deemed necessary and early consideration of alternative therapy.
We believe that patients with hepatic or renal failure are at greater risk for cyanide toxicity and that this risk is actual, rather than theoretical. Patients with compensatory hypertension from a primary vascular lesion, e.g., untreated coarctation of the aorta, and those patients with known inadequate cerebral perfusion, e.g., dangerously increased intracranial pressure or symptomatic carotid artery stenosis, are also considered to be inappropriate candidates for SNP therapy [18,89].
Caution in the use of SNP in patients undergoing cardiopulmonary bypass was advised due to the theoretical possibility of enhanced bleeding from increased bleeding time and decreased platelet aggregation [90,91]. SNP appears to impair platelet actions via NO . The clinical importance of this effect has been questioned, since no differences in blood product requirements, mediastinal drainage, or postoperative coagulation studies were noted in a retrospective study of cardiac surgical patients with postoperative hypertension treated with SNP . The duration of the SNP platelet effect is apparently 5-25 min .
SNP should be used cautiously in pregnant patients due to the potential for fetal cyanide toxicity [18,89,94]. However, this is not a major concern when modest SNP doses (<3 micro gram centered dot kg-1 centered dot min-1) are administered for short durations; SNP continues to be used for acute afterload reduction when indicated in parturients .
Dose and Administration
The manufacturers of SNP currently recommend that therapy be initiated by IV infusion at an initial rate of 0.3 micro gram centered dot kg-1 centered dot min-1 titrated to a maximum rate of 10 micro gram centered dot kg-1 centered dot min-1, with the maximum rate not to be infused longer than 10 min [6,89]. An indwelling arterial catheter for continuous blood pressure monitoring is recommended . Delivery is recommended by infusion pump with manual titration or via computerized closed-loop titration system . IV boluses of 1-2 ng/kg have also been recommended for rapid lowering of blood pressure, i.e., aneurysm clipping, direct laryngoscopy . SNP should be mixed only in 5% dextrose in water . It is important that the solution be protected from light continuously due to the rapid conversion of SNP to aquapentacyanoferrate ion, [Fe(CN)sH2 O]2-, which would readily cause release of hydrogen cyanide in the patient .
A healthy person can eliminate cyanide hepatically at a rate equivalent to the cyanide production during a SNP infusion of approximately 2 micro gram centered dot kg-1 centered dot min-1 [8,9,11]. SNP administered at rates higher than 2 micro gram centered dot kg-1 centered dot min-1 therefore results in dosedependent accumulation of cyanide radicals. Unless the clinician concurrently infuses sodium thiosulfate or hydroxocobalamin with SNP infusion at rates exceeding 2 micro gram centered dot kg-1 centered dot min-1, the dose-dependent risk of cyanide toxicity must be considered [6,8,9,11,89] Table 1.
One potentially useful way of avoiding toxicity from SNP is to combine SNP with another drug, e.g., trimetaphan or a beta-adrenergic receptor blocker. MacRae et al.  induced hypotension with a 10:1 mixture of trimetaphan:SNP. Controlled hypotension was produced easily with considerable reduction in drug doses compared to the two drugs administered separately [95,96]. These same authors also observed that the dose of trimetaphan:SNP required for controlled hypotension could be further reduced by oral administration of a beta-adrenergic receptor blocker prior to induction of anesthesia . These studies illustrate several ways that the clinician might prevent SNP toxicity by coadministering it with other drugs so as to reduce the total SNP dose.
SNP remains an effective, reliable, and commonly used drug for the rapid reduction of significant arterial hypertension regardless of the etiology, for afterload reduction in the face of low CO when blood volume is normal or increased, and for intraoperative induced hypotension. After establishing indwelling arterial monitoring, an initial infusion rate of 0.3-0.5 micro gram centered dot kg-1 centered dot min-1 is begun with titration as needed up to 2.0 micro gram centered dot kg (-1) centered dot min-1. Higher rates for brief periods of time (10 min) are acceptable. The use of alternative drugs to reduce the dose or shorten the duration of infusion should be considered when the 2.0 micro gram centered dot kg-1 centered dot min-1 range is exceeded Table 1.
SNP should not be used by individuals unfamiliar with its potency and metabolic pathways, as the many reports of adverse reactions testify. Careful attention to infusion rates, particularly in patients at risk for depleted thiosulfate stores, is mandatory, and the use of other drugs in conjunction with or instead of SNP should always be considered. As with many therapeutic interventions, SNP requires careful administration to appropriately selected patients by a clinician who knows its inherent hazards. Despite its toxicity, SNP is popular because it is often the most (in some cases, the only) effective drug in some difficult clinical circumstances.
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