Continuing Education Activity

Sodium nitroprusside is a medication used in the management of acute hypertension. It is a potent vasodilator and is administered as an IV infusion with intensive monitoring in place. This activity reviews the major indications, action, contraindications, and toxicity of sodium nitroprusside. This activity will also highlight the mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring) pertinent for members of the interprofessional healthcare team in the management of patients with acute hypertensive crises and related conditions.

Objectives:

• Identify the mechanism of action and administration of sodium nitroprusside.
• Describe the adverse effects and contraindications of sodium nitroprusside.
• Review the appropriate monitoring for the toxicity of sodium nitroprusside.
• Outline some interprofessional team strategies for improving care coordination and communication to optimize the clinical use of sodium nitroprusside and improve patient outcomes.

Indications

Sodium nitroprusside (SNP) is a potent vasodilator that first gained FDA approval for the treatment of severe hypertension in 1974. First discovered in 1849 by Playfair, its applications in human medicine can be traced back to the early 1920s, with the first safety and efficacy data published in 1955. After an initial delay in gaining FDA approval due to difficulty in development of a chemically stable formulation, SNP gained widespread use as a fast-acting antihypertensive agent and has been used clinically for hypertensive crises, heart failure, cardiac/vascular surgery, pediatric surgery, and a variety of other acute applications. While sodium nitroprusside potential adverse effects and toxicity have led to its replacement by newer agents in some practices, it remains a useful tool in certain difficult clinical situations that require a potent, fast-acting, titratable vasodilator.[1][2]

Sodium nitroprusside has the following FDA-approved indications:[3][4][5][6][7]

• Acute hypertensive crises
• Acute decompensated heart failure
• Induction of perioperative hypotension (to reduce blood loss)

 Off-label uses for nitroprusside include:

• Hypertension in the setting of acute ischemic stroke [8]
• Afterload reduction in acute mitral regurgitation 
• Increase cardiac output in cardiogenic shock and high SVR  
• Acute preload reduction in select patients with valvular aortic stenosis [9]

Emerging applications:

• Prevention and treatment of the "no-reflow" phenomenon in the percutaneous coronary intervention [10]
• Symptomatic treatment of schizophrenia [11]

Mechanism of Action

A water-soluble sodium salt, sodium nitroprusside is comprised of ferrous iron complexed with nitric oxide (NO) and five cyanide ions. Acting as a prodrug, SNP reacts with sulfhydryl groups on erythrocytes (as well as albumin and other proteins) to produce nitric oxide (NO). Upon binding to vascular smooth muscle, NO triggers intracellular cGMP-mediated activation of protein kinase G and subsequent inactivation of myosin light chains, resulting in relaxation of vascular smooth muscle. The result of this signaling cascade is peripheral vasodilation of both arteries and veins (with slightly more selectivity for veins). 

From a hemodynamic perspective, the net result is a decrease in systemic vascular resistance (afterload), ventricular filling pressures, and systemic blood pressure with an increase in cardiac output. Onset is rapid (within 2 minutes), and the duration of its hypotensive effect is roughly 10 minutes; these properties make nitroprusside useful in situations requiring an immediate reduction in preload or afterload. In contrast to nitroglycerin, nitroprusside causes a more balanced vasodilatory effect between arteries and veins.[12][13]

Administration

Nitroprusside is administered only as an IV infusion diluted in D5W (it is not suitable for direct injection). It must be protected from light at all times.[14]

Typical infusion rates range from 0.5 to 4 mcg/kg/minute which are then titrated to desired effect. Typical infusion concentrations for adults are 200 mcg/mL or 400 mcg/mL. 

The maximum infusion rate is approximately 10 mcg/kg/minute, not to be sustained for more than 10 minutes at a time. If sufficient blood pressure control has not been achieved at that point, alternative agents should be considered (e.g., clevidipine).

The half-life elimination of sodium nitroprusside in circulation is roughly 2 minutes. Once metabolized into thiocyanate, half-life elimination occurs in approximately three days; renal dysfunction can easily double or triple this figure.

SNP is ultimately excreted from the body via urine as thiocyanate. 

Adverse Effects

Adverse effects include the following:

• Cardiovascular:
  • Bradycardia
  • Tachycardia
  • Flushing
  • Palpitations
  • Severe hypotension
  • Electrocardiographic changes
  • Substernal chest pain
  • Shortness of breath
• Central Nervous System:
  • Headache
  • Dizziness
  • Increased intracranial pressure
  • Apprehension
  • Restlessness
• Dermatologic: 
  • Diaphoresis
  • Skin rash
  • Local skin irritation with erythematous streaking
• Endocrine/Metabolic:
  • Hypothyroidism
• Gastrointestinal:
  • Abdominal pain
  • Nausea
  • Vomiting/retching
• Hematologic/Oncologic:
  • Decreased platelet aggregation
  • Methemoglobinemia
• Musculoskeletal:
  • Muscle twitching 

Contraindications

Nitroprusside is Contraindicated in the Following Situations

• Treatment of compensatory hypertension, such as that seen with arteriovenous malformations or aortic coarctation
• SNP should not be used for inducing controlled perioperative hypotension in patients with known inadequate cerebral perfusion
• Acute heart failure with low systemic vascular resistance (e.g., septic shock)
• Leber's hereditary optic atrophy*
• Tobacco amblyopia*
• Vitamin B12 deficiency (or associated disease states)
• SNP must not be used simultaneously with phosphodiesterase inhibitors such as sildenafil, tadalafil, or Vardenafil (due to synergistic cGMP-mediated mechanism of action)
• Known hypersensitivity to nitroprusside or any component of the formulation 

*These patients are deficient in rhodanese. (rhodanese, also known as rhodanase, thiosulfate cyanide transsulfurase, thiosulfate sulfurtransferase, and thiosulfate thiotransferase, is a mitochondrial enzyme that detoxifies cyanide by converting it to thiocyanate).

Precautions

• Before use for controlled perioperative hypotension, correct any underlying hypovolemia and/or anemia (if possible) 
• Use extreme caution in the setting of acute myocardial infarction in consideration of SNP's potent hemodynamic effects and potential for inducing coronary steal
• In the setting of hepatic impairment, use extreme caution; monitor closely for cyanide toxicity 
• In the setting of renal dysfunction, use the lowest possible dose and monitor closely for thiocyanate toxicity

Additional Considerations

Pregnancy Category C

• Although there is only limited information regarding the use of SNP in pregnancy, there have been animal studies that demonstrate its ability to cross the placental barrier, causing a dose-dependent increase in fetal cyanide levels. 

Breastfeeding Considerations

• While it is unclear if SNP is present in breast milk, the potential for serious adverse reactions in the infant warrant either discontinuation of breastfeeding or discontinuation of SNP depending on the clinical scenario.

Monitoring

Intensive hemodynamic monitoring is critical when administering nitroprusside. As a result, the use of SNP has classically been restricted to highly monitored settings such as the ICU or operating theater. Continuous blood pressure monitoring is required using an indwelling arterial line. With prolonged infusions or high infusion rates, close attention should also be paid to acid-base balance and mixed venous oxygen concentration, as unexplained acidemia and/or hypoxemia are often early signs of cyanide toxicity. However, It should be noted that these laboratory measures may not always provide reliable guidance. In most settings, serum cyanide concentrations are not of practical use due to long turnaround times. Thiocyanate levels can be monitored in high-risk patients (those with renal dysfunction and/or infusions >3 days).[15]

Toxicity

The toxicity of nitroprusside is related to its potent antihypertensive effects and the accumulation of toxic metabolites (cyanide, thiocyanate, and methemoglobin).[16]

1. Cyanide toxicity: Nitroprusside combines with hemoglobin and is subsequently metabolized to 5 cyanide ions and cyanmethemoglobin. Cyanide then converts to thiocyanate via rhodanese-mediated donation of a sulfur group (from thiosulfate or cysteine); this final step can quickly become overwhelmed with large quantities of the drug.

• Patients at high risk for cyanide toxicity include those with hepatic impairment, malnourishment, vitamin B12 deficiency states, patients on cardiopulmonary bypass, and those undergoing therapeutic hypothermia. 
• Cyanide toxicity may manifest in the form of metabolic acidosis, hypoxemia, bradycardia, altered mental status (e.g., confusion), and/or convulsions.
• If cyanide toxicity is suspected, the administration should be stopped immediately, and antidotal therapy given, preferably using a combination of hydroxocobalamin (to bind intracellular cyanide) and sodium thiosulfate (to act as a sulfur donor). 

One strategy that has helped to combat cyanide toxicity in patients receiving high doses or prolonged infusions of nitroprusside involves the co-administration of sodium thiosulfate (a sulfur group donor) at a 10 to 1 ratio.[17] It is important to note that thiocyanate toxicity may still occur with this approach.[18]

2. Hypotension: Profound hypotension may occur with resultant compromised perfusion to vital organs

3. Thiocyanate toxicity: Thiocyanate toxicity rarely occurs, most often in the setting of renal failure and/or prolonged infusions (>72 hours).[19][20]

• The earliest signs of thiocyanate toxicity are frequently tinnitus, abdominal pain, weakness, and variable levels of altered mental status (agitation, disorientation), which can ultimately progress to lethargy, seizures, and coma if not recognized and treated. 
• Of note, serum thiocyanate levels are only useful if used for confirmation of suspected toxicity in symptomatic patients. Early signs (e.g., tinnitus) may be present at levels above 35 mcg/mL, while symptoms of serious toxicity are expected with serum levels >100 mcg/mL.[19]

4. Methemoglobinemia: Methemoglobinemia most often occurs in patients receiving infusions >10 mcg/kg/minute and presents with signs of impaired oxygen delivery despite normal PaO2 and cardiac output. 

• First-line treatment with methylene blue should be given in symptomatic patients or those with methemoglobin levels exceeding 30% (10% in those with preexisting conditions limiting tolerance to hypoxemia). 

5. Increased intracranial pressure: a result of cerebral vasodilation.

Enhancing Healthcare Team Outcomes

Nitroprusside is a fast-acting, easily titratable, highly effective antihypertensive agent that must be used with extreme care. While its use has declined in recent years as newer agents have become available, this drug still has a role in the treatment of hypertensive emergencies and other disease processes that require an urgent reduction in arterial blood pressure.  

Interprofessional communication is critical to the safe use of nitroprusside as these patients require intensive monitoring of hemodynamic parameters. All members of the interprofessional healthcare team must be familiar with the potential adverse effects and toxicity syndromes. Careful patient selection based on comorbidities and risk factors is required, and clinicians (surgeons, anesthesiologists, intensivists) should engage in shared decision making with their pharmacists to assess each patient's risk factors and determine an appropriate dosing protocol. In utilizing this team-oriented approach, sodium nitroprusside can be a safe and effective therapeutic option for managing the acutely hypertensive patient. [Level 5]