Therefore, in the absence of any significant renal or liver disease, nitroprusside is
the preferred treatment for M.R.
Nitroprusside has many pharmacologic effects that should improve M.R.’s condition.
It dilates both venous and arterial vessels, thereby increasing venous capacitance and
decreasing the venous return or preload on the heart (see Chapter 14, Heart Failure).
A decrease in the pulmonary capillary wedge pressure and ventricular filling
pressure will ultimately improve M.R.’s pulmonary edema. Afterload is also
decreased as a result of arterial dilation. This action increases cardiac output,
reduces arterial pressure, and increases tissue perfusion.
CASE 16-2, QUESTION 3: Should M.R. be given a diuretic before nitroprusside therapy is begun?
Administration of potent IV diuretics is relatively ineffective in the acute treatment
of hypertensive crisis except in patients with concomitant volume overload or HF.
Many patients with hypertensive emergencies are vasoconstricted and have normal or
reduced plasma volumes; therefore, diuretics have little effect and may actually
aggravate renal impairment or cause other adverse effects.
diuretics are given acutely in combination with other antihypertensive agents,
profound hypotension can occur.
The immediate value of diuretics in acute HF is related more to their hemodynamic
effects (venodilation) than to diuresis. Venodilation after IV diuretic administration
decreases right-sided cardiac filling pressures, decreases pulmonary artery and
wedge pressures, and increases cardiac output before diuresis occurs.
of HF and severely elevated BP in M.R. warrants IV administration of a loop
diuretic (e.g., furosemide 40 mg, torsemide [Demadex] 10–20 mg, or bumetanide
CASE 16-2, QUESTION 4: What dose of nitroprusside should be used initially?
Effective infusion rates range from 0.25 to 10 mcg/kg/minute.
infusion of nitroprusside should be initiated at a rate of 0.25 mcg/kg/minute. The dose
should be increased slowly by 0.25 mcg/kg/minute every 5 minutes until the desired
pressure is achieved. A maximum infusion rate of 10 mcg/kg/minute has been
recommended. If adequate BP reduction is not achieved within 10 minutes after
maximal dose infusion, nitroprusside should be discontinued.
individualized according to patient response using continuous intraarterial BP
recording and observing for signs or symptoms of toxicity.
Nitroprusside decomposes on exposure to light, so the solution should be shielded
with an opaque sleeve. It is not necessary to protect the tubing from light.
Reconstituted solutions are stable for 24 hours at room temperature. A change in the
solution’s color from light brown to dark brown, green, orange, or blue indicates a
loss in activity. The solution should be discarded if this change occurs.
CASE 16-2, QUESTION 5: A nitroprusside infusion is started. What is the goal of therapy?
For most patients BP should be reduced by no more than 25% within the first
minutes to hour, then if stable, therapy can be titrated to achieve a goal BP of
160/100 mm Hg during the next 2 to 6 hours. BPs can be reduced to near-normal
levels within 8 to 24 hours. However, because M.R. has cerebral occlusive disease
(carotid bruits), excessive reduction of his BP should be avoided. Overly aggressive
reduction of BP in the presence of major cerebral vessel stenosis may decrease
cerebral blood flow and produce strokes or other neurologic complications.
Normal cerebral blood flow remains relatively constant over a wide range of
systemic BP measurements through autoregulatory mechanisms.
autoregulatory effects can prevent large alterations in cerebral blood flow from
either slow or rapid changes in systemic arterial pressures. In addition, the arterial
BP required to maintain cerebral perfusion is higher in hypertensive patients than in
normotensive individuals. If M.R.’s BP is reduced excessively, cerebral blood flow
may decrease sharply. Therefore, a DBP of 100 to 105 mm Hg would be a
reasonable initial therapeutic goal for him in the first 6 hours. If hypotension occurs,
nitroprusside should be discontinued and M.R. should be placed in the
Trendelenburg position, in which the head is kept lower than the trunk.
A major concern when using sodium nitroprusside is toxicity secondary to the
accumulation of its metabolic by-products, cyanide, and thiocyanate. Sodium
nitroprusside decomposes within a few minutes after IV infusion. Free cyanide,
which represents 44% of nitroprusside by weight, is released into the bloodstream,
producing prussic acid (hydrogen cyanide), which is responsible for the acute
69 The amount of hydrogen cyanide released is dose related.
detoxification of cyanide occurs through a mitochondrial rhodanese system, which, in
the presence of a sulfur donor such as thiosulfate, converts cyanide to thiocyanate.
Theoretically, cyanide can be expected to accumulate in the body when the rate of the
sodium nitroprusside infusion exceeds 2 mcg/kg/minute for a prolonged period. The
presence of hepatic or renal impairment may also predispose the patient to cyanide
Symptomatic cyanide toxicity occurs infrequently; however, several deaths have
been reported after the use of sodium nitroprusside.
73 Cyanide toxicity occurs most
commonly when large doses (total dose 1.5 mg/kg) of nitroprusside are administered
rapidly to patients undergoing a surgical procedure that requires induction of
hypotension. However, cyanide toxicity and mortality
associated with nitroprusside exceed 3,000 and 1,000 cases per year,
respectively, according to two sources.
Although concurrent sodium thiosulfate administration has been recommended in
high-risk patients, no clinical data are available to indicate that it reduces overall
75 Furthermore, this intervention may result in the accumulation of
thiocyanate, particularly if sodium thiosulfate is given at high infusion rates or to
patients with renal insufficiency. Hydroxocobalamin has also been used to reduce the
risk of cyanide toxicity secondary to nitroprusside infusions, but its use is limited
because of poor availability and cost considerations.
72 With the availability of safer
alternatives (e.g., fenoldopam, IV labetalol, IV nicardipine) for use in high-risk
patients, the use of hydroxocobalamin or thiosulfate is rarely required.
Cyanide toxicity can be detected early by monitoring M.R.’s metabolic status.
Lactic acidosis is an early indicator of toxicity because the progressive inactivation
of cytochrome oxidase by cyanide results in increased anaerobic glycolysis.
low plasma bicarbonate concentration and low pH, accompanied by an increase in
the blood lactate or lactate-to-pyruvate ratio could indicate cyanide toxicity.
Additional signs of cyanide intoxication include tachycardia, altered consciousness,
coma, convulsions, and the occasional smell of almonds on the breath.
serum thiocyanate levels is of no value in detecting the onset of cyanide toxicity. If
toxicity develops, the infusion should be stopped and appropriate therapy for cyanide
intoxication instituted. The need for such a high-dose infusion of nitroprusside to
maintain M.R.’s pressure may increase his risk for cyanide toxicity, warranting close
monitoring of his acid–base balance.
thiocyanate concentrations necessary?
Sodium nitroprusside is more likely to produce thiocyanate toxicity. Although this
complication is also rare, patients with renal impairment who receive infusions
beyond 72 hours are particularly susceptible. Conversion of cyanide to thiocyanate,
via sulfation by the liver, proceeds relatively slowly. The half-life of thiocyanate is
2.7 days with normal renal function and up to 9 days in patients with renal failure.
When sodium nitroprusside is infused for several days at moderate dosages (2–5
mcg/kg/minute), toxic levels of thiocyanate can occur within 7 to 14 days in patients
with normal renal function and 3 to 6 days in patients with severe renal disease.
Thiocyanate causes a neurotoxic syndrome manifested by psychosis, hyperreflexia,
confusion, weakness, tinnitus, seizures, and coma.
thiocyanate can suppress thyroid function through inhibition of iodine uptake and
78 Measurement of blood levels of thiocyanate is only
recommended in patients with renal disease or when the duration of the nitroprusside
infusion exceeds 3 or 4 days. Nitroprusside should be discontinued if serum
thiocyanate levels exceed 10 to 12 mg/dL.
79,80 Life-threatening toxicity is of concern
when blood thiocyanate levels exceed 20 mg/dL. In emergency cases, thiocyanate can
be readily removed by hemodialysis.
For M.R., the potential for thiocyanate toxicity is low because his renal function is
normal and the anticipated infusion duration is relatively short. Therefore,
measurement of thiocyanate levels is not indicated.
Other side effects associated with nitroprusside therapy include nausea, vomiting,
diaphoresis, nasal stuffiness, muscular twitching, dizziness, and weakness. These
effects are usually acute and occur when nitroprusside is administered too rapidly.
They can be reversed by decreasing the infusion rate.
CASE 16-2, QUESTION 8: M.R.’s serum chemistries and arterial blood gas values indicate a metabolic
Although the duration of M.R.’s nitroprusside therapy has been short, tolerance to
the antihypertensive effect requires the use of a high-dose infusion to maintain BP
control. Thus, acidosis may represent toxicity as a result of cyanide accumulation.
The nitroprusside infusion should be discontinued at this time, and another rapidly
acting, easily titratable parenteral antihypertensive such as fenoldopam or IV
nicardipine should be initiated.
CASE 16-2, QUESTION 9: What are the advantages and disadvantages of fenoldopam compared with
Fenoldopam is a parenteral, rapidly acting, peripheral dopamine-1 agonist used to
manage hypertensive crisis when a rapid reduction in BP is required.
of the dopamine-1 receptors vasodilates coronary, renal, mesenteric, and peripheral
85,86 Fenoldopam has been used to control perioperative hypertension in
patients undergoing cardiac bypass surgery.
87 The use of low-dose fenoldopam had
been evaluated in those with acute kidney injury following cardiac surgery; therapy
was not associated with a reduced risk of renal replacement therapy or 30-day
88 This refutes prior theories that dilation of the renal arteries with
fenoldopam may reduce the risk of renal complications.
Fenoldopam is as effective as sodium nitroprusside for treatment of hypertensive
emergencies and does not cause either cyanide or thiocyanate toxicity.
Fenoldopam can be considered as an alternative to nitroprusside in patients who are
at high risk for cyanide or thiocyanate toxicity. Over the past several years, the use of
fenoldopam as an antihypertensive has decreased.
Clearance of fenoldopam is not altered by renal or liver disease. Like
nitroprusside, fenoldopam also has a short duration of action, with an elimination
half-life of approximately 5 minutes, thus allowing for easy titration.
rate should be frequently to avoid hypotension and dose-related reflex tachycardia.
Flushing and headache may occur. Serum potassium should be monitored and
repleted as necessary. Fenoldopam should be used cautiously in patients with
glaucoma or intraocular hypertension due to a dose-dependent increase in intraocular
CASE 16-2, QUESTION 10: Which antihypertensive agents should be avoided in M.R.? Why?
Labetalol, a potent, rapidly acting antihypertensive with both α- and β-blocking
activity, is very effective in the treatment of hypertensive emergencies,
should not be used in M.R. Hemodynamically, labetalol reduces peripheral vascular
resistance (afterload), BP, and heart rate, with almost no change in the resting
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