NOREPINEPHRINE

Norepinephrine is an a-receptor agonist that promotes widespread vasoconstriction. As a result of early reports of renal failure from norepinephrine, combined with a general decrease in enthusiasm for vasoconstrictor drugs, norepinephrine is no longer considered a first-line drug for the management of circulatory shock. In cases of hypotension refractory to dopamine, it can be added as a second agent.

There is some renewed interest in norepinephrine because of reports showing that there is less vasoconstriction and even improved organ perfusion in response to norepinephrine in patients with septic shock. However, it seems foolish to expect that a switch to norepinephrine will improve the clinical outcome in septic shock.

ACTIONS

Norepinephrine produces a dose-dependent increase in systemic vascular resistance. Although the drug can stimulate cardiac b-receptors over a wide range, the cardiac output is increased only at low doses. Over the remainder of the therapeutic dose range, the inotropic response to norepinephrine is overshadowed by the vasoconstrictor response. At high dose rates, the cardiac output decreases in response to the vasoconstriction and increased afterload.

Indications

In cases of septic shock where the desired vasoconstriction is not achieved by a dopamine infusion norepinephrine can be added as a second drug.

DRUG ADMINISTRATION

One milligram of norepinephrine is added to a diluent volume of 250 mL (4 ug/mL). The infusion should be begun at 1 ug/min (15 microdrops/min) and titrated to the desired effect. The usual dose rate is 2 to 4 ug/min, with a range of 1 to 12 ug/min. The effective dose of norepinephrine can vary widely, and in clinical reports involving patients with septic shock, the effective norepinephrine dose has varied from 0.7 to 210 ug/min.

ADVERSE EFFECTS

The administration of any vasoconstrictor agent carries a risk of hypoperfusion and ischemia involving any tissue bed or vital organ. For any condition that requires vasoconstrictor drugs to maintain a blood pressure, it may be difficult to distinguish adverse drug effects and adverse disease effects. Furthermore, if an adverse drug effect is identified or suspected, there may be little or no room for therapeutic manipulations.

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NITROPRUSSIDE

Nitroprusside is a vasodilator agent that shares many features with nitroglycerin. One of these is the participation of nitric oxide in the vasodilator actions of the drug. It contains one nitrosyl group (NO), and this is released in the bloodstream as nitric oxide, which then can move into the vessel wall and move along the pathway. As a result of their shared mechanisms of action, nitroprusside and nitroglycerin are classified as nitrovasodilators.

There is one feature that distinguishes nitroprusside from nitroglycerin: Nitroprusside is a dangerous drug and may be responsible for over 1000 deaths yearly. Because the major actions of nitroprusside may be its toxic effects, the adverse effects will be presented first.

TOXICOLOGY

The toxic nature of nitroprusside is due to its molecular composition. The nitroprusside molecule contains five cyanide ions, and almost half of the molecular weight of the parent molecule is cyanide. When nitroprusside disrupts to release nitric oxide and exert its actions, the cyanide is released into the bloodstream. Sulfur from a donor source combines with the free cyanide and forms thiocyanate (SCN), which is cleared by the kidneys. The sulfur donor for this reaction is thiosulfate.

Cyanide

The capacity of the human body to clear cyanide was grossly overestimated when nitroprusside was first introduced . The limiting factor is thiosulfate, which is stored in limited quantities and is easily depleted. The result is early and frequent accumulation of cyanide during nitroprusside infusions.

Thiocyanate

The clearance of thiocyanate by the kidneys is impaired when renal function or renal blood flow is compromised. The accumulation of thiocyanate produces a toxic syndrome that is distinct from cyanide intoxication. Thus, nitroprusside toxicity can be expressed as either cyanide or thiocyanate intoxication.

ACTIONS

Nitroprusside has been favored because the vascular responses are prompt and short lived and this allows for rapid dose titration. Vasodilator effects are often evident at low dose rates (0.5 ug/kg/min), and the sequence of hemodynamic responses is the same as described for nitroglycerin. Blood pressure does not usually decline at dose rates below 1 ug/kg/min. An immediate drop in blood pressure at low dose rates can be a sign of hypovolemia.

Indications

Because of the toxic potential of the drug, nitroprusside should be used only when there is no alternative available. The drug seems best suited for the management of severe hypertension combined with a low cardiac output.

DRUG ADMINISTRATION

Note the recommendation to add thiosulfate to the nitroprusside infusate. This provides the sulfur needed to detoxify cyanide and should be a mandatory practice. A proportional dose of 500 mg thiosulfate per 50 mg nitroprusside should be used. Thiosulfate is provided as sodium thiosulfate (290 mg sodium per gram thiosulfate) and is commercially available as a 10% solution (5 mL = 500 mg thiosulfate).

The FDA recommends starting nitroprusside at a low dose rate (0.2 ug/kg/min) and titrating the dose upward in 5-minute increments. The maximum allowable dose rate is 10 ug/kg/min for no longer than 10 minutes.

ADVERSE EFFECTS

In addition to cyanide and thiocyanate intoxication, nitroprusside has adverse hemodynamic effects that are identical to those described for nitroglycerin. Nitroprusside increases intracranial pressure, and thus it is not advised for patients with intracranial hypertension. Because hypertensive encephalopathy is associated with a raised intracranial pressure, nitroprusside seems ill-advised for managing hypertensive encephalopathy.

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NITROGLYCERIN

Nitroglycerin is a peculiar chemical because it is both an explosive powder and an effective antianginal agent. It is an organic nitrate (glyceryl trinitrate) that relaxes vascular smooth muscle and produces a generalized vasodilation.

NITRIC OXIDE

Nitroglycerin binds to the surface of endothelial cells and undergoes two chemical reductions to form nitric oxide (NO). The nitric oxide then moves out of the endothelial cell and into an adjacent smooth muscle cell, where it promotes the formation of cyclic guanosine monophosphate (cGMP), which then promotes muscle relaxation. Vasodilation is a prominent action of nitric oxide, which was known as endothelium-derived relaxing factor before its chemical identification.

ACTIONS

Nitroglycerin has a dose-dependent vasodilator effect in arteries and veins and is active in the systemic and pulmonary circulations. When the drug is given by continuous infusion, venous dilator effects are prominent at low dose rates (< 40 ug/min) and arterial dilator effects predominate at high dose rates (> 200 ug/min). As low-dose infusions are titrated upward, the earliest response is a decrease in cardiac filling pressures (i.e., central venous pressure and wedge pressure) with little or no change in cardiac output. As the dose rate is increased further, the cardiac output begins to rise as a result of progressive arterial vasodilation. Further increases in the dose rate will eventually produce a drop in blood pressure. The hemodynamic responses to intravenous nitroglycerin have a rapid onset and short duration, which permits rapid dose titration.

Antiplatelet Effects

Nitrates can inhibit platelet aggregation via the mechanism proposed for the vasodilator actions. Because platelet thrombi are believed to play an important role in the pathogenesis of acute myocardial infarction, the antiplatelet actions of nitroglycerin have been proposed as the mechanism for the antianginal effects of the drug. This may explain why the antianginal efficacy of nitroglycerin is not shared by other vasodilator agents.

Indications

Intravenous nitroglycerin can be used to decrease left-ventricular filling pressures (low dose), augment cardiac output (intermediate dose), or lower blood pressure (high dose). It is also useful in relieving anginal chest pain.

DRUG ADMINISTRATION

A nitroglycerin dose chart is shown in Table 18.6. The infusion rates in this chart are based on a drug concentration of 400 ug/mL in the infusion solution.

Sorption

Nitroglycerin binds to soft plastics such as polyvinylchloride (PVC), which is a common constituent in plastic bags and infusion tubing. As much as 80% of the drug can be lost by sorption. Glass and hard plastics do not adsorb nitroglycerin, so the problem of adsorption can be eliminated by using glass bottles and stiff polyethylene tubing. Drug manufacturers often provide specialized infusion sets to deliver nitroglycerin. (For a comprehensive description of nitroglycerin adsorption, see the Handbook on Injectable Drugs, pp 777-781.)

Nitroglycerin infusions should begin at a rate of 5 ug/min. The dose rate is then increased in 5-ug/min increments every 5 minutes until the desired effect is achieved. Although effective dose rates vary, the dose requirement should not exceed 400 ug/min in most patients. High dose requirements (e.g., > 350 ug/min) are often the result of drug loss via adsorption, or nitrate tolerance (see below).

ADVERSE EFFECTS

Nitroglycerin can produce three types of adverse reactions. One is flow related, another is related to oxidant stress, and the final one is related to the way the drug is administered.

Flow-Related Effects

Excessive flow in the cerebral and pulmonary circulations can create complications. Nitroglycerin seems adept at increasing cerebral blood flow (headache is a common complaint), and this can increase intracranial pressure and produce symptomatic intracranial hypertension . Because of this effect, nitroglycerin is avoided in patients with increased intracranial pressure. Increases in pulmonary blood flow can become a problem when the augmented flow occurs in areas of the lung that are poorly ventilated. This increases shunt fraction and can lead to hypoxemia. This effect can be prominent in the acute respiratory distress syndrome , where much of the lung is poorly ventilated.

Methemoglobinemia

Nitroglycerin metabolism produces inorganic nitrites, and accumulation of nitrites can result in the oxidation of heme-bound iron in hemoglobin, as shown below.

Hb – Fe(II) + NO2 + H+ —»  Hb – Fe(III) + HONO

(18.1)

The oxidation of iron from the Fe(II) to Fe(III) state creates methemoglobin (metHb). Oxidized iron does not carry oxygen effectively, and thus metHb accumulation can impair tissue oxygenation. Clinically significant methemoglobinemia is not a common complication of nitroglycerin therapy and usually occurs only at very high dose rates . MetHb accumulation has few specific manifestations other than the characteristic brown discoloration of blood (due to the brown color of metHb). MetHb can be detected by light reflection (oximetry). Pulse oximeters do not reliably detect metHb (30), and the measurement should be performed by more sophisticated oximeters (called co-oximeters) in the clinical laboratory.

MetHb levels above 3% (fraction of total hemoglobin) are abnormal. Levels above 40% can produce tissue ischemia, and levels above 70% are lethal . If there is no evidence of tissue hypoxia, discontinuing nitroglycerin is all that is required. If tissue oxygenation is impaired (e.g., lactic acidosis), metHb can be chemically converted back to normal hemoglobin with methylene blue (a reducing agent), 2 mg/kg IV over 10 minutes.

Solvent Toxicity

Nitroglycerin does not readily dissolve in aqueous solutions, and nonpolar solvents such as ethanol and propylene glycol are required to keep the drug in solution. These solvents can accumulate during continuous infusion.

Ethanol intoxication has been reported in association with nitroglycerin infusions. Manifestations include a change in mental status and garbled speech. Hypotension can also occur. A blood ethanol level will confirm the diagnosis. Propylene glycol toxicity has also been reported, and because some commercial nitroglycerin preparations contain 30 to 50% propylene glycol , clinical toxicity may be more common than suspected. Toxic manifestations include altered mental status that can progress to coma, metabolic acidosis, and hemolysis. The propylene glycol level in blood confirms the diagnosis.

In patients who develop a change in mental status during prolonged or high-dose nitroglycerin infusions, the serum osmolal gap (i.e., the difference between measured and calculated serum osmolality) might be a valuable screening test for possible solvent toxicity. The osmolal gap should be elevated (> 10 mOsm/kg) by the presence of either solvent in the bloodstream. An elevated gap would then prompt more specific assays to identify the toxin.

NITRATE TOLERANCE

Tolerance to the vasodilator and antiplatelet actions of nitroglycerin is more common than suspected and can appear after only 24 hours of continuous drug administration. No single mechanism seems to explain this phenomenon. One possible cause is the depletion of reducing agents in the vascular endothelium, which impairs the conversion of nitroglycerin to nitric oxide. This mechanism is supported by the association of nitrate tolerance with decreased nitric oxide production. However, the administration of reducing agents (e.g., N-acetylcysteine) does not consistently restore responsiveness in nitrate tolerance. At present, the most effective method for restoring nitroglycerin responsiveness is to discontinue drug administration for at least 6 to 8 hours each day.

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LABETALOL

Labetalol is an adrenergic-receptor antagonist that has proven effective in acute management of severe hypertension. Parenteral administration of labetalol can serve as a safer alternative to nitroprusside.

ACTIONS

Labetalol is a nonselective b-receptor antagonist that also blocks a-receptor-mediated vasoconstriction. The overall effect is a dose-related decrease in systemic vascular resistance and blood pressure, without a reflex tachycardia or increase in cardiac output. Unlike nitroglycerin and nitroprusside, labetalol does not increase intracranial pressure .

Indications

Labetalol is indicated for the acute management of severe hypertension associated with a normal or adequate cardiac output. It may be particularly effective in hypertension caused by excess circulating catecholamines, such as the hypertension that occurs in the early postoperative period. Because the antihypertensive actions of labetalol are not accompanied by an increase in cardiac output, the drug is particularly useful in the management of aortic dissection.

DRUG ADMINISTRATION

Labetalol is available in an aqueous solution (5 mg/mL) that can be given intravenously as a bolus injection or by continuous infusion.

Bolus Therapy

Patients should be placed in the supine position for bolus injections of labetalol to limit the risk of orthostatic hypotension. The initial dose is 20 mg, and repeat doses of 40 mg can be given at 10-minute intervals until the desired antihypertensive effect is achieved. Although the manufacturer recommends a maximum cumulative dose of 300 mg, larger cumulative doses of labetalol have been used without ill effects.

Continuous Infusion Therapy

Continuous infusions of labetalol should be preceded by a bolus dose of 20 mg, because the serum half-life of labetalol, which is 6 to 8 hours, indicates that 30 to 40 hours (5 half-lives) may be required to reach steady-state serum drug levels after the start of continuous infusion therapy.

To prepare the infusion solution, 200 mg (40 mL) labetalol is added to 160 mL of diluent for a final drug concentration of 1 mg/mL. The recommended infusion rate is 2 mL/min, which corresponds to a dose rate of 2 mg/min.

ADVERSE EFFECTS

The most notable complications of intravenous labetalol include orthostatic hypotension (ablockade), myocardial depression (b-1 blockade), and bronchospasm (b-2 blockade). Orthostasis should not be a problem in the ICU, because patients are rarely ambulatory or in the upright position. The drug should be avoided in patients with heart failure or asthma.

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EPINEPHRINE

Epinephrine is an endogenous catecholamine and the prototype sympathomimetic agent. Because of its potency and risk for adverse effects, epinephrine is used sparingly to support the circulation in conditions other than cardiac arrest.

ACTIONS

Like dopamine, epinephrine is primarily a b-receptor agonist at low doses and an a-receptor agonist at high doses. However, epinephrine is much more potent than dopamine, with an effective dose range that is two-to-three orders of magnitude below the effective dose range for dopamine. Epinephrine activates b-receptors at doses of only 0.005 to 0.02 ug/kg/min. a-Receptor vasoconstriction appears at slightly higher doses, and renal vasoconstriction develops early . Dose rates above 0.1 ug/kg/min can produce severe vasoconstriction.

Antiinflammatory Effects

Epinephrine blocks the release of inflammatory mediators by mast cells and basophils in response to an antigenic challenge. This effect may explain the salutary effects of epinephrine in anaphylactic reactions .

Metabolic Effects

Epinephrine has several metabolic effects that represent adaptive responses in healthy subjects but can be deleterious in the critically ill patient . The metabolic effects that deserve mention include (a) hypermetabolism (calorigenic response), (b) hyperglycemia (enhanced gluconeogenesis and diminished insulin release), (c) an increase in circulating ketoacids (via lipolysis), (d) hyperlactatemia (without ischemia), and (e) a decrease in serum potassium (usually < 1 mEq/L).

Indications

Intravenous epinephrine is indicated for the management of cardiac arrest associated with pulseless ventricular tachycardia and ventricular fibrillation, asystole, and pulseless electrical activity. It is also indicated for severe anaphylactic reactions and anaphylactic shock. Because of the narrow therapeutic range and risk of adverse reactions, it is not recommended as a first-line agent for the routine management of low cardiac output or circulatory shock.

DRUG ADMINISTRATION

Epinephrine is available as a 1:1000 solution (1 mg/mL) and can be diluted to create a 1:10,000 solution (0.1 mg/mL). As indicated in Table 18.5, epinephrine is a powerful b agonist, with b-receptor activation at dose rates of only 0.005 to 0.02 ug/kg/min. The safe range for epinephrine infusions is exceeded at dose rates above 0.1 ug/kg/min .

Epinephrine is the single most effective drug in the management of anaphylaxis, and delays in administering the drug can have adverse consequences .

Incompatibilities

Like other catecholamines, epinephrine is inactivated by alkaline solutions.

ADVERSE EFFECTS

Epinephrine is arrhythmogenic, particularly in combination with halothane or electrolyte abnormalities . Coronary ischemia can also occur and is not related to dose . Although renal vasoconstriction is prominent with epinephrine, ischemic renal failure is seen most often with accidental epinephrine overdose . Epinephrine can produce serious hypertension in patients receiving b-receptor antagonists, an effect attributed to unopposed a-receptor stimulation .

Calorigenic Effect

Therapeutic doses of epinephrine can produce a 35% increase in resting metabolic rate , and the increase in tissue oxygen needs can have adverse consequences in patients with impaired or borderline tissue oxygenation. Dopamine has a similar but less pronounced calorigenic effect , whereas dobutamine seems to have little or no effect on the metabolic rate in critically ill patients .

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DOPAMINE

Dopamine is an endogenous catecholamine that serves as a neurotransmitter. As an exogenous agent, it produces a dose-dependent activation of several types of adrenergic and dopaminergic receptors. The overall effect of the drug is determined by the pattern of receptor activation, as described below.

ACTIONS

When given at low dose rates (0.5 to 3 ug/kg/min), dopamine selectively activates dopamine-specific receptors in the renal, mesenteric, and cerebral circulations and increases blood flow in these regions. Dopaminergic activation in the kidneys also produces an increase in urinary sodium and water excretion that is independent of the changes in renal blood flow.

At intermediate dose rates (3 to 7.5 ug/kg/min), dopamine stimulates b-receptors in the heart and peripheral circulations, and this produces an increase in cardiac output. Note that the inotropic response to dopamine is modest when compared to dobutamine.

At high dose rates (> 7.5 ug/kg/min), dopamine produces a dose-dependent activation of a-receptors in the systemic and pulmonary circulations. This results in progressive vasoconstriction, and the resultant increase in ventricular afterload limits the ability of dopamine to augment cardiac output.

There is a dose-dependent increase in the wedge pressure, which is independent of the changes in stroke volume in the upper graph. This effect may be the result of vasoconstriction in pulmonary veins. Dopamine-induced constriction of pulmonary veins is an important consideration, because it invalidates the pulmonary capillary wedge pressure as a measure of left-ventricular filling pressures.

The hemodynamic responses to dopamine are blunted by continued drug administration. This tachyphylaxis may be due to dopamine’s ability to release norepinephrine from adrenergic nerve terminals. When tachyphylaxis to dopamine develops, discontinuing the drug for a few days (if possible) can restore some of the end-organ responsiveness.

Indications

Dopamine is indicated for the management of cardiogenic shock and any circulatory shock syndrome associated with systemic vasodilation (e.g., septic shock). The drug is particularly valuable for its ability (in intermediate-to-high dose rates) to promote vasoconstriction while preserving the cardiac stroke output. Low-dose dopamine is also used to preserve renal blood flow and to promote urine output in patients with oliguric acute renal failure, or in those at risk for oliguric renal failure. Although dopamine does not improve intrinsic renal function in this situation, it can promote urine output and limit fluid retention.

DRUG ADMINISTRATION

At low infusion rates of 0.5 to 3 ug/kg/min, natriuresis and diuresis are prominent. As the infusion rate is increased to 4 to 7 ug/kg/min, b-receptor stimulation and augmentation of cardiac output occurs. At dose rates above 8 ug/kg/min, progressive vasoconstriction is the dominant feature.

Incompatibilities

The precautions for alkaline fluids mentioned for dobutamine also apply to dopamine.

ADVERSE EFFECTS

Tachyarrhythmias are the most common complication of dopamine administration. Sinus tachycardia is common and can occur at b-agonist dose rates (i.e., 5 to 7 ug/kg/min). Malignant tachyarrhythmias (e.g., multifocal ventricular ectopics, ventricular tachycardia) can also occur, but are uncommon.

The most feared complication of dopamine administration is ischemic limb necrosis, which occurs more frequently with dopamine than with any other vasoconstrictor agent. Limb necrosis has been reported at dopamine doses as low as 1.5 ug/kg/min . Prompt administration of an a-receptor blocking agent such as phentolamine (5 mg as an intravenous bolus, followed by a continuous infusion at 1 to 2 mg/min) is indicated at the earliest signs of limb ischemia. Vasoconstrictor doses of dopamine should not be given through peripheral veins. Extravasation of the drug through a peripheral vein can be treated with a local injection of phentolamine (5 to 10 mg in 15 mL saline)

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DOBUTAMINE

Dobutamine is a synthetic catecholamine that is generally considered the inotropic drug of choice for the acute management of severe (systolic) heart failure. It is primarily a b1-receptor agonist (cardiac stimulation), but it also has mild b-2 effects (vasodilation).

ACTIONS

As demonstrated in Figure 18.1, dobutamine causes a dose-dependent increase in stroke volume (upper graph) accompanied by a decrease in cardiac filling pressures (lower graph). The increase in stroke output is usually accompanied by a proportional decrease in systemic vascular resistance (baroreceptor-mediated), and thus the arterial blood pressure usually remains unchanged. The drug is effective in both right- and left-sided heart failure.

The inotropic and chronotropic effects of dobutamine can vary widely in critically ill patients. This is partly due to variable pharmacokinetics and partly due to variable end-organ responsiveness. Elderly patients are relatively resistant to dobutamine and can have only half the inotropic responsiveness seen in younger patients. The variable response to dobutamine in critically ill patients emphasizes the need to guide dobutamine therapy by preselected hemodynamic end-points, not by preselected dose rates.

Indications

As mentioned, dobutamine is the preferred inotropic agent for the acute management of low output states due to systolic heart failure. Because dobutamine does not usually raise the arterial blood pressure, it is not indicated as monotherapy in patients with cardiogenic shock.

Dobutamine is also used in patients with septic shock and multiple organ failure who may have a normal cardiac output. These conditions are often accompanied by hypermetabolism, and in this situation, a normal cardiac output may be not be adequate for the increased oxygen requirements of hypermetabolism. The goal of dobutamine therapy in these conditions is to drive the cardiac output to supranormal levels (e.g., > 4.5 L/min/m2) to meet the increased oxygen consumption of the hypermetabolic state. The use of dobutamine to achieve a hyperdynamic state has had an inconsistent effect on survival, and thus is not universally accepted.

DRUG ADMINISTRATION

The drug is available in 250-mg vials and is infused in a concentration of 1 mg/mL. The usual dose range is 5 to 15 ug/kg/min, but doses as high as 200 ug/kg/min have been used to achieve a hyperdynamic state in patients with septic shock and multiple organ failure.

Incompatibilities

An alkaline pH inactivates catecholamines such as dobutamine, and thus sodium bicarbonate or other alkaline solutions should not be administered through intravenous tubing used for dobutamine infusions.

ADVERSE EFFECTS

Dobutamine has few serious side effects. As mentioned, tachycardia can develop in some patients. However, malignant tachyarrhythmias are uncommon.

Contraindications

Dobutamine is not indicated for the management of heart failure due to diastolic dysfunction and is contraindicated in patients with hypertrophic cardiomyopathy.

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