BP blood pressure CO cardiac output HR heart rate PCWP pulmonary capillary wedge pressure SVRf systemic vascular resistance t increase i decrease 0 no or little change

Table 6-11 Usual Doses and Monitoring of Commonly Used Hemodynamic Medications



Monitoring Variable**


0.5 -TO mog/kg/rfiin

BP, HR, unnary output and kidney function, ECGr extremity perfusion (higher doses only)


2.5-20 mcg^kg/min

BP, Hi urinary output and function, EGG


0,375—0.75 m eg/

ÎIR 11R, urinary output and


function, ECGh charges in ischemic symptoms {e.g., ch'/'St pain), electrolytes


0.1-3 mcg/kg/

BR Hfl, liver and kidney


function, blood cyanide and/or ihiocyariate concentrations if toxicity suspected (nausea, vomi liny, altered mental function)


5-200+ mcg/kg/

BPr HR, Ë0Gr changes in


ischemic symptoms


ßolu^: ') mcg/kg;

1iR# urinary output and

Infusion: aOl

kidney function, blood


fiWP concentrations

GNP. fê-type natriuretic peptide; RPr blood pressure; MR, heart rate tfln add 11 ion Lo pulmonary capillary wedge pressure and cardiac output.

Continuous infusions of nitroglycerin should be initiated at a dose of 5 to 10 mcg/ min and increased every 5 to 10 minutes until symptomatic or hemodynamic im-

provement. Effective doses range from 35 to 200 mcg/min. The most common adverse events reported are headache, dose-related hypotension, and tachycardia. A limitation to nitroglycerin's use is the development of tachyphylaxis, or tolerance to its effects, which can be evident within 12 hours after initiation of continuous infusion and necessitate additional titrations to higher doses.


Nitroprusside, like nitroglycerin, causes the formation of nitric oxide and vascular smooth muscle relaxation. In contrast to nitroglycerin, nitroprusside is both a venous and arterial vasodilator regardless of dosage. Nitroprusside causes a pronounced decrease in PCWP, SVR, and BP, with a modest increase in CO. Nitroprusside has been studied to a limited extent in AHF and no studies have evaluated its effects on mor-48

tality. Nitroprusside is initiated at 0.1 to 0.25 mcg/kg/min, followed by dose adjustments in 0.1 to 0.2 mcg/kg/min increments if necessary to achieve desired effect. Because of its rapid onset of action and metabolism, nitroprusside is administered as a continuous infusion that is easy to titrate and provides predictable hemodynamic effects. Nitroprusside requires strict monitoring of BP and HR. Nitroprusside's use is limited in AHF due to recommended hemodynamic monitoring with an arterial line and mandatory intensive care unit admission at many institutions. Abrupt withdrawal of therapy should be avoided, as rebound neurohormonal activation may occur. Therefore, the dose should be tapered slowly. Nitroprusside has the potential to cause cyanide and thiocyanate toxicity, especially in patients with hepatic and renal insufficiency, respectively. Toxicity is most common with use longer than 3 days and with higher doses. Nitroprusside should be avoided in patients with active ischemia, because its powerful afterload-reducing effects within the myocardium can "steal" coronary blood flow from myocardial segments that are supplied by epicardial vessels with high-grade lesions.


BNP is an endogenous neurohormone that is synthesized and released from the ventricles in response to chamber wall stretch or increased filling pressures. Recombinant BNP, or nesiritide, is the newest compound developed for AHF. Nesiritide binds to guanylate cyclase receptors in vascular smooth muscle and endothelial cells, causing an increase in cGMP concentrations leading to vasodilation (venous and arterial) and natriuresis. Nesiritide also antagonizes the effects of the RAAS and ET. Nesiritide reduces PCWP, right atrial pressure, and SVR. Consequently, it also increases SV and

CO without affecting HR. Continuous infusions result in sustained effects for 24 hours without tachyphylaxis, although experience with its use beyond 72 hours is limited.

Nesiritide has been shown to improve symptoms of dyspnea and fatigue. In a randomized clinical trial,53 nesiritide was found to significantly decrease PCWP more than nitroglycerin and placebo over 3 hours. Nesiritide improved patients' self-reported dyspnea scores compared to placebo at 3 hours, but there was no difference compared to nitroglycerin. There are no prospective mortality studies with nesiritide in AHF.

Currently, nesiritide is indicated for patients with AHF exhibiting dyspnea at rest or with minimal activity. The recommended dose regimen is a bolus of 2 mcg/kg, followed by a continuous infusion for up to 24 hours of 0.01 mcg/kg/min. Because nesiritide's effects are predictable and sustained at the recommended dosage, titration of the infusion rate (maximum of 0.03 mcg/kg/min) is not commonly required nor is invasive hemodynamic monitoring. Nesiritide should be avoided in patients with systolic BP less than 90 mm Hg. Although nesiritide's place in AHF therapy is not firmly defined, it is used as one of the first-line agents (in combination with diuretics) for many patients presenting in moderate to severe decompensation, mainly due to its proven benefits and unique mechanism of action. One potential disadvantage compared to other vasodilators is its longer half-life. If hypotension occurs, the effect can be prolonged (2 hours). There are also concerns relating to elevations in serum creatinine observed with nesiritide; however, whether this effect is clinically relevant remains unanswered.

Inotropic Agents

Currently available positive inotropic agents act via increasing intracellular cyclic adenosine monophosphate (cAMP) concentrations through different mechanisms. P-Agonists activate adenylate cyclase through stimulation of P-adrenergic receptors, which subsequently catalyzes the conversion of ATP to cAMP. In contrast, phosphod-iesterase inhibitors reduce degradation of cAMP. The resulting elevation in cAMP levels leads to enhanced phospholipase activity, which then increases the rate and extent of calcium influx during systole, thereby enhancing contractility. Additionally, during diastole, cAMP promotes uptake of calcium by the sarcoplasmic reticulum which improves cardiac relaxation. The inotropes approved for use in AHF are discussed in the following sections. Inotropes have been associated with increased risk for arrhythmias and higher mortality rates, and therefore require careful monitoring.

Dobutamine Dobutamine has historically been the inotrope of choice for AHF. As a synthetic catecholamine, it acts as an agonist mainly on Pi-and P-receptors and minimally on a1-receptors. The resulting hemodynamic effects are due to both receptor-and reflex-mediated activities. These effects include increased contractility and HR through P -(and P2-) receptors and vasodilation through a relatively greater effect on P2-than a1-receptors. Dobutamine can increase, decrease, or cause little change in mean arterial pressure depending on whether the resulting increase in CO is enough to offset the modest vasodilation. Although dobutamine displays a half-life of approximately 2 minutes, its positive hemodynamic effects can be observed for several days to months after administration. The use of dobutamine is supported by several small studies documenting improved hemodynamics, but large-scale clinical trials in AHF are lacking.54

Dobutamine is initiated at a dose of 2.5 to 5 mcg/kg/min, which can be gradually titrated to 20 mcg/kg/min based on clinical response. There are several practical considerations to dobutamine therapy in AHF. First, owing to its vasodilatory potential, monotherapy with dobutamine is reserved for patients with systolic BPs greater than 90 mm Hg. However, it is commonly used in combination with vasopressors in patients with lower systolic BPs. Second, due to downregulation of P1-receptors or uncoupling of P2-receptors from adenylate cyclase with prolonged exposure to dobutamine, attenuation of hemodynamic effects has been reported to occur as early as 48 hours after initiation of a continuous infusion, although tachyphylaxis is more evident with use spanning longer than 72 hours. Full sensitivity to dobutamine's effects can be restored 7 to 10 days after the drug is withdrawn. Third, many patients with AHF will be taking P-blockers on a chronic basis. Because of P-blockers' high affinity for P-receptors, the effectiveness of P-agonists such as dobutamine will be reduced. In patients on P-blocker therapy, it is recommended that consideration be given to the use of phosphodiesterase inhibitors such as milrinone, which are not dependent on P-receptors for effect.55,56 Although commonly practiced, use of high doses of dobutamine to overcome the P-blockade should be discouraged, as this negates any of the protective benefits of the P-blocker.


Dopamine is most commonly reserved for patients with low systolic BPs and those approaching cardiogenic shock. It may also be used in low doses (less than 3 mcg/kg/ min) to improve renal function in a patient with inadequate urine output despite high filling pressures and volume overload, although this indication is controversial.

Dopamine exerts its effects through direct stimulation of adrenergic receptors, as well as release of norepinephrine from adrenergic nerve terminals. Dopamine produces hemodynamic effects that differ based on dosing. At lower doses, dopamine stimulates dopamine type 1 (D1) receptors and thus increases renal perfusion. Positive inotropic effects are more pronounced at doses of 3 to 10 mcg/kg/min. CI is increased due to increased SV and HR. At doses higher than 10 mcg/kg/min, chronotropic and a1-mediated vasoconstriction effects are evident. This causes an increase in mean arterial pressure due to higher CI and SVR. The ultimate effect on cardiac hemodynam-ics will depend largely on the dosage prescribed and must be individually tailored to the patient's clinical status. Dopamine is generally associated with an increase in CO and BP, with a concomitant increase in PCWP. Dopamine increases myocardial oxygen demand and may decrease coronary blood flow through vasoconstriction and increased wall tension. As with other inotropes, dopamine is associated with a risk for arrhythmias.

Phosphodiesterase Inhibitors

Milrinone and inamrinone work by inhibiting phosphodiesterase III, the enzyme responsible for the breakdown of cAMP. The increase in cAMP levels leads to increased intracellular calcium concentrations and enhanced contractile force generation. Milrinone has replaced inamrinone as the phosphodiesterase inhibitor of choice due to the higher frequency of throm-bocytopenia seen with inamrinone.

Milrinone has both positive inotropic and vasodilating properties and as such is referred to as an "inodilator" Its vasodilating activities are especially prominent on venous capacitance vessels and pulmonary vascular beds, although a reduction in arterial tone is also noted. IV administration results in an increase in SV and CO, and usually only minor changes in HR. Milrinone also lowers PCWP through venodila-tion. Routine use of milrinone during acute decompensations in NYHA FC II to IV HF is not recommended, and milrinone use remains limited to patients who require inotropic support.57

Dosing recommendations for milrinone include a loading dose of 50 mcg/kg, followed by an infusion beginning at 0.5 mcg/kg/min (range 0.23 mcg/kg/min for patients with renal failure up to 0.75 mcg/kg/min). A loading dose is not necessary if immediate hemodynamic effects are not required or if patients have low systolic BPs (less than 90 mm Hg). Decreases in BP during an infusion may necessitate dose reductions as well. Lower doses are also used in patients with renal insufficiency.

Milrinone is a good option for patients requiring an inotrope who are also chronically receiving P-blockers, as the inotropic effects are achieved independent of P-ad-renergic receptors. However, milrinone exhibits a long distribution and elimination half-life compared to P-agonists, thus requiring a loading dose when an immediate response is desired. Potential adverse effects include hypotension, arrhythmias, and less commonly, thrombocytopenia. Milrinone should not be used in patients in whom vasodilation is contraindicated.

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