Guidelines for vasodilator therapy of congestive heart failure in infants and children

Michael Artman, M.D., and Thomas P. Graham, Jr., M.D. Mobile, Ala., and Nashville,

Tenn.

The application of vasodilator therapy to infants and children with inadequate systemic output is a relatively new concept. Numerous reports are available to define the theoretic rationale, acute hemodynamic effecta, and consequencesof long-term therapy with a variety of different vasodilating agents in adult patients. In contrast, there are considerably fewer experimental studies published which describe the effects of vasodilators in infants and children. Furthermore, it may be inappropriate to use the experience in adults as a basis for predicting the outcome of vasodilator therapy in young children. This is not only because of differences in underlying pathophysiologic states but, in addition, there exist age-related differences in myocardial contractile function, circulatory physiology, and drug disposition. Thus, the foundation upon which to construct guidelines for the use of vasodilators in young patients requires modification of the concepts already established in adults.1-5 Much of the physiologic framework for vasodilator therapy as modified for young patients has been presented recently6 and does not require reiteration. However, many of the consequences of these agerelated physiologic differences remain to be determined with regard to responsesto vasodilator therapy. In addition, the pharmacology of many vasoactive drugs has not been characterized in young patients. With these caveats in mind, we will attempt to provide a rational approach to vasodilator therapy in infants and children by combining physiologic and pharmacologic principles with the

I

of Pediatrics the Division

and Pharmacology, of Pediatric Cardiology,

Supported in part by Public Health Service Clinical No. HL01695 from the National Heart, Lung, and Artman). Received

for publication

Oct. 30, 1986;

Reprint requests: Michael University of South Alabama AL 36617.

994

Artman, Medical

accepted M.D., Center,

Dec.

University Vanderbilt

Investigator Blood Institute

Award (Dr.

2, 1966.

Department 2451 Fillingim

of

of Pediatrics, St., Mobile,

Post-Hz

Fig. 1. Effects of hydralazine on sy$emic arteriolar resistance and cardiac index in 13 infants with dilated cardiomyopathy. Values were obtained during cardiac catheterization prior to (Pre-Hz) and 30 minutes after (Post-Hz) admini&ration of hydralazine (0.5 to 1.0 mglkg intravenously).

available clinical experience. This report will not include discussions of the recognition, etiologies, or more traditional approaches to the management of congestive heart failure in infants and children. These topics have been reviewed recently.‘v8 PREYOUS

From the Departments South Alabama, and University.

I

Pre-Hz

CUB&CAL

REPQRTS

The use of vasodiitors in children was described initially for patients with low cardiac output immediately following cardiac surgery.@~*~ Infusions of nitroprusside or nitroglycerin during the early postoperative period were associated with clinical improvement in these children. Subsequently, vasodilator therapy was applied to the management of congestive heart failure in chil-

VOlumO 113 Number

Vasodilator

4

therapy

for CHF in pediatric

patients

995

P
Pre-Hz

1

Post - Hz

Prc - HZ

I

Post-Hz

2. Effects of hydralazine on magnitude of systemic-to-pulmonic shunt in eight infants with complete atrioventricular canal defects. Values were obtained during cardiac catheterization prior to (Pre-Hz) and 30 minutes after (Post-Hz) administration of hydralazine (0.5 to 1.0 mg/kg intravenously). (From Artman M et al. Circulation 1984;69:949.Reproduced with permission.) Fig.

dren with dilated cardiomyopathy. Dillon et all3 reported that nitroprusside was beneficial acutely in four of six children with severe cardiac failure. Hydralazine resulted in marked improvement when administered to an adolescent with adriamycin cardiotoxicity. l4 Beekman et all6 observed hemodynamic improvement after either hydralazine or nitroprusside was administered to a total of six children with dilated cardiomyopathy.15 We evaluated the acute hemodynamic responses to hydralazine in 13 infants with idiopathic dilated cardiomyopathy.le In this homogeneous group of young infants, hydralazme acutely decreased systemic resistance and increased cardiac index. Fig. 1 summarizes our results from these patients. Rao17 observed a similar beneficial acute effect of hydralazine in older children with primary myocardial disease. Furthermore, hydralazine appeared to provide sustained improvement during chronic theraPY.

16,17

Several studies have been published to characterize the acute effects of vasodilators in children with systemic-to-pulmonic shunts.ls-zsNitroprusside produced deleterious hemodynamic effects in infants with large ventricular septal defects.19 This was

attribu(sd cbti

kcrease 2, venous capackance with

decline in ventricular filling. In contrast, hydralazine (an arteriolar dilator) may decrease the magnitude of the shunt and increase systemic out-

a resultant

put

in

infants

with

intracardiac

left-to-right

shunts.20~22~23 Fig. ‘2 illustrates the acute effects of hydralazine on shunt magnitude that we observed in

a group of young infants with complete atrioventricular canal defects.“’ It appears that the individual hemodynamic

response to vasodilators

in these

patients is determined by the relative changes in both the systemic and puhnonic circulations. If systemic resistance falls and pulmonary resistance is low initially (or unreactive), then the left-to-right shunt will decrease. However, if pulmonary resistance also declines substantially, the shunt magnitude may not change.“’ The acute effects of nitroprusside and hydralazine have been reported in children with mitral regurgitation.15s24Each drug produced favorable hemodynamic results by decreasing the regurgitant volume and increasing forward cardiac output. The literature cited previously summarizes most of the published experience with vasodilator therapy for inadequate systemic output in pediatric patients. These reports are confined primarily to descriptions of the acute hemodynamic effects of nitroprusside or hydralazine in a relatively small number of patients. Even less information is available regarding the long-term consequences of vasodilator therapy in infants and children.16-” Clearly, additional studies are required to further characterize j&h the at@, and chronic effects of these and other drugs in a variety of clinical settings. PHARMACOLOGYOFSELECTEDDRUGS

It is helpful to classify vasodilators according to their predominant site of action. Table I categorizes various agents as either venous, arteriolar, or mixed

April

996

Artman and Graham

Table I. Predominant tors Venoz46

site of action of selected vasodila-

Hydralazine Nifedipine

Mixed

Nitroprusside Phentolamine Captopril Enalapril Prazosin

dilators. Mixed vasodilators are those which exert sign&ant effects on both the venous and arteriolar beds. We will limit our discussion to the drugs outlined in Table I, recognizing that many other agents have vasodilating properties. We will not discuss newer vasodilators which are currently being studied in adults (e.g., endralazine, diltiazem, nitrendipine), and we will not include prostaglandins or drugz which exert a major positive inotropic action (e.,g.,isoproterenol, dopamine, amrinone, milrinone). Table II outlines the mechanisms of action and Table III summarizes the recommended dosages and clinical indications for the drugz that we have selected. VENOUS DILATORS Nitroglycerin

Nitroglycerin is a directacting vasodilator that relaxes smooth muscle by stimulating guanylate cyclase.The active speciesis a free radical (nitric oxide) formed from the reduction of nitroglycerin. Nitric oxide then activates guanylate cyclase, resuhing in increased formation of guanosine 3’,5’-monophosphate (cyclic GMP). Elevated intracelhdar concentrations of cyclic GMP stimulate a cyclic GMP-dependent protein kinase, thereby aitering the state of phosphorylation of various regulatory proteins, ultimately resulting in smooth muscle relaxation.25 Nitroglycerin acts on virtually all smooth muscle structures in the cardiovascular, respiratory, and gastrointestinal systems.However, the predominant site of action, especially at the usual therape& concentrations, is on vascular smooth muscle in the large veins.3p4*26*26 Nitroglycerin exerts a lesser effect on arteriolar resistance vessels and preeapillary sphincters but does dilate postcapihary vessels. Hemodynamic effects.1~3*6*1225~ aa The principal effect of nitroglycerin is to increase venous capacitance, resulting in declines in atrial and ventricular filling preasuree. Pulmonary venous and pulmonary arterial pressures are usually reduced. In general, there are minor alterations in systemic vascular Mechunism

of action.

Heart

1997

Journal

Table II. Mechanism of action of selectedvasodilators Drug

Arteriolar

Nitroglycerin

American

Nitroglycerin Hydralazine Nifedipine Nitroprusside Phentolamine

CaptoprilandEnalapril Prazosin

Mechanism

of action

Direct vasodilation mediated by changes in intracellular cGMP Direct vasodilation by unknown mechanism Calcium channel blockade Same as nitroglycerin Competitive blockade of alpha-l and alpha-2 adrenergic receptors Competitive inhibition of angiotensin-converting enzyme Competitive blockade of alpha-l adrenergic receptors

resistance, systemic arterial pressure, heart rate, and cardiac output at the usual doses. Higher doses can produce sign&ant arteriolar dilation, hypotension, and reflex tachycardia. Nitroglycerin appears to be most beneficial in patients with elevated preload and symptoms of systemic and/or pulmonary venous congestion. In this situation, nitroglycerin can reduce filling pressures and relieve venous congestion without significantly affecting systemic arterial pressure or heart rate. Patients with low preload may be affected adversely by nitroglycerin because further declines in filling pressures may produce inadequate ventricular filling and a decrease in cardiac output. Clinical pharmacology. 26,26Nitroglycerin is metabolized in the liver by the enzyme glutathioneorganic nitrate reductase. This hepatic enzyme converts organic nitrates into inorganic nitrite and den&rated metabolites. The mono- and dinitrometabolites have little, if any, vasodilator activity. Because of the enormous metabolic capacity of the liver, nitroglycerin is not effective following oral administration. Nitroglycerin may be given intravenously, sublingually, or transdermally. The plasma half-life is 1 to

4 mint&e in adults.If the intrsmous routeis

utilized, nitroglycerin must be given by continuous infusion to maintain constant plasma concentrations. The sublingual route is used in adults to alleviate acutx attacks of angina pectoris or for immediate angina prophylaxis prior to exertion. Nitroglycerin may be administered transdermally, either as an ointment or in the form of a sustainedrelease adhesive disc. Few data are available regarding the clinical pharmacology of nitroglycerin in infants and chil-

V&m* numbw

Table

113 4

Vasodilator

III. Recommendations Drug

for vaaodilator

therapy

in infants

Usual dose and route of administration

Hydralasine

0.1 to 0.5 mg/kg/dose intravenously every 6to8hours 0.25 to 1.0 mg/kg/dose orally every 6 to 8 hours. Maximum 7 mg/kg/day 0.1 to 0.3 mg/kg/dose in infants 0.2 to 0.5 mg/kg/dose in children sublingually every 6 hours or orally every 8 hours 0.5 to 3.0 flg/kg/min intravenously Maximum 10 &kg/min

Phentolamine Captopril

Enalapril Prazosin

patients

997

Postoperative low cardiac output syndrome, pulmonary hypertension, and/or systemic venous congestion Chronic ventricular dysfunction. Aortic and/or mitral regurgitation. Systemic-to-pulmonic shunts Aortic and/or mitral regurgitation Systemic-to-pulmonic shunts Postoperative low cardiac output syndrome, pulmonary hypertension, and/or systemic venous congestion Postoperative low cardiac output syndrome Chronic ventricular dysfunction. Aortic and/or mitral regurgitation. Systemic-to-pulmonic shunts

2.5 to 15 &kg/min intravenously 0.1 to 0.5 mg/kg/dose orally every 8 to 12 hours in neonates. Maximum 4 mg/kglday 0.1 to 2.0 mg/kg/dose orally every 6 to 12 hours in infants and older children Maximum 6 mg/kg/day 6.25 to 12.5 mg/dose orally every 8 to 12 hours in adolescents. Maximum 50-75 mgfdose 0.08 mg/kg/dose orally every 12 or 24 hours in older children and adolescents

Chronic ventricular dysfunction. Aortic and/or mitral regurgitation. Systemic-to-pulmonic shunts Chronic ventricular dysfunction. Aortic and/or mitral regurgitation

0.01 to 0.05 mg/kg/dose orally every 6 to 8 hours. Maximum 0.10 mg/kg/dose

dren. Benson et aLlo administered nitroglycerin intravenously to children at doses ranging from 0.4 to 60 &kgmin. Their average infusion rate of 20 &kg/min is considerably higher than the usually effective dose in adult patients (5 to 10 ccgflrglmin).27 Ilbawi et al.12 observed significant hemodynamic effects when nitroglycerin was infused postoperatively in children at rates from 1 to 5 &kg/min.12 Earlier studies using polyvinylchloride infusion sets may be misleading because of significant adsorption of nitroglycerin, resulting in delivered doses much smaller than what was calculated.12~26*21 The currently available data are insufhcient to make any judgments regarding other routes of administration of nitroglycerin in infants and children. Adverse effects. The untoward responses are almost all attributable to effects on the cardiovascular system. Nitroglycerin is a potent and rapidly acting vasodilator which should be used cautiously with appropriate hemodynamic monitoring. Overdosage may result in hypotension, tachycardia, and hypoxemia. Nausea, vomiting, and headache have also been reported.26~26 Organic nltrates. A variety of organic nitrates are

CHF in pediatric

General clinical indications

1 to 5 &kg/min intravenously. Maximum 10 &kg/min

Nitroprusside

for

and children

Nitroglycerin

Nifedipine

therapy

available (isosorbide dinitrate, erythrityl tetranitrate, and pentaerythritol tetranitrate), but the information regarding their use in children is inadequate to allow for specific recommendations. The major advantage of these drugs over nitroglycerin is their longer duration of action following oral administration. Thus, they are better suited for maintaining more constant blood concentrations chronically. The pharmacology of these agents is otherwise quite similar to that discussed for nitroglycerin. The role of the long-acting nitrates in the management of congestive heart failure in infants and children remains to be established. ARTERIOLAR

DILATORS

Hydralazlne

Mechanism of action. The subcellular mechanism of action of hydralaxine is not known, but it appears to act directly to relax vascular smooth muscle. The effects of hydralaxine are confined almost exclusively to the arteriolar resistance vessels.*~6~25*28 Hydralaxine produces widespread vasodilation, but it does not affect all resistance beds equally. The coronary, cerebral, splanchnic, and renal vasculature are

99%

Artman and Graham

affected more than vessels in the skeletal muscle and skin63 25*26 In addition to effects on the vasculature, hydralazine appears to exert a mild positive inotropit effect,%, 29 which is of minor clinical significance. Hemodynamic efiects.1-3~6~25*26The major effects of hydralazine are increases in stroke volume and cardiac output resulting from a decrease in systemic arteriolar resistance (Figs. 1 and 2). Other hemodynamic effects are less consistent. Systemic arterial pressure and ventricular filling pressures may decrease slightly. Reflex-mediated increases in heart rate often occur, especially in patients being treated for systemic hypertension. Pulmonary vascular resistance may decrease in patients with left ventricular failure, but the response to hydralazine in patients with primary pulmonary hypertension is variable. Not all adult patients demonstrate sustained clinical improvement during chronic therapy with hydralazine.2p30-32 This may be the result of the development of resistance or tolerance to hydralazine. To date, this phenomenon has not been observed in children, but there are few reports of pediatric patients being treated with hydralazine on a long-term basis.14, ~3l7 Clinical pharmacology.16~17~25~26 Hydralazine may be administered orally, intravenously, or intramuscularly. It undergoes extensive first-pass clearance by the intestines and liver, resulting in low systemic bioavailability following enteral administration. Hydralazine is metabolized by enzymatic and nonenzymatic processes. The rate of metabolism via the enzymatic pathway is genetically determined according to the acetylator phenotype. Given the same dose orally, slow acetylators will achieve higher plasma concentrations than rapid acetylators. The incidence of adverse effects resulting from hydralazine is higher in slow acetylators, and these individuals should generally be treated with lower doses. Onset of action is approximately 30 to 60 minutes following oral administration, with duration of effects lasting up to 8 hours. Hemodynamic effects can be detected within 5 to 10 minutes after intravenous administration, the effects peak after approximately 30 minutes, and the duration of action is generally 2 to 4 hours. The recommended intravenous dose of hydralazine in infants and young children is 0.1 to 0.5 mg/kg, administered as a bolus every 6 to 8 hours. Hydralazine has been effective when administered by continuous intravenous infusion to adults (1.5 to 5.0 &kg/min),33 but we are unaware of any similar studies in children. When changing from intravenous to oral adminis-

American

April 1987 Heart Journal

tration, the dose generally should be doubled. Thus, most infants and children will require a total of 1 to 4 mg/kg/day when hydralazine is given orally. The maximum recommended oral dose is 7 mg/kg/day. The total daily dose should be divided equally and administered every 6 or 8 hours. Adverse effects. The incidence of unacceptable side effects is high (10% to 20% ) in adults treated with hydralazine. The most common undesirable effects are headache, excessive tachycardia, nausea, vomiting, dizziness, and postural hypotension. Less frequent reactions include nasal congestion, cutaneous flushing, lacrimation, paresthesias, and edema. Drug fever, urticaria, and bone marrow depression are rare complications which mandate cessation of therapy. Approximately 10 % of adult patients will develop a lupus-like syndrome. This syndrome is most commonly observed in patients who are slow acetylators receiving more than 200 mg/day. These patients invariably have antinuclear antibodies, but not all patient in whom antinuclear antibodies appear will subsequently develop clinical features of lupus erythematosus. The presence of antinuclear antibodies without clinical symptoms is not an indication to discontinue hydralazine. Thus, the routine periodic determination of antinuclear antibody does not appear to be justified in the absence of rheumatoid symptoms. However, symptomatic patients with antinuclear antibodies will require cessation of therapy. The syndrome is generally reversible, with disappearance of symptoms within 6 months after hydra.lazine is discontinued. The incidence of side effects is unknown in infants receiving hydralazine chronically. However, in the 10 infants we followed, we did not observe any adverse effects.16 Similarly, Rao17 did not report any serious side effects in 10 children on long-term hydralazine therapy. He also detected antinuclear antibodies in two children. The antibodies disappeared after hydralazine was discontinued and neither of these patients had rheumatoid symptoms. However, the classic lupus-like syndrome can occur in children. We know of one 12-month-old infant in whom typical rheumatoid features and antinuclear antibodies developed after approximately 3 months of therapy (Boerth RC: personal communication). Nifedipine

Mechanism of action. Nifedipine is classified as a calcium channel blocker.25,26’34 These agents inhibit calcium infhnr into a variety of cells. Calcium plays a central role in numerous cellular functions, and reduction of calcium influx may affect a number of calcium-dependent processes. Cardiovascular ef-

Volume113 Number 4

fects of calcium channel blockers include depression of myocardial contractility and conduction and relaxation of vascular smooth muscle. Hemodynamic effects. In general, the hemodynamic effects of calcium channel blockers are attributable to depression of myocardial contractility, depression of cardiac conduction (especially through the atrioventricular node), and vasodilation. The effects on vascular smooth muscle are confined primarily to the systemic arteriolar bed with little effect on venous capacitance. Thus, afterload is reduced, but a clinically significant decrease in preload does not occur. In addition, the coronary arterioles are dilated by calcium channel blockers. The net hemodynamic response to calcium channel blockers in patients with congestive heart failure may be complex and is related to the specific agent used, dose, and severity of cardiac decompensation. Nifedipine has been selected for this discussion because it appears to be the most potent vasodilator and has little dromotropic or chronotropic effect relative to the agents presently available commercially in the United States. Nifedipine will reduce systemic vascular resistance and increase cardiac output with minimal effect on heart rate in adult patients with mild-to-moderate impairment of left ventricular function.35-38 However, extreme caution should be exercised in patients with severely depressed myocardial contractile function. In these patients, nifedipine may precipitate further decompensation because of its negative inotropic effects.36, 3s Clinical pharmacology. 25,26Nifedipine may be given orally or sublingually. Intravenous preparations are not commercially available (the drug is extremely light sensitive). Sublingual administration has been used in hypertensive emergencies because of the rapid onset of action (onset within a few minutes; peak effects in 1 to 2 hours). Following oral administration, nifedipine effects are observed after 1 to 3 hours. The usual dosage in adults is 10 to 20 mg every 8 hours. This may be increased to 20 to 30 mg every 6 to 8 hours. Nifedipine is currently available in capsule form (10 mg) and the contents must be removed in order to prepare smaller doses. Nifedipine has been used acutely in children to treat systemic hypertensive emergencies.a Single doses of 0.25 to 0.50 mg/kg were administered sublingually to 21 children 8 to 16 years of age. In another report, two infants were treated chronically with oral nifedipine for hypertrophic cardiomyopathy at total daily doses of 0.6 to 0.9 mg/kg.41 Based on these limited data, we suggest starting with 0.1 to

Vasodilator

therapy for CHF in pediatric

patients

999

0.2 mg/kg/dose in infants and children with congestive heart failure. Nifedipine should be administered every 8 hours orally and every 6 hours sublingually. The dosage can be cautiously increased in small increments with careful attention to hemodynamic status. We do not recommend nifedipine for use in infants and children with severely impaired contractile function. In addition, caution should be exercised in neonates because immature myocardium may be more sensitive to the negative inotropic effects of calcium channel blockers.42,43 Adverse effects. Nifedipine has been reasonably well tolerated in adults. Most side effects are minor and serious adverse effects are rare. The overall incidence of adverse reactions in adults is estimated to be 20%. The most common problems are dizziness, edema, hypotension, headaches, cutaneous flushing, and gastrointestinal symptoms. Extreme caution should be used in patients with concomitant beta-adrenergic blockade or severely impaired contractile function. The information currently available is insufficient to allow additional conclusions regarding the clinical toxicity of nifedipine in infants and young children. MIXED VASODILATORS Nitroprusside

of action. 25.26 Nitroprusside is a direct-acting vasodilator with equal effects on venous and arterial smooth muscle. It has potent effects on the vasculature, but has little effect on gastrointestinal or uterine smooth muscle. The mechanism of action appears to be the same as that described for nitroglycerin. Mechanism

Hemodynumic effects. 613.

15,34-25944-45

The

c~culat+

ry responses to nitroprusside are the consequence of decreases in venous and arteriolar tone. In general, nitroprusside reduces systemic vascular resistance and increases cardiac output. Right atrial pressure, pulmonary capillary wedge pressure, and pulmonary vascular resistance decrease in response to nitroprusside. Heart rate may increase slightly during nitroprusside therapy but significant tachycardia is unusual. As the rate of infusion is increased, systemic arterial pressure will begin to decline. Nitroprusside is an excellent drug for treating hypertensive emergencies because it is such a powerful vasodilator and exhibits rapid onset of action. Clinical pharmacology. 25,26Nitroprusside must be administered by continuous intravenous infusion. The drug reacts rapidly with a variety of sulfhydryl compounds, including hemoglobin. Cyanide is released which is then metabolized by the liver to form thiocyanate. Thiocyanate is cleared by the

April

loo0

Artman and Graham

kidney, but the half-life is long (approximately 4 days). Nitroprusside undergoes photochemical degradation so solutions must be fresh and protected from light during the infusion. Nitroprusside demonstrates a very rapid onset of action (1 to 2 minutes) and, likewise, the effects dissipate quickly when the infusion is reduced or discontinued. Thus, the desired hemodynamic effects can be achieved by careful titration of the infusion rate. The usual starting dose is 0.5 pg/ kg/min. The rate of infusion can be increased to a maximum of 10.0 kg/kg/min. In general, satisfactory results are obtained with average infusion rates of 1 to 3 &kg/min. Aduerse effects. The major acute toxicity is related to the marked vasodilator activity of nitroprusside. Appropriate hemodynamic monitoring is imperative when using this agent in order to avoid excessive vasodilation and hypotension. During prolonged infusion, additional adverse effects may result from the accumulation of cyanide and/or thiocyanate. Principal symptoms of cyanide toxicity include tachycardia, tachypnea, vomiting, headache, and depression of consciousness. Excessive thiocyanate can produce fatigue, nausea, anorexia, and disorientation. In addition, chronic thiocyanate exposure can interfere with thyroid function. These toxic effects are more pronounced in patients receiving high doses and in those with impaired hepatic or renal function. The incidence of significant toxicity is minimal in patients receiving 52 bg/kg/min of nitroprusside. In high-risk patients or during protracted use, it is important to monitor red blood cell cyanide or serum thiocyanate concentrations on a daily basis. Toxic symptoms generally appear when these levels reach 50 to 100 nmol/ml or 5 to 10 mg/dl, respectively. In addition to the extensive experience with this drug in adults, there are a number of reports regarding its use in younger patients.13* *5*24,44-46 For example, Benitz et al.& administered nitroprusside to 58 neonates without serious toxic effects. When used carefully, nitroprusside can be very effective with a minimum of adverse reactions in infants and children. Phentolamine

Mechanism of action.25~47~48Phentolamine is an imidazoline derivative which produces competitive blockade of alpha-adrenergic receptors. It does not demonstrate selectivity toward either alpha-l or alpha-2 receptors. Presynaptic alpha-2 blockade may result in an increase in the amount of norepinephrine released by neural impulses. This may contribute to the tachycardia and dysrhythmias

American

Heart

1987

Journal

observed at high doses. Additional effects of phentolamine include inhibition of responses to 5hydroxytryptamine (serotonin), increased gastric acid secretion, and increased intestinal peristalsis. Hemodynamic effects. 25,48-50Phentolamine reduces systemic vascular resistance and increases cardiac output in patients with low-output failure. Cardiac filling pressures often decline but may remain unchanged. We have classified phentolamine as a mixed vasodilator, but its effects on venous capacitance are modest when compared to other drugs included in this category. Ie adults, phentolamine often produces significant tachycardia, but this response is unusual in infants and children. Systemic arterial pressure may decrease slightly during infusion of phentolamine, and pulmonary arterial pressure and vascular resistance decrease. Clinical pharmacology. 25,47-5oPhentolamine can be administered orally, intramuscularly, or intravenously. However, the experience in children is limited to acute intravenous infusion. Relatively little is known regarding the disposition of phentolamine in the body. Only approximately 10% is recovered in the urine, suggesting the drug undergoes extensive metabolism. We recommend administering phentolamine by constant intravenous infusion with a starting dose of 2.5 kglkglmin. The rate of infusion can be increased gradually to a maximum of 15 pg/kg/min. It is unlikely that doses higher than this will result in any further hemodynamic improvement.4gs 50 Adverse effects. 25+47Phentolamine can produce significant sinus tachycardia which limits its usefulness. The drug may also precipitate cardiac dysrhythmias. However, at the recommended doses, these reactions are uncommon in young patients. The gastrointestinal stimulation produced by phentolamine may result in abdominal pain, nausea, vomiting, diarrhea, and gastric hyperacidity. Phentolamine potentially could increase the risk of stress ulcer formation in critically ill patients. Captopril

Mechanism of action.25*26F51Captopril is the first orally effective inhibitor of angiotensin-converting enzyme. The inhibition is competitive with relatively high specificity for angiotensin-converting enzyme. This enzyme catalyzes the conversion of inactive angiotensin I to angiotensin II. Angiotensin II is a potent pressor which plays a major role in the regulation of blood pressure and sodium and water balance. Thus, captopril inhibits the actions of angiotensin II (by preventing its formation), resulting in vasodilation, decreased aldosterone secretion, increased renal blood ‘flow, and enhanced sodium

Volume Number

113 4

excretion. Angiotensin-converting enzyme also catalyzes the degradation of bradykinin to an inactive metabolite. A second important action of captopril, therefore, is to increase levels of bradykinin. Bradykinin exhibits vasodilator activity and may be involved in the modulation of prostaglandin release. Hemodynamic effects.25s51-53Captopril produces a decrease in systemic vascular resistance and an increase in venous capacitance. In patients with congestive heart failure, these actions result in an increase in cardiac output and a decrease in cardiac filling pressures. In general, heart rate is only minimally affected and blood pressure decreases slightly. Captopril reduces pulmonary vascular resistance and pulmonary arterial pressure in most patients with low-output cardiac failure. Renal blood flow increases and moderate diuresis ensues as a result of improved renal hemodynamics and a reduction in aldosterone release. Plasma renin activity increases during therapy with captopril. Clinical pharmacology. 25,27,51,54*55Captopril is only available for oral administration. Approximately 65% to 75% of an oral dose is absorbed, but food in the gastrointestinal tract will reduce absorption to less than 40%. Captopril is generally given 1 hour before a meal. The drug enters the circulation rapidly and is distributed to all tissues with the exception of the central nervous system. Peak plasma concentrations are observed approximately 60 minutes following a single oral dose. The plasma half-life is short (2 hours), but the duration of effect is generally about 8 hours. Captopril is almost completely eliminated in the urine; approximately 50% is excreted unchanged and the remainder as metabolites. Clearance is reduced in patients with impaired renal function. Most of the experience with captopril in the pediatric age group is in patients treated for systemic hypertension. 27,54-58 In newborn infants with congestive heart failure, we recommend beginning with 0.1 mg/kg given every 8 to 12 hours. Blood pressure should be monitored carefully, particularly following the first dose. If hypotension occurs, it can be managed with the administration of fluids and/or a pressor agent, such as phenylephrine. The dose of captopril may be increased gradually to 1 mg/ kg/dose, and the frequency may be decreased to 6 hours (total of 4 mg/kg/day). The majority of neonates will require no more than 0.6 mg/kg every 8 hours (1.5 mg/kg/day). Older infants and young children are treated with 0.3 to 6.0 mg/kg/day in 2 to 4 divided doses. The drug is administered to small infants by crushing one fourth or one half of a 25 mg

Vasodilator therapy

for

CHF in pediatric patients

1001

tablet (6.25 mg or 12.5 mg) and dissolving it in tap water (6 or 12 ml, respectively). The desired dose is then administered and the remaining solution is discarded. A fresh preparation should be used for each dose. Adolescents are started on 6.25 or 12.5 mg/dose every 8 to 12 hours. This may be gradually increased to 50 to 75 mg/dose. In all age groups, the minimally effective dose should be employed. Additional precautions are required when administering captopril to infants and children with impaired (or immature) renal function. Adverse efects.27*“-58 Despite the potential for serious toxic effects, captopril is generally well tolerated in the majority of pediatric patients. Symptomatic hypotension may occur in volume-depleted patients. Neutropenia can be profound and require cessation of therapy. Proteinuria may occur (especially in children with renal disease), but this rarely necessitates discontinuation of captopril therapy. More common side effects include erythematous rashes, taste impairment, and minor gastrointestinal disturbances. Potassium supplements and/or potassium-sparing diuretics should be avoided in patients receiving captopril because of the potential for hyperkalemia. Enalapril

Mechanism of action and hemodynamic effects. Enalapril is a second orally effective angiotensinconverting enzyme inhibitor which has been released recently. 5g Its mechanism of action, hemodynamic effects, and clinical indications are similar to those discussed for captopril. However, there is very little information available regarding the administration of enalapril to infants and children. Clinical pharmacology. 5g Enalapril is a prodrug, which undergoes hepatic deesterification to form the active agent enalaprilat. Approximately 60% of an oral dose of enalapril is absorbed. The ultimate bioavailability of enalaprilat amounts to 40% of the initial dose of enalapril. Peak concentrations of enalaprilat are observed in the plasma approximately 3 to 4 hours following oral administration of enalapril. The pharmacokinetics of enalaprilat are complex, but the drug exhibits a long terminal half-life of approximately 33 hours in adults. Enalaprilat is excreted unchanged in the urine and the dosage must be reduced in patients with impaired renal function. The usual effective dosage of enalapril in adults is 10 to 20 mg administered in one or two daily doses. The dosage may be increased to 40 n&day. Thus, one potential advantage of enalapril over captopril is that enalapril requires less frequent administration. Additional studies are necessary before specific dos-

April

1002

Artman and Graham

age recommendations can be proposed for infants and children. However, we currently use approximately 0.08 n&g/dose, administered every 12 to 24 hours. Enalaprilat can be administered intravenously, thereby providing a basis for testing the acute effects of this drug in infants and children. Aduerse effects. The adverse effects of enalapril are similar to those described for captopril. However, the overall incidence of side effects resulting from enalapril may be lower than that reported for captopril. Many of the side effects of captopril have been attributed to a sulfhydryl group which is not present in enalapril. Because of the long duration of action, prolonged hypotension may occur following enalapril administration.~ Until more information is available, enalapril should be regarded as an investigational agent in newborn and young infants.

American

Heart

1987

Journal

reasonably well and most side effects are minor and do not require cessation of therapy. The most serious adverse reaction is known as the “first-dose phenomenon.” This is characterized by marked hypotension with dizziness or syncope 30 to 90 minutes after the initial dose of prszosin. For this reason, the first dose should be administered at bedtime. Other side effects include dry mouth, nasal stufhness, and postural hypotension. A potential problem with chronic prazosin therapy is the development of tachyphylaxis. It remains to be determined whether or not this will limit the usefulness of prazosin in pediatric patients. DRUG THERAPY

BASED

ON CLINICAL

SETTING

Impaired ventricular function in the immediate postoperative period. Not all infants and children will

Mechanism of action. 25,26,47Prasosin is a quinasoline derivative which acts to block postynaptic alpha-l adrenergic receptors. Prasosin exerts a competitive blockade which is highly selective for alpha-l receptors with very little effect on alpha-2 receptors. This is in contrast to phentolamine, which demonstrates nonselective alpha blockade. Hemodynamic effects. 25,26*47Prazosin reduces systemic vascular resistance and systemic arterial pressure in hypertensive patients. In patients with congestive heart failure, praxosin also increases cardiac output and reduces preload (venous capacitance increases). In contrast to direct-acting arteriolar dilators, praxosin produces little or no increase in heart rate. is availClinical pharmacology. 139 1% 25.26 prmosin able only as an oral preparation. It is well absorbed from the gastrointestinal tract, and peak plasma concentrations are observed within 2 to 3 hours following a single oral dose. Praxosin undergoes extensive hepatic metabolism and approximately 90% is excreted in the bile as dealkylated metabolites. The drug is highly protein bound (approximately 95% bound to alpha-l acid glycoprotein), which may contribute to the lack of correlation

require vasodilator therapy during the early postoperative period. However, vasodilator therapy can be of dramatic benefit in those patients with low cardiac output despite adequate filling pressures (low cardiac output syndrome). These infants usually have elevated systemic vascular resistance. We find it helpful to use some index of systemic resistance as an aid in determining the need for, and response to, vasodilator therapy. The use of indwelling catheters to monitor cardiac index, filling pressures, and systemic and pulmonary arterial pressures can be invaluable. In the absence of a thermodilution catheter or other means of measuring flow, cardiac output and systemic resistance can be gauged clinically by carefully evaluating the quality of the peripheral pulses and distal perfusion. We find that the use of a thermistor on the toe or foot can be a useful adjunct to the assessment of peripheral perfusion. In those children requiring acute reduction of afterload, we use either nitroprusside or phentolamine. The effects of these agents can be titrated by carefully adjusting the rate of intravenous infusion. It is important to remember that both of these drugs will also increase venous capacitance (nitroprusside more than phentolamine). Thus, it may be necessary

betweenplasmadrug concentrationsand antihyper-

to provide additional volume support when these

tensive effect. The plasma half-life is 2.5 to 4 hours, but the duration of effect is much longer (12 hours in most patients). We recommend an initial dose in children of 0.01 mg/kg administered every 6 to 8 hours. This may be gradually increased to 0.05 n&kg/dose. Satisfactory results may be obtained with 12-hour dosing intervals, especially in infants. Adverse effects.1s~16*25*26.41 Prazosin is tolerated

drugs are started. In contrast, volume-overloaded patients with significant systemic or pulmonary venous congestion may benefit from the effects of these agents on the venous capacitance vessels. Infants and children with adequate cardiac output in the presence of systemic venous congestion (such as following a Fontan-type operation) may benefit from nitroprusside or nitroglycerin by virtue of their action to increase venous capacitance. These

Prazosin

Volume

113

Number

4

Vasodilator therapy

drugs may also be helpful in reducing pulmonary vascular resistance in patients with significant pulmonary hypertension postoperatively. Chronic ventricular dysfunction. In general, we use either hydralaxine, captopril or, less commonly, prazosin for long-term therapy in infants and children with impaired ventricular function (Fig. 1). Nefedipine should be avoided because of its negative inotropic effect. The combination of hydralaxine and nitroglycerin has been utilized in adults, but if combined afterload and preload reduction are desired, captopril alone is usually sufhcient. However, individual patients may differ in their responses, and if satisfactory results are not obtained with a particular regimen, alternative drugs or drug combinations may prove to be beneficial. Hydralazine and captopril have been used together in adult patients with resultant improvement in hemodynamics beyond that achieved with either drug alone. Further clinical studies are required to better define the appropriate use of long-term vasodilator therapy in pediatric patients. The response to vasodilator therapy must be assessed clinically during chronic therapy. Particular attention should be given to growth parameters. Noninvasive evaluations, such as by echocardiography or radionuclide ventriculography, may provide helpful information regarding chamber sizes, ventricular function, and systemic output. Cardiac function may return to normal in some patients, thereby justifying an attempt to gradually wean the child from vasodilator therapy. Mitral and/or aortic regurgitation. Many patients with mild to moderate left-sided valvular regurgitation will respond satisfactorily to arteriolar dilation with hydralaxine or nifedipine. In severe cases, there is often pulmonary venous congestion (and occasionally systemic venous congestion) for which captopril or praxosin might be helpful because of their venodilatory action. Echocardiography or radionuclide ventriculography can be applied to evaluate the degree of regurgitation before and after administration of a particular drug. Systemic-to-puimonic shunts. The direction and magnitude of an intracardiac or great vessel shunt is dependent upon the relative resistances to flow on either side of the abnormal communication. Thus, s&en&

a&r;olar

dilaiion will decrease ihe ma&-

tude of a systemic-to-puhnonic shunt if pulmonary resistance does not decrease significantly.‘* In these situations, we generally use hydralaxine or an angiotensin-converting enzyme inhibitor (Fig. 2). Ventricular systolic function is usually normal in

for

CHF in pediatric patients

1003

these patients and nifedipine would also be expected to be of benefit. We have limited experience with praxosin in this setting but it would likewise be a rational choice. Again, clinical estimation of the hemodynamic response can be enhanced by the application of noninvasive techniques to estimate shunt magnitude or by testing of the acute responses during cardiac catheterization. CONCLUSIONS

Our current recommendations regarding doses and clinical indications for vasodilator therapy in infants and children with inadequate systemic output are summarized in Table III. We rarely use a vasodilator as sole therapy. Almost all patients are treated concomitantly with a diuretic. Patients with impaired ventricular function usually receive digoxin in addition to a diuretic and vasodilator. It must be emphasized that many of the recommendations and guidelines that we have outlined are based on experience published regarding the pharmacology of these drugs in adult patients. Additional clinical studies are necessary to clarify the clinical pharmacology and consequences of long-term vasodilator therapy in infants and children with inadequate systemic output. We are grateful to Patty Albrecbt for superb secretarial assistance in the preparation of this manuscript.

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