Historical perspectives and update of amrinone

Historical

Perspectives

and Update

of Amrinone

Martin Goenen, MD The pathophysiological understanding and management of acute and chronic heart failure have changed dramatically in the past decade. Since the early 1980s. a major effort has been made to develop nonglycosidic, noncatecholamine agents that combine inotropic and vasodilating properties, in order to treat myocardial dysfunction unresponsive to current therapy. Within this context, increasing attention has been paid to the role of intracellular cyclic adenosine monophosphate (CAMP) in myocardial contractility. The pharmacologic use of catecholamines to stimulate @-receptors activates adenylate cyclase, which in turn leads to an increase in intracellular levels of CAMP. In addition, phosphodiesterase 3 (PDE 3) inhibition may prevent the degradation of CAMP, thus maintaining high intracellular levels of

P

HARMACOLOGIC EVIDENCE suggests that a deficient production of cyclic adenosine monophosphate (CAMP) may constitute an important cause of contractile dysfunction.’ A lack of CAMP may occur following the (1) chronic stimulation of P-receptors, causing their downward regulatior?; (2) excessive use of Bblockers; or (3) insufficient production of adenosine triphosphate (ATP), secondary to stunned myocardium.3 In acute myocardial dysfunction, ATP may be depleted because of recurrent ischemic attacks, inadequate myocardial protection, reperfusion lesions, or misuse of drugs. ATP depletion in acute heart failure and reduced P-receptor activity in chronic heart failure may reduce the efficacy of catecholamines (Fig 1). In this setting, phosphodiesterase (PDE)-3 inhibition may be a valuable alternative therapy. Moreover, the synergistic activity of catecholamines and PDE inhibitors (Figs 2 and 3) may contribute to significant improvement in patients with heart failure.4 For these reasons, the use of either a catecholamine, a PDE inhibitor, or both is a rational therapeutic concept for surgical and nonsurgical patients with ventricular dysfunction.‘-’ Based on experiences with the intravenous administration of amrinone, a clear hemodynamic profile for this agent has emerged. Amrinone produces significant increases in cardiac output and significant decreases in right and left ventricular filling pressures and systemic and pulmonary vascular resistances. These improvements occur without marked changes in heart rate, Journalof CardiothoracicAnesthesia.Vol3,

No 6, SuppI

the substance. Intravenous amrinone has been shown clinicallyto improve hemodynamic status remarkably in the patient experiencing a low cardiac output syndrome, by increasing CO while decreasing filling pressures and pulmonary arterial pressures, without increasing myocardial 0, demand. This report will review several studies of different types of patients and explain the effects of amrinone alone and in combination with the more traditionally used catecholamines. It must be stressed that amrinone, in spite of its dual action of inotropy and vasodilation, should not be considered a rival to catecholamines but rather an enhancer of them, which clinicians should consider using in the early stages of therapy in many different settings. 0 1933 by W.B. Saunders Company.

systemic blood pressure, and myocardial oxygen consumption.‘*” Regarding the future use of PDE-3 inhibition in the treatment of the low cardiac output syndrome, several important unanswered questions indicate the need for additional research. (1) Should the failing heart be stimulated?” Continuous positive inotropic therapy may exhaust limited contractile reserves, ie, the energy supplies of the depressed myocardium, and thus hasten the progression of myocardial disease. (2) Is it advisable to treat patients already in stage II congestive heart failure with inotropic agents? (3) Can PDE-3 inhibitors be used in candidates for heart transplantation? INTRAVENOUS ADMINISTRATION AMRINONE

OF

IN ACUTE HEART FAILURE

Because amrinone seems to address the underlying pathophysiology of acute and chronic heart failure, and because this agent seems to have a wide therapeutic profile, the use of intravenous amrinone (either alone or in combination with catecholamines) has been investigated. Within this context, amrinone has been used successfully to treat surgical and nonsurgical

From the Department of Intensive Care. Saint-Luc University Hospital, Brussels, Belgium. Address reprint requests to Martin Goenen. MD, Dept of Intensive Care, Saint-Luc University Hospital, Brussels, Belgium. 0 1989 by W.B. Saunders Company. 0888-6296/89/0306-2004$03.00/0

(December), 1969: pp 15-23

15

16

MARTIN GOENEN

ADRENBMilcDIuvE

RBCRUSE IN l.c. ASP SY ?lS?SlUWSlDN WASf&DUl

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Fig 3. Amrinone combined with dobutamine potentiates the hemodynemic effects of dobutemine in a significant way. The synergism persists with increasing doses of dobutamine. (A) Amrinone and dobutemine; (Cl dobutamine alone. Reprinted with permission.7

Fig 1. Hypothesis of postoperative myocardial dysfunction. CAMP may be decreased in chronic myocardial disease by downward regulation of the @-receptors and in acute heart failure by a decrease in ATP in the stunned myocardium. Both processes may coexist in the perioperative low output syndrome, decreasing the amount of CAMP.

THERAPEUTIC USE OF AMRINONE IN MEDICAL PATIENTS

patients in various critical hemodynamic states due to ventricular dysfunction (Table 1). Based on this clinical experience, PDE-3 inhibitors, possessing inotropic and vasodilating properties, are often compared with dobutamine.6V8 Unlike dobutamine, however, amrinone produces a more pronounced reduction in preload, afterload, and ventricular wall tension, without significantly changing heart rate and myocardial oxygen consumption. Although amrinone has significant direct and indirect vasodilating effects,12 the agent may be administered with a traditional vasodilator like nitroprusside to enhance myocardial performance, without decreasing blood pressure (Fig 4).

Many clinical investigations have evaluated the efficacy and safety of intravenous PDE-3 inhibition in patients with chronic congestive heart failure.g The results of these trials have led to the increased use of amrinone in patients experiencing acute hemodynamic deterioration, despite conventional therapy with inotropes and vasodilators. Although much is known about the hemodynamic profile of PDE-3 inhibitors in heart failure, only a few studies to date have reported on the therapeutic use of amrinone in patients with impaired myocardial function following acute myocardial infarction.1913T14The reluctance to use amrinone in acute myocardial

100 >Fc- l-l=4 (W Amrinone _ (0.2mmoM) 50

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1

10

100 c 1000

Isoprenaline Concentration (pmol!l)

0.1

1

10

Histamine Concentration (pmol/l)

100

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30

100

Dihydro-ouabain Concentration (I~moUl)

Fig 2. In 1981. Honerjager first showed the potentietion of positive inotropic drugs. Amrinone increased the inotropit potency of isopreneline and histamine, but not dihydro-ouabain. The synergism is selective. Reprinted with permission:

AMRINONE:

UPDATE AND HISTORICAL PERSPECTIVES

Table 1. Potential Indications for PDE-3 Inhibitors In nonsurgical patients Acute hemodynamic deterioration in chronic congestive heart failure Myocardial dysfunction after acute myocardial infarction Pulmonary hypertension and right ventricular dysfunction in neonates, children, and adults Cardiac depression secondary to negative inotropic agents Septic shock In surgical patients 0

Noncardiac surgery in cardiac patients

l Cardiac surgery Hemodynamic support in patients waiting for current heart surgery or heart transplantation Emergence from cardiopulmonary bypass Postoperative cardiovascular deterioration: moderate heart insufficiency severe cardiogenic shock pediatric cardiac surgery persistent high pulmonary resistance poor peripheral perfusion

infarction is so far questionable as the drug is currently administered to patients with perioperative ischemia or infarction. To date, clinical investigators have been more interested in evaluating the pulmonary vascular effects of amrinone. Nevertheless, controversy remains over whether or not amrinone is effective in decreasing pulmonary arterial pressure and resistance, based on contradictory findings from animal trials and from clinical investi-

17

gations of neonates, children, and adults with either primary or secondary pulmonary hypertension. In experimental studies, amrinone has been shown to dilate pulmonary vessels and to blunt hypoxic vasoconstriction in isolated rat lungs.15 In other animal studies, the peak effect of amrinone on pulmonary vascular resistance appears more pronounced than on systemic vascular resistance.16 However, the clinical results are mixed. Amrinone is reported to have no direct effect on persistent pulmonary hypertension in newborns.” In another study of patients with primary pulmonary hypertension, amrinone, nifedipine, and hydralazine produced a general increase in cardiac output and a decrease in pulmonary vascular resistance; only nifedipine, however, significantly reduced pulmonary arterial pressure.‘* On the other hand, in patients with pulmonary hypertension secondary to chronic congestive heart failure,” mitral valve disease,20 or pulmonary obstructive disease,21 short- and long-term intravenous therapy with amrinone enhanced cardiac performance and significantly reduced pulmonary arterial pressure and resistance. Long-term infusion of amrinone in patients with high pulmonary vascular resistance who are waiting for heart transplantation showed that 3 days after the beginning of the infusion, amrinone produced a significant decrease in pulmonary arterial pressure (from 66/34 mm Hg to

O=NITROPRUSSIDE GRAPHICS

Fig 4. Arminona may be combined with nitroprusside. The substantial increase in cardiac index is essentially related to the inotropic proparty, because blood pressure and filling pressure are not decreased (unpublished data).

(pg.kg.-f,iil)

NP (I~s)+AMR

loUs kg-lmin*l

d.m+dn-’

18

MARTIN GOENEN

41/22 mm Hg), transpulmonary gradient (from 19 to 10 mm Hg), and pulmonary vascular resistance (from 6.0 to 2.4 Wood units); cardiac output increased from 3.4 to 4.5 L/min.” Similar results have been obtained in this clinic (Fig 5). Consequently, some investigators propose the administration of amrinone or nitroprusside to potential candidates for heart transplantation who have severe pulmonary hypertension, to reach the criteria of operability (2.5 Wood units). In such a clinical setting, the administration of these agents may also help to predict early graft failure.‘9v22

infused for 48 hours in one patient and for 25 days in the other. Both were already receiving nitroglycerin and dobutamine (Fig 6). Each patient underwent a successful transplant. The candidate for retransplantation was readmitted 6 weeks after combined heart and kidney transplantation; the patient was in severe cardiogenic shock and was unresponsive to conventional inotropic and antirejection therapy. The addition of amrinone to the regimen significantly improved the patient’s hemodynamic condition up to day 7; unfortunately, the patient died because of the lack of a donor heart (Fig 7).

PREOPERATIVE INFUSION TO POTENTIAL

OVERDOSE OF NEGATIVE INTROPIC AGENTS

CANDIDATES FOR HEART TRANSPLANTATION

An overdose with a @-blocker or a calcium antagonist is not uncommon in clinical practice. Both classes of agents are used extensively in the treatment of angina and dysrhythmias. Iatrogenie, accidental, or deliberate overdose may occasionally lead to serious cardiovascular consequences. When combined with isoproterenol, amrinone helped to reverse a seriously compromised hemodynamic state in a 17-year-old girl who had verapamil intoxication.24

OR RETRANSPLANTATION

Inotropic support is not uncommon in patients waiting for heart transplantation. Because heart rate and myocardial oxygen consumption are not increased following therapy with amrinone, this agent may represent a very real alternative to adrenergic therapy in patients awaiting heart transplantation. Amrinone has been used occasionally over 24 hours to treat pulmonary hypertension in pediatric and adult patients.19,23 Amrinone was infused into three patients, two of whom were potential candidates for a first transplant, and one who was a candidate for retransplantation. In these two patients, amrinone was

SEPTIC SHOCK

Currently, septic shock with inadequate cardiac output is managed primarily by volume loading and catecholamine therapy. Until now,

EKG

PAP mmHg

AoP

RAP

Fig 5. High pulmonary resistance may be a contraindication for orthotopic heart transplantation. The vasoactivity of the pulmonary vessels should be tested before surgery to avoid early graft dysfunction. Pulmonary arterial pressure (PAP), pulmonary vascular resistance, and transpulmonary pressure gradient decreased respectively from 62 to 35 mm Hg, 7.0 to 4.2 Wood units, and 16 to 12 mm Hg during 10 pg/kg/min of amrinone infusion (case report). AMR. amrinone: PCWP, pulmonary capillary wedge pressure: RAP, right atria1 pressure; AoP, aortic pressure.

AMRINONE: UPDATE AND HISTORICAL PERSPECTIVES

19

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Fig 6. This patient was treated over the course of 26 days with an amrinone infusion combined with vasodilators and dopamine; the only side effect was a 10% decrease in platelets. Amrinone infusion was instituted because of a poor hemodynamic response, complicated by renal and hepatic dysfunction. Both functions improved markedly with amrinone. Cl, cardiac index: SBP, systolic blood pressure; PCWP, pulmonary capillary wedge pressure: NP, nitroprusside; DP, dopamine; NTG. nitroglycerin; CAP, capillary pressure: AMR. amrinone: DB, dobutamine.

only one study has evaluated the use of amrinone in patients with septic shock who were refractory to conventional therapy.25 When amrinone was combined with catecholamines, cardiac output

increased from 2.2 L/min to 4 L/min; hypotensive patients became normotensive, and heart rate was reduced significantly. Experimental data have confirmed the beneficial effects of amrinone LV-ANEURYSM

Fig 7. Efficacy of combining amrinone with catecholamines to improve a very compromised hemodynamic condition in a patient waiting for retransplantation. The patient died on day 7, before surgery. Notice the severe hemodynamic reaction to rat antithymocyte globulin (unpublished case). DOBU. dobutamine: NP, nitroprusside: AMR. amrinone: Cl, cardiac index; HR. heart rate: PAo, arterial pressure: PAP, pulmonary arterial pressure; PCWP. pulmonary capillary wedge pressure; PRA. right atria1 pressure; BVR. systemic vascular resistance: PVR. pulmonary vascular resistance: LVSWI, left ventricular stroke work index.

a

HR

PA0

PAP

f SEPTAL RUPTURE

PVR

Lvswl

20

MARTIN GOENEN

and norepinephrine, provided fluid replacement is optimal. 26Nevertheless, more clinical data are necessary to show the usefulness of PDE-3 inhibitors in patients with severe septic shock and low peripheral resistance. THERAPEUTIC INDICATIONS FOR AMRINONE IN SURGICAL PATIENTS

EMERGENCE FROM

After optimizing filling pressure, if cardiac function is not sufficient to sustain circulation, either before or after bypass, inotropic and vasodilating agents (and perhaps mechanical assistance) are required to support the patient until ventricular performance meets circulatory and metabolic demands. Provided the myocardium is only stunned, and not irreversibly injured, the depressed myocardium may need circulatory support for days until recovery.3 The number of patients requiring such management is likely to increase in the future because more operations are being performed on patients with preoperative ventricular dysfunction, recurrent ischemia, and acute myocardial infarction. A rational medical approach requires choosing a therapeutic regimen based on the known pathophysiological, hemodynamic, and clinical situation of each patient and the pharmacologic properties of the various adrenergic, phosphodiesterase-inhibiting, and vasodilating agents, which may be used either alone or in combination. No extensive clinical data are available AF 200 -!?

regarding the use of phosphodiesterase inhibitors in cardiac patients undergoing noncardiac surgery. Nevertheless, the efficacy and safety of amrinone in the management of perioperative low cardiac output during cardiac surgery have been extensively shown. CARDIOPULMONARY

BYPASS

Despite optimal volume loading, inotropic support is often needed during emergence from cardiopulmonary bypass. Unlike dobutamine, amrinone does not increase heart rate, and therefore may prove very useful in this clinical setting (Fig 8). Nevertheless, contradictory findings regarding the use of amrinone following cardiopulmonary bypass have been reported. In some studies, significant hemodynamic improvement has occurred after a single bolus injection of amrinone (alone or in combination with norepinephrine or phenylephrine) before coming off bypass.27-29 On the other hand, no significant hemodynamic effect3’ was seen in another evaluation. Additional intraoperative investigations are needed to clarify the role of amrinone during emergence from cardiopulmonary bypass. AMRINONE

IN POSTOPERATIVE

LOW-OUTPUT

SYNDROME

A rational approach to the appropriate management of postoperative low-output syn-

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AMR

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Fig 8. Emergence from bypass achieved first with dobutamine and then with amrinone: there was a major in-

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dobutamine, no change with amrinone, and an identical increase in arterial blood pressure; pulmonary arterial pressure decreased only with

amrinone.

AMRINONE:

21

UPDATE AND HISTORICAL PERSPECTIVES

drome requires continuous hemodynamic and clinical assessment and therapeutic adjustments3i Indications for amrinone have been investigated for the following postoperative settings: as single therapy in patients with moderate heart failure; as combined therapy in severe cardiogenic shock; and as vasoactive support in pediatric surgery. In postoperative cardiac insufficiency, characterized by excessive preload or afterload, and a cardiac index between 2 to 2.5 L/min/m*, amrinone may prove comparable to dobutamine in improving the hemodynamic status of the patient. Nevertheless, the ability to potentiate the effects of catecholamines remains the major contribution of PDE-3 inhibitors in the management of patients with more severe myocardial dysfunction, or patients in cardiogenic shock refractory to catecholamines and vasodilators.4,7,32v34 In one evaluation, 10 of 15 patients with a postoperative low cardiac output were given an infusion of amrinone over 12 hours. Cardiac index increased significantly by 3 l%, while left and right ventricular filling pressures decreased by 26% and 28%, respectively. In the 5 remaining patients in severe cardiogenic shock (refractory to catecholamines and intra-aortic balloon counterpulsation), amrinone in doses up to 20 pg/kg/ min increased cardiac index significantly (+ 60%) while decreasing pulmonary artery wedge pressure (- 29%). There was no significant change in heart rate or aortic pressure.6 These results were confirmed in a clinical investigation involving 40 patients (Fig 9), of whom 34 were restored to a satisfactory hemodynamic state; however, 6 patients died of refractory cardiogenic shock. 35Amrinone was infused in one patient with a low cardiac output after pericardiectomy, despite therapy with dopamine (12 pg/kg/min) and dobutamine (15 pg/kg/ min). One hour later, cardiac index increased I Hamodynamic Fig 9. changes obtained in 34 survivors of postoperative cardiogenie shock, refractory to currant catacholamine therapy. Amrinona wss administered in doses up to 20 pglkglmin for 1 to 7 days: there were major increases in cardiac index, stroke index, and LVSWI.

P

k

from 1.9 to 3.5 L/min/m*; aortic blood pressure significantly decreased soon after infusion, but subsequently increased; mean pulmonary artery pressure decreased from 44 mm Hg to 25 mm Hg; and left ventricular stroke work index (LVSWI) increased from 11 to 19 g-m/m* (Fig 10). It should be noted that patients with postoperative low output may show an excessive decrease in arterial blood pressure during bolus injection or during the continuous infusion of amrinone. This side effect may be prevented by the addition of a small dose of norepinephrine.33 PEDIATRIC CARDIAC SURGERY

The use of a PDE-3 inhibitor in the management of pediatric postoperative low cardiac output or excessive pulmonary vascular resistance remains the subject of controversy. Only a few evaluations have been undertaken. In one study, amrinone was administered to 10 patients; mean age was 2 months. Heart rate decreased while blood pressure increased by 12% and mean cardiac index by 40% (2.2 L/min/m* to 3.1 L/min/m*). There was no significant change in filling pressures. 36However, the results were not confirmed in 7 children after mitral valve replacement or correction of anomalous pulmonary venous drainage, despite doses of amrinone up to 40 pg/kg/min.37 In the latter study, an unexpectedly low plasma level of amrinone (0.7 to 2.3 pg/mL) and a significantly higher-than-normal control cardiac index (3.1 L/min/m* v 2.2 L/ min/m*) may partially explain the discrepancy between the findings of the two investigations. MODE OF ADMINISTRATION,

DOSAGES, AND

ADMINISTRATION

Amrinone’s hemodynamic effect begins within 2 minutes of bolus administration, with a

MARTIN GOENEN

22

to 20 mm Hg and from 38 to 24 mm Hg.

maximal effect after 20 minutes. Typically, a bolus injection of 0.5 to 1 mg/kg is given over 5 minutes, followed immediately by a continuous infusion, beginning with 5 to 10 pg/kg/min (depending on the patient’s hemodynamic state and the response to the bolus), and ranging up to 20 pg/kg/min. An excessive decrease in filling pressures and arterial blood pressure may occur, requiring prompt infusion of volume and/or vasopressors. Combined therapy with catecholamines or vasodilators may contribute significantly to beneficial effects in patients with excessive preload, or in patients who are in refractory cardiogenic shock. Kinetic studies show that, in neonates and infants, in order to obtain a therapeutic plasma concentration of 2 to 7 pg/mL, infants should receive an initial bolus dose of 3.0 to 4.4 mg/kg in divided doses, followed by an infusion rate of

10 pg/kg/min. Neonates should receive a similar bolus dose, but a lower infusion rate of 3 to 5 pg/kg/min.38 CONCLUSION

The phosphodiesterase inhibitors in general, and amrinone in particular, show combined inotropic and vasodilating properties. Amrinone has been shown to improve compromised hemodynamic states by increasing cardiac output and optimizing peripheral perfusion, without significantly changing heart rate and myocardial oxygen consumption (provided ventricular filling is adequate for specific cases). Side effects with amrinone are relatively minor with intravenous infusion. However, an excessive decrease in arterial blood pressure may occur; this can be corrected with norepinephrine, phenylephrine, or volume loading.

REFERENCES 1. Feldmann MD, Copelas L, Gwathmey JK, et ah Deficient production of CAMP: pharmacologic evidence of an important cause of contractile dysfunction in patients with end-stage heart failure. Circulation 75:331-339, 1987 2. Bristow MR, Ginsburg R, Minoke W: Decreasing catecholamine sensitivity and @-adrenergic receptor density in failing human hearts. N Engl J Med 307:205-211, 1982 3. Braunwald E, Kloner RA: The stunned myocardium: prolonged postischemic ventricular dysfunction. Circulation 66:1146-l 149, 1982 4. Honerjager P, Schafer-Korting M, Reiter M: In-

volvement of c-AMP in the direct inotropic effect of amrinone. Naunyn Schmiedebergs Arch Pharmacol3 l&112-120, 1981 5. Klein N, Suskind S, Frishman W, et al: Hemculynamic comparison of intravenous amrinone and dobutamine in patients with chronic congestive heart failure. Am J Cardiol48:170-175,198l 6. Goenen M, Pedemonte 0, Baele PH, Co1 J: Amrinone in the management of low cardiac output after open heart surgery. Am J Cardiol56:33B_38B, 1985 7. Gage J, Rutman H, Lucid0 D, LeJemtel TH:

AMRINONE:

UPDATE AND HISTORICAL PERSPECTIVES

Additive effects of dobutamine and amrinone on myocardial contractility and ventricular performance in patients with severe heart failure. Circulation 74:367-373, 1986 8. Rutman HI, LeJemtel TH, Sonnenblick EH: Newer cardiotonic agents: Implications for patients with heart failure and ischemic heart failure. J Cardiothorac Anesth 1:59-70, 1987 9. LeJemtel TH, Keunge E, Sonnenblick EH, et al: Amrinone: A new non-glycosidic, non-adrenergic cardiotonic agent effective in the treatment of intractable myocardial failure in man. Circulation 59:1098-l 104, 1979 10. Benotti J, Grossman W, Braunwald E, et al: Effects of amrinone on myocardial energy metabolism and hemodynamics in patients with severe congestive heart failure due to coronary artery disease. Circulation 62:24-34, 1980 11. LeJemtel TH, Sonnenblick EH: Should the failing heart bestimulated? N Engl J Med 310:1384-1385, 1984 12. Wilmshurst PT, Thompson DS, Juul SM, et al: Comparison of the effects of amrinone and nitroprusside on hemodynamics, contractility, and myocardial metabolism in patients with cardiac failure due to coronary artery disease and dilated cardiomyopathy. Br Heart J 52:38-48, 1984 13. Taylor SH, Verma SP, Hussman M, et al: Intravenous amrinone in left ventricular failure complicating acute myocardial infarction. Am J Cardiol56:29B_32B, 1985 14. Verma SP, Silke B, Taylor SH: Haemodynamic dose-response effects of amrinone in left ventricular failure complicating myocardial infarction. J Cardiovasc Pharm 7:1101-l 106, 1985 15. Hill S, Rounds SH: Amrinone dilates pulmonary vessels and blunts hypoxic vasoconstriction in isolated rat lungs. Pro Sot Exp Biol Med 173:202-212, 1983 16. Hammel MC, Einzig S, Kulik TJ, et al: Pulmonary vascular effects of amrinone in conscious lambs. Pediat Res 17:720-724, 1983 17. Kulik TJ, Lock JE: Pulmonary vasodilator therapy in persistent pulmonary hypertension of the newborn. Clin Perinatol 11:693-701, 1984 18. Rich S, Ganz R, Levy PS: Comparative actions of hydralazine, nifedipine, and amrinone in primary pulmonary hypertension. Am J Cardiol52:1104-1107, 1983 19. Bolling SF, Deeb GM, Crawley DC, et al: Prolonged amrinone therapy prior to orthotopic cardiac transplantation in patients with pulmonary hypertension. Transplant Proc 20:753-756, 1988 20. Hess W, Arnold B, Viet S: The haemodynamic effects of amrinone in patients with mitral stenosis and pulmonary hypertension. Eur Heart J 7:800-807, 1986 21. Klepzig M, Baur X, Hauser F, et al: Rechts ventrikulare haemodynamik und lungenfunktion nach Amrinone-injektion. Z Kardiol73:623-627, 1984 22. Costard A, Hill IR, Schroder JS, et al: Nitroprusside effect on pulmonary vascular resistance and systolic blood pressure predicts early transplant patient survival. J Heart Transplant 8:AlOO, 1989

23

23. Dunn JM, Cavarocchi NC, Balsara RK, et al: Pediatric heart transplantation at St. Christopher’s Hospital for Children. J Heart Transplant 6:334-342, 1987 24. Goenen M, Co1 J, Compere A, et al: Treatment of severe verapamil poisoning with combined amrinone-isoproterenol therapy. Am J Cardiol58:1142-1143, 1986 25. Hoffman P, Schockenhoff B: Amrinone beim katecholaminrefraktaren Herzversagen im septischem Schock. Anaesthesist 34:663-770, 1985 26. Vincent JL, de Boelpaepe C, Luypaert P, et al: Association of amrinone and norepinephrine in endotoxic shock in dogs. Crit Care Mcd 4:A402, 1988 27. Zeplin HE, Dransmann F, Verkenne P, et al: Amrinone in postoperative treatment after CABG. Preliminary report. Thorac Cardiovasc Surg 35:A88, 1987 28. Grayson RF, Kass DA. Hemodynamic effects of amrinone for low cardiac output immediately after CPB: Effective as a bolus. Anesthesiology 69:AlOl, 1988 29. Lathi KG, Shulman MS, Diehl JT, et al: The use of amrinone for inotropic support during emergence from CPB. Anesthesiology 69:A102, 1988 30. DeJesus JM, Wynands JE, Ramsay JR, et al: The role of amrinone in weaning patients from hypothermic cardiopulmonary bypass. Can J Anesth 33:S78, 1988 3 1. Goenen M, Jacquet L, Durandy Y: Heart failure after open heart surgery, in Vincent JL, Perret C (eds): Update in Intensive Care and Emergency Medicine: Acute Heart Failure. New York, NY, Springer-Verlag, 1988, pp 124-163 32. Gunnicker M, Hess W: Preliminary results with amrinone in perioperative low cardiac output syndrome. Thorac Cardiovasc Surg 35:219-225,1987 33. Robinson RJS, Tchervenkov C: Treatment of low cardiac output after aorto-coronary bypass surgery using a combination of norepinephrine and amrinone. J Cardiothorac Anesth 1:229-233, 1987 34. Gonzalez M, Desaeger JP, Jacquemart JL, Installe E: Efficacy of enoximone in the management of refractory low output states following cardiac surgery. J Cardiothorac Anesth 2:409-418, 1988 35. Goenen M. Severe perioperative cardiogenic shock in open heart surgery: Benefits of combined therapy, in Unger F (ed): Coronary Artery Surgery in the Nineties. New York, NY, Springer-Verlag, 1987, pp 213-216 36. Gundry SR, Behrendt DM, Rudd M: Amrinone for inotropic support of postoperative pediatric cardiac surgery. Washington, DC, World Congress Cardiology, 1986, p A2212 37. Jaccard C, Berner M, Oberhansli I, et al: Doseresponse curve of amrinone immediately after cardiac surgery in children. Pediatr Cardiol8:A220, 1987 38. Lawless S, Burckart G, Diven W, et al: Amrinone pharmacokinetics in neonates and infants. J Clin Pharmacol 28:283-284, 1988