Prostaglandin E1 infusion for right ventricular failure after cardiac transplantation

Prostaglandin E 1 infusion for right ventricular failure after cardiac transplantation The infusion of prostaglandin E., a vasodilating substance with predominant effects on the pulmonary vasculature, has been found effective in the management of pulmonary hypertension associated with various diseases. The reported experience with prostaglandin E 1 after cardiac transplantation is, however, limited. We used prostaglandin E 1 in 18 patients in whom acute right ventricular failure developed after orthotopic cardiac transplantation. The infusion was started within 24 hours after operation in 16 patients and was continued for up to 7 days. Maximal doses of prostaglandin E., administered via a central venous catheter, ranged from 30 to 120 ng/kg/min. Norepinephrine was simultaneously infused via a left atrial catheter in 10 patients to prevent a reduction in systemic arterial pressure. The prostaglandin E 1 infusion resulted in significant reductions in mean arterial pressure and pulmonary vascular resistance and simultaneous increases in cardiac index and stroke .index. Mean arterial pressure was stable and left ventricular stroke work increased. The alveolar oxygen tension/forced inspiratory oxygen index tended to decrease during the infusion. Three patients died, two of right heart failure and one of multiple organ failure associated with cardiac aUograft rejection. In patients in whom right ventricular failure associated with pulmonary hypertension develops after cardiac transplantation, prostaglandin E., combined with norepinephrine whenever the arterial pressure declines, can effectively reduce pulmonary artery pressures and improve global cardiac function without compromising systemic perfusion. (J THORAC CARDIOVASC SURG 1992;103:33-9)

J. L. Vincent, MD, E. earlier, MD, M. R. Pinsky, MD,* J. Goldstein, MD, R. Naeije, MD, P. Lejeune, MD, S. Brimioulle, MD, J. L. Leclerc, MD, R. J. Kahn, MD, and G. Primo, MD, Brussels, Belgium

Rght ventricular (RV) failure is a common lifethreatening complication after cardiac transplantation. It can result from a primary decrease in RV contractility owing to inadequate cardiac preservation, decreased sensitivity to catecholamines, or graft rejection. Most patients who have R V failure when first seen have coexisting pulmonary hypertension because of the longstanding left heart failure. Although an elevated pulmonary vascular resistance before transplantation has been From the Departments of Intensive Care and Cardiac Surgery, Erasme University Hospital, Free University of Brussels, Brussels, Belgium. Received for publication Feb. 23,1990. Accepted for publication Sept. 17, 1990. Address for reprints: Jean-Louis Vincent, MD, Department ofIntensive Care, Erasme University Hospital, Route de Lennik 808, B-1070 Brussels, Belgium. 'Visiting professor from the Department of Critical Care Medicine, University of Pittsburgh.

12/1/26551

considered a contraindication to cardiac transplantation, pulmonary hypertension may cause hemodynamic compromise after the operation. 1 Inotropic and vasodilating agents are commonly required in the postoperative period to improve R V function. Isoproterenol and dobutamine are commonly used to increase contractility and heart rate and reduce ventricular afterload, but they are sometimes inadequate to reverse RV failure. Vasodilators represent the best option for reduction of the elevated pulmonary vascular tone, but their administration is often complicated by a reduction in systemic arterial pressure, which may compromise RV coronary blood flow and worsen the myocardial failure. Prostaglandin E 1 (PGE 1) , when infused intravenously, is a vasodilating substance with predominant effects on the lung vasculature, because it is almost completely metabolized in the lung endothelium on first pass. 2, 3 PGE 1 administration has been found efficacious in the management of pulmonary hypertension associated with various diseases."? PG E I has also been used to reduce R V

33

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Table I. Clinical and preoperative data of the 18 patients Pretransplani values Patient

Age (yr)

I 2 3 4 5 6 7 8 9 10 II 12 13 14 15 16 17 18

62 50 43 59 53 47 58 61 64 52 47 50 61 37 56 62 54 34

Type 0/ cardiomyopathy

PAP (mmHg)

PAOP (mmHg)

CI (L/min/m 2)

Time 0/ ischemia (min)

Duration o/CPB (min)

Outcome

72/34 55/30 70/28 62/35 65/27 57/28 55/34 70/30 53/29 45/20 74/42 70/37 34/18 55/40 74/30 40/20 70/42 45/21

34 28 22 32 27 27 34 20

2.60 1.20 2.00 1.90 2.06 2.00 1.75* 2.53 1.86 1.33 2.40 2.34 2.40 1.78 1.93 2.21* 1.63* 1.89

106 135 79 135 145 120 84 148 85 206 70 62 171 210 216 72 249 204

125 110 169 120 162 148 100 123 125 140 140 109 156 185 153 115 180 III

Died (+5 days) Survived Died (+ 3 days) Survived Survived Survived Survived Died (+ 12 days) Survived Survived Survived Survived Survived Survived Survived Survived Survived Survived

Ischemic Ischemic Ischemic Ischemic Ischemic Ischemic Dilated Ischemic Ischemic Ischemic Ischemic Dilated Ischemic Ischemic Valvular Ischemic Hypertrophic Ischemic

20 35 35 18 35 30 18 30 24

Valuesare expressedas mean ± standard deviationof the mean. PAP, pulmonaryartery pressure;PAOP, pulmonaryartery occlusive pressure;CI, cardiac index. 'Undergoing adrenergic treatment at time of catheterization.

Table II. Baseline hemodynamic values and doses of PGE/ administered PGE/ Patient I 2 3 4 5 6 7 8 9 10 II 12 13 14 15 16 17 18

PAP (mm Hg)

RAP (mmHg)

LAP or PAOP (mmHg)

CI (Lfmin m 2)

24 28 33 31 23 27 24 32 30 36 31 25 35 32 35 24 43 29

17 18 14 16 17 18 7 18 17 11 13 14 4 28 17 14 6 8

9 16 14 15 16 15 10 14 16 9 13 8 5 25 18 15 5 10

1.76 2.36 1.58 2.06 1.54 2.51 2.41 1.53 1.39 1.75 3.08 2.47 1.70 1.47 2.78 3.00 2.23 2.59

Onset MV + + + + + + + + + + +

Vasoactive agents

Dop/Nepi Dop/Dob/Nepi

Iso/Nepi Iso/Dob/Nepi Dob Iso/NP Dob/Nepi Iso/Dop/Dob/Epi

Iso/Nepi Iso/Dob/Nepi Iso/Dob/Nepi Iso/Dob

+ +

Iso/Dob Isc/Dob/Nepi

+ +

Iso NP Iso/Dob Iso/Dob/NP

(POD)

Duration (No a/days)

Max doses (ng/kg/min)

I I I 1 I 1 1 1 1 1 I 2 1 1 I 3 1 1

I 4 3 3 2 4 2 I I 7 3 I I 7 1 2 2 2

50 40 70 60 40 60 30 100 60 100 40 60 40 65 40 50 120 60

PAP, Mean pulmonary artery pressure; RAP, right atrial pressure; LAP, left atrial pressure; PAOP, pulmonary artery occlusive pressure; CI, cardiac index; MV, mechanical ventilation; POD, postoperative day; Dop, dopamine; Nepi, norepinephrine; Dob, dobutamine; Iso, isoproterenol; NP, sodium nitroprusside; Epi, epinephrine.

afterload in patients after cardiac operations, but the reported experience is relatively limited. D' Ambra and coworkers" described the successful combination ofPGE\ infused with norepinephrine in five patients with severe

pulmonary hypertension after mitral valve operations. In a patient with RV failure after heart transplantation, Fonger and coworkers? successfully used a PGEI infusion in combination with RV assist. Armitage and col-

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dynes.see/emS

I/ml/M2

mmHg

45

35

1500

4

1250

40

1000

3 (55

750 30

500

2

25

20

250

CON

INF

1

INF

CON

p < 0.01

p < 0.001

o

CON

INF

p < 0.01

Fig. 1. Mean pulmonary artery pressure (PAP), cardiac index (CI), and pulmonary vascular resistance (PVR) before and within 4 hours ofPGE1.infusion. PGE 1doses at this time were 34 ± 18 ng/kg/min (range 10 to 80 ng/kg/min). CON, Control; INF, infusion.

leagues!" described the effectiveness of PGE I in three patients with R V failure after orthotopic heart transplantation. Other case reports have been presented recently. I I The present paper reports our clinical experience during a 2-year period with the use of PGE I in 18 patients with acute R V failure after orthotopic cardiac transplantation.

Patients and methods Between March 1987 and March 1989, 92 patients underwent an orthotopic cardiac transplantation in our institution. Myocardial preservation techniques included crystalloid cardioplegia with topical cooling. All patients are routinely admitted to the department of intensive care for the first postoperative days until complete hemodynamic stabilization is reached. The condition of all patients is monitored with a pulmonary artery catheter (Swan-Ganz; Baxter Healthcare Corporation, Edwards Division, Irvine, Calif.) and a left atrial catheter. Postoperative management of those patients consists of (t) blood transfusion to compensate for blood losses, (2) isoproterenol infusion to maintain heart rate between 100 and 120 beats/min, (3) dopamine or norepinephrine infusion (preferably through the left atrial catheter) to maintain a mean arterial pressure (MAP) higher than 75 mm Hg, (4) sodium nitroprusside or nitroglycerin to maintain MAP lower than 100 mm Hg, (5) colloidsto maintain cardiac filling pressures at the optimal levelfor the patient, (6) furosemide to maintain a urine output

greater than 30 ml/hr, (7) dobutamine according to cardiac output, mixed venous oxygen saturation, lactate, and signs of tissue perfusion, and (8) PGEI for pulmonary hypertension. The PGE 1infusion was started when pulmonary artery pressures were either substantially elevated (mean> 30 mm Hg) or moderately elevated (mean >22 mm Hg) in patients with an insufficient cardiac index, as reflected by peripheral vasoconstriction or reduced urine output, or both. PGE, (Prostin) was prepared as an infusion containing I mg (or 2 mg) in 500 ml of 5% dextrose in water, resulting in a concentration of 2 JLg/ml(or 4 JLg/mt). The solution was infused by volumetric pump into a central venous catheter at an initial rate of 10 ng/kg/min. The rate of the infusion was increased by increments of 10 rig/kg/min until there was an appropriate clinical response. When MAP decreased to less than 75 mm Hg, a norepinephrine infusion was added through the left atrial catheter. Intravascular pressure measurements, referred to the midchest level and taken at the end of expiration, were recorded at least every hour. Cardiac output was measured at least three times a day by the thermodilution technique with cold 5% dextrose in water and a closed system (CO-set, Baxter Edwards), three to five measurements being averaged. Derived hemodynamic parameters were obtained by standard formulas. Statistical evaluation was performed by one-way analysis of variance. Post hoc between-group differences were compared by a Newman-Keuls test. Significance was defined by differences with a p value less than 0.05. Data are presented as mean ± standard deviation.

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Vincent et al.

Surgery

mmHg

40 36 32 28 24 20 16 12 8

ml/M 2

I

MEAN PULM.ART.P.

I

RIGHT ATRIAL P. STROKE INDEX

35 30 25 20 15 10

I

dynes. sec.cm 5

1000 PULM.VASC.RES.

800 600

1+

400

1+

200 BEFORE LOWEST HIGHEST PGE1

PAP

mean + S.D.

CO

*p
1 AFTER PGE1

+p
Fig. 2. Effects of PGE 1 on mean pulmonary arterial pressure, right atrial pressure, stroke index, and pulmonary vascular resistance in 18 patients. Data are presented before PGE 1 infusion, at time of lowest pulmonary artery pressure (PAP), at time of highest cardiac output (CO), and after discontinuation of PGEI. S.D., Standard deviation.

Results Table I presents the clinical and preoperative data of 18 patients. All patients were male. PGE 1 infusion was started within 24 hours after operation in 16 of the 18 patients and was continued for up to 7 days (Table 11). The maximal dose was 120 ng/kg/hr. Norepinephrine was simultaneously administered via the left atrial catheter in 10 patients. Three patients died, two of right heart failure (3 and 5 days after operation, respectively) and one

of multiple system organ failure associated with cardiac allograft rejection (12 days after operation). Within 4 hours after the beginning of the PGE 1 infusion there were dramatic reductions in mean pulmonary artery pressure and pulmonary vascular resistance and increases in cardiac index in virtually each patient (Fig. I). Figs. 2 and 3 summarize the major hemodynamic changes observed later during the PGEI infusion.

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MEAN ART.P.

1~~l

mmHg

80 70

16j 12 .

mmHg

8

g.m/M

2

30J 20 10

dynes. see.em 5

3600 3200 2800 2400 2000 1600

I I I I I

I

I

PULM.ART.OCCL.P.

I

l ' 11 I I

LVSWI

SYST. VASC.RES.

I 1

I

BEFORE LOWEST HIGHEST AFTER PGE 1 PAP CO PGE 1 mean + S.D.

*p
+p
Fig. 3. Effects of PGE, on mean arterial pressure, pulmonary artery balloon-occluded pressure, left ventricular strokework index, and systemic vascularresistance. Data are presented as in Fig. 2.

Because changes in therapy were frequent in these patients, the measurements obtained during PGE 1 were grouped at the time of the lowest pulmonary artery pressure and at the time of the highest cardiac index. PGE 1 reduced mean pulmonary artery pressure and pulmonary vascular resistance and increased cardiac index and stroke index. The increase in cardiac output was associated with a reduction in systemic vascular resistance and an increase in left ventricular stroke work index. Systemic arterial pressure remained stable.

The arterial oxygen tension/inspiratory oxygen fraction (Paoj/Fio-) index was obtained within 3 hours both before and after PGE 1 administration was started in 16 of the 18 patients, and it decreased in 12 of them. Mean Pao2/Fio2 ratio decreased from 263 ± 92 to 232 ± 101 mm Hg (differences not significant). No other effect of PGE 1 infusion, such as increased bleeding or arrhythmia, was noted. Rare episodes of flushing and nausea could have been related to high doses ofPGE!.

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Vincent et al.

Discussion PGE 1 is a natural substance normally produced in small quantities by the cyclooxygenation of dihomogamma-linolenic acid. Like prostacyclin, PGE\ exerts powerful vasodilating properties related to its relaxing effects on the arteriolar smooth muscle.' These prostaglandins can also decrease platelet aggregation, inhibit leukocyte activation, and exert less well-defined effects on other susceptible cells to reduce cellular injury and decrease the vascular permeability in the presence of injury.v? The high clearance of intravenously delivered PGE\ by the pulmonary endothelium- 3 makes this substance particularly attractive in the management of pulmonary hypertension because PGE\-induced systemic hypotension is usually mild. Recently, Prielipp and coworkers \2, \3 compared the effects of PGE\ with those of prostacyclin, isoproterenol, nitroglycerin, sodium nitroprusside, hydralazine, and nifedipine on an experimental model of pulmonary hypertension induced by a thromboxane analog. They observed that PGE\ and isoproterenol had the greatest pulmonary specificityand that PGE\ induced the greatest decrease in pulmonary artery pressures. PGEI has already been found useful in the management of pulmonary hypertension associated with various diseases.v? The present study demonstrates the usefulness ofPGE I in the management of patients with pulmonary hypertension after cardiac transplantation. When arterial hypotension occurred, we added norepinephrine to counteract thevasodilating effects ofPGEI on the systemic circulation. As in other studies.v 9we infused norepinephrine through the left atrial catheter. This is to minimize vasoconstricting effects on the pulmonary circulation, because norepinephrine is largely removed systemically.v': \5 In these conditions, PGE\ could reduce pulmonary artery pressures without compromising systemic perfusion. Moreover, the PGE\ infusion was associated with a significant increase in cardiac output. Although a positive inotropic effect of PGE\ has been described, \6 this effect is probably mild. Thus the improvement in cardiac output was probably related also to a reduction in R V afterload. PGE 1, like other vasodilators, could alter gas exchange by increasing cardiac output and inhibiting hypoxic vasoconstriction. PGEI can alter gas exchange in patients with pulmonary hypertension associated with the adult respiratory distress syndrome. \7, \8 Although the changes in Pao2/Fio2 were not statistically significant in the present study, the acute deterioration in oxygenation in three fourths of our patients stresses that attention should be paid to a sufficient oxygenation before PGE\ infusion is begun in hypoxemic patients.

The Journal of Thoracic and Cardiovascular Surgery

PGEI can also exert immunosuppressive effects. Although these effects have been observed after pharmacologic doses in animals, \9,20 a recent study shows that the addition of a PGE\ analog to a standard immunosuppressive therapy regimen can reduce the prevalence of kidney graft rejection." REFERENCES 1. Kirklin JK, Naftel DC, Kirklin JW, Blackstone EH, White-WilliamsC, Bourge RC. Pulmonary vascularresistance and the risk of heart transplantation. J Heart Transplant 1988;7:331-6. 2. Ferreira SH, Vane JR. Prostaglandins:their disappearance fromand releaseintothe circulation.Nature 1967;216:86873. 3. Said SI. Pulmonary metabolism of prostaglandins and vasoactive peptides. Annu Rev PhysioI1982;44:257-68. 4. SzczeklikJ, Dubiel JS, MysikS, Pysik Z, Krol R, Horzela J. Effectsof prostaglandin E[ on pulmonary circulationin patients with pulmonary hypertension. Br Heart J 1978;40: 1397-1401. 5. Long WA, Rubin LJ. Prostacyclinand PGE 1 treatment of pulmonary hypertension. Am Rev Respir Dis 1987; 136:773-6. 6. HolcroftJW, Vassar MJ, WeberCJ. ProstaglandinE[ and survivalin patients with the adult respiratory distresssyndrome. Ann Surg 1986;203:371-8. 7. Bone RC, Siotman G, Maunder R, et al. Randomized double-blind, multicenter study of prostaglandin E[ in patients with the adult respiratorydistresssyndrome. Chest 1989;96:114-9. 8. D'Ambra MN, LaRaia PJ, Philbin DM, Watkills D, Hilgenberg AD, BuckleyMJ. Prostaglandin E[: a new therapy for refractory right heart failure and pulmonary hypertension after mitral valve replacement. J THORAC CARDlOVASC SURG 1985;89:567-72. 9. Fonger JD, Borkon AM, Baumgartner WA, Achuff SC, AugustineS, Reitz BA. Acute right ventricular failure following heart transplantation: improvement with prostaglandin El and right ventricular assist. J Heart Transplant 1986;5:317-21. 10. Armitage JM, Hardesty RL, GriffithBP.ProstaglandinE[: an effective treatment of right heart failure after orthotopic heart transplantation. J Heart Transplant 1987;6:34851. 11. Costa P, Ottino G. Successfultreatment of acute postoperative right heart failure with low-dose prostaglandinE j and assisted circulation. Texas Heart Inst J 1989;16:110-2. 12. Prielipp R~, Rosenthal MH, Pearl RG. Vasodilator therapy in vasoconstrictor-induced pulmonary hypertension in sheep. Anesthesiology 1988;68:552-8. 13. Prielipp RC, Rosenthal MH, Pearl RG. Hemodynamic profiles of prostaglandinE j , isoproterenol, prostacyclin, and nifedipine in vasoconstrictor pulmonary hypertension in sheep. Anesth Analg 1988;67:722-9. 14. Silverberg AB, Shah SD, Haymond MW, Cryer PE.

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15.

16.

17.

18.

Norepinephrine: hormone and neurotransmitter in man. Am J Physiol 1978;234:E252-6. Hilsted J, Christensen NJ, Madsbad S. Whole body clearance of norepinephrine: the significance of arterial sampling and of surgical stress. J Clin Invest 1983;71:500-5. Metsa-Ketela K. Cyclic AMP-dependent and independent effectsof prostaglandins on the contraction-relaxation cycle of spontaneously beating isolated rat atria. Acta Physiol Scand 1981;112:481-5. Melot C, Lejeune P, Leeman M, Moraine JJ, Naeije R. Prostaglandin E 1 in the adult respiratory distress syndrome: benefit for pulmonary hypertension and cost for pulmonary gas exchange. Am Rev Respir Dis 1989;139:106-10. Rademacher PA, Santak B, Becker H, et al. Prostaglandin E, and nitroglycerin reduce pulmonary capillary pressure

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but worsen ventilation-perfusion distributions in patients with adult respiratory distress syndrome. Anesthesiology 1989;70:601-6. 19. Kort W J, Bonta IL, Adolfs MJ, Westbroek DL. Synergism of (l5S)-15-methyl-prostagiandin E] with either azathioprine or prednisone on the survival of heart allografts in rats. Prostaglandins Leukotrienes Med 1982;8:661-4. 20. Foegh ML, Alijani MR, Helfrich GB, Ramwell PW. Eicosanoids and organ transplantation. Ann Clin Res 1984;16:318-23. 21. Moran M, Mozes MF, Maddux MS, et al. Prevention of acute graft rejection by the prostaglandin E] analogue misoprostol in renal-transplant recipients treated with cyclosporine and prednisone. N Engl J Med 1990;322:1183-8.