Prostaglandin e biosynthesis during cardiopulmonary bypass

JOURNAL

OF

SURGICAL

RESEARCH

Prostaglandin

24,

188-

192 (1978)

E Biosynthesis

during

Cardiopulmonary

Bypass

CRAIG R. SAUNDERS, M.D.,* EDWARD A. RITTENHOUSE, M.D.,* BERNARD M. JAFFE, M.D.,+ AND DONALD B. DOTY, M.D.*,’ ‘Division

of Thorucic Haspitul

und and

Curdiovuscular

Clinics, Washington Submitted

Surgery,

Iowa City. University, for

of’Surgeryp

University

1on.a 52242. and tDepartment Saint Louis. Missouri 63110

of Surgeryv.

publication

November

During cardiopulmonary bypass for intracardiac surgery, blood flow remains constant and complex changes occur in arterial pressure, peripheral vascular resistance, and distribution of organ blood flow. With the initiation of cardiopulmonary bypass, there is an initial drop in arterial blood pressure and peripheral vascular resistance [3, 5, 8, 18, 231. After a few minutes, complex neurohumoral mechanisms cause the resistance gradually to increase [3. 1 I, 18. 191. During this period, there is redistribution of blood flow so that flow to the heart, brain, and intestine increases while renal blood flow decreases [7, 221. Prostaglandins are vasoactive substances that have been found in almost all tissues. Prostaglandins of the E subgroup (PGE) are potent vasodilators released from tissue in response to ischemia or low flow states [ 1,9, 10, 20, 271. This study was designed to determine if moderately reduced blood flow which occurs during standard cardiopulmonary bypass would provide stimulus for PGE biosynthesis and to determine if PGE is one of the mechanisms that has an effect on peripheral vascular resistance during cardiopulmonary bypass.

* Biotronix, 3 Statham,

Fourteen dogs, weighing 16-20 kg (mean 18.2 kg), were anesthetized by intravenous administration of chloralose, 50 mg/kg, and

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Silver Spring, p23 dB, Statham

Puerto Rico. d Beckman Dynograph, ton, California. 5 Travenol Modular Morton Grove. Illinois. 6 Bently-Temptrol,

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Inc.,

0 1978 by Academic Press. Inc. of reproduction in any form reserved.

of lowu

urethane, 500 mg/kg. An endotracheal tube was inserted, and adequate tidal exchange of air was assured using a Harvard volume cycled respirator. A median sternotomy was made, and an electromagnetic flow probe2 was placed around the aortic root for measurement of cardiac output. Arterial blood pressure in the internal mammary artery and pressure in the supradiaphragmatic inferior vena cava were measured via pressure transducers.3 Heparinized blood samples for PGE determinations were obtained through a catheter in the thoracic portion of the inferior vena cava. Analog output of the flow meter, pressure transducers, and the electrocardiogram were recorded continuously on a multichannel recorder.J Cardiopulmonary bypass was instituted through a venous cannula in the right atrium and an arterial cannula in the ascending aorta, using a roller pump” and a bubble oxygenator.6 A vent cannula was placed in the left atrium through the appendage, and left atria1 pressure was monitored and maintained at zero during the procedure to assure complete bypass. The pump oxygenator circuit was primed with 1000 ml of 5% dextrose in lactated Ringer’s solution and flow was

METHODS

’ Author addressed.

Department

I88

Irving.

California.

Maryland. Company.

Beckman Pump, Q-l

IO.

Hato

Company,

Reye, Silver-

Travenol

Laboratories,

Bently

Laboratories,

SAUNDERS

ET AL .: PROSTAGLANDIN

E BIOSYNTHESIS

189

domethacin (2.5 mg/kg) prior to the initiation of cardiopulmonary bypass. RESULTS

2ooL’

’ C Imhed. B yOpnor*

‘5

’ 5oMiff5

., 60 %med. off Bypots

FIG. 1. Alterations in peripheral vascular resistance, cardiac output, mean blood pressure, and plasma prostaglandin E concentrations in response to cardiopulmonary bypass (80 ml/kg/min) in control animals.

maintained at 80 ml/kg/min throughout the bypass period. The temperature of the perfusate was 37°C to eliminate temperaturemediated vasomotor reflexes. Venous blood samples (10 ml) were obtained to correlate with hemodynamic measurements prior to cardiopulmonary bypass, immediately following the initiation of bypass, and at 15min intervals thereafter for a total of 1 hr, following which bypass was terminated and the measurements were repeated. The hematocrit was determined prior to and immediately after initiation of bypass to assess the hemodilution effect. Calculated peripheral vascular resistance was derived from the standard formula: mean arterial pressure (millimeters of Hg) - mean venous pressure (millimeters of Hg) PVR = cardiac output (liters/minute)

and expressed in absolute units (U). Venous blood samples were centrifuged and prostaglandins were extracted from the plasma fraction using a neutral organic solvent. PGE was separated from other groups of prostaglandins and nonprostaglandin lipids by silicic acid chromatography [12] and measured by radioimmunoassay [ 131. In six animals, biosynthesis of PGE was inhibited by the intravenous administration of in-

Peripheral vascular resistance and serum PGE levels were not significantly different when the control and the indomethacintreated group were compared prior to bypass. In both groups, initiation of cardiopulmonary bypass at the flow rate of 80 ml/ kg/min resulted in an immediate decrease in hematocrit from 44.4 + 7.6 to 27.4 + 6.3% and cardiac output decreased by 50% (3.3 + 0.3 to 1.55 2 0.04 liters/min). This resulted in a reduction of mean arterial pressure to 30 ? 2 mm Hg and a drop in calculated peripheral vascular resistance to 18 2 1.5 u. In the control animals these hemodynamic consequences were associated with an immediate increase in plasma PGE concentrations from 404 f 8 > to 619 1?1256 pg/ml. Fifteen minutes later PGE levels peaked at 652 + 107 pg/ml (P < 0.01) and peripheral vascular resistance increased by 56% (30 + 3 U). Plasma PGE concentrations returned to control level by 30 min and remained there during the final 45 min of bypass. Small increments of peripheral vascular resistance continued until bypass was terminated (Fig. 1). In the indomethacin-treated animals, biosynthesis of PGE was blocked and concentrations fell from 363 ? 94 to 218 + 96 pg/ml following administration of the drug. In marked contrast to the control group, there was no release of PGE in response to the initiation of cardiopulmonary bypass. PGE concentrations remained low and for the duration of the experiment plasma levels ranged from 146 t 38 to 240 + 44 pg/ml. In the first 15 min of bypass, peripheral vascular resistance increased more rapidly in these animals to 42 + 2 U which was significantly higher (P < 0.01) than the untreated animals (30 + 3 U). Plasma PGE concentration in the indomethacin-treated animals (240 ? 44 pgjml) was significantly

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1978

lower (P < 0.01) than in the untreated animals. During the remainder of the bypass procedure, resistance changes and PGE levels were roughly parallel in both groups, but the indomethacin-treated group had significantly lower levels of PGE (P < 0.05) at 30 and 45 min and higher calculated peripheral vascular resistance (P < 0.005 at 30 and 45 min and P < 0.05 at 60 min) (Fig. 2). DISCUSSION

The initiation of cardiopulmonary bypass is associated with a marked decline in arterial pressure as a consequence of several events. The flow is nonpulsatile and the flow rate achieved is usually less than the cardiac index prior to bypass. Gordon et al. [5] has emphasized the importance of the sudden decrease in viscosity as a result of hemodilution. Neural and humoral mechanisms may be involved as well. Prostaglandin E is synthesized and released during tissue ischemia and low flow states and exerts a direct vasodilatory effect on vascular smooth muscle without significant cardiac action [2, 4, 6, 13-15, 21, 2426]. The action of PGE on the intracellular processes is not clearly defined. In this study, the commencement of cardiopulmonary bypass was associated with an increase in PGE concentration in the venous blood for at least 15 min of bypass. Inhibition of PGE biosynthesis by indomethacin prevented the elevation in PGE during bypass and in that group significantly higher levels of arterial pressure and peripheral vascular resistance were observed. Thus, the initial release of PGE during perfusion may exhibit a vasodilatory effect on the peripheral vessels and act to reduce peripheral resistance. The appearance of PGE in the venous blood may have a more significant effect on arterial resistance changes during cardiopulmonary bypass than in other situations. Normally, the activity of PGE is reduced by approximately 90% of circulation through the lungs [lo]. However, during extracorporeal circulation the lungs are bypassed

FIG. 2. Alterations in prostaglandin E concentrations and peripheral vascular resistance in response to cardiopulmonary bypass in the control and indomethacin group.

and venous return is pumped directly into the arterial circuit. Since cardiopulmonary bypass is not associated with tissue ischemia, the release of PGE would appear to be related to the alteration in arterial pressure or possibly the change in systemic flow rates and characteristics. The sudden decline in arterial pressure and blood viscosity may well be the stimulus for PGE biosynthesis and release into the venous circulation. Although the source of PGE was not determined in this study, other investigators have documented the appearance of PGE in renal venous blood in response to an acute decline in blood pressure [ 1,9, 161. Renal biosynthesis of prostaglandin E may be one means of modifying renal blood flow during the acute drop in systemic arterial blood pressure and a decreased relative renal blood flow associated with cardiopulmonary bypass. Even though systemic flow was maintained at a constant rate during bypass, peripheral vascular resistance and mean arterial pressure gradually increased. The same observation has been reported by others [5, 11, 18, 201. However, the exact mechanism has not been elucidated. The rise in resistance has been attributed to increasing levels of circulating catecholamines or other vasoactive substances as a sign of sympato-adrenal response. Norden

SAUNDERS

ET AL.:

PROSTAGLANDIN

[17,-181 reported an increased resistance in the range of 22 to 25% above controls; however, when halothane anesthesia was utilized, the increase was less. Gordon et al. [5] demonstrated that both hemodiluted and nonhemodiluted patients exhibit resistance increases dependent on the duration of perfusion, a fact previously reported by Galletti and Brecher [3]. In the present study, resistance gradually increased during cardiopulmonary bypass in both groups. However, the appearance of PGE in the venous blood was associated with lower levels of arterial pressure and resistance suggesting that PGE exerts a regulatory control early in the bypass period. The fact that prostaglandin E levels returned to near control levels after 15 min of cardiopulmonary bypass suggests that the most important stimulus for biosynthesis of PGE is at the onset of bypass, perhaps in response to decreased systemic arterial pressure or flow associated with the initiation of cardiopulmonary bypass. During the remainder of the bypass period, PGE levels remained at prebypass levels and the indomethacin group remained much lower. Thus, the inhibition of PGE biosynthesis results in a higher level of total peripheral vascular resistance throughout the bypass period.

E BIOSYNTHESIS

191

and at 15min intervals. There were eight control animals (Group I) and six (Group II) had PGE inhibited by indomethacin (2.5 mg/kg). With the initiation of CPB, PVR decreased to 18 t 1 U in both groups. In Group I, PGE increased from 404 + 88 to 619 2 256 pg/ml. In Group II, PGE levels dropped from 363 & 94 to 218 + 96 pg/ml after indomethacin block and did not change in response to CPB. At 15 min, Group I PVR rose to 30 + 3 U while Group II PVR was higher at 42 & 2 U (P < 0.001). PGE concentrations at this time were 652 +- 106 in Group I and 260 & 92 pg/ml in Group II (P < 0.01). After 15 min, PGE returned to control in Group I but remained significantly elevated over Group II at 30 and 45 min. PVR continued to increase in both groups for the duration of CPB and Group II PVR remained significantly elevated (P < 0.05) compared to Group I, These data show that PGE is released in response to the initiation of CPB and is one of several factors affecting PVR during CPB. ACKNOWLEDGMENTS Acknowledgment is given to Mr. William Maixner and Mr. James Burr for their technical assistance in the preparation of this manuscript.

REFERENCES SUMMARY

Initiation of cardiopulmonary bypass (CPB) causes immediate drop in blood pressure and peripheral vascular resistance (PVR) with activation of complex neurohumoral reflex mechanisms and redistribution of systemic blood flow. Prostaglandin E (PGE) is a potent vasodilator released during ischemia and low flow states. This study was designed to determine if CPB provided stimulus for PGE biosynthesis and its effect on PVR. Fourteen dogs were placed on CPB for 60 min at 80 ml/kg/min. Plasma PGE concentration and PVR were determined prior to and immediately after the start of CPB

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