Increased prostacyclin and thromboxane production in man during cardiopulmonary bypass

J THORAC CARDIOVASC SURG 82:245-247, 1981

Increased prostacyclin and thromboxane production in man during cardiopulmonary bypass To study the effect of the cardiopulmonary bypass (CPB) on the productions of antiaggregatory prostacyclin (PG/ 2 ) and proaggregatory thromboxane A 2 (TxA 2 ) , we collected serial plasma samples from seven patients before, during, and after CPB and assayed them for 6-keto-PGF ta and thromboxane B 2 , the main metabolites of PG/ 2 and TxA 2' respectively. The PG/ 2 production rose significantly (p < 0.05) following cannulation of the large vessels and remained elevated during the CPB. After discontinuation of CPB, the PG/ 2 decreased progressively. The TxB 2production also rose during CPB, but later than the increase in PG/ 2 . There was a significant correlation between 6-keto-PGF t a and TxB 2 levels (r = 0.429, p < OJ)()I, n = 77). Thus the deficient PG/ 2 production, or an imbalance between PG/ 2 and TxA 2 , does not seem to be responsible for the platelet loss during CPB. By contrast, the human body appears to be protected from platelet aggregation by a surge in endogenous PG/ 2 during CPB.

Olavi Ylikorkala, M.D., Erkki Saarela, M.D., and Lasse Viinikka, M.D., Oulu, Finland

P

rostacyc1in (PGI 2 ) is a recently discovered hormone which is generated from prostaglandin endoperoxides by arteries and veins, particularly in the lungs. 1-4 It is the most potent inhibitor of platelet aggregation so far described." The opposite effect on platelet function is exerted by thromboxane A 2 (TxA 2 ) , generated by the platelets." A balance between these two prostanoids may regulate platelet aggregation in vivo. 4 On the other hand, it is well established that extracorporeal circulation is accompanied by profound changes in platelet number and function. 7 Therefore, to study the effect of extracorporeal circulation on the productions of PGI 2 and TxA 2 , we measured the concentrations of PGI 2 and TxA 2 metabolites, 6-keto-PGF 1a 8 and thromboxane B2 , 6 respectively, from plasma of seven patients before, during, and after the use of the cardiopulmonary bypass (CPB).

Patients and methods One woman and six men between 19 and 60 years of age volunteered for this study after receiving detailed From the Departments of Clinical Chemistry and Anesthesiology, University of Oulu, Oulu, Finland. Supported by the Medical Research Council, Academy of Finland. Received for publication Dec. 16, 1980. Accepted for publication Jan. 16, 1981. Address for reprints: Olavi Ylikorkala, M. D., Department of Clinical Chemistry, University of Oulu, SF-90220 Oulu 22, Finland.

information about its course and purpose. They had operations with CPB because of aortic (four) or mitral (one) valve disease or atrial (one) or ventricular (one) septal defects. None of the patients had used drugs known to interfere with the synthesis of prostaglandins for 10 days preceding the operation. One hour before induction of anesthesia, the patients were premedicated with diazepam (0.2 mg/kg), meperidine (1 mg/kg), and promethazine (l mg/kg). Anesthesia was induced with intravenous injection of ketamine and diazepam and was maintained with ketamine infusion (l mg/kg/hr) and ventilation with 50% nitrous oxide in oxygen. Muscular relaxation was produced by pancuronium bromide. Before the start of bypass , 20 mg of furosemide was administered intravenously. A membrane oxygenator with polyvinyl chloride tubing was used for the bypass. The heart-lung machine was primed with a mixture of 1,000 ml of oxypolygelatin, 500 ml of Ringer's acetate, and one unit of bank blood. The patients were given heparin (3 mg/kg) before connection to the machine, and the activated clotting time was maintained at over 500 seconds during CPB with intravenous injections of heparin. The blood losses were replaced with fresh blood (range 450 to 1,350 ml, mean 900 ml). The whole perfusion lasted from 30 to 163 minutes (mean 86 minutes). Blood samples were collected before anesthesia (I), before (II) and after (III) cannulation of the large vessels, at the onset of (IV) and during (V to VIII) CPB,

0022-5223/81/080245+03$00.30/0 © 1981 The C. V. Mosby Co.

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The Journal of Thoracic and Cardiovascular Surgery

Ylikorkala, Saarela, Viinikka

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Fig. 1. The concentrations (mean ± SE) of 6-keto-PGF la and thromboxane B2 (TxB 2 ) in plasmaof seven patients before, during, and after the cardiopulmonary bypass. a, Higher (p < 0.05) than II values. b, Lower(p < 0.05) than IV values. c, Lower (p < 0.05) than VIII values. and 15 to 60 minutes after CPB (IX to XI) via a catheter inserted into the superior vena cava. Before sampling, 20 rnl of blood was withdrawn into syringes. Sampling was carried out by allowing blood to drip freely into ice-cold tubes containing acetylsalicylic acid at a final concentration of 20 ILmole/L. Following this, the initial 20 ml was reinjected. Plasma was separated immediately by centrifugation at 40 C and stored frozen (-200 C) until assayed for 6-keto-PGF l a and TxB 2 with radioimmunoassays." 10 The 6-keto-PGF t a measurement was validated by demonstrating a linear relationship between infused PGI 2 doses (l to 8 ng/kg/min) and the measured 6-keto-PGF t a levels in the plasma of healthy volunteers. The paired two-tailed t test and regression analysis were employed for the statistical analysis of the results.

Results Cannulation of the large vessels was accompanied by a significant rise (p < 0.05) in plasma 6-keto-PGF t a (Fig. 1). Maximum levels occurred at the onset of CPB, after which the value gradually decreased until precannulation levels were reached at the start of the partial perfusion. Plasma TxB 2 rose to a maximum at the onset of CPB

and remained elevated during CPB (Fig. 1). Its level decreased after the termination of CPB. The 6-keto-PGF t a and TxB 2 concentrations correlated significantly during the whole procedure (r = 0.429, P < 0.001, n = 77). Discussion PGI 2 is predominantly produced by the lungs and released into the pulmonary veins. 2. 3 It was therefore surprising to find an increased level of PGI 2 during CPB, when the lungs are nonfunctioning and connected to the systemic circulation only via the bronchial vessels. This increase occurred immediately after cannulation of the large vessels and persisted throughout CPB. The peak level of 6-keto-PGF t a during CPB exceeds that of 808 pg/rnl in healthy subjects after a PGI 2 infusion of 8 ng/kg/rnin"; this higher level suggests even higher endogenous production of this prostanoid during CPB. Evidently this increased production is not enough, since further infusion of synthetic PGI 2 decreased or prevented platelet loss during charcoal hemoperfusion.!' hemodialysis;" or CPB 13-15 in man and dogs. Heparin inhibits PGI 2 synthesis;" and the moderately elevated 6-keto-PGF t a levels in plasma of blood used for transfusions (unpublished results) can-

Volume 82 Number 2 August, 1981

Prostacyclin and thromboxane production during CPB

not account for the high 6-keto-PGF l a concentrations during CPB either. Thus the cause of increased PGI 2 may be the manipulation of the heart and large vessels. We also observed a rise in plasma TxB 2 level, probably as a consequence of platelet activation and microaggregation on foreign surfaces. It has been speculated that platelets can release prostaglandin endoperoxides for the PGI 2 synthesis by the vascular endothelium. 4 In this view, the platelet activation might be a primary event leading to an increased endoperoxide supply to the endothelium, which, in turn, could increase PGI 2 production to prevent aggregation. A significant correlation between PGI 2 and TxA 2 , as observed in our study, may support this hypothesis. This correlation further shows that any inbalance between PGI 2 and TxA 2 cannot account for platelet loss during the CPB, as suggested before. 15 REFERENCES

2

3

4

5

6

Moncada S, Gryglewski RJ, Bunting S, Vane JR: An enzyme isolated from arteries transforms prostaglandin endoperoxides to unstable substance that inhibits platelet aggregation. Nature 263:663-665, 1976 Gryglewski RJ, Korbut R, Ocetkiewicz AC: Generation of prostacyclin by lungs in vivo and its release into the arterial circulation. Nature 273:765-767, 1978 Hensby CN, Barnes PJ, Dollery CT, Dargie H: Production of 6-keto-PGF l a by human lungs in vivo. Lancet 2: 1162-1163, 1980 Moncada S, Vane JR: Arachiodonic acid metabolites and the interactions between platelets and blood vessel walls. N Engl J Med 300:1142-1147,1979 Tateson JE, Moncada S, Vane JR: Effects of prostacyelin (PGX) on cyclic AMP concentrations in human platelets. Prostaglandins 13:389-396, 1977 Hamberg M, Svensson J, Samuelsson B: Thromboxanes. A new group of biologically active compounds derived from prostaglandin endoperoxides. Proc Nat! Acad Sci USA 72:2994-2998, 1975

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7 Barrer MJ, Ellison N: Platelet function. Anesthesiology 46:202-211, 1977 8 Johnson RA, Morton DR, Kinner JH, Gorman RR, McGuire JC, Sun FF, Whittaker N, Bunting S, Salmon J, Moncada S, Vane JR: The chemical characterization of prostaglandin X (prostacyclin). Prostaglandins 12:915928, 1976 9 Ylikorkala 0, Viinikka L: Measurement of 6-ketoprostaglandin Fla in human plasma with radioimmunoassay. Effect of prostacyelin infusion. Prostaglandins Med 6:427-436, 1981. 10 Viinikka L, Ylikorkala 0: Measurement of thromboxane B2 in human plasma or serum by radioimmunoassay. Prostaglandins (in press) 11 Gimson AES, Langley PG, Hughes RD, Canalese J, Mellon PJ, Williams R, Woods HF, Westom MJ: Prostacyelin to prevent platelet activation during charcoal haemoperfusion in fulminant hepatic failure. Lancet 1: 173-175, 1980 12 Woods HF, Ash G, Weston MJ: Prostacyclin can replace heparin in haemodialysis in dogs. Lancet 2: 1075- 1077, 1978 13 Longmore DB, Bennet G, Gueirrara 0, Smith M, Bunting S, Moncada S, Reed P, Read NG, Vane JR: Prostacyelin. A solution to some problems of extracorporeal circulation. Lancet 1: I 102- 1005, 1979 14 Radegran K, Egberg N, Papaconstantinou C: Prostacyelin infusion during cardiopulmonary bypass in man. Scandinavian Association for Thoracic and Cardiovascular Surgery, Annual Meeting, Oslo, Norway, August, 1980, Abstract book, p 42 15 Plachetka JR, Salomon NW, Larson OF, Copeland JG: Platelet loss during experimental cardiopulmonary bypass and its prevention with prostacyelin. Ann Thorac Surg 30:58-63, 1980 16 Buchanan MR, Dejana E, Cazenave J-P, Mustard JF, Hirsh J: Uncontrolled PGI 2 production by whole v.essel wall segments due to thrombin generation in vivo and its prevention by heparin. Thromb Res 16:551-555, 1979