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Ann Thorac Surg 1995;59:647-650
© 1995 The Society of Thoracic Surgeons

Prostacyclin and Thromboxane Levels in Pleural Space Fluid During Cardiopulmonary Bypass

Department of Cardiothoracic Surgery, Cork Regional Hospital, Cork, Ireland

Accepted for publication November 12, 1994.

	Abstract

Top Footnotes Abstract Introduction Material and Method Results Comment References

 
Prostaglandins exhibit a variety of cardiovascular actions that may affect the hemodynamic recovery of the ischemic myocardium after cardiopulmonary bypass. We have observed a decrease in the mean arterial pressure on autotransfusion of the accumulated pleural cavity fluid during operation. One aim of this study was to determine the concentrations of prostacyclin and thromboxane A₂ in the pleural cavity fluid by measuring their stable metabolites, 6-keto-PGF₁ and thromboxane B₂, respectively, in 8 consecutive patients undergoing myocardial revascularization, and to compare them with the arterial levels. A second aim was to quantify the hemodynamic effect of the pleural cavity fluid during operation. The concentration of 6-keto-PGF₁ in the pleural cavity fluid was significantly higher than the arterial concentration (mean, 21.6 ± 18.2 ng/mL; p < 0.01). The concentration of thromboxane B₂ was also raised compared with the arterial concentration (mean, 3.62 ± 5.96 ng/mL; p < 0.2). The percentage fall in the mean arterial pressure was 29.7% ± 8.86% (p < 0.02), which was transient and lasted 1 to 3.5 minutes. The hemoglobin concentration, potassium level, and pH were also measured. This study shows that the pleural cavity fluid during cardiac operations contains significant amounts of endogenous prostacyclin. Considering the potential benefit of prostacyclin on the recovering myocardium, we believe that this fluid should be transfused as a volume replacement, keeping in mind the transient phase of hemodynamic instability.

	Introduction

Top Footnotes Abstract Introduction Material and Method Results Comment References

 
Maintaining hemodynamic stability and minimizing reperfusion injury of the heart are important goals during the period of myocardial recovery after cardiopulmonary bypass. To replace volume and minimize transfusion, one of the procedures carried out toward the end of coronary artery operations is to transfuse the fluid accumulated in the pleural space. The fluid is essentially composed of slush, blood, and probably exudate from surrounding tissues. However, during transfusion, a rapid and unexplained decrease in the mean arterial pressure occurs. A similar observation has previously been reported for the transfusion of shed pulmonary venous blood from the pleural cavity, and was attributed to the effect of prostaglandin [1]. As the pulmonary venous blood was excluded by single-stage venous and pulmonary artery venting, the reason for our observation remains unclear.

Thromboxane A₂ and prostacyclin, the two principal metabolites of eicosanoids, have been demonstrated in increasing concentrations in the myocardium during cardiopulmonary bypass [2–4]. Higher cardiac concentrations of thromboxane A₂, which continue into the reperfusion and early postoperative phase, may promote coronary arterial vasoconstriction and intracoronary platelet aggregation [5]. In contrast, prostacyclin derived from the endothelium of arteries [6, 7] inhibits platelet aggregation [4, 8, 9] and is a potent vasodilator [4, 8] and a well-described hypotensive agent [10]. It helps pharmacologically to counteract the effects of thromboxane A₂ and may be beneficial for the recovering myocardium after cardiopulmonary bypass. The aim of this study was to evaluate the contribution of these prostaglandins in the hemodynamic response observed as the result of transfusion of pleural cavity fluid. The prostacyclin and thromboxane A₂ levels were estimated in the pleural space fluid by measuring their stable end-products 6keto-PGF₁ and thromboxane B₂, respectively.

	Material and Method

Top Footnotes Abstract Introduction Material and Method Results Comment References

 
Eight consecutive patients (mean age, 54 years; range, 50 to 59 years) undergoing coronary artery bypass grafting were studied. The use of all drugs known to interfere with the synthesis of prostaglandin, such as aspirin, was stopped 7 days before operation.

The patients were premedicated with 4 mg of lorazepam the night before operation. On the following morning, before the induction of anesthesia, a 10-mL blood aliquot was taken from the arterial line for estimation of the 6-keto-PGF₁ and thromboxane B₂ levels. The sample was collected in a heparinized test tube, immediately centrifuged, and stored at -20°C. General anesthesia was induced with fentanyl (50 mg/kg) and pancuronium (0.1 mg/kg), and maintained with fentanyl and enflurane.

A midline sternotomy was performed and the left internal mammary artery dissected, accessed through an opening made in the left pleural cavity. The patients were heparinized (3 U/kg), and the activated clotting time was measured with the Haemochron apparatus (model 801 instrument and FTCA 510 test tube; International Technidyne Corp, Edison, NJ) and maintained for more than 400 seconds with additional heparin when necessary. Cardiopulmonary bypass was established by aortic cannulation; bicaval cannulation was established by means of the right atrium and a pulmonary artery vent. The bypass system consisted of a COBE pump and a COBE CML oxygenator (COBE, Lakewood, CO). Bypass was maintained at 28°C with a flow rate of 2.4 L • min^-1 • m^-2. The mean arterial pressure was maintained between 40 and 60 mm Hg. The aorta was cross-clamped and cardiac standstill was obtained by the infusion of 1 L of cold St. Thomas' cardioplegia solution into the aortic root. The heart was immersed in cold slush (normal saline solution). After completion of the distal anastomosis and before removal of the cross-clamp, all fluid that had accumulated in the pleural space was aspirated and the volume measured in a separate reservoir. An aliquot from the pleural aspirate was taken, then centrifuged and stored at -20°C for prostaglandin analysis. The fluid was also analyzed for its hemoglobin concentration, electrolyte concentration, and pH. The remaining fluid was transfused over the next minute through the aortic cannula. Transient hypotension ensued, and blood pressure recordings were taken at 30-second intervals until there was evidence of recovery from the event. The cross-clamp was then removed and the patient rewarmed. The average cross-clamp time was 54 minutes.

The aliquots were analyzed for the 6-keto-PGF₁ and thromboxane B₂ contents by capillary column gas chromatography and electron-capture mass spectrometry. The samples were diluted 1:1 by volume with TRIS (tris[hydroxymethyl]amino methane) buffer at pH 8.0, and [2-H₄]6-oxo-PGF₁ (5 ng) was added as an internal standard. The prostaglandin was extracted using cyanogen bromide–activated sepharose columns containing immobilized antibodies that had been raised against 6-oxo-PGF₁. The samples were applied under vacuum to the columns, which were washed with water (10 mL). The 6-oxo-PGF₁ was eluted by adding 95% acetone–5% water (0.5 mL) and rotating the column for 15 minutes. The samples were dried in a stream of N₂, and the 6-oxo-PGF₁ in the residue was converted to a 3,5-bis-trifluoromethylbenzyl ester and trimethylsilyl ether derivative.

Samples were analyzed using a VG 70-SEQ (Fisons, Manchester, UK) gas chromatograph/mass spectrometer in the electron-capture mode using methane or ammonia as the reagent gas. Carboxylate anions were monitored at a mass/charge ratio of 585 for 6-oxo-PGF₁ and at a mass charge ratio of 589 for the deuterated internal standard (the detection limit for 6-oxo-PGF₁ is 5 pg/mL when a 10-mL sample is assayed).

Results were analyzed using Student's t test. All results are expressed as the mean ± standard deviation. The confidence limits were determined by a two-tailed t test.

	Results

Top Footnotes Abstract Introduction Material and Method Results Comment References

 
In the 8 patients, the volume of fluid aspirated ranged from 400 to 700 mL (mean, 562.5 mL). The hemoglobin concentration ranged from 1.5 to 4.2 g/dL (mean, 2.5 g/dL), and thus the total amount of hemoglobin ranged from 6 to 19 g (mean, 13.8 g). The potassium content ranged from 4.8 to 5.8 mmol/L (mean, 5.1 mmol/L) and the pH ranged between 7.35 and 7.58 (mean, 7.46) (Table 1).

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View larger version (25K): [in this window] [in a new window]   Fig 1. . Mean increase in the 6-keto-PGF1 concentration in pleural cavity fluid (PCF) compared with its arterial concentration.

View larger version (23K): [in this window] [in a new window]   Fig 2. . Mean rise in the thromboxane B2 (TBx2) concentration in pleural cavity fluid (PCF) compared with its arterial concentration.

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View larger version (11K): [in this window] [in a new window]   Fig 3. . Percentage decrease in the mean arterial pressure (MAP) in relation to the 6-keto-PGF1 and thromboxane B2 (TBx2) levels in accumulated pleural space fluid.

	Comment

Top Footnotes Abstract Introduction Material and Method Results Comment References

1

1

Under physiologic conditions, prostacyclin and thromboxane A₂ regulate platelet–vessel wall interaction and the formation of a hemostatic plug and intraarterial thrombi [9]. Rising levels of intracoronary thromboxane A₂, in both the reperfusion and early postoperative period of coronary artery bypass grafting [13], can be detrimental to the recovery of the ischemic myocardium [14] due to its vasoconstrictor and platelet aggregation properties. Prostacyclin may exert a protective influence on the myocardium, as it is a potent vasodilator; not only does it prevent platelet aggregation but it is also able to disaggregate and wash out platelets from the coronary circulation [15]. Prostacyclin also acts locally on the myocardium as an antiarrhythmic agent [8]. Even though the half-life of prostacyclin in blood is 3 minutes, its platelet aggregation response may have a half-life of up to 15 minutes versus its hypotensive response, which ranges from 0.6 to 2.7 minutes [12]. This prolonged antiplatelet response may be beneficial to the recovering myocardium after cardiopulmonary bypass, during which time the intracoronary deposition of platelets could occur as the result of several mechanisms. Myocardial ischemia [16], the release of thromboxane A₂ [14], ischemic injury to the vascular endothelium [17, 18], and extracorporeal circulation are all events that cause increased platelet aggregation. It can be assumed that prostacyclin exerts the dominant physiologic action, as the significant decrease in the mean arterial pressure is in keeping with the pharmacologic action of prostacylin [1].

We were unable to demonstrate any correlation between the amount of 6-keto-PGF₁ infused and the percentage decrease in the mean arterial pressure. A possible explanation for this could be the countering effect of variable concentrations of thromboxane A₂, which is supported by a trend toward correlation when compared with the ratio of PGF₁ to thromboxane B₂. Because the half-life of prostacyclin varies in blood and aqueous solutions, ranging from 1.6 to 3 minutes [14], another explanation for the lack of correlation with the hypotensive response could be the varying degree of hemodilution of the pleural space fluid noted in our study patients. To exclude other potential determinants of the hypotensive response, we analyzed this fluid for its potassium and hemoglobin concentration and its pH. The potassium concentration and pH were similar to those of normal plasma; the hemoglobin concentration was low and it constituted about 100 to 150 mL of the blood volume.

It is difficult to ascertain the source of prostacyclin production. The low hemoglobin concentration indicates little spillover of blood into the pleural space, largely due to the exclusion of myocardial and pulmonary blood. Because prostacyclin is produced by the endothelium of the entire body [19], a possible source may be the adjacent tissue endothelium-the lung and the parietal pleura.

Whereas the data are consistent with the possible decrease in the mean arterial pressure being due to prostaglandin metabolites, it is difficult to ascertain the ratio of the active compound to its stable metabolite in the pleural space fluid. It would be of interest to determine the increase in the prostacyclin levels in arterial blood after the transfusion of this fluid, and also to ascertain the effect of drugs such as aspirin that may influence the metabolic pathway of arachidonic acid.

In conclusion, we have shown that the fluid which collects in the pleural space during coronary artery bypass grafting is a rich source of endogenous prostacyclin from a noncardiac origin. Considering the beneficial effect of prostacyclin on the recovering myocardium, we believe that such fluid should be autotransfused. It also helps as an intravascular volume expander.

	Footnotes

Top Footnotes Abstract Introduction Material and Method Results Comment References

 
Address reprint requests to Dr Singh, Department of Cardiothoracic Surgery, Cork Regional Hospital, Cork, Ireland.

	References

Top Footnotes Abstract Introduction Material and Method Results Comment References

 

1. Lavee J, Naveh N, Dinbar I, Shinfeld A, Goor DA. Prostacyclin and prostaglandin E2 mediate reduction of increased mean arterial pressure during cardiopulmonary bypass by aspiration of shed pulmonary venous blood. J Thorac Cardiovasc Surg 1990;100:546–51.[Abstract]
2. Kobinia GS, LaRaia PJ, Peterson MB, et al. Cardiac prostacyclin kinetics during cardiopulmonary bypass. J Thorac Cardiovasc Surg 1984;88:965–71.[Abstract]
3. Downing WS, Edmunds LH Jr. Release of vasoactive substances during cardiopulmonary bypass. Ann Thorac Surg 1992;54:1236–43.[Abstract]
4. Coker SJ, Parratt JR. Prostacyclin-antiarrhythmic or arrhythmogenic? Comparison of the effects of intravenous and intracoronary prostacyclin and ZK36374 during coronary artery occlusion and reperfusion in anaesthetised greyhounds. J Cardiovasc Pharmacol 1982;4:557–67.
5. Faichney A, Davidson KG, Wheatley DJ, Davidson JF, Walker ID. Prostacyclin in cardiopulmonary bypass operations. J Thorac Cardiovasc Surg 1982;84:601–8.[Abstract]
6. Aherne T, Yee ES, Gollin G, Ebert PA. Does prostacyclin cardioplegic infusion improve myocardial protection after ischemic arrest? Ann Thorac Surg 1985;40:368–73.[Abstract]
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8. Ritter JM, Hamilton G, Barrow SE, et al. Prostacyclin in the circulation of patients with vascular disorders undergoing surgery. Clin Sci 1986;71:743–7.[Medline]
9. Cho MJ, Allen MA. Clinical stability of prostacyclin in aqueous solution. Prostaglandins 1978;15:943–54.[Medline]
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11. Byrne JG, Robert FA, Sun SC, et al. Cardiac derived thromboxane A2. An initiating mediator of reperfusion injury? J Thorac Cardiovasc Surg 1993;105:689–93.[Abstract]
12. Aiken JW, Gorman RR, Shebuski RJ. Prostacyclin prevents blockage of partially obstructed coronary arteries. In: Vane JR, Bergstrom S, eds. Prostacyclin. New York: Raven, 1979:311–21.
13. Parret J. Endogenous myocardial protective substances (antiarrhythmic) substances. Cardiovasc Res 1993;27:693–702.[Free Full Text]
14. Moncada S, Vane JR. Pharmacology and endogenous roles of prostaglandin endoperoxides, thromboxane A2 and prostacyclin. Pharmacol Rev 1979;30:293–331.[Medline]
15. Teoh KH, Fremes SE, Weisel RD, et al. Cardiac release of prostacyclin and thromboxane A2 during revascularization. J Thorac Cardiovasc Surg 1987;93:120–6.[Abstract]
16. Aherne T, Price DC, Yee ES, Hsieh WR, Ebert PA. Prevention of ischemia-induced myocardial platelet deposition by exogenous prostacyclin. J Thorac Cardiovasc Surg 1986;92:99–104.[Abstract]
17. Dusting GJ, Mocanda S, Vane JR. Disappearance of prostacyclin in the circulation of the dog. Br J Pharmacol 1978;62:414–5.
18. Romson JL, Haach DW, Abrams GD, Lucchesi BR. Prevention of occlusive coronary artery thrombosis by prostacyclin infusion in the dog. Circulation 1981;64:906–14.[Free Full Text]
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This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Harsh P. Singh Michael B. Murphy Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Singh, H. P. Articles by Aherne, T. Search for Related Content PubMed PubMed Citation Articles by Singh, H. P. Articles by Aherne, T.