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J Thorac Cardiovasc Surg 1999;117:987-993
© 1999 Mosby, Inc.

CARDIOPULMONARY SUPPORT AND PHYSIOLOGY

PLATELET ANESTHESIA WITH NITRIC OXIDE WITH OR WITHOUT EPTIFIBATIDE DURING CARDIOPULMONARY BYPASS IN BABOONS

From the Harrison Surgical Research Laboratories, Department of Surgery, University of Pennsylvania School of Medicine, and the Sol Sherry Thrombosis Research Center, Department of Medicine, Temple University, Philadelphia.

Supported by HL 47186 from the National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Md.

Received for publication Sept 18, 1998. Revisions requested Nov 19, 1998. Revisions received Jan 5, 1999. Accepted for publication Jan 11, 1999. Address for reprints: L. Henry Edmunds, Jr, MD, Department of Surgery, Hospital of the University of Pennsylvania, 6 Silverstein, 3400 Spruce St, Philadelphia, PA 19104-4283.

	Abstract

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Objective:This study tested the hypothesis that nitric oxide or nitric oxide and eptifibatide (Integrilin) reversibly inhibit platelet activation and consumption during cardiopulmonary bypass and rapidly restore platelet numbers and function after bypass.
Methods: Nitric oxide, a short-acting, reversible platelet inhibitor, was studied with and without eptifibatide, a short-acting, reversible glycoprotein IIb/IIIa inhibitor, in 21 baboons that underwent 60 minutes of normothermic cardiopulmonary bypass with peripheral cannulas. A control group, a group that received 80 ppm nitric oxide, and a group that received both nitric oxide and eptifibatide were studied. Blood samples were obtained at several time points to determine platelet count, aggregation in response to adenosine diphosphate, and levels of ß-thromboglobulin, prothrombin fragment 1.2, and thrombin-antithrombin complex. Template bleeding times were measured before and at 4 intervals after cardiopulmonary bypass.
Results: Both nitric oxide and the combination of the 2 drugs significantly attenuated platelet consumption, improved postbypass function, and reduced plasma ß-thromboglobulin release with respect to values in control animals. Both nitric oxide and the combination restored baseline bleeding times 55 minutes after cardiopulmonary bypass ended. No significant differences between nitric oxide and the combination were found for any measurement.
Conclusion: Nitric oxide with or without eptifibatide protects platelets during cardiopulmonary bypass and accelerates restoration of normal bleeding times after operation in a baboon model. Although nitric oxide and eptifibatide reversibly inhibit platelets by different mechanisms, in the absence of a wound no synergistic effect was demonstrated.

	Introduction

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Cardiac operations require full anticoagulation during cardiopulmonary bypass (CPB) and complete reversal immediately afterward. Despite drawbacks, heparin and its inhibitor protamine meet this requirement. Nevertheless, bleeding complications and excessive postoperative blood losses continue to contribute to the morbidity associated with cardiac surgery with CPB. The bleeding complications are mainly due to problems related to heparin, fibrinolysis, and loss of platelet numbers and function. ¹ Platelet losses and dysfunction are primarily due to hemodilution, adhesion to biomaterials, ² aggregation with other platelets and blood cells, ³ release of granule contents, and complete or partial destruction, with the formation of platelet microparticles. ^4,5

Platelet anesthesia is a strategy to preserve platelet numbers and function during cardiac surgery with CPB by inhibiting platelets to prevent activation in both the wound and the extracorporeal perfusion circuit. ⁶ Ideally the inhibitor must disappear or be completely reversed at the time that protamine is given to restore clotting. The goal of this strategy is a normal bleeding time, an overall measure of platelet function, at the time that protamine is given.

Nitric oxide (NO) is a reversible, potent platelet inhibitor ⁷ that can be given in the sweep gas of the oxygenator during CPB; however, because of an exceptionally short half-life in blood, ⁸ the chemical is inactive by the time that arterial blood reaches the patient. Eptifibatide (Integrilin; COR Therapeutics Inc, South San Francisco, Calif) is a short-acting, reversible platelet glycoprotein (Gp) IIb/IIIa membrane receptor inhibitor. ⁹ Eptifibatide is a synthetic cyclic peptide that contains a modified lysine–glycine–aspartic acid sequence and is based on the structure of the disintegrin barbourin. ¹⁰ During CPB in baboons, eptifibatide prevents platelet adhesion and aggregation and restores bleeding times to the normal range within an hour after protamine administration. ¹¹

NO and eptifibatide inhibit platelets by different mechanisms and therefore are potentially synergistic inhibitors. Synergistic inhibition offers the possibility of more complete inhibition of platelet activation during CPB and more rapid reversal at the end. ¹² This study tested the hypothesis that the combination of NO and eptifibatide provides complete platelet anesthesia during CPB in baboons and restores bleeding time to baseline values at the time that protamine is given, 15 minutes after CPB ends.

	Methods

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Juvenile baboons (Papio anubis) quarantined for at least 6 weeks and weighing 13 to 20 kg were used. For each study the baboon was placed in a squeeze cage, the animal was sedated intramuscularly with 10 mg/kg ketamine hydrochloride, and anesthesia was induced intravenously with 5 mg/kg thiopental sodium. The animal was intubated and general anesthesia was maintained with inhalational isoflurane. The right or left side of the neck and both groins were prepared and draped appropriately for sterile cutdown and cannulation of vessels. Hemodynamic monitoring was accomplished with an arterial line with a 22-gauge catheter placed in the femoral artery and a 5F Swan-Ganz catheter (Baxter Healthcare Corp, Edwards Division, Santa Ana, Calif) placed in a femoral vein. After anticoagulation with porcine sodium heparin (300 U/kg; Elkins-Sinn, Inc, Cherry Hills, NJ) a 10F to 14F Bio-Medicus wire-wrapped, polyurethane catheter (Medtronic Bio-Medicus, Inc, Eden Prairie, Minn) was introduced into the jugular vein and advanced into the right atrium. A similar but shorter 8F arterial catheter was inserted into the femoral artery for reinfusion. All animals received humane care in compliance with the "Guide for the Care and Use of Laboratory Animals" prepared by the Institute of Laboratory Animal Resources and published by National Institutes of Health (NIH Publication No. 86-23, revised 1985). This study was approved by the Institutional Animal Care and Utilization Committee of the University of Pennsylvania.

The bypass circuit consisted of silicone elastomer tubing (Dow Corning Inc, Midland, Mich); 2 polyurethane, wire-wrapped cannulas (Medtronic Inc, Eden Prairie, Minn); a bubble oxygenator (Bentley 5 Pediatric; Baxter Healthcare, Inc, Irvine, Calif) ¹³; an arterial line filter (Intersept Pediatric, Medtronic Inc, Anaheim, Calif); and a roller pump (Sarns model 13400; Sarns Inc, Ann Arbor, Mich). The oxygenator was ventilated with 95% oxygen and 5% carbon dioxide at 3 L/min. Because the mechanism of platelet activation and injury is similar with the 2 types of oxygenator, ¹⁴ a bubble oxygenator rather than a membrane oxygenator was used to increase the robustness of the model. ¹³ Baboon platelets are less sensitive than human platelets to many platelet agonists. ¹³

This perfusion system required only 500 mL Normosol solution (Abbott Laboratories, North Chicago, Ill) for priming. Normothermic bypass was begun at 50 mL · kg^–1 · min^–1, or approximately half the normal cardiac output. The heart continued to eject and supply approximately half of the circulation. Perfusion was maintained for 60 minutes, at which time CPB was terminated.

Animals were divided into 3 groups. Group 1 (n = 7) was the control group. In group 2 (n = 7) 800 ppm NO in nitrogen (Puritan-Bennett, Carlsbad, Calif) was blended with nitrogen (Bird air-oxygen blender; Bird Products Corp, Palm Springs, Calif). Beginning 30 seconds before perfusion the blender output was added to the oxygenator sweep gas to produce a mixed concentration of 80 ppm NO and approximately 85% concentration of oxygen. NO concentration was measured with the NOxBOX II electrochemical analyzer (Bedfont Scientific, Bedfont, United Kingdom). In group 3 (n = 7) NO was given as in group 2 and a bolus injection of eptifibatide (200 µg/kg) was administered before the start of CPB.

Eight blood samples (15-20 mL) were obtained at baseline before administration of heparin and platelet inhibitors, 2 minutes after heparin and platelet inhibitor administration but before CPB, 5 minutes after the start of CPB, 55 minutes after the start of CPB, 10 minutes after administration of 3 mg/kg protamine (25 minutes after the end of CPB), and 30, 60, and 120 minutes after the protamine sample was taken. Note that protamine was given 15 minutes after CPB ended and that the protamine sample was taken 10 minutes after that, or 25 minutes after CPB ended.

Blood samples were assayed for hematocrit, platelet count, white blood cell count, platelet aggregation in response to adenosine diphosphate (ADP), ß-thromboglobulin (ßTG) release, prothrombin fragment 1.2, and thrombin-antithrombin complex. Dilutions of formed blood elements and plasma markers were corrected using hematocrit.

Heart rate was continuously monitored electrocardiographically. Systemic arterial, central venous, and pulmonary arterial pressures were continuously monitored (Hewlett-Packard 78534C, Hewlett-Packard Company, Palo Alto, Calif). Intermittent thermodilution cardiac outputs were measured before and after CPB (Oximetrix 3 SO₂/CO computer; Abbott Laboratories, Abbott Park, Ill).

Measurements
Platelets were counted by phase microscopy or by Coulter Counter (model STKR; Coulter Corporation, Hialeah, Fla) in triplicate. For platelet studies blood (8 mL) was anticoagulated with 1 mg D-phenylalanine-proline-arginine-chloromethyl-ketone. ¹⁵ Platelet-rich plasma was obtained by centrifuging whole blood at 150g for 10 minutes. Platelet-poor plasma was prepared by centrifugation at 13,600g for 5 minutes. The platelet count of platelet-rich plasma was adjusted to 150,000 cells/µL by dilution with platelet-poor plasma for aggregation in response to ADP with a Payton aggregometer (model 440; Chrono-Log, Inc, Havertown, Pa). The concentration of ADP (5-50 µmol/L) required to produce complete second-wave aggregation was measured; complete second-wave aggregation was assumed when light transmission was 62.5% or greater within 5 minutes. ¹⁶ The concentration of ADP required to obtain full aggregation of the baseline sample was determined and the percentage aggregation was normalized to 100%. In subsequent samples the percentage aggregation observed at that ADP concentration was proportionally normalized to the baseline value.

For plasma ßTG analysis blood was withdrawn into centrifugation tubes containing 10% (by volume) of 3.8% acid citrate dextrose and alprostadil (prostaglandin E₁) solution at 0°C. ßTG was measured by radioimmunoassay. ¹⁷

Template bleeding times were measured in duplicate on the forearm with a blood pressure cuff inflated to 40 mm Hg at baseline and at 4 time points after protamine administration. The Simplate II (Organon Teknika Corporation, Durham, NC) lancet was used to create reproducible skin incisions for determinations of bleeding time.

Plasma levels of fragment 1.2 (Behring Diagnostics, Inc, Westwood, Mass) and thrombin-antithrombin complex (Behring Diagnostics) were measured by enzyme-linked immunosorbent assay with commercial assay kits.

Statistical analysis
Data points represent the mean ± SEM. Three-way, factorial, multivariate analysis of variance (ANOVA) for repeated measures with the Bonferroni adjustment (SPSS for Windows 7.5, SPSS Inc, Chicago, Ill) was used for statistical analysis of group and time effects. When group effects were significant (P < .05), 2-way ANOVAs between the control group and each experimental group (separately) were used to establish significant differences. The unpaired t statistic was used for specific comparisons at specific time points between groups when the group effect was significant according to 2-way ANOVA (with Bonferroni adjustment). The paired Student t test with Bonferroni correction was used for analysis of differences within groups when the time effect was significant according to multivariate ANOVA and 1-way ANOVA.

	Results

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No consistent differences were observed between groups in cardiac output, heart rate, and arterial, central venous, or pulmonary arterial pressures. All these values remained within reference ranges at all time points (data not shown).

Both group and time effects for changes in platelet count were significant (Table I). In control animals platelet counts were significantly lower than baseline at the end of CPB and thereafter and were significantly lower than platelet counts in each of the other 2 groups after CPB (Fig. 1). NO alone did not significantly inhibit platelet aggregation during CPB but preserved platelet function after CPB significantly with respect to that in control animals. The combination of NO and eptifibatide completely suppressed platelet function at the beginning of CPB, but function recovered and was significantly better than control values when protamine was given. NO, alone or in combination with eptifibatide, suppressed release of ßTG during CPB, and plasma ßTG concentrations were significantly lower at the end of CPB in groups 2 and 3 than in the control group (Fig. 2, Table I).

View larger version (24K): [in this window] [in a new window]   Fig 1. Platelet counts (mean ± SEM) corrected for dilution at 8 sampling points. Open circles represent control group (group 1); filled triangles represent NO only (group 2); filled squares represent NO plus eptifibatide (group 3). Base, Baseline; HEP, after heparin and drugs, before CPB; START, 5 minutes after starting CPB; END, 55 minutes after starting CPB; PROT, 10 minutes after protamine administration (25 minutes after stopping CPB); 30, 30 minutes after time PROT; 60, 60 minutes after time PROT; 120, 120 minutes after time PROT. Table I gives statistics.

View larger version (25K): [in this window] [in a new window]   Fig 2. Plasma ßTG concentrations (mean ± SEM). Open circles represent control group (group 1); filled triangles represent NO only (group 2); filled squares represent NO plus eptifibatide (group 3). Base, Baseline; HEP, after heparin and drugs, before CPB; START, 5 minutes after starting CPB; END, 55 minutes after starting CPB; PROT, 10 minutes after protamine administration (25 minutes after stopping CPB); 60, 60 minutes after time PROT.

View larger version (20K): [in this window] [in a new window]   Fig 3. Bleeding times (mean ± SEM). Open circles represent control group (group 1); filled triangles represent NO only (group 2); filled squares represent NO plus eptifibatide (group 3); filled circles represent high-dose eptifibatide data from Suzuki and associates. 11 Base, Baseline; Prot, 10 minutes after protamine administration (25 minutes after stopping CPB); 30, 30 minutes after time Prot; 60, 60 minutes after time Prot; 120, 120 minutes after time Prot. Bleeding times were not measured during CPB.

	Discussion

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NO stimulates soluble guanylate cyclase to increase platelet guanosine 3',5'-monophosphate (cGMP), which inhibits platelet aggregation and adhesion and also inhibits cGMP-inhibited cyclic adenosine 3',5'-monophosphate) phosphodiesterase activity. ^18,19 Inhibition of this phosphodiesterase increases platelet cyclic adenosine monophosphate, ²⁰ which decreases cytosolic calcium ion and inhibits the basic platelet reaction that includes aggregation, adhesion, secretion of dense and -granule contents, and release of acid hydrolases. ²¹ NO is rapidly metabolized by hemoglobin ⁸ and has a half-life in blood of less than 1 second. None of the metabolites of NO are known to be vasodilators. ⁸ Eptifibatide reversibly inhibits the platelet GpIIb/IIIa receptor and inhibits binding to fibrinogen, von Willebrand factor, and other ligands for this receptor. ⁹ Eptifibatide is partially cleared by the kidney and has a half-life in plasma of approximately 90 minutes. ²²

The rationale for using both NO and eptifibatide for platelet anesthesia during CPB is based on the potential for synergistic activity ¹² and the relative short plasma half-lives of both drugs. In this baboon model no surgical wound was present; in clinical cardiac surgery with CPB the wound is a major stimulus for thrombin formation and platelet activation. ²³ Because NO is metabolized so rapidly, its effect may be limited to the oxygenator and arterial portion of the CPB circuit. ⁸ Platelets exposed to the wound therefore may not be inhibited by NO alone. Mellgren and colleagues ²⁴ found that 40 ppm NO inhibited expression of the platelet GpIb receptor during cardiac surgery in patients but did not inhibit any other marker of platelet activation. During in vitro perfusion lasting 24 hours the same investigators found that concentrations of NO between 15 and 75 ppm protected platelet counts and reduced ßTG release but did not reduce GpIb expression or serotonin release. ²⁵ Mellgren and colleagues' data ^24,25 indicate that NO alone is not sufficient to provide platelet anesthesia during clinical cardiac surgery with CPB. The current study failed to demonstrate a synergistic effect between NO and eptifibatide during CPB, but this result does not negate the rationale for using this combination clinically because a major wound was absent.

In a previous study eptifibatide alone significantly shortened postoperative bleeding times with respect to control values at the time of protamine administration but did not restore preoperative bleeding times until 60 minutes after protamine administration (85 minutes after CPB ¹¹; Fig. 3). When eptifibatide was combined with low-dose iloprost (Berlex Laboratories; Cedar Knolls, NJ), bleeding time was 5.8 ± 0.6 minutes at the time of protamine administration (versus 5.1 ± 1.2 minutes with NO plus eptifibatide in this study) and was not significantly different from baseline values. High-dose eptifibatide alone attenuated ßTG release, but low-dose eptifibatide in combination with iloprost did not. ¹¹ Together, these 2 studies indicate that in the baboon model eptifibatide is just as efficacious as NO in inhibiting aggregation and adhesion but is not as effective in suppressing -granule release at the doses used.

NO and chemical donors of NO have been used in a variety of clinical applications, including acute respiratory distress syndrome, ²⁶ pulmonary hypertension, ²⁷ lung transplantation, congenital heart surgery, left ventricular circulatory assistance, and post-CPB cardiac surgery. Eptifibatide has been used safely and effectively for treatment of acute coronary arterial syndromes. ²⁸

In moderate doses (approximately 20 ppm) NO administered to the natural lung selectively dilates the pulmonary vasculature, but if given for prolonged periods NO is toxic because of its oxidant metabolites, NO₂– and NO₃–. ²⁷ Selective pulmonary vasodilation with minimal systemic vasodilation is due to rapid binding to hemoglobin to form S-nitrosyl hemoglobin and methemoglobin. ⁸ Short-term administration of NO for clinical cardiac surgery is not likely to seriously interfere with oxygen delivery; in animals doses between 500 and 1000 ppm have been used for as long as 90 minutes. ²⁹ Very high doses, however, decrease rather than increase the platelet inhibitory effect of the drug. The mechanism may be related to increasing platelet cGMP above concentrations that inhibit cGMP-inhibited cyclic adenosine monophosphate phosphodiesterase. ¹⁹

	Acknowledgments

 
We thank Mr Bradford Richardson, Dr Mihail Joutovski, and Ms Mariola Marcinkiewicz for their considerable help during this study.

	References

Top Abstract Introduction Methods Results Discussion References

 

1. Edmunds LH Jr. Extracorporeal perfusion in cardiac surgery in the adult. Edmunds LH Jr, editor. New York: McGraw-Hill; 1997. p. 255-94.
   
2. Wenger RK, Lukasiewicz H, Mikuta BS, Niewiarowski S, Edmunds LH Jr. Loss of platelet fibrinogen receptors during clinical cardiopulmonary bypass. J Thorac Cardiovasc Surg 1989;97:235-9. [Abstract]
   
3. Rinder CS, Bonan JL, Rinder HM, Mathew J, Hines R, Smith BR. Cardiopulmonary bypass induces leukocyte-platelet adhesion. Blood 1992;79:1201-5. [Abstract/Free Full Text]
   
4. Zilla P, Fasol R, Groscurth P, Klepetko W, Reichenspumer H, Wolner E. Blood platelets in cardiopulmonary bypass operations. J Thorac Cardiovasc Surg 1989;97:379-88. [Abstract]
   
5. Miyamoto S, Marcinkiewicz C, Edmunds LH Jr, Niewiarowski S. Measurement of platelet microparticles during cardiopulmonary bypass by means of captured ELISA for GPIIb/IIIa. Thromb Haemost 1998;80:225-30. [Medline]
   
6. Hiramatsu Y, Gikakis N, Anderson HL, Gorman JH, Marcinkiewicz C, Gould RJ, et al. Tirofiban provides "platelet anesthesia" during cardiopulmonary bypass in baboons. J Thorac Cardiovasc Surg 1996;113:182-93. [Abstract/Free Full Text]
   
7. Moncada S, Palmer RM, Higgs EA. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev 1991;43:109-42. [Medline]
   
8. Rimar S, Gillis CN. Selective pulmonary vasodilatation by inhaled nitric oxide is due to hemoglobin inactivation. Circulation 1993;88:2884-7. [Abstract/Free Full Text]
   
9. Phillips DR, Scarborough RM. Clinical pharmacology of eptifibatide. Am J Cardiol 1997;80:11B-20B. [Medline]
   
10. Scarborough RM, Rose JW, Naughton MA, Phillips DR, Nannizzi L, Arfsten A, et al. Characterization of the integrin specificities of disintegrins isolated from American pit viper venoms. J Biol Chem 1993;268:1058-65. [Abstract/Free Full Text]
    
11. Suzuki Y, Hillyer P, Miyamoto S, Niewiarowski S, Sun L, Rao AK, et al. Integrilin prevents prolonged bleeding times after cardiopulmonary bypass. Ann Thorac Surg 1998;66:373-81. [Abstract/Free Full Text]
    
12. Bernabei A, Gikakis N, Kowalska MA, Niewiarowski S, Edmunds LH Jr. Iloprost and echistatin protect platelets during simulated extracorporeal circulation. Ann Thorac Surg 1995;59:149-53. [Abstract/Free Full Text]
    
13. Hiramatsu Y, Gikakis N, Gorman JH 3rd, et al. A baboon model for hematologic studies of cardiopulmonary bypass. J Lab Clin Med 1997;130:412-20. [Medline]
    
14. Addonizio VP Jr, Strauss JF III, Colman RW, Edmunds LH Jr. Effects of prostaglandin E1 on platelet loss during in vivo and in vitro extracorporeal circulation with a bubble oxygenator. J Thorac Cardiovasc Surg 1979;77:119-26. [Abstract]
    
15. Phillips DR, Teng W, Arfsten A, et al. Effect of Ca²⁺ on GP Ib-IIIa interactions with Integrilin. Circulation 1997;96:1488-94. [Abstract/Free Full Text]
    
16. Carvalho AC, Colman RW, Lees RS. Platelet function in hyperlipoproteinemia. N Engl J Med 1974;290:434-8.
    
17. Rucinski B, Niewiarowski S, James P, Walz DA, Budzynski Z. Antiheparin proteins secreted by human platelets: purification, characterization and radioimmunoassay. Blood 1979;53:47-62. [Free Full Text]
    
18. Radomski MW, Vallance P, Whitley G, Foxwell N, Moncada S. Platelet adhesion to human vascular endothelium is modulated by constitutive and cytokine induced nitric oxide. Cardiovasc Res 1993;27:1380-2. [Abstract/Free Full Text]
    
19. Sheth SB, Colman RW Regulatory and catalytic domains of platelet cAMP phosphodiesterases: targets for drug design. Semin Hematol 1995;32:110-9. [Medline]
    
20. Maurice GH, Haslam RJ. Molecular basis of the synergistic inhibition of platelet function by nitrovasodilators and activators of adenylate cyclase: Inhibition of cyclic AMP breakdown by cyclic GMP. Mol Pharmacol 1990;37:671-81. [Abstract]
    
21. Holmsen H. Platelet secretion and energy metabolism. In: hemostasis and thrombosis: basic principles and clinical practice. 3rd ed. Colman RW, Hirsch J, Marder VJ, Salzman EW, editors. Philadelphia: JB Lippincott; 1994. p. 524-45.
    
22. Charo IF, Scarborough RM, Mee CP, Wolf D, Phillips DR, Swift RL. Pharmacodynamics of the GPIIb-IIIa antagonist Integrelin: phase I clinical studies in normal health volunteers [abstract]. Circulation 1992;86(Suppl):I260.
    
23. Chung JH, Gikakis N, Drake TA, Colman RW, Edmunds LH Jr. Pericardial blood activates the extrinsic coagulation pathway during clinical cardiopulmonary bypass. Circulation 1996;93:2014-8. [Abstract/Free Full Text]
    
24. Mellgren K, Mellgren G, Lundin S, Wennmalm A, Wadenvik H. Effect of nitric oxide gas on platelets during open heart operations. Ann Thorac Surg 1998;65:1335-41. [Abstract/Free Full Text]
    
25. Mellgren K, Friberg LG, Mellgren G, Hedner T, Wennmalm A, Wadenvik H. Nitric oxide in the oxygenator sweep gas reduces platelet activation during experimental perfusion. Ann Thorac Surg 1996;61:1194-8. [Abstract/Free Full Text]
    
26. Rossaint R, Falke KF, Lopez R, Slama K, Pison U, Zapol WM. Inhaled nitric oxide for the adult respiratory distress syndrome. N Engl J Med 1993;328:399-405. [Abstract/Free Full Text]
    
27. Zapol WM, Rimar S, Gillis N. Marletta H, Bosken CH. Nitric oxide and the lung: an NHLBI workshop summary. Am J Respir Crit Care Med 1994;149:1375-80. [Medline]
    
28. Anonymous. Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes. The PURSUIT Trial Investigators. Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy. N Engl J Med 1998;339:436-43. [Abstract/Free Full Text]
    
29. Sly MK, Prager MD, Eberhart RC, Jessen ME, Kulkarni PV. Inhibition of surface-induced platelet activation by nitric oxide. ASAIO J 1995;41:M394-8. [Medline]
    

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