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Ann Thorac Surg 2001;71:238-242
© 2001 The Society of Thoracic Surgeons

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Original article: cardiovascular

Effects of a platelet-activating factor antagonist on lung injury and ventilation after cardiac operation

^a Oxford Heart Centre, John Radcliffe Hospital, Oxford, England, UK

Accepted for publication April 26, 2000.

Address reprint requests to Dr Taggart, Oxford Heart Centre, John Radcliffe Hospital, Oxford OX3 9DU, England
e-mail: david.taggart{at}orh.anglox.nhs.uk

	Abstract

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Background. Platelet-activating factor is a mediator of lung injury during cardiac operation. Platelet-activating factor antagonists reduce lung injury in animal models of cardiopulmonary bypass but there is no confirmatory evidence in clinical practice.

Methods. The effect of a low or high dose of a platelet-activating factor antagonist (Lexipafant) was assessed in a single center, double-blind, placebo-controlled, parallel group study. One hundred fifty patients undergoing coronary artery bypass grafting were randomized by minimization into three groups to receive placebo infusion, 10 or 100 mg of lexipafant for over 24 hours. Serial arterial oxygen and carbon dioxide tension, alveolar arterial oxygen gradient, and percent saturation were measured before operation and at 1, 6, 24, 48 hours, and 5 days after operation.

Results. Patient groups were similar with respect to age, sex, body surface area, and urgency of operation. Likewise, the groups were similar with respect to duration of cardiopulmonary bypass and the number and type of grafts. Maximum lung injury occurred at 48 hours when the arterial oxygen tension and percent saturation reached a nadir (both p < 0.001) accompanied by the maximum increase in the alveolar arterial gradient (p < 0.001). All measurements demonstrated partial recovery by 5 days but remained significantly (p < 0.001) impaired in comparison to baseline values. Duration of ventilation was similar in all groups. Lexipafant, at low or high dose, did not moderate lung injury after cardiopulmonary bypass and did not influence the duration of postoperative ventilation.

Conclusions. Despite experimental and clinical evidence implicating platelet-activating factor in the pathophysiology of lung injury after cardiopulmonary bypass, no beneficial effect of a platelet-activating factor antagonist on lung function or ventilation could be demonstrated in this clinical trial.

	Introduction

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Lung injury persists as one of the most frequent complications of cardiac surgery using cardiopulmonary bypass [1, 2]. Its etiology is multifactorial reflecting the combined effects of general anesthesia, surgical injury, median sternotomy, and cardiopulmonary bypass (CPB). We previously reported that postoperative respiratory dysfunction was significantly more severe in patients undergoing coronary artery bypass grafting than general surgical operations and attributed the difference to the use of CPB [1].

Several inflammatory mediators, causing neutrophil activation, have been proposed as contributors to lung injury associated with CPB [3]. Platelet-activating factor (PAF), a glycerol phospholipid synthesized by a variety of proinflammatory cells, is one of the most powerful bioactive mediators of inflammation and produces cell damage by several mechanisms [4, 5]. In particular, PAF is a potent stimulator of neutrophil integrin expression, especially CD 11b/CD 18, the receptor most frequently implicated in neutrophil activation, chemotaxis, and diapedesis and responsible for neutrophil-mediated tissue injury [6]. In addition, PAF mediates tissue injury induced by tumor necrosis factor [7].

Platelet-activating factor is implicated as a key inflammatory mediator after CPB [8–13]. After CPB its circulating concentration can increase at least threefold [8–11] and large increases in PAF release have been correlated with the need for increased inotropy and prolonged ventilation [11]. A PAF antagonist has been reported to increase arterial oxygen tension, to decrease pulmonary vascular resistance, and to reduce histologic evidence of lung injury in a swine model of CPB [12]. In a randomized trial involving 18 patients a PAF antagonist improved pulmonary hemodynamic effects in comparison to placebo [13]. Lexipafant is a PAF antagonist with potent effects at both blood and tissue levels without clinically demonstrable adverse side effects. In a double-blind, placebo-controlled study the potential of Lexipafant, in low or high dose, to reduce lung injury was assessed in 150 patients undergoing coronary artery bypass grafting.

	Material and methods

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Ethical/regulatory requirements
The study was performed in accordance with the current version of the Declaration of Helsinki. The Central Oxford Research Ethics Committee approved the final protocol. All patients gave written informed consent to participate in the study after having read the information sheet and had an opportunity to discuss the study.

Lexipafant
Lexipafant (BB-882) is a PAF antagonist developed by British Biotech (Oxford, UK). It is well tolerated with potent ex vivo PAF antagonism at both blood (platelet aggregation) and tissue level (intradermal weal and flare response). Concentrations more than 0.25 mg/mL are associated with thrombophlebitis, but concentrations up to this level have no such effect.

Power calculations
A sample size of 50 patients per group was sufficient to show, with at least 80% power, a significant difference between an active treatment group and the placebo group in mean changes from baseline arterial oxygen tension, assuming population active versus placebo-treated mean changes of 2.5 to 4.0 Kpa, respectively (ie, a one-third reduction), and population within-group standard deviations of 2 Kpa [1].

Inclusion/exclusion criteria
The 150 patients in this trial were enrolled between February 1996 and March 1997. The inclusion criteria for the study included patients undergoing first-time coronary artery bypass grafting for angiographically demonstrated coronary stenoses. Exclusion criteria included emergency operation, significantly impaired ventricular function (ejection fraction, < 30%), or a previous cerebrovascular accident.

Randomization and minimization
This was a single center, double-blind, placebo-controlled, parallel group study. Patients received placebo, 10 mg of lexipafant (0.4 mg loading dose followed by 0.4 mg/h for 24 hours) or 100 mg of lexipafant (loading dose of 4 mg followed by 4 mg/h for 24 hours) commencing on induction of anesthesia. Treatment allocation was by a double-blind process of minimization so that the two treatment groups would be balanced with respect to age (< 40 , 40 to 49, 59 to 59, 60 to 69, > 70 years), sex, number of vessels affected (left main stem, three vessels, one or two vessels), previous percutaneous transluminal coronary angioplasty (yes/no), surgeon (DPT), aspirin therapy (yes/no), and left ventricular function (normal/impaired).

Anesthesia
The patients received a standard anesthetic regimen. Premedication was achieved with morphine (10 to 15 mg) and scopolamine (0.3 to 0.4 mg). Anesthesia was induced with fentanyl (1 mg), pancuronium (8 mg), and etomidate (4 to 10 mg). Anesthesia was maintained with a combination of oxygen, nitrous oxide, and halothane before CPB, and during CPB with propofol (6 mg · kg^-1 · h^-1). Benzodiazepines were not used.

Operation
All operations were performed through a median sternotomy incision. Harvest of the internal mammary artery, whether single or bilateral, was accompanied by pleurotomy and chest drainage of each pleural cavity entered and the mediastinum with separate drains.

Cardiopulmonary bypass
Cardiopulmonar bypass was achieved using a pump flow rate of 2.4 L/m² per minute at normothermia with temperature allowed to drift to 34°C. Topical cooling was not used, and there was no direct or indirect left ventricular venting. A Cobe CML membrane oxygenator (Cobe Cardiovascular, Inc, Arvada, CO) and a roller pump producing nonpulsatile flow were used without an arterial line filter. Alpha stat control of acid–base management was used and the mean arterial pressure maintained between 50 and 60 mm Hg with pharmacologic manipulation if necessary. Distal anastomoses were constructed during brief periods (approximately 10 minutes) of aortic clamping and induced fibrillation. On completion of the distal anastomosis the aortic clamp was released and the proximal anastomosis was constructed after isolation of a portion of the ascending aorta in a side-biting clamp. If the heart did not defibrillate spontaneously, this was achieved with 10 to 20 J. (In 15 patients operations were performed by trainees under supervision using 1 L of cold antegrade crystalloid cardioplegia to construct the distal anastomoses.)

Postoperative management
Patients were managed with standardized cardiovascular, respiratory, and renal protocols aimed at early extubation. Timing of extubation was managed by nursing staff in alert, hemodynamically stable patients capable of maintaining self ventilation (see below). Chest tubes were left in situ until the first postoperative day and when drainage was less than 100 mL in the previous 5 hours.

Perioperative ventilation
During anesthesia the lungs were ventilated with 100% oxygen. During CPB the lungs remained collapsed. In the postoperative period ventilation was managed according to blood gases resulting from a standardized protocol of supplementary intermittent mandatory ventilation consisting of 10 breaths/min; tidal volume of 10 mL/kg of body weight; fractional concentration of oxygen (inspired oxygen) of 60%; pressure support of 20 cm H₂O; positive end-expiratory pressure of 5 cm H₂O; and inspiratory-to-expiratory ratio of 1:2.

Blood gas sampling and analysis
Blood gases were taken predose and at 1, 6, 24, and 48 hours and 5 days. For the preoperative, 48-hour, and 5-day samples the patient breathed room air for 10 minutes to allow for equilibration and then samples of arterial blood were taken for oxygen partial pressure and carbon dioxide partial pressure. The alveolar arterial gradient was calculated from these values [1]. Samples obtained at 1 hour reflected intubation, whereas those at 6 and 24 hours reflected oxygen administered by face mask. Arterial oxygen saturation was obtained from blood gas determinations.

Statistical analysis
Statistical analysis was undertaken using the SPSS (version 9.0; SPSS Inc, Chicago, IL) computer program. Serial changes in blood gas measurements at various time points were performed using the generalized linear model for repeat analyses. Comparisons among the three groups were performed with analysis of variance for continuous variables and post-hoc analysis with independent t tests. Discrete variables among groups were compared using Pearson’s ² test. Bonferroni correction was used to correct for multiple comparisons and consequently a p value of less than 0.01 was considered significant.

	Results

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Of 150 patients undergoing CPB and enrolled into the study, 3 (2%) died within 5 days of operation. Two patients died from perioperative myocardial infarction (one on the operating table) and a third from an arrhythmia associated with a thrombosed vein graft.

Preoperative and intraoperative demographic data for the three groups is summarized in Table 1. Respiratory data for the three groups is summarized in Table 2.

There was no significant difference among the placebo and PAF antagonist groups when comparing changes in any respiratory measurement at any time point in the postoperative period. Until 48 hours patients received supplemental oxygen while ventilated (at 1 hour) or by face mask (at 6 and 24 hours). Blood gas data at 48 hours were obtained after the patient breathed room air for 10 minutes. Arterial oxygen tension and percent saturation reached a nadir at 48 hours (both p < 0.001) accompanied by the maximum increase in the alveolar arterial gradient (p < 0.001). All measures, except arterial carbon dioxide tension demonstrated some recovery by 5 days, although still remaining significantly (p < 0.001) impaired in comparison to baseline values. In contrast, arterial carbon dioxide tensions were significantly lower (p < 0.01) at 5 days than at 48 hours.

In the postoperative period there was no significant difference among the groups in the duration of ventilation, incidence of atrial fibrillation, or time to hospital discharge.

	Comment

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Lung injury is an inevitable consequence of cardiac surgery. Attempts to reduce it in the experimental and clinical setting have included pharmacologic and mechanical [14–17] efforts to block the action of activated white blood cells through which many inflammatory mediators are believed to exert their damaging effects [3, 14]. The rationale for the clinical trial of a PAF antagonist to reduce lung injury appeared particularly persuasive. Platelet-activating factor is a biologically potent activator of white blood cells [5–7] released in large quantities during CPB [8–11] and PAF antagonists have been shown to reduce lung injury in experimental models of CPB [13].

In this study Lexipafant did not reduce lung injury in either low or high dose and, consequently, did not influence duration of ventilation. This raises the possibility that Lexipafant is ineffective in ameliorating lung injury after cardiac surgery, or that the degree of lung injury observed in this study did not permit detection of a beneficial effect of Lexipafant or that the dose of Lexipafant was insufficient to achieve the desired effect.

The exact etiologic mechanisms of impaired gas exchange after CPB are multifactorial and complex but are believed to involve at least some inflammatory component [18]. Although general anesthesia impairs respiratory mechanics and ventilation-perfusion matching [18], inflammatory mediators released during CPB increase capillary permeability allowing macromolecules to enter the pulmonary interstitium and the alveoli [19, 20] contributing to alveolar–capillary block. Furthermore, pulmonary ischemia during CPB causes sequestration of activated neutrophils in the lung [21] resulting in capillary plugging and contributing to right-to-left intrapulmonary shunting and increases in the alveolar arterial gradient. We previously reported that postoperative respiratory dysfunction was significantly greater following coronary artery bypass grafting than general surgical operations and attributed the difference to the use of CPB [1]. The absence of any effect of even high dose Lexipafant on gas exchange in the current study may indicate that the inflammatory response is quantitatively of little importance in contributing to lung injury after CPB.

Was the dose of PAF antagonist adequate to achieve an effect? Pharmacokinetic extrapolations predicted that a plasma level of 2 ng/mL of Lexipafant would be sufficient to block exogenous effects of PAF such as platelet aggregation. A Lexipafant dose of 100 mg/24 hours provides steady-state levels of drug between 50 and 150 ng/mL and would be expected to be sufficiently high to block endogenous PAF release in direct cell-to-cell interactions. The safety profile of Lexipafant is excellent and more than 400 patients have received the drug in phase II studies of sepsis, ischemia reperfusion, ulcerative colitis, and pancreatitis without side effects directly attributable to the drug. In volunteers, steady-state blood levels in the range 500 to 800 ng/mL have been achieved without untoward effects.

In contrast to the findings in this study a PAF antagonist has been reported to increase arterial oxygen tension, to decrease pulmonary vascular resistance, and to reduce evidence of lung injury in a swine model of CPB [12]. Observations in that study were, however, completed 2 hours after the termination of CPB thereby missing peak lung injury that occurs at 48 hours in the clinical setting. Similarly, the beneficial effects of a PAF antagonist on pulmonary hemodynamics reported in a small randomized trial of 18 patients were observed for only a short period after the termination of CPB and disappeared after protamine administration [13]. Although Ansley and colleagues [11] correlated significantly elevated PAF levels with need for inotropic support and duration of ventilation, these observations were based on fewer than 10 patients.

In conclusion, despite experimental and clinical evidence implicating PAF in the pathophysiology of lung injury after CPB, no protective effect of a PAF antagonist on lung function could be demonstrated in this clinical trial.

	Acknowledgments

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I acknowledge British Biotech and in particular Dr Lloyd Curtis for providing financial support for the study, Tessa Longney for collecting blood samples, and Stuart Browne, Peter Halligan, and Derick Wade who provided assistance with other aspects of this study. This study was funded by British Biotech Pharmaceuticals Ltd, Watlington Rd, Oxford, OX4 5LY, England.

	References

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 

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