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Ann Thorac Surg 1995;59:598-603
© 1995 The Society of Thoracic Surgeons

Pulmonary Injury After Total or Partial Cardiopulmonary Bypass With Thromboxane Synthesis Inhibition

Division of Cardiothoracic Surgery, Department of Surgery, Beth Israel Hospital and Harvard Medical School, Boston, Massachusetts

Accepted for publication October 28, 1994.

	Abstract

Top Footnotes Abstract Introduction Methods Results Comment References

 
Previous studies have shown an increase in left atrial plasma thromboxane (TBX) level and associated increase in lung injury parameters after total cardiopulmonary bypass (t-CPB) but not after partial cardiopulmonary bypass (p-CPB). We used dazmegrel to study the effect of TBX synthesis inhibition on lung injury after t-CPB compared with p-CPB. Sheep were placed on t-CPB without ventilation and with pulmonary artery occlusion (n = 7) or p-CPB with ventilation and an unrestricted pulmonary artery (n = 7). All sheep were treated with dazmegrel. After 90 minutes we separated the sheep from CPB. Plasma TBX, platelets, white blood cells, protein concentration, lung lymph protein, flow, and pulmonary vascular resistance were measured before and after CPB. Lung biopsies were also obtained. Minimal derangement of these pulmonary parameters was seen after either p-CPB or t-CPB. Inhibition of TBX synthesis virtually eliminated the lung injury previously reported after t-CPB, when compared with p-CPB. Clearly TBX has an important role in mediating lung injury after t-CPB.

	Introduction

Top Footnotes Abstract Introduction Methods Results Comment References

 
Previous work from our laboratory demonstrated an increase in left atrial plasma thromboxane concentration (TBX) after total cardiopulmonary bypass (t-CPB) but not after partial cardiopulmonary bypass (p-CPB) [1]. In contrast to p-CPB, which was not associated with left atrial plasma TBX elevation, the transient elevation of left atrial plasma TBX in the t-CPB group was associated with pulmonary hypertension, increased pulmonary capillary permeability, and pulmonary cellular sequestration [2, 3]. These data demonstrated that after t-CPB pulmonary TBX production occurs in association with markers of pulmonary injury.

Thromboxane is associated with ischemic injury in organs such as skeletal muscle [4, 5] and heart [6]. Recent investigations have sought to reduce ischemic reperfusion injury associated with TBX by either blocking TBX receptors [7] or inhibiting TBX synthesis [8, 9]. The use of a TBX synthetase inhibitor seemed to ameliorate acute lung injury in laboratory models [10] and to reduce pulmonary hypertension and pulmonary vascular resistance after mitral valve replacement operation [11].

In this study we hypothesized that administration of dazmegrel, an inhibitor of TBX synthesis, before CPB would eliminate the pulmonary injury previously demonstrated after t-CPB when compared with p-CPB.

	Methods

Top Footnotes Abstract Introduction Methods Results Comment References

 
The preparation was identical to that described in our investigation comparing pulmonary parameters after p-CPB and t-CPB [1, 2].

Dorset-Rambouillet sheep (n = 14) weighing 25 to 31 kg (mean, 28.5 kg) were anesthetized with intravenous 80 mg/kg of alpha-chlorolose and 500 mg/kg of urethane. Animals were intubated and mechanically ventilated (Harvard Aparatus, Millis, MA). Arterial blood gas and pH measurements were performed during the procedure (pH blood gas analyzer 1306; Instruments Lab, Lexington, MA) and maintained within physiologic limits (pH, 7.35 to 7.45; oxygen tension, &gt;100 and <300 mm Hg; carbon dioxide tension, &gt;35 and <45 mm Hg). Systemic arterial pressure was monitored by percutaneous cannulation of the femoral artery.

We used the method described by Koike and colleagues [12] to collect the pulmonary lymph drainage. Through a right thoracotomy in the fifth intercostal space, we cannulated the efferent duct of the caudal mediastinal lymph node with a small heparin-coated silicone catheter. To eliminate any systemic lymph input to the node, through another right thoracotomy in the tenth intercostal space, we ligated the tail of this node at the caudal margin of the pulmonary ligament and cauterized the diaphragm around it.

A midline sternotomy was then performed and after systemic heparinization (400 U/kg) the right atrium and aorta were cannulated. As described by Bernard and Mitzner and their co-workers [13, 14], a 16F silicone-coated rubber Foley catheter with a 30 mL inflatable balloon was introduced into the left atrium to increase the left atrial pressure after 30 minutes of reperfusion. This stresses the capillary integrity of the upstream pulmonary circulation. An 8F Millar catheter (Houston, TX) was inserted into the left atrium for pressure recording. The pulmonary artery (PA) was cannulated to monitor the PA pressure, and a flowmeter (12SB234; Transonic System Inc, Ithaca, NY) was placed around the PA.

The extracorporeal circuit consisted of a roller pump (Cardiovascular Instrument Corp, Wakefield, MA) and a bubble oxygenator (Bentley Bio-2; Baxter Health Care Corp, Irvine, CA). The circuit was primed with Ringer's lactate solution (25 mL/kg).

Animals were cared for in accordance with the guidelines established by the Beth Israel Hospital's Animal Care and Use Committee and in compliance with the ``Guide for the Care and Use of Laboratory Animals'' published by the National Institutes of Health (NIH publication 85-23, revised 1985). The Beth Israel Hospital animal research facility is fully accredited by the AAALAC.

The protocol was identical to that published previously [3], with the addition of dazmegrel infusion before CPB in all animals. Dazmegrel powder [3-(1H-imidazol-1-yl-methyl)-2-methyl-1H-indole-1-propanoic acid (UK 38,485)] was graciously supplied by Pfizer Limited, Sandwich, Kent, United Kingdom. The dazmegrel powder was initially dissolved in 0.1 N sodium hydroxide solution to make a 4% solution with a pH of 8.5. The dazmegrel solution was infused intravenously at 3.4 mg/kg over a 10-minute period.

The study consisted of two experimental groups: one undergoing t-CPB and another subjected to p-CPB.

Total Cardiopulmonary Bypass Group
Animals (n = 7) were placed on t-CPB, the PA was clamped, and ventilation was halted. The PA clamp, although not used clinically, assured complete diversion of venous return to the extracorporeal circuit. Arterial flow was maintained at 80 to 100 mL • kg^-1 • min^-1 and regular blood gas analysis was performed to assess the adequacy of perfusion and gas exchange. Paired serial blood samples were taken from right atrium and left atrium before the establishment of CPB. Total CPB continued for 90 minutes, then the PA occluder was removed, ventilation restarted, and CPB stopped. Blood samples were taken just after PA reperfusion (cessation of CPB) and every 15 minutes until the end of the experiment. Thirty minutes after cessation of CPB the 30-mL Foley catheter balloon was inflated to increase the left atrial pressure (LAP) 10 to 15 mm Hg for 30 minutes. This increased the hydrostatic pressure of the pulmonary venous bed and served to amplify capillary permeability.

Partial Cardiopulmonary Bypass Group
The partial CPB group animals (n = 7) were placed on CPB as described above, but only a third of control pulmonary arterial flow was allowed to flow through the extracorporeal circuit. The remainder of venous return flowed through the PA. The lungs were ventilated normally. After 90 minutes CPB was terminated, blood samples were taken, and at 30 minutes after CPB the LAP was raised in the same fashion as the t-CPB group.

Sample Collection and Measurements
Samples were collected from both atria after aspiration of 5 mL for dead space. Two milliliters of blood were placed in ice cooled siliconized tubes containing 0.1 mL of 0.1 M EDTA and 0.05% (wt/vol) aspirin in a ratio of 2:1. Hematocrit was measured with each sample to permit correction for hemodilution.

Tubes that contained blood for TBX assay were immediately centrifuged at 4°C for 20 minutes at 2,000 g. Plasma was separated and stored in polypropylene test tubes at -25°C until assayed. All TBX B₂ assays were performed within 5 weeks of the experiment. Previous viability studies have shown no significant change in TBX levels for up to 8 weeks with this method of storage. The TBX B₂ is a stable, inactive metabolite of the physiologically active but unstable TBX A₂, whose half-life is 30 seconds at 37°C in aqueous solution [15]. We measured TBX B₂ using a competitive binding radioimmunoassay. Anti-TBX B₂ antibody (rabbit), iodine-125 TBX B₂ tracer, TBX B₂ standard, bovine serum albumin phosphate buffer, and magnetic goat anti-rabbit IgG antibody were obtained from Advanced Magnetic Inc. Cambridge, MA. Assays were carried out according to the manufacturer's instructions. All results were expressed as pg/0.1 mL.

Blood was centrifuged for 3 minutes at 2,000 rpm and the plasma protein concentration was then determined using a refractometer (Atago Hand Refractometer; NSG Precision Cells Inc. NY).

Lung lymph was collected three times over a 30-minute period: before CPB, after CPB, and after raising the LAP. The fluid was drained into cooled tubes containing EDTA and aspirin. We measured the quantity of the lymph in the tubes, and the protein concentration was determined by refractometry. The tubes were then centrifuged, stored at -25°C until assayed for TBX concentration.

Lung lymph protein clearance was calculated from the lymph flow rate (mL/30 min) and the ratio of the lymph to plasma protein concentrations by the formula: lymph flow x (lymph protein)/(plasma protein).

After centrifuging the blood, platelets were counted in the supernatant by a Coulter Counter (ZF-Coulter Electronic Inc, Hialeah, FL).

White blood cells from whole blood samples were counted by means of phase microscopy.

The pulmonary vascular resistance (PVR) was calculated using the following formula: mean PAP - mean LAP/PA flow x 1332 = PVR (dynes • s • cm^-5).

The water content of the lung tissue was determined by taking small lung biopsy specimens (less than 1 g) and placing them on tissue paper to absorb the blood. Samples were then weighed and desiccated for 3 days at 80°C at which time they were again weighed, and the percentage of water in the tissue was calculated: wet weight (g) - dry weight (g)/wet weight (g) x 100. Biopsies were performed before CPB and at the conclusion of reperfusion.

Statistical Analysis
Values are expressed as means ± standard error of mean. Means were compared between experimental groups by two-way analysis of variance with factorial measure design. Significance was determined at the p value less than 0.05. Statistical differences cited are between means of the two groups (total CPB versus partial CPB) except where otherwise specified.

	Results

Top Footnotes Abstract Introduction Methods Results Comment References

 
Plasma TBX from the right and left atria during t-CPB and p-CPB are shown in Figure 1. After 90 minutes of either p-CPB or t-CPB, with the initiation of reperfusion, there was a small decrease in TBX in the right atrium after p-CPB and after t-CPB (155 ± 24 to 151 ± 6 pg/0.1 mL and 134 ± 9 to 114 ± 15 pg/0.1 mL, respectively, p = not significant [NS]). Similar changes were noted in the left atrial TBX (167 ± 13 to 121 ± 14 pg/0.1 mL after p-CPB and 130 ± 6 pg/0.1 mL to 108 ± 14 pg/0.1 mL after t-CPB, p = NS). After 30 minutes of pulmonary arterial reperfusion, the LAP was elevated by atrial balloon inflation. With this manipulation the TBX did not change in either group or in either atrium.

View larger version (20K): [in this window] [in a new window]   Fig 1. . Plasma thromboxane B2 concentration in the right atrium (RA) and in the left atrium (LA) during partial cardiopulmonary bypass (p-CPB) and during total cardiopulmonary bypass (t-CPB). Samples were taken before CPB (time = -90), after separation from CPB (time 0) and every 15 minutes until the end of the experiment.

View larger version (16K): [in this window] [in a new window]   Fig 2. . Lymph thromboxane B2 concentration during partial cardiopulmonary bypass (p-CPB) and during total cardiopulmonary bypass (t-CPB). Samples were taken before CPB (time = -90) and every 30 minutes after separation from CPB until the end of the experiment.

View larger version (16K): [in this window] [in a new window]   Fig 3. . Lymph protein clearance from the lung calculated from lymph flow and lymphatic protein concentration, during partial cardiopulmonary bypass (p-CPB) and during total cardiopulmonary bypass (t-CPB). Protein clearance was calculated before CPB (time = -90), for the 30-minute period before the left atrial balloon was inflated and for 30 minutes after the balloon was inflated.

View larger version (13K): [in this window] [in a new window]   Fig 4. . Pulmonary vascular resistance during partial cardiopulmonary bypass (p-CPB) and during total cardiopulmonary bypass (t-CPB). Calculations were done before CPB (time = -90), after separation from CPB (time = 0) then every 15 minutes until 30 minutes after separation from CPB (at which time the left atrial balloon inflation obviated physiologic pulmonary vascular resistance).

	Comment

Top Footnotes Abstract Introduction Methods Results Comment References

It has been shown that TBX mediates injury in peripheral organs subjected to ischemia [4, 5, 17]. It has also been demonstrated that TBX is produced during CPB [18, 19] and is believed to have an important role in the elevation of pulmonary vascular resistance after CPB [20]. Investigators have established previously that a TBX synthetase inhibitor can reduce experimental cardiac reperfusion injury [8]. Thromboxane synthetase inhibition has been demonstrated clinically to reduce PVR after mitral valve replacement [11], and to augment the effect of nifedipine on PVR reduction in patients with primary pulmonary hypertension [21]. In the studies cited here a period of anatomically complete arterial occlusion has been included, such as aortic cross-clamping in the case of the heart. It is important to note that in our study there was no period of aortic cross-clamping, and that the pulmonary tissue was rendered ischemic or hypoxic only by virtue of the lack of blood flow from the right heart and the absence of ventilation. Bronchial arterial flow was uninterrupted and altered only as may occur due to nonpulsatile perfusion on CPB. A report from our laboratory previously quantified mean bronchial arterial return to the left atrium in sheep during CPB as 1.08 mL • min^-1 • kg^-1 [1].

The pulmonary derangements that occur after t-CPB compared with p-CPB have been documented previously in our laboratory [2, 3]. The post t-CPB derangements found included increased pulmonary vascular resistance, lung lymph flow, lung lymph protein clearance, lung water content, pulmonary leukosequestration, and platelet sequestration. The fact that these markers of lung injury were observed in association with pulmonary artery reperfusion and TBX release suggested the latter may play a critical role in their development. This hypothesis was studied by administering dazmegrel to groups of sheep before either t-CPB or p-CPB.

There was a slight difference between the p-CPB and t-CPB groups in terms of the pulmonary lymphatic protein clearance. This suggests a slightly greater increase in capillary permeability after t-CPB, despite the dazmegrel. This difference is, however, small compared with that seen in experiments without TXB synthetase inhibition. Without dazmegrel, in our previous study, the protein clearance increased by 65% after p-CPB and by 150% after t-CPB [2]. In these experiments, 1 hour after cessation of p-CPB, the lung protein clearance increased 40% over baseline, and after t-CPB only 65% (p = NS, see Fig 3). The effect of increased capillary permeability may be manifest by the water content of the lung tissue. Indeed in the prior study there was a 15% water content increase after t-CPB compared with an increase of only 3% after p-CPB. In this study, lung water content rose very slightly in both groups (4% after p-CPB and 5% after t-CPB) (see Table 5). These data indicate that TBX production is intimately involved, although perhaps not entirely responsible, for increased pulmonary capillary permeability seen after t-CPB.

In our previous study of animals not treated with dazmegrel pulmonary sequestration of white blood cells and platelets appeared after t-CPB but not after p-CPB. Similarly pulmonary vascular resistance increased significantly after t-CPB [2], but not after p-CPB. With dazmegrel given before CPB no pulmonary sequestration occurred (see Tables 3 and 4) and pulmonary vascular resistance did not increase immediately after either p-CPB or t-CPB (see Fig 4). These data provide evidence in the sheep model for TBX's primary role in pulmonary cellular sequestration and vasoconstriction after t-CPB. We acknowledge that sheep have been used by us and others [5, 9, 12] as a model for research of this type, but that the direct applicability of our results to humans has not yet been determined.

Using dazmagrel to inhibit pulmonary TBX production, we found little evidence of significant lung injury after t-CPB. In contrast with our previous work [2], after dazmegrel administration the t-CPB sheep respond, in terms of pulmonary derangements, much like the p-CPB animals. The lack of differences between t-CPB and p-CPB using a TBX synthetase inhibitor in a clinically relevant experimental model strongly suggests that thromboxane plays a major role in the pulmonary pathophysiology seen after t-CPB.

	Footnotes

Top Footnotes Abstract Introduction Methods Results Comment References

 
Address reprint requests to Dr Johnson, Division of Cardiothoracic Surgery, Beth Israel Hospital, Dana 905, 330 Brookline Ave, Boston, MA 02215.

	References

Top Footnotes Abstract Introduction Methods Results Comment References

 

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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): Frank W. Sellke Ronald M. Weintraub Robert G. Johnson Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Friedman, M. Articles by Johnson, R. G. Search for Related Content PubMed PubMed Citation Articles by Friedman, M. Articles by Johnson, R. G.