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J Thorac Cardiovasc Surg 1996;111:460-468
© 1996 Mosby, Inc.

CARDIOPULMONARY BYPASS, MYOCARDIAL MANAGEMENT, AND SUPPORT TECHNIQUES

NEUTROPHIL ADHESION BLOCKADE WITH NPC 15669 DECREASES PULMONARY INJURY AFTER TOTAL CARDIOPULMONARY BYPASS

Boston, Mass.

From the Division of Cardiothoracic Surgery, Department of Surgery, the Charles W. Dana Research Building, Beth Israel Hospital and Harvard Medical School, Boston, Mass.

Received for publication Feb. 24, 1995. Accepted for publication May 10, 1995. Address for reprints: Robert G. Johnson, MD, Division of Cardiothoracic Surgery, Beth Israel Hospital, Dana 905, 330 Brookline Ave., Boston, MA 02215.

Abstract

Background: Total cardiopulmonary bypass, in an ovine model, is associated with increased pulmonary thromboxane A₂ production, cellular sequestration of white cells and platelets, transient pulmonary hypertention, and increased lung lymph flow and lymph protein clearance when compared with respective findings with partial cardiopulmonary bypass. This study evaluates the effect of neutrophil adhesion blockade on lung injury after cardiopulmonary bypass. Methods: Two groups of anesthetized sheep were placed on total cardiopulmonary bypass without assisted ventilation. One group of seven sheep was treated before and during total cardiopulmonary bypass with the neutrophil adhesion blocker NPC 15669. A second group of seven sheep did not receive NPC 15669 treatment before total cardiopulmonary bypass. A third group of seven sheep was treated with NPC 15669 before initiation of partial cardiopulmonary bypass with continued assisted ventilation. Aortic occlusion and hypothermia were not used. After 90 minutes all sheep were separated from cardiopulmonary bypass, with resumption of assisted ventilation and pulmonary arterial flow. After 30 minutes the left atrial pressure was elevated mechanically. Hemodynamics, thromboxane A₂ levels, platelet levels, and white blood cell and plasma protein concentrations were measured before cardiopulmonary bypass and afterwards at four 15-minute intervals. Samples were taken from the right and left atria simultaneously. Lung lymph protein levels and flow were measured before and after cardiopulmonary bypass at two 30-minute intervals. Results: In the total cardiopulmonary bypass group not treated with NPC 15669 signs of lung injury developed after cardiopulmonary bypass. Animals treated with NPC 15669 did not manifest a similar degree of lung injury after either partial or total cardiopulmonary bypass. Increased pulmonary vascular resistance did not develop in treated sheep nor did sequestration of platelets or white blood cells occur. Despite the drug, increased pulmonary capillary permeability after total cardiopulmonary bypass persisted, but was reduced. Conclusions: Compared with unmodified total cardiopulmonary bypass, blockade of neutrophil adhesion with NPC 15669 reduces, but does not entirely eliminate, lung derangement after total cardiopulmonary bypass. (J THORAC CARDIOVASC SURG 1996;111:460-8)

Experimental models have established that lung injury occurs after total cardiopulmonary bypass (t-CPB). ^1,2 In a sheep model from our laboratory the pulmonary derangement includes an increase in left atrial (LA) plasma thromboxane level, pulmonary sequestration of white blood cells (WBCs) and platelets, transient pulmonary hypertension, and increased lung lymph flow and protein clearance. In contrast, these parameters are not much altered by partial CPB (p-CPB). ¹These specific manifestations of lung injury after t-CPB are eliminated or reduced by treating sheep with a thromboxane synthetase inhibitor before CPB. ³

The changes seen after t-CPB are consistent with a reperfusion lung injury. One of the potential instigators of post-CPB reperfusion injury is the neutrophil, ⁴ which may act as a mediator of acute inflammation. Gillinov and associates ² reported that a variety of different lung injury markers were ameliorated by the use of the neutrophil adhesion blocker NPC 15669 in a porcine t-CPB model. The present study examines the role of neutrophils in post-CPB lung injury by comparing sheep subjected to t-CPB with and without a neutrophil adhesion inhibitor administered before and during CPB. The effect of the drug in the absence of conditions known to promote lung injury was examined in sheep subjected to p-CPB, which has not been associated with acute lung injury.

Methods

The preparation was identical to that described in our previous investigations comparing pulmonary parameters after p-CPB and t-CPB. ^1,3 Briefly, Dorset-Rambouillet sheep (n = 21) weighing 25 to 31 kg (mean 28.5 kg) were anesthetized with intravenous -chloralose 80 mg/kg and urethane 500 mg/kg. Animals were intubated and the lungs mechanically ventilated (Harvard Apparatus, Millis, Mass.). Arterial blood gas and pH measurements were done during the procedure (pH blood gas analyzer 1306, Instruments Lab, Lexington, Mass.) and maintained within physiologic limits (pH = 7.35 to 7.45, oxygen tension >100 torr and <300 torr, carbon dioxide tension >35 torr and <45 torr). Systemic arterial pressure was monitored by percutaneous cannulation of the femoral artery.

We used the method described by Koike, Albertine, and Staub ⁵ 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 done and after systemic heparinization (400 u/kg) the right atrium (RA) and aorta were cannulated. As described by Bernard and colleagues ⁶ and Mitzner and Sylvester, ⁷ a 16F silicone-coated rubber Foley catheter with a 30 ml inflatable balloon was introduced into the LA to increase the left atrial pressure (LAP) after 30 minutes of reperfusion. This LAP increase elevated the hydrostatic pressure in the pulmonary venous bed and served to magnify capillary permeability changes. An 8F Millar catheter (Houston, Tex.) was inserted into the LA for pressure recording. The pulmonary artery (PA) was cannulated to monitor the PA pressure, and a flowmeter (model 12SB234, Transonic Systems Inc., Ithaca, N.Y.) was placed around the PA.

The extracorporeal circuit consisted of a roller pump (Cardiovascular Instrument Corp., Wakefield, Mass.) and bubble oxygenator (Bentley Bio-2, Baxter Healthcare Corp., Irvine, Calif.). 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 those prepared by the Committee on the Care and Use of Laboratory Animals of the Institute of Animal Resources, National Research Council (Department of Health and Human Services Publication No. 86-23, revised 1985). The Beth Israel Hospital animal research facility is fully accredited by the American Association for Accreditation of Laboratory Animal Care.

Study groups
The study consisted of three experimental groups. Two groups underwent t-CPB: one with NPC 15669 (N-[9H-|P[2,7-dimethylfluorenyl-9-methxy|P]carbonyl]-L-leucine), a neutrophil adhesion inhibitor, and one without. A third group was subjected to p-CPB with NPC 15669 treatment. In this model there was no period of aortic occlusion or associated myocardial ischemia, and hypothermia was not induced.

T-CPB with NPC 15669 (t-CPB + NPC; n = 7)
Before t-CPB an intravenous bolus dose of NPC 15669, 10 mg/kg, was delivered, followed by an infusion of 6 mg/kg per hour until the end of the experiment. T-CPB was established and the PA was clamped as ventilation was halted. Arterial flow was maintained at 80 to 100 ml/kg per minute and blood gas analysis was done to assess the adequacy of perfusion and gas exchange. Paired serial blood samples were taken from RA and LA before CPB. T-CPB continued for 90 minutes, at which time the PA occluder was removed, ventilation was restarted, and CPB discontinued. Blood samples were taken just after the ischemic period and every 15 minutes until the end of the experiment. Thirty minutes after cessation of CPB the 30 ml Foley catheter balloon was inflated for 30 minutes to increase the LAP by 10 to 15 mm Hg.

T-CPB without NPC 15669 (t-CPB/no NPC; n = 7)
This group underwent t-CPB as described in the previous section, but did not receive NPC 15669.

P-CPB with NPC 15669 (p-CPB + NPC; n = 7)
In this group animals received NPC 15669 according to the regimen described for the t-CPB + NPC group. Animals were then placed on CPB as previously described, but only one third of PA 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 and blood samples were taken, and at 30 minutes after CPB the LAP was raised as described for the other two groups.

Sample collection and measurements
Samples were collected from both atria after aspiration of 5 ml for dead space. Two milliliters of blood was placed in ice-cooled siliconized tubes containing 0.1 ml of 0.1 mol/L ethylenediaminetetraacetic acid and 0.05% (weight/volume) aspirin in a ratio of 2:1. Hematocrit concentration was measured with each sample to permit correction for hemodilution.

Thromboxane assay
Tubes that contained blood for thromboxane assay were immediately centrifuged at 4º C for 20 minutes at 2000 g. Plasma was separated and stored in polypropylene test tubes at -25º C until assayed. All thromboxane B₂ assays were done within 5 weeks of the experiment. Prior viability studies have shown no significant change in thromboxane levels for up to 8 weeks with this method of storage.

Thromboxane B₂ is a stable, inactive metabolite of the physiologically active but unstable thromboxane A₂, whose half-life is 30 seconds at 37º C in aqueous solution. ⁸ We measured thromboxane B₂ levels with use of a competitive binding radioimmunoassay. Anti–thromboxane B₂ antibody (rabbit), [¹²⁵I]thromboxane B₂ tracer, thromboxane B₂ standard, bovine serum albumin phosphate buffer, and magnetic goat anti-rabbit immunoglobulin G antibody were obtained from Advanced Magnetic Inc., Cambridge, Mass. Assays were done according to the manufacturer's instructions. All results were expressed as picograms per 0.1 ml.

Lymph collection and measurements
Lung lymph was collected three times over a 30-minute period: before CPB, after CPB, and after the LAP was raised. The fluid was drained into cooled tubes containing ethylenediaminetetraacetic acid and aspirin. We measured the quantity of the lymph in the tubes, and the protein concentration was determined by refractometry.

Plasma protein
Blood was centrifuged for 3 minutes at 2000 rpm and the plasma protein concentration was then determined with a refractometer (Atago Hand Refractometer, NSG Precision Cells Inc., Farmingdale, N.Y.).

Lymph protein clearance
Lung lymph protein clearance was calculated from the lymph flow rate (milliliters per 30 minutes) and the ratio of the lymph to plasma protein concentrations by the following formula: lymph flow x [lymph protein]/[plasma protein].

Platelet counts
After the blood was centrifuged, platelets were counted in the supernatant by a Coulter counter (model ZF, Coulter Electronic Inc., Hialeah, Fla.].

WBC counts
WBCs from whole blood samples were counted by means of phase microscopy.

Pulmonary vascular resistance
The pulmonary vascular resistance was calculated by the following formula: mean pulmonary arterial pressure - mean LAP/PA flow x 1332 = pulmonary vascular resistance in dynes · sec^-1 · cm^-5.

Water content
The water content of the lung tissue was determined by taking small lung biopsy samples (<1 gm) and placing them on tissue paper to absorb the blood. Samples were then weighed and desiccated for 3 days at 80º C at which time they were again weighed and the percentage of water in the tissue was calculated as follows:

Wet weight (in grams) - Dry weight (in grams) /Wet weight (in grams)

Biopsies were done before CPB and at the conclusion of reperfusion.

Statistical analysis.
Values are expressed as means plus or minus the standard error of the mean. Means were compared by a two-way analysis of variance. Scheffe's test for multiple sample comparisons was used to further evaluate the significant differences. Significance was determined at the p < 0.05 level.

Results

The mean RA/LA WBC concentrations are summarized in Fig. 1. With reperfusion, after 90 minutes of CPB, the t-CPB/no NPC group had a statistically significant increase in the RA/LA WBC ratio (from 1.07 ± 0.02 to 1.72 ± 0.05). Neither of the NPC 15669–treated groups had a significant change in the ratio (t-CPB/no NPC versus t-CPB + NPC and p-CPB + NPC; p < 0.001). Fifteen minutes later the ratio returned nearly to the baseline value in all three groups and remained stable between 1.0 and 1.2 until the end of the experiment. The slightly lower value in the p-CPB + NPC group did not differ to a statistically significant degree from values in the t-CPB groups.

View larger version (21K): [in this window] [in a new window]   Fig. 1. Mean ratio of RA to LA WBC concentration in sheep with no treatment before t-CPB (t-CPB/no NPC), NPC 15669 before t-CPB (t-CPB + NPC), and NPC 15669 before p-CPB (p-CPB + NPC). Samples were taken before CPB (time -90) and after separation from CPB (time 0) and then every 15 minutes until end of experiment. *p < 0.001; t-CPB/no NPC versus t-CPB + NPC.

View larger version (20K): [in this window] [in a new window]   Fig. 2. Mean ratio of RA to LA platelet concentration in sheep with no treatment before t-CPB (t-CPB/no NPC), NPC 15669 before t-CPB (t-CPB + NPC), and NPC 15669 before p-CPB (p-CPB + NPC). Samples were taken before CPB (time -90) and after separation from CPB (time 0) and then every 15 minutes until end of experiment. *p < 0.005; t-CPB/no NPC versus t-CPB + NPC.

View larger version (20K): [in this window] [in a new window]   Fig. 3. Pulmonary vascular resistance in sheep with no treatment before t-CPB (t-CPB/no NPC), NPC 15669 before t-CPB (t-CPB + NPC), and NPC 15669 before p-CPB (p-CPB + NPC). Calculations were done before CPB (time -90) and after separation from CPB (time 0) then every 15 minutes until 30 minutes after separation from CPB (at which time LA balloon inflation obviated physiologic pulmonary vascular resistance). *p < 0.01; t-CPB/no NPC versus t-CPB + NPC. p < 0.05; t-CPB/no NPC versus p-CPB + NPC.

View larger version (27K): [in this window] [in a new window]   Fig. 4. Lymph flow from lungs in sheep with no treatment before t-CPB (t-CPB/no NPC), NPC 15669 before t-CPB (t-CPB + NPC), and NPC 15669 before p-CPB (p-CPB + NPC). Lymph was collected over three 30-minute periods, one before CPB and two after CPB. First sample after CPB was before LA balloon inflation and second one after balloon was inflated. Results are mean percent increase from lymph flow measured before CPB. *p < 0.05; t-CPB/no NPC versus t-CPB + NPC. p < 0.05; t-CPB + NPC versus p-CPB + NPC.

View larger version (17K): [in this window] [in a new window]   Fig. 5. Lymph protein clearance from lung calculated from lymph flow and lymphatic protein concentration in sheep with no treatment before t-CPB (t-CPB/no NPC), NPC 15669 before t-CPB (t-CPB + NPC), and NPC 15669 before p-CPB (p-CPB + NPC). Protein clearance was calculated for each lymph flow collection period (before CPB, 30 minutes after CPB, and for 30 minutes after LA balloon inflation). *p < 0.05; t-CPB/no NPC versus p-CPB + NPC. p < 0.05; t-CPB + NPC versus p-CPB + NPC.

View larger version (24K): [in this window] [in a new window]   Fig. 6. Plasma thromboxane B2 concentration in RA and in LA in sheep with no treatment before t-CPB (t-CPB/no NPC), NPC 15669 before t-CPB (t-CPB + NPC), and NPC 15669 before p-CPB (p-CPB + NPC). Samples were taken before CPB (time -90) and after separation from CPB (time 0) and every 15 minutes until end of experiment. *p < 0.05; t-CPB/no NPC, LA, versus t-CPB/no NPC, RA.

Neutrophil function in inflammation requires activation and attachment to the endothelium before degranulation or migration. ⁹ NPC 15669 is an inhibitor to CD11/CD18 upregulation. ¹⁰ Neutrophil surface adherence receptors (CD11/CD18) have an important role in the interaction between neutrophils and endothelium. ¹¹ These neutrophil integrins are upregulated in response to an inflammatory process, promoting endothelial attachment and tissue migration. The blockade of neutrophil integrins impairs endothelial attachment and migration. Although the long-term toxicity of NPC 15669 eliminates its clinical use, less toxic drugs with a similar activity will become clinically available.

This study demonstrates the ability of the neutrophil adhesion inhibitor NPC 15669 to reduce markers of lung injury after t-CPB. Compared with findings in control animals, NPC 15669 administration before t-CPB eliminated the increase in LA thromboxane levels seen in sheep that were not treated. Furthermore, sheep treated with NPC 15669 before t-CPB had less sequestration of WBCs and platelets in the lung and no pulmonary vascular resistance increase. Pulmonary capillary permeability after t-CPB and NPC 15669 treatment was significantly decreased compared with that in untreated t-CPB animals, but the capillary permeability was not reduced to the levels seen in the p-CPB + NPC group.

With use of the same model as that used in this study we have previously demonstrated a variety of pulmonary derangements in sheep subjected to t-CPB, but not in those subjected to p-CPB. ¹ The results from the p-CPB + NPC group in this study were nearly identical to those seen previously after p-CPB alone, ¹ which suggests neither benefit nor adverse consequences of the drug itself in the absence of t-CPB. The amelioration of pulmonary injury after t-CPB provided by neutrophil adhesion blockade is similar to that provided by thromboxane synthase inhibition using dazmegrel. ³ The reduction in leukocyte and platelet sequestration and the reduction in pulmonary vasoconstriction were nearly identical in dazmegrel-treated animals subjected to t-CPB. As with NPC 15669, dazmegrel was not able to totally obviate an increase in capillary permeability, but clearly the elevation of LA serum thromboxane concentration is associated with lung injury after t-CPB. The elimination of a serum thromboxane concentration increase by NPC 15669, similar to the reduction seen in our prior study with dazmegrel, ³ may be the primary factor in its reducing post-CPB lung damage, but neutrophils may promote lung injury through a variety of mechanisms other than thromboxane release or production.

Neutrophils play an important role in the inflammatory response and in the damage that occurs with reperfusion. ^12,13 White cell depletion or neutrophil adhesion blockade before reperfusion of ischemic hearts decreases infarct size. ^14,15 With leukocyte-depleted blood reperfusion Breda and associates ¹⁶ reported improved myocardial function after ischemia, and Wilson and colleagues ¹⁷ reported reduced myocyte damage and better ventricular systolic function after global myocardial ischemia.

With respect to post-CPB lung injury, Johnson and associates ¹⁸ demonstrated that dogs treated with either indomethacin or a leukocyte filter before p-CPB had better arterial oxygenation after CPB than untreated dogs. Bando and associates ¹⁹ found that leukocyte depletion can reduce lung injury after t-CPB, and Cave and associates ²⁰ showed that neutrophils play an important role in pulmonary vasoconstriction after CPB. Our findings support those of these studies and particularly the work of Gillinov and colleagues, ² who subjected piglets to t-CPB with and without NPC 15669. They demonstrated a significant reduction in lung injury with the drug, manifest by a lack of pulmonary vasoconstriction, improved arterial oxygenation, absence of neutrophil sequestration, and less lung edema.

This study does not define the specific stimulus of the pulmonary inflammatory state and damage that occurs with total, but not partial, CPB. We did not use hypothermia, nor was there a period of cardiac ischemia. Simultaneously drawn RA and LA thromboxane levels localize at least a part of the inflammatory effect of CPB to the pulmonary circulation. The inflammation is consistent with postischemic reperfusion, and lung tissue ischemia may occur with t-CPB as ventilation and pulmonary arterial flow are stopped and only nonpulsatile bronchial arterial flow supplies oxygen to the lung tissue.

This study does confirm the critical role of neutrophils in lung damage after t-CPB. There are, however, mechanisms of lung damage other than neutrophil activation inasmuch as capillary leak after CPB is not totally prevented by NPC 15669. A better understanding of the stimulus of pulmonary damage after t-CPB is needed to more completely prevent this pathophysiologic condition.

References

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