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Ann Thorac Surg 1998;65:107-113
© 1998 The Society of Thoracic Surgeons

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Original Articles: Cardiovascular

Effects of Depletion of Leukocytes and Platelets on Cardiac Dysfunction After Cardiopulmonary Bypass

The Second Department of Surgery, Fukui Medical School, Fukui, Japan

Accepted for publication July 7, 1997.

Dr Chiba, The Second Department of Surgery, Fukui Medical School, 23-3 Shimoaizuki, Matsuoka-cho, Yoshida-gun, Fukui-ken, 910-11 Japan.

	Abstract

Top Abstract Introduction Patients and Methods Results Comment References

 
Background. This study examined the effects of the depletion of leukocytes and platelets from circulated blood on cardiac function after cardiopulmonary bypass in 37 patients who underwent coronary artery bypass grafting or aortic valve replacement.

Methods. Leukocytes and platelets were removed continuously using a blood cell separator, beginning immediately after the start of the operation and ending 1 hour after the release of the aortic cross-clamp in 19 patients (LPD group), but not in the remaining 18 patients (control group). Blood cell counts and levels of thromboxane B₂, 6-keto-prostaglandin F₁, leukocyte elastase, complements C3a and C4a, thrombin-antithrombin III complex, and D-dimer were determined periodically during and after the operation. The cardiac index, the difference between the central and peripheral core temperatures, and the doses of catecholamines and vasodilators required to support the circulation in the early postoperative period also were assessed.

Results. Leukocyte and platelet counts and levels of leukocyte elastase, thromboxane B₂, thromboxane₂/6-keto- prostaglandin F₁, thrombin-antithrombin III complex, and D-dimer were significantly lower in the LPD group than in the control group before and after the release of the aortic cross-clamp and during the perioperative period. There were no significant differences in the levels of 6-keto-prostaglandin F₁ or complements C3a and C4a between the two groups. The catecholamine dose was significantly lower in the LPD group than in the control group (1.1 ± 2.5 versus 5.0 ± 5.2 mg/kg, respectively). Fewer patients required the use of nitroprusside as a vasodilator in the LPD group than in the control group (1/19 versus 12/18, respectively).

Conclusions. The depletion of leukocytes and platelets using a blood cell separator prevents the deterioration of cardiac function after cardiac operations using cardiopulmonary bypass.

	Introduction

Top Abstract Introduction Patients and Methods Results Comment References

 
Cardiopulmonary bypass (CPB) induces systemic inflammatory responses that have been implicated in postoperative organ dysfunction [1][2][3]. Cardiopulmonary bypass activates complement factors, inducing the activation of leukocytes, which is believed to be primarily responsible for CPB-related inflammatory responses [4][5][6][7][8]. Cardiopulmonary bypass also causes changes in both the number and the function of platelets [9][10]. Prostacyclin and thromboxane A₂, prostanoids with antagonistic effects, regulate platelet aggregation. A CPB-induced alteration in the balance between these prostanoids also is believed to mediate myocardial damage [11][12]. Reperfusion with leukocyte-depleted blood has been found to prevent reperfusion injury, maintaining excellent myocardial function. We previously found that the depletion of both leukocytes and platelets from reperfused blood was more effective than the depletion of leukocytes alone for the prevention of reperfusion injury in an isolated heart-lung canine model of ischemia. We investigated the effects of continuous leukocyte and platelet depletion from circulated blood during CPB on postoperative cardiac function in patients who underwent elective cardiac operations with CPB.

	Patients and Methods

Top Abstract Introduction Patients and Methods Results Comment References

 
We studied 37 patients who underwent elective cardiac operations, including 21 patients who underwent coronary artery bypass grafting and 16 who underwent aortic valve replacement. This study was approved by our institutional review board, and informed consent was obtained from all patients. All patients were premedicated with atropine. General anesthesia was induced and maintained with a high dose of fentanyl (0.1 mg/kg of body weight), nitrous oxide, and vecuronium bromide. Before CPB, patients received intravenous infusions of heparin (300 U/kg of body weight) to achieve an activated clotting time of longer than 400 seconds.

Cardiopulmonary bypass was performed using a membrane oxygenator (Bentley UNIVOX; Baxter Healthcare Corp, Irvine, CA), a Sarns roller pump (9000 Perfusion System; Sarns, 3M Health Care Corp, Ann Arbor, MI), and nonpulsatile flow. The extracorporeal circuit and the membrane oxygenator were primed with 1,500 to 2,000 mL of a crystalloid solution containing 30 mg of heparin, and 1 to 2 units of packed red cells without leukocytes were added to the priming mixture when the patients had preoperative anemia. After the completion of a median sternotomy, the heart was cannulated with a venous cannula through the right atrium and with an aortic cannula. Cardiopulmonary bypass was initiated at a perfusion index of 2.0 to 2.5 L · min^-1 · m^-2 of body surface and mean arterial pressure was maintained at 50 to 70 mm Hg. Myocardial protection was provided by inducing systemic hypothermia (22°C by tympanic temperature) and by using pericardial cooling with ice slush. After an aortic cross-clamp was put into place, cardiac arrest was induced by injecting 500 mL of a crystalloid cardioplegic solution into the aortic root or directly into the left and right coronary arteries. Thereafter, 400 mL of cold blood cardioplegic solution was reinjected every 25 to 30 minutes. The myocardial temperature was maintained at 18°C at the ventricular septum throughout the period of cardiac arrest.

The 37 patients were divided randomly into two groups: 19 patients (11 undergoing coronary artery bypass grafting and 8 undergoing aortic valve replacement in whom leukocytes and platelets were separated from circulated blood (LPD group) and 18 patients (10 undergoing coronary artery bypass grafting and 8 undergoing aortic valve replacement in whom they were not (control group). There were no differences in age, sex, duration of CPB, duration of aortic cross-clamping, or lowest rectal temperature between the two groups (Table 1). In the LPD group, leukocytes and platelets were separated continuously using a Fenwall CS-3000 blood cell separator (Baxter Healthcare Corp) at a flow rate of 50 mL/min and a centrifugation speed of 1,000 rpm through a 12-gauge venovenous shunt cannula, which was inserted percutaneously into the femoral vein at the initiation of the operation and was kept in place until 1 hour after the release of the aortic cross-clamp. The separated leukocytes and platelets were returned transvenously to the body 6 hours after the release of the aortic cross-clamp.

All patients were ventilated mechanically using a Servo Ventilator 900C (Siemens-Elema AB, Solna, Sweden) at a tidal volume of 10 mL/kg and a respiratory rate of 12 breaths/min in the intensive care unit. Cardiac output was measured using a thermodilution catheter (Terumo Corp, Tokyo, Japan) and a cardiac output computer (Edwards SAT-2; Baxter Healthcare Corp). Catecholamines (dopamine or dobutamine), diuretics (furosemide), and vasodilators (nitroglycerin or nitroprusside) were injected to optimize blood pressure and diuresis, when necessary.

Collection of Samples
Venous blood samples were collected from a central venous catheter or from the arterial line of the oxygenator during CPB at 13 time points: (1) after the induction of general anesthesia, (2) 2 minutes before the initiation of CPB, (3) immediately after the initiation of CPB, (4) 2 minutes before the release of the aortic cross-clamp, (5) 2 minutes after the release of the cross-clamp, and (6) 15 minutes, (7) 30 minutes, (8) 1 hour, (9) 3 hours, (10) 6 hours, (11) 12 hours, (12) 24 hours, and (13) 48 hours after the release of the aortic cross-clamp. Blood cell counts were determined in samples containing ethylenediaminetetraacetic-2 sodium (EDTA-2Na) using a blood cell counter. Samples for assays of thromboxane B₂ (TXB₂), which is a stable metabolite of thromboxane A₂, and 6-keto-prostaglandin F₁ (6-keto-PGF₁), which is a stable metabolite of prostacyclin, were collected into tubes containing EDTA-2Na and indomethacin and centrifuged immediately at 1,500 rpm for 20 minutes at 4°C. The plasma was frozen at -70°C.

For assays of leukocyte elastase and complements C3a and C4a, samples were collected into tubes containing EDTA-2Na and centrifuged at 1,500 rpm for 5 minutes. The plasma was frozen at -70°C. The levels of TXB₂ and 6-keto-PGF₁ were determined using radioimmunoassays. The plasma concentration of leukocyte elastase was determined with elastase a₁ proteinase inhibitor by a two-site sandwich enzyme-linked immunosorbent assay that uses antisera against both elastase and elastase a₁ proteinase inhibitor. The plasma concentrations of complements C3a and C4a were determined by radioimmunoassays (two-antibody method). Determinations of TXB₂, 6-keto-PGF₁, leukocyte elastase, complements C3a and C4a, thrombin-antithrombin III complex, and D-dimer were performed at an outside laboratory (SRL, Tokyo, Japan).

Postoperative cardiac function was evaluated in terms of the doses of catecholamines (dopamine or dobutamine) and vasodilators (nitroglycerin or nitroprusside) required during the first 24 hours after operation. The cardiac index and the difference between the central and peripheral core temperatures, as measured by the Coretemp CTM 204 (Terumo Corp), also were determined.

Statistical Analysis
Results are expressed as the mean value plus or minus the standard deviation. Parametric data were analyzed by the unpaired Student’s t test. Nonparametric data were analyzed by the Mann-Whitney U test. The data were computerized and analyzed with the Statistical Package for the Social Sciences (SPSS Inc, Chicago, IL), and a p value of less than 0.05 was considered to represent statistical significance.

	Results

Top Abstract Introduction Patients and Methods Results Comment References

 
The total duration of blood cell separation was 296 ± 81 minutes. Separated leukocytes accounted for 3.4 ± 2.1 x 10¹⁰, which is equivalent to 119% ± 46% of the estimated number of leukocytes in circulated blood, and separated platelets accounted for 2.8 ± 2.1 x 10¹¹, which is equivalent to 27% ± 10% of the estimated number of platelets in circulated blood (Table 1).

Leukocyte Counts
The leukocyte count fell after the initiation of CPB and returned to the pre-CPB value 60 minutes after the release of the cross-clamp. The number of leukocytes then increased gradually, for up to 48 hours, after the release of the cross-clamp in the control group. In the LPD group, the number of leukocytes increased for 6 hours after the release of the cross-clamp and then began to decrease. The leukocyte count was significantly lower in the LPD group than in the control group from 2 minutes before the release of the cross-clamp to 30 minutes after the release of the clamp (Fig 1).

View larger version (20K): [in this window] [in a new window]   Leukocyte counts and platelet counts before, during, and after cardiopulmonary bypass (CPB) in the LPD group (closed circles) and the control group (open circles). (WBC = white blood cell; *p < 0.05 versus the LPD group; ***p < 0.005 versus the LPD group.)

Leukocyte Elastase
The plasma concentration of leukocyte elastase increased gradually after the initiation of the operation, peaking at 1 hour after the release of the cross-clamp and falling to the preoperative value at 48 hours. The concentration of leukocyte elastase was significantly lower in the LPD group than in the control group from 2 minutes before the release of the cross-clamp to 6 hours after the release of the clamp (Fig 2).

View larger version (16K): [in this window] [in a new window]   The plasma concentration of leukocyte elastase before, during, and after cardiopulmonary bypass (CPB) in the LPD group (closed circles) and the control group (open circles). (*p < 0.05 versus the LPD group.)

View this table: [in this window] [in a new window]   Plasma Concentrations of Thromboxane B2 and 6-Keto-Prostaglandin F1, and the Ratio of Thromboxane B2 to 6-Keto-Prostaglandin F1 Before, During, and After Cardiopulmonary Bypass in the Two Study Groups1

6-Keto-Prostaglandin F₁

1

Thromboxane B₂/6-Keto-Prostaglandin F₁ Ratio
The ratio of TXB₂ to 6-keto-PGF₁ increased after the initiation of the operation. The TXB₂/6-keto-PGF₁ ratio ranged from 1.0 to 1.5 in the LPD group but increased to more than 2.0 in the control group. The TXB₂/6-keto-PGF₁ ratio was significantly lower in the LPD group than in the control group after the release of the cross-clamp (Table 2).

Complement
Plasma concentrations of complements C3a and C4a increased after the initiation of CPB, peaking 1 hour after the release of the cross-clamp. Complement C3a decreased to the pre-CPB value by 12 hours, but complement C4a did not fall to the pre-CPB value even 24 hours after the release of the cross-clamp. There were no significant differences in C3a and C4a concentrations between the two study groups (Table 3).

Thrombin-Antithrombin III Complex and -Dimer

Vasodilators
The dose of nitroglycerin required 1 and 3 hours after operation was significantly lower in the LPD group than in the control group (Table 6). In addition, fewer patients in the LPD group (1/19) than in the control group (12/18) required the additional use of nitroprusside for the first 24 hours after operation.

	Comment

Top Abstract Introduction Patients and Methods Results Comment References

 
Our technique has three characteristics: (1) it can remove not only leukocytes, but also platelets from circulated blood; (2) it can remove a great number of leukocytes and platelets, because the duration of removal is long, extending from the initiation of operation to 1 hour after the release of the aortic cross-clamp; and (3) the leukocyte- and platelet-depleted blood is circulated not only through the heart, but also throughout the whole body during CPB.

Cardiopulmonary bypass induces systemic inflammatory reactions [1][2][3] that have been implicated in postoperative organ dysfunction. It activates complement factors, inducing leukocyte activation, which has been implicated as a possible source of postoperative myocardial damage [4][5][6][7][8] in patients who undergo cardiac operations using CPB. Leukocyte depletion has been found to reduce myocardial dysfunction in patients with global ischemia [13][14] and after heart-lung preservation [15]. The interaction among leukocytes, platelets, and endothelial cells [16][17][18] also has received attention in patients with multiple organ dysfunction after CPB. We previously found that the depletion of both leukocytes and platelets resulted in better preservation of cardiac and respiratory function, as indicated by the cardiac index, arterial oxygen tension, alveolar-arterial oxygen tension gradient, and respiratory index, than the depletion of leukocytes alone in an isolated heart-lung canine model of ischemia. Platelets are activated during CPB as a result of the contact of the blood with the extracorporeal circuit. Activated platelets produce aggregate and stimulate thromboxane synthesis and release and the release of lysosomal granule constituents [19][20]. Platelets generate thromboxane A₂, which is a potent vasoconstrictor and a proaggregatory agent. Its actions are balanced by the generation of prostacyclin, a potent vasodilator and an antiaggregatory agent, by blood vessels. A state of equilibrium between thromboxane A₂ and prostaglandin I₂ is essential for the regulation of vascular tone and platelet homeostasis. An imbalance in the distribution of these two prostanoids induced by platelet activation is followed by platelet aggregation and the formation of microemboli in the systemic circulation [21]. Thus, platelet activation is associated with a widespread systemic inflammatory response involving neutrophils and numerous circulating inflammatory mediators. This response can damage various organs.

Reperfusion injury has been thought to be a main cause of cardiac dysfunction after cardiac operations. It occurs just after the aortic cross-clamp is released and blood is reperfused to the ischemic myocardium. It is not known whether reperfusion injury is a risk only at the moment of release of the cross-clamp. In our laboratory, free radicals were measured by the spin-trapping method using electron spin resonance in a global ischemia-reperfusion model of the rat liver. We found that free radicals increased gradually after the initiation of reperfusion, peaking at 10 minutes. These findings are similar to the results of a study by Davies and colleagues [22]. In the present study, the plasma concentrations of complements, leukocyte elastase, TXB₂, TXB₂/6-keto-PGF₁, thrombin-antithrombin III complex, and D-dimer increased about 1 hour after the release of the cross-clamp in the control group. These data suggest that leukocyte- and platelet-depleted blood should be circulated for at least 1 hour after the release of the cross-clamp.

Use of the blood cell separator made it possible to remove leukocytes and platelets during operation and to reperfuse the leukocyte- and platelet-depleted blood continuously after the release of the cross-clamp. In the present study, 3.4 ± 2.1 x 10¹¹ leukocytes and 2.8 ± 1.2 x 10¹¹ platelets in circulated blood were removed. This level of removal is greater than that reported in previous studies [23][24]. Accordingly, plasma concentrations of leukocyte elastase, TXB₂, TXB₂/6-keto-PGF₁, thrombin-antithrombin III complex, and D-dimer were reduced significantly during the initial 6-hour period after the release of the cross-clamp. There have been some previous studies of cardioplegia with attenuation of reperfusion injury by leukocyte-depleted blood [25]. These studies focused on the prevention of cardiac dysfunction resulting from ischemia-reperfusion injury of the heart. However, an inflammatory reaction resulting from ischemia-reperfusion injury and CPB itself occurs not just in the heart but in multiple organs, including the lung. Our technique makes it possible to circulate leukocyte- and platelet-depleted blood to the whole body during CPB.

We previously reported that continuous removal of leukocytes and platelets using a blood cell separator prevented the postoperative deterioration of respiratory function after cardiac operations using CPB [26]. In the present study, we evaluated the effects of this technique on postoperative cardiac function in patients who underwent cardiac operations using CPB. Most control patients required a higher dose of catecholamines to maintain adequate cardiac output and the use of the stronger vasodilator to alleviate the load to the heart and improve the peripheral circulation. Therefore, there were no significant differences in the cardiac index values or the central and peripheral core temperatures between the two study groups.

In summary, the depletion of leukocytes and platelets using a blood cell separator throughout CPB suppressed the activation of leukocytes and platelets and the release of reactive substances from these cells, leading to reductions in the dose of catecholamines and vasodilators required to support cardiac function for the first 24 hours after cardiac operations. These results suggest that our technique for the removal of leukocytes and platelets prevents the deterioration of cardiac function after cardiac operations using CPB.

	References

Top Abstract Introduction Patients and Methods Results Comment References

 

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This Article Abstract Full Text (PDF) 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): Yukio Chiba Ryusuke Muraoka Akio Ihaya Katsuhiko Matsuyama Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Chiba, Y. Articles by Matsuyama, K. Search for Related Content PubMed PubMed Citation Articles by Chiba, Y. Articles by Matsuyama, K.