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Ann Thorac Surg 2004;77:956-961
© 2004 The Society of Thoracic Surgeons

Original article: cardiovascular

Neutrophil depletion reduces myocardial reperfusion morbidity

George M. Palatianos, MDa*, Gilbert Balentine, ECCPa, Emmanuel G. Papadakis, MDa, Constantine D. Triantafillou, MDa, Mary I. Vassili, MDa, Angela Lidoriki, ECCPa, Athanasios Dinopoulos, ECCPa, George M. Astras, MDa

a Third Department of Cardiac Surgery, Onassis Cardiac Surgery Center, Athens, Greece

* Address reprint requests to Dr Palatianos, Onassis Cardiac Surgery Center, 356 Sygrou Ave, Athens 176 74, Greece
e-mail: palatianos{at}otenet.gr

Presented at the Poster Session of the Thirty-sixth Annual Meeting of The Society of Thoracic Surgeons, Fort Lauderdale, FL, Jan 31–Feb 2, 2000. *Dr Balentine passed away on Dec 14, 2001.


   Abstract
Top
 Abstract
Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 
BACKGROUND: We tested the hypothesis that depletion of neutrophil leukocytes from the cardioplegic and the initial myocardial reperfusion perfusates reduces clinical indices of reperfusion injury in patients undergoing elective coronary artery bypass.

METHODS: We studied 160 consecutive patients who underwent standard coronary revascularization with cardiopulmonary bypass. Patients with recent myocardial infarction or coronary angioplasty were excluded. Cold blood cardioplegia was used. Just before aortic unclamping, the hearts were perfused retrograde with 250 mL of normothermic cardioplegic solution and 750 mL of blood (pump perfusate). Patients were randomly assigned to two groups. In 80 patients (treated), neutrophils and platelets were removed from all cardiac perfusate during aortic crossclamping with leukocyte filtration. In the remaining 80 patients (control group), leukocyte filtration was not used.

RESULTS: There was no significant difference between groups in age, sex, severity of disease, and number of bypass grafts implanted. Treated patients showed lower prevalence of low cardiac index and reperfusion ventricular fibrillation and lower levels of creatinine kinase MB isoenzyme and troponin I early postoperatively (p < 0.05).

CONCLUSIONS: Neutrophil-filtered blood cardioplegia/reperfusion significantly reduced clinical and biochemical indices of myocardial reperfusion injury after elective coronary revascularization with cardiopulmonary bypass.


   Introduction
Top
 Abstract
 Introduction
Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Postoperative myocardial dysfunction, early after open heart operations with induced cardiac arrest, is commonly the result of myocardial damage occurring during the initial phase of postischemic myocardial reperfusion [1, 2]. This damage, sustained by the microvascular coronary endothelium and the myocytes, is characterized by increased capillary permeability and diffuse neutrophil infiltration [3] and is commonly manifested clinically as reduced cardiac output or as ventricular ectopy requiring use of inotropic or antiarrythmic agents [4]. The damage is closely related to the length of myocardial ischemic time, and is usually reflecting suboptimal myocardial cardioplegic preservation [1].

Reperfusion injury is produced by oxygen free radicals and proteolytic enzymes brought to the reperfused tissue by activated neutrophil leukocytes [5–8]. Neutrophil activation occurs during cardiopulmonary bypass [9–12] and early after percutaneous transluminal coronary angioplasty [13]. The neutrophils have been implicated in mediating postischemic myocardial damage by several studies demonstrating that neutrophil-depleted postischemic reperfusion reduces infarct size and the extend of the no-reflow zone [14–17].

In an effort to prevent or ameliorate myocardial reperfusion injury, we tested the hypothesis that removal of activated neutrophils from the cardioplegic perfusate and from the reperfusate at the initial phase of myocardial reperfusion will result in less reperfusion-related myocardial damage and better myocardial performance after coronary revascularization operations.


   Material and methods
Top
 Abstract
 Introduction
 Material and methods
Results
 Comment
 Acknowledgments
 References
 
Patient groups
We studied 160 consecutive patients without a recent (< 30 days) myocardial infarction or a recent percutaneous transluminal coronary angioplasty who underwent first time, elective, standard coronary artery bypass with cardiopulmonary bypass by our department. All patients had severe coronary artery disease confirmed preoperatively with cardiac catheterization and coronary angiography.

This was a prospective, randomized study. The patients were divided in two groups on the basis of their hospital number: Patients with an odd hospital number were considered controls. None of them received any kind of leukocyte filtration during the operation. In patients with an even hospital number, all the blood used for cardioplegic perfusate and for controlled myocardial reperfusion before aortic cross-clamp removal, was filtered through a leukocyte removal filter (Purecell RC400; Pall, East Hills, NY). Patients with severe comorbidity, patients who underwent concomitant procedures, and patients operated without cardioplegic arrest were excluded from the study. Complete blood counts were obtained using a Coulter HmX Hematology Analyzer (Coulter, Miami, FL). An informed consent was signed preoperatively by each patient.

Anesthesia protocol
The premedication protocol included lorazepam 2.5 mg orally the night before surgery, morphine sulfate 0.1 to 0.75 mg/kg intramuscularly 1 hour before surgery, and promethazine 25 to 50 mg intramuscularly 30 minutes before anesthesia induction. Anesthesia was induced with etomidate 0.2 to 0.3 mg/kg intravenous bolus, midazolam 1 to 2 mg, fentanyl 10 to 15 µg/kg, and pancuronium or vecuronium 0.15 mg/kg intravenously. Maintainance of anesthesia was carried out with additional doses of fentanyl up to a maximum total dose of 50 µg/kg, isoflurane or seroflurane, and additional doses of neuromuscular blocking agents as needed. Cardiac output was measured with the thermodilution technique using an SC 9000 monitor (Siemens, Erlangen, Germany).

Intraoperative management and extracorporeal circulation
The patients were operated on with cardiopulmonary bypass (CPB) at 33°C (esophageal temperature) using a hollow fiber membrane oxygenator (Quadrox; Jostra, Hirrlingen, Germany) and an arterial filter. All patients were treated with heparin before cannulation for CPB. The activated coagulation time (ACT) was maintained longer than 480 s throughout extracorporeal perfusion. Pump flow was maintained in the range 2.0 to 2.5 L per minute per m2 of body surface area, and the arterial blood pressure was kept between 50 and 75 mm Hg. The aorta was cross-clamped 3 to 5 minutes after initiation of CPB. In this length of time, enough blood was filtered through the leukocyte filter and was collected for induction cardioplegia in the treated group. Additional amounts of blood were filtered and collected between cardioplegia boluses for maintenance cardioplegia as needed and for controlled reperfusion. After the aorta was unclamped, the return of myocardial activity was recorded. If ventricular fibrillation (VF) appeared (reperfusion VF), a xylocaine 100 mg bolus was administered in the extracorporeal circuit. Internal defibrillation with 10 to 30 J was employed if VF persisted for more than 30 seconds after the xylocaine bolus. After discontinuation of extracorporeal circulation, protamine sulfate was given for neutralization of heparin. Low cardiac index (less than 2.2 L · min-1 · m-2) and hypotension (arterial systolic blood pressure < 100 mm Hg) persisting despite adequate volume administration were treated with intravenous infusion of inotropic agents.

Cardioplegia and controlled reperfusion protocol
Induced global myocardial ischemia and cardioprotection with hyperkalemic blood cardioplegia were used during construction of distal coronary anastomoses. The cardioplegic solution was prepared using blood and a commercial cardioplegic solution (Cardioplegia Infusion; Martindale, Romford, UK) at 4°C, in a 4:1 ratio, in a standard blood cardioplegia setting (Avecor, Myotherm XP 4:1; Medtronic, Minneapolis, MN), and it was administered in each patient retrograde through the coronary sinus and antegrade through the ascending aorta. The myocardial temperature was monitored with an 18-mm, 22-gauge Mon-a-therm myocardial temperature probe (Mallinckrodt Medical, St. Louis, MO) placed in the anterior interventricular septum. During aortic occlusion, myocardial temperature was kept between 10°C and 18°C with repeated infusions of cardioplegic solution and topical ice slush solution. In the treated patients, a leukocyte removal filter (Purecell RC400; Pall, East Hills, NY) was placed in a line draining blood from the recirculation line of the oxygenator for preparation of the cardioplegic solution (Fig 1). This leukocyte filter retains neutrophils in a layered wad of proprietary surface-modified polyester fibers. The filter was custom-modified to fit appropriately in the plastic tubing. In case of filter blockage, the filter was changed between cardioplegic boluses. After completion of all distal coronary anastomoses and before removal of the aortic cross-clamp, all patients received controlled myocardial reperfusion in a retrograde fashion. The reperfusion perfusate (1 L) consisted of 250 mL of warm blood cardioplegic solution ("hot shot") that was chased by 750 mL of pump blood ("chase"). The reperfusion perfusate was leukocyte-filtered for the treated patients only.



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  		Fig 1. Schematic presentation of leukocyte-filtered cardioplegia/reperfusion circuit. (AF = arterial filter; AL = arterial line; BC = blood collection; BT = bubble trap; CA = cardioplegia line, HC = high concentration cardioplegic solution; HE = heat exchanger; LC = low concentration cardioplegic solution; LF = leukocyte filter; OX = oxygenator; PC = pump circuit; PS = pump; RL = recirculation line; VL = venous line; VR = venous reservoir.)

 
Postoperative management
After surgery, the patients were transferred intubated to the intensive care unit where a standard postoperative management took place. The electrocardiogram, the arterial and central venous pressures, and the mixed venous oxygen saturation were continuously monitored. Inotropic agents (dobutamine or epinephrine, or both) were infused intravenously when needed (systolic blood pressure < 100 mm Hg not responding to volume administration, cardiac index < 2.2 L · min-1 · m-2). When necessary, vasodilators (nitroglycerin, nitroprusside) were administered intravenously to control hypertension, xylocaine to control ventricular ectopy, and furosemide to enhance diuresis. Red blood cell transfusions took place when needed to keep the hematocrit above 26%.

Appearance of ventricular arrhythmias, low cardiac output, or any complication including the need for inotropic or antiarrhythmic agents or the need for pacing were recorded.

Indexes of myocardial damage
Myocardial damage was assessed with measurements of cardiac enzymes. In 20 patients (the first 10 of each group) without electrocardiographic changes indicative of recent infarction, creatinine kinase MB bands and cardiac troponin I levels were measured with heterogeneous immunoassay methods (MMB and CTNI, respectively; Dimension RxL; Dade Behring, Newark, DE) preoperatively and at 6 and 12 hours postoperatively. Appearance of new Q waves in the postoperative electrocardiogram with or without the presence of elevated values of myocardial enzymes (creatinine kinase MB and cardiac troponin I, normal values < 5 ng/mL and < 0.6 ng/mL, respectively) were recorded as indicative of perioperative or postoperative myocardial infarction.

Statistical analysis
Values are presented as mean ± standard deviation. Comparison between the two groups of patients was carried out with Student's t test for evaluation of mean values difference. The Fisher exact test ({chi}2) with Yate's correction was used for comparison of proportion between groups. Statistical significance was determined for p values less than 0.05.


   Results
Top
 Abstract
 Introduction
 Material and methods
 Results
Comment
 Acknowledgments
 References
 
There was no difference in patient characteristics between the two groups (Table 1). There were 2.8 ± 0.8 coronary artery bypass grafts constructed per patient in the control group versus 2.7 ± 1.0 per patient in the treated group (not significant [NS]). There were no significant differences in the procedures performed between groups. Internal mammary artery grafts were used in 79 (98.8%) of the controls and in all treated patients. Aortic cross-clamp times and cardiopulmonary bypass times were 53 ± 19 minutes and 88 ± 28 minutes in the control group, respectively, and 52 ± 20 minutes and 87 ± 30 minutes in the treated group, respectively (NS). In the treated group, the cardioplegic and reperfusion solutions were effectively neutrophil- and platelet-depleted by filtration (Table 2). The use of leukocyte filtration did not affect the systemic white blood cell counts in the treated patients.


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  		Table 1. Patient Characteristics

 

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  		Table 2. Effect of Filtration on Cellular Blood Elements

 
Operative mortality (30-day) was 1 patient (0.6%) of the control group who died of cardiac failure the third postoperative day. Intraoperatively, treated-group patients had significantly less reperfusion VF (3 of 80) and needed less electrical defibrillations (0 of 80) than control patients (17 of 80 and 12 of 80, respectively; p < 0.00001). Also, fewer patients of the treated group needed inotropic support (2 of 80) and antiarrhythmics (0 of 80) than controls (12 of 80 and 22 of 80, respectively; p < 0.00001). Postoperative complications appear in Table 3. In 1 patient of the treated group, postpericardiotomy syndrome developed with a mild pericardial effusion and pericardial rub on the fifth postoperative day. He was treated effectively with nonsteroidal antiinflammatory medication. There were no renal, neurologic, or gastrointestinal complications, wound infections, or other septic complications.


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  		Table 3. Postoperative Complications

 
Preoperative creatinine kinase MB bands and cardiac troponin I levels were normal in both groups. Postoperatively, values of these enzymes indicative of myocardial damage were lower among treated patients than among controls (p < 0.05; Fig 2).



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  		Fig 2. Myocardial enzyme levels (mean ± SD) at 6 and 12 hours postoperatively (postop). (A) Levels of creatinine kinase-MB (CPK-MB). (B) Levels of cardiac troponin I. *p less than 0.05. Open bars = treated group; shaded bars = control group.

 

   Comment
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
Acknowledgments
 References
 
Our study addressed both clinical and biochemical indexes of myocardial damage to evaluate the effectiveness of this cardioplegia/reperfusion protocol. Reperfusion VF is a sensitive index of myocardial reperfusion injury. It often appears at early reperfusion during open-heart operations, soon after removal of the aortic cross-clamp, after thrombolysis of acute myocardial infarction and after coronary artery dilatation with percutaneous coronary angioplasty. Although it is usually either self-limited or readily responsive to defibrillation, reperfusion VF presents a dangerous side effect of reperfusion. Furthermore, postoperative ventricular ectopy in the absence of ischemia or electrolytic disturbance may indicate intraoperative myocardial damage [18]. Also, the need for inotropic support after open-heart operations is often indicative of myocardial damage from inadequate intraoperative myocardial preservation resulting in low cardiac output early postoperatively [19]. Creatinine kinase MB bands and troponin I are highly sensitive indicators of myocardial necrosis [20]. The clinical and biochemical indexes of myocardial injury were lower among patients who received neutrophil-depleted cardioprotection, suggesting a lower degree of myocardial damage during induced myocardial ischemia and reperfusion.

It is generally considered that the activated neutrophil is the main cause of reperfusion injury. Neutrophils are activated during CPB from the activated complement and the kallikrein of the contact system [12, 21] within the frame of a generalized inflammatory reaction (systemic inflammatory response syndrome) [11, 22]. At the initial phase of postischemic reperfusion, activated neutrophils decelerate during passage through the microvascular system and roll on the vascular endothelium under the regulation of special transmembranous glycoproteins, the selectins. Rolling neutrophils may adhere firmly on the microvascular endothelium by the effect of special adhesion molecules, the integrins [12, 21]. Activated neutrophils release proteolytic enzymes, toxic oxygen metabolites, and various other cytotoxic and vasoactive substances causing local endothelial damage and systemic inflammatory effects. Adhered neutrophils are attracted by chemotactic stimuli, may transmigrate through the endothelium in neighboring myocardium, and cause myocardial injury [12, 21].

The filter used for neutrodepletion in this study was effective in retaining neutrophils and platelets (Table 2). Activated platelets play an important role in neutrophil activation and in reperfusion injury [21]. The cardioplegic solution we used was practically devoid of neutrophils and platelets. It has been shown that platelet retention in leukocyte filters is essential for efficient neutrophil depletion [23]. The formation of platelet-neutrophil aggregates during open-heart operations as a result of platelet and neutrophil activation [24] may contribute to the removal of activated platelets along with neutrophils during leukocyte filtration. It is known that activated platelets secrete substances (ie, thromboxane A2, serotonin, adenosine diphosphate) that participate in the generation of the systemic inflammatory reaction and may produce harmful local effects [11, 25]. It has been shown that during postischemic myocardial reperfusion, rabbit hearts release platelet-activating factor (PAF), a potent mediator of inflammation, and that PAF activates platelets and neutrophils and contributes significantly in reperfusion injury [26, 27]. Indeed, administration of PAF-aldehyde, a natural PAF- inhibitor, markedly reduced reperfusion injury [27]. It has been shown that neutrophils and platelets are synergistic in the development of reperfusion myocardial dysfunction [28]. Removal of activated platelets from the cardioplegic and reperfusion solutions may be contributing to the protective effect provided by neutrophil depletion [29].

Several experimental studies have shown a cardioprotective effect of leukocyte depleted postischemic myocardial perfusate [30–33]. In our study, neutrophil-depleted blood cardioplegia and myocardial reperfusion were effective in reducing clinical and biochemical indexes of reperfusion injury, namely, the incidence of reperfusion VF and the need for postoperative use of inotropic or antiarrhythmic agents. We have observed this in our practice since 1992 [34]. The results have been mostly impressive among patients with low (< 40%) preoperative ejection fraction and also in cases requiring prolonged aortic cross-clamp times. Our findings are in accord with the reported beneficial cardioprotective effects of leukocyte-depleted cardioplegia to hearts with impaired contractility [35]. Similar cardioprotective effects have been reported with leukocyte-depleted cardioplegia/reperfusion [36] and with leukodepletion limited to reperfusion of the postischemic myocardium [37, 38]. However, leukocyte-depletion limited to terminal cardioplegia has been reported to have beneficial cardioprotective effects in emergency coronary artery revascularization surgery but not on elective cases [39]. Using neutrophil depletion for both cardioplegic and reperfusion solutions, we demonstrated beneficial effects on our elective coronary artery bypass patients. Since intermittent administration of cardioplegic solution represents an ischemia-reperfusion setting, utilization of leukocyte-filtered blood for all cardioplegia and initial myocardial reperfusion had a significant cardioprotective effect.

The improved performance of hearts and the lower levels of cardiac enzymes early after surgery in patients for whom neutrophil and platelet-depleted blood cardioplegia and controlled reperfusion were used suggest a beneficial myocardial effect of neutrophil and platelet depletion. Perhaps, neutrophil-depleted or neutrophil and platelet-depleted postischemic reperfusion of tissues prevents or ameliorates reperfusion injury. Removal of the activated neutrophils at the initial phase of reperfusion allows the reintroduction of aerobic metabolism to the vulnerable myocardium without the injurious factors that usually produce endothelial and myocardial damage during this phase. Maybe, once the aerobic metabolism is reestablished in the vulnerable endothelium and myocardium by the neutrophil-free reperfusate without causing severe myocardial damage, the unharmed endothelium and myocardium can subsequently face the circulating toxic agents without sustaining significant injury.

In conclusion, neutrophil- and platelet-depleted blood cardioplegia and controlled reperfusion is a superior cardioprotective technique, easily implemented, and effective in preserving myocardial performance after coronary artery bypass operations. Its beneficial effect is probably related to prevention or amelioration of the reperfusion myocardial injury.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
References
 
The authors wish to thank Dr Dimitrios Vassilopoulos for the statistical analysis.


   References
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 

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Ann. Thorac. Surg., April 1, 2005; 79(4): 1467 - 1467.
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B. S. Coller
Leukocytosis and Ischemic Vascular Disease Morbidity and Mortality: Is It Time to Intervene?
Arterioscler Thromb Vasc Biol, April 1, 2005; 25(4): 658 - 670.
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