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Ann Thorac Surg 2004;78:1339-1344
© 2004 The Society of Thoracic Surgeons

Original article: cardiovascular

Clinical Effectiveness of Leukocyte Filtration During Cardiopulmonary Bypass in Patients with Chronic Obstructive Pulmonary Disease

Theodoros E. Karaiskos, MDa, George M. Palatianos, MDa,*, Constantine D. Triantafillou, MDa, George H. Kantidakis, MDa, George M. Astras, MDa, Emmanuel G. Papadakis, MD, Mary I. Vassili, MD

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

Accepted for publication April 12, 2004.

* Address reprint requests to Dr Palatianos, Onassis Cardiac Surgery Center, 356 Sygrou Ave, 17674 Athens, Greece
palatianos{at}otenet.gr


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Comment
 Acknowledgments
 References
 
BACKGROUND: We tested the hypothesis that leukocyte filtration during pulmonary reperfusion preserves pulmonary function and results in improved oxygenation after cardiopulmonary bypass (CPB) in patients with chronic obstructive pulmonary disease (COPD).

METHODS: In a prospective, randomized study, the treatment group consisted of 20 patients with COPD from consecutive open-heart procedures. A primed leukocyte filter was connected to the arterial line downstream of the standard arterial filter but was excluded from circulation. Circulated blood was directed through the leukocyte filter approximately 10 minutes before aortic cross-clamp removal and at early reperfusion for up to 30 minutes. These patients were compared to 20 additional COPD patients (controls) on whom systemic leukocyte filtration was not used during open-heart surgery.

RESULTS: There was no significant difference in gender, age, left ventricular ejection fraction, type of procedure, aortic cross-clamp time, perfusion time, preoperative FEV1 and preoperative respiratory index (PaO2/FiO2 ratio) between treatment and control groups. The respiratory index changed in the treatment group by +9.8% of baseline after completion of CPB, by –14.2% upon arrival in the intensive care unit (ICU), and by –19.6% 12 hours later, whereas in the control group, it changed by –14.5% (p < 0.05), –27.7%, and –24%, respectively. Leukocyte-depleted patients required shorter intubation time (20.4 ± 16.1 hours), ICU stay (46.2 ± 40.1 hours) and length of hospitalization (8.3 ± 2.8 days) than controls (29.5 ± 21.9 hours, p < 0.05; 75.5 ± 34.9 hours, p < 0.005; and 10.4 ± 3.5 days, p < 0.05, respectively). Surgical (30-day) mortality was zero in both groups.

CONCLUSIONS: In COPD patients having CPB, systemic leukocyte depletion at early reperfusion was associated with better oxygenation, shorter intubation time, and shorter ICU and hospital stays. Leukocyte filtration during CPB most likely preserves pulmonary function by ameliorating pulmonary reperfusion injury.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Comment
 Acknowledgments
 References
 
Cardiopulmonary bypass (CPB) affects lung function by inducing a systemic inflammatory response in which activated neutrophils play an important causative role in the development of postischemic reperfusion injury [1]. During CPB, the lungs are relatively ischemic due to the direction of the venous blood return through the extracorporeal perfusion circuit. There is experimental evidence that the flow through the bronchial arteries is not sufficient to prevent lung ischemia during CPB [2]. Neutrophils are activated during CPB and adhere to the pulmonary endothelium at the early phase of lung reperfusion after the aortic cross-clamp is removed [1, 3]. Activated leukocytes release toxic agents that can cause lung injury resulting in respiratory gas exchange impairment and reduced arterial oxygenation [3].

The concept of leukocyte filtration in the extracorporeal circuits during open-heart operations has been tested on the prevention of development or the amelioration of severity of lung reperfusion injury. Although satisfactory results with leukocyte filtration have been reported by some authors [4, 5], others place the effectiveness of these filters in doubt [6–10].

Chronic obstructive pulmonary disease (COPD) is a risk factor for prolonged intubation and early postoperative mortality in patients undergoing open heart surgery [11]. COPD patients have reduced pulmonary function reserves. Therefore, any injury on their lungs could have a demonstrable clinical effect after CPB [12].

This prospective study focuses on the effects of leukocyte filtration during the early phase of reperfusion during open-heart procedures in COPD patients. We tested the hypothesis that removal of activated leukocytes from the systemic circulation would result in improved postoperative lung function, decreased intubation time, and shorter postoperative hospitalization in this patient population.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Comment
 Acknowledgments
 References
 
Patients
Between May 1999 and February 2000, 40 patients with COPD underwent open heart surgery with CPB. Patient characteristics are shown in Table 1. All patients had cardiac catheterization and coronary angiography preoperatively. Pulmonary function studies and clinical assessments were performed on each patient preoperatively. The patients were randomly assigned to two groups. Twenty patients chosen by simple random sampling received a leukocyte-depleting filter in the extracorporeal circuit and made up the leukocyte depletion group (group LD). In the remaining patients (group C [controls], n = 20), leukocyte filters were not used. The diagnosis of COPD was based on the Summit database definition: each patient required treatment for chronic pulmonary compromise or had an FEV1 less than 75% of predicted value. Each patient underwent a spirometry test and was seen by a pneumonologist preoperatively. All patients were instructed to stop smoking and to do breathing exercises with incentive spirometry for 4 to 6 weeks preoperatively. Steroids received orally or as inhalation continued until surgery and were resumed postoperatively after extubation, for pulmonary function optimization. An informed consent was obtained preoperatively from each patient.


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  		Table 1. Patient Characteristics

 
Anesthesia
All patients received preoperative medication that included lorazepam (1 mg), 90 minutes before surgery, morphine sulfate (0.1 mg/kg of body weight) and ondansetron (8 mg), 1 hour before surgery. Each patient had a radial artery and a pulmonary artery catheter inserted for continuous pressure measurements. Anesthesia was induced with etomidate (0.3 mg/kg), midazolam (0.05 to 0.075 mg/kg), and fentanyl (10 to 15 µg/kg). Neuromuscular block was induced by intravenous bolus administration of pancuronium (0.15 mg/kg) and was maintained by continuous infusion of cisatracurium (1.5 to 2 µg/kg). Anesthesia was maintained using either sevoflurane (0.5 to 2% in oxygen/air) and additional bolus doses of fentanyl as needed, or using sevoflurane (0.5 to 2% in oxygen/air) and a continuous infusion of remifentanil (0.2 to 1.0 µg · kg–1 · min–1). Cefuroxime (1.5 g) was administered intravenously after the induction of anesthesia. Ventilation was discontinued when ventricular ejection stopped during CPB. However, lungs were partially inflated with appropriate oxygen flow to maintain a continuous positive airway pressure of 5 mm Hg.

Cardiopulmonary Bypass
The CPB circuit was open and uncoated. It consisted of a multiflow roller pump (Stöckett; Shilley, Munich, Germany), a microporous, polypropylene membrane oxygenator (Quadrox; Jostra, Hirrlingen, Germany) and an arterial filter (Safeline; Jostra, Hirrlingen, Germany). Priming was done with 1500 mL of Ringer's lactate solution plus 500 mL of 10% hydroxyethyl starch solution. Anticoagulation was achieved with intravenous heparin (300 U/kg) 5 minutes before initiation of CPB and during perfusion as needed. The activated coagulation time (ACT) was maintained longer than 480 seconds throughout CPB. Myocardial preservation during aortic cross-clamping was achieved with cold-blood cardioplegic solution. The crystalloid cardioplegic component was made with 40 or 60 mL sterile concentrate for cardioplegia infusion (Martindale Pharmaceuticals, Romford, Essex, UK) diluted immediately before use in 1 L of Ringer's Solution in which potassium chloride (2 to 4 g) and sodium bicarbonate (20 mEq) were added. The final crystalloid solution was mixed with blood (1 part crystalloid cardioplegic solution with 4 parts blood) and was infused in the myocardium retrograde through the coronary sinus and antegrade through the aortic root at 8 degrees centigrade. Perfusion was carried out with pump flow at 2.4 L · min–1 · m–2 and with moderate hypothermia (28° to 30° C). After CPB, protamine chloride was administered to neutralize the heparin. Hypotension was prevented or treated with fluids or inotropic support or both as needed. Cardiac output was measured using the thermodilution technique. Operative data are shown in Table 2.


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  		Table 2. Operative Data

 
Leukocyte Filtration
Leukocyte filtration during CPB was achieved with a leukocyte-depleting arterial blood filter (LeukoGard 6; Pall Biomedical Products, East Hills, NY). This filter has been shown to effectively retain activated neutrophil leukocytes during extracorporeal perfusion [13]. In our protocol, the leukocyte filter was connected into the main arterial line of the extracorporeal circuit, just downstream the standard arterial filter. After priming, the leukocyte filter was excluded from the circulation for most of the duration of perfusion. About 10 minutes before the aortic cross-clamp was removed, the filter's bypass line was clamped, so that all of the circulating blood was directed through the leukocyte filter for the remainder of the perfusion or for a maximum of 30 minutes if the perfusion lasted longer.

Patient Monitoring
Complete blood counts were measured in all patients before surgery, upon arrival in the ICU, and on the first and second postoperative days. Blood cell counts were determined on samples containing ethylenediaminetetraacetic acid using a Coulter HmX Hematology Analyser (Hialeah, FL). Postoperative blood test values were corrected for hemodilution according to the hematocrit. Arterial blood gases and oxygen saturation were measured in all patients immediately after intubation in the operating room, at the end of CPB, shortly after arrival to ICU, and 12 hours later. The respiratory index (defined as [PaO2/FiO2] x 100) was calculated. Chest x-rays and electrocardiograms were done preoperatively, upon arrival in ICU, and every 24 hours thereafter until discharge from ICU. All patients were monitored hemodynamically in the ICU with continuous Swan-Ganz and radial artery catheters in continuous pressure displays. The ICU personnel were blinded to the intaoperative use or not of leukocyte filtration. The patients were extubated when they were fully awake, stable, cooperative, and they had satisfactory arterial blood gases. Analgesic therapy was individualized and consisted of morphine sulfate or nonsteroid antiinflammatory medications as needed. The patients were discharged from the ICU after they were judged as stable by the ICU medical staff. The patients were mobilized out of bed as soon as their condition allowed it, and they received intense chest physiotherapy postoperatively. Intubation time, ICU stay and postoperative hospital stay were recorded for each patient.

Statistical Analysis
Data are expressed as mean ± standard deviation. All univariate comparisons were performed using Student's t test in cases where the data were normally distributed. Since the normality assumption was not valid for FEV1, intubation time, duration of ICU stay and duration of hospitalization, the Wilcoxon's rank sum test was used. All outcome comparisons were one-sided, with an alternative hypothesis that the treatment group (group LD) had improved outcomes compared to the control group (group C). Comparisons of patient characteristics were two-sided. A p value less than 0.05 was considered statistically significant.

All longitudinal comparisons were performed using repeated measures analysis of variance (RM-ANOVA). The variables analyzed were the four RI values from each patient and the percent change from pretreatment to posttreatment respiratory index calculations (three values per patient). The method of analysis accounts for the fact that the multiple respiratory index values per patient are interdependent.

Longitudinal comparisons of blood cell counts also were performed using RM-ANOVA. To deal with the apparent lack of normality of some variables, the method was applied twice: once to the observations themselves and once to the ranks of the observations, using the methodology proposed by Spearman. Thus, the results of the parametric analysis were confirmed in all instances by the nonparametric test. The values at each time-point were also compared using Wilcoxon's rank sum test.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Comment
 Acknowledgments
 References
 
There was no statistical difference in gender, age, left ventricular ejection fraction, additional morbidity, and preoperative use of steroids between the two groups. However, although there was no significant difference in FEV1 between the groups, the LD group patients had significantly lower FEV1 as a percent of predicted value (Table 1). There was no significant difference between groups in types of operations, aortic cross-clamp times and CPB times (Table 2). There were no problems related to the use of the filters. All patients recovered uneventfully after the operation. No infections or major blood losses needing reoperation occurred. Surgical (30 day) mortality was zero. There were no major complications.

Hematologic Studies
The hematocrit was reduced in both groups during CPB due to hemodilution as expected, without significant differences between groups. A borderline difference was detected between groups in the time progression of the white blood cell counts with higher values observed among controls than among treated patients (p = 0.0719). Control patients had higher white cell counts upon arrival to ICU (21235 ± 6936/µL) than patients in group LD (17050 ± 5360/µL, p = 0.0429, Wilcoxon). However, no significant differences were observed between neutrophil, lymphocyte and monocyte counts compared to respective base line values. Control patients experienced a constant decline in platelet counts. Patients in group LD had significantly more platelets the second postoperative day (197548 ± 58899/µL) than control patients (142901 ± 39632/µL, p value = 0.0256), but the differences from base line values (257875 ± 88219/µL and 214750 ± 53109/µL, respectively) were not significantly different (p = 0.3412, Wilcoxon).

Pulmonary Function
Changes in pH, respiratory index, and pCO2 are summarized in Table 3. There was no significant difference in respiratory index between groups preoperatively. However, there was statistically significant group difference in respiratory index (treatment effect, p = 0.041, RM-ANOVA), with the treatment group exhibiting higher values. In group LD, respiratory index rose by 9.8% of baseline after CPB, but it fell by 14.2% of baseline upon arrival to ICU, and by 19.6% 12 hours later. In group C, respiratory index fell by 14.5%, 27.7% and 24% of baseline, respectively. Patients in group LD exhibited significantly higher respiratory indexes immediately post-CPB than controls (p = 0.0044, Wilcoxon test), and this difference remained significant controlling for base line values (p = 0.035, RM-ANOVA, group effect). There were no significant differences in pH and pCO2 changes between groups.


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  		Table 3. Changes in pH, Respiratory Index, and pCO2

 
Hemodynamic Parameters
There was no significant difference in mean cardiac index (CI) between group LD and control patients upon arrival in the ICU (2.5 ± 0.7 L · min–1 · m–2 vs 2.5 ± 0.4 L · min–1 · m–2, respectively) or 12 hours later (2.5 ± 0.8 L · min–1 · m–2 vs 2.4 ± 0.7 L · min–1 · m–2, respectively). Also, there was no significant difference between groups in mean arterial pressure, pulmonary artery pressure, central venous pressure and systemic vascular resistance index (Table 4).


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  		Table 4. Hemodynamic Parameters

 
Intubation Time and Hospital Stay
Compared with control patients, patients in group LD needed less postoperative intubation time (group LD: 20.4 ± 16.1 hours, group C: 29.5 ± 21.9 hours, p = 0.043) and shorter ICU stay (group LD: 46.2 ± 40.1 hours, group C: 75.5 ± 34.9 hours, p = 0.001). Also, the postoperative hospital stay was shorter for group LD patients than for controls (8.3 ± 2.8 vs 10.4 ± 3.5 days, respectively, p = 0.038).


   Comment
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
Acknowledgments
 References
 
It is currently accepted that postperfusion lung disorder is an expression of lung reperfusion injury and is usually manifested after CPB with compromised oxygenation [1, 3]. Lung reperfusion injury is caused mostly by the activated neutrophils during the early phase of pulmonary reperfusion [1, 3]. Neutrophils are activated during CPB through the complements C5a and C3a and the kallikrein of the contact system [14]. During reperfusion, activated neutrophils upregulate the expression of the adhesion molecule CD11b–CD18 and they decelerate in the blood stream [15, 16]. This glycoprotein complex binds to an expressed intercellular adhesion molecule ligand of the endothelial cells resulting in rolling and adhesion of the neutrophils to the endothelium; neutrophil transmigration to subendothelial tissues may follow in response to chemotactic stimuli [16–19]. An essential component of post perfusion lung dysfunction results from the effect of activated neutrophils to the pulmonary endothelium. Once they adhere to the microvascular pulmonary endothelium, neutrophils exert local damage with the toxic oxygen metabolites and the proteolytic enzymes they produce, and may transmigrate to subendothelial tissues where they cause further damage [14, 17]. Neutrophil sequestration to the lungs after CPB has been studied clinically and in experimental animals [3, 5–8]. Attenuation of postperfusion pulmonary injury was achieved by leukofiltration [20], by inhibition of leukocyte activation by pentoxifyllin [21], and by inhibition of neutrophil-derived proteolytic enzymes [22], indicating the importance of activated leukocytes in the development of postperfusion lung dysfunction.

Postperfusion lung dysfunction usually results in prolonged intubation. Leukocyte filtration has been used in extracorporeal perfusion circuits in an effort to prevent CPB-related lung injury [4–10]. However, beneficial effects of leukofiltration to pulmonary function preservation are not always clinically evident among patients with normal pulmonary reserve [7–10]. Normal lungs may undertake certain insults without a clinically evident consequence. However, patients with COPD have reduced pulmonary reserve and frequently require prolonged mechanical ventilatory support after open-heart operations. In these patients, a relatively small intraoperative lung injury, along with the existing lung compromise, may cause significant postoperative pulmonary morbidity.

Among our patients on whom leukocyte filtration was utilized at reperfusion, respiratory index was preserved after CPB despite the fact that they had lower percent of predicted FEV1 preoperatively in comparison to controls. The respiratory index is an indicator of the lungs' ability to transfer oxygen across the alveolar-capillary barrier and is very useful in evaluating reperfusion lung injury. Using the respiratory index, we demonstrated a beneficial effect of leukocyte filtration during pulmonary reperfusion among patients with limited pulmonary reserve.

Although the idea of leukodepletion is sound theoretically, its implementation may be burdened by the length of filtration because the filters entrap a large number of activated neutrophils that can cause flow obstruction or still exert harmful systemic effects by releasing toxic substances [10, 23]. Indeed, increased levels of elastase were detected at 30 minutes of leukocyte filtration and continued to further increase with time during CPB [10]. To prevent this adverse effect, we limited leukofiltration to a maximum of 30 minutes. In our study, leukocyte filtration begun during the final period of extracorporeal perfusion and continued through the initial phase of reperfusion since this is considered as the most dangerous period for the development of reperfusion injury.

Problems related to the use of the leukocyte filter did not occur in our study. High-pressure gradients were not observed across the leukocyte filters. None of our patients developed sepsis or any postoperative infection. As a rule, neutrophil counts increase after CPB due to the generalized inflammatory reaction. However, upon arrival to ICU, neutrophil counts were increased less in our treated group than among controls, probably due to leukocyte filtration. However, despite leukocyte filtration, no significant difference in neutrophil counts from base line was observed between groups. This may be explained by the selective removal of activated neutrophils by the filter [13, 24]. In addition, neutropenia was not observed after perfusion, probably because new neutrophils, which normally have a half-life of 6 to 8 hours, entered the circulation from the bone marrow.

Our study showed that leukocyte filtration limited to the early phase of lung reperfusion during CPB had a beneficial effect in preserving lung function among patients with COPD. In our patient population, this was demonstrated by the preservation of the postperfusion respiratory index, as well as the reduction in intubation time and in length of postoperative ICU stay. In conclusion, leukocyte filtration at early reperfusion preserves pulmonary function in COPD patients undergoing open-heart surgery, probably by preventing or ameliorating lung reperfusion injury.


   Acknowledgments
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 Acknowledgments
References
 
We wish to acknowledge the participation of the late Gil Balentine, Clinical Perfusionist, in the implementation of this protocol. Also, we thank our perfusionists Angela Lidoriki, Thanos Dinopoulos, and Andromahi Papagiannaki for providing their expertise and technical support. We also wish to thank Yannis Bassiakos, PhD for the statistical evaluation of the data.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 Acknowledgments
 References
 

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