Ann Thorac Surg 2005;79:2032-2038
© 2005 The Society of Thoracic Surgeons
Original article: Cardiovascular
Total Leukocyte Control for Elective Coronary Bypass Surgery Does Not Improve Short-Term Outcome
Robert F. Salamonsen, MDa,b,*,
James Anderson, CCPa,b,
Michael Anderson, FJFICMa,b,
Michael Bailey, MSd,
Geoff Magrin, BS, FAIMSc,
Franklin Rosenfeldt, FRACSe
a Department of Intensive Care, Alfred Hospital, Melbourne, Australia
b Department of Cardiac Surgery, Alfred Hospital, Melbourne, Australia
c Department of Haematology Unit, Alfred Hospital, Melbourne, Australia
d Departments of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia
e Department of Surgery, Monash University, Melbourne, Australia
Accepted for publication November 19, 2004.
* Address reprint requests to Dr Salamonsen, Intensive Care Unit, Alfred Hospital, Prahran Vic 3181, Australia (E-mail: r.salamonsen{at}alfred.org.au).
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Abstract
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BACKGROUND: Despite early promise as a means of reducing the inflammatory response to surgery and subsequent organ damage, the evidence of the clinical value of leukocyte filtration remains equivocal.
METHODS: Three hundred patients presenting for routine coronary artery bypass surgery were randomized to a total leukocyte filtration group (filters in five different locations) and a control group with a standard 40-µm filter in the bypass return line only. Data on efficacy and safety of leukocyte filtration were collected by research and postoperative care staff who were blinded to the mode of filtration.
RESULTS: Leukofiltration achieved a transient fall in white cells immediately after surgery (p = 0.07) and a sustained fall in platelets, which was still significant on the second postoperative day (p = 0.0001). However, there were no significant differences in postoperative hospital stay, the primary outcome variable (p = 0.35), in ICU stay (p = 0.92), or mortality (p = 1.0). There were no differences in postoperative cardiac status including cardiac output (p = 0.16), inotrope (p = 0.93) or balloon pump (p = 0.48) requirement, or 24-hour troponin (p = 0.60). Similarly there were no differences in pulmonary or renal function (intubation time (p = 0.83), respiratory index (p = 0.19) rise in creatinine (p = 0.13) or hemofiltration (1.0)). Leukofitration was not associated with a statistically significant increase in bleeding or requirement for blood or blood products. It was associated with a decrease approaching significance (p = 0.1) in number and severity of postoperative wound infections. Three filters were blocked during use but were changed without incident or compromise to patient safety.
CONCLUSIONS: Leukocyte filtration is safe but not efficacious in improving short-term outcome.
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Introduction
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Leukocyte filtration was introduced into cardiac surgery in the early 1990s as a result of animal experiments that showed that leukocyte filtration was able to reduce inflammation-mediated organ damage [1]. Leukocyte mediated reperfusion injury requires that neutrophils be both activated and in contact with the endothelium of the target tissue. Interfering with either activation or contact can in theory ameliorate the injury [2]. The rationale for the use of leukocyte filtration is that the leukofilter substantially reduces contact of activated neutrophils with the capillary endothelium [3], thereby reducing the degree of inflammatory response and subsequent organ injury. A number of leukocyte filtration modalities have been described including filtration of blood in the return line from the oxygenator [4], and in the cardioplegia delivery line [5]. Leukocyte filtration has also been proposed for infusion of oxygenator blood [6], homologous blood [7], and platelets [8].
The LG6 filter (Pall Australia, Melbourne, Australia) developed for use in the arterial return line, with a 6 L/min flow capacity and standard 40-µm filter component as well, removes up to 75% of leukocytes predominantly as activated neutrophils [9]. The BCB1 filter for filtering of blood cardioplegia with a flow capacity of 500 mL/min removes more than 70% of all white cells and 11% of platelets [5]. The manufacturers claim that the RS1 filter for blood salvaged from bypass circuits removes 99% of leukocytes and 83% of fat globules [10], also that the LRP6 filter for platelet concentrates removes 99.99% of white cells while preserving greater than 90% platelets [11]. The RC400 filter for homologous blood transfusion removes 99.9% of all white cells without significant loss of red cells or platelets [12]. The simultaneous use of all modalities has been designated total leukocyte control [3].
There have been many reports of trials using different modalities of leukocyte filtration during and after cardiac surgery that claim significant reductions in cellular morphologic damage [13], inflammatory mediators [14–16], markers of organ injury [5, 17], and improvements in functional or clinical outcome [18–20]. However, these are balanced by others claiming little or no benefit [16, 21, 22]. Many of the reports claiming advantage show transient improvement of one or two outcome variables only without evidence of sustained benefit [2, 18, 19, 23, 24] and almost all are inadequately powered [25]. This single-blinded, randomized, controlled study was designed to establish whether the use of total leukocyte control could significantly reduce postoperative organ dysfunction and recovery time after elective (low risk) coronary artery bypass graft surgery.
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Patients and Methods
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All patients presenting for routine coronary artery bypass graft surgery with cardiopulmonary bypass at the Alfred Hospital between January and December 2001, who gave informed consent, were included in the trial. The study protocol was approved by the institutional ethics committee (approval on September 28, 2000). Anesthesia and cardiopulmonary bypass were performed in accordance with standard protocols established in our institution. Patients were randomized to total leukocyte control (leukofilter group) or nonleukofilter groups in blocks of four using a random number generator (Excel; Microsoft Corporation, Melbourne Australia).
The bypass circuit included a Jostra roller pump (Cardio-research, Sydney, Australia), membrane oxygenator with a cardiotomy reservoir (Terumo, Melbourne Australia). In the leukofilter group, leukocyte filters (Pall Australia), were used in five locations (Fig 1) in the bypass circuit and in lines transfusing blood and platelets in the operating theater. A bypass line was fitted to the arterial return line to facilitate isolation and replacement of the LG6 (arterial line) filter if it blocked without interrupting flow to the patient. In the nonleukofilter group a standard 40-µm filter (Pall Australia) alone was used. All intraoperative data were recorded by perfusionists. Intensive care unit (ICU) staff and research staff collecting preoperative and postoperative data had no access to group allocation and were thus effectively blinded. Blood and platelets administered to patients in the leukofilter group in the intensive care unit were filtered by blood bank staff who had separate access to the randomization schedule. If there was an unacceptable delay in supply of filtered blood, the patient was then removed from the trial and unfiltered blood and platelets administered. Hemodynamic data and doses of inotropic drugs were recorded hourly during the first 8 hours after admission to the ICU. Hemodynamic data were reported as 8 hours means and inotrope doses as cumulative (total) doses over first 8 hours.
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Fig 1. Locations of leukocyte filters in bypass circuit and blood flow lines. The RC400 and the GRP6 filters are also used postoperatively in the blood bank before delivery to the intensive care unit. (BC1B = cardioplegia line leukocyte filter; CPS = cardioplegia solution; LG6 = arterial return line leukocyte filter; LRP6 = inline leukofilter for platelet infusion; RC400 = inline filter for homologous blood infusion; RS1 = inline leukocyte filter for residual oxygenator contents.)
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Outcome Variables
Efficacy
White cell counts were measured before and immediately after surgery and on the second postoperative day. The primary outcome variable indicating efficacy of total leukocyte control was the total duration of postoperative hospital stay (ICU + ward) in days, while secondary outcome variables were length of ICU stay postoperatively (hours), hospital mortality, and a range of organ function indices. To indicate cardiac function, 8-hour means of cardiac index, mean arterial and central venous pressures and cumulative doses of epinephrine and nor-epinephrine infused over first 8 hours were used. Requirement for intraaortic balloon pump or atrioventricular pacing in the first 8 hours postoperatively was recorded. In addition, assays for cardiac troponin I at 6 and 24 hours postoperatively were conducted. Respiratory function was estimated by recording the duration of endotracheal intubation and the respiratory index (PaO2/FiO2). Renal function was monitored by recording the ratio of maximum creatinine level postoperatively to the preoperative value. Use of hemofiltration was also recorded.
Safety
Platelet counts were measured immediately before and after surgery and on the second postoperative day. Bleeding tendency after platelet reduction was assessed by recording the volume of mediastinal bleeding in the first 8 hours in the ICU, the incidence of resternotomy for bleeding, the requirement for blood and blood products, and fall in hemoglobin. The incidence of surgical wound infection for the first 3 months postoperatively was documented. A surgical wound infection (sternal or vascular donor site) was recorded if there was surgical site drainage, edema, or swelling requiring surgical debridement [26]. Sternal infections were considered deep if they were deep to the sternum and donor site infections were those penetrating below the deep subcutaneous fascia. All others were labeled as superficial. Filter blockage during cardiopulmonary bypass was considered an adverse event and followed up in detail.
Statistical Analysis
A power calculation based on existing data in our unit for postoperative hospital stay indicated that a total sample size of 300 was required to achieve an 80% power to detect a 15% (1 day) difference in hospital stay between the groups with a significance of 0.05. Data were assessed for normality and log-transformed where appropriate. Results for continuous variables are presented as means or as geometric means with 95% confidence limits (CL). Categorical variables are reported as prevalences (percentages) with 95%CL where appropriate. Statistical significance was determined using 
2-tests for equal proportions and Student t tests. Statistical significance was set at p less than 0.05. All data were analyzed by the SAS system (SAS Institute Inc., Cary, NC).
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Results
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Three hundred patients were randomized into two groups of 150, a leukofilter group (total leukocyte control) and a nonleukofilter group having a standard 40-µm filter in the arterial line of the bypass circuit only. Table 1 confirms that the leukofilter and nonleukofilter groups did not differ significantly in any of 18 recorded preoperative and intraoperative variables. In addition, 95% CL were closely grouped about means for continuous variables and prevalences (percentages) for categorical variables.
The dynamics of changes in white cells and platelets over the perioperative period are presented in Table 2. Before surgery, leukocyte counts in both groups were similar. After return to the ICU, counts were elevated in both groups, by 54% in control and 34% in the leukofilter group, but the between-group difference, approximately 10%, was not significant (p = 0.07). Immediate postoperative neutrophil counts were less in the filtered group (p = 0.05). By day 2 total leukocyte and neutrophil counts were very similar in the leukofilter and control groups. For platelets, although levels were both lower immediately after surgery, the filtered group had fallen to significantly lower levels (p = 0.0001) than the nonfiltered group – an effect that was still significant (p = 0.0001) on the second postoperative day.
Table 3 lists differences in efficacy-related outcome variables between leukofilter and nonleukofilter groups. There was no significant difference in the primary outcome variable of hospital stay. Also there were no significant differences in secondary outcome variables including length of stay in intensive care, hospital mortality and measurements of postoperative organ function.
Outcome variables indicating safety of total leukocyte control are presented in Tables 4 and 5, which present data on postoperative bleeding and infections. The marked and sustained fall in platelet levels in the leukofilter group postoperatively (see Table 2) did not increase bleeding as measured by mediastinal drainage in the first 8 hours and frequency of resternotomy for bleeding. However the hemoglobin level was significantly lower in the leukofilter group on the second postoperative day despite the fact that this group required slightly more blood and fresh frozen plasma. Also, the fall in white cells was not associated with any increase in surgical wound infection postoperatively. The incidence of wound infection was actually approximately 50% lower in the leukofilter group – an effect that bordered on significance (p = 0.1). In virtually all wound infections the infecting organism was either methicillin-sensitive or -resistant Staphylococcus aureus.
The arterial line filter (LG6) in the leukofilter group blocked on two occasions; 1 patient required marginally early wean from bypass, and the other patient required replacement during bypass. The cardioplegia filter (BC1B) in the leukofilter group line blocked in 1 patient and was replaced without incident. The recovery of these 3 patients was not affected, although the first patient had transient hemoglobinuria.
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Comment
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This prospective randomized, semi-blinded study of 300 patients presenting for elective coronary artery bypass graft surgery clearly indicates that total leukocyte control using all five modalities of leukocyte filtration together failed to improve clinical short-term outcome. Our results did not demonstrate any significant shortening of hospital stay, intubation time, and ICU stay. In addition, measurements indicating cardiac, respiratory or renal function were not significantly different between the two groups. There were also no differences in markers of perioperative cardiac damage.
We believe this is the largest randomized clinical trial of routine elective coronary artery bypass graft patients to date and the only trial powered to provide conclusive evidence of efficacy or otherwise in patients presenting for low-risk cardiac surgery. When the power analysis on sample size was repeated with the actual mean and standard deviation from our study it gives a power of 95% to detect a 15% (1 day) difference in postoperative hospital stay between the study groups with a significance of p less than 0.01 Two other studies on a large group of patients deserve specific mention. The trial of total leukocyte control in 400 patients published by Gott and colleagues [20] in 1998, reported significant shortening of hospital stay and costs. However this study was not truly applicable to coronary artery bypass patients as patients undergoing valve replacement and surgery of the aorta were included. In addition all patients were stratified for preoperative risk and analyzed in subgroups and the study compared four protective strategies, thus reducing the sample size for elective coronary bypass graft surgery to approximately 75 patients without a formally constituted control group. Finally, the staff involved with intraoperative and postoperative care were not blinded as to filter type. As in our study, there were no significant differences in postoperative organ function. In 2003 Olivencia-Yurvati and associates [3] reported on the effect of total leukocyte control in 226 coronary surgery patients; although reporting impressive benefits is not strictly comparable with our study, they combined leukocyte filtration with administration of aprotonin. In addition, the staff controlling postoperative care were not blinded as to whether leukofiltration had been used. Also, it was not clear whether the patients presenting for primary coronary artery bypass surgery were all classifiable as low risk.
Our results are surprising considering the wealth of basic science data supporting a therapeutic effect of leukocyte filtration. Our serial white cell counts confirmed the transient nature of the leukocyte depletion in the filtered group. Although slightly lower in the filtered group than the nonfiltered group, white cell counts in both groups were markedly elevated on return to the ICU and on the second postoperative day, presumably as a result of the inflammatory response to bypass and surgery. This postoperative increase demonstrates the ability of the body to overcome short-term depletion in circulating white cells by release of the considerable number of white cells stored outside the circulation. We also found that there was no sustained postoperative depletion of neutrophils. Any effects of leukofiltration must be limited to the period of cardiopulmonary bypass. Although we did not document the immediate fall in white cells postfiltration, our results indicate that any transient reduction that may have occurred did not improve clinical outcome.
In the light of published studies, the design of future studies could be modified to produce and detect beneficial effects. Deployment of total leukocyte control for the whole of bypass involves the risk of filter exhaustion before the critical phase of myocardial reperfusion after release of the cross-clamp and lung reperfusion on cessation of bypass [27]. Our mean cross-clamp time was 57 minutes, whereas studies indicate that leukofilter efficiency tails off markedly after the first 30 minutes of bypass [28]. Limitation of filtration through the arterial and cardioplegia line filters to the time immediately before and after reperfusion might improve results. However reports of such strategies are equivocal [3, 24, 29, 30]. In the absence of suitable validated criteria to define the systemic inflammatory response syndrome we were not able to explore the incidence and severity of this syndrome. The criteria suggested by Bone and coworkers [31] (increased, heart rate, temperature, white cells, and respiratory rate) are of dubious value for obvious reasons in the early recovery phase after hypothermic cardiac surgery. One modality that has not been explored is the filtration of all white cells, fat globules, and tissue debris in blood before return to the oxygenator through the cardiotomy suction, which is likely to be a potent source of inflammatory mediators. This would require 6 filters for total leukocyte control and there must come a point where the increased complexity becomes counterproductive.
In terms of safety of leukocyte filtration, although total leukocyte control in our hands caused a significant reduction in platelets this did not translate into marked bleeding complications. All we were able to do was document a slight fall in hemoglobin on the second postoperative day despite a small increase in blood and fresh frozen plasma given to leukofiltered patients. Similarly, the significant reduction in white cells did not increase surgical infection. In fact, our study demonstrated a trend toward a 50% reduction in surgical wound infections that was clinically, if not statistically, significant (p = 0.1). This is interesting as it is supported by other work [7] and might achieve significance in a study of adequate power. Blockage of the arterial line filter did not have any adverse sequelae, because of the presence of an arterial line filter bypass line filter.
Our study also was limited to stable patients presenting for elective coronary artery bypass graft surgery. There have been reports suggestive of benefit of leukocyte filtration in emergency surgery [20, 24], in elective surgery on patients with compromised hearts [15, 18, 24, 32], and in cardiac transplantation [33].
In conclusion, this study indicates clearly that although the technique is safe, there is no clinical benefit in leukofiltration during cardiopulmonary bypass in patients undergoing elective, low-risk coronary artery bypass surgery.
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Acknowledgments
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Leukofilters were supplied by Pall Australia, Ltd. Pall also provided financial support for employment of a data collection research nurse. We thank the nurses in the intensive care and the postoperative ward for their assistance; and Robbie Brown for data acquisition and processing.
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Abstract
Introduction
