Eur J Cardiothorac Surg 2006;30:621-627
© 2006 Elsevier Science NL
The role of leukocyte depleting filters in heart transplantation: early outcomes in prospective, randomized clinical trial
Lubos Dvoraka,*,
Jan Pirka,
Stepan Cernya,
Jan Kovarb
a Department of Cardiovascular Surgery, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
b Department of Clinical Biochemistry, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
Received 10 April 2006;
received in revised form 20 July 2006;
accepted 25 July 2006.
* Corresponding author. Address: Budovatelu 2620, Tabor 39002, Czech Republic. Tel.: +420 608442280; fax: +420 261362776. (Email: lubos.dvorak{at}seznam.cz).
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Abstract
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Objective: Leukocyte-mediated reperfusion injury to cardiac allograft in the perioperative period is most likely associated with the early and late mortality after heart transplantation (Htx). Our aim is to determine the efficacy and safety of using leukocyte-depleting filters in a cardiopulmonary bypass (CPB) and secondary blood cardioplegia (SBC) circuit in Htx. Methods: A prospective, randomized trial was performed in 40 patients undergoing orthotopic Htx. These patients were divided into two groups, to be treated with either leukocyte-depleted (LD) reperfusion (n
= 20) in the LD group, or whole blood reperfusion (n
= 20) in the Control group. The SBC was used in both groups. Results: Intraoperatively, the LD group presented the reduced markers of reperfusion injury. The course of the creatine kinase MB (CK-MB) releases was significantly lower in the LD group (p
< 0.05). The LD hearts showed better spontaneous rhythm resumption (60% vs 10%; p
< 0.001), and lower need for isoprenaline (0.02 ± 0.01 µg/(kg min) vs 0.03 ± 0.02 µg/(kg min); p
< 0.05) and epicardial pacing (25% vs 60%; p
< 0.05) for weaning off CPB. Postoperatively, lower and shorter need for inotropic support (48 ± 46, median = 35 h vs 131 ± 68, median = 109 h; p
< 0.001), shorter temporary epicardial pacing (6 ± 14, median = 0 h vs 25 ± 52, median = 1 h; p
< 0.01), and lower 24-h chest drainage (551 ± 274, median = 500 ml vs 973 ± 836, median = 665 ml; p
< 0.05) in the LD group contributed to the shorter mechanical ventilation time (8 ± 3, median = 7.5 h vs 14 ± 12, median = 8.5 h; p
< 0.05) and the shorter stay at an intensive care unit (ICU) (70 ± 24 h vs 116 ± 73 h; p
< 0.05). The 30-day mortality was zero in both groups. Conclusions: The use of leukocyte depleting filters in heart transplantation is an effective, easy and safe method of myocardial protection, reducing significant myocardial reperfusion injury and improving posttransplant graft functional recovery.
Key Words: Heart transplantation • Leukocyte depletion • Blood cardioplegia • Reperfusion injury
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1. Introduction
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Heart transplantation (Htx) can successfully treat a heart failure in its terminal phase [1]. However, the Htx remains unavailable to most patients, mainly due to the lack of donors and an increasing number of patients indicated to Htx. That leads to the liberalization of classic donor selection criteria and the growing use of ‘marginal’ cardiac grafts with suboptimal functioning [2,3]. That suggests the need to improve the donor heart preservation and thus enhance graft functioning after Htx. The cardiac allograft is affected by various preoperative and perioperative risk factors, possibly resulting in myocardial ischemia–reperfusion injury.
Leukocytes play a crucial role in pathogenesis of myocardial reperfusion injury after a period of ischemia. Especially activated neutrophils are the central and most aggressive component of local inflammatory reaction to postischemic reperfusion. Neutrophils are the primary mediators of reperfusion injury by the series of interactions whose endpoints include: mechanical capillary obstruction (plugging), direct endothelial injury, complement activation, release of oxygen-derived free radicals, release of harmful arachidonic acid metabolites [4], production of proteases and other cytotoxic substances, and interaction with thrombocytes and other leukocytes. All these adverse effects lead to disorders of microcirculation, metabolic impairment, and necrosis of cardiomyocytes [5,6]. Leukocyte-mediated reperfusion injury is also partly responsible for decreased graft function. The resulting endothelial injury may even contribute to posttransplantation cardiac allograft vasculopathy, the main limit to long-term survival of patients after Htx.
The leukocyte-depleted (LD) reperfusion has been shown experimentally to improve graft functional recovery after cold ischemic arrest [7]. Depletion of leukocytes has also been shown to reduce infarction size in a regional ischemia model in animals [8–10]. The LD reperfusion further prevents the significant ultrastructural injury found with whole blood reperfusion [11].
Over the last decade, there has been a trend in the application of blood cardioplegia in Htx, based on extensive experimental and clinical evidence [12–14]. In our previous clinical trial we had presented that a technique of secondary blood cardioplegia (SBC) with controlled graft reperfusion is associated with less postoperative myocardial injury and earlier cardiac graft recovery. This technique offers further potential improvement in myocardial protection of cardiac grafts [15].
In view of the proven benefit of leukocyte-depleted reperfusion and SBC, to improve donor myocardial protection, we have conducted a randomized, prospective clinical trial in patients undergoing Htx. In the trial, we have studied the effect of leukocyte-depleting filters incorporated in cardiopulmonary bypass (CPB) and SBC in Htx. This study indicates that the leukocyte-depleting filters in Htx diminish the significant myocardial reperfusion injury and improve posttransplant graft functional recovery.
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2. Materials and methods
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2.1 Study design
To determine the efficacy and safety of using leukocyte-depleting filters, we prospectively randomized 40 adult patients undergoing primary orthotopic Htx between April 2002 and July 2003. The randomization was done by computer-generated random numbers. Neither the patients nor the staff of postoperative care and laboratories were told the randomization results. The patients were divided into the LD group (n
= 20) and the Control group (n
= 20). Before entering the trial, we obtained an informed consent from each patient. The study protocol was approved by our institutional ethical committee on human research.
2.2 Transplantation techniques
To achieve the depletion of leukocytes in the LD group, we used two leukocyte-depleting filters (Pall Corp., Biomedical LeukoGuard, Glen Cove, NY, USA). The arterial blood filter (LeukoGuard-6) was inserted in the CPB circuit and active throughout the whole CPB. The blood cardioplegia filter (LeukoGuard BC1) was inserted in the SBC circuit.
We harvested and transplanted hearts identically in both groups. We used an aortic root cannula (model 20014 Aortic root cannula, Medtronic DLP, Minneapolis, USA) to deliver St. Thomas crystalloid cardioplegic solution at the pressure of 150 mmHg in the dose of 10–15 ml/kg of the donor weight. We left the cannula in the aortic root for application of SBC and for blood sampling until weaning off CPB. Donor hearts were stored in St. Thomas solution at 0–4 °C, packed in ice and transported in a cooling box [16].
The implantation was carried out in the standard fashion using the bicaval orthotopic technique. After the CPB was established at 34 °C, and the common triple-drug (antilymphocyte or antithymocyte immunoglobulin, azathioprin, methylprednisolone) immunosuppression regimen initiated, the cardiac graft was removed from the cooling box and trimmed for implantation. While trimming, an initial dose (1000 ml) of antegrade cold (10–12 °C) SBC was delivered for 4 min at the flow rate of 250 ml/min. Cardioplegic solution (‘Kalte Reinfusion’ A + B, Blutkardioplegie nach Buckberg, Dr Franz Köhler Chemie GmbH, Alsbach-Hänlein, Germany) was mixed in a 4:1 ratio (blood from CPB:cardioplegic solution), and delivered by the original set of blood cardioplegia (Versaplegia® 4:1 system, COBE Laboratories Ltd, Gloucester, England). In the period of 20 min during surgical implantation, we repeated delivering SBC in half doses for 2 min at the same temperature and flow rate. We used topical cooling with slush ice and an insulation pad throughout the implantation.
After completing the aortic suture line, the heart was reperfused with terminal normothermic amino acid-enriched blood cardioplegia for 4 min at the flow rate of 150–200 ml/min. Cardioplegic solution (‘Hot Shot’ A + B, Blutkardioplegie nach Buckberg, Dr Franz Köhler Chemie GmbH, Alsbach-Hänlein, Germany) was mixed with the blood from CPB in the same 4:1 ratio. Then we unclamped the ascending aorta to re-establish the native coronary perfusion. After sufficient time for reperfusion (at least 30 min), the CPB was terminated and Swan–Ganz catheter introduced to monitor the cardiac output with a calculation of other hemodynamic parameters.
2.3 Observed parameters
2.3.1 Perioperative data
We collected preoperative data in donors (Table 1
) and recipients (Table 2
). All patients were evaluated according to Rogers index [17], combining donors’ and recipients’ risk factors, and divided into a low-risk, medium-risk and high-risk category (0, 1–2 and 3 risk factors, respectively). We excluded high-risk patients with more than three risk factors from the study. We recorded the main intraoperative characteristics, including conditions for rhythm resumption and weaning off CPB (Table 3
).
2.3.2 Effectiveness of leukocyte depletion
To determine the efficacy of leukocyte depletion, we analyzed blood count after the start of CPB, at the first SBC, at Hot Shot, and before weaning off CPB. Blood samples were obtained first from CPB, then from a side port of the aortic root cannula. After Htx, we cut the filters and made an electron micrograph to demonstrate the leukocytes caught inside.
2.3.3 Markers of reperfusion injury
To assess the degree of reperfusion injury and metabolic condition, we analyzed intraoperatively creatine kinase MB (CK-MB), troponin I, thromboxane B2 (Tx-B2), lactate, and partial pressure of O2 and CO2. Blood samples from the aortic cannula and coronary sinus were taken for determination of myocardial arteriovenous differences at each SBC, at Hot Shot, and at 5, 15, and 30 min of reperfusion. Troponin I (samples taken only from the coronary sinus) and Tx-B2 were analyzed only at the first SBC, at Hot Shot, and at 30 min of reperfusion. The Tx-B2 concentration was determined using EIA kits (Amersham Pharmacia Biotech) after solid phase extraction in the procedure recommended by the manufacturer.
2.3.4 Postoperative monitoring
The hemodynamics, blood activity of CK-MB, and inotropes doses were recorded over the first 48 h (at 1, 3, 6, 12, 24, 48 h) after Htx. Heart rate, cardiac output, cardiac index, mean arterial pressure, pulmonary artery diastolic pressure, left and right atrial pressure, systemic vascular resistance, and left and right ventricle stroke work index were recorded. We carried out postoperative 30-day clinical surveillance (Table 4
) to establish the early clinical outcomes and benefit of leukocyte depletion in Htx.
2.4 Statistical analysis
All data were analyzed by standard statistical methods and calculated by software (SYSTAT 10, SPSS Inc., Chicago, IL, USA). Quantitative values were expressed as the mean plus or minus the standard deviation (SD) or median. Comparison of continuous variables between groups was done by t-test or Mann–Whitney test. We applied analysis of variance with repeated measures or Friedman's test when the values obtained within each group at various times were compared with the baseline value. Chi-square test was applied for discrete variables and Yates correction was used whenever appropriate. Values p
< 0.05 were considered statistically significant.
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3. Results
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3.1 Perioperative data
Forty patients undergoing Htx were randomized into two groups. The LD group consisted of patients receiving leukocyte-depleted reperfusion and the Control group consisted of patients receiving whole blood reperfusion. Donors in both groups were similar in all recorded parameters (Table 1). Patients in the LD group were 6 years younger and had lower preoperative serum creatinine, both with borderline statistical significance (p
< 0.05). Patients in the LD group had lower weight and body surface area (p
< 0.05). All other data were similar in both groups (Table 2). The average number of risk factors of donors and patients was similar in both groups (1.2 ± 0.8 in the LD group vs 1.1 ± 0.8 in the Control group). The number of patients in each risk category was identical in both groups.
Patients in both groups did not differ in the main operative characteristics (Table 3). After aortic declamping, patients differed in conditions for rhythm resumption and for weaning off CPB. The LD group presented more frequent spontaneous rhythm resumption (p
< 0.001), lower need for defibrillation with more successful resumption of sinus rhythm (p
< 0.05), and lower need for temporary epicardial pacing to achieve rhythm resumption (p
< 0.01). At weaning off CPB, patients in the LD group needed fewer times epicardial stimulation (p
< 0.05) and lower doses of isoprenaline (p
< 0.05) (Table 3).
3.2 Effectiveness of leukocyte depletion
The efficacy of leukocyte depleting filters was confirmed by the blood count analysis, and by the electron microscopic exploration of filters after Htx. Leukocyte filters did not affect the level of erythrocytes in blood. Thrombocytes in the LD group were lowered (50 ± 30 cells x 109/l vs 83 ± 42 cells x 109/l; p
< 0.01) with lower volume (7.6 ± 1.3 fl vs 11 ± 2.8 fl; p
= 0.01) only at the first SBC. The total leukocyte, neutrophil, lymphocyte, and monocyte counts dropped nearly to zero in the LD group at the first SBC (p
< 0.001). A significant decrease continued until aortic declamping (p
< 0.001), then the white blood count was restored but remained lower in the LD group over the reperfusion (Fig. 1
). Lymphocytes remained significantly lower in both groups at the end of CPB compared to the start of CPB (p
< 0.001), mainly due to the immunosuppression. We analyzed all subpopulations of lymphocytes at the start and end of CPB. Identically in both groups, there was a significant decrease in all subpopulations (p
< 0.001), slightly more in the LD group.
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Fig. 1. Intraoperative course of neutrophils. We noted a similar decrease in all white blood cells in the LD group; ***
p
< 0.001 versus Control.
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After the filters had been cut, the electron microscopy scanning of the inner mesh documented the presence of cells with dendrites and leukocytes, caught during filtration (Fig. 2
).
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Fig. 2. Scanning electron micrograph of the arterial blood filter (LeukoGuard-6) after Htx. Cells with dendrites and leukocytes adhere to the 40 µm filter media designed to remove potentially harmful leukocytes and debris from CPB.
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3.3 Markers of reperfusion injury
Intraoperatively, the overall course of CK-MB releases was significantly lower in the LD group (p
< 0.05). At reperfusion, CK-MB release was lower in the LD group than in the Control group at each time point (p
< 0.05) (Fig. 3
).
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Fig. 3. Intraoperative release of CK-MB measured by myocardial arteriovenous difference of enzymatic activity. The curve in the LD group is significantly lower (p
< 0.05); *
p
< 0.05 versus Control.
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The troponin I concentration in the coronary sinus raised significantly in both groups throughout the operation (p
< 0.001), with non-significantly lower values in the LD group (from 13 ± 7 ng/ml vs 16 ± 6 ng/ml at first SBC, to 55 ± 33 ng/ml vs 68 ± 36 ng/ml at 30 min of reperfusion).
Tx-B2 heart release was analyzed as a marker of metabolic cascade of arachidonic acid, activated by neutrophils. The course of arterial concentrations was significantly lower (p
< 0.05) in the LD group. Although there were no other statistically significant differences between the groups, venous blood Tx-B2 concentration tended to be lower in the LD group as well. The same applies to Tx-B2 release as assessed by comparison of arteriovenous differences in Tx-B2 concentration.
The lactate release dropped after aortic declamping in both groups. This decrease was significantly greater (p
= 0.01) in the LD group (from 1.41 ± 0.5 mmol/l at Hot Shot to 0.04 ± 0.1 mmol/l at 15 min of reperfusion). However, the lactate release was non-significantly lower in the LD group than in the Control group at reperfusion.
The evaluation of partial pressure of O2 and CO2, and saturation of O2 in blood did not show any significant difference between the groups.
3.4 Postoperative monitoring
Over the first 48 h after Htx, similar hemodynamic comparison did not show any significant differences between the groups but for the higher heart rate curve in the LD group (p
< 0.05), and the lower left atrial pressure curve in the LD group (p
< 0.05).
The CK-MB enzymatic activity in serum was lower in the LD group over the all 48 h, with a significant difference (p
< 0.05) at 24 h after Htx. Among inotropes, only isoprenaline was used regularly, in significantly lower doses in the LD group (p
< 0.001) (Fig. 4
).
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Fig. 4. Isoprenaline postoperative doses are significantly lower in the LD group at each time point; **
p
< 0.01; ***
p
< 0.001 versus Control.
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Postoperative clinical follow-up over the first 30 days after Htx presented clinical benefits of LD Htx. The following parameters were significantly lower in the LD group than in the Control group: the time of epicardial stimulation (p
< 0.01), inotropic support (p
< 0.001), mechanical ventilation (p
< 0.05), the volume of 24-h chest drainage (p
< 0.05), cases of renal failure (p
< 0.05), and the time of intensive care unit (ICU) stay (p
< 0.05). The 30-day mortality was zero in both groups (Table 4).
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4. Discussion
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Over the last two decades clinical Htx has evolved into a successful form of surgical treatment of terminal heart failure. Early and late outcomes after Htx have been improved mainly due to better immunosuppression and advances in myocardial preservation strategies [18]. Nevertheless, the main limit to Htx is donor organ availability and relatively short safe ischemic times compared to other organs. Ischemic times beyond 3 h are associated with a decreased graft survival [19], partly due to postischemic leukocyte-mediated myocardial reperfusion injury. Leukocyte depletion may prevent significant reperfusion injury and improve posttransplant graft functioning when graft ischemia is long. This might enable safe extension of the ischemic time, which would expand the donor pool. In this view we studied patients with graft ischemia over 3 h, but there were only four and five grafts with the mean ischemic time of 204 and 194 min in the LD and the Control group, respectively. This was not enough to show any statistically significant difference.
Although the patients in the LD group were 6 years younger, we did not make any data correction to age because none of the parameters of interest directly depended on age. The lower preoperative serum creatinine in the LD group may have been associated with less frequent renal failure in the LD group at postoperative follow-up. However, that is not related to other results. The patients in the LD group had lower weight and body surface area, which does not matter, because patients in both groups were well matched with donors. All other preoperative data were similar in both groups, including risk factors and allocation to risk categories.
The use of leukocyte depleting filters does not cause any serious trouble in Htx, and does not significantly affect the operative time. Interestingly, the mean time of aortic clamp, ischemia until first SBC, and implantation was slightly longer, but the mean CPB time slightly shorter in the LD group than in the Control group.
The arterial blood filter incorporated in CPB and the blood cardioplegia filter in SBC remove not only leukocytes but also gaseous and particulate microemboli originated in CPB. Numerous emboli include gas, fibrin, fat, denatured protein, platelet and leukocyte aggregates, red cell debris, tissue debris, and foreign material (calcium, glass, metallic particles, cellulose, starch, lacquer flakes, rubber, talc, suture material) [20].
CPB activates an immune system and causes ‘whole body inflammatory response’ with activated neutrophils playing a key role. Typically leukocyte levels fall during CPB in response to dilution (leukopenia), then start rising at reperfusion (leukophilia after the operation), reflecting the development of the inflammatory process, mobilization of a leukocyte pool in the spleen, and activation of circulating neutrophils by agonists like C3a, C5a, kallikrein, Factor XIIa, and neutrophil-activating peptide 2 (NAP-2) from platelets.
In this study, we noted a similar trend in white blood count during CPB in both groups, but with a significant drop in leukocytes nearly to zero at SBC in the LD group. Leukocytes then were restored at reperfusion but still remained a bit lower than those in the Control group. There does not seem to be a significant difference between the two groups with respect to systemic circulating leukocytes at the end of CPB. That suggests that the effect of arterial blood filter (LeukoGuard-6) on leukocyte depletion measured at the end of CPB is less impressive. The blood cardioplegia filter (LeukoGuard BC1) obviously has a good efficacy (Fig. 1), considering that the blood entering SBC is already filtrated in the CPB circuit. In spite of the absence of a significant drop in circulating leukocytes, there are important clinical benefits of leukocyte depletion. A possible explanation for the clinical effect of depletion would be selective depletion of important leukocyte subpopulations. For example, macrophages and other antigen presenting cells (APC) tend to stick firmer to foreign surfaces than other leukocytes. In line with this speculation, the electron microscopy of the arterial blood filter revealed mainly cells with dendrites that could well be precursors of dendritic cells (Fig. 2). Besides, macrophages and other APC are important in the early events of ischemia–reperfusion injury. Future studies could be designed to evaluate the efficacy of systemic leukocyte filtration separately in CPB, with analyses of leukocyte subpopulations.
Although leukocyte depletion was achieved mainly in SBC, decreased markers of leukocyte-mediated reperfusion injury (CK-MB) appear statistically significant mostly later in the reperfusion period and then in the postoperative course. It suggests that leukocyte-mediated events occurring during SBC within the implantation period bring about substantial myocardial injury with consequences long afterwards. Another study [21] also presents a lower CK-MB release in LD hearts. Leukocyte depletion lowers non-significantly the release of another marker of reperfusion injury, troponin I. We would have needed a few more patients in the trial to reach the statistically significant difference between the groups. The same applies to lactate and Tx-B2. Lower Tx-B2 concentrations in patients being treated with the LD reperfusion indicate the decreased activation of the arachidonic acid pathway, one of many pathways of reperfusion injury. Despite the lower Tx-B2 release in LD hearts, the difference between the groups was not statistically significant, except for the course of arterial Tx-B2 concentrations (p
< 0.05). However, Pearl et al. [21] has reached a statistically significant decrease of Tx-B2 released in LD hearts. Anyway, we suppose that hearts with longer ischemic times than those in this study would be subject to more severe reperfusion injury, and LD reperfusion would alleviate reperfusion injury more significantly in these patients.
Although the groups did not differ in postoperative cardiac output, the rhythm resumption and graft function at weaning off CPB was much better in LD hearts. In postoperative clinical follow-up, all findings were in favor of LD patients. Lower 24-h and total chest drainage contributed to fewer cases of chest reopening for bleeding in LD patients. The LD group presented no serious complications within the first week, unlike the Control group with two cases of cardiac arrest and one case of generalized spasm with unconsciousness. Neither chest reopening nor complications reached statistical significance.
We have not found any other similar work in literature sources comparable to this study with regard to the combination of preservation techniques, large number of patients involved, and a wide variety of parameters analyzed. Leukocyte depleting filters combined with SBC significantly improve myocardial protection at graft implantation and reperfusion in Htx. This technique of heart preservation is safe and easily applied in the operating theatre without protracting or interfering the operation course and perioperative care. Leukocyte depletion in Htx is associated with less myocardial reperfusion injury and an earlier, enhanced posttransplant graft functional recovery. The filters reduce operative and postoperative markers of reperfusion injury, improve spontaneous rhythm recovery, and lower the need for inotropes and for epicardial stimulation at weaning off CPB. In the early postoperative course, leukocyte depletion results in lower and shorter need for inotropic support, shorter temporary epicardial pacing, and lower chest drainage, which helps reduce the mechanical ventilation time and ICU stay. Subsequently, the risk of infection is reduced. All that is beneficial not only for patients, but also for medical cost savings. Fortunately, the mortality was zero in both groups over the first 30 days after Htx, which indicates that myocardial preservation with mere SBC in the Control group is beneficial by itself in this respect. In our previous study, Cerny et al. [15] noted the 30-day mortality of 8.2% (4/49) in the patients with SBC.
Leukocyte depletion extends a new potential for further improvement in myocardial preservation in Htx. Consequently, the donor pool could expand as grafts not accepted for Htx with standard preservation techniques may be accepted even with suboptimal functioning when using the LD technique. Moreover, elderly and more hazardous patients might be considered for LD Htx.
At present, we have been carrying on a long-term follow-up of patients involved in the study to evaluate the long-term outcomes of LD technique in Htx. We have been investigating an incidence of cellular and humoral rejection episodes, a long-term clinical course, and a relation to posttransplant coronary artery disease. Along with this study, we also examined hearts as to ultrastructural evidence of reperfusion injury. All data will be analyzed and published. However, many more patients would have been needed in the study to reach statistical significance in more parameters observed. Based on all the acquired knowledge, we think that leukocyte-depleting filters should be regularly used in Htx.
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Acknowledgments
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We thank Dr Vera Lanska, Department of Statistics, Institute for Clinical and Experimental Medicine, Prague, for statistical analysis. This study is realized within the grant project ND/7052-4 of the Internal Grant Agency. We thank the Internal Grant Agency of the Ministry of Health, Czech Republic, for the financial support.
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References
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Top
Abstract
1. Introduction
