- Email: [email protected]
What is the Role of Leukocyte Depletion in Cardiac Surgery?
LETTERS TO THE EDITOR
Letters to the Editor
What is the Role of Leukocyte Depletion in Cardiac Surgery?
W
e read with interest the recent article by Lim et al. and applaud the novel way in which they address the potential impact of leukodepletion in cardiac surgery.1 Whilst we agree with their conclusions, we feel that there are certain areas that deserve further consideration. We recognise that the authors do not claim to have performed a systematic search, but the selection criteria for the included studies is unclear and those selected reflect under half of the current human literature.2 Furthermore, 16 of these studies involve cardioplegic leukofiltration, which is an over-representation of this method when considering the literature as a whole. This creates a potential selection bias, has led to important randomised trials and certain outcomes not being considered within the article, and as such makes the reported data synthesis (Table 4) very difficult to interpret. The authors report that leukodepleting filters do achieve their primary goal of leukocyte removal, both in vitro and in vivo. Whilst it is indisputable that leukodepleting filters remove leukocytes from a stream of blood they do not appear to consistently lower leukocyte concentrations within the circulation, or they do it only transiently.3 Knowing this, some have suggested that leukodepleting filters may preferentially remove activated leukocytes from the circulation. Given the significant body of evidence both for3,4 and against5,6 such claims, the issue remains controversial. It is well recognised that cardiopulmonary bypass is an important contributor to post-operative renal failure, coagulopathy and neurological injury. Whilst they were not considered in the article, studies assessing the effect of leukodepletion upon these outcomes have been performed, and may support some of the authors’ conclusions. Tang et al investigated the effect of systemic leukofiltration upon renal function and found sensitive indicators of renal injury were significantly higher in controls.7 Whilst this was in patients with normal preoperative renal function, research involving those with pre-existing renal disease is warranted. Many authors have considered that leukodepletion might influence postoperative haemostasis.8 Our group has recently metaanalysed thirteen randomised control trials to investigate this possibility, and found leukofiltration to have no significant effect on either chest tube drainage or transfusion requirements.9 Finally, Whitaker et al used Trans-Cranial Doppler and a battery of neurocognitive tests to assess any
benefit in using leukodepleting filters compared to standard practice. In patients randomised to leukodepletion, significantly fewer microemboli were detected and there was a trend towards greater post-operative improvement in neuropsychological performance.10 Whilst there exists a large number of trials investigating this technology, most are small and have limitations in their methodology.2 We join the authors in calling for well-powered future trials to investigate any effect on hard clinical endpoints, as opposed to surrogate markers of organ damage. These trials should incorporate strategies to prevent filter exhaustion at critical times, one of the factors that may have previously limited any positive findings, and consider incorporating other methods of maximising the impact of leukofiltration, such as simultaneous aprotinin administration, which may have a synergistic effect.11 Finally, they should target (as opposed to exclude) high risk, fragile patients, as this cohort may have the most to gain. Oliver Warren, BSc (Hons), MRCS (Eng) a,∗ Ara Darzi, MD, FMedSci, HonFREng, KBE a Thanos Athanasiou, MD, PhD, FETCS a,b a Department of BioSurgery and Surgical Technology, Imperial College, St. Mary’s Hospital, London, United Kingdom b Department of Cardiothoracic Surgery, Imperial College, St. Mary’s Hospital, London, United Kingdom Corresponding author at: Department of BioSurgery and Surgical Technology, Imperial College, 10th Floor QEQM Building, St. Mary’s Hospital, London W2 1NY, United Kingdom. Tel.: +44 207 886 1947; fax: +44 207 886 1810. E-mail address: [email protected] (O. Warren) Available online 30 July 2007
References 1. Lim HK, Anderson J, Leong JY, Pepe S, Salamonsen RF, Rosenfeldt FL. What is the Role of Leukocyte Depletion in Cardiac Surgery? Heart Lung Circ 2007;16:243–53. 2. Warren O, Alexiou C, Massey R, Leff D, Purkayastha S, Kinross J, Darzi A, Athanasiou T. The effects of various leukocyte filtration strategies in cardiac surgery. Eur J Cardiothorac Surg 2007;31:665–76. 3. Samankatiwat P, Samartzis I, Lertsithichai P, Stefanou D, Punjabi PP, Taylor KM, Gourlay T. Leucocyte depletion in cardiopulmonary bypass: a comparison of four strategies. Perfusion 2003;18(2):95–105. 4. Chen YF, Tsai WC, Lin CC, Tsai LY, Lee CS, Huang CH, Pan PC, Chen ML. Effect of leukocyte depletion on endothelial cell activation and transendothelial migration of
© 2007 Australasian Society of Cardiac and Thoracic Surgeons and the Cardiac Society of Australia and New Zealand. Published by Elsevier Inc. All rights reserved.
1443-9506/04/$30.00
5.
6.
7.
8.
9.
10.
11.
leukocytes during cardiopulmonary bypass. Ann Thorac Surg 2004;78(2):634–42, discussion 642-633. Stefanou DC, Gourlay T, Asimakopoulos G, Taylor KM. Leucodepletion during cardiopulmonary bypass reduces blood transfusion and crystalloid requirements. Perfusion 2001;16(1):51–8. Fabbri A, Manfredi J, Piccin C, Soffiati G, Carta MR, Gasparotto E, Nardon G. Systemic leukocyte filtration during cardiopulmonary bypass. Perfusion 2001;16(Suppl.): 11–8. Tang AT, Alexiou C, Hsu J, Sheppard SV, Haw MP, Ohri SK. Leukodepletion reduces renal injury in coronary revascularization: a prospective randomized study. Ann Thorac Surg 2002;74(2):372–7, discussion 377. Gu YJ, de Vries AJ, Boonstra PW, van Oeveren W. Leukocyte depletion results in improved lung function and reduced inflammatory response after cardiac surgery. J Thorac Cardiovasc Surg 1996;112(2):494–500. Warren O, Wallace S, Massey R, Tunnicliffe C, Alexiou C, Powell J, Meisuria N, Darzi A, Athanasiou T. Does systemic leukocyte filtration affect peri-operative haemorrhage in cardiac surgery? A systematic review and meta-analysis. ASAIO J 2007;53:514–21. Whitaker DC, Newman SP, Stygall J, Hope-Wynne C, Harrison MJ, Walesby RK. The effect of leucocyte-depleting arterial line filters on cerebral microemboli and neuropsychological outcome following coronary artery bypass surgery. Eur J Cardiothorac Surg 2004;25(2):267–74. Gott JP, Cooper WA, Schmidt Jr FE, Brown IIIrd WM, Wright CE, Merlino JD, Fortenberry JD, Clark WS, Guyton RA. Modifying risk for extracorporeal circulation: trial of four antiinflammatory strategies. Ann Thorac Surg 1998;66(3):747–53, discussion 753-744.
doi: 10.1016/j.hlc.2007.06.520
Response to Letter to the Editor
W
e wish to thank Warren and co-workers for their comments on our review of leucocyte filtration (LF) in cardiac surgery and would like to respond to some of the critical comments they raised. Warren and co-workers claim that we have published a ‘selective review’ encompassing under half of the current human literature and that this created a potential selection bias which ‘makes the data synthesis difficult to interpret’. We did not set out to perform a systematic search of all the literature, but rather focused on, as indicated in our introduction, ‘the highest quality clinical studies available’. In practice we actually retrieved 69 articles. From these we identified and reviewed 42 prospective randomised clinical trials. We acknowledge that some papers may have escaped our attention, but having read the recent systematic review on leucocyte filtration by Warren and co-workers in the European Journal of Cardiothoracic Surgery,1 our conclusions remain unchanged. Warren and co-workers stated in their letter, ‘The authors report the leuco-depleting filters do achieve their primary goal of leucocyte removal both in vitro and in vivo’, but that ‘leucocyte depleting filters do not appear consistently to lower leucocyte concentration in the circulation or they do so only transiently’. We would agree
Letters to the Editor
399
with this. In our clinical study,2 one of the largest in the literature, we performed a randomised trial in 300 patients of ‘total leucocyte filtration’, involving five filters in each patient. Here we found a marginal reduction in leucocyte and neutrophil counts upon arrival in the intensive care unit but not thereafter. Clearly, the filters remove leucocytes during surgery, but afterwards these are rapidly restored to the circulation from the bone marrow and other sources. However even if leucocytes are reduced only during the post cross-clamp and post-bypass period (the period of reperfusion injury), then this could have an important clinical benefit. Warren and co-workers claim that we did not consider the effect L.F. on renal failure, coagulopathy and neurological injuries. We respond that we did actually examine the evidence of any effects of L.F. on these end points and did in fact mention the effect L.F. on renal failure in Table 1. But as there were few effects, we did not discuss this aspect of leucocyte filtration separately. Currently there is inconclusive evidence of a beneficial effect of L.F on neurological function. Finally Warren and co-workers agree with our conclusions that future trials should target high-risk patients with important clinical outcomes. We concur wholeheartedly with this but would emphasise that our review already separated out, and analysed in detail, the existing trials on this group of patients. Our conclusion was that when studies of the effect of L.F. on high-risk cardiac surgery patients (especially those using cardioplegia filters) are focused upon, then beneficial effects of L.F. are seen. We concluded that the patients likely to benefit from L.F. are the (high risk) group with any of the following: left ventricular hypertrophy, diminished ejection fraction, cardiogenic shock or obstructive airways disease. Other groups likely to benefit are, patients undergoing prolonged aortic crossclamping, paediatric cardiac surgery emergency coronary artery bypass grafting or cardiac transplantation. During transplantation of the heart or the lungs the transplanted organ is subjected to a prolonged period of ischaemia, sustains substantial ischaemic injury and is therefore very vulnerable to reperfusion injury involving leucocytes. We believe that this is the scenario where the benefits of L.F. could most readily be seen. The two published studies in patients undergoing heart transplantation showed benefit of L.F. manifested by reduced levels of CPKMB and thromboxane B23 and lessened histological damage.4 Warren and co-workers recently published a comprehensive review of L.F. strategies in cardiac surgery.1 However, a careful reading of this review fails to find any useful advice for the practising surgeon other than that further research needs to be done. We believe that from the 14 years of published L.F. studies some conclusions can be drawn. Yes, further trials are indicated, but in the meantime we can expect some benefits with proper use of the filter where there is evidence of substantial reperfusion injury, namely high-risk patients and those undergoing prolonged or complicated procedures. We stand by our recommendation to use leucocyte depleting filters these high-risk surgical groups.
LETTERS TO THE EDITOR
Heart, Lung and Circulation 2007;16:398–400
Letters to the Editor
What is the Role of Leukocyte Depletion in Cardiac Surgery?
W
e read with interest the recent article by Lim et al. and applaud the novel way in which they address the potential impact of leukodepletion in cardiac surgery.1 Whilst we agree with their conclusions, we feel that there are certain areas that deserve further consideration. We recognise that the authors do not claim to have performed a systematic search, but the selection criteria for the included studies is unclear and those selected reflect under half of the current human literature.2 Furthermore, 16 of these studies involve cardioplegic leukofiltration, which is an over-representation of this method when considering the literature as a whole. This creates a potential selection bias, has led to important randomised trials and certain outcomes not being considered within the article, and as such makes the reported data synthesis (Table 4) very difficult to interpret. The authors report that leukodepleting filters do achieve their primary goal of leukocyte removal, both in vitro and in vivo. Whilst it is indisputable that leukodepleting filters remove leukocytes from a stream of blood they do not appear to consistently lower leukocyte concentrations within the circulation, or they do it only transiently.3 Knowing this, some have suggested that leukodepleting filters may preferentially remove activated leukocytes from the circulation. Given the significant body of evidence both for3,4 and against5,6 such claims, the issue remains controversial. It is well recognised that cardiopulmonary bypass is an important contributor to post-operative renal failure, coagulopathy and neurological injury. Whilst they were not considered in the article, studies assessing the effect of leukodepletion upon these outcomes have been performed, and may support some of the authors’ conclusions. Tang et al investigated the effect of systemic leukofiltration upon renal function and found sensitive indicators of renal injury were significantly higher in controls.7 Whilst this was in patients with normal preoperative renal function, research involving those with pre-existing renal disease is warranted. Many authors have considered that leukodepletion might influence postoperative haemostasis.8 Our group has recently metaanalysed thirteen randomised control trials to investigate this possibility, and found leukofiltration to have no significant effect on either chest tube drainage or transfusion requirements.9 Finally, Whitaker et al used Trans-Cranial Doppler and a battery of neurocognitive tests to assess any
benefit in using leukodepleting filters compared to standard practice. In patients randomised to leukodepletion, significantly fewer microemboli were detected and there was a trend towards greater post-operative improvement in neuropsychological performance.10 Whilst there exists a large number of trials investigating this technology, most are small and have limitations in their methodology.2 We join the authors in calling for well-powered future trials to investigate any effect on hard clinical endpoints, as opposed to surrogate markers of organ damage. These trials should incorporate strategies to prevent filter exhaustion at critical times, one of the factors that may have previously limited any positive findings, and consider incorporating other methods of maximising the impact of leukofiltration, such as simultaneous aprotinin administration, which may have a synergistic effect.11 Finally, they should target (as opposed to exclude) high risk, fragile patients, as this cohort may have the most to gain. Oliver Warren, BSc (Hons), MRCS (Eng) a,∗ Ara Darzi, MD, FMedSci, HonFREng, KBE a Thanos Athanasiou, MD, PhD, FETCS a,b a Department of BioSurgery and Surgical Technology, Imperial College, St. Mary’s Hospital, London, United Kingdom b Department of Cardiothoracic Surgery, Imperial College, St. Mary’s Hospital, London, United Kingdom Corresponding author at: Department of BioSurgery and Surgical Technology, Imperial College, 10th Floor QEQM Building, St. Mary’s Hospital, London W2 1NY, United Kingdom. Tel.: +44 207 886 1947; fax: +44 207 886 1810. E-mail address: [email protected] (O. Warren) Available online 30 July 2007
References 1. Lim HK, Anderson J, Leong JY, Pepe S, Salamonsen RF, Rosenfeldt FL. What is the Role of Leukocyte Depletion in Cardiac Surgery? Heart Lung Circ 2007;16:243–53. 2. Warren O, Alexiou C, Massey R, Leff D, Purkayastha S, Kinross J, Darzi A, Athanasiou T. The effects of various leukocyte filtration strategies in cardiac surgery. Eur J Cardiothorac Surg 2007;31:665–76. 3. Samankatiwat P, Samartzis I, Lertsithichai P, Stefanou D, Punjabi PP, Taylor KM, Gourlay T. Leucocyte depletion in cardiopulmonary bypass: a comparison of four strategies. Perfusion 2003;18(2):95–105. 4. Chen YF, Tsai WC, Lin CC, Tsai LY, Lee CS, Huang CH, Pan PC, Chen ML. Effect of leukocyte depletion on endothelial cell activation and transendothelial migration of
© 2007 Australasian Society of Cardiac and Thoracic Surgeons and the Cardiac Society of Australia and New Zealand. Published by Elsevier Inc. All rights reserved.
1443-9506/04/$30.00
5.
6.
7.
8.
9.
10.
11.
leukocytes during cardiopulmonary bypass. Ann Thorac Surg 2004;78(2):634–42, discussion 642-633. Stefanou DC, Gourlay T, Asimakopoulos G, Taylor KM. Leucodepletion during cardiopulmonary bypass reduces blood transfusion and crystalloid requirements. Perfusion 2001;16(1):51–8. Fabbri A, Manfredi J, Piccin C, Soffiati G, Carta MR, Gasparotto E, Nardon G. Systemic leukocyte filtration during cardiopulmonary bypass. Perfusion 2001;16(Suppl.): 11–8. Tang AT, Alexiou C, Hsu J, Sheppard SV, Haw MP, Ohri SK. Leukodepletion reduces renal injury in coronary revascularization: a prospective randomized study. Ann Thorac Surg 2002;74(2):372–7, discussion 377. Gu YJ, de Vries AJ, Boonstra PW, van Oeveren W. Leukocyte depletion results in improved lung function and reduced inflammatory response after cardiac surgery. J Thorac Cardiovasc Surg 1996;112(2):494–500. Warren O, Wallace S, Massey R, Tunnicliffe C, Alexiou C, Powell J, Meisuria N, Darzi A, Athanasiou T. Does systemic leukocyte filtration affect peri-operative haemorrhage in cardiac surgery? A systematic review and meta-analysis. ASAIO J 2007;53:514–21. Whitaker DC, Newman SP, Stygall J, Hope-Wynne C, Harrison MJ, Walesby RK. The effect of leucocyte-depleting arterial line filters on cerebral microemboli and neuropsychological outcome following coronary artery bypass surgery. Eur J Cardiothorac Surg 2004;25(2):267–74. Gott JP, Cooper WA, Schmidt Jr FE, Brown IIIrd WM, Wright CE, Merlino JD, Fortenberry JD, Clark WS, Guyton RA. Modifying risk for extracorporeal circulation: trial of four antiinflammatory strategies. Ann Thorac Surg 1998;66(3):747–53, discussion 753-744.
doi: 10.1016/j.hlc.2007.06.520
Response to Letter to the Editor
W
e wish to thank Warren and co-workers for their comments on our review of leucocyte filtration (LF) in cardiac surgery and would like to respond to some of the critical comments they raised. Warren and co-workers claim that we have published a ‘selective review’ encompassing under half of the current human literature and that this created a potential selection bias which ‘makes the data synthesis difficult to interpret’. We did not set out to perform a systematic search of all the literature, but rather focused on, as indicated in our introduction, ‘the highest quality clinical studies available’. In practice we actually retrieved 69 articles. From these we identified and reviewed 42 prospective randomised clinical trials. We acknowledge that some papers may have escaped our attention, but having read the recent systematic review on leucocyte filtration by Warren and co-workers in the European Journal of Cardiothoracic Surgery,1 our conclusions remain unchanged. Warren and co-workers stated in their letter, ‘The authors report the leuco-depleting filters do achieve their primary goal of leucocyte removal both in vitro and in vivo’, but that ‘leucocyte depleting filters do not appear consistently to lower leucocyte concentration in the circulation or they do so only transiently’. We would agree
Letters to the Editor
399
with this. In our clinical study,2 one of the largest in the literature, we performed a randomised trial in 300 patients of ‘total leucocyte filtration’, involving five filters in each patient. Here we found a marginal reduction in leucocyte and neutrophil counts upon arrival in the intensive care unit but not thereafter. Clearly, the filters remove leucocytes during surgery, but afterwards these are rapidly restored to the circulation from the bone marrow and other sources. However even if leucocytes are reduced only during the post cross-clamp and post-bypass period (the period of reperfusion injury), then this could have an important clinical benefit. Warren and co-workers claim that we did not consider the effect L.F. on renal failure, coagulopathy and neurological injuries. We respond that we did actually examine the evidence of any effects of L.F. on these end points and did in fact mention the effect L.F. on renal failure in Table 1. But as there were few effects, we did not discuss this aspect of leucocyte filtration separately. Currently there is inconclusive evidence of a beneficial effect of L.F on neurological function. Finally Warren and co-workers agree with our conclusions that future trials should target high-risk patients with important clinical outcomes. We concur wholeheartedly with this but would emphasise that our review already separated out, and analysed in detail, the existing trials on this group of patients. Our conclusion was that when studies of the effect of L.F. on high-risk cardiac surgery patients (especially those using cardioplegia filters) are focused upon, then beneficial effects of L.F. are seen. We concluded that the patients likely to benefit from L.F. are the (high risk) group with any of the following: left ventricular hypertrophy, diminished ejection fraction, cardiogenic shock or obstructive airways disease. Other groups likely to benefit are, patients undergoing prolonged aortic crossclamping, paediatric cardiac surgery emergency coronary artery bypass grafting or cardiac transplantation. During transplantation of the heart or the lungs the transplanted organ is subjected to a prolonged period of ischaemia, sustains substantial ischaemic injury and is therefore very vulnerable to reperfusion injury involving leucocytes. We believe that this is the scenario where the benefits of L.F. could most readily be seen. The two published studies in patients undergoing heart transplantation showed benefit of L.F. manifested by reduced levels of CPKMB and thromboxane B23 and lessened histological damage.4 Warren and co-workers recently published a comprehensive review of L.F. strategies in cardiac surgery.1 However, a careful reading of this review fails to find any useful advice for the practising surgeon other than that further research needs to be done. We believe that from the 14 years of published L.F. studies some conclusions can be drawn. Yes, further trials are indicated, but in the meantime we can expect some benefits with proper use of the filter where there is evidence of substantial reperfusion injury, namely high-risk patients and those undergoing prolonged or complicated procedures. We stand by our recommendation to use leucocyte depleting filters these high-risk surgical groups.
LETTERS TO THE EDITOR
Heart, Lung and Circulation 2007;16:398–400