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Continuous and discontinuous cell-washing autotransfusion systems
REVIEW ARTICLES Martin J. London, MD Section Editor
Continuous and Discontinuous Cell-Washing Autotransfusion Systems Biao Dai, CCP, CPC,* Lexin Wang, MD, PhD,† George Djaiani, MD, FRCPC,‡ and C. David Mazer, MD, FRCPC‡
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ENTRIFUGE-BASED cell-washing autotransfusion systems have been used as a method of blood conservation since the 1970s. The advantages of diminishing the requirements of allogeneic blood, thereby reducing risk of hepatitis C and human immunodeficiency virus transmission, have been well documented.1,2 The quality of washed red blood cells (RBCs) is at least as good as banked blood,1,3-6 with an excellent safety record of intraoperative autotransfusion.7 However, the extent to which the salvaged blood is contaminated with activated leukocytes, platelets, or other plasma elements, such as fat particles, is unclear. The clinical significance of these issues remains controversial. With the recent introduction of the continuous autotransfusion system (CATS), the dominance of conventional, discontinuous autotransfusion systems (DATS) has been challenged. The differences between both systems in terms of the quality of washed blood are currently under investigation. The aim of this review is to summarize the developments in the area of cell-washing autotransfusion, with an attempt to introduce new research possibilities. PRINCIPLE OF DISCONTINUOUS AND CONTINUOUS AUTOTRANSFUSION
Autotransfusion devices were developed in the 1960s based on a conical-shaped collection container (Latham bowl).8 These devices are discontinuous systems. The shed blood that is collected in a reservoir from the surgical field via suction is first pumped into a spinning Latham bowl (approximate volume 225 mL). The RBCs that are heavier than other blood components are spun to the periphery of the bowl and become concentrated with centrifugation. In the meantime, the waste plasma overflows into a waste-collecting bag. Once RBCs in the centrifugation bowl are concentrated to a certain level (determined by
From the Departments of ‡Anesthesia and *Cardiovascular Perfusion, St. Michael’s Hospital and Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada; and †School of Biomedical Sciences, Charles Sturt University, Wagga Wagga, NSW, Australia. Address reprint requests to C. David Mazer, MD, FRCPC, Department of Anesthesia, St. Michael’s Hospital, 30 Bond Street, Toronto M5B 1W8, Canada. E-mail: [email protected] © 2004 Elsevier Inc. All rights reserved. 1053-0770/04/1802-0020$30.00/0 doi:10.1053/j.jvca.2004.01.001 Key words: autotransfusion, blood-washing systems, blood loss, transfusions, complications 210
a special sensor), the flow of blood from the reservoir is stopped and the washing procedure is started. The free hemoglobin, coagulation factors, debris, and other plasma components that are lighter than RBCs are replaced by the washing saline that is pumped through the layers of RBCs during the washing period. Once the required washing volume is reached, the centrifuge is stopped. The washed concentrated RBCs are collected into a reinfusion bag. The entire procedure can be repeated again if additional blood needs to be processed. Therefore, the blood is discontinuously processed in units9 (Fig 1). In 1995, Fresenius introduced the first continuous autotranfusion system (CATS; Fresenius AG, Bad Homburg, Germany). The shed blood collected in a reservoir from the surgical field is suctioned by the first pump into a spinning separation chamber (approximate volume 30 mL), which contains a blood channel in the shape of a double spiral, instead of a Latham bowl. The RBCs that initially come into the separation chamber via the inner spiral move to the outer spiral because of centrifugal force, and on their way, they are washed with saline that is added by a second pump. The free hemoglobin, coagulation factors, fat, debris, and other plasma components that are separated with heavier RBCs by centrifugal force leave the double spiral at the innermost point with washing solution. Meanwhile, washed concentrated RBCs are collected by a third pump into a reinfusion bag. Three steps including filling, washing, and emptying are performed simultaneously until all the blood is processed. Thus, the blood is processed continuously (Fig 2). In contrast with the discontinuous system, the washed blood is collected into the reinfusion bag while the separation chamber is still rotating. This method allows continuous blood processing, including washing and hemoconcentration, instead of processing in units.9 Thus, this method is independent of the blood volume to be processed, allowing the operator of the equipment to reinfuse autologous erythrocytes to the patient as required. Other possible advantages of the CATS include smaller priming volumes (30 mL v 225 mL), smaller centrifugal forces generated,8 and higher hematocrit of the processed red cells10 (Tables 1 and 2). RED BLOOD CELLS
The quality of RBCs of processed blood with autotransfusion devices has been previously studied. The washed RBCs were shown to be at least as good as banked blood cells,1,3-5 although some researchers found evidence of red cell damage during the suction and centrifugation of autotransfusion. Paravicini11 showed with electron microscopy that washed red cells ap-
Journal of Cardiothoracic and Vascular Anesthesia, Vol 18, No 2 (April), 2004: pp 210-217
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washed RBCs and nonwashed cells in terms of mean corpuscular volume, mean corpuscular hemoglobin concentration, and mean corpuscular hemoglobin. Measurement of erythrocyte adenosine triphosphate level and their survival rate with 51Cr or 111In may be even better indicators for assessing the quality of red cells. However, to date, no studies using this technology for processed RBCs have been reported. The comparison between DATS and CATS in terms of red cell quality is also lacking at present, whereas the red cell recovery rate of both systems is similar.15 PLATELETS
coworkers15
Fig 1. Discontinuous autotransfusion system. (I) Blood collected in a reservoir from the surgical field is pumped into the centrifuging bowl. (II) With centrifugation, the heavier red blood cells are spun to the periphery of the bowl and become more concentrated. The waste plasma overflows into a waste-collecting bag. (III) Once the centrifuging bowl is filled with a certain number of red blood cells, the flow of blood from the reservoir is stopped and washing is started. The free hemoglobin, coagulation factors, debris, and other plasma components are replaced by the saline that is pumped through the layers of red blood cells. (IV) Once washing is completed, the centrifuge is stopped. The washed red blood cells are collected into a reinfusion bag. The entire procedure will be repeated again if additional blood needs to be processed. Therefore, the blood is discontinuously processed in units.
peared to have increased membrane folding and protuberances, similar to that of packed RBCs. Kirkpatrick and coworkers12 found that salvaged red cells have reduced deformability, similar to stored bank blood, which was supported by Mortelmans et al6 as well. Because shed blood could be exposed to more adverse factors during orthopedic surgery relative to other operations, Mortelmans et al6 studied the quality of washed shed blood during the total hip replacement. Indices of red cell quality examined included mean corpuscular volume, mean corpuscular hemoglobin concentration, red cell distribution width, total hemolysis, osmotic fragility, filterability ratio, glutathione reductase, and glutathione stability. All parameters were normal compared with the patient’s baseline, with the exception of moderate hemolysis and decreased filterability.6 They speculated that hemolysis might be reduced and filterability might be better maintained in other less-invasive surgical procedures. In other studies, no changes in the 2,3-diphosphoglycerate level were observed during the cell-washing procedure, which suggests the oxygen-carrying capability of red cells is maintained.6,13 Walpoth et al14 evaluated the quality of washed red cells in cardiac surgery. They failed to show any differences between
Geiger and studied the elimination of platelets by several autotransfusion devices. CATS was shown to have the lowest platelet elimination rate (75%), compared with discontinuous devices (88%-93%). Thus, the platelet count in the processed blood may be only 10% of the patient’s hematocritcorrected counts.16 Platelets obtained from salvaged blood do not aggregate normally to stimuli, which may indicate platelet dysfunction.17 This may result from platelet activation. Furthermore, platelets have been implicated in the Cell Salvage Syndrome, described by Bull et al18 in 1988. In their study, the Haemonetics Cell Saver (Haemonetics Corp, Braintree, MA) was used in 21 dogs to examine the formation and potency of procoagulant and leukoattractant material during autologous blood salvage. Washed red cell suspensions were found to contain toxic degradation products that had been released from deposition of platelets and white cells adherent to the wall of the centrifuge bowl. When reinfused into dogs, these toxic products resulted in a “salvaged blood syndrome” that consisted of intravascular clotting, pulmonary edema, and hemorrhage.18 This may be attenuated by avoidance of exogenous calcium, partially clotted blood, or excessive saline during intraoperative red cell salvage.19 Bull and Bull19 also reported a clinical case in which disseminated intravascular coagulopathy (DIC) and/or acute respiratory distress syndrome (ARDS) were observed after the administration of washed autologous red cells. They hypothesized that mechanically activated platelets during the cellwashing procedure release leukoattractant substances, including arachidonate-rich phospholipids, which trigger the oxidative burst enzymatic pathway in exposed phagocytic cells. These substances, when reinfused, cause increased vascular permeability that presents clinically as ARDS, whereas DIC results from reinfused platelet phospholipid and accompanying cellular debris.20 However, Tawes and Duvall7 challenged this theory with a retrospective review of more than 36,000 cellsalvaging cases during an 18-year experience in an attempt to link the occurrence of this syndrome with the use of cell-saving technology. A total of 18 cases (0.05%) were identified: 10 associated with ruptured aneurysms, 6 after massive trauma, and 2 after complex redo cardiac surgery. The mean transfusion requirement was 28 units. They concluded that DIC and ARDS occur infrequently and are more likely a result of the complex interaction of shock, hypothermia, multiple transfusions, reperfusion injury, and multiorgan failure, instead of resulting from cell saving.7 It should be noted that the majority of the evidence of platelet activation was reported in association with DATS. The
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Fig 2. Continuous autotransfusion system. The shed blood collected in a reservoir from the surgical field is first suctioned by a pump into a spinning separation chamber (approximate volume 30 mL) that contains a blood channel in the shape of a double spiral, instead of a Latham bowl. The red blood cells that initially come into the separation chamber via the inner spiral move to the outer spiral due to centrifugal force, and on their way, they are washed with saline that is added by a second pump. The free hemoglobin, coagulation factors, fat, debris, and other plasma components that are separated with heavier red blood cells by centrifugal force leave the double spiral at the innermost point with washing solution. Meanwhile, washed concentrated red blood cells (PRC) are collected by a third pump into a reinfusion bag. Three steps including filling, washing, and emptying are performed simultaneously until all the blood is processed. Thus, the blood is processed continuously. The CATS system has 3 separate pumps whereas discontinuous systems use only one pump for all stages of processing. (Figure modified with permission from Fresenius CATS Operating Instructions, Nov 1997.)
effect of CATS on platelet function is an area for potential future investigation, especially because CATS eliminates fewer platelets than DATS. In cardiac surgery, it is well known that the cardiopulmonary bypass (CPB) causes activation of platelets.21-24 It has been reported that processing salvaged blood during CPB using autotransfusion devices reduced the load of activated platelets being reinfused.25 However, the clinical benefits of this may also be related to fat particle removal instead of platelets alone. Table 1. Specifications of Selected Continuous and Discontinuous Systems10 Parameter
Centrifugal speed (rpm) Gravity force Geometry of bowl/chamber Priming volume (mL) RBC collecting mode
Sequestra 1000*
Brat 2†
LEUKOCYTES
Although the washing process is intended to remove the buffy coat that contains platelets and leukocytes, Holleufer and von Bormann17 reported only a 50% leukocyte elimination rate for DATS. Furthermore, Walpoth et al14 found that the leukocyte elimination rate for CATS was only 35%. Geiger et al15 studied 8 autotransfusion devices to determine their capability for leukocyte elimination. In that study, CATS eliminated 50% of leukocytes,
Table 2. Comparison Between DATS and CATS
CATS‡
5600 820–1070g
4400 1220–1400g
2000 330–680g
Conical
Cylindrical
Channel
225
225
30
Discontinuous
Discontinuous
Continuous
Abbreviations: RBC, red blood cell; CATS, continuous autotransfusion system. *Sequestra 1000: Medtronic, Inc, Minneapolis, MN. †Brat 2: COBE Cardiovascular, Inc, Arvada, CO. ‡CATS: Fresenius AG, Bad Homburg, Germany.
Red cell recovery Red cell quality* Leukocyte removal Leukocyte activation* Platelet removal Platelet activation* Fat removal Tumor cell removal† Cytokine and complement removal
DATS
CATS
⫹⫹⫹ ⫹⫹ ⫹⫹ ⫹⫹ ⫹⫹ ⫹⫹ ⫹ ⫹⫹ ⫹⫹
⫹⫹⫹ ⫹⫹ ⫹ ⫹ ⫹ ⫹ ⫹⫹⫹ ⫹ ⫹⫹
Abbreviations: DATS, discontinuous autotransfusion system; CATS, continuous autotransfusion system; ⫹, effect present; ⫹⫹, market effect; ⫹⫹⫹, very marked effect. *Limited information. †Based on the assumption that tumor cell removal is similar to leukocytes.
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whereas the range for DATS was 80% to 94%. This report confirmed the previous findings that both systems were relatively ineffective in completely removing leukocytes.14,26 McShane et al5 found microscopic damage to 75% of neutrophils in patients having cardiac surgery involving CPB. Seidel et al27 reported significant impairment of the chemotactic response and superoxide generation of polymorphonuclear leukocytes (PMNs) after cell washing, as compared to PMNs of healthy volunteers. Connall et al26 quantified the surface expression of the leukocyte adhesion receptors CD11b (n ⫽ 6) and CD18 (n ⫽ 6). They found CD 11b was about 3 times greater on PMNs and 4 times greater on monocytes from salvaged blood compared with arterial blood. CD18 was increased 3 times on PMNs and 21⁄2 times on lymphocytes in salvaged blood compared with arterial blood, consistent with activation of PMNs in the salvaged blood. Perttila et al28 studied respiratory burst of leukocytes in autologous blood during cardiac surgery and found that PMN activity in the processed blood was 30% higher in 4 of 10 patients. The authors recommended that processed blood should not be retransfused when reperfusion injury is likely to occur. These findings have been further confirmed by assaying hydrogen peroxide formation in blood processed with DATS.12 However, Innerhofer et al29 studied activation of PMN with CATS instead of DATS, evaluating chemotactic response and respiratory burst (n ⫽ 20). The results indicated that PMNs contained in the CATS-processed blood were neither impaired nor activated relative to the priming threshold. Siriwardhana et al30 suggested that leukocytes might be activated by the autotransfusion device, as a result of activation of the complement cascade shown by high level of C3a in the waste bag. Bull and Bull18 also indicated in their animal study that the autotransfusion device might be the main site of leukocyte activation. However, previous reports of patients undergoing orthopedic surgery found that collected wound blood itself contained inflammatory mediators from activated complements, lysosomal enzymes, and cytokines from activated leukocytes.31,32 Bengtsson et al33 studied 18 patients undergoing hip replacement surgery, reporting significantly increased concentration of C3a and SC5b-9 in the collected reservoir blood compared with the patients’ preoperative levels. These concentrations could be substantially reduced by the washing procedure. In cardiac surgery, CPB may be the source of activation of leukocytes in extravasated wound blood.34 Exposure of blood to tissue, air, and subsequent mechanical stress caused by the pump suction may also play an important role in leukocyte activation.25,35,36 Washing of shed blood by autotransfusion devices might not have a major influence on the activation process itself, however, because these devices fail to completely remove proinflammatory cytokines present before washing.25,37 If leukocytes are already activated before entering the centrifugal chamber, different autotransfusion systems may not yield different results with respect to the degree of leukocyte activation. Therefore, only systems with low elimination rates of leukocytes may be of concern. Activated leukocytes may be detrimental if they are infused back to the patient. In a canine model, Bull and Bull18,19 found
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an association between activation of leukocyte/platelet and acute lung injury. If the main activation site is in the separation chamber or the Latham bowl in which the centrifugation takes place, the clinical safety of autotransfusion systems needs to be reevaluated, or improvements on the system biocompatibility are required. If the leukocytes are activated before entering the centrifugal chamber, autotransfusion systems reduce their load and, hence, a beneficial clinical effect is expected. This hypothesis is supported by Walpoth et al38 who reported that CATS processing of CPB blood reduced the load of activated leukocytes and relevant mediators (⬎93%). Reents et al25 reported similar results with a DATS (Haemonetics). Previous studies reported significantly lower elimination rates of leukocytes with CATS compared with DATS.12,14,15,26 However, the research of Innerhofer et al29 in an orthopedic patient population suggested that PMNs were not activated with CATS to the threshold that may induce endothelial damage, indicating CATS may have a better biocompatibility in terms of leukocyte activation. Although activation of leukocytes with DATS has been well shown,12,14,26,27 leukocyte activation with CATS requires further research. In light of evidence that activation of leukocytes may occur before entering both types of autotransfusion systems, the disadvantage of lower elimination rate of leukocytes with CATS needs further clinical evaluation. Mortelmans et al6 showed that the quality of washed RBCs was significantly better with heparin than citrate as anticoagulant. On the other hand, Bull and Bull19 suggested that citrate might be preferable because it could minimize the concentration of calcium ions. This might reduce the phorbol myristate acetate-stimulated respiratory burst (PMA-RB) of PMNs (the receptor-independent pathway of leukocyte activation), potentially avoiding the salvaged blood syndrome due to the presence of activated platelets and leukocytes.20 Innerhofer et al29 did not detect any differences in PMA-RB between heparin (n ⫽ 10) and citrate groups (n ⫽ 10) using CATS, but this study was limited by a small sample size and a relatively large SD of PMA-RB measurements. They also observed that leukocyte and platelet counts were lower in the processed autologous blood from patients in the heparin group. It is speculated that heparin promotes PMN-platelet interactions, leading to formation of PMN-platelet complexes that are removed by the washing process.29 Further study is needed to identify the best anticoagulant for autotransfusion with respect to the activation of leukocytes. Given the evidence indicating that retransfused leukocytes are potentially detrimental, it might seem reasonable to attempt to remove any residual leukocytes in the retransfusion bag. Leukocyte-depleting filters could be effective in achieving this goal. Gu et al39 showed that leukocyte-depleting filters remove as much as 97% of the leukocyte load. Ramirez et al40 tested 4 leukocyte-depleting filters (BIO R, BIO R Plus, Fresenius AG; RC100KLE, Pall Biomedical; Immugard III-RC, Terumo). All filters evaluated were capable of removing almost all leukocytes.40 However, 2 questions have been raised: (1) Is there a clinical benefit? and (2) Is the use of leukodepletion safe? Leukodepletion has recently been evaluated in the setting of cardiopulmonary bypass but the clinical benefits have not been firmly established.41-43 In 1999, the US Food and Drug Admin-
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istration issued an alert addressing the association between bedside leukodepletion and hypotensive events.44 Evidence suggested that this might be caused by bradykinin production after platelet exposure to negatively charged leukocyte filters.45 However, cell-saving devices are able to remove at least 75% of platelets.15 Therefore, filtration of washed blood with leukocyte filters may not pose as many problems as when used for other blood products. CYTOKINES AND COMPLEMENTS
As a result of surgical trauma, activated leukocytes release proinflammatory cytokines.30,31,42,46-48 Tissue trauma has been also shown to activate the complement cascade (via the alternative pathway), which results in the formation of the anaphylatoxins (C3a, C5a) and the terminal complement complexes (C5b-9).32,49 This may result in damage to end-organ systems.50,51 CPB facilitates this process as does cell-saving processing because of the foreign material contact and shear stress of suction and centrifugation.30,34 However, cell-washing systems appear able to remove the inflammatory mediators effectively during the washing procedure.32,33,52 These systems also effectively remove polymorphonuclear elastase, which is released by activated leukocytes.31 Walpoth et al14 found that CATS was able to eliminate as much as 93% of water-soluble elements including cytokines (interleukin [IL]-6) and complement (C3a, C5b-9). However, the removal of IL8 was only 65%.14 Arnestad et al32 reported that reinfusion of washed blood did not alter plasma concentrations of IL-6. The clinical effects of reinfusion of cytokines and/or complement need to be further investigated, especially when large amounts of shed blood are processed. FAT ELIMINATION
Blood collected during orthopedic and cardiac surgery often contains fat particles from bone marrow and/or subcutaneous fat deposits.53 If these enter the circulation, they may cause fat embolism syndrome, characterized by pulmonary dysfunction,54 neurologic deficits,55-58 and coagulopathy.59 If salvaged blood is returned through an arterial line, as in cardiac surgery with CPB, neurologic complications can occur.60-62 A recent canine study examined postmortem brain tissue after the animals were exposed to CPB. It showed that the majority of microembolic material originated from shed blood collected in the cardiotomy reservoir, which contained cellular debris and fat from dissected tissues and sternal bone marrow. Discarding the cardiotomy blood prevented brain microembolization in these animals.60 Thus, reinfusion of fat particles present in the salvaged shed blood should be avoided whenever possible. DATS may not reliably remove all fat in the collected shed blood.53,63,64 Booke and his colleagues9,65 carried out an in vitro comparison between CATS and DATS (Cell Saver 5, Haemonetics Corp) with respect to fat elimination. The results showed that CATS completely removed fat particles, whereas DATS removed 85% of the fat. In another canine model, Kincaid et al66 examined various methods of processing shed blood during CPB and their impact on cerebral lipid microembolic burden. In the control group (n
⫽ 12), shed blood was collected in a cardiotomy reservoir and reinfused through the arterial circuit. In the cell-saver group (n ⫽ 12), shed blood was collected in a cell saver (DATS or CATS) and reinfused through the CPB circuit. Brain tissue was examined for presence of small capillary and arteriolar dilations (SCADs). Mean SCAD density (SCAD/cm2) was less in the cell-saver group than in the cardiotomy group. Mean SCAD density was reduced even further with CATS versus DATS, although in this small study statistical significance was not achieved. The authors concluded that use of a cell saver to scavenge shed blood during CPB decreased cerebral lipid microembolization. During centrifugation with discontinuous devices, a certain quantity of lighter particles, including fat, may stay in the center of the separation bowl and may not be removed with other waste. Once centrifugation is stopped for emptying, these particles remix with denser red blood cells and are then emptied into the reinfusion bag. In contrast to DATS, CATS is able to continue centrifuging while emptying the washed blood. Therefore, the lighter particles should not remix with the red cells and contamination of the red cells with fat might be avoided.9 Ordinary blood filters do not effectively remove fat.67 Booke et al65 compared efficiency of 3 types of filters: 1 routine blood filter (Microfilter Sangopur 40 m; B. Braun Medical Division, Melsungen, Germany), 1 fat-removing filter (LipiGuard; Pall Corporation, Portsmouth, England), and 1 leukocyte-depleting filter (Purecell RC 400; Pall Corporation, Portsmouth, England). It was observed that the LipiGuard was only as effective as the routine blood filter. About 38% of the fat load remained after filtration. However, the Purecell RC 400 removed 99% of the fat. Ramirez et al40 tested various standard blood filters with a pore size from 40 to 200 m (Sangofix, B. Braun Medical Division, Melsungen, Germany; SQ40SJKL, Pall Biomedical, Portsmouth, England; and BIOM40, Fresenius AG, Bad Homburg, Germany) and leukocyte-depleting surface filters (BIO R, BIO R Plus, Fresenius AG, Bad Homburg, Germany; RC100KLE, Pall Biomedical, Portsmouth, England; Immugard III-RC, Terumo, Japan), together with a specially designed fat and leukocyte-depleting surface filter (LeukoGuard RS, Pall Biomedical, Portsmouth, England). Blood filters were ineffective in removing fat, whereas all surface filters removed almost all fat particles and leukocytes, with the exception of the LeukoGuard RS. It removed some but not all fat particles. During CPB, arterial line blood filters, such as Duraflo II AF-1025D (Baxter Healthcare Corp, Irvine, CA), are ineffective in removing fat particles, likely because of the deformability of the lipid particles that pass through small filter pores.66 Therefore, the combination of autotransfusion systems and an effective leukocyte-depleting surface filter may provide the most complete fat removal. TUMOR CELLS
Oncologic surgery is considered a contraindication to use of cell-washing autotransfusion systems because of the possibility of contamination of processed blood with tumor cells and subsequent metastases after reinfusion. However, there is little evidence that reinfusion of contaminated washed blood increases metastasis.68 Fujimoto et al69 reported no difference between a cell-washing group (n ⫽ 54) and a
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non– cell-washing group (n ⫽ 50) in surgery for hepatocellular carcinoma in terms of tumor recurrence rate or survival rate. The effectiveness of leukocyte depletion filters for eliminating tumor cells left in processed shed blood is also controversial. Edelman et al70 reported that a leukocyte depletion filter (RC-400, DLP Incorporated, Grand Rapids, MI) was able to completely remove tumor cells from urologic malignancies in an in vitro study. However, in another in vitro study, Jones et al71 were only able to eliminate about 75% of cultured hepatocarcinoma cells remaining in the washed blood with either type of leukocyte depletion filters (Pall Leukoguard RS, Pall Purecell RCQ, Pall Biomedical). In this study, neither CATS nor DATS (BRAT2, STAT-P; COBE Cardiovascular Inc, Arvada, CO) removed more than 60% of tumor cells. CONCLUSIONS
Intraoperative cell-washing autotransfusion has been used as an effective method of blood conservation for more than 30 years. The quality of the washed red cells seems to be at least as good as banked red cells. The majority of platelets are removed during the washing procedure, but the effects of retransfusion of residual platelets need to be further investigated, especially as they relate to DIC and/or ARDS. Previous studies have confirmed that both discontinuous and continuous cell-washing autotransfusion systems are ineffective in eliminating leukocytes. Leukocyte activation may be
caused by the exposure of blood to tissue, air, mechanical stress induced by suction, centrifugation, and foreign materials in the cell-washing equipment. Whether CATS is superior to DATS requires further investigation as does the role of residual leukocytes in the occurrence of the “cell-salvage syndrome.” Leukocyte-depleting filters are efficient, although documentation of their clinical benefits also requires further investigation. Cell-washing systems are able to remove as much as 93% of all water-soluble elements including cytokines and complement. However, caution is required when large amounts of processed blood are reinfused because these factors are implicated in many adverse clinical outcomes. Residual fat particles may cause fat embolism syndrome and neurologic complications. Discontinuous cell-washing systems are less effective than CATS in terms of fat removal. The combination of cell-washing autotransfusion systems and leukocyte-depleting filters may provide the most complete fatremoving capability. Use of cell-washing autotransfusion systems remains contraindicated in oncologic surgery. More research is needed to determine if retransfusion of processed blood that may be contaminated with tumor cells adversely affects clinical outcome. Cell-washing autotransfusion systems are a valuable adjunct to the clinical management of patients undergoing a variety of surgical procedures. Future research will help clarify the optimal system to use in specific clinical settings.
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13. Noon GP, Solis T, Natelson EA: A simple method of intraoperative autotransfusion. Surg Gynecol Obstet 143:65-70, 1976 14. Walpoth BH, Eggensperger N, Walpoth-Aslan BN, et al: Qualitative assessment of blood washing with the continuous autologous transfusion system (CATS). Int J Artif Organs 20:234-239, 1997 15. Geiger P, Platow K, Bartl A, et al: New developments in autologous transfusion systems. Anaesthesia 53:32-35, 1998 16. Godet G, Arock M, De Almeida P, et al: Comparison of quality of processed blood obtained from five cell-washing devices during aortic surgery. Br J Anaesth 74:A66, 1995 (abstr) 17. Holleufer RF, von Bormann B: Continuous autotransfusion system (CATS-Fresenius) vs Dideco autotransfusion system (Autotrans-Dideco). First clinical results with a new continuous operating autotransfusion device in vascular surgery. Br J Anaesth 74:A64, 1995 (abstr) 18. Bull MH, Bull BS, Van Arsdell GS, et al: Clinical implications of procoagulant and leukoattractant formation during intraoperative blood salvage. Arch Surg 123:1073-1078, 1988 19. Bull BS, Bull MH: Enhancing the safety of intraoperative RBC salvage. J Trauma 29:320-325, 1989 20. Bull BS, Bull MH: The salvaged blood syndrome: A sequel to mechanochemical activation of platelets and leukocytes? Blood Cells 16:5-23, 1990 21. Rinder CS, Mathew J, Rinder HM, et al: Modulation of platelet surface adhesion receptors during cardiopulmonary bypass. Anesthesiology 75:563-570, 1991 22. Metzelaar MJ, Korteweg J, Sixma JJ, et al: Comparison of platelet membrane markers for the detection of platelet activation in vitro and during platelet storage and cardiopulmonary bypass. J Lab Clin Med 121:579-587, 1993 23. Wahba A, Black G, Koksch M, et al: Cardiopulmonary bypass leads to a preferential loss of activated platelets. A flow cytometric
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assay of platelet surface antigens. Eur J Cardiothorac Surg 10:768-773, 1996 24. Mazer CD, Hornstein A, Freedman J: Platelet activation in warm and cold heart surgery. Ann Thorac Surg 59:1481-1486, 1995 25. Reents W, Babin-Ebell J, Misoph MR, et al: Influence of different autotransfusion devices on the quality of salvaged blood. Ann Thorac Surg 68:58-62, 1999 26. Connall TP, Zhang J, Vaziri ND, et al: Leukocyte CD11b and CD18 expression are increased in blood salvaged for autotranfusion. Am Surg 60:797-800, 1994 27. Seidel J, Schaps D, Pralat U, et al: Veranderungen von Granulozytenfunktionen bei intraoperativem Cell-Saving mit dem Haemonetics Cell Saver. Beitr Infusionsther Klin Ernahr 18:83-86, 1987 28. Perttila J, Leino L, Poyhonen M, et al: Leukocyte content in blood processed by autotransfusion devices during open-heart surgery. Acta Anaesthesiol Scand 39:445-448, 1995 29. Innerhofer P, Wiedermann FJ, Tiefenthaler W, et al: Are leukocytes in salvaged washed autologous blood harmful for the recipient? The results of a pilot study. Anesth Analg 93:566-572, 2001 30. Siriwardhana SA, Kawas A, Lipton JL, et al: Activation of complement by the Haemonetics cell saver 4 system. Can J Anaesth 36:S120, 1990 31. Sieunarine K, Langton S, Lawrence-Brown MMD, et al: Elastase levels in salvaged blood and the effect of cell washing. Aust N Z J Surg 60:203-208, 1990 32. Arnestad JP, Bengtsson A, Bengtson JP, et al: Release of cytokines, polymorphonuclear elastase and terminal C5b-9 complement complex by infusion of wound drainage blood. Acta Orthop Scand 66:334-338, 1995 33. Bengtsson A, Avall A, Tylman M, et al: Effects on complement activation of a new continuous autotransfusion system. Transfus Med 7:107-113, 1997 34. Ornick P, Taylor KM: Immune and inflammatory response after cardiopulmonary bypass, in Gravlee GP (ed): Cardiopulmonary Bypass: Principle and Practice (ed 2). Philadelphia, PA, Williams & Wilkins, 2000, pp 303-319 35. De Haan J, Boonstra PW, Monnink SHJ, et al: Retransfusion of suctioned blood during cardiopulmonary bypass impairs hemostasis. Ann Thorac Surg 59:901-907, 1995 36. Chung JH, Gikakis N, Rao K, et al: Pericardial blood activates the extrinsic coagulation pathway during clinical cardiopulmonary bypass. Circulation 93:2014-2018, 1996 37. Tabuchi N, Sunamori M, Koyama T, et al: Remaining procoagulant property of wound blood washed by a cell-saving device. Ann Thorac Surg 71:1749-1750, 2001 38. Walpoth BH, Eggensperger N, Hauser SP, et al: Effects of unprocessed and processed cardiopulmonary bypass blood retransfused into patients after cardiac surgery. Int J Artif Organs 22:210-216, 1999 39. Gu YJ, deVries AJ, Boonstra PW, et al: Leukocyte depletion results in improved lung function and reduced inflammatory response after cardiac surgery. J Thorac Cardiovasc Surg 112:494-500, 1996 40. Ramirez G, Romero A, Garcia-Vallejo JJ, et al: Detection and removal of fat particles from postoperative salvaged blood in orthopedic surgery. Transfusion 42:66-75, 2002 41. Hurst T, Johnson D, Cujec B, et al: Depletion of activated neutrophils by a filter during cardiac valve surgery. Can J Anaesth 44:131-139, 1997 42. Mair P, Hoermann C, Mair J, et al: Effects of a leukocytedepleting arterial line filter on perioperative proteolytic enzyme and oxygen free radical release in patients undergoing aortocoronary bypass surgery. Acta Anaesthesiol Scand 43:452-457, 1999 43. Fabbri A, Manfredi J, Piccin C, et al: Systemic leukocyte filtration during cardiopulmonary bypass. Perfusion 16:11-18, 2001
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44. Zoon KC, Jacobsen ED, Woodcock J: Hypotension and bedside leukocyte-reduction filters: Letters to Industry/Healthcare providers. Rockville, MD, US Food and Drug Administration Center for Biologics Evaluation and Research, 1999 45. Shiba M, Tadokoro K, Sawanobori M, et al: Activation of the contact system by filtration of platelet concentrates with a negatively charged white cell removal filter and measurement of venous blood bradykinin level in patients who received filtered platelets. Transfusion 37:457-462, 1997 46. Redl H, Schlag G, Bahrami S, et al: Experimental and clinical evidence of leukocyte activation in trauma and sepsis. Prog Clin Biol Res 388:221-245, 1994 47. Arnestad JP, Bengtsson A, Bengtson JP, et al: Formation of cytokines by retransfusion of shed whole blood. Br J Anaesth 72:422425, 1994 48. Ellstrom M, Bengtsson A, Tylman M, et al: Evaluation of tissue trauma after laparoscopic and abdominal hysterectomy: Measurements of neutrophil activation and release of interleukin-6, cortisol, and C-reactive protein. J Am Coll Surg 182:423-430, 1996 49. Avall A, Hyllner M, Bengtson JP, et al: Greater increase in cytokine concentration after salvage with filtered whole blood than with washed red cells, but no difference in postoperative hemoglobin recovery. Transfusion 39:271-276, 1999 50. Bengtsson A: Cascade system activation in shock. Acta Anaesthesiol Scand 37:7-10, 1993 51. Bengtsson A, Heideman M: Altered anaphylatoxin activity during induced hypoperfusion in acute and elective abdominal surgery. J Trauma 73:631-636, 1986 52. Bengtsson A, Lisander B: Anaphylatoxin and terminal complement complexes in red cell salvage. Acta Anaesthesiol Scand 34:339341, 1990 53. Henn-Beilharz A, Holfman R, Hempel V, et al: The origin of non-emulsified fat during autotransfusion in elective hip surgery. Anaesthesist 39:88-95, 1990 54. Johnson MJ, Lucas GL: Fat embolism syndrome. Orthopedics 19:41-49, 1996 55. Ozelsel TJ, Tillman Hein HA, Marcel RJ, et al: Delayed neurological deficit after total hip arthroplasty. Anesth Analg 87:12091210, 1998 56. Byrick RJ: Fat embolism and neurological dysfunction. Anesth Analg 88:1427, 1999 57. Brown WR, Moody DM, Challa VR, et al: Longer duration of cardiopulmonary bypass is associated with greater numbers of cerebral microemboli. Stroke 31:707-713, 2000 58. Ahmad K: Cerebral dysfunction after cardiopulmonary bypass linked to length of surgery. Lancet 355:903, 2000 59. Byrick RJ: Fat embolism and postoperative coagulopathy. Can J Anaesth 48:618-619, 2001 60. Brooker RF, Brown WR, Moody DM, et al: Cardiotomy suction: a major source of brain lipid emboli during cardiopulmonary bypass. Ann Thorac Surg 65:1651-1655, 1998 61. Murkin JM: Attenuation of neurologic injury during cardiac surgery. Ann Thorac Surg 72:S1838-1844, 2001 62. Arrants JE, Gadsden RH, Huggins MB, et al: Effects of extracorporeal circulation upon blood lipids. Ann Thorac Surg 15:230-242, 1973 63. Henn-Beilharz C, Krier C: Retransfusion in bone surgery: What happens to the fat? Anaesthesiol Intensivmed Notfallmed Schmerzther 26:224-225, 1991 64. Kaza AK, Cope JT, Fiser SM, et al: Elimination of fat microemboli during cardiopulmonary bypass. Ann Thorac Surg 75:555-559, 2003 65. Booke M, Aken HV, Storm M, et al: Fat elimination from autologous blood. Anesth Analg 92:341-343, 2001
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66. Kincaid EH, Jones TJ, Stump DA, et al: Processing scavenged blood with a cell saver reduces cerebral lipid microembolization. Ann Thorac Surg 70:1296-1300, 2000 67. Turner E, Nebel H, Stephan-Onasanya H, et al: Intraoperative autotransfusion: studies on preserved blood for retransfusion. Anaesthesist 33:504-506, 1984 68. Valbonesi M, Bruni R, Lercari G, et al: Autoapheresis and intraoperative blood salvage in oncologic surgery. Transfus Sci 21:129-139, 1999 69. Fujimoto J, Okamoto E, Yamanaka N, et al: Efficacy of autotrans-
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fusion in hepatectomy for hepatocellular carcinoma. Arch Surg 128:10651069, 1993 70. Edelman MJ, Potter P, Mahaffey KG, et al: The potential for reintroduction of tumor cells during intraoperative blood salvage: Reduction of risk with use of the RC-400 leukocyte-depletion filter. Urology 47:179-181, 1996 71. Jones CC, Stammers AH, Fristoe LW, et al: Removal of hepatocarcinoma cells from blood via cell washing and filtration techniques. J Extra Corpor Technol 31:169-176, 1999
Continuous and Discontinuous Cell-Washing Autotransfusion Systems Biao Dai, CCP, CPC,* Lexin Wang, MD, PhD,† George Djaiani, MD, FRCPC,‡ and C. David Mazer, MD, FRCPC‡
C
ENTRIFUGE-BASED cell-washing autotransfusion systems have been used as a method of blood conservation since the 1970s. The advantages of diminishing the requirements of allogeneic blood, thereby reducing risk of hepatitis C and human immunodeficiency virus transmission, have been well documented.1,2 The quality of washed red blood cells (RBCs) is at least as good as banked blood,1,3-6 with an excellent safety record of intraoperative autotransfusion.7 However, the extent to which the salvaged blood is contaminated with activated leukocytes, platelets, or other plasma elements, such as fat particles, is unclear. The clinical significance of these issues remains controversial. With the recent introduction of the continuous autotransfusion system (CATS), the dominance of conventional, discontinuous autotransfusion systems (DATS) has been challenged. The differences between both systems in terms of the quality of washed blood are currently under investigation. The aim of this review is to summarize the developments in the area of cell-washing autotransfusion, with an attempt to introduce new research possibilities. PRINCIPLE OF DISCONTINUOUS AND CONTINUOUS AUTOTRANSFUSION
Autotransfusion devices were developed in the 1960s based on a conical-shaped collection container (Latham bowl).8 These devices are discontinuous systems. The shed blood that is collected in a reservoir from the surgical field via suction is first pumped into a spinning Latham bowl (approximate volume 225 mL). The RBCs that are heavier than other blood components are spun to the periphery of the bowl and become concentrated with centrifugation. In the meantime, the waste plasma overflows into a waste-collecting bag. Once RBCs in the centrifugation bowl are concentrated to a certain level (determined by
From the Departments of ‡Anesthesia and *Cardiovascular Perfusion, St. Michael’s Hospital and Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada; and †School of Biomedical Sciences, Charles Sturt University, Wagga Wagga, NSW, Australia. Address reprint requests to C. David Mazer, MD, FRCPC, Department of Anesthesia, St. Michael’s Hospital, 30 Bond Street, Toronto M5B 1W8, Canada. E-mail: [email protected] © 2004 Elsevier Inc. All rights reserved. 1053-0770/04/1802-0020$30.00/0 doi:10.1053/j.jvca.2004.01.001 Key words: autotransfusion, blood-washing systems, blood loss, transfusions, complications 210
a special sensor), the flow of blood from the reservoir is stopped and the washing procedure is started. The free hemoglobin, coagulation factors, debris, and other plasma components that are lighter than RBCs are replaced by the washing saline that is pumped through the layers of RBCs during the washing period. Once the required washing volume is reached, the centrifuge is stopped. The washed concentrated RBCs are collected into a reinfusion bag. The entire procedure can be repeated again if additional blood needs to be processed. Therefore, the blood is discontinuously processed in units9 (Fig 1). In 1995, Fresenius introduced the first continuous autotranfusion system (CATS; Fresenius AG, Bad Homburg, Germany). The shed blood collected in a reservoir from the surgical field is suctioned by the first pump into a spinning separation chamber (approximate volume 30 mL), which contains a blood channel in the shape of a double spiral, instead of a Latham bowl. The RBCs that initially come into the separation chamber via the inner spiral move to the outer spiral because of centrifugal force, and on their way, they are washed with saline that is added by a second pump. The free hemoglobin, coagulation factors, fat, debris, and other plasma components that are separated with heavier RBCs by centrifugal force leave the double spiral at the innermost point with washing solution. Meanwhile, washed concentrated RBCs are collected by a third pump into a reinfusion bag. Three steps including filling, washing, and emptying are performed simultaneously until all the blood is processed. Thus, the blood is processed continuously (Fig 2). In contrast with the discontinuous system, the washed blood is collected into the reinfusion bag while the separation chamber is still rotating. This method allows continuous blood processing, including washing and hemoconcentration, instead of processing in units.9 Thus, this method is independent of the blood volume to be processed, allowing the operator of the equipment to reinfuse autologous erythrocytes to the patient as required. Other possible advantages of the CATS include smaller priming volumes (30 mL v 225 mL), smaller centrifugal forces generated,8 and higher hematocrit of the processed red cells10 (Tables 1 and 2). RED BLOOD CELLS
The quality of RBCs of processed blood with autotransfusion devices has been previously studied. The washed RBCs were shown to be at least as good as banked blood cells,1,3-5 although some researchers found evidence of red cell damage during the suction and centrifugation of autotransfusion. Paravicini11 showed with electron microscopy that washed red cells ap-
Journal of Cardiothoracic and Vascular Anesthesia, Vol 18, No 2 (April), 2004: pp 210-217
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washed RBCs and nonwashed cells in terms of mean corpuscular volume, mean corpuscular hemoglobin concentration, and mean corpuscular hemoglobin. Measurement of erythrocyte adenosine triphosphate level and their survival rate with 51Cr or 111In may be even better indicators for assessing the quality of red cells. However, to date, no studies using this technology for processed RBCs have been reported. The comparison between DATS and CATS in terms of red cell quality is also lacking at present, whereas the red cell recovery rate of both systems is similar.15 PLATELETS
coworkers15
Fig 1. Discontinuous autotransfusion system. (I) Blood collected in a reservoir from the surgical field is pumped into the centrifuging bowl. (II) With centrifugation, the heavier red blood cells are spun to the periphery of the bowl and become more concentrated. The waste plasma overflows into a waste-collecting bag. (III) Once the centrifuging bowl is filled with a certain number of red blood cells, the flow of blood from the reservoir is stopped and washing is started. The free hemoglobin, coagulation factors, debris, and other plasma components are replaced by the saline that is pumped through the layers of red blood cells. (IV) Once washing is completed, the centrifuge is stopped. The washed red blood cells are collected into a reinfusion bag. The entire procedure will be repeated again if additional blood needs to be processed. Therefore, the blood is discontinuously processed in units.
peared to have increased membrane folding and protuberances, similar to that of packed RBCs. Kirkpatrick and coworkers12 found that salvaged red cells have reduced deformability, similar to stored bank blood, which was supported by Mortelmans et al6 as well. Because shed blood could be exposed to more adverse factors during orthopedic surgery relative to other operations, Mortelmans et al6 studied the quality of washed shed blood during the total hip replacement. Indices of red cell quality examined included mean corpuscular volume, mean corpuscular hemoglobin concentration, red cell distribution width, total hemolysis, osmotic fragility, filterability ratio, glutathione reductase, and glutathione stability. All parameters were normal compared with the patient’s baseline, with the exception of moderate hemolysis and decreased filterability.6 They speculated that hemolysis might be reduced and filterability might be better maintained in other less-invasive surgical procedures. In other studies, no changes in the 2,3-diphosphoglycerate level were observed during the cell-washing procedure, which suggests the oxygen-carrying capability of red cells is maintained.6,13 Walpoth et al14 evaluated the quality of washed red cells in cardiac surgery. They failed to show any differences between
Geiger and studied the elimination of platelets by several autotransfusion devices. CATS was shown to have the lowest platelet elimination rate (75%), compared with discontinuous devices (88%-93%). Thus, the platelet count in the processed blood may be only 10% of the patient’s hematocritcorrected counts.16 Platelets obtained from salvaged blood do not aggregate normally to stimuli, which may indicate platelet dysfunction.17 This may result from platelet activation. Furthermore, platelets have been implicated in the Cell Salvage Syndrome, described by Bull et al18 in 1988. In their study, the Haemonetics Cell Saver (Haemonetics Corp, Braintree, MA) was used in 21 dogs to examine the formation and potency of procoagulant and leukoattractant material during autologous blood salvage. Washed red cell suspensions were found to contain toxic degradation products that had been released from deposition of platelets and white cells adherent to the wall of the centrifuge bowl. When reinfused into dogs, these toxic products resulted in a “salvaged blood syndrome” that consisted of intravascular clotting, pulmonary edema, and hemorrhage.18 This may be attenuated by avoidance of exogenous calcium, partially clotted blood, or excessive saline during intraoperative red cell salvage.19 Bull and Bull19 also reported a clinical case in which disseminated intravascular coagulopathy (DIC) and/or acute respiratory distress syndrome (ARDS) were observed after the administration of washed autologous red cells. They hypothesized that mechanically activated platelets during the cellwashing procedure release leukoattractant substances, including arachidonate-rich phospholipids, which trigger the oxidative burst enzymatic pathway in exposed phagocytic cells. These substances, when reinfused, cause increased vascular permeability that presents clinically as ARDS, whereas DIC results from reinfused platelet phospholipid and accompanying cellular debris.20 However, Tawes and Duvall7 challenged this theory with a retrospective review of more than 36,000 cellsalvaging cases during an 18-year experience in an attempt to link the occurrence of this syndrome with the use of cell-saving technology. A total of 18 cases (0.05%) were identified: 10 associated with ruptured aneurysms, 6 after massive trauma, and 2 after complex redo cardiac surgery. The mean transfusion requirement was 28 units. They concluded that DIC and ARDS occur infrequently and are more likely a result of the complex interaction of shock, hypothermia, multiple transfusions, reperfusion injury, and multiorgan failure, instead of resulting from cell saving.7 It should be noted that the majority of the evidence of platelet activation was reported in association with DATS. The
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Fig 2. Continuous autotransfusion system. The shed blood collected in a reservoir from the surgical field is first suctioned by a pump into a spinning separation chamber (approximate volume 30 mL) that contains a blood channel in the shape of a double spiral, instead of a Latham bowl. The red blood cells that initially come into the separation chamber via the inner spiral move to the outer spiral due to centrifugal force, and on their way, they are washed with saline that is added by a second pump. The free hemoglobin, coagulation factors, fat, debris, and other plasma components that are separated with heavier red blood cells by centrifugal force leave the double spiral at the innermost point with washing solution. Meanwhile, washed concentrated red blood cells (PRC) are collected by a third pump into a reinfusion bag. Three steps including filling, washing, and emptying are performed simultaneously until all the blood is processed. Thus, the blood is processed continuously. The CATS system has 3 separate pumps whereas discontinuous systems use only one pump for all stages of processing. (Figure modified with permission from Fresenius CATS Operating Instructions, Nov 1997.)
effect of CATS on platelet function is an area for potential future investigation, especially because CATS eliminates fewer platelets than DATS. In cardiac surgery, it is well known that the cardiopulmonary bypass (CPB) causes activation of platelets.21-24 It has been reported that processing salvaged blood during CPB using autotransfusion devices reduced the load of activated platelets being reinfused.25 However, the clinical benefits of this may also be related to fat particle removal instead of platelets alone. Table 1. Specifications of Selected Continuous and Discontinuous Systems10 Parameter
Centrifugal speed (rpm) Gravity force Geometry of bowl/chamber Priming volume (mL) RBC collecting mode
Sequestra 1000*
Brat 2†
LEUKOCYTES
Although the washing process is intended to remove the buffy coat that contains platelets and leukocytes, Holleufer and von Bormann17 reported only a 50% leukocyte elimination rate for DATS. Furthermore, Walpoth et al14 found that the leukocyte elimination rate for CATS was only 35%. Geiger et al15 studied 8 autotransfusion devices to determine their capability for leukocyte elimination. In that study, CATS eliminated 50% of leukocytes,
Table 2. Comparison Between DATS and CATS
CATS‡
5600 820–1070g
4400 1220–1400g
2000 330–680g
Conical
Cylindrical
Channel
225
225
30
Discontinuous
Discontinuous
Continuous
Abbreviations: RBC, red blood cell; CATS, continuous autotransfusion system. *Sequestra 1000: Medtronic, Inc, Minneapolis, MN. †Brat 2: COBE Cardiovascular, Inc, Arvada, CO. ‡CATS: Fresenius AG, Bad Homburg, Germany.
Red cell recovery Red cell quality* Leukocyte removal Leukocyte activation* Platelet removal Platelet activation* Fat removal Tumor cell removal† Cytokine and complement removal
DATS
CATS
⫹⫹⫹ ⫹⫹ ⫹⫹ ⫹⫹ ⫹⫹ ⫹⫹ ⫹ ⫹⫹ ⫹⫹
⫹⫹⫹ ⫹⫹ ⫹ ⫹ ⫹ ⫹ ⫹⫹⫹ ⫹ ⫹⫹
Abbreviations: DATS, discontinuous autotransfusion system; CATS, continuous autotransfusion system; ⫹, effect present; ⫹⫹, market effect; ⫹⫹⫹, very marked effect. *Limited information. †Based on the assumption that tumor cell removal is similar to leukocytes.
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whereas the range for DATS was 80% to 94%. This report confirmed the previous findings that both systems were relatively ineffective in completely removing leukocytes.14,26 McShane et al5 found microscopic damage to 75% of neutrophils in patients having cardiac surgery involving CPB. Seidel et al27 reported significant impairment of the chemotactic response and superoxide generation of polymorphonuclear leukocytes (PMNs) after cell washing, as compared to PMNs of healthy volunteers. Connall et al26 quantified the surface expression of the leukocyte adhesion receptors CD11b (n ⫽ 6) and CD18 (n ⫽ 6). They found CD 11b was about 3 times greater on PMNs and 4 times greater on monocytes from salvaged blood compared with arterial blood. CD18 was increased 3 times on PMNs and 21⁄2 times on lymphocytes in salvaged blood compared with arterial blood, consistent with activation of PMNs in the salvaged blood. Perttila et al28 studied respiratory burst of leukocytes in autologous blood during cardiac surgery and found that PMN activity in the processed blood was 30% higher in 4 of 10 patients. The authors recommended that processed blood should not be retransfused when reperfusion injury is likely to occur. These findings have been further confirmed by assaying hydrogen peroxide formation in blood processed with DATS.12 However, Innerhofer et al29 studied activation of PMN with CATS instead of DATS, evaluating chemotactic response and respiratory burst (n ⫽ 20). The results indicated that PMNs contained in the CATS-processed blood were neither impaired nor activated relative to the priming threshold. Siriwardhana et al30 suggested that leukocytes might be activated by the autotransfusion device, as a result of activation of the complement cascade shown by high level of C3a in the waste bag. Bull and Bull18 also indicated in their animal study that the autotransfusion device might be the main site of leukocyte activation. However, previous reports of patients undergoing orthopedic surgery found that collected wound blood itself contained inflammatory mediators from activated complements, lysosomal enzymes, and cytokines from activated leukocytes.31,32 Bengtsson et al33 studied 18 patients undergoing hip replacement surgery, reporting significantly increased concentration of C3a and SC5b-9 in the collected reservoir blood compared with the patients’ preoperative levels. These concentrations could be substantially reduced by the washing procedure. In cardiac surgery, CPB may be the source of activation of leukocytes in extravasated wound blood.34 Exposure of blood to tissue, air, and subsequent mechanical stress caused by the pump suction may also play an important role in leukocyte activation.25,35,36 Washing of shed blood by autotransfusion devices might not have a major influence on the activation process itself, however, because these devices fail to completely remove proinflammatory cytokines present before washing.25,37 If leukocytes are already activated before entering the centrifugal chamber, different autotransfusion systems may not yield different results with respect to the degree of leukocyte activation. Therefore, only systems with low elimination rates of leukocytes may be of concern. Activated leukocytes may be detrimental if they are infused back to the patient. In a canine model, Bull and Bull18,19 found
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an association between activation of leukocyte/platelet and acute lung injury. If the main activation site is in the separation chamber or the Latham bowl in which the centrifugation takes place, the clinical safety of autotransfusion systems needs to be reevaluated, or improvements on the system biocompatibility are required. If the leukocytes are activated before entering the centrifugal chamber, autotransfusion systems reduce their load and, hence, a beneficial clinical effect is expected. This hypothesis is supported by Walpoth et al38 who reported that CATS processing of CPB blood reduced the load of activated leukocytes and relevant mediators (⬎93%). Reents et al25 reported similar results with a DATS (Haemonetics). Previous studies reported significantly lower elimination rates of leukocytes with CATS compared with DATS.12,14,15,26 However, the research of Innerhofer et al29 in an orthopedic patient population suggested that PMNs were not activated with CATS to the threshold that may induce endothelial damage, indicating CATS may have a better biocompatibility in terms of leukocyte activation. Although activation of leukocytes with DATS has been well shown,12,14,26,27 leukocyte activation with CATS requires further research. In light of evidence that activation of leukocytes may occur before entering both types of autotransfusion systems, the disadvantage of lower elimination rate of leukocytes with CATS needs further clinical evaluation. Mortelmans et al6 showed that the quality of washed RBCs was significantly better with heparin than citrate as anticoagulant. On the other hand, Bull and Bull19 suggested that citrate might be preferable because it could minimize the concentration of calcium ions. This might reduce the phorbol myristate acetate-stimulated respiratory burst (PMA-RB) of PMNs (the receptor-independent pathway of leukocyte activation), potentially avoiding the salvaged blood syndrome due to the presence of activated platelets and leukocytes.20 Innerhofer et al29 did not detect any differences in PMA-RB between heparin (n ⫽ 10) and citrate groups (n ⫽ 10) using CATS, but this study was limited by a small sample size and a relatively large SD of PMA-RB measurements. They also observed that leukocyte and platelet counts were lower in the processed autologous blood from patients in the heparin group. It is speculated that heparin promotes PMN-platelet interactions, leading to formation of PMN-platelet complexes that are removed by the washing process.29 Further study is needed to identify the best anticoagulant for autotransfusion with respect to the activation of leukocytes. Given the evidence indicating that retransfused leukocytes are potentially detrimental, it might seem reasonable to attempt to remove any residual leukocytes in the retransfusion bag. Leukocyte-depleting filters could be effective in achieving this goal. Gu et al39 showed that leukocyte-depleting filters remove as much as 97% of the leukocyte load. Ramirez et al40 tested 4 leukocyte-depleting filters (BIO R, BIO R Plus, Fresenius AG; RC100KLE, Pall Biomedical; Immugard III-RC, Terumo). All filters evaluated were capable of removing almost all leukocytes.40 However, 2 questions have been raised: (1) Is there a clinical benefit? and (2) Is the use of leukodepletion safe? Leukodepletion has recently been evaluated in the setting of cardiopulmonary bypass but the clinical benefits have not been firmly established.41-43 In 1999, the US Food and Drug Admin-
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istration issued an alert addressing the association between bedside leukodepletion and hypotensive events.44 Evidence suggested that this might be caused by bradykinin production after platelet exposure to negatively charged leukocyte filters.45 However, cell-saving devices are able to remove at least 75% of platelets.15 Therefore, filtration of washed blood with leukocyte filters may not pose as many problems as when used for other blood products. CYTOKINES AND COMPLEMENTS
As a result of surgical trauma, activated leukocytes release proinflammatory cytokines.30,31,42,46-48 Tissue trauma has been also shown to activate the complement cascade (via the alternative pathway), which results in the formation of the anaphylatoxins (C3a, C5a) and the terminal complement complexes (C5b-9).32,49 This may result in damage to end-organ systems.50,51 CPB facilitates this process as does cell-saving processing because of the foreign material contact and shear stress of suction and centrifugation.30,34 However, cell-washing systems appear able to remove the inflammatory mediators effectively during the washing procedure.32,33,52 These systems also effectively remove polymorphonuclear elastase, which is released by activated leukocytes.31 Walpoth et al14 found that CATS was able to eliminate as much as 93% of water-soluble elements including cytokines (interleukin [IL]-6) and complement (C3a, C5b-9). However, the removal of IL8 was only 65%.14 Arnestad et al32 reported that reinfusion of washed blood did not alter plasma concentrations of IL-6. The clinical effects of reinfusion of cytokines and/or complement need to be further investigated, especially when large amounts of shed blood are processed. FAT ELIMINATION
Blood collected during orthopedic and cardiac surgery often contains fat particles from bone marrow and/or subcutaneous fat deposits.53 If these enter the circulation, they may cause fat embolism syndrome, characterized by pulmonary dysfunction,54 neurologic deficits,55-58 and coagulopathy.59 If salvaged blood is returned through an arterial line, as in cardiac surgery with CPB, neurologic complications can occur.60-62 A recent canine study examined postmortem brain tissue after the animals were exposed to CPB. It showed that the majority of microembolic material originated from shed blood collected in the cardiotomy reservoir, which contained cellular debris and fat from dissected tissues and sternal bone marrow. Discarding the cardiotomy blood prevented brain microembolization in these animals.60 Thus, reinfusion of fat particles present in the salvaged shed blood should be avoided whenever possible. DATS may not reliably remove all fat in the collected shed blood.53,63,64 Booke and his colleagues9,65 carried out an in vitro comparison between CATS and DATS (Cell Saver 5, Haemonetics Corp) with respect to fat elimination. The results showed that CATS completely removed fat particles, whereas DATS removed 85% of the fat. In another canine model, Kincaid et al66 examined various methods of processing shed blood during CPB and their impact on cerebral lipid microembolic burden. In the control group (n
⫽ 12), shed blood was collected in a cardiotomy reservoir and reinfused through the arterial circuit. In the cell-saver group (n ⫽ 12), shed blood was collected in a cell saver (DATS or CATS) and reinfused through the CPB circuit. Brain tissue was examined for presence of small capillary and arteriolar dilations (SCADs). Mean SCAD density (SCAD/cm2) was less in the cell-saver group than in the cardiotomy group. Mean SCAD density was reduced even further with CATS versus DATS, although in this small study statistical significance was not achieved. The authors concluded that use of a cell saver to scavenge shed blood during CPB decreased cerebral lipid microembolization. During centrifugation with discontinuous devices, a certain quantity of lighter particles, including fat, may stay in the center of the separation bowl and may not be removed with other waste. Once centrifugation is stopped for emptying, these particles remix with denser red blood cells and are then emptied into the reinfusion bag. In contrast to DATS, CATS is able to continue centrifuging while emptying the washed blood. Therefore, the lighter particles should not remix with the red cells and contamination of the red cells with fat might be avoided.9 Ordinary blood filters do not effectively remove fat.67 Booke et al65 compared efficiency of 3 types of filters: 1 routine blood filter (Microfilter Sangopur 40 m; B. Braun Medical Division, Melsungen, Germany), 1 fat-removing filter (LipiGuard; Pall Corporation, Portsmouth, England), and 1 leukocyte-depleting filter (Purecell RC 400; Pall Corporation, Portsmouth, England). It was observed that the LipiGuard was only as effective as the routine blood filter. About 38% of the fat load remained after filtration. However, the Purecell RC 400 removed 99% of the fat. Ramirez et al40 tested various standard blood filters with a pore size from 40 to 200 m (Sangofix, B. Braun Medical Division, Melsungen, Germany; SQ40SJKL, Pall Biomedical, Portsmouth, England; and BIOM40, Fresenius AG, Bad Homburg, Germany) and leukocyte-depleting surface filters (BIO R, BIO R Plus, Fresenius AG, Bad Homburg, Germany; RC100KLE, Pall Biomedical, Portsmouth, England; Immugard III-RC, Terumo, Japan), together with a specially designed fat and leukocyte-depleting surface filter (LeukoGuard RS, Pall Biomedical, Portsmouth, England). Blood filters were ineffective in removing fat, whereas all surface filters removed almost all fat particles and leukocytes, with the exception of the LeukoGuard RS. It removed some but not all fat particles. During CPB, arterial line blood filters, such as Duraflo II AF-1025D (Baxter Healthcare Corp, Irvine, CA), are ineffective in removing fat particles, likely because of the deformability of the lipid particles that pass through small filter pores.66 Therefore, the combination of autotransfusion systems and an effective leukocyte-depleting surface filter may provide the most complete fat removal. TUMOR CELLS
Oncologic surgery is considered a contraindication to use of cell-washing autotransfusion systems because of the possibility of contamination of processed blood with tumor cells and subsequent metastases after reinfusion. However, there is little evidence that reinfusion of contaminated washed blood increases metastasis.68 Fujimoto et al69 reported no difference between a cell-washing group (n ⫽ 54) and a
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non– cell-washing group (n ⫽ 50) in surgery for hepatocellular carcinoma in terms of tumor recurrence rate or survival rate. The effectiveness of leukocyte depletion filters for eliminating tumor cells left in processed shed blood is also controversial. Edelman et al70 reported that a leukocyte depletion filter (RC-400, DLP Incorporated, Grand Rapids, MI) was able to completely remove tumor cells from urologic malignancies in an in vitro study. However, in another in vitro study, Jones et al71 were only able to eliminate about 75% of cultured hepatocarcinoma cells remaining in the washed blood with either type of leukocyte depletion filters (Pall Leukoguard RS, Pall Purecell RCQ, Pall Biomedical). In this study, neither CATS nor DATS (BRAT2, STAT-P; COBE Cardiovascular Inc, Arvada, CO) removed more than 60% of tumor cells. CONCLUSIONS
Intraoperative cell-washing autotransfusion has been used as an effective method of blood conservation for more than 30 years. The quality of the washed red cells seems to be at least as good as banked red cells. The majority of platelets are removed during the washing procedure, but the effects of retransfusion of residual platelets need to be further investigated, especially as they relate to DIC and/or ARDS. Previous studies have confirmed that both discontinuous and continuous cell-washing autotransfusion systems are ineffective in eliminating leukocytes. Leukocyte activation may be
caused by the exposure of blood to tissue, air, mechanical stress induced by suction, centrifugation, and foreign materials in the cell-washing equipment. Whether CATS is superior to DATS requires further investigation as does the role of residual leukocytes in the occurrence of the “cell-salvage syndrome.” Leukocyte-depleting filters are efficient, although documentation of their clinical benefits also requires further investigation. Cell-washing systems are able to remove as much as 93% of all water-soluble elements including cytokines and complement. However, caution is required when large amounts of processed blood are reinfused because these factors are implicated in many adverse clinical outcomes. Residual fat particles may cause fat embolism syndrome and neurologic complications. Discontinuous cell-washing systems are less effective than CATS in terms of fat removal. The combination of cell-washing autotransfusion systems and leukocyte-depleting filters may provide the most complete fatremoving capability. Use of cell-washing autotransfusion systems remains contraindicated in oncologic surgery. More research is needed to determine if retransfusion of processed blood that may be contaminated with tumor cells adversely affects clinical outcome. Cell-washing autotransfusion systems are a valuable adjunct to the clinical management of patients undergoing a variety of surgical procedures. Future research will help clarify the optimal system to use in specific clinical settings.
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