M undergoing coronary artery bypass grafting

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1 Comparison of Blood Reinfusion Techniques Used During Coronary Artery Bypass Grafting Victor A. Ferraris, MD, PhD, William R. Berry, MD, and Robert R. Klingman, MD Division of Cardiothoracic Surgery, Albany Medical College, Albany, New York, and Department of Surgery, F. Edward Hebert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland A comparison of intraoperative autologous blood conservation techniques was carried out in 100 patients undergoing coronary artery bypass grafting. To facilitate comparisons of similar groups, patients were stratified into high-risk and low-risk groups based on the ratio of preoperative bleeding time to preoperative red blood cell volume. Our previous work suggested that patients with an elevated ratio have increased risk of excessive postoperative blood transfusion. We used this ratio to stratify the 100 patients to either the high-risk (39 patients) or low-risk (61 patients) strata. Within each stratum, patients were randomized to one of three groups: no intraoperative autologous blood conservation (control group), infusion of autologous platelet-rich plasma obtained from intraoperative plasmapheresis (PRP group), and infusion of autologous whole blood harvested immediately before cardiopulmonary bypass (whole blood group). Variables of postoperative blood loss and transfusion requirements were measured in each patient. Analysis of variance showed significant differences in blood product transfusions between groups. Patients in the high-risk stratum required significantly more blood product transfusions than those in the low-risk stratum ( versus 2.0 f 0.6 units per patient; p < 0.001). In the high-risk stratum, PRP patients required significantly less postoperative blood transfusion compared with patients in the high-risk control group (2.9 * 2.1 versus units per patient; p = 0.05). In the low-risk stratum, no intraoperative blood infusion method resulted in significant improvement in postoperative blood use. We conclude that intraoperative autologous blood reinfusion methods are not helpful in lowrisk patients but, for high-risk patients, infusion of autologous PRP is associated with significantly less postoperative blood transfusion. This suggests that the added cost of intraoperative autologous blood conservation techniques is justified in patients at high risk for excessive postoperative blood transfusion but not in patients at low risk. (Ann Thorac Surg 1993;56:43340) ost observers believe that the patient population M undergoing coronary artery bypass grafting (CABG) is subtly changing to reflect a sicker, high-risk cohort [l-31. Complications such as bleeding with concomitant blood product transfusion are partly responsible for the morbidity associated with cardiac procedures [l-61. Postoperative bleeding can take various forms, from overt hemorrhage requiring reoperation for control of bleeding to the use of multiple transfusions to replace shed blood. The risk of reexploration for postoperative hemorrhage is of concern, but this complication occurs in less than 5% of all patients undergoing open heart operation [7-91. However, blood transfusion after CABG is far more common and carries with it more unpredictable risks, including the risks of infection [7, 101 and disease transmission from contaminated blood products [ll, 121. Strategies that minimize postoperative bleeding and concomitant blood product transfusion will lessen the risks associated with operation and improve the outcome after CABG. Multiple strategies to conserve blood during CABG Presented at the Twenty-ninth Annual Meeting of The Society of Thoracic Surgeons, San Antonio, TX, Jan 25-27, Address reprint requests to Dr Ferraris, Division of Cardiothoracic Surgery, Albany Medical College, Suite A330/A-61, Albany, NY have been described [8, 9, 13, 141, and these methods attempt either to conserve the patient's own blood or to prevent blood loss by pharmacologic means. These strategies involve use of one or more of the following: (1) predonation of autologous blood products, (2) intraoperative withdrawal of autologous blood (either whole blood or platelet-rich plasma [PRP]) immediately before cardiopulmonary bypass (CPB), (3) normovolemic hemodilution using crystalloid oxygenator prime, (4) intraoperative blood salvage using cell-saving devices, (5) intraoperative hemofiltration, (6) postoperative autotransfusion of shed mediastinal blood, and (7) pharmacologic interventions (eg, desmopressin acetate, aprotinin, or eaminocaproic acid therapy). Although it is likely that a multifaceted approach to blood conservation is best, the ideal combination of blood conservation steps is uncertain. Autologous predonation of blood is indicated in almost all elective CABG procedures [15]. As more and more operations are done under urgent or emergent circumstances, the value of autologous predonation diminishes, and techniques that involve intraoperative harvest of whole blood or PRP offer attractive alternatives. Recent technological developments allow convenient harvest of PRP in the operating room immediately before CABG. Several studies of intraoperative harvest of autologous PRP with varying results have been published [1&20] by The Society of Thoracic Surgeons /93/$6.00

2 434 FERRARIS ET AL Ann Thorac Surg 1993:56:43340 One of the better-designed studies in this group was by Boldt and colleagues [17]. This study suggests that the plasma component of PRP may be involved in decreasing postoperative chest tube blood loss and that PRP does not seem to limit the amount of blood products transfused after operation. Others [16, 18-20] have found that intraoperative harvest of autologous PRP caused significant reductions in blood loss and homologous blood transfusion. On the basis of these conflicting reports, the exact value of autologous PRP in blood conservation is uncertain. Some surgeons use autologous whole blood, harvested intraoperatively, in an attempt to limit postoperative bleeding. Those authors [ who report benefit from this technique attribute decreased bleeding to clotting factors and platelets that have been spared exposure to the extracorporeal circuit. No mechanism for this reported benefit has been proved, and in spite of these optimistic reports, this method of blood conservation is not applicable in all patients and is not universally accepted as beneficial by all cardiac surgeons. Our previous work [24] found that between 10% and 20% of patients required more than 5 units of blood products after operation, and that more than 50% of the postoperative blood products transfused were given to these high-risk 10% to 20% of patients. We were able to show that two factors were significant predictors of excessive postoperative blood transfusion-the template bleeding time and the preoperative packed red blood cell volume. We hypothesized that blood conservation techniques using autologous blood products might be more beneficial in the high-risk subset of patients having CABG and that evaluation of the efficacy of any blood conservation intervention should involve stratification of patients according to their risk of bleeding. Consequently, we undertook a randomized, stratified comparison of intraoperative autologous blood conservation techniques. Because of the possible benefit of autologous PRP or whole blood, the study was designed to compare control patients with those who received intraoperatively harvested PRP and those who received intraoperatively harvested whole blood. To facilitate comparisons of similar groups, patients were stratified into high-risk and low-risk groups depending on the preoperative bleeding time and packed red blood cell volume. The results of this comparison are presented in this report. Material and Methods Patient Population Over a 3-year period, 100 patients were entered into a randomized, comparative study of blood conservation techniques. Before its inception, this study was approved by the institutional review board. The criteria for patient entry are shown in Table 1. Approximately 80% of patients who were asked to participate in the study gave their consent. Although the final study group consisted of 100 patients, a total of 107 patients agreed to participate. Seven patients were excluded from the final study group, 4 of them because postoperative bleeding was found to be due to a surgical cause at reexploration and 3 because of Table 1. Eliaibilitu Criteria for Studu Patients Characteristic Age (Y) Coagulation status Hemodynamics Renal function Liver function Drug therapy Prior operations Predonation blood donor Patient consent Criteria No upper age limit, age > 35 Normal PT/PTT Normal platelet count BT/RBCVOL determined before entry Systolic blood pressure > 90 mm Hg No cardiotonic drugs LVEDP < 15 mm Hg (if available) Serum creatinine < 2.5 mg/dl No abnormalities in liver function tests No thrombolytic therapy within 24 hours (aspirin or NSAID not included) No prior cardiac procedures No predonation of blood products Consent form signed before randomization BT = template bleeding time; LVEDP = left ventricular end-diastolic pressure; NSAlD = nonsteroidal, antiinflammatory drug; PT = prothrombin time; PTT = partial thromboplastin time; RBCVOL = packed red blood cell volume. incomplete data for analysis or inadvertent randomization to the wrong stratum. Randomization Scheme and Experimental Design After all preoperative data were obtained, patients were stratified into the high-risk and low-risk groups. The stratification process was intended to facilitate comparisons of similar groups of patients based on their risk of excessive postoperative bleeding. In our previous studies [24], preoperative template bleeding time and packed red blood cell volume were shown to be significantly associated with excessive postoperative blood transfusion. Consequently, the ratio of template bleeding time to packed red blood cell volume was used as the variable to stratify patients. An arbitrary ratio of was used to divide patients into the high-risk or low-risk stratum, with patients having a ratio greater than or equal to being considered high risk. The packed red blood cell volume was calculated by multiplying blood volume by hematocrit. The blood volume was determined using a nomogram based on sex, age, and body weight. Based on past experience, approximately 30% to 40% of patients seen for CABG will have a bleeding time to packed red blood cell volume ratio greater than or equal to and hence a higher risk of requiring excessive postoperative transfusion. This method of stratification amounts to an adaptive design according to the definition of Fleiss [25]. With the use of a ratio of , relatively more patients will be entered into the high-risk stratum. Because it seems likely, on the basis of accumulated data, that patients with a high ratio of bleeding time to packed red blood cell volume are most likely to benefit from the intended therapy, we thought it more ethical to broaden the subset of patients who might be entered into the high-risk stratum. As discussed by Fleiss [25], the impact of this type of stratification on experimental bias is uncertain. Within each stratum, patients were randomly assigned

3 Ann Thorac Surg 1993;56:43MO FERRARIS ET AL 435 to one of three groups: a control group having no intraoperative autologous blood conservation intervention, a PRP group having autologous PRP (8 to 10 ml/kg) harvested immediately before operation and infused after operation, and a whole blood group having fresh whole blood harvested after heparinization and immediately before institution of CPB. A simple blocked randomization scheme was used to assign patients to one of the three treatment groups [25]. Although sample size considerations suggested that 100 patients should be entered into the study, a total of 180 random numbers (90 per stratum) was generated at the beginning of the study to allow for the possibility of patient withdrawal or exclusion after entry. Six blocks (three per stratum) of 30 random numbers were used. After assignment to a stratum and beginning with the first block in that stratum, patients were assigned to one of the three treatment groups (control, PRP, or whole blood) based on the next assignment in the block. The study was terminated when 100 evaluable patients were entered into the study. Two outcome variables were measured in each study patient: chest tube drainage in the first 12 hours after operation and number of nonautologous blood products transfused within the first 72 hours after operation. The number of nonautologous blood product transfusions was expressed as units per patient. Apheresed platelet transfusions were counted as six transfusions. Before the study was begun, some approximations were made to allow estimation of an appropriate sample size for the study group. The outcome variable used for the sample size calculations was the number of nonautologous transfusion units per patient. It was assumed that the control group would require 4 units and that any of the treatment groups would require 2 units. The standard deviation of the outcome variable was assumed to be between 2 and 3 units. Computer software (STATGRAPHICS PLUS) was used to determine the sample size that would result in a statistical power of 90% with an a error of The result of these assumptions and associated calculations suggested that a sample size of between 66 and 144 patients (ie, between 11 and 24 patients in each of six treatment groups-three groups per stratum) would be ideal. Consequently, a sample size of 100 patients was chosen for the study group. Operative Techniques and Criteria for Blood Transfusion The conditions of CPB were standardized, and each participating surgeon agreed, in advance, to adhere to standard bypass techniques. Cannulation for CPB consisted of a single venous cannula and a standard aortic cannula. Heparin sodium was administered at a dose of 3 to 3.5 mg/kg, and anticoagulation was monitored using activated clotting times. Activated clotting time was maintained at greater than 400 seconds for the entire bypass time. A membrane oxygenator was used in the extracorporeal circuit. Systemic cooling to between 28 and 32 C was maintained during the cardiac ischemic interval. Blood cardioplegia of standard formulation (Buckberg solution) was administered as an initial bolus of 8 to 10 ml/kg to produce initial arrest during the ischemic cross-clamp time, followed by intermittent boluses (3 to 5 ml/kg) of low-potassium cardioplegia to maintain myocardial cooling. An attempt was made to standardize the criteria for blood product transfusion in the postoperative period. The following guidelines were discussed with all participating surgeons and agreed upon as indications for transfusion of blood products after operation: (1) packed red blood cells-hematocrit less than 25% with age less than 70 years; (2) packed red blood cells-hematocrit less than 27% with age greater than 70 years; (3) platelet concentrates-platelet count less than 75,OOO/pL; and (4) fresh frozen plasma-partial thromboplastin time ratio greater than 1.3. Of course, the surgeon s judgment was paramount in determining the need for postoperative blood transfusion, and the responsible surgeon ultimately determined the need for transfusion based on clinical assessment of the patient s hemorrhagic risk. Methods of PRP Harvest and Whole Blood Harvest Autologous PRP was harvested from the patients randomized to the PRP group using a commercially available plasma saver (Electromedics, Denver, CO; or Haemonetics, Braintree, MA). For this process, a central venous line was used to draw off whole blood into the apparatus that separated PRP from red cells, with slow centrifugation used for the separation process. Care was taken to monitor the filling pressures of patients and to replace volume with crystalloid solution if necessary. Eight to 10 ml/kg was harvested from each patient, if possible. In 2 patients, machine malfunction resulted in blood passing into the plasma-saving machine without receiving adequate anticoagulation solution. Each time, 200 to 400 ml of blood was lost from the patient and could not be infused in the postoperative period. This is an unusual complication of use of the plasma-saving apparatus, but one that might actually add to the blood product requirements of the patient, rather than diminish them. Platelet counts were measured in the harvested PRP and were found to be nearly the same as the platelet count measured in the patient s whole blood before the induction of anesthesia. Based on these platelet counts, it is estimated that between 10% to 15% of the circulating platelets are harvested by conventional plasma saving as carried out in this study. Autologous whole blood was harvested from patients after systemic heparinization and immediately before institution of CPB. Eight to 10 ml/kg was harvested from each patient randomized to the whole blood group. Whole blood was drawn from the extracorporeal circuit into blood bags. No complications were encountered using this technique for whole blood harvest. Statistical Methods Patient demographic variables in the high-risk and lowrisk groups were compared using Student s t test or Fisher s exact test. Two-factor analysis of variance was used to test the hypothesis that blood conservation intervention was successful in altering the outcome variables (chest tube drainage in the first 12 hours after operation and units of nonautologous blood products transfused

4 436 FERRARIS ET AL INTRAOI'ERATIVE BLOOD CONSERVATION Ann Thorac Surg 1993;56:43340 Table 2. Patient Variables in High-Risk and Low-Risk Strata" High Risk Low Risk Variable (n = 39) (n = 61) Age (Y) 64 f 2 58 f lb Female 18 lb BT 6.22 t t 0.15b BT/RBCVOL * b ASA Heparin Total CPB time 110 * (rnin) CC time (min) 57 * 3 53 * 2 CAB x 3.44 t f 0.13 No transfusions 4 30b CTl2H 743 * * 48 T, 5.4 f t 0.6b a Where applicable, data are shown as the mean? the standard error. Significance: p < compared with high-risk stratum by Student's t test or Fisher's exact test. ASA = preoperative aspirin therapy; BT = template bleeding time; CAB x = number of distal coronary artery anastomoses; CC time = ischemic cross-clamp time; CPB = cardiopulmonary bypass; CT12H = chest tube output in first 12 hours after operation; Heparin = preoperative heparin therapy; RBCVOL = packed red blood cell volume; T, = number of units of donor exposure per patient. within the first 72 hours after operation). Independent factors used in the analysis of variance were the risk category (high or low) and the blood conservation therapy (control, PRP, or whole blood). Within the analysis of variance, individual differences between treatment groups were evaluated using multiple range analysis. For this purpose, the Student-Newman-Keuls test was used to test for differences in outcomes in the various treatment groups. A probability of 0.05 or less was considered significant. Results Patient Demographics Table 2 compares variables of interest in patients in the high-risk and low-risk strata. In general, the patients in the high-risk stratum were significantly older, were more anemic, and had a prolonged preoperative bleeding time with decreased blood volume, as would be predicted because of the variables used to stratify patients. There was a significantly greater number of transfusions per patient in the high-risk stratum compared with the lowrisk stratum (5.4 * 0.7 versus 2.0? 0.6; p < by Student's t test). Predictably, more women were in the Table 3. Volumes of Whole Blood or Platelet-Rich Plasma Harvested in Each Treatment Stratum" Blood component Low Risk High Risk Platelet-rich plasma 730 * 40 (n = 23) 740 f 69 (n = 12) Whole blood 719 f 58 (n = 17) 729 f 179 (n = 13) a Data are shown as mean volume of blood component 2 the standard error with number of patients in parentheses. high-risk group. This is not surprising, as women in general, and older women in particular, have decreased blood volume compared with men. There was a significant difference in bleeding time between the high-risk and low-risk groups (6.22 * 0.2 versus 4.46? 0.15, respectively; p = by Student's t test). This difference in bleeding time was not due to a quantitative platelet disorder, as there was no difference in the preoperative platelet count between groups (results not shown). There was no difference in the perioperative variables (bypass time, ischemic time, and number of distal anastomoses) between groups, suggesting that the operations performed were similar in each group. Likewise, there was no difference in the number of patients on a preoperative regimen of medication that might affect bleeding, such as aspirin or heparin, suggesting that drug-related causes of increased blood loss are similar in each stratum. Effects of Blood Conservation Interventions The average amounts of autologous blood products harvested from patients randomized to the two treatment strata are shown in Table 3. There were no significant differences between strata in regard to the amounts of either whole blood or PRP, suggesting that equivalent treatment interventions were administered in each stratum. Figure 1 shows the average number of units of nonautologous donor exposure per patient in each of the six treatment groups. Patients in the high-risk control group required significantly more nonautologous donor units than either low-risk controls (8.1 * 2.2 versus 2.0 * 0.7; p = 0.02) or high-risk PRP patients (8.1 * 2.2 versus 2.9 * 2.1; p = 0.05). There were significantly more nonautologous donor units transfused per patient in the high-risk than in the low-risk stratum (5.4? 0.7 versus ; p < 0.001). In the low-risk stratum, nearly half of the patients (30/61) did not receive any nonautologous blood products, whereas in the high-risk stratum, only 4 of 39 patients did not receive a blood transfusion (see High risk Low risk dnl I U Units per patient Control High risk ~4.02 W: IW dtk-... **~=O.O~MHRCONT mlowrisk I I I PRP T Whole blood Fig 1. Effect of autologous blood conservation intervention on the number of units of donor exposure per patient. (HR CONT = highrisk control; PRP = platelet-rich plasma harvested intraoperatively using plasma-saving apparatus; Whole blood = autologous whole blood harvested intraoperatively.)

5 Ann Thorac Surg 1993;56:43?-40 FERRARlS ET AL 437 Table 4. Units of Nonautologous Blood Products Required by the Va, ;OMS Treatment Groups PRBC FFP PLT Total Treatment Group (U) (U) (U) (U) Low risk Control (n = 21) PRP (n = 23) Whole blood (n = 17) High risk Control (n = 14) PRP (n = 12) Whole blood (n = 13) Total FFP = fresh frozen plasma; PLT = platelet transfusions; PRBC = packed red blood cells; PRP = autologous platelet-rich plasma donors; Whole blood = autologous whole-blood donors. Table 2). These results suggest that intraoperative autologous PRP harvest is beneficial in high-risk patients and that evaluation of the efficacy of any autologous blood conservation technique should involve stratification of patients according to their preoperative risk of bleeding. For patients in the low-risk stratum, no autologous blood conservation intervention was beneficial in limiting the amount of nonautologous blood transfusion (see Fig 1). The impact of blood reinfusion techniques on transfusion of the various types of blood products (packed red blood cells, platelets, and fresh frozen plasma) was investigated. These results are shown in Table 4. Most of the blood products transfused (197/341) were packed red blood cells. Patients in the high-risk treatment groups were more likely to receive blood transfusions that were not packed red blood cells (ie, plasma and platelets). Likewise, patients who received more than 4 units of packed red blood cells after operation were highly likely to also require transfusion of plasma and platelets. The chest tube drainage per patient within 12 hours after operation did not differ between strata or between groups within a stratum. Table 2 shows these results for differences between strata, but the results for each group within a given stratum are not shown. The inability to detect a difference between groups may reflect the insensitivity of chest tube drainage as an indicator of the need for postoperative blood product transfusion or may reflect the fact that operative blood loss, as reflected by chest catheter drainage, is a less important cause of postoperative blood product transfusion than preoperative or preexisting patient variables. Results of Operation The morbidity and mortality resulting from operation in the study group were analyzed. There were no reoperations for bleeding in the study patients, but 4 patients who were originally entered into the study and randomized into a treatment group were excluded because of a surgical cause of bleeding found at reoperation. There were three operative deaths. None of them resulted from postoperative bleeding or blood conservation intervention. Four patients (2 in each stratum) sustained perioperative myocardial infarctions as defined by the appearance of new Q waves on postoperative electrocardiograms or the need for intraaortic balloon pumping for weaning from CPB. Comment One of our two original hypotheses was that blood conservation interventions are more likely to be beneficial in patients at high risk for excessive postoperative blood transfusion. The results of this study support this contention. This observation has intuitive appeal. Our results show that control patients in the high-risk stratum have a significantly increased chance of requiring excessive postoperative blood transfusion (greater than 8 units of nonautologous blood products per patient) and that the use of autologous PRP diminishes this risk to less than 3 units in high-risk patients. For patients in the low-risk stratum, no blood conservation intervention affected donor exposure. This supports our second hypothesis that risk stratification is important in determining the efficacy of blood conservation methods. In addition, the difference in the effects of blood conservation between the high-risk and low-risk strata suggests that the methods used to stratify patients were appropriate. The use of bleeding time and red blood cell volume as indicators of risk of postoperative blood transfusion is validated by this study. We showed that the important determinants of the risk of excessive postoperative blood product transfusion are bleeding time, hematocrit, and blood volume, as these are the components that make up the template bleeding time to packed red blood cell volume ratio. Not only is prolonged bleeding time an indicator of platelet dysfunction, but it is also an important indicator of excessive postoperative blood product transfusion. There is abundant evidence to support the concept of platelet dysfunction as a cause of postoperative bleeding after CPB [9, 26, 271. It is logical to assume that patients with elevation of preoperative bleeding time are at increased risk of having excessive platelet dysfunction after CPB. So, to the extent that preoperative bleeding time reflects a tendency toward platelet dysfunction, it is not surprising that bleeding time elevation correlates with excessive postoperative blood transfusion. Several authors [28, 291 have questioned the usefulness of bleeding time as a preoperative indicator of risk of bleeding. We [24] have found that bleeding time, when used as described in this study, is a useful, inexpensive indicator of risk of excessive postoperative blood transfusion, and we continue to use it routinely. Hemodilution resulting from crystalloid pump-oxygenator priming solution may have played a role in the need for postoperative blood product transfusion because two determinants of the risk of excessive postoperative blood product transfusion, blood volume and preoperative hematocrit, are adversely affected by hemodilution. The volume of priming solution used for the oxygenators in this study was between 1,500 and 2,000 ml. The average blood volume in the high-risk group was 4,867 ml, and

6 438 FERRARIS ET AL Ann Thorac Surg 1993;56:43?-40 the average hematocrit in this group was 38%. This means that the average hemodilution from the crystalloid prime would be expected to lower the hematocrit to between 27% and 29% for high-risk patients. This hematocrit at the beginning of CPB, coupled with operative blood loss and further dilution from cardioplegia and other sources, may have pushed certain patients beyond the transfusion threshold. On the other hand, hemodilution does not entirely explain the fact that excessive blood product transfusion is required more frequently in the high-risk group, as hemodilution to an average hematocrit of 27% would not be expected to require an average replacement of 8.1 nonautologous donor units of blood products, as was seen in the high-risk control group. In addition, if hemodilution were an important issue, then replacement of an average of 740 ml of PRP, as was done in the high-risk PRP group, would not be expected to limit the amount of blood product transfusion, as was observed. In fact, the addition of PRP just after CPF might even cause further hemodilution of red cell mass. So, although hemodilution may play some role in the excessive blood product transfusion seen in the high-risk stratum, it cannot fully explain this phenomenon. A more reasonable hypothesis is that, in high-risk patients, the added stress of the damaging effects of CPB on platelet function is enough to tip the balance of hemostasis and result in the need for excessive nonautologous blood product transfusion. It is likely that the beneficial effects of PRP are due to replacement of hemostatically competent platelets and plasma that have not been exposed to the damaging effects of CPB. Dilution of clotting factors and platelets in the perioperative period may be a factor in determining the use of nonautologous blood product transfusions. The results shown in Table 4 suggest that patients who require excessive postoperative packed red blood cell transfusions are more likely to require other blood components (ie, fresh frozen plasma and platelets) as well. This observation seems an obvious consequence of dilution of clotting factors and platelets by the transfused red cells. This suggests that patients in the high-risk stratum are more likely to require replacement of all components of the blood clotting system, not just red cells, and that measures that limit postoperative packed red blood cell use are more likely to limit the transfusion of blood products other than packed red blood cells as well. It is worth pointing out that transfusion of products besides packed red blood cells is likely to carry a higher risk of transfusion-related disease transmission because of the amounts required to reverse the specific defects being treated. The blood loss measured in the output of chest drainage catheters was not significantly different between high-risk and low-risk strata. The statistical power of this negative observation is low (less than 0.5), and inability to detect a difference between strata may reflect the insensitivity of chest tube drainage as an indicator of postoperative blood loss. Other studies of blood conservation [16-20, have also found that chest catheter output does not correlate with the need of postoperative blood transfusion. Chest catheter drainage not only reflects continued blood loss from the operative site, but also reflects the sum of surgical irrigation and topical iced saline solution or slush not removed before the chest was closed. The main clinical utility of chest catheter drainage is in detecting surgical bleeding after operation, as only a large amount of drainage is a useful indicator of active bleeding. In this respect, chest catheter drainage is a qualitative, rather than a quantitative, tool for assessing postoperative bleeding and the need for subsequent blood transfusion. The results of our study support the insensitivity of chest catheter drainage as an outcome variable in assessing disordered hemostasis and abnormal blood product transfusion. The results of this study suggest a more cost-effective way to use blood conservation techniques, especially autologous PRP harvest, before CABG. At our hospital, the cost of using the PRP harvesting equipment is $147 per patient. A hypothetical calculation suggests that to use this apparatus for each patient undergoing CABG at our institution during a year would cost $123,480 (840 CABG patients X $147 per apparatus setup per patient). On the other hand, to use this apparatus for only the high-risk patients (as many as 30% of all CABG patients) would cost only $37,044, a savings of $86,436. In addition, there is a possible savings of approximately 5 donor units of blood products that would result from use of PRP harvest in the high-risk group. At our institution, the average cost of a nonautologous donor unit is approximately $80 per unit. This translates to a potential savings of $400 per high-risk patient, or $100,800 yearly savings in cost of nonautologous blood products resulting from use of autologous PRP harvest. This savings in nonautologous blood products cost more than offsets the cost of setting up the PRP harvest apparatus. This hypothetical calculation clearly shows the cost benefit of a selective approach to the use of PRP harvesting techniques and underscores the advantages of preoperative risk stratification in regard to blood conservation. Several shortcomings of this study should be mentioned. First, as it was not possible to blind the surgeons to the type of blood conservation intervention that was being used in a given patient, there is a possibility that experimental bias played a role in the outcome. For example, a surgeon who thought that PRP harvesting was beneficial might have unknowingly, but consistently, refrained from transfusing patients in the high-risk PRP group. This possibility, although real, is impossible to measure, and only further controlled studies will validate these findings. Secopd, the numbers of patients in the high-risk groups are small, ranging between 12 and 14 patients depending on the treatment group. Because of the small number of patients in these groups, it is possible that some important effects were missed. Despite these shortcomings, we believe that the major findings described are valid and should serve as the basis for further definitive studies to elaborate the usefulness of various blood conservation techniques. Another potential shortcoming of this study is the lack of quantitation of platelets harvested using the PRP devices. Our study does not separate the effect of platelets from that of autologous plasma, and hence cannot quantitate the beneficial effects of autologous platelets on blood

7 Ann Thorac Surg 1993;56:43340 FERRARIS ET AL 439 transfusion. Random measurements of the platelet counts in harvested PRP suggest that the platelet yield from the intraoperative procedure is both variable and limited. The platelet count in 600 to 800 ml of PRP ranged from 150,000 to 250,00O/pL. This means that between 10% and 15% of the circulating platelets are removed by PRP harvest. It is not clear whether reinfusion of this amount of platelets substantially increased the circulating platelet count or, more importantly, increased the platelet function in patients in the PRP group. The beneficial effects of PRP in high-risk patients found in our study cannot be attributed to platelets alone, as there was a large component of autologous plasma in the PRP and as the exact level of platelets reinfused in the PRP is uncertain. In summary, our study shows that intraoperative autologous blood reinfusion methods are not helpful in low-risk patients, but for high-risk patients, infusion of autologous PRP is associated with significantly less postoperative blood transfusion. This suggests that the added cost of intraoperative autologous blood conservation techniques is justified in patients at high risk for excessive postoperative blood transfusion but not in patients at low risk. We thank Dr Haywood Gilliam and Dr Carl Adams for supporting the studies described in this report and for providing helpful comments during its preparation. References 1. Lytle BW, Loop FD, Cosgrove DM, et al. Fifteen hundred coronary reoperations. Results and determinants of early and late survival. J Thorac Cardiovasc Surg 1987;93: McGrath LB, Laub GW, Graf D, Gonzalez-Lavin L. Hospital death on a cardiac surgical service: negative influence of changing practice patterns. 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8 440 FERRARIS ET AL INTRAOI ERATIVE BLOOD CONSERVATION Ann Thorac Surg 1993;56:43340 DISCUSSION DR ROBERT L. THURER (Boston, MA): I enjoyed this report very much. This study is one of several that purport to show that intraoperative plasmapheresis is effective in reducing the number of homologous transfusions given to patients having coronary operations. It seems intuitive that removal of platelets and plasma before bypass coupled with infusion after bypass would reduce damage to these procoagulants and improve hemostasis. Nevertheless, I and others have voiced criticism of this method, not because of any inherent flaw but because it is clearly not indicated in the vast majority of patients and because it may encourage the use of homologous platelets and plasma, which are already being transfused inappropriately in many instances. Doctor Ferraris and colleagues have shown that they can select patients at high risk for homologous transfusion and limit their intervention to those patients most likely to benefit. Although I find this appealing and I certainly cannot deny that many studies are in agreement with their conclusions, I think we have to examine the data carefully to be sure that the biases inherent in the small numbers of patients and the lack of a blinded design do not lead us to adapt this strategy incorrectly. Toward that end, I have several questions for Dr Ferraris. First, the manuscript did not contain platelet counts in the salvaged plasma. These are needed to determine whether the number of platelets sequestered are substantial enough to support the clinical result, and I hope Dr Ferraris can provide them. Second, I am concerned that a homologous platelet transfusion was counted as six exposures when pooled and one exposure if derived from a single donor. Although this is correct, a bias toward which group received single-donor platelets could lead to an incorrect conclusion. Would significant differences still exist if the single-donor platelets were calculated as equivalent to the pooled transfusions? Third, 4 patients were excluded because of reoperation for surgical bleeding. As bleeding from a surgical site can reflect a hemostatic derangement, I do not think those patients should be excluded, and I wonder if their inclusion would change the outcome. Fourth, because the elevated bleeding times in the high-risk patients were likely due to platelet dysfunction, how does salvage of these ineffective platelets lead to improved hemostasis? This is a very well done study with clear transfusion criteria and good outcomes. Although a blinded design would be ideal, careful analysis of these and other data should allow us to reach an appropriate conclusion. In closing, I ask Dr Ferraris to tell us further why he thinks platelet-rich plasma sequestration works whereas whole blood sequestration does not, and why postoperative chest tube drainage was not affected by either intervention. DR JAMES W. JONES (Houston, TX): Thank you, Dr Ferraris, for your fine report. I believe you did a particularly good job of describing the patient population who can best benefit from intraoperative plasmapheresis. Also, you have shown that obtaining whole blood by intraoperative phlebotomy is not as effective as platelet-rich plasma in reducing homologous transfusions. I think that you have explained why there is some confusion in the literature on these conservation methods. Ten principal studies on the efficacy of intraoperative plasmapheresis illustrate the current controversy. The results of five nonrandomized, nonblinded studies that show beneficial results are the most suspect on the basis of design. Four studies were randomized but not blinded. Only one study was randomized and blinded. In this last study, those who made the decision to transfuse left the room during the presumptive plasmapheresis procedures. Your study clearly shows that neither plasmapheresis nor phlebotomy significantly affects the need for homologous blood transfusions in low-risk patients. Doctor DeCastro and associates used a very high risk group (patients having redo valve procedures) but averaged only 2.5 units of platelets in the platelet-rich plasma. With this technique, at least 5 units of platelets must be produced to see a therapeutic effect. If not sufficiently cautious, a practitioner could produce platelet-poor plasma, and no one would expect 1 or 2 units of homologous platelets to make any difference whatsoever. I am interested in learning whether you considered that withdrawing whole blood after giving heparin as the anticoagulant may actually induce platelet dysfunctions that other anticoagulants do not. Also, I would like to know whether you distinguished between the number of transfusions completed in the operating room and those done afterward, as plasmapheresis or whole-blood phlebotomy would have no bearing on those intraoperative homologous transfusions. DR FERRARIS: I thank the discussants for their questions. Doctor Thurer raised the issue of patients who received pooled platelets versus nonpooled platelets. The vast majority of transfused components were red cells (packed red blood cells), and the platelets were a minority of the transfusions. Whether they were pooled or nonpooled did not affect the outcome. Doctor Thurer asked why the platelet functinn in platelet-rich plasma harvested from patients with a prolonged bleeding time or the high-risk group should be more hemostatically important than platelets in the low-risk group, his thinking being that platelets in patients receiving aspirin might not be as hemostatically effective. I do not have the answer to that. I think it has to do with the fact that high-risk patients are unable to tolerate the stress of cardiopulmonary bypass as well as low-risk patients, and any intervention such as cardiopulmonary bypass, any stress on their platelets, is not well tolerated. The mechanistic issues are not answered by our report and represent something else we have to look at. As for why the whole blood did not work in the high-risk group or did not limit postoperative transfusion in that group, I think part of the answer has to do with the sample size. As mentioned, there were only 12 to 14 patients in each of the high-risk groups. Perhaps studying a greater number of patients would show an effect. Doctor Jones asked about the issue of heparin in the whole blood group. Heparin was present in the whole blood that was harvested and reinfused. The presence of heparin did not seem to matter in terms of postoperative bleeding. In the high-risk group, transfusion of heparinized whole blood postoperatively was nearly beneficial probably by virtue of its uninjured platelets and packed red cells, or blood cells that had not been exposed to cardiopulmonary bypass. I think whole blood reinfusion might be effective if it were studied in a greater number of patients, but the effect of heparin in the whole blood reinfused is uncertain. There was also a question about transfusion in the operating room or in the recovery room. I think almost all of the transfusions were administered after operation; they were not given during bypass.