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Intraoperative cell salvage in radical retropubic prostatectomy1
ADULT UROLOGY
INTRAOPERATIVE CELL SALVAGE IN RADICAL RETROPUBIC PROSTATECTOMY CHRISTINE L. GRAY, CHRISTOPHER L. AMLING, GREGORY R. POLSTON, CURTIS R. POWELL, CHRISTOPHER J. KANE
AND
ABSTRACT Objectives. To investigate the efficacy and safety of intraoperative cell salvage with autotransfusion using leukocyte reduction filters in patients undergoing radical retropubic prostatectomy (RRP). Methods. Between September 1996 and March 1999, 62 patients (age range 48 to 70 years) with clinically localized prostate cancer underwent RRP with intraoperative cell salvage as the sole blood management technique. Salvaged blood was passed through a leukocyte reduction filter before autotransfusion. The 62 cell salvage patients were compared with a cohort who predonated 1 to 3 U autologous blood (n ⫽ 101). The estimated blood loss, preoperative and postoperative hematocrit, need for homologous transfusion, and biochemical recurrence rates were compared between the two groups. The progression-free survival rates were compared using the Kaplan-Meier method. Results. No difference was found in preoperative prostate-specific antigen level, pathologic stage, or estimated blood loss between the cell salvage and autologous predonation groups. The preoperative and postoperative hematocrit levels were higher in the cell salvage group (42.7% versus 39.6% and 31.3% versus 27.9%, respectively; P ⬍0.001 for each). The homologous transfusion rates were lower in the cell salvage group (3% versus 14%, P ⫽ 0.04). The incidence of progression-free survival (prostate-specific antigen level 0.4 ng/mL or greater) was no different between the groups (P ⫽ 0.41). Conclusions. Intraoperative cell salvage with autotransfusion using leukocyte reduction filters in RRP results in higher perioperative hematocrit levels and low homologous transfusion rates and eliminates the need for autologous predonation. Cell salvage does not appear to be associated with an increased risk of early biochemical progression after RRP. UROLOGY 58: 740–745, 2001. © 2001, Elsevier Science Inc.
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adical retropubic prostatectomy (RRP) is commonly performed to treat clinically localized prostate cancer. Although modifications in the surgical technique have resulted in lower intraoperative blood loss, a significant number of patients undergoing RRP may require blood transfusion. Numerous risks have been identified with the use of homologous transfusions, including allergic reactions, hemolysis, and infection transmission.1
Additional funding for this project was from the Center for Prostate Disease Research and the Naval School of Health Sciences. The views expressed in this article are those of the authors and do not reflect the official policy or position of the Department of the Navy, Department of Defense, or the United States Government. From the Departments of Urology and Anesthesiology, Naval Medical Center, San Diego, California Reprint requests: Christine L. Gray, M.D., Clinical Investigation Department, KCA, Naval Medical Center, San Diego, 34800 Bob Wilson Drive, Suite 5, San Diego, CA 92134-5000 Submitted: April 13, 2001, accepted (with revisions): July 3, 2001
740
© 2001, ELSEVIER SCIENCE INC. ALL RIGHTS RESERVED
Allogeneic blood transfusion can also result in immunosuppression, which may affect the cancer recurrence rate.2,3 These risks have led to the common use of autologous blood predonation before radical prostatectomy. Although autologous blood avoids many of the risks associated with allogeneic transfusion, it, too, has several potential disadvantages. Some patients are not able to give blood before surgery because of a low baseline hematocrit. Surgery may be delayed to allow time to donate. In addition, preoperative autologous donation costs two to three times more per unit than homologous blood, and nearly 50% of the predonated units are discarded.4 Several recent series have questioned the cost effectiveness of autologous predonation and have recommended against its routine use before radical prostatectomy.5–7 One alternative is to perform normovolemic hemodilution, which has been shown to be more cost-effective than autologous predonation; however, this can decrease the blood pressure intraoperatively.5,8 0090-4295/01/$20.00 PII S0090-4295(01)01365-6
Intraoperative cell salvage (ICS) with autotransfusion is an alternative to homologous or autologous transfusion. Many of the risks associated with homologous transfusion can be avoided, and the advantages of autologous transfusion remain. Washed red blood cells obtained intraoperatively may also have better viability and greater oxygencarrying capacity than allogenic or predonated autologous blood.9 Despite these advantages, the use of ICS in oncologic surgery remains controversial. Although several investigators have found no increase in the rate of disease recurrence when ICS is used in urologic surgery,10,11 concern remains that shed malignant cells may not be completely eliminated in the cell-washing process. The introduction of leukodepletion filters has alleviated some of this concern. Leukodepletion filters eliminate viable nucleated cells by mechanical and affinitybinding processes and produce a 4 to 5-log reduction in peripheral leukocytes.12 In vitro studies have also demonstrated the ability of these filters to eliminate viable tumor cells from urologic cancer cell lines.12,13 Our group has used ICS with autotransfusion using leukodepletion filters in patients undergoing RRP since September 1996. We report our experience with this blood loss management technique. We compared the hematocrit levels and homologous transfusion rates of patients who received cell salvage blood with those of the patients who received predonated blood. MATERIAL AND METHODS Between September 1996 and March 1999, 62 patients underwent RRP using ICS and autotransfusion as the sole blood management technique. To initiate ICS, blood from the operative field was captured in a suction device. All used laparotomy tapes were also rinsed in normal saline and added to the suction fluid. ICS was then performed with the Sequestra 1000 (Medtronic) using a 125-mL bell-shaped Latham bowl. The processed blood was washed with 1 L 0.9% normal saline and passed through an RC-400 leukodepletion filter before autotransfusion. The estimated blood loss (EBL) was calculated in this cohort from the volume and hematocrit (Hct) of the processed blood. The cell salvage-calculated EBL assumed a 75% recovery of shed blood. The cell salvage patients were eliminated from analysis if they underwent ICS but did not undergo retransfusion (n ⫽ 14). The ICS group (n ⫽ 62) was compared with 101 patients who underwent autologous blood predonation before RRP between May 1991 and February 1998. The EBL was estimated by the anesthesiologist in this cohort by the amount of suction canister blood, laparotomy tape saturation, and intraoperative Hct decrease. Patients were excluded from analysis if they predonated blood but did not receive it (n ⫽ 9). Patients who underwent prostatectomy during the study period were also excluded if both blood management techniques were used (n ⫽ 21), if neither technique was used (n ⫽ 29), if they underwent radical perineal prostatectomy (n ⫽ 71), or if the data were incomplete (n ⫽ 26). A team of one attending urologist and one chief resident in urology performed all prostatectomies. Multiple attending UROLOGY 58 (5), 2001
physicians and chief residents were represented in both groups. The decision to proceed with allogeneic blood transfusion was made by the attending urologist and was performed in both groups for symptomatic anemia or an Hct less than 30% if the patient had pre-existing coronary artery disease. Patient age, serum prostate-specific antigen (PSA) level, pathologic stage, Gleason sum, EBL, preoperative and postoperative Hct levels, and homologous transfusion rates were determined for both groups. The postoperative Hct was measured the morning of the first postoperative day. The biochemical progression rates were also compared. Biochemical progression was defined as a single serum PSA level of 0.4 ng/mL or greater or adjuvant radiation therapy in conjunction with any elevated PSA level any time after radical prostatectomy. The assay used was the AXIM microparticulate assay (lower limit of detection less than 0.1 ng/mL). The Student t test was used to determine the differences between the groups regarding age, EBL, and preoperative and postoperative Hct levels. The differences in the preoperative PSA levels, Gleason sum, and pathologic stage were analyzed using the rank-sum test. Fisher’s exact test was used to determine the statistical differences between the homologous transfusion rates. Biochemical progression was assessed according to the Kaplan-Meier method using the Wilcoxon-Gehan statistic.
RESULTS Patients in the cell salvage group were younger than those in the autologous predonation group (62.0 versus 63.3 years, P ⫽ 0.02), and the Gleason sum was higher in the cell salvage patients (6.5 versus 5.9, P ⫽ 0.03). No difference was found between the groups with regard to preoperative serum PSA level (9.50 versus 9.47 ng/mL, P ⫽ 0.32) or pathologic stage distribution (P ⫽ 0.30). The volume of transfused blood ranged from 150 to 1800 mL (mean 534) in the cell salvage group. A comparison of the EBL, preoperative and postoperative Hct levels, and homologous transfusion rates is shown in Table I. Although the EBL was not significantly different between the cell salvage and autologous transfusion groups, both the preoperative and postoperative Hct levels were higher in the cell salvage group. Homologous transfusion was significantly more common in the autologous predonation group (14% versus 3%, P ⫽ 0.04). Patients not transfused were also analyzed for blood loss data, although the sample size was prohibitive for recurrence data. Of the 14 patients who underwent ICS but were not transfused, the mean preoperative and postoperative Hct was 42.1% and 29.1%, respectively. The mean EBL was 758 mL in that cohort, and 1 patient with a T3aN0Mx tumor had recurrence. Of the 29 patients during the study period who had neither autologous predonation nor cell salvage retrieval, 12 (41%) received homologous blood. The mean EBL in those who were not transfused was 752 mL and that of those who were transfused was 1700 mL. The mean preoperative Hct was 41% for those not transfused and 44% for those transfused. The mean postoperative 741
TABLE I. Comparison of estimated blood loss, preoperative and postoperative hematocrit, and homologous transfusion rates in radical prostatectomy patients using intraoperative cell salvage or autologous predonation Cell Salvage (n ⴝ 62) Preoperative Hct (%) Postoperative Hct (%) EBL (mL) Homologous transfusion
42.7 31.3 1315 2
⫾ 3.3 ⫾ 3.5 ⫾ 823 (3)
Autologous Predonation (n ⴝ 101) 39.6 27.9 1410 14
⫾ 4.2 ⫾ 3.4 ⫾ 764 (14)
P Value ⬍0.001 ⬍0.001 0.46 0.04
KEY: Hct ⫽ hematocrit; EBL ⫽ estimated blood loss. Numbers in parentheses are percentages.
FIGURE 1. Progression-free survival in years by the Kaplan-Meier method.
Hct was 29% for those not transfused and 28% for those transfused. The mean follow-up interval in the cell salvage and autologous predonation groups was 7 months and 43 months, respectively. Three patients (5%) in the cell salvage group and 24 patients (24%) in the autologous predonation group developed biochemical recurrence during follow-up, as defined by a PSA level of 0.4 ng/mL or greater or administration of adjuvant radiotherapy. An additional 2 patients in the cell salvage group had isolated PSA levels of 0.2 ng/mL during follow-up. Another 5 patients in the autologous group had a PSA level that was detectable but was 0.4 ng/mL or less. Kaplan-Meier curves comparing the progressionfree survival (PSA 0.4 ng/mL or greater) in these two groups are shown in Figure 1. No difference in progression was observed (P ⫽ 0.41). 742
COMMENT RRP may result in substantial blood loss. Although allogeneic transfusion has been used commonly in the past, the potential risks of homologous blood use have led to alternative blood management strategies. In addition to the risk of transfusion and/or hemolytic reactions and the chance of transmitting blood-borne viral infections, homologous blood transfusion may also alter the immune system. Some have suggested that transfusion-related immunosuppression may result in higher cancer recurrence rates after surgical treatment of various malignancies, including prostate cancer.3 Although other series have failed to confirm these findings,14 –16 the immunomodulatory effect of allogenic blood transfusion is well recognized. Patients undergoing radical prostatecUROLOGY 58 (5), 2001
tomy are often concerned about the real and perceived risks of blood transfusion and many wish to avoid exposure to homologous blood. Many of the deleterious effects associated with homologous blood transfusion may be avoided with the use of predonated autologous blood. In general, autologous blood is associated with fewer infectious complications and a lower risk of transfusion reaction. Despite these apparent benefits, the use of autologous blood predonation does have potential disadvantages. Although rare, complications can occur during blood donation, ranging from mild reactions to serious complications.17 The risk of a transfusion reaction from clerical error, although low, is still present with the use of predonated blood. Several investigators have shown that patients who donate blood before surgery have lower starting Hct levels.5– 8 Hogue et al.18 have shown that lower Hct levels correlate with myocardial ischemia during radical prostatectomy. Acute normovolemic hemodilution is another blood management option that has been shown to compare favorably with predonation. However, patients undergo the removal and retransfusion of blood regardless of whether their blood loss is significant enough to warrant transfusion. In addition, although no adverse effects have been noted, a decrease in systemic blood pressure and central venous pressure can be noted.5,8 The routine use of autologous blood predonation before radical prostatectomy has been questioned, particularly as the average blood loss has decreased.5– 8 Our series and others have documented that autologous predonation decreases patients’ Hct preoperatively.5– 8 In addition, many patients who undergo radical prostatectomy do not require blood transfusion, and many autologous units remain unused and discarded. Das et al.19 collected 4 U autologous blood from patients before radical prostatectomy and noted that 43% of these units were not transfused. In the series reported by Goh et al.7 with an average EBL of 700 mL, only 27% of patients who had predonated blood received their blood. Koch et al.20 reported a 0% homologous transfusion rate in 17 patients after the implementation of a critical pathway for radical prostatectomy. A summation of this series reported the cessation of autologous predonation and a 1% homologous transfusion rate, with an average EBL of 645 mL.21 The data from our 14 patients who underwent ICS but were not transfused (mean EBL 758 mL) and the data from our 17 patients with neither blood management technique who were not transfused (mean EBL 752 mL) support the position that in series with an EBL of less than 800 mL, no blood management technique is necessary. However, the EBL in our cell salvage and autoloUROLOGY 58 (5), 2001
gous groups was more reflective of that in most series. The EBL and homologous transfusion rate in the predonation group in our series was similar to that reported elsewhere.8,19,22,23 With an equal EBL, the homologous transfusion rate in our cell salvage group (3%) remains lower than that reported in most radical prostatectomy series. In the present series, we describe our experience with the use of ICS and autotransfusion. ICS has several potential advantages over other blood loss management strategies. Blood salvaged from the operative field may be of higher quality than banked or predonated blood. Homologous blood has a lower oxygen-carrying capacity, increased red blood cell fragility, and more potential for minor cytokine-release reactions than cell-salvaged blood.9 Because there is no requirement for preoperative blood donation, use of ICS requires no delay in surgery. In our series, the cell salvage patients had higher preoperative and postoperative Hct levels than did the patients who had predonated blood. In addition, 3% of the cell salvage group required homologous transfusion compared with 14% of those in the autologous predonation group. Smaller series have also shown higher homologous transfusion rates in autologous predonation groups when compared with ICS. A recent series of 14 patients using 2 U autologous blood combined with ICS were compared with 8 patients using autologous blood alone. Although the EBL in that series was higher than usually reported for radical prostatectomy (mean EBL 2135 mL), homologous transfusions were given in 29% of the group using both forms of blood management and in 69% of the autologous-only group.24 Although ICS with autotransfusion is commonly used in a variety of surgical settings, its role in oncologic surgery remains controversial. Because prostate cells may be shed into the surgical field at the time of prostatectomy,25 there is concern that reinfusion of salvaged blood might result in hematogenous dissemination of viable malignant cells. However, leukocyte depletion filters have been shown in vitro to eliminate viable tumor cells from salvaged blood.13 There is also clinical evidence of the safety of cell salvage with autotransfusion for radical prostatectomy patients. Klimberg et al.10 reported a series of 49 patients with ICS, of whom 10 underwent radical prostatectomy. The only recurrence was in 1 patient with an incompletely resected carcinoma.10 Pisters and Wajsman26 used cell salvage in 20 urologic oncology patients, of whom 14 underwent radical prostatectomy with cell salvage and autologous predonation. The recurrence rates were not reported, but autotransfusion was reported as having no immediate complications.26 In the current series, the early biochemical recurrence rates were not statistically 743
different between the cell salvage and autologous predonation groups. The follow-up of these patients was too short to make conclusions about the long-term recurrence rates, but the early recurrence rates do not appear to be increased with ICS. If reinfusion of viable tumor cells had occurred in our patients, the early progression of tumor burden might be expected. This was not observed in our cell salvage patients. Because no clinical recurrences occurred in either group, PSA was used as a surrogate for progression. The use of a serum PSA level greater than 0.4 ng/mL as a marker for biochemical failure has recently been supported.27 The collection of autologous blood is expensive, time-consuming, and inconvenient for the patient. The cost of cell salvage is variable, depending on the cost of the processor, technical support staff, and disposables. The cost of the disposables to recover shed blood at our institution is $100, plus an additional disposable cost of $50 per unit to process and transfuse the blood. Our cost per unit from the local blood bank to collect autologous predonated blood is $200. The cost in military practice is probably underestimated for both techniques, as the technician and facilities costs are fixed and therefore difficult to quantify. Local civilian rates for cell salvage rental, including technicians, disposables, and processor charges are $300 for 2 hours, plus $50 for each additional hour. The list price for the processor is $40,000, but can be shared among different surgical services. Because the setup cost of ICS is fixed, and the cost per unit transfused is low, the savings advantage of cell salvage becomes more significant with greater EBLs. Furthermore, the entire cost of autologous blood is incurred when the blood is donated, whether or not the patient requires a blood transfusion. This analysis does not include the cost of erythropoietin, if needed, or the time lost from work to predonate the blood, both of which also favor cell salvage as a less expensive alternative. There are several limitations to our series. First, the patients were not randomized to either blood management technique, although the clinical and pathologic criteria usually used to predict progression were similar between the groups and actually more favorable in the predonation cohort because of its lower Gleason sum. Second, when cell salvage was initially used at our institution, there was a transition period in which patients received both autologous predonation and cell salvage. Because these patients were excluded from this analysis, it did not affect the comparison of the techniques, but did decrease our sample size. The relatively large number of perineal prostatectomies performed in the beginning of the study period also decreased the sample size. Another critique may be that because the cohorts were consecutive rather 744
than contemporary, the allogeneic transfusion criteria may have differed. Because both cohorts underwent surgery in the 1990s, after the requirements for transfusion were made more stringent, this is unlikely. Our criteria, namely symptomatic anemia or Hct less than 30% in patients with cardiac disease, were identical for both groups. CONCLUSIONS ICS is an effective and safe technique for blood management in patients undergoing radical prostatectomy. Compared with patients using autologous blood predonation, it results in higher preoperative and postoperative Hct levels and a lower homologous transfusion rate. Additionally, ICS does not appear to increase early biochemical recurrence rates in radical prostatectomy patients. REFERENCES 1. Goodnough LT, Brecher ME, Kanter MH, et al: Transfusion medicine: blood transfusion. N Engl J Med 340: 438, 1999. 2. Landers JF, Hill GE, Wong KG, et al: Blood transfusion induced immunomodulation. Anesth Analg 82: 187–204, 1996. 3. Vamvakas EC: Transfusion-associated cancer recurrence and postoperative infection: meta-analysis of randomized, controlled clinical trials. Transfusion 36: 175–186, 1996. 4. Wallace EL, Surgenor DM, Hao HS, et al: Collection and transfusion of blood in the United States, 1989. Transfusion 33: 139 –144, 1993. 5. Monk TG, Goodnough LT, Birkmeyer JD, et al: Acute normovolemic hemodilution is a cost-effective alternative to preoperative autologous blood donation by patients undergoing radical retropubic prostatectomy. Transfusion 35: 559 – 565, 1995. 6. Goad JR, Eastham JA, Fitzgerald KB, et al: Radical retropubic prostatectomy: limited benefit of autologous blood donation. J Urol 154: 2103–2109, 1995. 7. Goh M, Kleer CG, Kielczewski P, et al: Autologous blood donation prior to anatomic radical retropubic prostatectomy: is it necessary? Urology 49: 569 –573, 1997. 8. Monk TG, Goodnough LT, Brecher ME, et al: Acute normovolemic hemodilution can replace preoperative autologous blood donation as a standard of care for autologous blood procurement in radical prostatectomy. Anesth Analg 85: 953– 958, 1997. 9. Ray JM, Flynn JC, and Bierman AH: Erythrocyte survival following intraoperative autotransfusion in spinal surgery: an in vivo comparative study and 5-year update. Spine 11: 879 – 882, 1986. 10. Klimberg I, Sirois R, Wajsman Z, et al: Intraoperative autotransfusion in urologic oncology. Arch Surg 121: 1326 – 1329, 1986. 11. Hart OJ III, Klimberg IW, Wajsman Z, et al: Intraoperative autotransfusion in radical cystectomy for carcinoma of the bladder. Surg Gynecol Obstet 168: 302–306, 1989. 12. Kongsgaard UE, Wang MY, and Kvalheim G: Leukocyte depletion filter removes cancer cells in human blood. Acta Anaesthesiol Scand 40: 118 –120, 1996. 13. 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. 14. Eickhoff JH, Gote H, and Baeck J: Peri-operative blood UROLOGY 58 (5), 2001
transfusion in relation to tumor recurrence and death after surgery for prostatic cancer. Br J Urol 68: 608 – 611, 1991. 15. Ness PM, Walsh PC, Zahurak M, et al: Prostate cancer recurrence in radical surgery patients receiving autologous or homologous blood. Transfusion 32: 31–36, 1992. 16. Velagapudi SRC, Frydenberg ME, Osterling JE, et al: Homologous blood transfusion in patients with prostate cancer: no effect on tumor progression or survival. Urology 43: 821– 827, 1994. 17. AuBuchon JP, and Popovsky MA: The safety of preoperative autologous blood donation in the non-hospital setting. Transfusion 31: 513–517, 1991. 18. Hogue CW Jr, Goodnough LT, and Monk TG: Perioperative myocardial ischemic episodes are related to hematocrit level in patients undergoing radical prostatectomy. Transfusion 38: 924 –931, 1998. 19. Das A, Strup S, Canfield S, et al: Utilization of autologous blood donation during radical retropubic prostatectomy. Tech Urol 4: 131–135, 1998. 20. Koch MO, Smith JA Jr, Hodge EM, et al: Prospective development of a cost-efficient program for radical retropubic prostatectomy. Urology 44: 311–318, 1994. 21. Koch MO, and Smith JA Jr: Cost containment in urology. Urology 46: 14 –24, 1995.
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22. Litwiller SE, Djavan B, Klopukh BV, et al: Radical retropubic prostatectomy for localized carcinoma of the prostate in a large metropolitan hospital: changing trends over a 10year period (1984 –1994). Urology 45: 813– 822, 1995. 23. Andriole GL, Smith DS, Rao G, et al: Early complications of contemporary anatomical radical retropubic prostatectomy. J Urol 152(5 Pt 2): 1858 –1860, 1994. 24. Chiusano MA, Finkelstein LH, Mene M, et al: Use of predeposit autologous blood plus intraoperative autotransfusion compared with use of predeposited autologous blood alone in radical retropubic prostatectomy. J Am Osteopath Assoc 96: 160 –164, 1996. 25. Ward JF, Nowacki M, Sands JP, et al: Malignant cytological washings from radical prostatectomy specimens: a possible mechanism for local recurrence of prostate cancer following surgical treatment of organ confined disease. J Urol 156: 1381–1384, 1996. 26. Pisters LL, and Wajsman Z: Use of predeposit autologous blood and intraoperative autotransfusion in urologic cancer surgery. J Urol 40: 211–215, 1992. 27. Amling CL, Bergstrath EJ, Blute ML, et al: Defining prostate specific antigen progression after radical prostatectomy: what is the most appropriate cutpoint? J Urol 165: 1146 –1151, 2001.
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INTRAOPERATIVE CELL SALVAGE IN RADICAL RETROPUBIC PROSTATECTOMY CHRISTINE L. GRAY, CHRISTOPHER L. AMLING, GREGORY R. POLSTON, CURTIS R. POWELL, CHRISTOPHER J. KANE
AND
ABSTRACT Objectives. To investigate the efficacy and safety of intraoperative cell salvage with autotransfusion using leukocyte reduction filters in patients undergoing radical retropubic prostatectomy (RRP). Methods. Between September 1996 and March 1999, 62 patients (age range 48 to 70 years) with clinically localized prostate cancer underwent RRP with intraoperative cell salvage as the sole blood management technique. Salvaged blood was passed through a leukocyte reduction filter before autotransfusion. The 62 cell salvage patients were compared with a cohort who predonated 1 to 3 U autologous blood (n ⫽ 101). The estimated blood loss, preoperative and postoperative hematocrit, need for homologous transfusion, and biochemical recurrence rates were compared between the two groups. The progression-free survival rates were compared using the Kaplan-Meier method. Results. No difference was found in preoperative prostate-specific antigen level, pathologic stage, or estimated blood loss between the cell salvage and autologous predonation groups. The preoperative and postoperative hematocrit levels were higher in the cell salvage group (42.7% versus 39.6% and 31.3% versus 27.9%, respectively; P ⬍0.001 for each). The homologous transfusion rates were lower in the cell salvage group (3% versus 14%, P ⫽ 0.04). The incidence of progression-free survival (prostate-specific antigen level 0.4 ng/mL or greater) was no different between the groups (P ⫽ 0.41). Conclusions. Intraoperative cell salvage with autotransfusion using leukocyte reduction filters in RRP results in higher perioperative hematocrit levels and low homologous transfusion rates and eliminates the need for autologous predonation. Cell salvage does not appear to be associated with an increased risk of early biochemical progression after RRP. UROLOGY 58: 740–745, 2001. © 2001, Elsevier Science Inc.
R
adical retropubic prostatectomy (RRP) is commonly performed to treat clinically localized prostate cancer. Although modifications in the surgical technique have resulted in lower intraoperative blood loss, a significant number of patients undergoing RRP may require blood transfusion. Numerous risks have been identified with the use of homologous transfusions, including allergic reactions, hemolysis, and infection transmission.1
Additional funding for this project was from the Center for Prostate Disease Research and the Naval School of Health Sciences. The views expressed in this article are those of the authors and do not reflect the official policy or position of the Department of the Navy, Department of Defense, or the United States Government. From the Departments of Urology and Anesthesiology, Naval Medical Center, San Diego, California Reprint requests: Christine L. Gray, M.D., Clinical Investigation Department, KCA, Naval Medical Center, San Diego, 34800 Bob Wilson Drive, Suite 5, San Diego, CA 92134-5000 Submitted: April 13, 2001, accepted (with revisions): July 3, 2001
740
© 2001, ELSEVIER SCIENCE INC. ALL RIGHTS RESERVED
Allogeneic blood transfusion can also result in immunosuppression, which may affect the cancer recurrence rate.2,3 These risks have led to the common use of autologous blood predonation before radical prostatectomy. Although autologous blood avoids many of the risks associated with allogeneic transfusion, it, too, has several potential disadvantages. Some patients are not able to give blood before surgery because of a low baseline hematocrit. Surgery may be delayed to allow time to donate. In addition, preoperative autologous donation costs two to three times more per unit than homologous blood, and nearly 50% of the predonated units are discarded.4 Several recent series have questioned the cost effectiveness of autologous predonation and have recommended against its routine use before radical prostatectomy.5–7 One alternative is to perform normovolemic hemodilution, which has been shown to be more cost-effective than autologous predonation; however, this can decrease the blood pressure intraoperatively.5,8 0090-4295/01/$20.00 PII S0090-4295(01)01365-6
Intraoperative cell salvage (ICS) with autotransfusion is an alternative to homologous or autologous transfusion. Many of the risks associated with homologous transfusion can be avoided, and the advantages of autologous transfusion remain. Washed red blood cells obtained intraoperatively may also have better viability and greater oxygencarrying capacity than allogenic or predonated autologous blood.9 Despite these advantages, the use of ICS in oncologic surgery remains controversial. Although several investigators have found no increase in the rate of disease recurrence when ICS is used in urologic surgery,10,11 concern remains that shed malignant cells may not be completely eliminated in the cell-washing process. The introduction of leukodepletion filters has alleviated some of this concern. Leukodepletion filters eliminate viable nucleated cells by mechanical and affinitybinding processes and produce a 4 to 5-log reduction in peripheral leukocytes.12 In vitro studies have also demonstrated the ability of these filters to eliminate viable tumor cells from urologic cancer cell lines.12,13 Our group has used ICS with autotransfusion using leukodepletion filters in patients undergoing RRP since September 1996. We report our experience with this blood loss management technique. We compared the hematocrit levels and homologous transfusion rates of patients who received cell salvage blood with those of the patients who received predonated blood. MATERIAL AND METHODS Between September 1996 and March 1999, 62 patients underwent RRP using ICS and autotransfusion as the sole blood management technique. To initiate ICS, blood from the operative field was captured in a suction device. All used laparotomy tapes were also rinsed in normal saline and added to the suction fluid. ICS was then performed with the Sequestra 1000 (Medtronic) using a 125-mL bell-shaped Latham bowl. The processed blood was washed with 1 L 0.9% normal saline and passed through an RC-400 leukodepletion filter before autotransfusion. The estimated blood loss (EBL) was calculated in this cohort from the volume and hematocrit (Hct) of the processed blood. The cell salvage-calculated EBL assumed a 75% recovery of shed blood. The cell salvage patients were eliminated from analysis if they underwent ICS but did not undergo retransfusion (n ⫽ 14). The ICS group (n ⫽ 62) was compared with 101 patients who underwent autologous blood predonation before RRP between May 1991 and February 1998. The EBL was estimated by the anesthesiologist in this cohort by the amount of suction canister blood, laparotomy tape saturation, and intraoperative Hct decrease. Patients were excluded from analysis if they predonated blood but did not receive it (n ⫽ 9). Patients who underwent prostatectomy during the study period were also excluded if both blood management techniques were used (n ⫽ 21), if neither technique was used (n ⫽ 29), if they underwent radical perineal prostatectomy (n ⫽ 71), or if the data were incomplete (n ⫽ 26). A team of one attending urologist and one chief resident in urology performed all prostatectomies. Multiple attending UROLOGY 58 (5), 2001
physicians and chief residents were represented in both groups. The decision to proceed with allogeneic blood transfusion was made by the attending urologist and was performed in both groups for symptomatic anemia or an Hct less than 30% if the patient had pre-existing coronary artery disease. Patient age, serum prostate-specific antigen (PSA) level, pathologic stage, Gleason sum, EBL, preoperative and postoperative Hct levels, and homologous transfusion rates were determined for both groups. The postoperative Hct was measured the morning of the first postoperative day. The biochemical progression rates were also compared. Biochemical progression was defined as a single serum PSA level of 0.4 ng/mL or greater or adjuvant radiation therapy in conjunction with any elevated PSA level any time after radical prostatectomy. The assay used was the AXIM microparticulate assay (lower limit of detection less than 0.1 ng/mL). The Student t test was used to determine the differences between the groups regarding age, EBL, and preoperative and postoperative Hct levels. The differences in the preoperative PSA levels, Gleason sum, and pathologic stage were analyzed using the rank-sum test. Fisher’s exact test was used to determine the statistical differences between the homologous transfusion rates. Biochemical progression was assessed according to the Kaplan-Meier method using the Wilcoxon-Gehan statistic.
RESULTS Patients in the cell salvage group were younger than those in the autologous predonation group (62.0 versus 63.3 years, P ⫽ 0.02), and the Gleason sum was higher in the cell salvage patients (6.5 versus 5.9, P ⫽ 0.03). No difference was found between the groups with regard to preoperative serum PSA level (9.50 versus 9.47 ng/mL, P ⫽ 0.32) or pathologic stage distribution (P ⫽ 0.30). The volume of transfused blood ranged from 150 to 1800 mL (mean 534) in the cell salvage group. A comparison of the EBL, preoperative and postoperative Hct levels, and homologous transfusion rates is shown in Table I. Although the EBL was not significantly different between the cell salvage and autologous transfusion groups, both the preoperative and postoperative Hct levels were higher in the cell salvage group. Homologous transfusion was significantly more common in the autologous predonation group (14% versus 3%, P ⫽ 0.04). Patients not transfused were also analyzed for blood loss data, although the sample size was prohibitive for recurrence data. Of the 14 patients who underwent ICS but were not transfused, the mean preoperative and postoperative Hct was 42.1% and 29.1%, respectively. The mean EBL was 758 mL in that cohort, and 1 patient with a T3aN0Mx tumor had recurrence. Of the 29 patients during the study period who had neither autologous predonation nor cell salvage retrieval, 12 (41%) received homologous blood. The mean EBL in those who were not transfused was 752 mL and that of those who were transfused was 1700 mL. The mean preoperative Hct was 41% for those not transfused and 44% for those transfused. The mean postoperative 741
TABLE I. Comparison of estimated blood loss, preoperative and postoperative hematocrit, and homologous transfusion rates in radical prostatectomy patients using intraoperative cell salvage or autologous predonation Cell Salvage (n ⴝ 62) Preoperative Hct (%) Postoperative Hct (%) EBL (mL) Homologous transfusion
42.7 31.3 1315 2
⫾ 3.3 ⫾ 3.5 ⫾ 823 (3)
Autologous Predonation (n ⴝ 101) 39.6 27.9 1410 14
⫾ 4.2 ⫾ 3.4 ⫾ 764 (14)
P Value ⬍0.001 ⬍0.001 0.46 0.04
KEY: Hct ⫽ hematocrit; EBL ⫽ estimated blood loss. Numbers in parentheses are percentages.
FIGURE 1. Progression-free survival in years by the Kaplan-Meier method.
Hct was 29% for those not transfused and 28% for those transfused. The mean follow-up interval in the cell salvage and autologous predonation groups was 7 months and 43 months, respectively. Three patients (5%) in the cell salvage group and 24 patients (24%) in the autologous predonation group developed biochemical recurrence during follow-up, as defined by a PSA level of 0.4 ng/mL or greater or administration of adjuvant radiotherapy. An additional 2 patients in the cell salvage group had isolated PSA levels of 0.2 ng/mL during follow-up. Another 5 patients in the autologous group had a PSA level that was detectable but was 0.4 ng/mL or less. Kaplan-Meier curves comparing the progressionfree survival (PSA 0.4 ng/mL or greater) in these two groups are shown in Figure 1. No difference in progression was observed (P ⫽ 0.41). 742
COMMENT RRP may result in substantial blood loss. Although allogeneic transfusion has been used commonly in the past, the potential risks of homologous blood use have led to alternative blood management strategies. In addition to the risk of transfusion and/or hemolytic reactions and the chance of transmitting blood-borne viral infections, homologous blood transfusion may also alter the immune system. Some have suggested that transfusion-related immunosuppression may result in higher cancer recurrence rates after surgical treatment of various malignancies, including prostate cancer.3 Although other series have failed to confirm these findings,14 –16 the immunomodulatory effect of allogenic blood transfusion is well recognized. Patients undergoing radical prostatecUROLOGY 58 (5), 2001
tomy are often concerned about the real and perceived risks of blood transfusion and many wish to avoid exposure to homologous blood. Many of the deleterious effects associated with homologous blood transfusion may be avoided with the use of predonated autologous blood. In general, autologous blood is associated with fewer infectious complications and a lower risk of transfusion reaction. Despite these apparent benefits, the use of autologous blood predonation does have potential disadvantages. Although rare, complications can occur during blood donation, ranging from mild reactions to serious complications.17 The risk of a transfusion reaction from clerical error, although low, is still present with the use of predonated blood. Several investigators have shown that patients who donate blood before surgery have lower starting Hct levels.5– 8 Hogue et al.18 have shown that lower Hct levels correlate with myocardial ischemia during radical prostatectomy. Acute normovolemic hemodilution is another blood management option that has been shown to compare favorably with predonation. However, patients undergo the removal and retransfusion of blood regardless of whether their blood loss is significant enough to warrant transfusion. In addition, although no adverse effects have been noted, a decrease in systemic blood pressure and central venous pressure can be noted.5,8 The routine use of autologous blood predonation before radical prostatectomy has been questioned, particularly as the average blood loss has decreased.5– 8 Our series and others have documented that autologous predonation decreases patients’ Hct preoperatively.5– 8 In addition, many patients who undergo radical prostatectomy do not require blood transfusion, and many autologous units remain unused and discarded. Das et al.19 collected 4 U autologous blood from patients before radical prostatectomy and noted that 43% of these units were not transfused. In the series reported by Goh et al.7 with an average EBL of 700 mL, only 27% of patients who had predonated blood received their blood. Koch et al.20 reported a 0% homologous transfusion rate in 17 patients after the implementation of a critical pathway for radical prostatectomy. A summation of this series reported the cessation of autologous predonation and a 1% homologous transfusion rate, with an average EBL of 645 mL.21 The data from our 14 patients who underwent ICS but were not transfused (mean EBL 758 mL) and the data from our 17 patients with neither blood management technique who were not transfused (mean EBL 752 mL) support the position that in series with an EBL of less than 800 mL, no blood management technique is necessary. However, the EBL in our cell salvage and autoloUROLOGY 58 (5), 2001
gous groups was more reflective of that in most series. The EBL and homologous transfusion rate in the predonation group in our series was similar to that reported elsewhere.8,19,22,23 With an equal EBL, the homologous transfusion rate in our cell salvage group (3%) remains lower than that reported in most radical prostatectomy series. In the present series, we describe our experience with the use of ICS and autotransfusion. ICS has several potential advantages over other blood loss management strategies. Blood salvaged from the operative field may be of higher quality than banked or predonated blood. Homologous blood has a lower oxygen-carrying capacity, increased red blood cell fragility, and more potential for minor cytokine-release reactions than cell-salvaged blood.9 Because there is no requirement for preoperative blood donation, use of ICS requires no delay in surgery. In our series, the cell salvage patients had higher preoperative and postoperative Hct levels than did the patients who had predonated blood. In addition, 3% of the cell salvage group required homologous transfusion compared with 14% of those in the autologous predonation group. Smaller series have also shown higher homologous transfusion rates in autologous predonation groups when compared with ICS. A recent series of 14 patients using 2 U autologous blood combined with ICS were compared with 8 patients using autologous blood alone. Although the EBL in that series was higher than usually reported for radical prostatectomy (mean EBL 2135 mL), homologous transfusions were given in 29% of the group using both forms of blood management and in 69% of the autologous-only group.24 Although ICS with autotransfusion is commonly used in a variety of surgical settings, its role in oncologic surgery remains controversial. Because prostate cells may be shed into the surgical field at the time of prostatectomy,25 there is concern that reinfusion of salvaged blood might result in hematogenous dissemination of viable malignant cells. However, leukocyte depletion filters have been shown in vitro to eliminate viable tumor cells from salvaged blood.13 There is also clinical evidence of the safety of cell salvage with autotransfusion for radical prostatectomy patients. Klimberg et al.10 reported a series of 49 patients with ICS, of whom 10 underwent radical prostatectomy. The only recurrence was in 1 patient with an incompletely resected carcinoma.10 Pisters and Wajsman26 used cell salvage in 20 urologic oncology patients, of whom 14 underwent radical prostatectomy with cell salvage and autologous predonation. The recurrence rates were not reported, but autotransfusion was reported as having no immediate complications.26 In the current series, the early biochemical recurrence rates were not statistically 743
different between the cell salvage and autologous predonation groups. The follow-up of these patients was too short to make conclusions about the long-term recurrence rates, but the early recurrence rates do not appear to be increased with ICS. If reinfusion of viable tumor cells had occurred in our patients, the early progression of tumor burden might be expected. This was not observed in our cell salvage patients. Because no clinical recurrences occurred in either group, PSA was used as a surrogate for progression. The use of a serum PSA level greater than 0.4 ng/mL as a marker for biochemical failure has recently been supported.27 The collection of autologous blood is expensive, time-consuming, and inconvenient for the patient. The cost of cell salvage is variable, depending on the cost of the processor, technical support staff, and disposables. The cost of the disposables to recover shed blood at our institution is $100, plus an additional disposable cost of $50 per unit to process and transfuse the blood. Our cost per unit from the local blood bank to collect autologous predonated blood is $200. The cost in military practice is probably underestimated for both techniques, as the technician and facilities costs are fixed and therefore difficult to quantify. Local civilian rates for cell salvage rental, including technicians, disposables, and processor charges are $300 for 2 hours, plus $50 for each additional hour. The list price for the processor is $40,000, but can be shared among different surgical services. Because the setup cost of ICS is fixed, and the cost per unit transfused is low, the savings advantage of cell salvage becomes more significant with greater EBLs. Furthermore, the entire cost of autologous blood is incurred when the blood is donated, whether or not the patient requires a blood transfusion. This analysis does not include the cost of erythropoietin, if needed, or the time lost from work to predonate the blood, both of which also favor cell salvage as a less expensive alternative. There are several limitations to our series. First, the patients were not randomized to either blood management technique, although the clinical and pathologic criteria usually used to predict progression were similar between the groups and actually more favorable in the predonation cohort because of its lower Gleason sum. Second, when cell salvage was initially used at our institution, there was a transition period in which patients received both autologous predonation and cell salvage. Because these patients were excluded from this analysis, it did not affect the comparison of the techniques, but did decrease our sample size. The relatively large number of perineal prostatectomies performed in the beginning of the study period also decreased the sample size. Another critique may be that because the cohorts were consecutive rather 744
than contemporary, the allogeneic transfusion criteria may have differed. Because both cohorts underwent surgery in the 1990s, after the requirements for transfusion were made more stringent, this is unlikely. Our criteria, namely symptomatic anemia or Hct less than 30% in patients with cardiac disease, were identical for both groups. CONCLUSIONS ICS is an effective and safe technique for blood management in patients undergoing radical prostatectomy. Compared with patients using autologous blood predonation, it results in higher preoperative and postoperative Hct levels and a lower homologous transfusion rate. Additionally, ICS does not appear to increase early biochemical recurrence rates in radical prostatectomy patients. REFERENCES 1. Goodnough LT, Brecher ME, Kanter MH, et al: Transfusion medicine: blood transfusion. N Engl J Med 340: 438, 1999. 2. Landers JF, Hill GE, Wong KG, et al: Blood transfusion induced immunomodulation. Anesth Analg 82: 187–204, 1996. 3. Vamvakas EC: Transfusion-associated cancer recurrence and postoperative infection: meta-analysis of randomized, controlled clinical trials. Transfusion 36: 175–186, 1996. 4. Wallace EL, Surgenor DM, Hao HS, et al: Collection and transfusion of blood in the United States, 1989. Transfusion 33: 139 –144, 1993. 5. Monk TG, Goodnough LT, Birkmeyer JD, et al: Acute normovolemic hemodilution is a cost-effective alternative to preoperative autologous blood donation by patients undergoing radical retropubic prostatectomy. Transfusion 35: 559 – 565, 1995. 6. Goad JR, Eastham JA, Fitzgerald KB, et al: Radical retropubic prostatectomy: limited benefit of autologous blood donation. J Urol 154: 2103–2109, 1995. 7. Goh M, Kleer CG, Kielczewski P, et al: Autologous blood donation prior to anatomic radical retropubic prostatectomy: is it necessary? Urology 49: 569 –573, 1997. 8. Monk TG, Goodnough LT, Brecher ME, et al: Acute normovolemic hemodilution can replace preoperative autologous blood donation as a standard of care for autologous blood procurement in radical prostatectomy. Anesth Analg 85: 953– 958, 1997. 9. Ray JM, Flynn JC, and Bierman AH: Erythrocyte survival following intraoperative autotransfusion in spinal surgery: an in vivo comparative study and 5-year update. Spine 11: 879 – 882, 1986. 10. Klimberg I, Sirois R, Wajsman Z, et al: Intraoperative autotransfusion in urologic oncology. Arch Surg 121: 1326 – 1329, 1986. 11. Hart OJ III, Klimberg IW, Wajsman Z, et al: Intraoperative autotransfusion in radical cystectomy for carcinoma of the bladder. Surg Gynecol Obstet 168: 302–306, 1989. 12. Kongsgaard UE, Wang MY, and Kvalheim G: Leukocyte depletion filter removes cancer cells in human blood. Acta Anaesthesiol Scand 40: 118 –120, 1996. 13. 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. 14. Eickhoff JH, Gote H, and Baeck J: Peri-operative blood UROLOGY 58 (5), 2001
transfusion in relation to tumor recurrence and death after surgery for prostatic cancer. Br J Urol 68: 608 – 611, 1991. 15. Ness PM, Walsh PC, Zahurak M, et al: Prostate cancer recurrence in radical surgery patients receiving autologous or homologous blood. Transfusion 32: 31–36, 1992. 16. Velagapudi SRC, Frydenberg ME, Osterling JE, et al: Homologous blood transfusion in patients with prostate cancer: no effect on tumor progression or survival. Urology 43: 821– 827, 1994. 17. AuBuchon JP, and Popovsky MA: The safety of preoperative autologous blood donation in the non-hospital setting. Transfusion 31: 513–517, 1991. 18. Hogue CW Jr, Goodnough LT, and Monk TG: Perioperative myocardial ischemic episodes are related to hematocrit level in patients undergoing radical prostatectomy. Transfusion 38: 924 –931, 1998. 19. Das A, Strup S, Canfield S, et al: Utilization of autologous blood donation during radical retropubic prostatectomy. Tech Urol 4: 131–135, 1998. 20. Koch MO, Smith JA Jr, Hodge EM, et al: Prospective development of a cost-efficient program for radical retropubic prostatectomy. Urology 44: 311–318, 1994. 21. Koch MO, and Smith JA Jr: Cost containment in urology. Urology 46: 14 –24, 1995.
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