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Perioperative blood transfusion associated with infectious complications after colorectal cancer operations
SCIENTIFIC PAPERS
Perioperative Blood Transfusion Associated With Infectious Complications After Colorectal Cancer Operations
Paul Ian Tartter, MD, Sandra Ouintero, BA, and Deborah M. Barron, BA, New York, New York
Studies of infectious complications after elective colorectal operations have focused on the use of various prophylactic antibiotic regimens [I-4]. Variables that may have influenced the outcome of these trials (for example, age, sex, diagnosis, and operative procedure) have not been considered in the published reports [5]. Additional factors that may contribute to the development of infectious complications have not been well studied recently. Perioperative factors associated with suppression of immunity may contribute to the development of infectious complications because immune suppression is associated with postoperative infection, septicemia, and death related to infection [S]. Anesthesia [7,8], blood loss [8], transfusion [9,10], the magnitude of the procedure [II], and duration of operation [9] have been linked to postoperative immunosuppression. To clarify the clinical significance of these findings, we investigated the relationship between numerous perioperative factors and infectious complications after colorectal cancer operations. Material and Methods The study population consisted of 168consecutive patients scheduled for elective colorectal cancer operation without evidence of liver or other metastases. Patients were identified preoperatively between August 1, 1983 and December 31,1984. All patients received bowel preparation with laxatives, enemas, oral neomycin and erythromycin base, and intravenous cefazolin. Cefazolin was continued for 24 hours postoperatively. Patients were followed for at least 1 week postoperatively until dis-
From the Department of Surgery, The Mount Slnai Medical Center, New York, New York. Supported in part by the Frieda and George Zinberg Foundation, New York, New York, and NCI-NlH Grant 1 ROI-CA-35558-01, Natlonal lnstltutes of Health, Bethesda. Maryland. Requests for reprints should be addressed to Paul Ian Tartter, MO, Annenberg 25-60, Mount Sinal Medical Center, 1 Gustave L. Levy Place, New York, New York 10029.
vofunm 152, November 1sas
charge. A purulent exudate was accepted as irrefutable evidence of wound infection. Urinary tract infection was accepted as the cause of fever and leukocytosis when urine yielded more than 100,000 pathogens/ml or signs and symptoms of urinary tract infection were present in the absence of other possible sources. Pneumonia was diagnosed by fever, leukocytosis, and infiltrate on chest radiograph. Both patients who had development of pneumonia in this study also had positive blood cultures. Intraabdominal collections were localized by ultrasonography and computerized tomographic scanning when other cultures failed to reveal a source for fever and leukocytosis. Age, sex, operative procedure, length of biopsy specimen, degree of differentiation, number of involved nodes, disease stage, hematocrit value on admission, operative blood loss, duration of operation, and number and time (preoperatively, intraoperatively, and postoperatively) of blood transfusions administered during hospitalization were recorded. Tumor differentiation was graded as well, moderate, or poor by the pathologists. Tumor size was calculated from the pathologists’ measurements in the fresh state using the formula (length/2 X width/Z X 7r). The pathologists also measured the length of each specimen in the fresh state. Staging was by a modification of Dukes’ classification wherein Dukes’ A indicated that disease was limited to the mucosa and submucosa; Bl, infiltration of the muscularis without nodal involvement; B2, infiltration of the serosa without nodal involvement; Cl, one to three involved nodes; C2, more than three involved nodes; and D, hepatic or other metastases. Multivariate analysis of the data was accomplished using SAS BMDP@ stepwise logistic regression software [12,13] run on an IBM 370’s computer housed at the City University of New York Computing Center. This program investigates the relation between a binarv-denendent < . variable, such as infectious complication, and a set of independent variables which may be categoric, such as operative procedure and sex, or interval-scaled variables, such as age, operative blood loss, and duration of procedure. The significance of the observed differences was
479
Tartter et al
TABLE I
Multivariate Analysis With infectious Complication as a Dependent Variable
Variable
TABLE II
Chi-Square Value
p Value
Degrees of Freedom
6.63 0.06 0.00 1.13 10.75 0.66 0.82 1.84 5.49
0.0100 0.7601 0.9540 0.287 1 0.1497 0.4165 0.3649 0.1748 0.0191
1 1 1 1 7 3 5 1 1
0.3395 0.3272 0.6972
1 1 1
lnfectlon Rates Compared With Tlmlng of Transfuslons
Data
Number
Infected
Percent
12 158
3 21
25 13
39 129
9 15
23 12
22 146
8 16
36 11
69 99
17 7
25 7
Preoperative Transfusion Age Sex Blood loss Operative procedure Tumor differentiation Stage Nodes Admission hematocrit value (%) Duration of surgery Specimen length Tumor size
0.91 0.96 0.15
evaluated using the chi-square where appropriate.
and Student’s
t tests
Results Infection developed postoperatively in 24 of the 168 patients (14 percent). Nine patients (5.4 percent) had wound infections, seven (4.2 percent) had urinary infections, five (3 percent) had abdominal and pelvic infections, two (1.2 percent) had pneumonia, and one (0.6 percent) had sepsis. Dehiscence of the abdominal wound subsequently occurred in two of the patients with wound infections and both died with multiple septic complications. One patient with a suspected pelvic collection died in septic shock while undergoing ultrasonography to localize and drain the collection. One patient died with multiple septic complications after reexploration for intestinal obstruction 13 days after an uneventful sigmoid resection. Seven patients had postoperative urinary tract infections which resolved with intravenous antibiotics. All patients in this study were routinely catheterized with indwelling Foley balloon catheters preoperatively. Of the two patients with pneumonia, one also had a cerebrovascular accident and myocardial infarction, but he recovered and was discharged home. One patient with fever, leukocytosis, and positive blood cultures was successfully treated with intravenous antibiotics without a source of infection being found. Colon resection had included a splenectomy for iatrogenic injury. Multivariate analysis with infection as the dependent variable indicated that admission hematocrit value and blood transfusion were the only variables significantly related to infection (p = 0.0191 and p = 0.010, respectively) (Table I). The incidence of infection among anemic patients (admission hematocrit value of less than 40 percent) was significantly lower than the incidence among patients with normal blood counts (6 percent versus 17 percent, chi-
480
Transfused Not transfused lntraoperative Transfused Not transfused Postoperative Transfused Not transfused Overall Transfused Not transfused
square = 5.759, p = 0.0164). Apparently, anemia was not a risk factor for infectious complications in this group of patients. Blood transfusions were significantly associated with infectious complications. Seventeen of the 69 patients (25 percent) who received blood transfusions had subsequent infectious complications compared with 7 of 99 patients (7 percent) who did not receive blood transfusions (Table II). The mean number of blood transfusions in the patients with infectious complications significantly exceeded that in the patients without complications (2.14 f 2.75 versus 0.82 f 1.37, p = 0.0005) (Table III). The administration of blood had a significant association with a low admission hematocrit value, high operative blood loss, prolonged operative time, and long specimens (p <0.005). However, none of these factors was associated with infectious complications (p >O.lO). Blood transfusions were associated with infectious complications when given preoperatively, intraoperatively, or postoperatively (Table III). None of the transfused patients had infectious complications before receiving the first unit of blood. Since the observed association of infectious complications with blood transfusion could have been a reflection of intraoperative hypovolemic shock, the anesthesia records of the 17 transfused patients with infectious complications were reviewed. None of these patients were in shock at any time during colon resection. The lowest systolic blood pressure was 99 f 13 mmHg (range 78 to 120 mmHg) and the highest pulse was 92 f 14 beats/min (range 65 to 120 beats/min). Intraoperative transfusions were administered to 11 patients to compensate for estimated operative losses exceeding 500 ml. The remaining patients were transfused before or after operation if the hematocrit value was less than 30 percent in the absence of clinical signs of anemia. Comments This multivariate study found that blood transfusion and admission hematocrit value were significantly associated with infectious complications of
The American Journal 01 Surgery
Transfusion and Infection in Colorectal Cancer Operations
cancer operations. The relationship of blood transfusion to infectious complications may reflect the influence of an unmeasured related variable. Blood transfusion may be a reflection of operative difficulty or trauma related to the severity of disease and reflected by the need for transfusion. The lack of association of anemia, operative procedure, duration of operation, blood loss, specimen length, stage, or tumor size with infectious complications suggests that this is not the case. Alternately, the findings of this study may be related to immunosuppressive viral diseases transmitted in transfused blood. Recently it has been suggested that carcinogenic organic compounds that leak from the plastic used in conventional blood bags may be immunosuppressive [14,15]. Blood transfusion may be a more significant factor affecting postoperative immune function and susceptibility to infectious complications than previously recognized. Immunologic changes are associated with blood transfusions in several clinical situations. For example, transfusion in patients receiving dialysis is followed by inhibition of lymphocyte responses to mitogens and antigens, increased plasma lymphocyte suppressive activity, and inversion of helper-to-suppressor T-cell ratios [16-191. A long-term transfusion regimen for thalassemia [20], sickle cell disease [20-221, pyruvate kinase deficiency [22], or hemophilia [20,22] is also associated with inverted helper-to-suppressor T-cell ratios and, in addition, with reduced natural-killer cell cytotoxicity [20]. Perioperative blood transfusion in patients with inflammatory bowel disease is followed by prolonged depression of peripheral lymphocytes and T cells [IO]. Perioperative blood transfusions for abdominal and thoracic operative procedures are associated with depressed lymphocyte responses to phytohemagglutinin, pokeweed mitogen, and concanavalin A for up to 4 weeks postoperatively [9]. The observed alterations in immune function after transfusion may have clinical significance [IO]. In the dialysis patient, tranfusion-induced alteration in the immune cells is associated with prolonged subsequent renal allograft survival [23]. In general surgical patients, preoperative anergy is associated with increased risk of postoperative sepsis and septic death [6]. Blood transfusion has been implicated as a risk factor for the development of postoperative septic complications in patients with intestinal perforation after penetrating abdominal trauma [24]. The significance of the observed changes after transfusion for hematologic or inflammatory bowel diseases just alluded to is not clear at this time. The lack of association of anemia with infectious complications in this study cannot be explained from experimental or clinical studies of immune function in anemic patients. Most reports have shown defects in cell-mediated immunity in a sigcolorectal
Volume 152, November 1996
TABLE III
Comparisonof Continuous Variables in Patients With and Wlthout lnfectlous Compllcatlons
Variables Age W) Admission hematocrit value (%) Blood loss (dl) Duration of operation (min) Tumor size (ml) Specimen length (cm) Mean no. of blood transfusions
Infected
Not Infected
p Value
68 40.1
67 38.5
0.8535 0.1887
5.48 178
4.73 174
0.3911 0.7700
59.2 29 2.14
64.8 26 0.82
0.6123 0.3058 0.0005
nificant number of patients [25]. In animal studies, it has been shown that iron deficiency increases susceptibility to infections [26], although one report has indicated that iron deficiency stimulates mitogen-induced proliferative responses of rat lymphocytes [27]. It is unlikely that anemia could cause sufficient immune stimulation to prevent infectious complications after operation for colorectal cancer. The low incidence of infectious complications in anemic patients in this study counters the argument that the association of blood transfusion with infectious complications is merely a manifestation of advanced malignancy reflected by anemia requiring transfusion. This study indicates that infectious complications after operations for elective colorectal cancer may be related to blood transfusions. The observed association of blood transfusion with septic complications in this study, together with with the observed transfusion-associated immune alterations in other clinical situations, suggests that blood transfusion may be a more significant factor in postoperative immunosuppression than previously recognized. Summary We prospectively studied 168 consecutive patients with colorectal cancer to identify perioperative determinants of infectious complications. All patients received preoperative bowel preparation with laxatives, enemas, oral neomycin and erythromycin base, and intravenous cefazolin. Age, sex, admission hematocrit value, operative procedure, specimen length, duration of operation, blood loss, transfusions, tumor size, tumor differentiation, nodal status, and Dukes’ stage were evaluated in relation to infectious complications using multivariate analysis. Infectious complications developed in 24 of the 168 patients in the study (14 percent) and these accounted for the four deaths. Blood transfusion (p = 0.0100) and admission hematocrit value (p = 0.0191) were significantly related to postoperative
481
Tartter et al
infectious complications. Low admission hematocrit values appeared to protect patients from infectious complications. Patients who had postoperative infectious complications received 2.14 f 2.75 units of blood compared with 0.82 f 1.37 units in patients without infectious complications (p = 0.0005). Although blood transfusion was associated with high operative blood loss, prolonged procedures, and large specimens (p <0.005), none of these factors was significantly associated with infectious complications (p >O.lO). Blood transfusion is immunosuppressive in other clinical situations and may be a more significant factor affecting postoperative immune function and susceptibility to infectious complications than previously recognized. References 1. Hoffmann CEJ, McDonald PJ, Watts JM. Use of peroperative cefoxitin to prevent infection after colonic and rectal surgery. Ann Surg 1981;193:353-8. 2. Wapnick S, Guinto R, Reizis I, LeVeen HH. Reduction of postoperative infection in elective colon surgery with preoperative administration of kanamycin and erythromycin. Surgery 1979;85:317-21. 3. Nichols RL, Broido P, Condon RE, Gorbach SL. Nyhus LM. Effect of preoperative neomycin-erythromycin intestinal preparation on the incidence of infectious complications following colon surgery. Ann Surg 1973; 178:453-62. 4. Hojer H, Wetterfors J. Systemic prophylaxis with doxycycline in surgery of the colon and rectum. Ann Surg 1978; 187:362-8. 5. Baum ML, Anish DS, Chalmers. TC, Sacks HS, Smith H, Fagerstrom RM. A survey of clinical trials of antibiotic prophylaxis in colon surgery: evidence against further use of no treatment controls. N Engl J Med 1981;305:795-9. 6. MacLean LD, Meakins JL, Taguchi K, Duignan JP, Dhillon KS, Gordon J. Host resistance in sepsis and trauma. Ann Surg 1975;182:207-17. 7. Tarpley JL, Twomey PL, Catalona WJ, Chretien PB. Suppression of cellular immunity by anesthesia and operation. J Surg Res 1977;22:195-201. 8. Jubert AV, Lee ET, Hersh EM, McBride CM. Effects of surgery, anesthesia and intraoperative blood loss on immunocompetence. J Surg Res 1973; 15:399-403. 9. Roth JA, Golub EA, Grimm BA, Eilber MD, Morton DL. Effects of operation on immune response in cancer patients: sequential evaluation of in vitro lymphocyte function. Surgery 1976;79:46-51.
See page 562for a
482
10. Tartter PI, Heimann TH, Aufses AH Jr. Blood transfusion, skin test reactivity, and lymphocytes in inflammatory bowel disease. Am J Surg 1986;151:358-61. 11. Vose BM, Moudgil GC. Effect of surgery on tumor-directed leukocyte responses. Br Med J 1975;1:56-8. 12. Engelman L. Stepwise logistic regression. In: Dixon WJ, ed. BMDP statistical software. Berkeley, CA: University of California Press, 1981. 13. Cox DR. The analysis of binary data. London: Methuen, 1970. 14. Rosenberg SA, Seipp CA, White DE, Wesley R. Perioperative blood transfusions are associated with increased rate of recurrence and decreased survival in patients with highgrade soft-tissue sarcomas of the extremities. J Clin Oncol 1985;3:698-709. 15. Jacobson MS, Keny SV, Grand RJ. Effects of a plasticizer leached from polyvinyl chloride on the subhuman primate: a consequence of chronic transfusion therapy. J Lab Clin Med 1977;89:1066-79. 16. Kerman RM, VanBuren CT, Payne W. Influence of blood transfusions on immune responsiveness. Transplant Proc 1982;14:335-7. 17. Fischer E, Lenhard V, Seiffert P, Kluge A, Johannsen R. Blood transfusion-induced suppression of cellular immunity in man. Hum lmmunol 1980;1:187-94. 18. Proud G, Shenton BU, Smith BM. Blood transfusion and renal transplantation. Br J Surg 1966;66:678-82. 19. Gascon P, Zoumbos NC, Young NS. Immunologic abnormalities in patients receiving multiple blood transfusion. Ann Intern Med 1984;100:173-7. 20. Kaplan J, Sarnaik S, Gitlin J, Lusher J. Diminished helpersuppressor lymphocyte ratios and natural killer activity in recipients of repeated blood transfusions. Blood 1984; 64:308-10. 21. Luban NLC, Kelleher JK Jr, Zaloudek J, Reaman GH. Chronic transfusion alters T lymphocyte subpopulations in children in sickle cell disease (abstract). Blood 1983;621:114. 22. Wang W, Herrod H, Presbury G, Wilimag J. Immunologic studies in chronically transfused children (abstract). Blood 1983;62:241. 23. Watson MA, Diamandopoulos AA, Briggs JD, Hamilton DNH, Dick HM. Endogenous cell-mediated immunity, blood transfusion, and outcome of renal transplantation. Lancet 1979; 2: 1323-6. 24. Nichols RL, Smith JW, Klein DB, et al. Risk of infection after penetrating abdominal trauma. N Engl J Med 1984; 311:1065-70. 25. Gross RL, Newburne PM. Role of nutrition in immunologic function. Physiol Rev 1980;60:188-302. 26. Baggs RB, Miller SA. Nutritional iron deficiency as a determinant of host resistance in the rat. J Nutr 1973; 103: X154-60. 27. Soyano A, Chandellet D, Layrisse M. Effect of iron deficiency on the mitogen-Induced proliferative response of rat lymphocytes. Int Arch Allergy Appl lmmunol 1982;69:353-7.
coFFesponding
CME
test.
The American Journal ol Surgery
Perioperative Blood Transfusion Associated With Infectious Complications After Colorectal Cancer Operations
Paul Ian Tartter, MD, Sandra Ouintero, BA, and Deborah M. Barron, BA, New York, New York
Studies of infectious complications after elective colorectal operations have focused on the use of various prophylactic antibiotic regimens [I-4]. Variables that may have influenced the outcome of these trials (for example, age, sex, diagnosis, and operative procedure) have not been considered in the published reports [5]. Additional factors that may contribute to the development of infectious complications have not been well studied recently. Perioperative factors associated with suppression of immunity may contribute to the development of infectious complications because immune suppression is associated with postoperative infection, septicemia, and death related to infection [S]. Anesthesia [7,8], blood loss [8], transfusion [9,10], the magnitude of the procedure [II], and duration of operation [9] have been linked to postoperative immunosuppression. To clarify the clinical significance of these findings, we investigated the relationship between numerous perioperative factors and infectious complications after colorectal cancer operations. Material and Methods The study population consisted of 168consecutive patients scheduled for elective colorectal cancer operation without evidence of liver or other metastases. Patients were identified preoperatively between August 1, 1983 and December 31,1984. All patients received bowel preparation with laxatives, enemas, oral neomycin and erythromycin base, and intravenous cefazolin. Cefazolin was continued for 24 hours postoperatively. Patients were followed for at least 1 week postoperatively until dis-
From the Department of Surgery, The Mount Slnai Medical Center, New York, New York. Supported in part by the Frieda and George Zinberg Foundation, New York, New York, and NCI-NlH Grant 1 ROI-CA-35558-01, Natlonal lnstltutes of Health, Bethesda. Maryland. Requests for reprints should be addressed to Paul Ian Tartter, MO, Annenberg 25-60, Mount Sinal Medical Center, 1 Gustave L. Levy Place, New York, New York 10029.
vofunm 152, November 1sas
charge. A purulent exudate was accepted as irrefutable evidence of wound infection. Urinary tract infection was accepted as the cause of fever and leukocytosis when urine yielded more than 100,000 pathogens/ml or signs and symptoms of urinary tract infection were present in the absence of other possible sources. Pneumonia was diagnosed by fever, leukocytosis, and infiltrate on chest radiograph. Both patients who had development of pneumonia in this study also had positive blood cultures. Intraabdominal collections were localized by ultrasonography and computerized tomographic scanning when other cultures failed to reveal a source for fever and leukocytosis. Age, sex, operative procedure, length of biopsy specimen, degree of differentiation, number of involved nodes, disease stage, hematocrit value on admission, operative blood loss, duration of operation, and number and time (preoperatively, intraoperatively, and postoperatively) of blood transfusions administered during hospitalization were recorded. Tumor differentiation was graded as well, moderate, or poor by the pathologists. Tumor size was calculated from the pathologists’ measurements in the fresh state using the formula (length/2 X width/Z X 7r). The pathologists also measured the length of each specimen in the fresh state. Staging was by a modification of Dukes’ classification wherein Dukes’ A indicated that disease was limited to the mucosa and submucosa; Bl, infiltration of the muscularis without nodal involvement; B2, infiltration of the serosa without nodal involvement; Cl, one to three involved nodes; C2, more than three involved nodes; and D, hepatic or other metastases. Multivariate analysis of the data was accomplished using SAS BMDP@ stepwise logistic regression software [12,13] run on an IBM 370’s computer housed at the City University of New York Computing Center. This program investigates the relation between a binarv-denendent < . variable, such as infectious complication, and a set of independent variables which may be categoric, such as operative procedure and sex, or interval-scaled variables, such as age, operative blood loss, and duration of procedure. The significance of the observed differences was
479
Tartter et al
TABLE I
Multivariate Analysis With infectious Complication as a Dependent Variable
Variable
TABLE II
Chi-Square Value
p Value
Degrees of Freedom
6.63 0.06 0.00 1.13 10.75 0.66 0.82 1.84 5.49
0.0100 0.7601 0.9540 0.287 1 0.1497 0.4165 0.3649 0.1748 0.0191
1 1 1 1 7 3 5 1 1
0.3395 0.3272 0.6972
1 1 1
lnfectlon Rates Compared With Tlmlng of Transfuslons
Data
Number
Infected
Percent
12 158
3 21
25 13
39 129
9 15
23 12
22 146
8 16
36 11
69 99
17 7
25 7
Preoperative Transfusion Age Sex Blood loss Operative procedure Tumor differentiation Stage Nodes Admission hematocrit value (%) Duration of surgery Specimen length Tumor size
0.91 0.96 0.15
evaluated using the chi-square where appropriate.
and Student’s
t tests
Results Infection developed postoperatively in 24 of the 168 patients (14 percent). Nine patients (5.4 percent) had wound infections, seven (4.2 percent) had urinary infections, five (3 percent) had abdominal and pelvic infections, two (1.2 percent) had pneumonia, and one (0.6 percent) had sepsis. Dehiscence of the abdominal wound subsequently occurred in two of the patients with wound infections and both died with multiple septic complications. One patient with a suspected pelvic collection died in septic shock while undergoing ultrasonography to localize and drain the collection. One patient died with multiple septic complications after reexploration for intestinal obstruction 13 days after an uneventful sigmoid resection. Seven patients had postoperative urinary tract infections which resolved with intravenous antibiotics. All patients in this study were routinely catheterized with indwelling Foley balloon catheters preoperatively. Of the two patients with pneumonia, one also had a cerebrovascular accident and myocardial infarction, but he recovered and was discharged home. One patient with fever, leukocytosis, and positive blood cultures was successfully treated with intravenous antibiotics without a source of infection being found. Colon resection had included a splenectomy for iatrogenic injury. Multivariate analysis with infection as the dependent variable indicated that admission hematocrit value and blood transfusion were the only variables significantly related to infection (p = 0.0191 and p = 0.010, respectively) (Table I). The incidence of infection among anemic patients (admission hematocrit value of less than 40 percent) was significantly lower than the incidence among patients with normal blood counts (6 percent versus 17 percent, chi-
480
Transfused Not transfused lntraoperative Transfused Not transfused Postoperative Transfused Not transfused Overall Transfused Not transfused
square = 5.759, p = 0.0164). Apparently, anemia was not a risk factor for infectious complications in this group of patients. Blood transfusions were significantly associated with infectious complications. Seventeen of the 69 patients (25 percent) who received blood transfusions had subsequent infectious complications compared with 7 of 99 patients (7 percent) who did not receive blood transfusions (Table II). The mean number of blood transfusions in the patients with infectious complications significantly exceeded that in the patients without complications (2.14 f 2.75 versus 0.82 f 1.37, p = 0.0005) (Table III). The administration of blood had a significant association with a low admission hematocrit value, high operative blood loss, prolonged operative time, and long specimens (p <0.005). However, none of these factors was associated with infectious complications (p >O.lO). Blood transfusions were associated with infectious complications when given preoperatively, intraoperatively, or postoperatively (Table III). None of the transfused patients had infectious complications before receiving the first unit of blood. Since the observed association of infectious complications with blood transfusion could have been a reflection of intraoperative hypovolemic shock, the anesthesia records of the 17 transfused patients with infectious complications were reviewed. None of these patients were in shock at any time during colon resection. The lowest systolic blood pressure was 99 f 13 mmHg (range 78 to 120 mmHg) and the highest pulse was 92 f 14 beats/min (range 65 to 120 beats/min). Intraoperative transfusions were administered to 11 patients to compensate for estimated operative losses exceeding 500 ml. The remaining patients were transfused before or after operation if the hematocrit value was less than 30 percent in the absence of clinical signs of anemia. Comments This multivariate study found that blood transfusion and admission hematocrit value were significantly associated with infectious complications of
The American Journal 01 Surgery
Transfusion and Infection in Colorectal Cancer Operations
cancer operations. The relationship of blood transfusion to infectious complications may reflect the influence of an unmeasured related variable. Blood transfusion may be a reflection of operative difficulty or trauma related to the severity of disease and reflected by the need for transfusion. The lack of association of anemia, operative procedure, duration of operation, blood loss, specimen length, stage, or tumor size with infectious complications suggests that this is not the case. Alternately, the findings of this study may be related to immunosuppressive viral diseases transmitted in transfused blood. Recently it has been suggested that carcinogenic organic compounds that leak from the plastic used in conventional blood bags may be immunosuppressive [14,15]. Blood transfusion may be a more significant factor affecting postoperative immune function and susceptibility to infectious complications than previously recognized. Immunologic changes are associated with blood transfusions in several clinical situations. For example, transfusion in patients receiving dialysis is followed by inhibition of lymphocyte responses to mitogens and antigens, increased plasma lymphocyte suppressive activity, and inversion of helper-to-suppressor T-cell ratios [16-191. A long-term transfusion regimen for thalassemia [20], sickle cell disease [20-221, pyruvate kinase deficiency [22], or hemophilia [20,22] is also associated with inverted helper-to-suppressor T-cell ratios and, in addition, with reduced natural-killer cell cytotoxicity [20]. Perioperative blood transfusion in patients with inflammatory bowel disease is followed by prolonged depression of peripheral lymphocytes and T cells [IO]. Perioperative blood transfusions for abdominal and thoracic operative procedures are associated with depressed lymphocyte responses to phytohemagglutinin, pokeweed mitogen, and concanavalin A for up to 4 weeks postoperatively [9]. The observed alterations in immune function after transfusion may have clinical significance [IO]. In the dialysis patient, tranfusion-induced alteration in the immune cells is associated with prolonged subsequent renal allograft survival [23]. In general surgical patients, preoperative anergy is associated with increased risk of postoperative sepsis and septic death [6]. Blood transfusion has been implicated as a risk factor for the development of postoperative septic complications in patients with intestinal perforation after penetrating abdominal trauma [24]. The significance of the observed changes after transfusion for hematologic or inflammatory bowel diseases just alluded to is not clear at this time. The lack of association of anemia with infectious complications in this study cannot be explained from experimental or clinical studies of immune function in anemic patients. Most reports have shown defects in cell-mediated immunity in a sigcolorectal
Volume 152, November 1996
TABLE III
Comparisonof Continuous Variables in Patients With and Wlthout lnfectlous Compllcatlons
Variables Age W) Admission hematocrit value (%) Blood loss (dl) Duration of operation (min) Tumor size (ml) Specimen length (cm) Mean no. of blood transfusions
Infected
Not Infected
p Value
68 40.1
67 38.5
0.8535 0.1887
5.48 178
4.73 174
0.3911 0.7700
59.2 29 2.14
64.8 26 0.82
0.6123 0.3058 0.0005
nificant number of patients [25]. In animal studies, it has been shown that iron deficiency increases susceptibility to infections [26], although one report has indicated that iron deficiency stimulates mitogen-induced proliferative responses of rat lymphocytes [27]. It is unlikely that anemia could cause sufficient immune stimulation to prevent infectious complications after operation for colorectal cancer. The low incidence of infectious complications in anemic patients in this study counters the argument that the association of blood transfusion with infectious complications is merely a manifestation of advanced malignancy reflected by anemia requiring transfusion. This study indicates that infectious complications after operations for elective colorectal cancer may be related to blood transfusions. The observed association of blood transfusion with septic complications in this study, together with with the observed transfusion-associated immune alterations in other clinical situations, suggests that blood transfusion may be a more significant factor in postoperative immunosuppression than previously recognized. Summary We prospectively studied 168 consecutive patients with colorectal cancer to identify perioperative determinants of infectious complications. All patients received preoperative bowel preparation with laxatives, enemas, oral neomycin and erythromycin base, and intravenous cefazolin. Age, sex, admission hematocrit value, operative procedure, specimen length, duration of operation, blood loss, transfusions, tumor size, tumor differentiation, nodal status, and Dukes’ stage were evaluated in relation to infectious complications using multivariate analysis. Infectious complications developed in 24 of the 168 patients in the study (14 percent) and these accounted for the four deaths. Blood transfusion (p = 0.0100) and admission hematocrit value (p = 0.0191) were significantly related to postoperative
481
Tartter et al
infectious complications. Low admission hematocrit values appeared to protect patients from infectious complications. Patients who had postoperative infectious complications received 2.14 f 2.75 units of blood compared with 0.82 f 1.37 units in patients without infectious complications (p = 0.0005). Although blood transfusion was associated with high operative blood loss, prolonged procedures, and large specimens (p <0.005), none of these factors was significantly associated with infectious complications (p >O.lO). Blood transfusion is immunosuppressive in other clinical situations and may be a more significant factor affecting postoperative immune function and susceptibility to infectious complications than previously recognized. References 1. Hoffmann CEJ, McDonald PJ, Watts JM. Use of peroperative cefoxitin to prevent infection after colonic and rectal surgery. Ann Surg 1981;193:353-8. 2. Wapnick S, Guinto R, Reizis I, LeVeen HH. Reduction of postoperative infection in elective colon surgery with preoperative administration of kanamycin and erythromycin. Surgery 1979;85:317-21. 3. Nichols RL, Broido P, Condon RE, Gorbach SL. Nyhus LM. Effect of preoperative neomycin-erythromycin intestinal preparation on the incidence of infectious complications following colon surgery. Ann Surg 1973; 178:453-62. 4. Hojer H, Wetterfors J. Systemic prophylaxis with doxycycline in surgery of the colon and rectum. Ann Surg 1978; 187:362-8. 5. Baum ML, Anish DS, Chalmers. TC, Sacks HS, Smith H, Fagerstrom RM. A survey of clinical trials of antibiotic prophylaxis in colon surgery: evidence against further use of no treatment controls. N Engl J Med 1981;305:795-9. 6. MacLean LD, Meakins JL, Taguchi K, Duignan JP, Dhillon KS, Gordon J. Host resistance in sepsis and trauma. Ann Surg 1975;182:207-17. 7. Tarpley JL, Twomey PL, Catalona WJ, Chretien PB. Suppression of cellular immunity by anesthesia and operation. J Surg Res 1977;22:195-201. 8. Jubert AV, Lee ET, Hersh EM, McBride CM. Effects of surgery, anesthesia and intraoperative blood loss on immunocompetence. J Surg Res 1973; 15:399-403. 9. Roth JA, Golub EA, Grimm BA, Eilber MD, Morton DL. Effects of operation on immune response in cancer patients: sequential evaluation of in vitro lymphocyte function. Surgery 1976;79:46-51.
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