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Objectives: Poor prognosis after resection of primary colorectal cancer may be related to the combination of perioperative blood transfusion and subsequent development of infectious complications. Various white cell- and platelet-derived cancer-growth substances may be involved in this process. Therefore, we studied the in vitro release of substances from white cells and platelets stimulated by bacterial antigens and supernatants from stored red-cell components., Methods: Eight units of whole blood (WB) and 8 U of buffy-coat-depleted red-cell (SAGM) blood were donated by healthy blood donors. Subsequently, one-half of each unit was leucocyte-depleted by filtration, and all 32 half-units were stored under standard conditions for 35 d. Just after storage, and on d 7, 21, and 35 during storage, aliquots of the supernatants were removed from the units and frozen at -80 degrees C. WB from other healthy donors was stimulated for 2 h with sodium chloride (controls), with Escherichia coli (E. coli) lipopolysaccharide (LPS) alone, or with LPS plus supernatants from the WB units (diluted 1:10), or from the SAGM units (diluted 1:20) stored for 0, 7, 21, or 35 d, respectively. Similar assays were performed using Staphylococcus aureus-derived protein A as a stimulatory antigen. The concentration of eosinophil cationic protein (ECP), myeloperoxidase (MPO), histamine (HIS), and plasminogen-activator inhibitor-1 (PAI-1) were determined in supernatants from the stored blood and in assay supernatants by using enzyme-linked immunosorbent assay (ELISA) and radioimmunoassay (RIA) methods., Results: The extracellular concentration of ECP, MPO, and HIS increased significantly in a storage-time-dependent manner in nonfiltered WB and SAGM blood, and the increase was abrogated by prestorage leukofiltration. Similarly, PA-1 increased significantly in nonfiltered WB, and the increase was abrogated by prestorage leukofiltration. The supernatant concentrations of the four substances were significantly increased in LPS-stimulated (0.5-4 fold) and in protein A-stimulated (0.5-13.5-fold) assays compared with controls. The addition of supernatants from stored nonfiltered WB or SAGM blood significantly increased the assay supernatant of ECP, MPO, HIS, and PAU-1 concentrations storage-time-dependently in LPS-stimulated assays. Prestorage leukofiltration abrogated the additional effect of supernatants from stored blood. Similar results were observed for ECP and HIS through the addition of supernatants from stored blood to protein A-stimulated assays. Protein A stimulation did not lead to increased PA-1 release in assays diluted by supernatants from stored blood. However, the MPO concentrations were significantly (p = 0.004), and independent of storage time and leukofiltration, increased in protein A-stimulated assays diluted by supernatants from stored blood compared with sodium chloride dilution., Conclusion: Extracellular ECP, MPO, HIS, and PA-1 accumulate during storage of nonfiltered red-cell components, but the accumulation can be prevented by prestorage leukofiltration. In addition, bacterial antigens appear to induce significant release of the substances from white cells and platelets. Addition of supernatants from stored, nonfiltered WB and SAGM blood may increase the substance levels in a storage-time-dependent manner, and prestorage leukofiltration may prevent further increase by supernatants, except for MPO.

Background: The frequency of postoperative infectious complications is significantly increased in patients with colorectal cancer receiving perioperative blood transfusion. It is still debated, however, whether perioperative blood transfusion alters the incidence of disease recurrence or otherwise affects the prognosis., Methods: Patient risk variables, variables related to operation technique, blood transfusion and the development of infectious complications were recorded prospectively in 740 patients undergoing elective resection for primary colorectal cancer. Endpoints were overall survival (n = 740) and time to diagnosis of recurrent disease in the subgroup of patients operated on with curative intention (n = 532). The patients were analysed in four groups divided with respect to administration or not of perioperative blood transfusion and development or non-development of postoperative infectious complications., Results: Overall, 19 per cent of 288 non-transfused and 31 per cent of 452 transfused patients developed postoperative infectious complications (P< 0.001). The median observation period was 6.8 (range 5.4-7.9) years. In a multivariate analysis, risk of death was significantly increased among patients developing infection after transfusion (n = 142) compared with patients receiving neither blood transfusion nor developing infection (n = 234): hazard ratio 1.38 (95 per cent confidence interval (c.i.) 1.05-1.81). Overall survival of patients receiving blood transfusion without subsequent infection (n = 310) and patients developing infection without preceding transfusion (n = 54) was not significantly decreased. In an analysis of disease recurrence the combination of blood transfusion and subsequent development of infection (hazard ratio 1.79 (95 per cent c.i. 1.13-2.82)), localization of cancer in the rectum and Dukes classification were independent risk factors., Conclusion: Blood transfusion per se may not be a risk factor for poor prognosis after colorectal cancer surgery. However, the combination of perioperative blood transfusion and subsequent development of postoperative infectious complications may be associated with a poor prognosis.

Background: We have studied the impact of storage time of transfused allogeneic blood together with other known risk factors on postoperative infectious complications after operation for rectal cancer., Methods: Intra-abdominal abscess, anastomotic leakage, septicaemia, wound infection, and pneumonia were prospectively recorded in 303 patients undergoing elective resection for primary rectal cancer in 18 Danish hospitals. Patient risk variables and variables related to operation technique and transfusion were recorded prospectively, whereas amount given before infectious complication and storage time of saline-adenine-glucose-mannitol (SAGM) blood, administered to each patient, were recorded retrospectively., Results: The overall infection rate was 24% in 78 non-transfused and 40% in 225 transfused patients (P = 0.011). The proportion of SAGM blood stored for > or = 21 days administered to each transfused patient was a median of 60% in patients developing postoperative infections versus 25% (P = 0.037) in patients without infections. A multivariate analysis of significant risk variables showed weight > 75 kg (odds ratio, 2.0 versus < 65 kg) and transfusion of SAGM blood stored > or = 21 days (odds ratio, 2.5 versus no transfusion) to be independent variables predicting infectious complications., Conclusion: Blood storage time may, along with other risk factors, play a significant role in blood transfusion-associated development of postoperative infectious complications.

Objectives: Potentially harmful leukocyte- and platelet-derived bioactive substances are accumulated extracellularly during storage of different blood products. Therefore, we studied the effect of prestorage leukocyte filtration on concentrations of bioactive substances in whole blood (WB) and saline-adenine-glucose-mannitol (SAGM) erythrocyte suspension during storage., Methods: Ten units of WB and 10 units of SAGM blood from 20 blood donors were stored at + 4 degrees C for 24 h. Subsequently, half of every unit was leukocyte-reduced by filtration. The 40 half units (20 filtered and 20 unfiltered) were stored at + 4 degrees C for further 34 days. Samples were collected from all 40 half blood units on day 1, 21 and 35. Total content and extracellular concentration of myeloperoxidase (MPO), eosinophil cationic protein (ECP), histamine and plasminogen activator inhibitor-1 (PAI-1) was analysed by ELISA or RIA methods., Results: In unfiltered WB, the total content of all 4 substances decreased during storage, and extracellular concentrations increased significantly and storage time dependently. Similarly, this was also seen with MPO and ECP in unfiltered SAGM blood. Prestorage filtration of WB resulted in a significant reduction of total content and of extracellular concentrations of all 4 substances as well. Additionally, storage time dependent extracellular accumulation was prevented for all substances. Prestorage filtration of SAGM blood significantly reduced total content and extracellular concentrations of MPO and ECP and prevented storage time dependent extracellular accumulation. Filtered SAGM blood contained significantly lower concentrations of all analysed substances compared to filtered WB., Conclusion: Prestorage leukocyte filtration reduces total content of leukocyte- and platelet-derived bioactive substances and prevents the storage time dependent extracellular accumulation of these substances in WB and the partly accumulation in SAGM blood.

Objective: To evaluate the influence of preoperative abstinence on postoperative outcome in alcohol misusers with no symptoms who were drinking the equivalent of at least 60 g ethanol/day., Design: Randomised controlled trial., Setting: Copenhagen, Denmark., Subjects: 42 alcoholic patients without liver disease admitted for elective colorectal surgery., Interventions: Withdrawal from alcohol consumption for 1 month before operation (disulfiram controlled) compared with continuous drinking., Main Outcome Measures: Postoperative complications requiring treatment within the first month after surgery. Perioperative immunosuppression measured by delayed type hypersensitivity; myocardial ischaemia and arrhythmias measured by Holter tape recording; episodes of hypoxaemia measured by pulse oximetry. Response to stress during the operation were assessed by heart rate, blood pressure, serum concentration of cortisol, and plasma concentrations of glucose, interleukin 6, and catecholamines., Results: The intervention group developed significantly fewer postoperative complications than the continuous drinkers (31% v 74%, P=0.02). Delayed type hypersensitivity responses were better in the intervention group before (37 mm2 v 12 mm2, P=0.04), but not after surgery (3 mm2 v 3 mm2). Development of postoperative myocardial ischaemia (23% v 85%) and arrhythmias (33% v 86%) on the second postoperative day as well as nightly hypoxaemic episodes (4 v 18 on the second postoperative night) occurred significantly less often in the intervention group. Surgical stress responses were lower in the intervention group (P

Objective and Design: To study the potential effect of ranitidine on postoperative infectious complications following emergency colorectal surgery. A randomized, placebo-controlled, double-blind trial was carried out in three university clinics and two county hospitals in Denmark., Patients and Treatment: One hundred and ninety-four consecutive patients undergoing acute colorectal surgery for perforated and/or obstructed large bowel were randomized in a double-blind fashion to receive ranitidine 100 mg i.v. twice a day commencing at induction of anesthesia and continued for five days (group I) or i.v. placebo (group II). All patients were given 1.5 g metronidazole plus 3.0 g cefuroxime at the time of surgery. Patients with perforation of the colon or rectum were given metronidazole and cefuroxime for further 3 days. All patients were assessed daily until discharge from the hospital. Thirty patients were withdrawn from the study (for reasons such as other diagnosis, refused to continue, medication not given as prescribed)., Main Outcome Measures: Patients were observed for signs of infectious complications; such as wound infection, intra-abdominal abscess, septicemia, and pneumonia., Results: Both groups were similar with respect to age, sex, weight, duration of surgery, blood transfusions, and site of the procedure, as well as the histologic nature of the underlying disease process. However, the Mannheim Peritonitis Index (MPI) was significantly higher in group I compared with group II (p < 0.05). Wound infection, intraabdominal abscess, septicemia, and pneumonia were 12.9%, 5.2%, 3.8% and 14%, respectively in group I. In group II, the infectious complications were 16.1%, 6.8%, 6.9% and 22%, respectively. Twelve patients (13.8%) in the placebo group developed more than one complication compared with 5 patients (6.5%) in the ranitidine group., Conclusion: Ranitidine may have a beneficial effect on postoperative infectious complications in patients following acute colorectal surgery.

Background: The histamine H2-receptor antagonist ranitidine hydrochloride has been shown to improve trauma-, blood transfusion-, and sepsis-induced immunosuppression., Objective: To evaluate the effect of ranitidine on postoperative impairment in monocyte and neutrophil function., Methods: Twenty-four patients undergoing major elective abdominal surgery were randomized to receive adjuvant treatment with ranitidine hydrochloride (100 mg) administered twice a day intravenously from skin incision for 4 days, followed by oral ranitidine hydrochloride (150 mg) administered twice a day for 5 days (n = 11), or no adjuvant treatment (n = 13). Blood monocyte and neutrophil chemotaxis and chemiluminescence were analyzed before the operation and on postoperative days 1, 3, and 9., Results: Monocyte chemotaxis to C5a in the 13 control patients was significantly decreased on day 1 compared with day 0. Chemotaxis in the 11 ranitidine-treated patients increased significantly from day 0 to day 1 (P < .01 between groups). Neutrophil chemiluminescence to zymosan and N-f-methionyl-leucyl-phenylalanine was significantly increased in control patients on day 1 compared with day 0 (P < .05), while ranitidine reduced chemiluminescence to zymosan insignificantly on day 1 (P < .07 between groups). Five of the 13 control patients developed postoperative infectious complications, which were related to decreased monocyte chemotaxis to C5a and increased neutrophil chemiluminescence to zymosan, compared with noninfected patients. A significant difference (P < .05) in chemiluminescence to zymosan between infected and noninfected control patients was observed on day 3 before clinical signs of infectious disease could be detected. There were no infectious complications in ranitidine-treated patients., Conclusion: These results support previous studies on the effect of ranitidine to improve postoperative immunosuppression.

Retrospective studies suggest increased postoperative morbidity among alcohol misusers. We have prospectively studied the risk associated with alcohol intake among patients undergoing surgery. We investigated 15 persons who required colorectal surgery and who were drinking at least five Danish drinks per day. These patients were matched for sex, nutrition, age, weight, cardio-pulmonary disease, diagnosis anesthesia, and surgery to 15 control persons who were consuming no more than two drinks daily. None of the patients showed signs of liver disease. The alcohol group developed more postoperative complications than controls (67 vs 20%, p < 0.05) and hospital stay was prolonged (20 vs 12 days, p < 0.05). Preoperatively, alcohol misusers had reduced left ventricular ejection fraction (54 vs 68%, p < 0.01). Delayed-type hypersensitivity responses were reduced in the alcohol group before (53 mm2 vs 78, p < 0.05) and after (18 mm2 vs 55, p < 0.01) surgery. Alcohol misusers had significantly longer bleeding times. Surgical stress responses, as assessed by changes in plasma cortisol and catecholamines, were higher among alcohol misusers (p < 0.05). Postoperative morbidity was increased in alcohol misusers without signs of liver damage. The mechanisms may include subclinical cardiac insufficiency, immunosuppression, and decreased haemostatic function. Preoperative alcohol consumption may be a more important risk factor for postoperative morbidity than previously thought.

Retrospective studies suggest that there is an increased postoperative morbidity among alcohol misusers. We have prospectively studied the risk of alcohol intake among patients undergoing surgery. We investigated 15 symptom-free subjects who required colorectal surgery and who were drinking at least 60 g of alcohol per day. These patients were matched for sex, nutrition, age, weight, cardiovascular and pulmonary disease, diagnosis, anaesthesia, and surgery to 15 control subjects who were consuming below 25 g of alcohol daily. Those drinking at least 60 g of alcohol per day developed more postoperative complications than controls (67% vs 20%, p less than 0.05) and hospital stay was prolonged (20 vs 12 days, p less than 0.05). Preoperatively, alcohol misusers had reduced left ventricular ejection fraction (median, 54% vs 68%, p less than 0.01). Delayed hypersensitivity responses were smaller in the alcohol group before (53 mm2 vs 78 mm2, p less than 0.05) and after (18 mm2 vs 55 mm2, p less than 0.01) surgery. Alcohol misusers had longer bleeding times during the first postoperative week (p less than 0.01). Surgical stress responses, as assessed by changes in plasma cortisol and catecholamines, were higher among alcoholics (p less than 0.05). Postoperative morbidity is increased in symptom-free alcohol misusers. The mechanism is probably subclinical cardiac insufficiency, immunosuppression, and decreased haemostatic function. Preoperative alcohol consumption may be a more important risk factor than previously thought.

The effect of the histamine-2 receptor antagonist ranitidine (100 mg intravenously every 12 hours for 72 hours) on postoperative serum antibody responses to preoperative immunization with six limit of flocculation tetanus toxoid and six limit of flocculation diphtheria toxoid was assessed in a double-blind, placebo-controlled randomized study in 26 patients undergoing major abdominal surgery. The preoperative antitetanus antibody level was less than 0.1 IU/ml in all patients, and they were inoculated with both antigens 48 hours before surgery. Serum samples for analysis of antitetanus toxoid and antidiphtheria toxoid were drawn before skin incision and on postoperative days 1, 3, 5, 7, 10, 14, 21, and 28. Ranitidine significantly increased the postoperative antibody response to tetanus toxoid, (p less than 0.01) and insignificantly increased that to diphtheria toxoid vaccination (p less than 0.2) compared with placebo.

The influence of perioperative whole-blood transfusion and transfusion with erythrocyte suspension (SAG-M blood) on postoperative depression of cell-mediated immunity (CMI) was investigated in 67 patients who underwent elective resection for colorectal cancer. Cell-mediated immunity was assessed pre- and postoperatively by skin testing with seven common delayed-type hypersensitivity (DTH) antigens. The postoperative skin-test response decreased more in the patients who received whole blood (15 patients) than in those who received SAG-M blood (16 patients) (60% versus 42%, p less than 0.001) and in those who did not receive a blood transfusion (36 patients) (60% versus 40%, p less than 0.001). The enhanced postoperative immunosuppression in patients who received whole-blood transfusions persisted after matching according to age, sex, height, weight, hemoglobin and serum albumin levels, duration of surgery and diagnosis. Thus, perioperative transfusion with SAG-M blood does not enhance surgically induced immunosuppression as effectively as does transfusion with whole blood.

Twenty-five patients admitted to intensive or high-dependency surgical care units were randomized to receive ranitidine intravenously 50 mg every 6 hours for 8 days or no ranitidine. All had septicemia or intra-abdominal sepsis, with body temperature greater than or equal to 38.5 degrees C for more than 48 hours despite comprehensive medical and/or surgical treatment. Cell-mediated immunity was assessed by skin testing with seven common delayed type hypersensitivity antigens applied on days 1, 4 and 7 and all tests were read at 48 hours, i.e. on days 3, 6 and 9. The ranitidine/non-ranitidine regimen was initiated on day 1 and continued until day 9. Severity of illness was evaluated before and 3, 6 and 8 days after initiating the study, using the APACHE II scoring system. The scores before and during the study were similar in the ranitidine and non-ranitidine groups. Delayed type hypersensitivity improved in patients treated with ranitidine (p less than 0.001), but was unchanged in the untreated group (p greater than 0.7). These observations may suggest potential beneficial effects of ranitidine therapy in patients with trauma-induced immunosuppression.

Cell-mediated immunity was assessed by skin testing with seven delayed-type common antigens in 20 patients undergoing major abdominal surgery and in 20 nonoperative control subjects. The 20 surgical patients were randomized to perioperative ranitidine (50 mg every 6 hours for 72 hours) or no ranitidine. The 20 control subjects received either no ranitidine or ranitidine in the same dosage as the surgical patients. Skin tests were performed 2 days before and 1 day after operation with the same time schedule in the control subjects. Postoperatively, the diameter of the positive skin test area decreased in each of 10 patients without ranitidine (p less than 0.006) but increased in 9 and was unchanged in 1 of the ranitidine-treated patients (p less than 0.01). The skin test changes were similar during the two tests in ranitidine-treated surgical patients and the nonoperative control subjects. Ranitidine did not amplify the response in the nonoperated group. The potential role of histamine blockade in reversal of other aspects of postoperative immunosuppression and reduction in the risk of infection should be explored.

The influence of perioperative blood transfusion on postoperative depression of cell-mediated immunity (CMI) and the effect of ranitidine on transfusion-induced changes in postoperative CMI were investigated. CMI was assessed preoperatively and postoperatively by skin testing with seven common delayed-type antigens in 83 consecutive patients undergoing major elective abdominal surgery. Sixty-six of these patients were randomly divided into ranitidine or no-ranitidine-treatment groups, and the remaining 17 patients were operated on without ranitidine. Thus, 50 patients were operated on without ranitidine therapy, and whole blood transfusion was given to 24 of these patients. Postoperative skin test response was more reduced in transfused vs nontransfused patients (-57% vs -38%, p less than 0.0001). Fourteen of the 24 patients receiving blood transfusion could be exactly matched to 14 patients not receiving transfusion (age, sex, B-hemoglobin, S-albumin, type and duration of surgery, etc.), which confirmed that a more pronounced reduction in postoperative skin test response was found in transfused patients (-55% vs -31%, p less than 0.0001). Seventeen of the 33 patients treated with perioperative ranitidine, 50 mg intravenously every 6 hours for 72 hours, received perioperative blood transfusion. Eleven of these patients could be matched to 11 transfused patients not receiving perioperative ranitidine. Ranitidine prevented postoperative reduction in skin test response (+6% vs -55%, p less than 0.0001). It is concluded that perioperative transfusion with whole blood amplifies the postoperative impairment in delayed hypersensitivity and that transfusion-induced postoperative impairment in delayed hypersensitivity may be prevented by perioperative ranitidine treatment.