Gary E. Hill

Allogeneic blood transfusion increases the risk of postoperative bacterial infection: A meta-analysis

Background: Immunosuppression is a consequence of allogeneic (homologous) blood transfusion (ABT) in humans and is associated with an increased risk in cancer recurrence rates after potentially curative surgery as well as an increase in the frequency of postoperative bacterial infections. Although a meta-analysis has been reported demonstrating the relationship between ABT and colon cancer recurrence, no meta-analysis has been reported demonstrating the relationship of ABT to postoperative bacterial infection. Methods: Twenty peer-reviewed articles published from 1986 to 2000 were included in a meta-analysis. Criteria for inclusion included a clearly defined control group (nontransfused) compared with a treated (transfused) group and statistical analysis of accumulated data that included stepwise multivariate logistic regression analysis. In addition, a subgroup of publications that included only the traumatically injured patient was included in a separate meta-analysis. A fixed effects analysis was conducted with odds ratios obtained by using the conditional maximum likelihood method and 95% confidence intervals on the obtained odds ratios were determined using the mid-p technique. Results: The total number of subjects included in this meta-analysis was 13,152 (5,215 in the transfused group and 7,937 in the nontransfused group). The common odds ratio for all articles included in this meta-analysis evaluating the association of ABT to the incidence of postoperative bacterial infection was 3.45 (range, 1.43-15.15), with 17 of the 20 studies demonstrating a value of p < or = 0.05. These results provide overwhelming evidence that ABT is associated with a significantly increased risk of postoperative bacterial infection in the surgical patient. The common odds ratio of the subgroup of trauma patients was 5.263 (range, 5.03-5.43), with all studies showing a value of p < 0.05 (0.005-0.0001). These results demonstrate that ABT is associated with a greater risk of postoperative bacterial infection in the trauma patient when compared with those patients receiving ABT during or after elective surgery. Conclusion: These results demonstrate that ABT is an associated and apparently significant and frequently overlooked risk factor for the development of postoperative bacterial infection in the surgical patient. Allogeneic blood transfusion is a greater risk factor in the traumatically injured patient when compared with the elective surgical patient for the development of postoperative bacterial infection.

Aprotinin and methylprednisolone equally blunt cardiopulmonary bypass–induced inflammation in humans ☆ ☆☆ ★ ★★

Cardiopulmonary bypass induces an inflammatory state characterized by tumor necrosis factor-alpha release. Integrin CD11b is a neutrophil surface adhesive glycoprotein integrin that is rapidly and permanently unregulated by tumor necrosis factor-alpha exposure. The CD11b integrin is known to be the primary neutrophil integrin responsible for neutrophil lung and myocardial entrapment after cardiopulmonary bypass and subsequent reperfusion injury. Twenty-four adults admitted to the hospital for myocardial revascularization were equally randomized to one of three groups: group A (control), group B (methylprednisolone before cardiopulmonary bypass), and group C (low-dose aprotinin protocol). Blood was collected at three times: (1) baseline, (2) 50 minutes of cardiopulmonary bypass duration, and (3) 30 minutes after cardiopulmonary bypass termination. Neutrophil CD11b integrin expression was measured by fluorescence-activated cell sorter analysis and plasma tumor necrosis factor-alpha levels measured by enzyme-linked immunosorbent assay. Group A demonstrated significant (p < 0.05) increases in CD11b expression at times 2 and 3 when results were compared with those of the same group baseline and with those of groups B and C at similar times. No significant changes were noted between groups B and C at any time. Group A demonstrated a significant (p < 0.05) increase in levels of tumor necrosis factor-alpha at time 3 when results were compared with those of the same group baseline and of groups B and C at the same time. No significant changes were noted between B and C at any time. These results demonstrate low-dose aprotinin has a similar antiinflammatory effect to that of methylprednisolone in blunting cardiopulmonary bypass-induced systemic tumor necrosis factor-alpha release and neutrophil integrin CD11b upregulation.

Blood transfusion-induced immunomodulation

Blood transfusion therapy is associated with many risks, including major or minor blood transfusion reaction, non-A non-B hepatitis, hepatitis B, and HIV infection. Blood transfusion may result in immunologic changes (immunomodulation) that are beneficial in some patients but harmful in others. After reports of increased renal allograft survival in patients receiving pretransplant transfusion (1), Gantt (2) questioned whether transfusion might diminish or retard the immune response. Clinical studies have shown a beneficial effect of blood transfusion on graft survival (3,4), but an adverse effect on cancer recurrence (5-10) and postoperative infection (10-14). Approximately two thirds of 11,000 transfusions (15,16) given perioperatively are administered by anesthesiologists (17), and 26% are given inappropriately (18,19). This review will focus on the immunomodulatory effects of transfusion therapy. It will begin with a brief review of the immune system and then discuss 1) the effect of transfusion therapy on modulating the immune system, and 2) transfusion-induced immunomodulatory effects on vascularized graft survival, cancer recurrence, and postoperative infections.

Aprotinin reduces interleukin-8 production and lung neutrophil accumulation after cardiopulmonary bypass.

Pulmonary neutrophil entrapment and resultant oxidative injury is thought to be the primary mechanism of cardiopulmonary bypass (CPB) induced lung injury.Interleukin-8 (IL-8), a potent neutrophil chemoattractant induced by cytokines, including tumor necrosis factor-alpha (TNF), is found in increased concentrations in bronchial alveolar lavage fluid (BALF) in lung inflammation. Since aprotinin reduces TNF release during CPB, the effects of aprotinin on BALF IL-8 concentrations and neutrophil levels were determined after CPB in adult humans. Study patients were equally divided into a control group (n = 8, Group 1) and an aprotinin treated group (n = 8, Group 2). In vitro neutrophil chemotaxis was done with volunteer neutrophils using three different chemoattractants: 1) N-formyl-1-methionyl-1-leucyl-1-phenylalanine (FMLP); 2) the supernatant of a human bronchial epithelial cell culture line, A549, after 24 h of TNF stimulation with or without aprotinin or N-alpha-tosyl-L-lysine chloromethyl ketone (TLCK) (a potent protease inhibitor), and 3) BALF. Aprotinin treatment significantly (P < 0.05) reduced post-CPB BALF IL-8 concentrations and percentage of neutrophils. In vitro, BALF from Group 1 had significantly greater chemotactic ability when compared with Group 2. The TNF stimulated A549 cell culture supernatant had significantly (P < 0.05) greater chemotactic ability than control supernatant, while aprotinin and TLCK significantly (P < 0.05) reduced this chemotactic ability. These results demonstrate that aprotinin blunts IL-8 production and reduces neutrophil lung accumulation post-CPB. (Anesth Analg 1996;83:696-700)

Glucocorticoids Blunt Neutrophil Cd11b Surface Glycoprotein Upregulation During Cardiopulmonary Bypass in Humans

Neutrophil-endothelial adhesion is the initiating event in neutrophil migration to areas of infection or injury. The binding of neutrophils to endothelium depends upon adhesive glycoproteins, of which the CD11/CD18 glycoproteins are the most important. Because of known upregulation of one of these adhesive glycoproteins (CD11b) during cardiopulmonary bypass (CPB) in humans, we evaluated CD11a, CD11b, and CD11c surface expression before, during, and after CPB in humans, with or without pre-CPB administration of a glucocorticoid (methylprednisolone). Fourteen patients were randomized into two groups: Group S received methylprednisolone (1 g intravenously) 5 min prior to CPB; Group N received no steroid. CD11b was significantly upregulated (P < 0.01) during, and 24 h after, CPB in Group N when compared with controls and Group S at similar time intervals, while in Group S no significant changes were found. Since interleukin-1, tumor necrosis factor, and endotoxin are known to upregulate neutrophil CD11b surface expression and are released during CPB in humans, while steroids are known to suppress the release of these cytokines, the authors conclude that the blunting effect by steroids on CD11b surface expression upregulation during and after CPB in humans is attributed to suppressed cytokine release.

Association of malondialdehyde-acetaldehyde (MAA) adducted proteins with atherosclerotic-induced vascular inflammatory injury

Atherosclerosis is a vascular injury characterized by elevated tissue levels of tumor necrosis factor-alpha (TNF-alpha), increased expression of endothelial cell adhesion molecules, and vascular wall inflammatory cell infiltration. Foam cells are associated with atherosclerotic plaque material, and low density lipoprotein (LDL) is a lipid component of foam cells. Malondialdehyde (MDA) is an oxidative product of unsaturated fatty acids and is also present in atherosclerotic lesions. MDA-modified (adducted) proteins, including MDA-modified LDL, are present in atherosclerotic human vascular tissue. Acetaldehyde (AA) is the major metabolic product of ethanol oxidation. Both MDA and AA are highly reactive aldehydes and will combine with proteins to produce an antigenically distinct protein adduct, termed the MAA adduct. This study demonstrates that proteins modified in the presence of high concentrations of MDA can produce MAA-modified proteins in vitro. In addition, MAA adducted proteins are capable of inducing rat heart endothelial cell cultures (rHEC) to produce and release TNF-alpha, and cause rHEC upregulation of endothelial adhesion molecule expression, including ICAM-1. These adhesion molecules are required for circulating inflammatory cells to adhere to endothelium which allows inflammatory cell tissue infiltration. Additionally, MAA modified proteins were defected in human atherosclerotic aortic vascular tissue but not in normal aortic tissue. Since atherosclerosis is associated with an inflammatory vascular injury characterized by elevated tissue TNF-alpha concentrations and inflammatory cell infiltration, these data suggest that MAA-adducted proteins may be formed in atherosclerotic plaque material and may be involved in the inflammatory reaction that occurs in atherosclerosis. These data further suggest that previous studies demonstrating MDA modified protein in atherosclerotic plaque may in fact have MAA modified proteins associated with them.

Does the duration of cardiopulmonary bypass or aortic cross-clamp, in the absence of blood and/or blood product administration, influence the IL-6 response to cardiac surgery?

Cardiopulmonary bypass (CPB) induces a systemic inflammatory response characterized by release of proinflammatory cytokines, including interleukin 6 (IL-6). Recent reports suggest that plasma IL-6 is increased after CPB. Previous studies evaluating the influence of duration of CPB and/or aortic cross-clamp time on the release of IL-6 are conflicting. Infusion of blood and blood products during these studies may have influenced plasma concentrations of proinflammatory cytokines by inducing host cell (monocyte) activation and IL-6 release. The purpose of our investigation was to determine, in an environment free from blood and/or blood product administration, the influence of duration of CPB and/or aortic cross-clamp on the magnitude of the IL-6 response in patients undergoing cardiac surgery. We prospectively evaluated plasma IL-6 levels preinduction (T0) and at sternal closure in 16 patients undergoing CPB (coronary artery bypass grafting, n = 9; valvular cardiac surgery, n = 7) to determine whether there is a correlation between the absolute increase in IL-6 and the duration of CPB or aortic cross-clamp time. None of the patients received blood and/or blood products during the study to control for the introduction of additional activated cells and soluble mediators, including IL-6. The results demonstrate that the magnitude of the IL-6 response to CPB is positively correlated with the duration of CPB but not with duration of aortic cross-clamp. It seems that induction of IL-6 release is part of a normal response to CPB and does not depend on activation of host cells during prolonged aortic cross-clamp. The activation or presence of inflammatory cytokines associated with administration of blood and/or blood products could have influenced previously published investigations relating the influence of duration of CPB and/or aortic cross-clamp time to the magnitude of the IL-6 response. Implications: This study found a positive correlation between the magnitude of the interleukin 6 response to cardiopulmonary bypass and duration of cardiopulmonary bypass (but not duration of aortic cross-clamp) when measurements were made in the absence of blood/blood product transfusion. Future studies evaluating strategies to reduce cytokine responses to cardiopulmonary bypass should therefore control for cardiopulmonary bypass duration.

Cardiovascular responses to nitrous oxide exposure for two hours in man

Cardiovascular responses to increasing (20, 40, and 60%) concentrations of nitrous oxide or nitrogen in oxygen for 15 minutes as well as responses to 2 hours of exposure to 60% nitrous oxide or nitrogen in oxygen were determined and compared in 30 healthy, supine, untrained volunteers who received no other drugs or medications. No concentration of nitrogen produced a significant change in any cardiovascular variable measured, nor did 20 and 40% N2O. Sixty percent nitrous oxide for 15 minutes significantly increased Paco2. heart rate, stroke volume, cardiac output, mean arterial blood pressure, and central venous pressure. Inhalation of 60% nitrogen also produced no significant change in any cardiovascular variable. In contrast, inhalation of nitrous oxide for 2 hours transiently increased arterial blood pressure (at 15 minutes), heart rate (at 15 and 30 minutes), stroke volume (at 15, 30, and 45 minutes) and decreased systemic vascular resistance (at 15 minutes). Cardiac output significantly increased for the 1 st hour of exposure to 60% nitrous oxide but returned to values similar to control (room air) during the 2nd hour. Prolonged inhalation of nitrous oxide resulted in a constant increase in Paco2 and progressive but mild decreases in arterial pH and calculated base deficit but no change in dead space/tidal volume ratios. These findings demonstrate that nitrous oxide stimulates the cardiovascular system in supine, healthy, untrained volunteers but that the stimulation is transient. The data suggest that early stimulation of the cardiovascular system during nitrous oxide breathing may be related to central nervous system excitation secondary to incomplete anesthesia and/or an increase in Paco2.

Lithium Carbonate and Neuromuscular Blocking Agents

The effects of lithium carbonate on the responses to five neuromuscular blocking agents were evaluated in dogs anesthetized with halothane (1 per cent) and N2O (60 per cent) in O2. Latency (time from first twitch-height depression to maximal blockade), maximal twitch-height depression, and times to return to 50 per cent and 100 per cent control twitch tension were measured before and after intravenous infusion of lithium carbonate (1 mg/kg/min for one hour) during neuromuscular blockades produced by succinylcholine, decamethonium, gallamine, d-tubocurarine, or pancuronium. Lithium prolonged the latencies of neuromuscular blockades produced by 0.1 mg/kg succinylcholine and 0.1 mg/kg decamethonium by 248.1 per cent and 49.0 per cent, respectively, but had no effect on latency produced by 0.02 mg/kg pancuronium. The times for return to 50 per cent of control twitch height were prolonged by 69.5, 40.0, and 120.1 per cent, respectively. Lithium had no effect on latency or duration of blockades produced by 0.15 mg/kg d-tubocurarine and 0.6 mg/kg gallamine, but enhanced maximal twitch-height depressions produced by 0.9 mg/kg gallamine and 0.02 mg/kg pancuronium by 22.9 and 9.9 per cent, respectively. Twitch tensions decreased 5-10 per cent over three hours in three dogs receiving lithium infusion without relaxants. Twitch tension was depressed 0-2 per cent in three dogs after five hours of anesthesia in the absence of lithium or relaxants. Lithium prolonged the time required for neostigmine to reverse neuromuscular blockade produced by pancuronium in two of three dogs from a mean of 60 seconds to 135 seconds.

Neutrophil chemotaxis during and after general anesthesia and operation.

The neutrophil granulocytes of 43 patients undergoing general anesthesia and operation were examined to determine if altered function occurs during these procedures. Neutrophil chemotaxis, random migration, and total and differential leukocyte counts were determined immediately before anesthesia; after 35 to 60 minutes of anesthesia but before operation; 60 minutes after initiation of operation; and 60 minutes after operation. Anesthetic agents included 1 to 3.5% enflurane, 0.5 to 2% halothane, or 0.5 to 1.1 mg/kg of morphine plus N2O-O2 (60:40).Neutrophil and total white blood cell counts were uninfluenced by any of the anesthetics; however, marked rises in both occurred during operation and persisted postoperatively after each of the anesthetic technics. Neutrophil chemotaxis was reduced an average of 36, 32, and 21%, respectively, by halothane, enflurane, and morphine before operation and 20, 10, and 5 % intraoperatively. Preoperative reductions in chemotaxis were statistically significant after all anesthetics. However, only halothane produced a significant intraoperative reduction in chemotaxis. Postoperative neutrophil chemotaxis did not differ from control (preanesthesia) values after any of the anesthetics. Halothane and enflurane reduced leukocytic random migration before but not after operation. Morphine had no effect on random migration at any time. These data demonstrate that anesthesia impairs neutrophil function in man but that operation appears to reverse this depression.