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. ImplicationsThis 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.
Cardiopulmonary bypass (CPB) is characterized by systemic endotoxemia immediately after its onset as well as the systemic release of proinflammatory cytokines, including tumor necrosis factor-α and ...the interleukins 1 and 6. Recent studies document that increased morbidity and mortality rates correlate with elevated systemic concentrations of these proinflammatory cytokines during adult and neonatal sepsis, following thoracoabdominal aortic aneurysm repair, as well as following CPB. These proinflammatory cytokines induce increased neutrophil and endothelial surface adhesive molecule expression, thereby promoting enhanced neutrophil-endothelial adherence. Increased neutrophil-endothelial adherence and subsequent neutrophil organ binding are thought to be a “final common pathway” of organ injury during clinical inflammatory conditions. Proinflammatory cytokines also increase cellular expression of inducible nitric oxide synthase, thus increasing cellular production of nitric oxide, a known inflammatory mediator. This review discusses recent evidence of the adverse effects of proinflammatory cytokine release during CPB and therapeutic modalities that can reduce the systemic concentrations of these mediators of inflammation.
Commonly, cocaine abusing patient are scheduled for elective surgery with a positive urine test for cocaine metabolites. As many of these patients were clinically non-toxic normal arterial pressure ...and heart rate, normothermic, and a normal (or unchanged from previous) ECG, including a QTc interval <500 ms, we have recently proceeded with elective surgery requiring general anaesthesia in this patient group.
Forty urine cocaine positive patients were compared with an equal number of drug-free controls in a prospective, non-randomized, blinded analysis. Intraoperative mean arterial blood pressure, ST segment analysis, heart rate and body temperature were recorded and compared.
Cardiovascular stability during and after general anaesthesia in cocaine positive, non-toxic patients was not significantly different when compared with an age and ASA matched drug-free control group.
These results demonstrate that the non-toxic cocaine abusing patient can be administered general anaesthesia with no greater risk than comparable age and ASA matched drug-free patients.
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 ≤ 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.
Background. Cardiopulmonary bypass (CPB) is characterized by the systemic release of proinflammatory cytokines, such as tumor necrosis factor-α and the interleukins 1 and 6, as well as endogenous ...antiinflammatory cytokines, including interleukin-10 (IL-10). Glucocorticoids reduce tumor necrosis factor-α plasma concentrations while enhancing IL-10 plasma concentrations after CPB. Aprotinin, a serine protease inhibitor used primarily to reduce blood loss after CPB, reduces CPB-induced proinflammatory cytokine tumor necrosis factor-α release similarly to glucocorticoids. This study evaluates the effect of full-dose aprotinin on the plasma concentrations of IL-10 after CPB.
Methods. Twenty adults were randomized into a control (group C, n = 10) and a full-dose aprotinin-treated group (group A, n = 10). Plasma levels of IL-10 were measured by enzyme-linked immunosorbent assay technique at baseline (before anesthetic induction), and at 1 and 24 hours after CPB termination.
Results. A significant (
p < 0.05) increase of IL-10 occurred in both groups at 1 and 24 hours after termination of CPB when compared with the same group at baseline. In group A, the increase in IL-10 was significantly greater than in group C (
p < 0.05) at 24 hours after CPB.
Conclusions. These results demonstrate an endogenous antiinflammatory response generated after CPB, characterized by IL-10 release, that is enhanced by aprotinin therapy. This study demonstrates a unique antiinflammatory activity of aprotinin that may be of clinical significance.
Selenoprotein P (SEPP1), an extracellular glycoprotein of unknown function, is a unique member of the selenoprotein family that, depending on species, contains 10–17 selenocysteines in its primary ...structure; in contrast, all other family members contain a single selenocysteine residue. The SEPP1-null (Sepp1−/−) male but not the female mice are infertile, but the cellular basis of this male phenotype has not been defined. In this study, we demonstrate that mature spermatozoa of Sepp1−/− males display a specific set of flagellar structural defects that develop temporally during spermiogenesis and after testicular maturation in the epididymis. The flagellar defects include a development of a truncated mitochondrial sheath, an extrusion of a specific set of axonemal microtubules and outer dense fibers from the principal piece, and ultimately a hairpin-like bend formation at the midpiece-principal piece junction. The sperm defects found in Sepp1−/− males appear to be the same as those observed in wild-type (Sepp1+/+) males fed a low selenium diet. Supplementation of dietary selenium levels for Sepp1−/− males neither reverses the development of sperm defects nor restores fertility. These data demonstrate that SEPP1 is required for development of functional spermatozoa and indicate that it is an essential component of the selenium delivery pathway for developing germ cells.
The proinflammatory cytokines, including tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma), are increased in heart failure and sepsis, clinical conditions for which the IV ...anesthetic ketamine is useful. The proinflammatory cytokines cause beta-adrenergic receptor (beta AR) hypofunction secondary to reduced function of the enzyme adenylylcyclase (AC). In this study, we evaluated the effect of ketamine alone, TNF-alpha and IFN-gamma, and ketamine plus TNF-alpha and IFN-gamma, on isoproterenol (ISO, a beta AR agonist) and forskolin (FSK, an activator of AC)-induced intracellular accumulation of cAMP. An in vitro culture of a rat heart cell line (H9c2) was labeled with () Hadenine to produce () HATP, and we measured the intracellular accumulation of () HcAMP after stimulation with ISO or FSK to convert the () HATP to () HcAMP. Pretreatment with either cytokine alone did not significantly affect ISO or FSK-induced intracellular cAMP accumulation, whereas the combination of TNF-alpha and IFN-gamma caused a significant (P < 0.05 compared with untreated cells) reduction. Pretreatment with ketamine caused a significant (P < 0.05 compared with untreated cells) increase in ISO or FSK-induced cAMP accumulation. Pretreatment of the H9c2 cells with ketamine, plus the combination of TNF-alpha and IFN-gamma, inhibited the reduction of ISO or FSK-induced intracellular cAMP accumulation caused by the proinflammatory cytokines alone. These results demonstrate that the combination of the proinflammatory cytokines TNF-alpha and IFN-gamma reduce poststimulation (ISO or FSK) intracellular cAMP accumulation. This action of the proinflammatory cytokines is consistent with the observation of beta AR hyporesponsiveness to beta AR agonist therapy in sepsis and heart failure. Ketamine augments the poststimulation cAMP accumulation in H9c2 cells while inhibiting the cytokine-induced reduction of cAMP accumulation. This may partly explain the improvement in cardiac function after ketamine use in clinical conditions known to have increased systemic levels of proinflammatory cytokines, such as sepsis and heart failure. ImplicationsTumor necrosis factor-alpha and interferon-gamma reduced poststimulation intracellular cAMP levels, whereas ketamine inhibits this action of the proinflammatory cytokines. Because cAMP is the second messenger for the beta-adrenergic receptor, this may be a mechanism for improved blood pressure and cardiac output in sepsis and heart failure after ketamine use.(Anesth Analg 1998;87:1015-9)
Background. The expression of neutrophil integrin CD11b is up-regulated after cardiopulmonary bypass (CPB) and is the neutrophil adhesive molecule of most importance in neutrophil–endothelial ...adherence. This neutrophil–endothelial adherence is responsible for post-CPB neutrophil-induced reperfusion injury. Low-dose aprotinin protocols inhibit the CPB-induced neutrophil CD11b up-regulation. This investigation was undertaken to evaluate the effects of pump prime only aprotinin (280 mg) on the CPB-induced up-regulation of this neutrophil integrin.
Methods. Twenty-two patients scheduled for elective myocardial revascularization were randomized into two groups: (1) control (n = 12), or (2) pump prime only aprotinin (280 mg) (n = 10). Neutrophils were isolated at baseline, 50 minutes of CPB, and 30 minutes after CPB and neutrophil CD11b expression was measured.
Results. The control group demonstrated a significant (
p < 0.05) increase in neutrophil CD11b immunofluorescent staining at 50 minutes of CPB and at 30 minutes after CPB when compared to same group baseline and to the pump prime only aprotinin group at similar time intervals.
Conclusions. These results indicate that pump prime only aprotinin modulates the CPB-induced up-regulation of neutrophil CD11b integrin, an important indicator of the systemic inflammatory response to CPB. In addition to blunting of the CPB-induced up-regulation of this neutrophil integrin expression, this pump prime only dose of aprotinin is also reported to be effective at reducing post-CPB bleeding and transfusion requirements. This salutary effect of pump prime only aprotinin suggests that such low-dose regimens can be both therapeutically effective and cost effective.
Background
. Cardiopulmonary bypass (CPB) is associated with an increase in airway nitric oxide (NO), plasma levels of tumor necrosis factor-α (TNF-α), and interleukin-1β. Cytokine induction of the ...inducible form of nitric oxide synthase (iNOS) has been implicated in organ injury. In addition, serine protease inhibitors reduce cytokine-induced iNOS expression. Aprotinin, a serine protease inhibitor, has been demonstrated to exhibit significant antiinflammatory effects. We hypothesized that aprotinin administration during CPB would significantly reduce endogenous airway NO production.
Methods
. Airway NO was measured during CPB in 10 patients receiving aprotinin and in 10 control subjects. In vitro, aprotinin was added to cultures of a murine lung epithelial cell line and was stimulated with cytomix, a combination of TNF, interleukin-1, and interferon-γ.
Results
. Airway NO concentration was increased after 50 minutes of CPB duration compared with that measured at 5 minutes in control subjects (53 ± 5 versus 19 ± 3 parts per billion, p < 0.05) but not in the aprotinin group (21 ± 6 versus 15 ± 3 parts per billion). Aprotinin reduced nitrite concentrations in the cell culture supernatant fluids after 24 hours (cytomix, 21.5 ± 2.1 μmol/L; cytomix plus aprotinin, 2.7 ± 0.6 μmol/L, p < 0.05). Immunohistochemistry showed a reduction in cytokine-induced iNOS expression and Northern blot analysis showed a decrease in iNOS mRNA.
Conclusions
. These data demonstrate that aprotinin reduces NO production in vivo and reduces cytokine-induced iNOS expression in vitro.
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