https://cdr.lib.unc.edu/downloads/9p290c48k

ACC/AHA Guidelines for Coronary Artery Bypass Graft Surgery A Report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1991 Guidelines for Coronary Artery Bypass Graft Surgery)

ACC/AHA 2004 guideline update for coronary artery bypass graft surgery: Summary article. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (committee to update the 1999 guidelines for coronary artery bypass graft surgery)

Objective To attempt to determine the relative value of preclinical cardiac electrophysiology data (in vitro and in vivo) for predicting risk of torsade de pointes (TdP) in clinical use. Methods Published data on hERG (or I(Kr)) activity, cardiac action potential duration (at 90% repolarisation; APD(90)), and QT prolongation in dogs were compared against QT effects and reports of TdP in humans for 100 drugs. These data were set against the free plasma concentrations attained during clinical use (effective therapeutic plasma concentrations; ETPC(unbound)). The drugs were divided into five categories: (1) Class Ia and III antiarrhythmics; (2) Withdrawn from market due to TdP; (3) Measurable incidence/numerous reports of TdP in humans; (4) Isolated reports of TdP in humans; (5) No reports of TdP in humans. Results Data from hERG (or I(Kr)) assays in addition to ETPC(unbound) data were available for 52 drugs. For Category 1 drugs, data for hERG/I(Kr) IC(50), APD(90), QTc in animals and QTc in humans were generally close to or superimposed on the ETPC(unbound) values. This relationship was uncoupled in the other categories, with more complex relationships between the data. In Category 1 (except amiodarone), the ratios between hERG/I(Kr) IC(50) and ETPC(unbound) (max) ranged from 0.1- to 31-fold. Similar ranges were obtained for drugs in Category 2 (0.31- to 13-fold) and Category 3 (0.03- to 35-fold). A large spread was found for Category 4 drugs (0.13- to 35700-fold); this category embraced an assortment of mechanisms ranging from drugs which may well be affecting I(Kr) currents in clinical use (e.g. sparfloxacin) to others such as nifedipine (35700-fold) where channel block is not involved. Finally, for the majority of Category 5 drugs there was a >30-fold separation between hERG/I(Kr) activity and ETPC(unbound) values, with the notable exception of verapamil (1.7-fold), which is free from QT prolongation in man; this is probably explained by its multiple interactions with cardiac ion channels. Conclusions The dataset confirms the widely-held belief that most drugs associated with TdP in humans are also associated with hERG K(+) channel block at concentrations close to or superimposed upon the free plasma concentrations found in clinical use. A 30-fold margin between C(max) and hERG IC(50) may suffice for drugs currently undergoing clinical evaluation, but for future drug discovery programmes, pharmaceutical companies should consider increasing this margin, particularly for drugs aimed at non-debilitating diseases. However, interactions with multiple cardiac ion channels can either mitigate or exacerbate the prolongation of APD and QT that would ensue from block of I(Kr) currents alone, and delay of repolarisation per se is not necessarily torsadogenic. Clearly, an integrated assessment of in vitro and in vivo data is required in order to predict the torsadogenic risk of a new candidate drug in humans.

Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs : Evidence for a provisional safety margin in drug development

National High Blood Pressure Education Program.

There is increasing concern that most current published research findings are false. The probability that a research claim is true may depend on study power and bias, the number of other studies on the same question, and, importantly, the ratio of true to no relationships among the relationships probed in each scientific field. In this framework, a research finding is less likely to be true when the studies conducted in a field are smaller; when effect sizes are smaller; when there is a greater number and lesser preselection of tested relationships; where there is greater flexibility in designs, definitions, outcomes, and analytical modes; when there is greater financial and other interest and prejudice; and when more teams are involved in a scientific field in chase of statistical significance. Simulations show that for most study designs and settings, it is more likely for a research claim to be false than true. Moreover, for many current scientific fields, claimed research findings may often be simply accurate measures of the prevailing bias. In this essay, I discuss the implications of these problems for the conduct and interpretation of research.

Why most published research findings are false

The inflammatory response to cardiopulmonary bypass

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.

http://www.nimbot.com/Med/Articles/Journal%20Clubs/2006-10/Blood%20transfusion%20increases%20risk%20of%20post-op%20infection.pdf

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

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

BACKGROUND\nImmunosuppression 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.\n\n\nMETHODS\nTwenty 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.\n\n\nRESULTS\nThe 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.\n\n\nCONCLUSION\nThese 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.

Allogeneic Blood Transfusion Increases the Risk of Postoperative Bacterial Infection: A Meta-Analysis: [2002][A-423]

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.

Gary E. Hill

Papers

The inflammatory response to cardiopulmonary bypass

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

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

Allogeneic Blood Transfusion Increases the Risk of Postoperative Bacterial Infection: A Meta-Analysis: [2002][A-423]

Blood transfusion-induced immunomodulation.