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Original Article |

Effects of Decreased Preoperative Endotoxin Core Antibody Levels on Long-term Mortality After Coronary Artery Bypass Graft Surgery FREE

Eugene W. Moretti, MD, MHSc; Mark F. Newman, MD; Lawrence H. Muhlbaier, PhD; David Whellan, MD, MHSc; Rebecca P. Petersen, MD, MSc; Daniel Rossignol, PhD; Charles B. McCants Jr, BS; Barbara Phillips-Bute, PhD; Elliott Bennett-Guerrero, MD
[+] Author Affiliations

Author Affiliations: Departments of Anesthesiology (Drs Moretti, Newman, Phillips-Bute, and Bennett-Guerrero), Biostatistics and Bioinformatics (Dr Muhlbaier), and Surgery (Drs Muhlbaier and Petersen) and Duke Clinical Research Institute (Drs Newman, Muhlbaier, Whellan, and Bennett-Guerrero and Mr McCants), Duke University Medical Center, Durham, NC; Eisai Global Clinical Research Inc, Ridgefield Park, NJ (Dr Rossignol); and Division of Cardiology, Department of Medicine, Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pa (Dr Whellan).


Arch Surg. 2006;141(7):637-641. doi:10.1001/archsurg.141.7.637.
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Hypothesis  Decreased preoperative levels of antiendotoxin core antibody (EndoCAb) in patients undergoing cardiac surgery with cardiopulmonary bypass are associated with increased long-term mortality.

Design  Observational study.

Setting  Academic medical center.

Patients  A total of 474 patients undergoing coronary artery bypass graft surgery with cardiopulmonary bypass.

Interventions  Preoperative serum IgM EndoCAb levels were determined, and established preoperative risk factors were assessed. Patients were assigned a risk score using a validated method.

Main Outcome Measures  The primary end point was mortality. Statistical analysis used the Cox proportional hazards regression model with log EndoCAb as the predictor of interest and Parsonnet additive risk score as a covariate. Kaplan-Meier survival curves were generated to visually compare groups with high vs low EndoCAb levels.

Results  Forty-six deaths occurred in 5 years. Annual follow-up rates during the 5 years were 100%, 94%, 93%, 98%, and 98% for the 1-, 2-, 3-, 4-, and 5-year periods, respectively. Parsonnet additive risk score (hazard ratio, 1.07; 95% confidence interval [CI], 1.04-1.11; P<.001) and log EndoCAb (hazard ratio, 0.73; 95% CI, 0.53-0.99; P = .04) were independent predictors of long-term mortality in the final model. Kaplan-Meier analysis revealed that the preoperative EndoCAb level was significantly associated with mortality up to 5 years (P = .01 by log-rank test)

Conclusion  Lower preoperative serum EndoCAb level is a significant predictor of long-term mortality independent of other known risk factors.

Figures in this Article

Every year, more than 800 000 coronary artery bypass graft (CABG) procedures are performed worldwide.1 Complications remain common after cardiac surgery, and much of this morbidity may be due to an exaggerated pro-inflammatory response known to occur in this setting.24 Endotoxin is believed to be a major stimulus for development of the inflammatory response.5,6 Some of its effects include myocardial dysfunction, increased tissue oxygen demand, complement activation, contact activation, coagulopathy, and microvascular thrombosis with subsequent organ failure.79

Endogenous endotoxin immunity (antibodies to various serotypes of endotoxin) is conferred early in fetal life from maternal transfer, and it is enhanced by subsequent exposure throughout an individual's life.10 In contrast to the variety of serotype epitopes present in endotoxins, the inner core region of the endotoxin molecule is highly conserved across the entire spectrum of gram-negative organisms.11,12 An assay for antiendotoxin core antibody (EndoCAb) has been used in numerous clinical studies.1319 Most patients undergoing cardiac surgery involving cardiopulmonary bypass (CPB) are exposed to endotoxin20; therefore, it is attractive to speculate that endotoxin may be partially responsible for the exaggerated systemic inflammatory response that is commonly observed.

A previous study14 demonstrated an association between preoperative endotoxin immune status and short-term outcome after cardiac surgery. However, the relationship between preoperative endotoxin immune status and long-term survival is unknown. Therefore, we decided to study the association of preoperative EndoCAb level and long-term outcome in a large cohort of cardiac surgical patients.

After institutional review board approval and written informed consent, we prospectively followed 475 patients at Duke University Medical Center who underwent isolated CABG surgery with CPB between October 1, 1997, and March 12, 2001. Unrelated data regarding endotoxin immunity and cognitive decline were collected from many of these patients and have been reported elsewhere.15

PATIENT MANAGEMENT

General anesthesia was induced and maintained with infusions of midazolam hydrochloride and fentanyl citrate and supplemented with 0.5% to 1% isoflurane. Pancuronium chloride was used for neuromuscular blockade. Patients underwent nonpulsatile hypothermic (30°C-32°C) CPB, with a membrane oxygenator. Porcine heparin sodium, 300 U/kg, was administered and supplemented as necessary to maintain an activated clotting time of 450 seconds during CPB. After termination of CPB, heparin was neutralized with protamine sulfate. Patients were managed postoperatively in the cardiothoracic intensive care unit based on a standard “care pathway” whereby patients without significant complications were discharged from the hospital on postoperative day 4 or 5.

IgM EndoCab LEVEL DETERMINATION

Immediately before the induction of general anesthesia, blood samples were obtained through a radial arterial catheter. Samples were collected in additive-free glass tubes, centrifuged at 2000g, and stored at –70°C until assayed. Dr Robin Barclay, Scotland, provided endotoxin-coated enzyme-linked immunosorbent assay plates and standard serum containing 165 median units (MU) of IgM EndoCAb. Validated enzyme-linked immunosorbent assay conditions have been previously described16,17 and included the use of horseradish peroxidase–conjugated anti–IgM antibody (A-6907; Sigma-Aldrich Corp, St Louis, Mo) and tetramethylbenzidine (T-0440; Sigma-Aldrich Corp), with the exception that the phosphate-buffered saline wash buffer contained 0.3% Triton X-100 and sample incubation was performed at 37°C for 60 minutes. The conjugate incubation and substrate incubation were performed at room temperature for 30 minutes. All serum standards and samples were diluted (≥1:100) with enzyme-linked immunosorbent assay dilution buffer (1% bovine serum albumin, 2.5% adult bovine serum, 0.1% Triton X-100, and 0.1% sodium azide in phosphate-buffered saline). The IgM EndoCAb levels were measured, as in previous publications,1317 because this class of antibody remains intravascular, and levels are unaltered by fluid shifts between the intravascular and extravascular compartments.

PATIENT CHARACTERISTICS AND RISK SCORING

Demographic and clinical information were collected on all patients. Similar to a previous study,14 each patient was assigned a mortality risk score using the Parsonnet additive risk score.21 This is a scoring system, developed based on 3500 cardiac surgery cases and validated on an additional 1300, that generates a score between 0 and 148 based on 19 factors known to increase mortality after cardiac surgery. This score was used in the Cox proportional hazards regression model to adjust for the effects of individual patient comorbidities. Definitions of diabetes mellitus, angina, congestive heart failure, hypertension, and left ventricular ejection fraction were as previously reported.14 Data regarding CPB, aortic cross-clamp, anesthesia, and surgical durations were collected from the patient's intraoperative anesthetic record. Chronic obstructive pulmonary disease was defined as being present based on patient history, physical examination findings, and medication regimen. Significant obesity was defined as a body mass index (calculated as weight in kilograms divided by the square of height in meters) of 35 or greater. Hyperlipidemia was considered to be present based on the patient's lipid profile and medication regimen. Patients who were currently smoking at least a half pack per day or who had stopped smoking for less than 2 years were considered to have a positive smoking history. A family history of coronary artery disease was present if it was documented in the patient's medical record or patient history or if there was a first-degree relative who had received a diagnosis based on documented evidence of significant coronary disease. Renal insufficiency was determined to be present if a patient's preoperative serum creatinine level exceeded 3.0 mg/dL (265 μmol/L). Liver disease was considered to be present if the patient had a history of any of the following: cirrhosis, chronic active hepatitis, primary biliary cirrhosis, ascites, esophageal varices, portal hypertension, or hepatic encephalopathy.

OUTCOME

The primary outcome variable was mortality assessed for 5 years. Assessment of this outcome was facilitated by the fact that all the patients undergoing cardiac surgery at Duke University Medical Center, including those in this study, are followed by the Duke Database for Cardiovascular Disease. Outcome data from this database have been used in numerous previously published clinical studies.2225 The Duke Database for Cardiovascular Disease has supported the prospective entry of clinical care and outcome data since 1971. Outcome data are obtained for the determination of clinical efficacy and quality assurance in all patients undergoing CABG surgery. The quality of these data are verified by features designed to reduce transcription errors (coded data-entry algorithms, error limit checking, dual entry, etc). Data quality has been further ensured by having senior clinicians review and then sign the reports, which thus provides a review of the data files stored in the database. Death and date of death were determined by contact with the next of kin, contact with the referring physician, or a match in the National Death Index and were confirmed by hospital records or death certificates.

STATISTICAL ANALYSIS

Group differences for continuous variables were assessed using the 2-tailed t test. The Fisher exact test (2-sided probability) assessed group differences for categorical variables. The main outcome of time to mortality was assessed using the Cox proportional hazards regression model with log EndoCAb as the primary predictor of interest and Parsonnet additive risk score as a covariate, with censoring occurring at the date of last follow-up. Because EndoCAb level is positively skewed, a logarithmic transformation was performed to achieve a linear fit. Model assumptions were checked in the data. Hazard ratios and 95% confidence intervals (CIs) are reported.

We also examined age, height, weight, body surface area, history of congestive heart failure, and preoperative hematocrit level as potentially important covariates in the Cox proportional hazards regression model. Because of the limitations of the sample size, these variables were investigated one at a time in a model containing log EndoCAb and Parsonnet additive risk score as predictors.

For the purposes of displaying Kaplan-Meier survival curves illustrating time to death, IgM EndoCAb level was dichotomized at 80 MU/mL. This characterization of EndoCAb levels has been shown to be a clinically significant threshold based on previous studies.1416 Cumulative event plots according to EndoCAb level were compared using the log-rank test. For all outcomes and comparisons, P values were 2-sided, and P<.05 was considered statistically significant. All statistical analyses were performed using statistical software packages (SAS version 8.2; SAS Institute Inc, Cary, NC, and STATA version 7.0; STATA Technology Corp, College Station, Tex).

Between October 1, 1997, and March 12, 2001, 474 patients were enrolled. Baseline (Table 1), clinical (Table 2), and intraoperative (Table 3) characteristics of the overall study population are given for the dichotomized groups. There were 46 deaths in the study population. Mean follow-up was 3.7 years (1361 days), with the longest follow-up being 6.25 years. The last patient was enrolled on March 12, 2001. Rates of follow-up per year during the 5 years were 100% (474/474), 94% (432/457), 93% (416/446), 98% (386/395), and 99% (261/264) for the 1-, 2-, 3-, 4-, and 5-year periods, respectively.

Table Graphic Jump LocationTable 1. Patient Demographics and Baseline Characteristics
Table Graphic Jump LocationTable 2. Preoperative Medications and Laboratory Values
Table Graphic Jump LocationTable 3. Intraoperative Characteristics

The Cox proportional hazards regression model demonstrated that log IgM EndoCAb level was a significant predictor of hazard even after adjusting for Parsonnet additive risk score (hazard ratio, 0.73; 95% CI, 0.53-0.99; P = .04). Parsonnet additive risk score was also significant in this model (hazard ratio, 1.07; 95% CI, 1.04-1.11; P<.001). No other variable was a significant predictor of mortality after adjusting for Parsonnet additive risk score.

Mean Parsonnet additive risk scores between the groups with high vs low EndoCAb levels were not significantly different (P = .24). The EndoCAb concentrations and preoperative Parsonnet additive risk score were not highly correlated (Spearman correlation coefficient, −0.079). Eleven deaths (5.4%) occurred in the group with high EndoCAb levels, and 35 deaths (12.8%) occurred in the group with low EndoCAb levels. Kaplan-Meier 5-year survival curves illustrate that survival was lower for the group with low EndoCAb levels (P = .01 by log-rank test) (Figure 1).

Place holder to copy figure label and caption
Figure 1.

Kaplan-Meier estimates of the probability of 5-year survival based on high vs low antiendotoxin core antibody (EndoCAb) levels. P = .01 using the log-rank test.

Graphic Jump Location

This is the first study, to our knowledge, to evaluate the association between preoperative antiendotoxin immune status and long-term survival in patients after cardiac surgery. The data demonstrate that decreased IgM EndoCAb levels are associated with decreased long-term survival up to 5 years after CABG surgery. This association persists even when risk-adjusted statistical analysis is applied, using the Cox proportional hazards regression model, controlling for Parsonnet additive risk score.

Endotoxin is now widely accepted as a major stimulus for development of the systemic inflammatory response syndrome.5 Intravenous administration of endotoxin causes cytokine release, as evidenced by an increase in tumor necrosis factor levels and, within 3 hours, by elevations in interleukin (IL) 1, IL-6, and IL-8 levels.2628 Exposure to endotoxin is also associated with complement, plasminogen, and neutrophil activation; hypercoagulability; and synthesis of bradykinin.29 Endotoxin exposure is common during cardiac surgery and most likely results from hypoperfusion of the gut mucosa, resulting in leakage of endotoxin across the gut mucosal barrier. Depletion of EndoCAb occurs intraoperatively through its consumption during endotoxemia, adherence to CPB tubing, and decreased production.30 Rothenburger et al30 studied 100 patients who underwent CABG with CPB and demonstrated that lower preoperative EndoCAb levels are associated with a greater rise in endotoxin and IL-8 release. In a smaller study involving 26 patients, Mythen et al18 revealed that higher EndoCAb levels are associated with less endotoxin-induced contact activation and neutrophil degranulation. Finally, in a study of 29 medical intensive care patients diagnosed as having sepsis syndrome, low EndoCAb levels were associated with increased mortality.31 In contrast to all previous studies,13,14,18,30,31 which focused only on short-term postoperative end points, the present study is the first to assess the association of preoperative endotoxin immune status with long-term mortality.

The potential mechanisms by which patients with lower preoperative endotoxin immunity have increased risk of long-term mortality are unclear. Speculative mechanisms include the following. (1) Greater endotoxin immunity seems to be associated with less injury in the perioperative period,13,14,30,31 and this may translate into long-term outcome differences through some other mechanisms. This has been demonstrated in other settings. For example, Mangano et al32 showed that patients randomized to only 7 days of β-adrenergic blockade (vs placebo) exhibited a lower mortality up to 2 years after surgery. These data and others3234 suggest that subtle injury in the perioperative period may have an effect on long-term outcome. (2) Patients with low EndoCAb levels may have a genetic predisposition to unfavorable outcomes. Our use of risk adjustment using a validated risk score minimizes, but does not rule out, this possibility. (3) Patients with low preoperative endotoxin immunity may be more likely to have a low level of immunity to endotoxin several years later, which might predispose them to greater risk during a subsequent insult.

As implied previously herein, a limitation of any observational study such as this one is that low antiendotoxin immunity may not be causally related to adverse outcome but merely a marker for sicker patients at higher operative risk. We addressed this possibility by using a validated preoperative risk scoring system to quantify the degree of risk. Although Parsonnet additive risk score is a statistically significant predictor of mortality, the association of low EndoCAb levels with decreased long-term survival is independent of Parsonnet score, suggesting that preoperative health status is not a significant confounder. However, without mechanistic inference it is difficult to know why patients with decreased EndoCAb levels have higher long-term mortality.

The theory that endotoxemia is an important cause of postoperative morbidity is subject to certain criticisms. One relates to the low incidence of culture-positive bacteremia in surgical patients and intensive care unit patients.6,3537 Endotoxemia clearly exists in these patients and does so in the setting of negative blood cultures.3841 The routine administration of antibiotics for surgical prophylaxis would be expected to kill or prevent the growth of susceptible gram-negative bacteria and could conceivably elevate endotoxin serum concentrations through increased shedding of endotoxin.42 Because of the intermittent nature of endotoxemia, studies attempting to detect endotoxemia probably underestimate its incidence. Another criticism resides in the failure of 2 anti–lipid A monoclonal antibodies (HA-1A; Centocor, Malvern, Pa, and E5; Xoma, Berkeley, Calif) to improve outcome on an intention-to-treat basis in intensive care unit patients with established sepsis.43,44 The anti–lipid A monoclonal antibodies failed to bind to endotoxin with high affinity45 and, in fact, are likely to bind to epitopes on lipid A not present on endotoxin,46 helping explain their lack of demonstrable efficacy.

These previous monoclonal antibody studies are not relevant to the present study. They were tested in patients with established sepsis and organ failure, which is in an entirely different setting than in elective surgical patients, who are more likely to benefit from prophylaxis with other endotoxin-related strategies. This is borne out by a resurgence in the development of antiendotoxin strategies that may benefit the high-risk surgical patient.4753

This study is the first, to our knowledge, to demonstrate that decreased preoperative EndoCAb levels are associated with increased long-term mortality in cardiac surgery patients. Results from well-designed randomized studies in which endotoxin is selectively neutralized are necessary to confirm the clinical relevance of these findings. Several antiendotoxin agents are currently in development that may benefit cardiac surgery patients if given prophylactically.4753

Correspondence: Eugene W. Moretti, MD, MHSc, Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710 (moret002@mc.duke.edu).

Accepted for Publication: June 1, 2005.

Funding/Support: Assays were funded by Eisai Global Clinical Research Inc and were performed by Zeptometrix. All other work was funded by Duke University.

Role of the Sponsor: Eisai Global Clinical Research Inc did not influence the design or conduct of this study; the collection, analysis, or interpretation of the data; or the preparation, review, or approval of the manuscript. These functions were entirely the purview of the authors.

 American Heart Association. Heart disease and stroke statistics: 2005 update. http://www.americanheart.org. Accessed December 31, 2003
Hammermeister  KEBurchfiel  CJohnson  RGrover  FL Identification of patients at greatest risk for developing major complications at cardiac surgery. Circulation 1990;82 ((suppl 5)) IV380- IV389
PubMed
Goris  RJte Boekhorst  TPNuytinck  JKGimbrere  JS Multiple-organ failure: generalized autodestructive inflammation? Arch Surg 1985;1201109- 1115
PubMed
Bone  RCBalk  RACerra  FB  et al. ACCP/SCCM Consensus Conference Committee, American College of Chest Physicians/Society of Critical Care Medicine, Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Chest 1992;1011644- 1655
PubMed
Danner  RLElin  RJHosseini  JMWesley  RAReilly  JMParillo  JE Endotoxemia in human septic shock. Chest 1991;99169- 175
PubMed
Rush  BF  JrSori  AJMurphy  TFSmith  SFlanagan  JJ  JrMachiedo  GW Endotoxemia and bacteremia during hemorrhagic shock: the link between trauma and sepsis? Ann Surg 1988;207549- 554
PubMed
Suffredini  AFFromm  REParker  MM  et al.  The cardiovascular response of normal humans to the administration of endotoxin. N Engl J Med 1989;321280- 287
PubMed
Bjork  JHugli  TESmedegard  G Microvascular effects of anaphylatoxins C3a and C5a. J Immunol 1985;1341115- 1119
PubMed
Morrison  DCCochrane  CG Direct evidence for Hageman factor (factor XII) activation by bacterial lipopolysaccharides (endotoxins). J Exp Med 1974;140797- 811
PubMed
Barclay  GR Bacterial Endotoxins: Lipopolysaccharides From Genes to Therapy.  New York, NY John Wiley & Sons1995;
Poxton  IR Antibodies to lipopolysaccharide. J Immunol Methods 1995;1861- 15
PubMed
Baumgartner  JD Immunotherapy with antibodies to core lipopolysaccharide: a critical appraisal. Infect Dis Clin North Am 1991;5915- 927
PubMed
Bennett-Guerrero  EPanah  MHBarclay  GR  et al.  Decreased endotoxin immunity is associated with greater mortality and/or prolonged hospitalization after surgery. Anesthesiology 2001;94992- 998
PubMed
Bennett-Guerrero  EAyuso  LHamilton-Davies  C  et al.  Relationship of preoperative antiendotoxin core antibodies and adverse outcomes following cardiac surgery. JAMA 1997;277646- 650
PubMed
Mathew  JPGrocott  HPPhillips-Bute  B  et al.  Lower endotoxin immunity predicts increased cognitive dysfunction in elderly patients after cardiac surgery. Stroke 2003;34508- 513
PubMed
Hamilton-Davies  CBarclay  GRCardigan  RA  et al.  Relationship between preoperative endotoxin immune status, gut perfusion, and outcome from cardiac valve replacement surgery. Chest 1997;1121189- 1196
PubMed
Bennett-Guerrero  EBarclay  GRYoussef  ME  et al.  Exposure to bacteroides fragilis endotoxin during cardiac surgery. Anesth Analg 2000;90819- 823
PubMed
Mythen  MGBarclay  GRPurdy  G  et al.  The role of endotoxin immunity, neutrophil degranulation and contact activation in the pathogenesis of post-operative organ dysfunction. Blood Coagul Fibrinolysis 1993;4999- 1005
PubMed
Windsor  JAFearon  KCRoss  JA  et al.  Role of serum endotoxin and antiendotoxin core antibody levels in predicting the development of multiple organ failure in acute pancreatitis. Br J Surg 1993;801042- 1046
PubMed
Andersen  LWBaek  LDegn  H Presence of circulating endotoxin during cardiac operations. J Thorac Cardiovasc Surg 1987;93115- 119
PubMed
Parsonnet  VDean  DBernstein  AD A method of uniform stratification of risk for evaluating the results of surgery in acquired adult heart disease. Circulation 1989;79I3- I12
PubMed
Califf  RMHarrell  FE  JrLee  KL  et al.  The evolution of medical and surgical therapy for coronary artery disease: a 15-year perspective. JAMA 1989;2612077- 2086
PubMed
Jones  RHKesler  KPhillips  HR  III  et al.  Long-term survival benefits of coronary artery bypass grafting and percutaneous transluminal angioplasty in patients with coronary artery disease. J Thorac Cardiovasc Surg 1996;1111013- 1025
PubMed
Mark  DBNelson  CLCaliff  RM  et al.  Continuing evolution of therapy for coronary artery disease: initial results from the era of coronary angioplasty. Circulation 1994;892015- 2025
PubMed
Califf  RMDeLong  EROstbye  T  et al.  Underuse of aspirin in a referral population with documented coronary artery disease. Am J Cardiol 2002;89653- 661
PubMed
Luca  RLijnen  HRSuffredini  AF  et al.  Increased angiostatin levels in bronchoalveolar lavage fluids from ARDS patients and from human volunteers after lung instillation of endotoxin. Thromb Haemost 2002;87966- 971
PubMed
O'Grady  NPPreas  HLPugin  J  et al.  Local inflammatory responses following bronchial endotoxin instillation in humans. Am J Respir Crit Care Med 2001;1631591- 1598
PubMed
Suffredini  AFFromm  REParker  MM  et al.  The cardiovascular response of normal humans to the administration of endotoxin. N Engl J Med 1989;321280- 287
PubMed
Martich  GDBoujoukos  AJSuffredini  AF Response of man to endotoxin. Immunobiology 1993;187403- 416
PubMed
Rothenburger  MSoeparwata  RDeng  MC  et al.  The impact of anti-endotoxin core antibodies on endotoxin and cytokine release and ventilation time after cardiac surgery. J Am Coll Cardiol 2001;38124- 130
PubMed
Strutz  FHeller  GKrasemann  KKrone  BMuller  GA Relationship of antibodies to endotoxin core to mortality in medical patients with sepsis syndrome. Intensive Care Med 1999;25435- 444
PubMed
Mangano  DTLayug  ELWallace  ATateo  IMulticenter Study of Perioperative Ischemia Research Group, Effect of atenolol on mortality and cardiovascular morbidity after noncardiac surgery. N Engl J Med 1996;3351713- 1720
PubMed
Poldermans  DBoersma  EBax  JJ  et al. Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography Study Group, The effect of bisoprolol on perioperative mortality and myocardial infarction in high-risk patients undergoing vascular surgery. N Engl J Med 1999;3411789- 1794
PubMed
Landesberg  GShatz  VAkopnik  I  et al.  Association of cardiac troponin, CK-MB, and postoperative myocardial ischemia with long-term survival after major vascular surgery. J Am Coll Cardiol 2003;421547- 1554
PubMed
DeCamp  MMDemling  RH Posttraumatic multisystem organ failure. JAMA 1988;260530- 534
PubMed
Moore  FAMoore  EEPoggetti  R  et al.  Gut bacterial translocation via the portal vein: a clinical perspective with major torso trauma. J Trauma 1991;31629- 636
PubMed
Ford  EGBaisden  CEMatteson  MLPicone  AL Sepsis after coronary bypass grafting: evidence for loss of the gut mucosal barrier. Ann Thorac Surg 1991;52514- 517
PubMed
Buller  HRten Cate  JWSturk  AThomas  LL Validity of the endotoxin assay in post surgical patients. Prog Clin Biol Res 1985;189405- 417
PubMed
Munster  AMSmith-Meek  MDickerson  CWinchurch  RA Translocation: incidental phenomenon or true pathology? Ann Surg 1993;218321- 326
PubMed
Bion  JFBadger  ICrosby  HA  et al.  Selective decontamination of the digestive tract reduces gram-negative pulmonary colonization but not systemic endotoxemia in patients undergoing elective liver transplantation. Crit Care Med 1994;2240- 49
PubMed
Deitch  EAMorrison  JBerg  RSpecian  RD Effect of hemorrhagic shock on bacterial translocation, intestinal morphology, and intestinal permeability in conventional and antibiotic-decontaminated rats. Crit Care Med 1990;18529- 536
PubMed
Giamarellou-Bourboulis  EJPerdios  JLelekis  MEoconomou  ETsouroulas  PGiamarellou  H Impact of cefuroxime administration on endotoxin (LPS) and tumour necrosis factor-α (TNFα) blood levels in patients suffering from acute pyelonephritis: a preliminary report. Int J Antimicrob Agents 1999;11115- 119
PubMed
Ziegler  EJFisher  CJ  JrSprung  CL  et al. HA-1A Sepsis Study Group, Treatment of gram-negative bacteremia and septic shock with HA-1A human monoclonal antibody against endotoxin: a randomized, double-blind, placebo-controlled trial. N Engl J Med 1991;324429- 436
PubMed
Greenman  RLSchein  RMMartin  MA  et al. XOMA Sepsis Study Group, A controlled clinical trial of E5 murine monoclonal IgM antibody to endotoxin in the treatment of gram-negative sepsis. JAMA 1991;2661097- 1102
PubMed
Warren  HSAmato  SFFitting  C  et al.  Assessment of ability of murine and human anti-lipid A monoclonal antibodies to bind and neutralize lipopolysaccharide. J Exp Med 1993;17789- 97
PubMed
Brade  LEngel  RChrist  WJRietschel  ET A nonsubstituted primary hydroxyl group in position 6' of free lipid A is required for binding of lipid A monoclonal antibodies. Infect Immun 1997;653961- 3965
PubMed
Mullarkey  MRose  JRBristol  J  et al.  Inhibition of endotoxin response by e5564, a novel Toll-like receptor 4-directed endotoxin antagonist. J Pharmacol Exp Ther 2003;3041093- 1102
PubMed
Lynn  MRossignol  DPWheeler  JL  et al.  Blocking of responses to endotoxin by E5564 in healthy volunteers with experimental endotoxemia. J Infect Dis 2003;187631- 639
PubMed
Rossignol  DPLynn  M Antagonism of in vivo and ex vivo response to endotoxin by E5564, a synthetic lipid A analogue. J Endotoxin Res 2002;8483- 488
PubMed
Gordon  BRParker  TSLevine  DM  et al.  Safety and pharmacokinetics of an endotoxin-binding phospholipid emulsion. Ann Pharmacother 2003;37943- 950
PubMed
Woo  YJTaylor  MDCohen  JE  et al.  Ethyl pyruvate preserves cardiac function and attenuates oxidative injury after prolonged myocardial ischemia. J Thorac Cardiovasc Surg 2004;1271262- 1269
PubMed
Sappington  PLFink  MEYang  RDelude  RLFink  MP Ethyl pyruvate provides durable protection against inflammation-induced intestinal epithelial barrier dysfunction. Shock 2003;20521- 528
PubMed
Rossignol  DPWasan  KMChoo  E  et al.  Safety, pharmacokinetics, pharmacodynamics, and plasma lipoprotein distribution of eritoran (E5564) during continuous intravenous infusion into healthy volunteers. Antimicrob Agents Chemother 2004;483233- 3240
PubMed

Figures

Place holder to copy figure label and caption
Figure 1.

Kaplan-Meier estimates of the probability of 5-year survival based on high vs low antiendotoxin core antibody (EndoCAb) levels. P = .01 using the log-rank test.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Patient Demographics and Baseline Characteristics
Table Graphic Jump LocationTable 2. Preoperative Medications and Laboratory Values
Table Graphic Jump LocationTable 3. Intraoperative Characteristics

References

 American Heart Association. Heart disease and stroke statistics: 2005 update. http://www.americanheart.org. Accessed December 31, 2003
Hammermeister  KEBurchfiel  CJohnson  RGrover  FL Identification of patients at greatest risk for developing major complications at cardiac surgery. Circulation 1990;82 ((suppl 5)) IV380- IV389
PubMed
Goris  RJte Boekhorst  TPNuytinck  JKGimbrere  JS Multiple-organ failure: generalized autodestructive inflammation? Arch Surg 1985;1201109- 1115
PubMed
Bone  RCBalk  RACerra  FB  et al. ACCP/SCCM Consensus Conference Committee, American College of Chest Physicians/Society of Critical Care Medicine, Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Chest 1992;1011644- 1655
PubMed
Danner  RLElin  RJHosseini  JMWesley  RAReilly  JMParillo  JE Endotoxemia in human septic shock. Chest 1991;99169- 175
PubMed
Rush  BF  JrSori  AJMurphy  TFSmith  SFlanagan  JJ  JrMachiedo  GW Endotoxemia and bacteremia during hemorrhagic shock: the link between trauma and sepsis? Ann Surg 1988;207549- 554
PubMed
Suffredini  AFFromm  REParker  MM  et al.  The cardiovascular response of normal humans to the administration of endotoxin. N Engl J Med 1989;321280- 287
PubMed
Bjork  JHugli  TESmedegard  G Microvascular effects of anaphylatoxins C3a and C5a. J Immunol 1985;1341115- 1119
PubMed
Morrison  DCCochrane  CG Direct evidence for Hageman factor (factor XII) activation by bacterial lipopolysaccharides (endotoxins). J Exp Med 1974;140797- 811
PubMed
Barclay  GR Bacterial Endotoxins: Lipopolysaccharides From Genes to Therapy.  New York, NY John Wiley & Sons1995;
Poxton  IR Antibodies to lipopolysaccharide. J Immunol Methods 1995;1861- 15
PubMed
Baumgartner  JD Immunotherapy with antibodies to core lipopolysaccharide: a critical appraisal. Infect Dis Clin North Am 1991;5915- 927
PubMed
Bennett-Guerrero  EPanah  MHBarclay  GR  et al.  Decreased endotoxin immunity is associated with greater mortality and/or prolonged hospitalization after surgery. Anesthesiology 2001;94992- 998
PubMed
Bennett-Guerrero  EAyuso  LHamilton-Davies  C  et al.  Relationship of preoperative antiendotoxin core antibodies and adverse outcomes following cardiac surgery. JAMA 1997;277646- 650
PubMed
Mathew  JPGrocott  HPPhillips-Bute  B  et al.  Lower endotoxin immunity predicts increased cognitive dysfunction in elderly patients after cardiac surgery. Stroke 2003;34508- 513
PubMed
Hamilton-Davies  CBarclay  GRCardigan  RA  et al.  Relationship between preoperative endotoxin immune status, gut perfusion, and outcome from cardiac valve replacement surgery. Chest 1997;1121189- 1196
PubMed
Bennett-Guerrero  EBarclay  GRYoussef  ME  et al.  Exposure to bacteroides fragilis endotoxin during cardiac surgery. Anesth Analg 2000;90819- 823
PubMed
Mythen  MGBarclay  GRPurdy  G  et al.  The role of endotoxin immunity, neutrophil degranulation and contact activation in the pathogenesis of post-operative organ dysfunction. Blood Coagul Fibrinolysis 1993;4999- 1005
PubMed
Windsor  JAFearon  KCRoss  JA  et al.  Role of serum endotoxin and antiendotoxin core antibody levels in predicting the development of multiple organ failure in acute pancreatitis. Br J Surg 1993;801042- 1046
PubMed
Andersen  LWBaek  LDegn  H Presence of circulating endotoxin during cardiac operations. J Thorac Cardiovasc Surg 1987;93115- 119
PubMed
Parsonnet  VDean  DBernstein  AD A method of uniform stratification of risk for evaluating the results of surgery in acquired adult heart disease. Circulation 1989;79I3- I12
PubMed
Califf  RMHarrell  FE  JrLee  KL  et al.  The evolution of medical and surgical therapy for coronary artery disease: a 15-year perspective. JAMA 1989;2612077- 2086
PubMed
Jones  RHKesler  KPhillips  HR  III  et al.  Long-term survival benefits of coronary artery bypass grafting and percutaneous transluminal angioplasty in patients with coronary artery disease. J Thorac Cardiovasc Surg 1996;1111013- 1025
PubMed
Mark  DBNelson  CLCaliff  RM  et al.  Continuing evolution of therapy for coronary artery disease: initial results from the era of coronary angioplasty. Circulation 1994;892015- 2025
PubMed
Califf  RMDeLong  EROstbye  T  et al.  Underuse of aspirin in a referral population with documented coronary artery disease. Am J Cardiol 2002;89653- 661
PubMed
Luca  RLijnen  HRSuffredini  AF  et al.  Increased angiostatin levels in bronchoalveolar lavage fluids from ARDS patients and from human volunteers after lung instillation of endotoxin. Thromb Haemost 2002;87966- 971
PubMed
O'Grady  NPPreas  HLPugin  J  et al.  Local inflammatory responses following bronchial endotoxin instillation in humans. Am J Respir Crit Care Med 2001;1631591- 1598
PubMed
Suffredini  AFFromm  REParker  MM  et al.  The cardiovascular response of normal humans to the administration of endotoxin. N Engl J Med 1989;321280- 287
PubMed
Martich  GDBoujoukos  AJSuffredini  AF Response of man to endotoxin. Immunobiology 1993;187403- 416
PubMed
Rothenburger  MSoeparwata  RDeng  MC  et al.  The impact of anti-endotoxin core antibodies on endotoxin and cytokine release and ventilation time after cardiac surgery. J Am Coll Cardiol 2001;38124- 130
PubMed
Strutz  FHeller  GKrasemann  KKrone  BMuller  GA Relationship of antibodies to endotoxin core to mortality in medical patients with sepsis syndrome. Intensive Care Med 1999;25435- 444
PubMed
Mangano  DTLayug  ELWallace  ATateo  IMulticenter Study of Perioperative Ischemia Research Group, Effect of atenolol on mortality and cardiovascular morbidity after noncardiac surgery. N Engl J Med 1996;3351713- 1720
PubMed
Poldermans  DBoersma  EBax  JJ  et al. Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography Study Group, The effect of bisoprolol on perioperative mortality and myocardial infarction in high-risk patients undergoing vascular surgery. N Engl J Med 1999;3411789- 1794
PubMed
Landesberg  GShatz  VAkopnik  I  et al.  Association of cardiac troponin, CK-MB, and postoperative myocardial ischemia with long-term survival after major vascular surgery. J Am Coll Cardiol 2003;421547- 1554
PubMed
DeCamp  MMDemling  RH Posttraumatic multisystem organ failure. JAMA 1988;260530- 534
PubMed
Moore  FAMoore  EEPoggetti  R  et al.  Gut bacterial translocation via the portal vein: a clinical perspective with major torso trauma. J Trauma 1991;31629- 636
PubMed
Ford  EGBaisden  CEMatteson  MLPicone  AL Sepsis after coronary bypass grafting: evidence for loss of the gut mucosal barrier. Ann Thorac Surg 1991;52514- 517
PubMed
Buller  HRten Cate  JWSturk  AThomas  LL Validity of the endotoxin assay in post surgical patients. Prog Clin Biol Res 1985;189405- 417
PubMed
Munster  AMSmith-Meek  MDickerson  CWinchurch  RA Translocation: incidental phenomenon or true pathology? Ann Surg 1993;218321- 326
PubMed
Bion  JFBadger  ICrosby  HA  et al.  Selective decontamination of the digestive tract reduces gram-negative pulmonary colonization but not systemic endotoxemia in patients undergoing elective liver transplantation. Crit Care Med 1994;2240- 49
PubMed
Deitch  EAMorrison  JBerg  RSpecian  RD Effect of hemorrhagic shock on bacterial translocation, intestinal morphology, and intestinal permeability in conventional and antibiotic-decontaminated rats. Crit Care Med 1990;18529- 536
PubMed
Giamarellou-Bourboulis  EJPerdios  JLelekis  MEoconomou  ETsouroulas  PGiamarellou  H Impact of cefuroxime administration on endotoxin (LPS) and tumour necrosis factor-α (TNFα) blood levels in patients suffering from acute pyelonephritis: a preliminary report. Int J Antimicrob Agents 1999;11115- 119
PubMed
Ziegler  EJFisher  CJ  JrSprung  CL  et al. HA-1A Sepsis Study Group, Treatment of gram-negative bacteremia and septic shock with HA-1A human monoclonal antibody against endotoxin: a randomized, double-blind, placebo-controlled trial. N Engl J Med 1991;324429- 436
PubMed
Greenman  RLSchein  RMMartin  MA  et al. XOMA Sepsis Study Group, A controlled clinical trial of E5 murine monoclonal IgM antibody to endotoxin in the treatment of gram-negative sepsis. JAMA 1991;2661097- 1102
PubMed
Warren  HSAmato  SFFitting  C  et al.  Assessment of ability of murine and human anti-lipid A monoclonal antibodies to bind and neutralize lipopolysaccharide. J Exp Med 1993;17789- 97
PubMed
Brade  LEngel  RChrist  WJRietschel  ET A nonsubstituted primary hydroxyl group in position 6' of free lipid A is required for binding of lipid A monoclonal antibodies. Infect Immun 1997;653961- 3965
PubMed
Mullarkey  MRose  JRBristol  J  et al.  Inhibition of endotoxin response by e5564, a novel Toll-like receptor 4-directed endotoxin antagonist. J Pharmacol Exp Ther 2003;3041093- 1102
PubMed
Lynn  MRossignol  DPWheeler  JL  et al.  Blocking of responses to endotoxin by E5564 in healthy volunteers with experimental endotoxemia. J Infect Dis 2003;187631- 639
PubMed
Rossignol  DPLynn  M Antagonism of in vivo and ex vivo response to endotoxin by E5564, a synthetic lipid A analogue. J Endotoxin Res 2002;8483- 488
PubMed
Gordon  BRParker  TSLevine  DM  et al.  Safety and pharmacokinetics of an endotoxin-binding phospholipid emulsion. Ann Pharmacother 2003;37943- 950
PubMed
Woo  YJTaylor  MDCohen  JE  et al.  Ethyl pyruvate preserves cardiac function and attenuates oxidative injury after prolonged myocardial ischemia. J Thorac Cardiovasc Surg 2004;1271262- 1269
PubMed
Sappington  PLFink  MEYang  RDelude  RLFink  MP Ethyl pyruvate provides durable protection against inflammation-induced intestinal epithelial barrier dysfunction. Shock 2003;20521- 528
PubMed
Rossignol  DPWasan  KMChoo  E  et al.  Safety, pharmacokinetics, pharmacodynamics, and plasma lipoprotein distribution of eritoran (E5564) during continuous intravenous infusion into healthy volunteers. Antimicrob Agents Chemother 2004;483233- 3240
PubMed

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