Background The genetic determinants of the human innate immune response are poorly understood. Apolipoprotein (Apo) E, a lipid-trafficking protein that affects inflammation, has well-described ...wild-type (ε3) and disease-associated (ε2 and ε4) alleles, but its connection to human innate immunity is undefined. Objective We sought to define the relationship of APOε4 to the human innate immune response. Methods We evaluated APOε4 in several functional models of the human innate immune response, including intravenous LPS challenge in human subjects, and assessed APOε4 association to organ injury in patients with severe sepsis, a disease driven by dysregulated innate immunity. Results Whole blood from healthy APOε3 / APOε4 volunteers induced higher cytokine levels on ex vivo stimulation with Toll-like receptor (TLR) 2, TLR4, or TLR5 ligands than blood from APOε3 / APOε3 patients, whereas TLR7/8 responses were similar. This was associated with increased lipid rafts in APOε3/APOε4 monocytes. By contrast, APOε3 / APOε3 and APOε3 / APOε4 serum neutralized LPS equivalently and supported similar LPS responses in Apoe -deficient macrophages, arguing against a differential role for secretory APOE4 protein. After intravenous LPS, APOε3/APOε4 patients had higher hyperthermia and plasma TNF-α levels and earlier plasma IL-6 than APOε3/APOε3 patients. APOE4-targeted replacement mice displayed enhanced hypothermia, plasma cytokines, and hepatic injury and altered splenic lymphocyte apoptosis after systemic LPS compared with APOE3 counterparts. In a cohort of 828 patients with severe sepsis, APOε4 was associated with increased coagulation system failure among European American patients. Conclusions APOε4 is a determinant of the human innate immune response to multiple TLR ligands and associates with altered patterns of organ injury in human sepsis.
Background Development of infectious complications after high volume elective surgical procedures imposes a significant clinical burden to the United States population. This study evaluated the ...association of in-hospital delay of elective procedures and the subsequent impact on infectious complications after coronary artery bypass graft (CABG) surgery, colon resection, and lung resection. Study Design The Nationwide Inpatient Sample was queried between 2003 and 2007, and patients who developed postoperative infectious complications were identified. Time to elective surgery in days from admission was calculated: 0, 1 day, 2 to 5 days, and 6 to 10 days. Infectious complications evaluated included pneumonia, urinary tract infections, postoperative sepsis, and surgical site infections. Chi-square, multivariable logistic regression analyses, analysis of variance, and Cochran-Armitage trend test were used. Results There were 87,318 CABG procedures, 46,728 colon resections, and 28,960 lung resections evaluated. Total infection rates significantly increased after elective surgery delays: CABG: 0 days, 5.73%;1 day, 6.68%; 2 to 5 days, 9.33%; 6 to 10 days,18.24%; colon resections: 0 days, 8.43 %;1 day, 11.86%; 2 to 5 days,15.79%;6 to 10 days,21.62%; and lung resections: 0 days, 10.17%;1 day, 14.53%; 2 to 5 days, 15.53%; 6 to 10 days, 20.56%, p < 0.0001 for all trends. Trends for increasing infections after delay were significant for pneumonia and sepsis for all procedures (p < 0.0001); urinary tract infections and surgical site infections significantly increased after CABG and colon resection. Age 80 years and older, female gender, black and Hispanic race or ethnicity, and comorbidities including congestive heart failure, chronic pulmonary disease, and renal failure were associated with delay in surgery. Postoperative hospital mortality after delayed procedures was also greater. Mean cost increased after all procedures with delays: CABG, from $25,164 to $42,055 (p < 0.0001); colon resections, from $13,660 to $25,307) (p < 0.0001); and lung resections, from $18,519 to $25,054 (p < 0.0001). Conclusions In-hospital delay of elective surgery from the day of admission was associated with a significant increase in infectious complications and mortality. This delay was also associated with a significant increase in hospital cost. Future policy directed toward preventing in-hospital delay of elective surgery may offer significant cost savings and decrease infectious complications after elective surgery.
Objective This study was conducted to evaluate and compare the rates of postoperative infectious complications and death after elective vascular surgery, define vascular procedures with the greatest ...risk of developing nosocomial infections, and assess the effect of infection on health care resource utilization. Methods The Nationwide Inpatient Sample (2002-2006) was used to identify major vascular procedures by International Classification of Diseases, 9th Clinical Modification (ICD-9-CM) codes. Infectious complications identified included pneumonia, urinary tract infections (UTI), postoperative sepsis, and surgical site infections (SSI). Case-mix-adjusted rates were calculated using a multivariate logistic regression model for infectious complication or death as an outcome and indirect standardization. Results A total of 870,778 elective vascular surgical procedures were estimated and evaluated with an overall postoperative infection rate of 3.70%. Open abdominal aortic surgery had the greatest rate of postoperative infections, followed by open thoracic procedures and aorta-iliac-femoral bypass. Thoracic endovascular aneurysm repair (TEVAR) infectious complication rates were two times greater than after EVAR ( P < .0001). Pneumonia was the most common infectious complication after open aortic surgery (6.63%). UTI was the most common after TEVAR (2.86%) and EVAR (1.31%). Infectious complications were greater in octogenarians ( P < .0002), women ( P < .0001), and blacks ( P < .0001 vs whites and Hispanics). Nosocomial infections after elective vascular surgery significantly increased hospital length of stay (13.8 ± 15.4 vs 3.5 ± 4.2 days; P < .001) and reported total hospital cost ($37,834 ± $42,905 vs $11,851 ± $11,816; P < .001). Conclusions Elective vascular surgical procedures vary widely in the estimated risk of postoperative infection. Open aortic surgery and endarterectomy of the head and neck vessels have, respectively, the greatest and the lowest reported incidence for postoperative infectious complications. Women, octogenarians, and blacks have the highest risk of infectious complications after elective vascular surgery. Disparities in the development of infectious complications on a systems level were also found in larger hospitals and teaching hospitals. Hospital infectious complications were found to significantly increase health care resource utilization. Strategies that reduce nosocomial complications and target high-risk procedures may offer significant future cost savings.
The cognate signals from sterile or pathogen-induced sources converge on the same recognition or response pathways. In the surgical patient, a systemic response to infection most often occurs in the ...context of ongoing inflammatory stress. Such an inflammatory response is modulated initially by the magnitude of injury and by patient-specific (endogenous) factors, such as confounding illness, age, and genetic variation. Over an extended period of stress, treatmentrelated (exogenous) factors add unpredictability to host responses to subsequent challenges, such as acquired infection. The host response is discussed in the context of how existing sterile stressors may modify the response to acquired infection in surgical patients.
Modeling the human injury response Shanker, Beth-Ann, MD, MS; Coyle, Suzette M., RN; Reddell, Michael T., BS ...
Journal of the American College of Surgeons,
2010, Letnik:
211, Številka:
3
Journal Article
The Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial examined the safety and efficacy of drotrecogin alfa (activated) (Xigris) in adult patients with severe sepsis. A clinical ...evaluation committee examined clinical data for each patient enrolled in PROWESS. However, there were no surgeons on the committee, and thus questions remained regarding the safety and efficacy of drotrecogin alfa (activated) in surgical patients.
Masked to treatment, a Surgical Evaluation Committee adjudicated the presence and type of operation, timing of surgery, infection, and adequacy of source control of surgical patients included in PROWESS.
Twenty-eight percent of PROWESS cases were confirmed as surgical. The absolute risk reduction for mortality in all surgical patients was 3.2% and 9.1% for patients undergoing intraabdominal procedures. Serious bleeding during the infusion and 28-day period was similar between surgical and nonsurgical patients.
Consistent with the overall PROWESS results, drotrecogin alfa (activated) has a favorable benefit/risk profile in surgical patients.
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