Reduction of Surgical Site Infection After Trauma Laparotomy Through Use of a Specific Protocol for Antibiotic Prophylaxis.

Background: Emergency laparotomy for abdominal trauma is associated with high rates of surgical site infection (SSI). A protocol for antimicrobial prophylaxis (AMP) for trauma laparotomy was implemented to determine whether SSI could be reduced by adhering to established principles of AMP. Patients and Methods: A protocol utilizing ertapenem administered immediately before initiation of trauma laparotomy was adopted. Compliance with measures of adequate AMP were determined before and after protocol implementation, as were rates of SSI and other infections related to abdominal trauma. Univariable and multivariable analyses were performed to determine risk factors for development of infection related to trauma laparotomy. Results: Over a four-year period, 320 patient operations were reviewed. Ertapenem use for prophylaxis increased to 54% in the post-intervention cohort. Compliance with individual measures of appropriate AMP improved modestly. Overall, infections related to trauma laparotomy decreased by 46% (absolute decrease of 13%) in the post-intervention cohort. Multivariable analysis confirmed that treatment during the post-intervention phase was associated with this decrease, with a separate analysis suggesting that ertapenem use was an important factor in this decrease. Conclusions: Development of a standardized protocol for AMP in trauma laparotomy led to decreases in infectious complications after that procedure.

Evaluating the Impact of Technique and Mesh Type in Complicated Ventral Hernia Repair: A Prospective Randomized Multicenter Controlled Trial.

BACKGROUND: To our knowledge, there is an absence of prospective randomized multicenter controlled trials evaluating both the impact of technique and mesh type on outcomes in complicated ventral hernia repair. STUDY DESIGN: A prospective randomized multicenter controlled trial of 120 patients at 3 sites was conducted in which patients were randomized to either overlay (anterior component separation) or underlay mesh placement (posterior component separation) and mesh type (human acellular dermis [HADM] vs porcine acellular dermis [PADM]). Key inclusion criteria included hernia size (>200 cm2), BMI < 40 kg/m2, hemoglobin A1C < 7%, tobacco free > 6 weeks and primary fascial closure. Primary outcome was hernia recurrence at 1 year, determined by independent examiner/imaging. Secondary outcomes included complications and patient satisfaction (short form [SF]-36v2). Standardized investigator training included a porcine model followed by a proctored first case by the lead investigator. RESULTS: There were no significant differences in demographics between the 4 groups (age 60 ±12 years, BMI 32 ± 5 kg/m2, 51% female). The overall 1-year recurrence rate was 10.8%. There was no significant difference in recurrence rate by location of mesh placement (overlay 9.8%, underlay 11.9%) or mesh type (HADM 10.3%, PADM 11.3%). Overlay patients had a significantly lower surgical site infection rate (1.6% vs 11.9% p = 0.03), reported better physical functioning (p = 0.001) and role limitation scores (p = 0.04) in the early postoperative period, and achieved the highest physical functioning score during the 12-month period (p < 0.03). CONCLUSIONS: Recurrence rates were not affected by either anatomic location or type of mesh used. To our knowledge, this represents the first prospective randomized multicenter controlled trial that demonstrates similar clinical outcomes using HADM vs PADM (not inferiority, contrary to previously published literature), with several advantages identified using the overlay technique.

Reactivation of multiple viruses in patients with sepsis.

A current controversy is whether patients with sepsis progress to an immunosuppressed state. We hypothesized that reactivation of latent viruses occurred with prolonged sepsis thereby providing evidence of clinically-relevant immunosuppression and potentially providing a means to serially-monitor patients' immune status. Secondly, if viral loads are markedly elevated, they may contribute to morbidity and mortality. This study determined if reactivation of herpesviruses, polyomaviruses, and the anellovirus TTV occurred in sepsis and correlated with severity. Serial whole blood and plasma samples from 560 critically-ill septic, 161 critically-ill non-septic, and 164 healthy age-matched patients were analyzed by quantitative-polymerase-chain-reaction for cytomegalovirus (CMV), Epstein-Barr (EBV), herpes-simplex (HSV), human herpes virus-6 (HHV-6), and TTV. Polyomaviruses BK and JC were quantitated in urine. Detectable virus was analyzed with respect to secondary fungal and opportunistic bacterial infections, ICU duration, severity of illness, and survival. Patients with protracted sepsis had markedly increased frequency of detectable virus. Cumulative viral DNA detection rates in blood were: CMV (24.2%), EBV (53.2%), HSV (14.1%), HHV-6 (10.4%), and TTV (77.5%). 42.7% of septic patients had presence of two or more viruses. The 50% detection rate for herpesviruses was 5-8 days after sepsis onset. A small subgroup of septic patients had markedly elevated viral loads (>104-106 DNA copies/ml blood) for CMV, EBV, and HSV. Excluding TTV, DNAemia was uncommon in critically-ill non-septic patients and in age-matched healthy controls. Compared to septic patients without DNAemia, septic patients with viremia had increased fungal and opportunistic bacterial infections. Patients with detectable CMV in plasma had higher 90-day mortality compared to CMV-negative patients; p<0.05. Reactivation of latent viruses is common with prolonged sepsis, with frequencies similar to those occurring in transplant patients on immunosuppressive therapy and consistent with development of an immunosuppressive state. Whether reactivated latent viruses contribute to morbidity and mortality in sepsis remains unknown.

Development of an immunoassay for the kidney-specific protein myo-inositol oxygenase, a potential biomarker of acute kidney injury.

BACKGROUND: Acute kidney injury (AKI) affects 45% of critically ill patients, resulting in increased morbidity and mortality. The diagnostic standard, plasma creatinine, is nonspecific and may not increase until days after injury. There is significant need for a renal-specific AKI biomarker detectable early enough that there would be a potential window for therapeutic intervention. In this study, we sought to identify a renal-specific biomarker of AKI. METHODS: We analyzed gene expression data from normal mouse tissues to identify kidney-specific genes, one of which was Miox. We generated monoclonal antibodies to recombinant myo-inositol oxygenase (MIOX) and developed an immunoassay to quantify MIOX in plasma. The immunoassay was tested in animals and retrospectively in patients with and without AKI. RESULTS: Kidney tissue specificity of MIOX was supported by Western blot. Immunohistochemistry localized MIOX to the proximal renal tubule. Serum MIOX, undetectable at baseline, increased 24 h following AKI in mice. Plasma MIOX was increased in critically ill patients with AKI [mean (SD) 12.4 (4.3) ng/mL, n = 42] compared with patients without AKI [0.5 (0.3) ng/mL, n = 17] and was highest in patients with oliguric AKI [20.2 (7.5) ng/mL, n = 23]. Plasma MIOX increased 54.3 (3.8) h before the increase in creatinine. CONCLUSIONS: MIOX is a renal-specific, proximal tubule protein that is increased in serum of animals and plasma of critically ill patients with AKI. MIOX preceded the increases in creatinine concentration by approximately 2 days in human patients. Large-scale studies are warranted to further investigate MIOX as an AKI biomarker.

Targeting the programmed cell death 1: programmed cell death ligand 1 pathway reverses T cell exhaustion in patients with sepsis.

INTRODUCTION: A major pathophysiologic mechanism in sepsis is impaired host immunity which results in failure to eradicate invading pathogens and increased susceptibility to secondary infections. Although many immunosuppressive mechanisms exist, increased expression of the inhibitory receptor programmed cell death 1 (PD-1) and its ligand (PD-L1) are thought to play key roles. The newly recognized phenomenon of T cell exhaustion is mediated in part by PD-1 effects on T cells. This study tested the ability of anti-PD-1 and anti-PD-L1 antibodies to prevent apoptosis and improve lymphocyte function in septic patients. METHODS: Blood was obtained from 43 septic and 15 non-septic critically-ill patients. Effects of anti-PD-1, anti-PD-L1, or isotype-control antibody on lymphocyte apoptosis and interferon gamma (IFN-γ) and interleukin-2 (IL-2) production were quantitated by flow cytometry. RESULTS: Lymphocytes from septic patients produced decreased IFN-γ and IL-2 and had increased CD8 T cell expression of PD-1 and decreased PD-L1 expression compared to non-septic patients (P<0.05). Monocytes from septic patients had increased PD-L1 and decreased HLA-DR expression compared to non-septic patients (P<0.01). CD8 T cell expression of PD-1 increased over time in ICU as PD-L1, IFN-γ, and IL2 decreased. In addition, donors with the highest CD8 PD-1 expression together with the lowest CD8 PD-L1 expression also had lower levels of HLA-DR expression in monocytes, and an increased rate of secondary infections, suggestive of a more immune exhausted phenotype. Treatment of cells from septic patients with anti-PD-1 or anti-PD-L1 antibody decreased apoptosis and increased IFN-γ and IL-2 production in septic patients; (P<0.01). The percentage of CD4 T cells that were PD-1 positive correlated with the degree of cellular apoptosis (P<0.01). CONCLUSIONS: In vitro blockade of the PD-1:PD-L1 pathway decreases apoptosis and improves immune cell function in septic patients. The current results together with multiple positive studies of anti-PD-1 and anti-PD-L1 in animal models of bacterial and fungal infections and the relative safety profile of anti-PD-1/anti-PD-L1 in human oncology trials to date strongly support the initiation of clinical trials testing these antibodies in sepsis, a disorder with a high mortality.