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The role of NIGMS P50 sponsored team science in our understanding of multiple organ failure.

ABSTRACT: The history of the National Institute of General Medical Sciences (NIGMS) Research Centers in Peri-operative Sciences (RCIPS) is the history of clinical, translational, and basic science research into the etiology and treatment of posttraumatic multiple organ failure (MOF). Born out of the activism of trauma and burn surgeons after the Viet Nam War, the P50 trauma research centers have been a nidus of research advances in the field and the training of future academic physician-scientists in the fields of trauma, burns, sepsis, and critical illness. For over 40 years, research conducted under the aegis of this funding program has led to numerous contributions at both the bedside and at the bench. In fact, it has been this requirement for team science with a clinician-scientist working closely with basic scientists from multiple disciplines that has led the RCIPS to its unrivaled success in the field. This review will briefly highlight some of the major accomplishments of the RCIPS program since its inception, how they have both led and evolved as the field moved steadily forward, and how they are responsible for much of our current understanding of the etiology and pathology of MOF. This review is not intended to be all encompassing nor a historical reference. Rather, it serves as recognition to the foresight and support of many past and present individuals at the NIGMS and at academic institutions who have understood the cost of critical illness and MOF to the individual and to society.

SUBMITTER: Moore FA

PROVIDER: S-EPMC5573617 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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The role of NIGMS P50 sponsored team science in our understanding of multiple organ failure.

Moore Frederick A FA Moore Ernest E EE Billiar Timothy R TR Vodovotz Yoram Y Banerjee Anirban A Moldawer Lyle L LL

The journal of trauma and acute care surgery 20170901 3

The history of the National Institute of General Medical Sciences (NIGMS) Research Centers in Peri-operative Sciences (RCIPS) is the history of clinical, translational, and basic science research into the etiology and treatment of posttraumatic multiple organ failure (MOF). Born out of the activism of trauma and burn surgeons after the Viet Nam War, the P50 trauma research centers have been a nidus of research advances in the field and the training of future academic physician-scientists in the ...[more]

PMID: 28538636

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Project description:The impact of extrapulmonary organ dysfunction, independent from sepsis and lung injury severity, on outcomes in pediatric acute respiratory failure is unclear. We sought to determine the frequency, timing, and risk factors for extrapulmonary organ dysfunction and the independent association of multiple organ dysfunction syndrome with outcomes in pediatric acute respiratory failure.Secondary observational analysis of the Randomized Evaluation of Sedation Titration for Respiratory Failure cluster-randomized prospective clinical trial conducted between 2009 and 2013.Thirty-one academic PICUs in the United States.Two thousand four hundred forty-nine children mechanically ventilated for acute respiratory failure enrolled in Randomized Evaluation of Sedation Titration for Respiratory Failure.Organ dysfunction was defined using criteria published for pediatric sepsis. Multiple organ dysfunction syndrome was defined as respiratory dysfunction one or more extrapulmonary organ dysfunctions. We used multivariable logistic regression to identify risk factors for multiple organ dysfunction syndrome, and logistic or proportional hazards regression to compare clinical outcomes. All analyses accounted for PICU as a cluster variable. Overall, 73% exhibited extrapulmonary organ dysfunction, including 1,547 (63%) with concurrent multiple organ dysfunction syndrome defined by onset on day 0/1 and 244 (10%) with new multiple organ dysfunction syndrome with onset on day 2 or later. Most patients (93%) with indirect lung injury from sepsis presented with concurrent multiple organ dysfunction syndrome, whereas patients with direct lung injury had both concurrent (56%) and new (12%) multiple organ dysfunction syndrome. Risk factors for concurrent multiple organ dysfunction syndrome included older age, illness severity, sepsis, cancer, and moderate/severe lung injury. Risk factors for new multiple organ dysfunction syndrome were moderate/severe lung injury and neuromuscular blockade. Both concurrent and new multiple organ dysfunction syndrome were associated with 90-day in-hospital mortality (concurrent: adjusted odds ratio, 6.54; 95% CI, 3.00-14.25 and new: adjusted odds ratio, 3.21; 95% CI, 1.48-6.93) after adjusting for sepsis, moderate/severe lung injury, and other baseline characteristics.Extrapulmonary organ dysfunction was common, generally occurred concurrent with respiratory dysfunction (especially in sepsis), and was a major risk factor for mortality in pediatric acute respiratory failure.

Project description:ContextSevere sepsis is typically characterized by initial cytokine-mediated hyperinflammation. Whether this hyperinflammatory phase is followed by immunosuppression is controversial. Animal studies suggest that multiple immune defects occur in sepsis, but data from humans remain conflicting.ObjectivesTo determine the association of sepsis with changes in host innate and adaptive immunity and to examine potential mechanisms for putative immunosuppression.Design, setting, and participantsRapid postmortem spleen and lung tissue harvest was performed at the bedsides of 40 patients who died in intensive care units (ICUs) of academic medical centers with active severe sepsis to characterize their immune status at the time of death (2009-2011). Control spleens (n = 29) were obtained from patients who were declared brain-dead or had emergent splenectomy due to trauma; control lungs (n = 20) were obtained from transplant donors or from lung cancer resections.Main outcome measuresCytokine secretion assays and immunophenotyping of cell surface receptor-ligand expression profiles were performed to identify potential mechanisms of immune dysfunction. Immunohistochemical staining was performed to evaluate the loss of immune effector cells.ResultsThe mean ages of patients with sepsis and controls were 71.7 (SD, 15.9) and 52.7 (SD, 15.0) years, respectively. The median number of ICU days for patients with sepsis was 8 (range, 1-195 days), while control patients were in ICUs for 4 or fewer days. The median duration of sepsis was 4 days (range, 1-40 days). Compared with controls, anti-CD3/anti-CD28-stimulated splenocytes from sepsis patients had significant reductions in cytokine secretion at 5 hours: tumor necrosis factor, 5361 (95% CI, 3327-7485) pg/mL vs 418 (95% CI, 98-738) pg/mL; interferon γ, 1374 (95% CI, 550-2197) pg/mL vs 37.5 (95% CI, -5 to 80) pg/mL; interleukin 6, 3691 (95% CI, 2313-5070) vs 365 (95% CI, 87-642) pg/mL; and interleukin 10, 633 (95% CI, -269 to 1534) vs 58 (95% CI, -39 to 156) pg/mL; (P < .001 for all). There were similar reductions in 5-hour lipopolysaccharide-stimulated cytokine secretion. Cytokine secretion in sepsis patients was generally less than 10% that in controls, independent of age, duration of sepsis, corticosteroid use, and nutritional status. Although differences existed between spleen and lung, flow cytometric analysis showed increased expression of selected inhibitory receptors and ligands and expansion of suppressor cell populations in both organs. Unique differences in cellular inhibitory molecule expression existed in immune cells isolated from lungs of sepsis patients vs cancer patients and vs transplant donors. Immunohistochemical staining showed extensive depletion of splenic CD4, CD8, and HLA-DR cells and expression of ligands for inhibitory receptors on lung epithelial cells.ConclusionsPatients who die in the ICU following sepsis compared with patients who die of nonsepsis etiologies have biochemical, flow cytometric, and immunohistochemical findings consistent with immunosuppression. Targeted immune-enhancing therapy may be a valid approach in selected patients with sepsis.

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The role of NIGMS P50 sponsored team science in our understanding of multiple organ failure.

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The role of NIGMS P50 sponsored team science in our understanding of multiple organ failure.

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