Sepsis: Current Dogma and New Perspectives

Sepsis, a clinical syndrome occurring in patients following infection or injury, is a leading cause of morbidity andmortality worldwide. Current immunological mechanisms do not explain the basis of cellular dysfunction and organ failure, the ultimate cause of death. Here we review current dogma and argue that it is time to delineate novel immunometabolic and neurophysiological mechanisms underlying the altered cellular bioenergetics and failure of epithelial and endothelial barriers that produce organ dysfunction and death. These mechanisms might hold the key to future therapeutic strategies

Ultraviolet television data from the Orbiting Astronomical Observatory. 1: Instrumentation and analysis techniques for the celescope experiment

The celescope instrumentation and data analysis system is described, the major problems encountered during orbital operation are summerized, and a few major problems that were anticipated but did not materialize are listed

The Surviving Sepsis Campaign: Basic/Translational Science Research Priorities∗

© 2020 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved. Objectives: Expound upon priorities for basic/translational science identified in a recent paper by a group of experts assigned by the Society of Critical Care Medicine and the European Society of Intensive Care Medicine. Data Sources: Original paper, search of the literature. Study Selection: By several members of the original task force with specific expertise in basic/translational science. Data Extraction: None. Data Synthesis: None. Conclusions: In the first of a series of follow-up reports to the original paper, several members of the original task force with specific expertise provided a more in-depth analysis of the five identified priorities directly related to basic/translational science. This analysis expounds on what is known about the question and what was identified as priorities for ongoing research. It is hoped that this analysis will aid the development of future research initiatives

Physiologic Response to Angiotensin II Treatment for Coronavirus Disease 2019-Induced Vasodilatory Shock: A Retrospective Matched Cohort Study.

Objectives:To assess the early physiologic response to angiotensin-II treatment in patients with coronavirus disease 2019-induced respiratory failure and distributive shock. Design:Retrospective consecutive-sample cohort study. Setting:Three medical ICUs in New York during the coronavirus disease 2019 outbreak. Patients:All patients were admitted to the ICU with respiratory failure and were receiving norepinephrine for distributive shock. Interventions:The treatment groups were patients who received greater than or equal to 1 hour of angiotensin-II treatment. Time-zero was the time of angiotensin-II initiation. Controls were identified using a 2:1 hierarchical process that matched for 1) date and unit of admission; 2) specific organ support modalities; 3) age; 4) chronic lung, cardiovascular, and kidney disease; and 5) sex. Time-zero in the control group was 21 hours post vasopressor initiation, the mean duration of vasopressor therapy prior to angiotensin-II initiation in the treated group. Measurements and Main Results:Main outcomes were trajectories of vasopressor requirements (in norepinephrine-equivalent dose) and mean arterial pressure. Additionally assessed trajectories were respiratory (Pao2/Fio2, Paco2), metabolic (pH, creatinine), and coagulation (d-dimer) dysfunction indices after time-zero. We also recorded adverse events and clinical outcomes. Trajectories were analyzed using mixed-effects models for immediate (first 6 hr), early (48 hr), and sustained (7 d) responses. Twenty-nine patients (n = 10 treated, n = 19 control) were identified. Despite matching, angiotensin-II-treated patients had markedly greater vasopressor requirements (mean: 0.489 vs 0.097 µg/kg/min), oxygenation impairment, and acidosis at time-zero. Nonetheless, angiotensin-II treatment was associated with an immediate and sustained reduction in norepinephrine-equivalent dose (6 hr model: β = -0.036 µg/kg/min/hr; 95% CI: -0.054 to -0.018 µg/kg/min/hr, p interaction=0.0002) (7 d model: β = -0.04 µg/kg/min/d, 95% CI: -0.05 to -0.03 µg/kg/min/d; p interaction = 0.0002). Compared with controls, angiotensin-II-treated patients had significantly faster improvement in mean arterial pressure, hypercapnia, acidosis, baseline-corrected creatinine, and d-dimer. Three thrombotic events occurred, all in control patients. Conclusions:Angiotensin-II treatment for coronavirus disease 2019-induced distributive shock was associated with rapid improvement in multiple physiologic indices. Angiotensin-II in coronavirus disease 2019-induced shock warrants further study

Mitochondrial dysfunction in peripheral blood mononuclear cells in pediatric septic shock

OBJECTIVES: Mitochondrial dysfunction in peripheral blood mononuclear cells has been linked to immune dysregulation and organ failure in adult sepsis, but pediatric data are limited. We hypothesized that pediatric septic shock patients exhibit mitochondrial dysfunction within peripheral blood mononuclear cells which in turn correlates with global organ injury. DESIGN: Prospective observational study. SETTING: Academic PICU. PATIENTS: Thirteen pediatric patients with septic shock and greater than or equal to two organ failures and 11 PICU controls without sepsis or organ failure. INTERVENTIONS: Ex vivo measurements of mitochondrial oxygen consumption and membrane potential (DeltaPsim) were performed in intact peripheral blood mononuclear cells on day 1-2 and day 5-7 of septic illness and in controls. The Pediatric Logistic Organ Dysfunction score, inotrope score, and organ failure-free days were determined from medical records. MEASUREMENTS AND MAIN RESULTS: Spare respiratory capacity, an index of bioenergetic reserve, was lower in septic peripheral blood mononuclear cells on day 1-2 (median, 1.81; interquartile range, 0.52-2.09 pmol O2/s/10 cells) compared with controls (5.55; 2.80-7.21; p = 0.03). Spare respiratory capacity normalized by day 5-7. Patients with sepsis on day 1-2 exhibited a higher ratio of LEAK to maximal respiration than controls (17% vs \u3c 1%; p = 0.047) with normalization by day 5-7 (1%; p = 0.008), suggesting mitochondrial uncoupling early in sepsis. However, septic peripheral blood mononuclear cells exhibited no differences in basal or adenosine triphosphate-linked oxygen consumption or DeltaPsim. Oxygen consumption did not correlate with Pediatric Logistic Organ Dysfunction score, inotrope score, or organ failure-free days (all p \u3e 0.05). Although there was a weak overall association between DeltaPsim on day 1-2 and organ failure-free days (Spearman rho = 0.56, p = 0.06), patients with sepsis with normal organ function by day 7 exhibited higher DeltaPsim on day 1-2 compared with patients with organ failure for more than 7 days (p = 0.04). CONCLUSIONS: Mitochondrial dysfunction was present in peripheral blood mononuclear cells in pediatric sepsis, evidenced by decreased bioenergetic reserve and increased uncoupling. Mitochondrial membrane potential, but not respiration, was associated with duration of organ injury

Use of Organ Dysfunction as a Primary Outcome Variable Following Cecal Ligation and Puncture: Recommendations for Future Studies

Outcomes variables for research on sepsis have centered on mortality and changes in the host immune response. However, a recent task force (Sepsis-3) revised the definition of sepsis to life-threatening organ dysfunction caused by a dysregulated host response to infection. This new definition suggests that human studies should focus on organ dysfunction. The appropriate criteria for organ dysfunction in either human sepsis or animal models are, however, poorly delineated, limiting the potential for translation. Further, in many systems, the difference between dysfunction and injury may not be clear. In this review, we identify criteria for organ dysfunction and/or injury in human sepsis and in rodents subjected to cecal ligation and puncture (CLP), the most commonly used animal model of sepsis. We further examine instances where overlap between human sepsis and CLP is sufficient to identify translational endpoints. Additional verification may demonstrate that these endpoints are applicable to other animals and to other sepsis models, for example, pneumonia. We believe that the use of these proposed measures of organ dysfunction will facilitate mechanistic studies on the pathobiology of sepsis and enhance our ability to develop animal model platforms to evaluate therapeutic approaches to human sepsis