Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure: The CITRIS-ALI Randomized Clinical Trial.

This article by Fowler et al was published in JAMA during October 2019 in volume 322 issue 13.
Importance:  Experimental data suggest that intravenous vitamin C may attenuate inflammation and vascular injury associated with sepsis and acute respiratory distress syndrome (ARDS).
Objective:  To determine the effect of intravenous vitamin C infusion on organ failure scores and biological markers of inflammation and vascular injury in patients with sepsis and ARDS.
Design, Setting, and Participants:  The CITRIS-ALI trial was a randomized, double-blind, placebo-controlled, multicenter trial conducted in 7 medical intensive care units in the United States, enrolling patients (N = 167) with sepsis and ARDS present for less than 24 hours. The study was conducted from September 2014 to November 2017, and final follow-up was January 2018.InterventionsPatients were randomly assigned to receive intravenous infusion of vitamin C (50 mg/kg in dextrose 5% in water, n = 84) or placebo (dextrose 5% in water only, n = 83) every 6 hours for 96 hours.
Main Outcomes and Measures:  The primary outcomes were change in organ failure as assessed by a modified Sequential Organ Failure Assessment score (range, 0-20, with higher scores indicating more dysfunction) from baseline to 96 hours, and plasma biomarkers of inflammation (C-reactive protein levels) and vascular injury (thrombomodulin levels) measured at 0, 48, 96, and 168 hours.
Results:  Among 167 randomized patients (mean [SD] age, 54.8 years [16.7]; 90 men [54%]), 103 (62%) completed the study to day 60. There were no significant differences between the vitamin C and placebo groups in the primary end points of change in mean modified Sequential Organ Failure Assessment score from baseline to 96 hours (from 9.8 to 6.8 in the vitamin C group [3 points] and from 10.3 to 6.8 in the placebo group [3.5 points]; difference, -0.10; 95% CI, -1.23 to 1.03; P = .86) or in C-reactive protein levels (54.1 vs 46.1 μg/mL; difference, 7.94 μg/mL; 95% CI, -8.2 to 24.11; P = .33) and thrombomodulin levels (14.5 vs 13.8 ng/mL; difference, 0.69 ng/mL; 95% CI, -2.8 to 4.2; P = .70) at 168 hours.
Conclusions and Relevance:  In this preliminary study of patients with sepsis and ARDS, a 96-hour infusion of vitamin C compared with placebo did not significantly improve organ dysfunction scores or alter markers of inflammation and vascular injury. Further research is needed to evaluate the potential role of vitamin C for other outcomes in sepsis and ARDS.
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Rescue stem cell allograft in intensive care unit patients during septic shock with multi-organ failure

This research by Lepretre and colleagues was first published online in the Journal of Critical Care during July 2019.
Purpose:  We describe what we believe to be the first two cases of patients who received an allograft in intensive care unit (ICU) despite severe septic shock with multi-organ failure (MOF).
Results:  One patient had aggressive large B-cell lymphoma. After allograft, the patient initially improved after withdrawing norepinephrine and renal replacement therapy but he subsequently died thirty-two days later because of a new relapse of the disease. The second patient had acute myeloid leukemia type 1 with a need for an allograft after a first complete remission. She was discharged from ICU at D23 after allograft and still alive 7 months later with complete remission. For the two patients, allograft conditioning was performed before admission to our ICU. These two cases highlight one major problem in such situations which is to find the best time to perform the allograft, particularly in ventilated patients with septic shock and MOF. We performed the allograft when we thought that the risk-benefit ratio was in favor of restoring immunity.
Conclusion:  Allograft should be considered as a rescue therapy in ICU for patients with aplasia, during septic shock with multi-organ failure, however close multidisciplinary discussion is required between intensivists and onco-hematologists.
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A Comparison of the Quick Sequential (Sepsis-Related) Organ Failure Assessment Score and the National Early Warning Score in Non-ICU Patients With/Without Infection

This research by Redfern and colleagues was published in Critical Care Medicine in August 2018.
Objectives:  The Sepsis-3 task force recommended the quick Sequential (Sepsis-Related) Organ Failure Assessment score for identifying patients with suspected infection who are at greater risk of poor outcomes, but many hospitals already use the National Early Warning Score to identify high-risk patients, irrespective of diagnosis. We sought to compare the performance of quick Sequential (Sepsis-Related) Organ Failure Assessment and National Early Warning Score in hospitalized, non-ICU patients with and without an infection.
Design:  Retrospective cohort study.  Setting:  Large U.K. General Hospital.
Patients:  Adults hospitalized between January 1, 2010, and February 1, 2016.
Measurement and main results:  We applied the quick Sequential (Sepsis-Related) Organ Failure Assessment score and National Early Warning Score to 5,435,344 vital signs sets (241,996 hospital admissions). Patients were categorized as having no infection, primary infection, or secondary infection using International Classification of Diseases, 10th Edition codes. National Early Warning Score was significantly better at discriminating in-hospital mortality, irrespective of infection status (no infection, National Early Warning Score 0.831 [0.825-0.838] vs quick Sequential [Sepsis-Related] Organ Failure Assessment 0.688 [0.680-0.695]; primary infection, National Early Warning Score 0.805 [0.799-0.812] vs quick Sequential [Sepsis-Related] Organ Failure Assessment 0.677 [0.670-0.685]). Similarly, National Early Warning Score performed significantly better in all patient groups (all admissions, emergency medicine admissions, and emergency surgery admissions) for all outcomes studied. Overall, quick Sequential (Sepsis-Related) Organ Failure Assessment performed no better, and often worse, in admissions with infection than without.
Conclusions:  The National Early Warning Score outperforms the quick Sequential (Sepsis-Related) Organ Failure Assessment score, irrespective of infection status. These findings suggest that quick Sequential (Sepsis-Related) Organ Failure Assessment should be re-evaluated as the system of choice for identifying non-ICU patients with suspected infection who are at greater risk of poor outcome.
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Serial Daily Organ Failure Assessment Beyond ICU Day 5 Does Not Independently Add Precision to ICU Risk-of-Death Prediction.

This research was published by Holder et al in the September 2017 issue of Critical Care Medicine.

Objectives:  To identify circumstances in which repeated measures of organ failure would improve mortality prediction in ICU patients.

Design:  Retrospective cohort study, with external validation in a deidentified ICU database.

Setting:  Eleven ICUs in three university hospitals within an academic healthcare system in 2014.

Patient:  Adults (18 yr old or older) who satisfied the following criteria: 1) two of four systemic inflammatory response syndrome criteria plus an ordered blood culture, all within 24 hours of hospital admission; and 2) ICU admission for at least 2 calendar days, within 72 hours of emergency department presentation.

Intervention:  None

Measurement and Main Results:  Data were collected until death, ICU discharge, or the seventh ICU day, whichever came first. The highest Sequential Organ Failure Assessment score from the ICU admission day (ICU day 1) was included in a multivariable model controlling for other covariates. The worst Sequential Organ Failure Assessment scores from the first 7 days after ICU admission were incrementally added and retained if they obtained statistical significance (p < 0.05). The cohort was divided into seven subcohorts to facilitate statistical comparison using the integrated discriminatory index. Of the 1,290 derivation cohort patients, 83 patients (6.4%) died in the ICU, compared with 949 of the 8,441 patients (11.2%) in the validation cohort. Incremental addition of Sequential Organ Failure Assessment data up to ICU day 5 improved the integrated discriminatory index in the validation cohort. Adding ICU day 6 or 7 Sequential Organ Failure Assessment data did not further improve model performance.

Conclusions:  Serial organ failure data improve prediction of ICU mortality, but a point exists after which further data no longer improve ICU mortality prediction of early sepsis.

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Early intervention of patients at risk for acute respiratory failure and prolonged mechanical ventilation with a checklist aimed at the prevention of organ failure

Gong, M.N. et al. BMJ Open. 2016. 6:e011347

Introduction: Acute respiratory failure (ARF) often presents and progresses outside of the intensive care unit. However, recognition and treatment of acute critical illness is often delayed with inconsistent adherence to evidence-based care known to decrease the duration of mechanical ventilation (MV) and complications of critical illness. The goal of this trial is to determine whether the implementation of an electronic medical record-based early alert for progressive respiratory failure coupled with a checklist to promote early compliance to best practice in respiratory failure can improve the outcomes of patients at risk for prolonged respiratory failure and death.

Methods and analysis: A pragmatic stepped-wedged cluster clinical trial involving 6 hospitals is planned. The study will include adult hospitalised patients identified as high risk for MV >48 hours or death because they were mechanically ventilated outside of the operating room or they were identified as high risk for ARF on the Accurate Prediction of PROlonged VEntilation (APPROVE) score. Patients with advanced directives limiting intubation will be excluded. The intervention will consist of (1) automated identification and notification of clinician of high-risk patients by APPROVE or by invasive MV and (2) checklist of evidence-based practices in ARF (Prevention of Organ Failure Checklist—PROOFCheck). APPROVE and PROOFCheck will be developed in the pretrial period. Primary outcome is hospital mortality. Secondary outcomes include length of stay, ventilator and organ failure-free days and 6-month and 12-month mortality. Predefined subgroup analysis of patients with limitation of aggressive care after study entry is planned. Generalised estimating equations will be used to compare patients in the intervention phase with the control phase, adjusting for clustering within hospitals and time.

Ethics and dissemination: The study was approved by the institutional review boards. Results will be published in peer-reviewed journals and presented at international meetings.

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Multiple organ dysfunction syndrome in critically ill children: clinical value of two lists of diagnostic criteria

Villeneuve, A. et al. Annals of Intensive Care2016. 6:40.

Background: Two sets of diagnostic criteria of paediatric multiple organ dysfunction syndrome (MODS) were published by Proulx in 1996 and by Goldstein in 2005. We hypothesized that this changes the epidemiology of MODS. Thus, we determined the epidemiology of MODS, according to these two sets of diagnostic criteria, we studied the intra- and inter-observer reproducibility of each set of diagnostic criteria, and we compared the association between cases of MODS at paediatric intensive care unit (PICU) entry, as diagnosed by each set of diagnostic criteria, and 90-day all-cause mortality.

Methods: All consecutive patients admitted to the tertiary care PICU of Sainte-Justine Hospital, from April 21, 2009 to April 20, 2010, were considered eligible for enrolment into this prospective observational cohort study. The exclusion criteria were gestational age < 40 weeks, age < 3 days or > 18 years at PICU entry, pregnancy, admission immediately after delivery. No patients were censored. Daily monitoring using medical chart ended when the patient died or was discharged from PICU. Mortality was monitored up to death, hospital discharge, or 90 days post PICU entry, whatever happened first. Concordance rate and kappa score were calculated to assess reproducibility. The number of MODS identified with Proulx and Goldstein definitions was compared using 2-by-2 contingency tables. Student’s t test or Wilcoxon signed-ranked test was used to compare continuous variables with normal or abnormal distribution, respectively. We performed a Kaplan–Meier survival analysis to assess the association between MODS at PICU entry and 90-day mortality.

Results: The occurrence of MODS was monitored daily and prospectively in 842 consecutive patients admitted to the PICU of Sainte-Justine Hospital over 1 year. According to Proulx and Goldstein diagnostic criteria, 180 (21.4 %) and 314 patients (37.3 %) had MODS over PICU stay, respectively. Concordance of MODS diagnosis over PICU stay was 81.3 % (95 % CI 78.6–83.9 %), and kappa score was 0.56 (95 % CI 0.50–0.61). Discordance was mainly attributable to cardiovascular or neurological dysfunction criteria. The proportion of patients with MODS at PICU entry who died within 90 days was higher with MODS diagnosed with Proulx criteria (17.8 vs. 11.5 %, p = 0.038), as well as the likelihood ratio of death (4.84 vs. 2.37). On the other hand, 90-day survival rate of patients without MODS at PICU entry was similar (98.6 vs. 98.9 % (p = 0.73).

Conclusions: Proulx and Goldstein diagnostic criteria of paediatric MODS are not equivalent. The epidemiology of paediatric MODS varies depending on which set of diagnostic criteria is applied.

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