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Objectives: Patients in ICUs are susceptible to subacute potentially catastrophic illnesses such as respiratory failure, sepsis, and hemorrhage that present as severe derangements of vital signs. More subtle physiologic signatures may be present before clinical deterioration, when treatment might be more effective. We performed multivariate statistical analyses of bedside physiologic monitoring data to identify such early subclinical signatures of incipient life-threatening illness., Design: We report a study of model development and validation of a retrospective observational cohort using resampling (Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis type 1b internal validation) and a study of model validation using separate data (type 2b internal/external validation)., Setting: University of Virginia Health System (Charlottesville), a tertiary-care, academic medical center., Patients: Critically ill patients consecutively admitted between January 2009 and June 2015 to either the neonatal, surgical/trauma/burn, or medical ICUs with available physiologic monitoring data., Interventions: None., Measurements and Main Results: We analyzed 146 patient-years of vital sign and electrocardiography waveform time series from the bedside monitors of 9,232 ICU admissions. Calculations from 30-minute windows of the physiologic monitoring data were made every 15 minutes. Clinicians identified 1,206 episodes of respiratory failure leading to urgent unplanned intubation, sepsis, or hemorrhage leading to multi-unit transfusions from systematic individual chart reviews. Multivariate models to predict events up to 24 hours prior had internally validated C-statistics of 0.61-0.88. In adults, physiologic signatures of respiratory failure and hemorrhage were distinct from each other but externally consistent across ICUs. Sepsis, on the other hand, demonstrated less distinct and inconsistent signatures. Physiologic signatures of all neonatal illnesses were similar., Conclusions: Subacute potentially catastrophic illnesses in three diverse ICU populations have physiologic signatures that are detectable in the hours preceding clinical detection and intervention. Detection of such signatures can draw attention to patients at highest risk, potentially enabling earlier intervention and better outcomes.

Importance: The role of cytomegalovirus (CMV) reactivation in mediating adverse clinical outcomes in nonimmunosuppressed adults with critical illness is unknown.Objective: To determine whether ganciclovir prophylaxis reduces plasma interleukin 6 (IL-6) levels in CMV-seropositive adults who are critically ill.Design, Setting, and Participants: Double-blind, placebo-controlled, randomized clinical trial (conducted March 10, 2011-April 29, 2016) with a follow-up of 180 days (November 10, 2016) that included 160 CMV-seropositive adults with either sepsis or trauma and respiratory failure at 14 university intensive care units (ICUs) across the United States.Interventions: Patients were randomized (1:1) to receive either intravenous ganciclovir (5 mg/kg twice daily for 5 days), followed by either intravenous ganciclovir or oral valganciclovir once daily until hospital discharge (n = 84) or to receive matching placebo (n = 76).Main Outcomes and Measures: The primary outcome was change in IL-6 level from day 1 to 14. Secondary outcomes were incidence of CMV reactivation in plasma, mechanical ventilation days, incidence of secondary bacteremia or fungemia, ICU length of stay, mortality, and ventilator-free days (VFDs) at 28 days.Results: Among 160 randomized patients (mean age, 57 years; women, 43%), 156 patients received 1or more dose(s) of study medication, and 132 patients (85%) completed the study. The mean change in plasma IL-6 levels between groups was -0.79 log10 units (-2.06 to 0.48) in the ganciclovir group and -0.79 log10 units (-2.14 to 0.56) in the placebo group (point estimate of difference, 0 [95% CI, -0.3 to 0.3]; P > .99). Among secondary outcomes, CMV reactivation in plasma was significantly lower in the ganciclovir group (12% [10 of 84 patients] vs 39% [28 of 72 patients]); absolute risk difference, -27 (95% CI, -40 to -14), P < .001. The ganciclovir group had more median VFDs in both the intention-to-treat (ITT) group and in the prespecified sepsis subgroup (ITT group: 23 days in ganciclovir group vs 20 days in the placebo group, P = .05; sepsis subgroup, 23 days in the ganciclovir group vs 20 days in the placebo group, P = .03). There were no significant differences between the ganciclovir and placebo groups in duration of mechanical ventilation (5 days for the ganciclovir group vs 6 days for the placebo group, P = .16), incidence of secondary bacteremia or fungemia (15% for the ganciclovir group vs 15% for the placebo group, P = .67), ICU length of stay (8 days for the ganciclovir group vs 8 days for the placebo group, P = .76), or mortality (12% for the ganciclovir group vs 15% for the placebo group, P = .54).Conclusions and Relevance: Among CMV-seropositive adults with critical illness due to sepsis or trauma, ganciclovir did not reduce IL-6 levels and the current study does not support routine clinical use of ganciclovir as a prophylactic agent in patients with sepsis. Additional research is necessary to determine the clinical efficacy and safety of CMV suppression in this setting.Trial Registration: clinicaltrials.gov Identifier: NCT01335932. [ABSTRACT FROM AUTHOR]