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OBJECTIVES: Randomized clinical trials (RCTs) conducted in adult ICU patients increasingly include patient-important outcomes other than mortality. This comes with challenges regarding outcome choices/definitions, handling of deceased patients and missing data in analyses, and choices of effect measures and statistical methods due to complex distributions. This scoping review aimed to characterize how these challenges are handled in relevant contemporary RCTs.DATA SOURCES: We systematically searched 10 selected journals for RCTs conducted primarily in adult ICU patients published between 1 January 2018 and 5 May 2022 reporting at least one patient-important outcome other than mortality, including "days alive without"…-type outcomes, functional/cognitive/neurologic outcomes, health-related quality of life (HRQoL) outcomes, and ordinal/other outcomes.STUDY SELECTION: Abstracts and full-texts were assessed independently and in duplicate by two reviewers.DATA EXTRACTION: Data were extracted independently and in duplicate by two reviewers using predefined and pilot-tested extraction forms and subsequently categorized to facilitate analysis.DATA SYNTHESIS: We included 687 outcomes from 167 RCTs, with 32% of RCTs using a patient-important outcome other than mortality as a (co-)primary outcome, most frequently "days alive without"…-type outcomes. Many different functional/cognitive/neurologic (103) and HRQoL (29) outcomes were reported. Handling of deceased patients varied, with analyses frequently restricted to survivors only for functional/cognitive/neurologic (62%) and HRQoL (89%) outcomes. Follow-up was generally longer and missing data proportions higher for functional/cognitive/neurologic and HRQoL outcomes. Most outcomes were analyzed using nonparametric tests (31%), linear regression/t tests (27%), chi-square-like tests (12%), and proportional odds logistic regression (9%), often without presentation of actual treatment effects estimates (38%).CONCLUSIONS: In this sample of RCTs, substantial variation in practice and suboptimal methodological choices were observed. This calls for increased focus on standardizing outcome choices and definitions, adequate handling of missing data and deceased patients in analyses, and use of statistical methods quantifying effect sizes.

Supplemental Digital Content is available in the text., Objectives: Caregivers use clinical examination to timely recognize deterioration of a patient, yet data on the prognostic value of clinical examination are inconsistent. In the Simple Intensive Care Studies-I, we evaluated the association of clinical examination findings with 90-day mortality in critically ill patients. Design: Prospective single-center cohort study. Setting: ICU of a single tertiary care level hospital between March 27, 2015, and July 22, 2017. Patients: All consecutive adults acutely admitted to the ICU and expected to stay for at least 24 hours. Interventions: A protocolized clinical examination of 19 clinical signs conducted within 24 hours of admission. Measurements Main Results: Independent predictors of 90-day mortality were identified using multivariable logistic regression analyses. Model performance was compared with established prognostic risk scores using area under the receiver operating characteristic curves. Robustness of our findings was tested by internal bootstrap validation and adjustment of the threshold for statistical significance. A total of 1,075 patients were included, of whom 298 patients (28%) had died at 90-day follow-up. Multivariable analyses adjusted for age and norepinephrine infusion rate demonstrated that the combination of higher respiratory rate, higher systolic blood pressure, lower central temperature, altered consciousness, and decreased urine output was independently associated with 90-day mortality (area under the receiver operating characteristic curves = 0.74; 95% CI, 0.71–0.78). Clinical examination had a similar discriminative value as compared with the Simplified Acute Physiology Score-II (area under the receiver operating characteristic curves = 0.76; 95% CI, 0.73–0.79; p = 0.29) and Acute Physiology and Chronic Health Evaluation-IV (using area under the receiver operating characteristic curves = 0.77; 95% CI, 0.74–0.80; p = 0.16) and was significantly better than the Sequential Organ Failure Assessment (using area under the receiver operating characteristic curves = 0.67; 95% CI, 0.64–0.71; p < 0.001). Conclusions: Clinical examination has reasonable discriminative value for assessing 90-day mortality in acutely admitted ICU patients. In our study population, a single, protocolized clinical examination had similar prognostic abilities compared with the Simplified Acute Physiology Score-II and Acute Physiology and Chronic Health Evaluation-IV and outperformed the Sequential Organ Failure Assessment score.

Objectives We investigated whether preexisting kidney function determines if ICU patients may benefit from increased (2.0 g/kg/d) protein intake. Design Post hoc, hypothesis-generating, subgroup analysis of a multicenter, phase 2, randomized clinical trial. All analyses were conducted by intention to treat and maintained group allocation. Ninety-day mortality was the primary outcome. Setting ICUs of 16 hospitals throughout Australia and New Zealand. Patients Adult critically ill patients expected to remain in the study ICU for longer than 2 days. Interventions Random allocation to receive a daily supplement of up to 100 g of IV amino acids to achieve a total protein intake of 2.0 g/kg/d or standard nutrition care. Measurements and main results A total of 474 patients were randomized: 235 to standard care and 239 to IV amino acid supplementation. There was a statistically significant interaction between baseline kidney function and supplementation with study amino acids (p value for interaction = 0.026). Within the subgroup of patients with normal kidney function at randomization, patients who were allocated to receive the study amino acid supplement were less likely to die before study day 90 (covariate-adjusted risk difference, -7.9%; 95% CI, -15.1 to -0.7; p = 0.034). Furthermore, amino acid supplementation significantly increased estimated glomerular filtration rate in these patients (repeated-measures treatment × time interaction p = 0.009). Within the subgroup of patients with baseline kidney dysfunction and/or risk of progression of acute kidney injury, a significant effect of the study intervention on mortality was not found (covariate-adjusted risk difference, -0.6%; 95% CI, -16.2 to 15.2; p = 0.95). Conclusions In this post hoc, hypothesis-generating, subgroup analysis, we observed reduced mortality and improved estimated glomerular filtration rate in ICU patients with normal kidney function who were randomly allocated to receive increased protein intake (up to 2.0 g/kg/d). We strongly recommend confirmation of these results in trials with low risk of bias before this treatment is recommended for routine care.

Objective:To provide an update to “Surviving Sepsis Campaign Guidelines for Management of Sepsis and Septic Shock: 2012.”Design:A consensus committee of 55 international experts representing 25 international organizations was convened. Nominal groups were assembled at key international meetings (for

ICU admission is associated with decreased physical function for years after discharge. The underlying mechanisms responsible for this muscle function impairment are undescribed. The aim of this study was to describe the biomechanical properties of the quadriceps muscle in ICU survivors 12 months after ICU discharge.Case-control study with consecutive inclusion of ICU survivors and age- and sex-matched controls.Patients were treated at a mixed 18-bed ICU at a tertiary care university hospital and tested at a biomechanical university laboratory.We included 16 male ICU patients (Acute Physiology and Chronic Health Evaluation II score 20 ± 7, mean ± SD), who had stayed in the ICU72 hrs and survived to 12 months and 15 age- and sex-matched controls.None.An extensive battery of biomechanical tests, including maximum, fast, and endurance contractions, was administered during isometric knee extensions while simultaneously recording surface electromyography (quadriceps and hamstrings). Compared to controls, ICU survivors had reduced maximal voluntary torque (22%, 179 ± 64 Nm vs. 230 ± 57 Nm, p = 0.03), absolute rate of force development (50%, 868 ± 372 Nm/sec vs. 1739 ± 470 Nm/sec, p0.001) and relative rate of force development (32%, 512 ± 260% maximum voluntary contraction/sec vs. 754 ± 189% maximum voluntary contraction/sec, p0.01), and endurance time (40%, 136 ± 84 sec vs. 226 ± 111 sec, p0.02). Rate of force development, but not maximal voluntary torque, was significantly reduced after adjusting for muscle mass. Electromyography data indicated no impairment of motor activation strategy or central motor drive. Also, no difference in reaction time was found between patients and controls.ICU survivors had reduced rate of force development and muscular endurance 1 yr after ICU discharge. Our data indicate that the functional deficits experienced by ICU survivors originate in muscle tissue rather than the nervous system. Also, increased attention to velocity-orientated exercise during rehabilitation of ICU patients may have the potential to better physical outcome after critical illness.

High patient age is a strong predictor of poor outcome in trauma patients. The present study investigated the effect of age on mortality and biomarkers of sympathoadrenal activation, tissue, endothelial, and glycocalyx damage, coagulation activation/inhibition, fibrinolysis, and inflammation in trauma patients at admission.Prospective observational study.Single level I trauma center.Eighty adult trauma patients (≥18 yrs) who met criteria for full trauma team activation and had an arterial cannula.Blood sampling a median of 68 min (interquartile range 48-88) post injury.Data on demography, biochemistry, Injury Severity Score, and 30-day mortality were recorded and plasma/serum was analyzed for biomarkers reflecting sympathoadrenal activation (adrenaline, noradrenaline), tissue/endothelial cell/glycocalyx damage (histone-complexed DNA fragments, annexin V, thrombomodulin, syndecan-1), platelet activation (soluble CD40 ligand), coagulation activation/inhibition (prothrombin fragment 1.2, thrombin/antithrombin complex, antithrombin, protein C, activated protein C, protein S, soluble endothelial protein C receptor, tissue factor pathway inhibitor, von Willebrand factor, fibrinogen, factor XIII), fibrinolysis (D-dimer, tissue-type plasminogen activator, plasminogen activator inhibitor-1), and inflammation (interleukin-6, terminal complement complex). Patients were stratified according to the median age (46 yrs) of the full cohort.Older trauma patients had markedly higher noradrenaline (p.001) but an attenuated increase in adrenaline with increasing Injury Severity Score and lower platelets and leukocytes (both p.05) compared to the younger patients. Older patients displayed a biomarker profile suggestive of enhanced release, activation, and consumption of the natural anticoagulants (low antithrombin, high activated protein C, protein S, and tissue factor pathway inhibitor) and hyperfibrinolysis (high tissue-type plasminogen activator) (all p.05 vs. younger patients). Age was an independent predictor of mortality (hazard ratio 1.04 [95% confidence interval 1.01-1.07], p = .005) after adjusting for Injury Severity Score, prehospital Glasgow Coma Scale, and plasma catecholamines.In trauma patients, the association between age and mortality was confirmed. Older patients had high plasma noradrenaline but attenuated adrenaline release with higher Injury Severity Score, impaired platelet and leukocyte mobilization, enhanced consumption of anticoagulants, and hyperfibrinolysis, which may all contribute to the poor outcome in these patients.