BackgroundThe sequential organ failure assessment score (SOFA) is increasingly used as an endpoint in intensive care randomized controlled trials (RCTs). Although serially measured SOFA is independently associated with mortality in observational cohorts, the association between treatment effects on SOFA vs. effects on mortality has not yet been quantified in RCTs. The aim of this study was to quantify the relationship between SOFA and mortality in RCTs and to identify which SOFA derivative best reflects between-group mortality differences.MethodsThe review protocol was prospectively registered (Prospero CRD42016034014). We performed a literature search (up to May 1, 2016) for RCTs reporting both SOFA and mortality, and analyzed between-group differences in these outcomes. Treatment effects on SOFA and mortality were calculated as the between-group SOFA standardized difference and log odds ratio (OR), respectively. We used random-effects meta-regression to (1) quantify the linear relationship between RCT treatment effects on mortality (logOR) and SOFA (i.e. responsiveness) and (2) quantify residual heterogeneity (i.e. consistency, expressed as I 2).ResultsOf 110 eligible RCTs, 87 qualified for analysis. Using all RCTs, SOFA was significantly associated with mortality (slope = 0.49 (95% CI 0.17; 0.82), p = 0.006, I 2 = 5%); the overall mortality effect explained by SOFA score (R 2) was 9%. Fifty-eight RCTs used Fixed-day SOFA as an endpoint (i.e. the score on a fixed day after randomization), 25 studies used Delta SOFA as an endpoint (i.e. the trajectory from baseline score) and 15 studies used other SOFA derivatives as an endpoint. Fixed-day SOFA was not significantly associated with mortality (slope = 0.35 (95% CI −0.04; 0.75), p = 0.08, I 2 = 12%) and explained 3% of the overall mortality effect (R 2). Delta SOFA was significantly associated with mortality (slope = 0.70 (95% CI 0.26; 1.14), p = 0.004, I 2 = 0%) and explained 32% of the overall mortality effect (R 2).ConclusionsTreatment effects on Delta SOFA appear to be reliably and consistently associated with mortality in RCTs. Fixed-day SOFA was the most frequently reported outcome among the reviewed RCTs, but was not significantly associated with mortality. Based on this study, we recommend using Delta SOFA rather than Fixed-day SOFA as an endpoint in future RCTs.Electronic supplementary materialThe online version of this article (doi:10.1186/s13054-017-1609-1) contains supplementary material, which is available to authorized users.

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IMPORTANCE Hyperoxemia may increase organ dysfunction in critically ill patients, but optimal oxygenation targets are unknown.OBJECTIVE To determine whether a low-normal PaO 2 target compared with a high-normal target reduces organ dysfunction in critically ill patients with systemic inflammatory response syndrome (SIRS).DESIGN, SETTING, AND PARTICIPANTS Multicenter randomized clinical trial in 4 intensive care units in the Netherlands. Enrollment was from February 2015 to October 2018, with end of follow-up to January 2019, and included adult patients admitted with 2 or more SIRS criteria and expected stay of longer than 48 hours. A total of 9925 patients were screened for eligibility, of whom 574 fulfilled the enrollment criteria and were randomized.INTERVENTIONS Target PaO 2 ranges were 8 to 12 kPa (low-normal, n = 205) and 14 to 18 kPa (high-normal, n = 195). An inspired oxygen fraction greater than 0.60 was applied only when clinically indicated.MAIN OUTCOMES AND MEASURES Primary end point was SOFA RANK , a ranked outcome of nonrespiratory organ failure quantified by the nonrespiratory components of the Sequential Organ Failure Assessment (SOFA) score, summed over the first 14 study days. Participants were ranked from fastest organ failure improvement (lowest scores) to worsening organ failure or death (highest scores). Secondary end points were duration of mechanical ventilation, in-hospital mortality, and hypoxemic measurements. RESULTS Among the 574 patients who were randomized, 400 (70%) were enrolled within 24 hours (median age, 68 years; 140 women [35%]), all of whom completed the trial. The median PaO 2 difference between the groups was −1.93 kPa (95% CI, −2.12 to −1.74; P < .001). The median SOFA RANK score was −35 points in the low-normal PaO 2 group vs −40 in the high-normal PaO 2 group (median difference, 10 [95% CI, 0 to 21]; P = .06). There was no significant difference in median duration of mechanical ventilation (3.4 vs 3.1 days; median difference, −0.15 [95% CI, −0.88 to 0.47]; P = .59) and in-hospital mortality (32% vs 31%; odds ratio, 1.04 [95% CI, 0.67 to 1.63]; P = .91). Mild hypoxemic measurements occurred more often in the low-normal group (1.9% vs 1.2%; median difference, 0.73 [95% CI, 0.30 to 1.20]; P < .001). Acute kidney failure developed in 20 patients (10%) in the low-normal PaO 2 group and 21 patients (11%) in the high-normal PaO 2 group, and acute myocardial infarction in 6 patients (2.9%) in the low-normal PaO 2 group and 7 patients (3.6%) in the high-normal PaO 2 group.CONCLUSIONS AND RELEVANCE Among critically ill patients with 2 or more SIRS criteria, treatment with a low-normal PaO 2 target compared with a high-normal PaO 2 target did not result in a statistically significant reduction in organ dysfunction. However, the study may have had limited power to detect a smaller treatment effect than was hypothesized.

PurposeAlthough the definition of septic shock has been standardized, some variation in mortality rates among clinical trials is expected. Insights into the sources of heterogeneity may influence the design and interpretation of septic shock studies. We set out to identify inclusion criteria and baseline characteristics associated with between-trial differences in control group mortality rates.MethodsWe conducted a systematic review of RCTs published between 2006 and 2018 that included patients with septic shock. The percentage of variance in control-group mortality attributable to study heterogeneity rather than chance was measured by I2. The association between control-group mortality and population characteristics was estimated using linear mixed models and a recursive partitioning algorithm.ResultsSixty-five septic shock RCTs were included. Overall control-group mortality was 38.6%, with significant heterogeneity (I2 = 93%, P < 0.0001) and a 95% prediction interval of 13.5–71.7%. The mean mortality rate did not differ between trials with different definitions of hypotension, infection or vasopressor or mechanical ventilation inclusion criteria. Population characteristics univariately associated with mortality rates were mean Sequential Organ Failure Assessment score (standardized regression coefficient (β) = 0.57, P = 0.007), mean serum creatinine (β = 0.48, P = 0.007), the proportion of patients on mechanical ventilation (β = 0.61, P < 0.001), and the proportion with vasopressors (β = 0.57, P = 0.002). Combinations of population characteristics selected with a linear model and recursive partitioning explained 41 and 42%, respectively, of the heterogeneity in mortality rates.ConclusionsAmong 65 septic shock trials, there was a clinically relevant amount of heterogeneity in control group mortality rates which was explained only partly by differences in inclusion criteria and reported baseline characteristics.Electronic supplementary materialThe online version of this article (10.1007/s00134-018-5134-8) contains supplementary material, which is available to authorized users.

Background The lateral abdominal wall muscles are recruited with active expiration, as may occur with high breathing effort, inspiratory muscle weakness, or pulmonary hyperinflation. The effects of critical illness and mechanical ventilation on these muscles are unknown. This study aimed to assess the reproducibility of expiratory muscle (i.e., lateral abdominal wall muscles and rectus abdominis muscle) ultrasound and the impact of tidal volume on expiratory muscle thickness, to evaluate changes in expiratory muscle thickness during mechanical ventilation, and to compare this to changes in diaphragm thickness. Methods Two raters assessed the interrater and intrarater reproducibility of expiratory muscle ultrasound (n = 30) and the effect of delivered tidal volume on expiratory muscle thickness (n = 10). Changes in the thickness of the expiratory muscles and the diaphragm were assessed in 77 patients with at least two serial ultrasound measurements in the first week of mechanical ventilation. Results The reproducibility of the measurements was excellent (interrater intraclass correlation coefficient: 0.994 [95% CI, 0.987 to 0.997]; intrarater intraclass correlation coefficient: 0.992 [95% CI, 0.957 to 0.998]). Expiratory muscle thickness decreased by 3.0 ± 1.7% (mean ± SD) with tidal volumes of 481 ± 64 ml (P &lt; 0.001). The thickness of the expiratory muscles remained stable in 51 of 77 (66%), decreased in 17 of 77 (22%), and increased in 9 of 77 (12%) patients. Reduced thickness resulted from loss of muscular tissue, whereas increased thickness mainly resulted from increased interparietal fasciae thickness. Changes in thickness of the expiratory muscles were not associated with changes in the thickness of the diaphragm (R2 = 0.013; P = 0.332). Conclusions Thickness measurement of the expiratory muscles by ultrasound has excellent reproducibility. Changes in the thickness of the expiratory muscles occurred in 34% of patients and were unrelated to changes in diaphragm thickness. Increased expiratory muscle thickness resulted from increased thickness of the fasciae. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

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Background Lung ultrasound can adequately monitor disease severity in pneumonia and acute respiratory distress syndrome. We hypothesize lung ultrasound can adequately monitor COVID-19 pneumonia in critically ill patients. Methods Adult patients with COVID-19 pneumonia admitted to the intensive care unit of two academic hospitals who underwent a 12-zone lung ultrasound and a chest CT examination were included. Baseline characteristics, and outcomes including composite endpoint death or ICU stay > 30 days were recorded. Lung ultrasound and CT images were quantified as a lung ultrasound score involvement index (LUSI) and CT severity involvement index (CTSI). Primary outcome was the correlation, agreement, and concordance between LUSI and CTSI. Secondary outcome was the association of LUSI and CTSI with the composite endpoints. Results We included 55 ultrasound examinations in 34 patients, which were 88% were male, with a mean age of 63 years and mean P/F ratio of 151. The correlation between LUSI and CTSI was strong (r = 0.795), with an overall 15% bias, and limits of agreement ranging − 40 to 9.7. Concordance between changes in sequentially measured LUSI and CTSI was 81%. In the univariate model, high involvement on LUSI and CTSI were associated with a composite endpoint. In the multivariate model, LUSI was the only remaining independent predictor. Conclusions Lung ultrasound can be used as an alternative for chest CT in monitoring COVID-19 pneumonia in critically ill patients as it can quantify pulmonary involvement, register changes over the course of the disease, and predict death or ICU stay > 30 days. Trial registration: NTR, NL8584. Registered 01 May 2020—retrospectively registered, https://www.trialregister.nl/trial/8584