Sepsis-associated acute kidney injury in patients with chronic kidney disease: Patient characteristics, prevalence, timing, trajectory, treatment and associated outcomes.

AIM: The features and outcomes of sepsis-associated acute kidney injury (SA-AKI) may be affected by chronic kidney disease (CKD). Accordingly, we aimed to compare SA-AKI in patients with or without CKD. METHODS: Retrospective cohort study in 12 intensive care units (ICU). We studied the prevalence, patient characteristics, timing, trajectory, treatment and outcomes of SA-AKI with and without CKD. RESULTS: Of 84 240 admissions, 7255 (8.6%) involved patients with CKD. SA-AKI was more common in patients with CKD (21% vs 14%; p < .001). CKD patients were older (70 vs. 60 years; p < .001), had a higher median Charlson co-morbidity index (5 vs. 3; p < .001) and acute physiology and chronic health evaluation (APACHE) III score (78 vs. 60; p < .001) and were more likely to receive renal replacement therapy (RRT) (25% vs. 17%; p < .001). They had less complete return to baseline function at ICU discharge (48% vs. 60%; p < .001), higher major adverse kidney events at day 30 (MAKE-30) (38% vs. 27%; p < .001), and higher hospital and 90-day mortality (21% vs. 13%; p < .001, and 27% vs. 16%; p < .001, respectively). After adjustment for patient characteristics and severity of illness, however, CKD was not an independent risk factor for increased 90-day mortality (OR 0.88; 95% CI 0.76-1.02; p = .08) or MAKE-30 (OR 0.98; 95% CI 0.80-1.09; p = .4). CONCLUSION: SA-AKI is more common in patients with CKD. Such patients are older, more co-morbid, have higher disease severity, receive different ICU therapies and have different trajectories of renal recovery and greater unadjusted mortality. However, after adjustment day-90 mortality and MAKE-30 risk were not increased by CKD.

Assessment of fluid responsiveness using pulse pressure variation, stroke volume variation, plethysmographic variability index, central venous pressure, and inferior vena cava variation in patients undergoing mechanical ventilation: a systematic review and meta-analysis.

IMPORTANCE: Maneuvers assessing fluid responsiveness before an intravascular volume expansion may limit useless fluid administration, which in turn may improve outcomes. OBJECTIVE: To describe maneuvers for assessing fluid responsiveness in mechanically ventilated patients. REGISTRATION: The protocol was registered at PROSPERO: CRD42019146781. INFORMATION SOURCES AND SEARCH: PubMed, EMBASE, CINAHL, SCOPUS, and Web of Science were search from inception to 08/08/2023. STUDY SELECTION AND DATA COLLECTION: Prospective and intervention studies were selected. STATISTICAL ANALYSIS: Data for each maneuver were reported individually and data from the five most employed maneuvers were aggregated. A traditional and a Bayesian meta-analysis approach were performed. RESULTS: A total of 69 studies, encompassing 3185 fluid challenges and 2711 patients were analyzed. The prevalence of fluid responsiveness was 49.9%. Pulse pressure variation (PPV) was studied in 40 studies, mean threshold with 95% confidence intervals (95% CI) = 11.5 (10.5-12.4)%, and area under the receiver operating characteristics curve (AUC) with 95% CI was 0.87 (0.84-0.90). Stroke volume variation (SVV) was studied in 24 studies, mean threshold with 95% CI = 12.1 (10.9-13.3)%, and AUC with 95% CI was 0.87 (0.84-0.91). The plethysmographic variability index (PVI) was studied in 17 studies, mean threshold = 13.8 (12.3-15.3)%, and AUC was 0.88 (0.82-0.94). Central venous pressure (CVP) was studied in 12 studies, mean threshold with 95% CI = 9.0 (7.7-10.1) mmHg, and AUC with 95% CI was 0.77 (0.69-0.87). Inferior vena cava variation (∆IVC) was studied in 8 studies, mean threshold = 15.4 (13.3-17.6)%, and AUC with 95% CI was 0.83 (0.78-0.89). CONCLUSIONS: Fluid responsiveness can be reliably assessed in adult patients under mechanical ventilation. Among the five maneuvers compared in predicting fluid responsiveness, PPV, SVV, and PVI were superior to CVP and ∆IVC. However, there is no data supporting any of the above mentioned as being the best maneuver. Additionally, other well-established tests, such as the passive leg raising test, end-expiratory occlusion test, and tidal volume challenge, are also reliable.

High PEEP with recruitment maneuvers versus Low PEEP During General Anesthesia for Surgery - a Bayesian individual patient data meta-analysis of three randomized clinical trials.

BACKGROUND: The influence of high positive end-expiratory pressure (PEEP) with recruitment maneuvers on the occurrence of postoperative pulmonary complications after surgery is still not definitively established. Bayesian analysis can help to gain further insights from the available data and provide a probabilistic framework that is easier to interpret. Our objective was to estimate the posterior probability that the use of high PEEP with recruitment maneuvers is associated with reduced postoperative pulmonary complications in patients with intermediate-to-high risk under neutral, pessimistic, and optimistic expectations regarding the treatment effect. METHODS: Multilevel Bayesian logistic regression analysis on individual patient data from three randomized clinical trials carried out on surgical patients at Intermediate-to-High Risk for postoperative pulmonary complications. The main outcome was the occurrence of postoperative pulmonary complications in the early postoperative period. We studied the effect of high PEEP with recruitment maneuvers versus Low PEEP Ventilation. Priors were chosen to reflect neutral, pessimistic, and optimistic expectations of the treatment effect. RESULTS: Using a neutral, pessimistic, or optimistic prior, the posterior mean odds ratio (OR) for High PEEP with recruitment maneuvers compared to Low PEEP was 0.85 (95% Credible Interval [CrI] 0.71 to 1.02), 0.87 (0.72 to 1.04), and 0.86 (0.71 to 1.02), respectively. Regardless of prior beliefs, the posterior probability of experiencing a beneficial effect exceeded 90%. Subgroup analysis indicated a more pronounced effect in patients who underwent laparoscopy (OR: 0.67 [0.50 to 0.87]) and those at high risk for PPCs (OR: 0.80 [0.53 to 1.13]). Sensitivity analysis, considering severe postoperative pulmonary complications only or applying a different heterogeneity prior, yielded consistent results. CONCLUSION: High PEEP with recruitment maneuvers demonstrated a moderate reduction in the probability of PPC occurrence, with a high posterior probability of benefit observed consistently across various prior beliefs, particularly among patients who underwent laparoscopy.

Association of Age, Frailty, and Strategy for Initiation of Renal-Replacement Therapy: A Post Hoc analysis of the STARRT-Acute Kidney Injury Trial.

INTRODUCTION: This study was designed to assess the association of age and frailty with clinical outcomes in patients with severe acute kidney injury (AKI), according to accelerated and standard renal-replacement therapy (RRT) initiation strategies in the STARRT-AKI trial. METHODS: This was a secondary analysis of an international randomized trial. Older age was defined as ≥65 years. Frailty was assessed using the clinical frailty scale (CFS) score and defined as a score ≥5. The primary outcome was all-cause mortality at 90 days. Secondary outcomes included RRT dependence and RRT-free days at 90 days. We used logistic and linear regression and interaction testing to explore the impact of age and frailty on clinical outcomes. RESULTS: Of 2,927 patients randomized in the STARRT-AKI trial, 1,616 (55.2%) were aged ≥65 years (median [interquartile range] 73.9 [69.4-78.9]). Older patients had greater comorbid cardiovascular and chronic kidney disease, were more likely to be surgical admissions and to receive vasopressors at baseline. Older patients had higher 90-day mortality (50.4% vs. 35.6%, adjusted-odds ratio (OR), 1.81 [1.53-2.13], p < 0.001). There was no significant difference in RRT dependence at 90 days between older and younger patients (8.7% vs. 7.8%, adjusted-OR, 1.21 [0.82-1.79], p = 0.325). Patients with frailty had higher mortality; but no difference in RRT dependence at 90 days. There was no significant interaction between age and CFS score in relation to mortality, RRT dependence at 90 days, and other secondary outcomes. There was no significant difference in the proportion of patients who received RRT in the standard-strategy stratified by age groups (adjusted-OR, 0.85 [0.67-1.08], p = 0.180). CONCLUSION: In this secondary analysis of the STARRT-AKI trial, older and frail patients had higher mortality at 90 days; however, there was no difference in RRT dependence. Mortality and RRT dependence were not modified by RRT initiation strategy in older or frail patients.

Twenty percent human albumin solution fluid bolus administration therapy in patients after cardiac surgery-II: a multicentre randomised controlled trial.

PURPOSE: After cardiac surgery, fluid bolus therapy (FBT) with 20% human albumin may facilitate less fluid and vasopressor administration than FBT with crystalloids. We aimed to determine whether, after cardiac surgery, FBT with 20% albumin reduces the duration of vasopressor therapy compared with crystalloid FBT. METHODS: We conducted a multicentre, parallel-group, open-label, randomised clinical trial in six intensive care units (ICUs) involving cardiac surgery patients deemed to require FBT. We randomised 240 patients to receive up to 400 mL of 20% albumin/day as FBT, followed by 4% albumin for any subsequent FBT on that day, or to crystalloid FBT for at least the first 1000 mL, with use of crystalloid or 4% albumin FBT thereafter. The primary outcome was the cumulative duration of vasopressor therapy. Secondary outcomes included fluid balance. RESULTS: Of 480 randomised patients, 466 provided consent and contributed to the primary outcome (mean age 65 years; median EuroSCORE II 1.4). The cumulative median duration of vasopressor therapy was 7 (interquartile range [IQR] 0-19.6) hours with 20% albumin and 10.8 (IQR 0-22.8) hours with crystalloids (difference - 3.8 h, 95% confidence interval [CI] - 8 to 0.4; P = 0.08). Day one fluid balance was less with 20% albumin FBT (mean difference - 701 mL, 95% CI - 872 to - 530). CONCLUSIONS: In patients after cardiac surgery, when compared to a crystalloid-based FBT, 20% albumin FBT was associated with a reduced positive fluid balance but did not significantly reduce the duration of vasopressor therapy.

Effect of automated versus conventional ventilation on mechanical power of ventilation-A randomized crossover clinical trial.

INTRODUCTION: Mechanical power of ventilation, a summary parameter reflecting the energy transferred from the ventilator to the respiratory system, has associations with outcomes. INTELLiVENT-Adaptive Support Ventilation is an automated ventilation mode that changes ventilator settings according to algorithms that target a low work-and force of breathing. The study aims to compare mechanical power between automated ventilation by means of INTELLiVENT-Adaptive Support Ventilation and conventional ventilation in critically ill patients. MATERIALS AND METHODS: International, multicenter, randomized crossover clinical trial in patients that were expected to need invasive ventilation > 24 hours. Patients were randomly assigned to start with a 3-hour period of automated ventilation or conventional ventilation after which the alternate ventilation mode was selected. The primary outcome was mechanical power in passive and active patients; secondary outcomes included key ventilator settings and ventilatory parameters that affect mechanical power. RESULTS: A total of 96 patients were randomized. Median mechanical power was not different between automated and conventional ventilation (15.8 [11.5-21.0] versus 16.1 [10.9-22.6] J/min; mean difference -0.44 (95%-CI -1.17 to 0.29) J/min; P = 0.24). Subgroup analyses showed that mechanical power was lower with automated ventilation in passive patients, 16.9 [12.5-22.1] versus 19.0 [14.1-25.0] J/min; mean difference -1.76 (95%-CI -2.47 to -10.34J/min; P < 0.01), and not in active patients (14.6 [11.0-20.3] vs 14.1 [10.1-21.3] J/min; mean difference 0.81 (95%-CI -2.13 to 0.49) J/min; P = 0.23). CONCLUSIONS: In this cohort of unselected critically ill invasively ventilated patients, automated ventilation by means of INTELLiVENT-Adaptive Support Ventilation did not reduce mechanical power. A reduction in mechanical power was only seen in passive patients. STUDY REGISTRATION: Clinicaltrials.gov (study identifier NCT04827927), April 1, 2021. URL OF TRIAL REGISTRY RECORD: https://clinicaltrials.gov/study/NCT04827927?term=intellipower&rank=1.

Intubation of critically ill patients: A pilot study of minute-by-minute physiological changes within an Australian tertiary intensive care unit.

BACKGROUND: There are no published minute-by-minute physiological assessment data for endotracheal intubation (ETT) performed in the intensive care unit (ICU). The majority of physiological data is available from Europe and North America where etomidate is the induction agent administered most commonly. AIMS: The aim of this study was to describe the feasibility of obtaining minute-by-minute physiological and medication data surrounding ETT in an Australian tertiary ICU and to assess its associated outcomes. METHODS: We performed a single-centre feasibility observational study. We obtained minute-by-minute data on physiological variables and medications for 15 min before and 30 min after ETT. We assessed feasibility as enrolled to screened patient ratio and completeness of data collection in enrolled patients. Severe hypotension (systolic blood pressure < 65 mmHg) and severe hypoxaemia (pulse oximetry saturation < 80%) were the secondary clinical outcomes. RESULTS: We screened 43 patients and studied 30 patients. The median age was 58.5 (interquartile range: 49-70) years, and 18 (60%) were male. Near-complete (97%) physiological and medication data were obtained in all patients at all times. Overall, 15 (50%) ETTs occurred after hours (17:30-08:00) and 90% were by video laryngoscopy with a 90% first-pass success rate. Prophylactic vasopressors were used in 50% of ETTs. Fentanyl was used in all except one ETT at a median dose of 2.5 mcg/kg. Propofol (63%) or midazolam (50%) were used as adjuncts at low dose. Rocuronium was used in all but one patient. There were no episodes of severe hypotension and only one episode of short-lived severe hypoxaemia. CONCLUSION: Minute-by-minute recording of ETT-associated physiological changes in the ICU was feasible but only fully available in two-thirds of the screened patients. ETT was based on fentanyl induction, low-dose adjunctive sedation, and frequent prophylactic vasopressor therapy and was associated with no severe hypotension and a single short-lived episode of severe hypoxaemia.

Dapagliflozin for Critically Ill Patients With Acute Organ Dysfunction: The DEFENDER Randomized Clinical Trial.

Importance: Sodium-glucose cotransporter 2 (SGLT-2) inhibitors improve outcomes in patients with type 2 diabetes, heart failure, and chronic kidney disease, but their effect on outcomes of critically ill patients with organ failure is unknown. Objective: To determine whether the addition of dapagliflozin, an SGLT-2 inhibitor, to standard intensive care unit (ICU) care improves outcomes in a critically ill population with acute organ dysfunction. Design, Setting, and Participants: Multicenter, randomized, open-label, clinical trial conducted at 22 ICUs in Brazil. Participants with unplanned ICU admission and presenting with at least 1 organ dysfunction (respiratory, cardiovascular, or kidney) were enrolled between November 22, 2022, and August 30, 2023, with follow-up through September 27, 2023. Intervention: Participants were randomized to 10 mg of dapagliflozin (intervention, n = 248) plus standard care or to standard care alone (control, n = 259) for up to 14 days or until ICU discharge, whichever occurred first. Main Outcomes and Measures: The primary outcome was a hierarchical composite of hospital mortality, initiation of kidney replacement therapy, and ICU length of stay through 28 days, analyzed using the win ratio method. Secondary outcomes included the individual components of the hierarchical outcome, duration of organ support-free days, ICU, and hospital stay, assessed using bayesian regression models. Results: Among 507 randomized participants (mean age, 63.9 [SD, 15] years; 46.9%, women), 39.6% had an ICU admission due to suspected infection. The median time from ICU admission to randomization was 1 day (IQR, 0-1). The win ratio for dapagliflozin for the primary outcome was 1.01 (95% CI, 0.90 to 1.13; P = .89). Among all secondary outcomes, the highest probability of benefit found was 0.90 for dapagliflozin regarding use of kidney replacement therapy among 27 patients (10.9%) in the dapagliflozin group vs 39 (15.1%) in the control group. Conclusion and Relevance: The addition of dapagliflozin to standard care for critically ill patients and acute organ dysfunction did not improve clinical outcomes; however, confidence intervals were wide and could not exclude relevant benefits or harms for dapagliflozin. Trial Registration: ClinicalTrials.gov Identifier: NCT05558098.

Alternative approaches to analyzing ventilator-free days, mortality and duration of ventilation in critical care research.

OBJECTIVE: To discuss the strengths and limitations of ventilator-free days and to provide a comprehensive discussion of the different analytic methods for analyzing and interpreting this outcome. METHODS: Using simulations, the power of different analytical methods was assessed, namely: quantile (median) regression, cumulative logistic regression, generalized pairwise comparison, conditional approach and truncated approach. Overall, 3,000 simulations of a two-arm trial with n = 300 per arm were computed using a two-sided alternative hypothesis and a type I error rate of α = 0.05. RESULTS: When considering power, median regression did not perform well in studies where the treatment effect was mainly driven by mortality. Median regression performed better in situations with a weak effect on mortality but a strong effect on duration, duration only, and moderate mortality and duration. Cumulative logistic regression was found to produce similar power to the Wilcoxon rank-sum test across all scenarios, being the best strategy for the scenarios of moderate mortality and duration, weak mortality and strong duration, and duration only. CONCLUSION: In this study, we describe the relative power of new methods for analyzing ventilator-free days in critical care research. Our data provide validation and guidance for the use of the cumulative logistic model, median regression, generalized pairwise comparisons, and the conditional and truncated approach in specific scenarios.

The interaction of net ultrafiltration rate with urine output and fluid balance after continuous renal replacement therapy initiation: A multi-Centre study.

PURPOSE: During continuous renal replacement therapy (CRRT), a high net ultrafiltration rate (NUF) may worsen the decrease in urine output (UO) associated with starting CRRT. However, fluid balance (FB) may modulate this association. We aimed to examine the relationship between NUF, UO and FB at the start of CRRT. METHODS: A retrospective cohort study of 1030 CRRT-treated patients admitted to two tertiary ICUs. RESULTS: Median age was 60 years (IQR, 48-70), median APACHE III was 94 (IQR, 76-114) and median NUF rate was 0.7 mL/kg/h. In the 24 h after CRRT started, the mean hourly UO decreased from 25.5 mL to 11.9 mL (P < 0.001). Moreover, after adjusting for multiple confounders on multivariable analysis, a higher NUF was not significantly associated with a lower UO (-1.5 mL/kg for every 1 mL/kg/h increase in NUF; 95% CI -3.1 to 0.04; p = 0.064). In addition, pre-CRRT FB did not modulate the above relationship between higher NUF and lower UO. CONCLUSION: A higher NUF rate was not significantly associated with a greater immediate and sustained reduction in UO after CRRT commencement. FB before CRRT was also not associated with a greater reduction in UO. These findings do not provide evidence for an effect of NUF on renal function.

Impact of High-Dose Early Mobilization on Outcomes for Patients with Diabetes: A Secondary Analysis of the TEAM Trial.

Rationale: Patients with diabetes represent almost 20% of all ICU admissions and might respond differently to high-dose early active mobilization. Objectives: To assess whether diabetes modified the relationship between the dose of early mobilization on clinical outcomes in the TEAM trial. Methods: All TEAM trial patients were included. The primary outcome was days alive and out of the hospital at Day 180. Secondary outcomes included 180-day mortality and long-term functional outcomes at Day 180. Logistic and median regression models were used to explore the effect of high-dose early mobilization on outcomes by diabetes status. Measurements and Main Results: All 741 patients from the original trial were included. Of these, 159 patients (21.4%) had diabetes. Patients with diabetes had fewer days alive and out of the hospital at Day 180 (124 [0-153] vs. 147 [82-164]; P = 0.013) and higher 180-day mortality (30% vs. 18%; P = 0.044). In patients receiving high-dose early mobilization, the number of days alive and out of the hospital at Day 180 was 73.0 (0.0-144.5) in patients with diabetes and 146.5 (95.8-163.0) in patients without diabetes (P value for interaction = 0.108). However, in patients with diabetes, high-dose early mobilization increased the odds of mortality at 180 days (adjusted odds ratio, 3.47; 95% confidence interval, 1.67-7.61; P value for interaction = 0.001). Conclusions: In this secondary analysis of the TEAM trial, in patients with diabetes, a high-dose early mobilization strategy did not significantly decrease the number of days alive and out of the hospital at Day 180, but it increased 180-day mortality.

How a positive fluid balance develops in acute kidney injury: A binational, observational study.

PURPOSE: A positive fluid balance (FB) is associated with harm in intensive care unit (ICU) patients with acute kidney injury (AKI). We aimed to understand how a positive balance develops in such patients. METHODS: Multinational, retrospective cohort study of critically ill patients with AKI not requiring renal replacement therapy. RESULTS: AKI occurred at a median of two days after admission in 7894 (17.3%) patients. Cumulative FB became progressively positive, peaking on day three despite only 848 (10.7%) patients receiving fluid resuscitation in the ICU. In those three days, persistent crystalloid use (median:60.0 mL/h; IQR 28.9-89.2), nutritional intake (median:18.2 mL/h; IQR 0.0-45.9) and limited urine output (UO) (median:70.8 mL/h; IQR 49.0-96.7) contributed to a positive FB. Although UO increased each day, it failed to match input, with only 797 (10.1%) patients receiving diuretics in ICU. After adjustment, a positive FB four days after AKI diagnosis was associated with an increased risk of hospital mortality (OR 1.12;95% confidence intervals 1.05-1.19;p-value <0.001). CONCLUSION: Among ICU patients with AKI, cumulative FB increased after diagnosis and was associated with an increased risk of mortality. Continued crystalloid administration, increased nutritional intake, limited UO, and minimal use of diuretics all contributed to positive FB. KEY POINTS: Question How does a positive fluid balance develop in critically ill patients with acute kidney injury? Findings Cumulative FB increased after AKI diagnosis and was secondary to persistent crystalloid fluid administration, increasing nutritional fluid intake, and insufficient urine output. Despite the absence of resuscitation fluid and an increasing cumulative FB, there was persistently low diuretics use, ongoing crystalloid use, and a progressive escalation of nutritional fluid therapy. Meaning Current management results in fluid accumulation after diagnosis of AKI, as a result of ongoing crystalloid administration, increasing nutritional fluid, limited urine output and minimal diuretic use.

Consensus statements on the utility of defining ARDS and the utility of past and current definitions of ARDS-protocol for a Delphi study.

INTRODUCTION: Acute respiratory distress syndrome (ARDS), marked by acute hypoxemia and bilateral pulmonary infiltrates, has been defined in multiple ways since its first description. This Delphi study aims to collect global opinions on the conceptual framework of ARDS, assess the usefulness of components within current and past definitions and investigate the role of subphenotyping. The varied expertise of the panel will provide valuable insights for refining future ARDS definitions and improving clinical management. METHODS: A diverse panel of 35-40 experts will be selected based on predefined criteria. Multiple choice questions (MCQs) or 7-point Likert-scale statements will be used in the iterative Delphi rounds to achieve consensus on key aspects related to the utility of definitions and subphenotyping. The Delphi rounds will be continued until a stable agreement or disagreement is achieved for all statements. ANALYSIS: Consensus will be considered as reached when a choice in MCQs or Likert-scale statement achieved ≥80% of votes for agreement or disagreement. The stability will be checked by non-parametric χ2 tests or Kruskal Wallis test starting from the second round of Delphi process. A p-value ≥0.05 will be used to define stability. ETHICS AND DISSEMINATION: The study will be conducted in full concordance with the principles of the Declaration of Helsinki and will be reported according to CREDES guidance. This study has been granted an ethical approval waiver by the NMC Healthcare Regional Research Ethics Committee, Dubai (NMCHC/CR/DXB/REC/APP/002), owing to the nature of the research. Informed consent will be obtained from all panellists before the start of the Delphi process. The study will be published in a peer-review journal with the authorship agreed as per ICMJE requirements. TRIAL REGISTRATION NUMBER: NCT06159465.

Association of active mobilisation variables with adverse events and mortality in patients requiring mechanical ventilation in the intensive care unit: a systematic review and meta-analysis.

BACKGROUND: Mobilisation during critical illness is now included in multiple clinical practice guidelines. However, a large, randomised trial and systematic review have recently identified an increased probability of adverse events and mortality in patients who received early active mobilisation in the intensive care unit (ICU). We aimed to determine the effects of mobilisation compared with usual care on adverse events and mortality in an acute ICU setting. In subgroup analyses, we specifically aimed to investigate possible sources of harm, including the timing and duration of mobilisation achieved, ventilation status, and admission diagnosis. METHODS: In this systematic review with frequentist and Bayesian analyses, we searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials, CINAHL, SPORTDiscus, SCOPUS, Web of Science, and PEDro electronic databases, as well as clinical trial registries (ICTRP and ClinicalTrials.gov), from inception to March 16, 2023, without language restrictions. Eligible studies were randomised controlled trials that examined active mobilisation compared with either no mobilisation or mobilisation commencing later, or at a lower frequency or intensity, in adults who were critically ill during or after a period of mechanical ventilation in an acute ICU setting. Two authors independently screened reports, extracted data, and assessed the risk of bias using the Cochrane risk-of-bias tool (version 1). The primary outcome was the number of adverse events that occurred during the implementation of mobilisation, with the effect of mobilisation on mortality being the secondary outcome. Risk ratios (RRs) with 95% CIs were calculated in R (version 4.0.3) using random-effects modelling, with Bayesian analysis completed to calculate the probability of treatment harm (ie, RR >1). Subgroup analyses were completed to investigate the association of various factors of mobilisation on adverse events and mortality: duration of mobilisation (longer [≥20 min per day] vs shorter [<20 min per day]), timing of commencement (early [≤72 h from ICU admission] vs late [>72 h from ICU admission]), ventilation status at commencement (all patients mechanically ventilated vs all patients extubated), and ICU admission diagnosis (surgical vs medical). This study was registered with PROSPERO, CRD42022369272. FINDINGS: After title and abstract screening of 14 440 studies and review of 466 full texts, 67 trials with 7004 participants met inclusion criteria, with 59 trials contributing to the meta-analysis. Of the 67 included studies, 15 (22%) did not mention adverse events and 13 (19%) reported no adverse events occurring across the trial period. Overall, we found no effect of mobilisation compared with usual care on the occurrence of adverse events (RR 1·09 [95% CI 0·69-1·74], p=0·71; I2 91%; 32 731 events, 20 studies; very low certainty), with a 2·96% occurrence rate (693 events in 23 395 intervention sessions; 25 studies). Mobilisation did not have any effect on mortality (RR 0·98 [95% CI 0·87-1·12], p=0·81; I2 0%; n=6218, 58 studies; moderate certainty). Subgroup analysis was hindered by the large amount of data that could not be allocated and analysed, making the results hypothesis generating only. INTERPRETATION: Implementation of mobilisation in the ICU was associated with a less than 3% chance of an adverse event occurring and was not found to increase adverse events or mortality overall, providing reassurance for clinicians about the safety of performing this intervention. Subgroup analyses did not clearly identify any specific variable of mobilisation implementation that increased harm. FUNDING: None.

Hierarchical endpoints in critical care: A post-hoc exploratory analysis of the standard versus accelerated initiation of renal-replacement therapy in acute kidney injury and the intensity of continuous renal-replacement therapy in critically ill patients trials.

PURPOSE: To perform a post-hoc reanalysis of the Standard versus Accelerated Initiation of Renal-Replacement Therapy in Acute Kidney Injury (STARRT-AKI) and the Intensity of Continuous Renal-Replacement Therapy in Critically Ill Patients (RENAL) trials through hierarchical composite endpoint analysis using win ratio (WR). MATERIAL AND METHODS: All patients with complete information from the STARRT-AKI (which compared accelerated versus standard approaches for renal replacement therapy - RRT initiation) and RENAL (which compared two different RRT doses in critically ill patients) trials were selected. WR was defined as a hierarchical composite endpoint using 90-day mortality, RRT dependency at 90-days, intensive care unit (ICU) length-of-stay (LOS), and hospital LOS (primary analysis); values above the unit represent a benefit of the intervention for the hierarchical composite endpoint. A secondary analysis replacing LOS by days alive and free of RRT was performed. Stratified analyses were performed according to illness severity score, surgical status, and the presence of sepsis. RESULTS: The WR analysis produced 2,141,830 pairs for the STARRT-AKI trial and 536,446 pairs for the RENAL trial, respectively. The WR results for STARRT-AKI and RENAL were 1.04 (95% confidence interval [CI] 0.96-1.13; p = 0.33) and 1.02 (95% CI; 0.90-1.15; p = 0.75) for the primary analysis, and 0.88 (95% CI; 0.79-0.99; p = 0.03) and 1.02 (95% CI; 0.87-1.21; p = 0.77) for the secondary analysis, respectively. The stratified analysis of the primary suggested possible benefit of the accelerated-strategy in the STARRT-AKI trial for non-surgical patients with sepsis, while the secondary analysis suggested possible harm of the accelerated-strategy for surgical patients without sepsis. There was no evidence of heterogeneity in treatment effects in stratified analyses in the RENAL trial. CONCLUSION: WR approach using a hierarchical composite endpoint is feasible for trials in critical care nephrology. The primary re-analyses of the STARRT-AKI and RENAL trials both yielded neutral results; however, there was suggestion of heterogeneity in treatment effect in stratified analyses of the STARRT-AKI trial by surgical status and sepsis. Selection of the endpoints and hierarchical ordering before trial design using the WR approach can have important implications for trial interpretation. TRIAL REGISTRY: ClinicalTrials.gov number NCT02568722 (STARRT-AKI) and NCT00076219 (RENAL).

Regional Practice Variation and Outcomes in the Standard Versus Accelerated Initiation of Renal Replacement Therapy in Acute Kidney Injury (STARRT-AKI) Trial: A Post Hoc Secondary Analysis.

OBJECTIVES: Among patients with severe acute kidney injury (AKI) admitted to the ICU in high-income countries, regional practice variations for fluid balance (FB) management, timing, and choice of renal replacement therapy (RRT) modality may be significant. DESIGN: Secondary post hoc analysis of the STandard vs. Accelerated initiation of Renal Replacement Therapy in Acute Kidney Injury (STARRT-AKI) trial (ClinicalTrials.gov number NCT02568722). SETTING: One hundred-fifty-three ICUs in 13 countries. PATIENTS: Altogether 2693 critically ill patients with AKI, of whom 994 were North American, 1143 European, and 556 from Australia and New Zealand (ANZ). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Total mean FB to a maximum of 14 days was +7199 mL in North America, +5641 mL in Europe, and +2211 mL in ANZ (p < 0.001). The median time to RRT initiation among patients allocated to the standard strategy was longest in Europe compared with North America and ANZ (p < 0.001; p < 0.001). Continuous RRT was the initial RRT modality in 60.8% of patients in North America and 56.8% of patients in Europe, compared with 96.4% of patients in ANZ (p < 0.001). After adjustment for predefined baseline characteristics, compared with North American and European patients, those in ANZ were more likely to survive to ICU (p < 0.001) and hospital discharge (p < 0.001) and to 90 days (for ANZ vs. Europe: risk difference [RD], -11.3%; 95% CI, -17.7% to -4.8%; p < 0.001 and for ANZ vs. North America: RD, -10.3%; 95% CI, -17.5% to -3.1%; p = 0.007). CONCLUSIONS: Among STARRT-AKI trial centers, significant regional practice variation exists regarding FB, timing of initiation of RRT, and initial use of continuous RRT. After adjustment, such practice variation was associated with lower ICU and hospital stay and 90-day mortality among ANZ patients compared with other regions.

Nutrition delivery across hospitalisation in critically ill patients with COVID-19: An observational study of the Australian experience.

BACKGROUND: Data on nutrition delivery over the whole hospital admission in critically ill patients with COVID-19 are scarce, particularly in the Australian setting. OBJECTIVES: The objective of this study was to describe nutrition delivery in critically ill patients admitted to Australian intensive care units (ICUs) with coronavirus disease 2019 (COVID-19), with a focus on post-ICU nutrition practices. METHODS: A multicentre observational study conducted at nine sites included adult patients with a positive COVID-19 diagnosis admitted to the ICU for >24 h and discharged to an acute ward over a 12-month recruitment period from 1 March 2020. Data were extracted on baseline characteristics and clinical outcomes. Nutrition practice data from the ICU and weekly in the post-ICU ward (up to week four) included route of feeding, presence of nutrition-impacting symptoms, and nutrition support received. RESULTS: A total of 103 patients were included (71% male, age: 58 ± 14 years, body mass index: 30±7 kg/m2), of whom 41.7% (n = 43) received mechanical ventilation within 14 days of ICU admission. While oral nutrition was received by more patients at any time point in the ICU (n = 93, 91.2% of patients) than enteral nutrition (EN) (n = 43, 42.2%) or parenteral nutrition (PN) (n = 2, 2.0%), EN was delivered for a greater duration of time (69.6% feeding days) than oral and PN (29.7% and 0.7%, respectively). More patients received oral intake than the other modes in the post-ICU ward (n = 95, 95.0%), and 40.0% (n = 38/95) of patients were receiving oral nutrition supplements. In the week after ICU discharge, 51.0% of patients (n = 51) had at least one nutrition-impacting symptom, most commonly a reduced appetite (n = 25; 24.5%) or dysphagia (n = 16; 15.7%). CONCLUSION: Critically ill patients during the COVID-19 pandemic in Australia were more likely to receive oral nutrition than artificial nutrition support at any time point both in the ICU and in the post-ICU ward, whereas EN was provided for a greater duration when it was prescribed. Nutrition-impacting symptoms were common.