Prevalence of frailty and association with patient centered outcomes:A prospective registry-embedded cohort study from India

Purpose:We aimed to study the prevalence of frailty, evaluate risk factors, and understand impact on outcomes in India. Methods:This was a prospective registry-embedded cohort study across 7 intensive care units (ICUs) and included adult patients anticipated to stay for at least 48hrs. Primary exposure was frailty, as defined by a score ≥5 on the Clinical Frailty Scale and primary outcome was ICU mortality. Secondary outcomes included in-hospital mortality and resource utilization. We used generalized linear models to evaluate risk factors and model association between frailty and outcomes. Results:838 patients were included, with median (IQR) age 57 (42,68) yrs.; 64.8% were male. Prevalence of frailty was 19.8%. Charlson comorbidity index (OR:1.73 (95%CI:1.39,2.15)), Subjective Global Assessment categories mild/moderate malnourishment (OR:1.90 (95%CI:1.29, 2.80)) and severe malnourishment [OR:4.76 (95% CI:2.10,10.77)] were associated with frailty. Frailty was associated with higher odds of ICU mortality (adjusted OR:2.04 (95% CI:1.25,3.33)), hospital mortality (adjusted OR:2.36 (95%CI:1.45,3.84)), development of stage2/3 AKI (unadjusted OR:2.35 (95%CI:1.60, 3.43)), receipt of non-invasive ventilation (unadjusted OR:2.68 (95%CI:1.77, 4.03)), receipt of vasopressors (unadjusted OR:1.47 (95%CI:1.04, 2.07)), and receipt of kidney replacement therapy (unadjusted OR:3.15 (95%CI:1.90, 5.17)). Conclusions:Frailty is common among critically ill patients in India and is associated with worse outcomes. <br/

Operationalisation of the Randomized Embedded Multifactorial Adaptive Platform for COVID-19 trials in a low and lower-middle income critical care learning health system

The Randomized Embedded Multifactorial Adaptive Platform (REMAP-CAP) adapted for COVID-19) trial is a global adaptive platform trial of hospitalised patients with COVID-19. We describe implementation in three countries under the umbrella of the Wellcome supported Low and Middle Income Country (LMIC) critical care network: Collaboration for Research, Implementation and Training in Asia (CCA). The collaboration sought to overcome known barriers to multi centre-clinical trials in resource-limited settings. Methods described focused on six aspects of implementation: i, Strengthening an existing community of practice; ii, Remote study site recruitment, training and support; iii, Harmonising the REMAP CAP- COVID trial with existing care processes; iv, Embedding REMAP CAP- COVID case report form into the existing CCA registry platform, v, Context specific adaptation and data management; vi, Alignment with existing pandemic and critical care research in the CCA. Methods described here may enable other LMIC sites to participate as equal partners in international critical care trials of urgent public health importance, both during this pandemic and beyond

Awake prone positioning in adults with COVID-19

Importance: The impact of awake prone positioning (APP) on clinical outcomes in patients with COVID-19 and acute hypoxemic respiratory failure (AHRF) remains uncertain. Objective: To assess the association of APP with improved clinical outcomes among patients with COVID-19 and AHRF, and to identify potential effect modifiers. Data Sources: PubMed, Embase, the Cochrane Library, and ClinicalTrials.gov were searched through August 1, 2024. Study Selection: Randomized clinical trials (RCTs) examining APP in adults with COVID-19 and AHRF that reported intubation rate or mortality were included. Data Extraction and Synthesis: Individual participant data (IPD) were extracted according to PRISMA-IPD guidelines. For binary outcomes, logistic regression was used and odds ratio (OR) and 95% CIs were reported, while for continuous outcomes, linear regression was used and mean difference (MD) and 95% CIs were reported. Main Outcomes and Measures: The primary outcome was survival without intubation. Secondary outcomes included intubation, mortality, death without intubation, death after intubation, escalation of respiratory support, intensive care unit (ICU) admission, time from enrollment to intubation and death, duration of invasive mechanical ventilation, and hospital and ICU lengths of stay. Results: A total of 14 RCTs involving 3019 patients were included; 1542 patients in the APP group (mean [SD] age, 59.3 [14.1] years; 1048 male [68.0%]) and 1477 in the control group (mean [SD] age, 59.9 [14.1] years; 979 male [66.3%]). APP improved survival without intubation (OR, 1.42; 95% CI, 1.20-1.68), and it reduced the risk of intubation (OR, 0.70; 95% CI, 0.59-0.84) and hospital mortality (OR, 0.77; 95% CI, 0.63-0.95). APP also extended the time from enrollment to intubation (MD, 0.93 days; 95% CI, 0.43 to 1.42 days). In exploratory subgroup analyses, improved survival without intubation was observed in patients younger than age 68 years, as well as in patients with a body mass index of 26 to 30, early implementation of APP (ie, less than 1 day from hospitalization), a pulse saturation to inhaled oxygen fraction ratio of 155 to 232, respiratory rate of 20 to 26 breaths per minute (bpm), and those receiving advanced respiratory support at enrollment. However, none of the subgroups had significant interaction with APP treatment. APP duration 10 or more hours/d within the first 3 days was associated with increased survival without intubation (OR, 1.85; 95% CI, 1.37-2.49). Conclusions and Relevance: This IPD meta-analysis found that in adults with COVID-19 and AHRF, APP was associated with increased survival without intubation and with reduced risks of intubation and mortality, including death after intubation. Prolonged APP duration (10 or more hours/d) was associated with better outcomes

Heterogeneous treatment effects of therapeutic-dose heparin in patients hospitalized for COVID-19

Importance Randomized clinical trials (RCTs) of therapeutic-dose heparin in patients hospitalized with COVID-19 produced conflicting results, possibly due to heterogeneity of treatment effect (HTE) across individuals. Better understanding of HTE could facilitate individualized clinical decision-making. Objective To evaluate HTE of therapeutic-dose heparin for patients hospitalized for COVID-19 and to compare approaches to assessing HTE. Design, Setting, and Participants Exploratory analysis of a multiplatform adaptive RCT of therapeutic-dose heparin vs usual care pharmacologic thromboprophylaxis in 3320 patients hospitalized for COVID-19 enrolled in North America, South America, Europe, Asia, and Australia between April 2020 and January 2021. Heterogeneity of treatment effect was assessed 3 ways: using (1) conventional subgroup analyses of baseline characteristics, (2) a multivariable outcome prediction model (risk-based approach), and (3) a multivariable causal forest model (effect-based approach). Analyses primarily used bayesian statistics, consistent with the original trial. Exposures Participants were randomized to therapeutic-dose heparin or usual care pharmacologic thromboprophylaxis. Main Outcomes and Measures Organ support–free days, assigning a value of −1 to those who died in the hospital and the number of days free of cardiovascular or respiratory organ support up to day 21 for those who survived to hospital discharge; and hospital survival. Results Baseline demographic characteristics were similar between patients randomized to therapeutic-dose heparin or usual care (median age, 60 years; 38% female; 32% known non-White race; 45% Hispanic). In the overall multiplatform RCT population, therapeutic-dose heparin was not associated with an increase in organ support–free days (median value for the posterior distribution of the OR, 1.05; 95% credible interval, 0.91-1.22). In conventional subgroup analyses, the effect of therapeutic-dose heparin on organ support–free days differed between patients requiring organ support at baseline or not (median OR, 0.85 vs 1.30; posterior probability of difference in OR, 99.8%), between females and males (median OR, 0.87 vs 1.16; posterior probability of difference in OR, 96.4%), and between patients with lower body mass index (BMI 90% for all comparisons). In risk-based analysis, patients at lowest risk of poor outcome had the highest propensity for benefit from heparin (lowest risk decile: posterior probability of OR >1, 92%) while those at highest risk were most likely to be harmed (highest risk decile: posterior probability of OR <1, 87%). In effect-based analysis, a subset of patients identified at high risk of harm (P = .05 for difference in treatment effect) tended to have high BMI and were more likely to require organ support at baseline. Conclusions and Relevance Among patients hospitalized for COVID-19, the effect of therapeutic-dose heparin was heterogeneous. In all 3 approaches to assessing HTE, heparin was more likely to be beneficial in those who were less severely ill at presentation or had lower BMI and more likely to be harmful in sicker patients and those with higher BMI. The findings illustrate the importance of considering HTE in the design and analysis of RCTs. Trial Registration ClinicalTrials.gov Identifiers: NCT02735707, NCT04505774, NCT04359277, NCT0437258

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

A Comparative Study on Caprini RAM Vs DOH Tool for Thromboprophylaxis in ICU Setting at Tertiary Care Hospital

The aim of the study was to assess DVT prophylaxis using two models (Caprini RAM &amp; DOH tool) for the prevention of DVT in postoperative or critically ill patients and for better predictability of disease. In this prospective observational study, we compared the Caprini RAM and DOH tool in the ICU setting on 229 patients (140 men and 89 women). 205 patients were considered in the study, out of which 97 had Caprini RAM and 108 had DOH tool. A Prospective, observational comparative study was carried out in a tertiary care hospital for a period of 6 months. Patients were divided into two groups according to the RAM. The data were analyzed using SPSS software and the results were compared using the student t-test. Both GROUP A and GROUP B revealed that the majority of the patients (67.1% &amp; 55.6%) were above 60 years and a large proportion of them required DVT prophylaxis. In GROUP A 93% of forms were complete with 79% accuracy. In GROUP B 83% were complete. The most appropriate prophylaxis received by patients was Enoxaparin sodium 40 mg OD for about 97 (30%) patients and Heparin 5000 IU BD for 108 (30%) based on their Caprini scores and NICE guidelines respectively. The majority of patients in Group A did not require dosage adjustments, but in 20% of cases, it was necessary. Statistical significance was achieved with a p-value less than 0.05. The study demonstrates DOH tool is better than Caprini RAM to be used in hospitals, for risk assessment of VTE in both medical and surgical patients for accuracy and predictability of the prophylaxis. Keywords: DVT, Risk assessment, Caprini RAM, DOH tool, pharmacological and mechanical Prophylaxis

Standard care vs. awake prone position in adult non-intubated patients with acute hypoxaemic respiratory failure secondary to COVID-19 infection – A multi-centre feasibility randomized controlled trial

AbstractBackgroundThe primary manifestation of Corona Virus Disease −2019 (COVID-19) is acute hypoxic respiratory failure secondary to pneumonia and/or acute respiratory distress syndrome. Prone position has been shown to improve outcomes in ventilated patients with moderate to severe acute respiratory distress syndrome. The feasibility and safety of awake prone positioning and its impact on outcomes if any, in non-intubated patients with mild to moderate acute respiratory distress syndrome secondary to COVID-19 is unknown. Results of the observational studies published thus far in this pandemic have been conflicting. In this context, we conducted a multi-centre, parallel group, randomised controlled feasibility study on awake prone positioning in non-intubated patients with COVID-19 pneumonia requiring supplemental oxygen.Methods60 patients diagnosed with acute hypoxic respiratory failure secondary to COVID −19 pneumonia requiring 4 or more litres of oxygen to maintain a saturation of ≥ 92% were recruited in this study. Thirty patients each were randomised to either standard care or awake prone group. Patients randomised to the standard care were allowed to change their position as per comfort and patients randomized to the prone group were encouraged to self-prone for at least 6 hours a day. The primary outcome was the proportion of patients adhering to the protocol in each group. Secondary outcomes include failure of therapy leading to escalation of respiratory support, number of hours prone, maximum hours of continuous prone positioning in a day, length of stay in ICU, ICU mortality, total number of patients needing intubation and adverse events.ResultsIn the prone group, 43% (13 out of 30) of patients were able to self-prone for 6 or more hours a day. The median maximum prone duration per session was 2 hours. In the supine group, 47% (14 out of 30) were completely supine and 53% spent some hours in the prone position, but none exceeded 6 hours. There was no significant difference in any of the secondary outcomes between the two groups and there were no adverse events.InterpretationAwake proning in non-intubated patients with acute hypoxic respiratory failure is feasible and safe under clinical trial conditions. The results of our feasibility study will potentially help in the design of larger definitive trials to address this key knowledge gap.</jats:sec

Standard Care Versus Awake Prone Position in Adult Nonintubated Patients With Acute Hypoxemic Respiratory Failure Secondary to COVID-19 Infection—A Multicenter Feasibility Randomized Controlled Trial

Rationale: The feasibility and safety of awake prone positioning and its impact on outcomes in non-intubated patients with acute respiratory distress syndrome secondary to COVID-19 is unknown. Results of the observational studies published during this pandemic have been conflicting. In this context, we conducted a multi-center, parallel group, randomized controlled feasibility study on awake prone positioning in non-intubated patients with COVID-19 pneumonia requiring supplemental oxygen. Methods: 60 patients with acute hypoxic respiratory failure secondary to COVID-19 pneumonia requiring 4 or more liters of oxygen to maintain a saturation of ≥92% were recruited in this study. Thirty patients each were randomized to either standard care or awake prone group. Patients randomized to the prone group were encouraged to self-prone for at least 6 hours a day. The primary outcome was the proportion of patients adhering to the protocol in each group. Results: In the prone group, 43% (13 out of 30) of patients were able to self-prone for 6 or more hours a day. In the supine group, 47% (14 out of 30) were completely supine and 53% spent some hours in the prone position, but none exceeded 6 hours. There was no significant difference in any of the secondary outcomes between the 2 groups and there were no adverse events. Conclusions: Awake prone positioning in non-intubated patients with acute hypoxic respiratory failure is feasible and safe under clinical trial conditions. The results of our feasibility study will potentially help in the design of larger definitive trials to address this key knowledge gap. </jats:sec