Predictors and outcomes of withholding and withdrawal of life-sustaining treatments in intensive care units in Singapore: a multicentre observational study.

BACKGROUND: Clinical practice guidelines on limitation of life-sustaining treatments (LST) in the intensive care unit (ICU), in the form of withholding or withdrawal of LST, state that there is no ethical difference between the two. Such statements are not uniformly accepted worldwide, and there are few studies on LST limitation in Asia. This study aimed to evaluate the predictors and outcomes of withholding and withdrawal of LST in Singapore, focusing on the similarities and differences between the two approaches. METHODS: This was a multicentre observational study of patients admitted to 21 adult ICUs across 9 public hospitals in Singapore over an average of three months per year from 2014 to 2019. The primary outcome measures were withholding and withdrawal of LST (cardiopulmonary resuscitation, invasive mechanical ventilation, and vasopressors/inotropes). The secondary outcome measure was hospital mortality. Multivariable generalised mixed model analysis was used to identify independent predictors for withdrawal and withholding of LST and if LST limitation predicts hospital mortality. RESULTS: There were 8907 patients and 9723 admissions. Of the former, 80.8% had no limitation of LST, 13.0% had LST withheld, and 6.2% had LST withdrawn. Common independent predictors for withholding and withdrawal were increasing age, absence of chronic kidney dialysis, greater dependence in activities of daily living, cardiopulmonary resuscitation before ICU admission, higher Acute Physiology and Chronic Health Evaluation (APACHE) II score, and higher level of care in the first 24 h of ICU admission. Additional predictors for withholding included being of Chinese race, the religions of Hinduism and Islam, malignancy, and chronic liver failure. The additional predictor for withdrawal was lower hospital paying class (with greater government subsidy for hospital bills). Hospital mortality in patients without LST limitation, with LST withholding, and with LST withdrawal was 10.6%, 82.1%, and 91.8%, respectively (p < 0.001). Withholding (odds ratio 13.822, 95% confidence interval 9.987-19.132) and withdrawal (odds ratio 38.319, 95% confidence interval 24.351-60.298) were both found to be independent predictors of hospital mortality on multivariable analysis. CONCLUSIONS: Differences in the independent predictors of withholding and withdrawal of LST exist. Even after accounting for baseline characteristics, both withholding and withdrawal of LST independently predict hospital mortality. Later mortality in patients who had LST withdrawn compared to withholding suggests that the decision to withdraw may be at the point when medical futility is recognised.

Individualised, short-course antibiotic treatment versus usual long-course treatment for ventilator-associated pneumonia (REGARD-VAP): a multicentre, individually randomised, open-label, non-inferiority trial.

BACKGROUND: Ventilator-associated pneumonia (VAP) is associated with increased mortality, prolonged hospitalisation, excessive antibiotic use and, consequently, increased antimicrobial resistance. In this phase 4, randomised trial, we aimed to establish whether a pragmatic, individualised, short-course antibiotic treatment strategy for VAP was non-inferior to usual care. METHODS: We did an individually randomised, open-label, hierarchical non-inferiority-superiority trial in 39 intensive care units in six hospitals in Nepal, Singapore, and Thailand. We enrolled adults (age ≥18 years) who met the US Centers for Disease Control and Prevention National Healthcare Safety Network criteria for VAP, had been mechanically ventilated for 48 h or longer, and were administered culture-directed antibiotics. In culture-negative cases, empirical antibiotic choices were made depending on local hospital antibiograms reported by the respective microbiology laboratories or prevailing local guidelines. Participants were assessed until fever resolution for 48 h and haemodynamic stability, then randomly assigned (1:1) to individualised short-course treatment (≤7 days and as short as 3-5 days) or usual care (≥8 days, with precise durations determined by the primary clinicians) via permuted blocks of variable sizes (8, 10, and 12), stratified by study site. Independent assessors for recurrent pneumonia and participants were masked to treatment allocation, but clinicians were not. The primary outcome was a 60-day composite endpoint of death or pneumonia recurrence. The non-inferiority margin was prespecified at 12% and had to be met by analyses based on both intention-to-treat (all study participants who were randomised) and per-protocol populations (all randomised study participants who fulfilled the eligibility criteria, met fitness criteria for antibiotic discontinuation, and who received antibiotics for the duration specified by their allocation group). This study is registered with ClinicalTrials.gov, number NCT03382548. FINDINGS: Between May 25, 2018, and Dec 16, 2022, 461 patients were enrolled and randomly assigned to the short-course treatment group (n=232) or the usual care group (n=229). Median age was 64 years (IQR 51-74) and 181 (39%) participants were female. 460 were included in the intention-to-treat analysis after excluding one withdrawal (231 in the short-course group and 229 in the usual care group); 435 participants received the allocated treatment and fulfilled eligibility criteria, and were included in the per-protocol population. Median antibiotic treatment duration for the index episodes of VAP was 6 days (IQR 5-7) in the short-course group and 14 days (10-21) in the usual care group. 95 (41%) of 231 participants in the short-course group met the primary outcome, compared with 100 (44%) of 229 in the usual care group (risk difference -3% [one-sided 95% CI -∞ to 5%]). Results were similar in the per-protocol population. Non-inferiority of short-course antibiotic treatment was met in the analyses, although superiority compared with usual care was not established. In the per-protocol population, antibiotic side-effects occurred in 86 (38%) of 224 in the usual care group and 17 (8%) of 211 in the short-course group (risk difference -31% [95% CI -37 to -25%; p<0·0001]). INTERPRETATION: In this study of adults with VAP, individualised shortened antibiotic duration guided by clinical response was non-inferior to longer treatment durations in terms of 60-day mortality and pneumonia recurrence, and associated with substantially reduced antibiotic use and side-effects. Individualised, short-course antibiotic treatment for VAP could help to reduce the burden of side-effects and the risk of antibiotic resistance in high-resource and resource-limited settings. FUNDING: UK Medical Research Council; Singapore National Medical Research Council. TRANSLATIONS: For the Thai and Nepali translations of the abstract see Supplementary Materials section.

Association of anticoagulation use during continuous kidney replacement therapy and 90-day outcomes: A multicentre study.

Introduction: Anticoagulation is recommended during continuous kidney replacement therapy (CKRT) to prolong the filter lifespan for optimal filter performance. We aimed to evaluate the effect of anticoagulation during CKRT on dialysis dependence and mortality within 90 days of intensive care unit (ICU) admission. Method: Our retrospective observational study evaluated the first CKRT session in critically ill adults with acute kidney injury (AKI) in Singapore from April to September 2017. The primary outcome was a composite of dialysis dependence or death within 90 days of ICU admission; the main exposure variable was anticoagulation use (regional citrate anticoagulation [RCA] or systemic heparin). Multivariable logistic regression was performed to adjust for possible confounders: age, female sex, Acute Physiology and Chronic Health Evaluation (APACHE II) score, liver dysfunction, coagulopathy (international normalised ratio[INR] >1.5) and platelet counts of less than 100,000/uL). Results: The study cohort included 276 patients from 14 participating adult ICUs, of whom 176 (63.8%) experienced dialysis dependence or death within 90 days of ICU admission (19 dialysis dependence, 157 death). Anticoagulation significantly reduced the odds of the primary outcome (adjusted odds ratio [AOR] 0.47, 95% confidence interval [CI] 0.27-0.83, P=0.009). Logistic regression analysis using anticoagulation as a 3-level indicator variable demonstrated that RCA was associated with mortality reduction (AOR 0.46, 95% CI 0.25-0.83, P=0.011), with heparin having a consistent trend (AOR 0.51, 95% CI 0.23-1.14, P=0.102). Conclusion: Among critically ill patients with AKI, anticoagulation use during CKRT was associated with reduced dialysis or death at 90 days post-ICU admission, which was statistically significant for regional citrate anticoagulation and trended in the same direction of benefit for systemic heparin anticoagulation. Anticoagulation during CKRT should be considered whenever possible.

Point-of-care ultrasound for critically-ill patients: A mini-review of key diagnostic features and protocols.

Point-of-care ultrasonography (POCUS) for managing critically ill patients is increasingly performed by intensivists or emergency physicians. Results of needs surveys among intensivists reveal emphasis on basic cardiac, lung and abdominal ultrasound, which are the commonest POCUS modalities in the intensive care unit. We therefore aim to describe the key diagnostic features of basic cardiac, lung and abdominal ultrasound as practised by intensivists or emergency physicians in terms of accuracy (sensitivity, specificity), clinical utility and limitations. We also aim to explore POCUS protocols that integrate basic cardiac, lung and abdominal ultrasound, and highlight areas for future research.

Separation from mechanical ventilation and survival after spinal cord injury: a systematic review and meta-analysis.

BACKGROUND: Prolonged need for mechanical ventilation greatly impacts life expectancy of patients after spinal cord injury (SCI). Weaning outcomes have never been systematically assessed. In this systematic review and meta-analysis, we aimed to investigate the probability of weaning success, duration of mechanical ventilation, mortality, and their predictors in mechanically ventilated patients with SCI. METHODS: We searched six databases from inception until August 2021 for randomized-controlled trials and observational studies enrolling adult patients (≥ 16 years) with SCI from any cause requiring mechanical ventilation. Titles and abstracts were screened independently by two reviewers. Full texts of the identified articles were then assessed for eligibility. Data were extracted independently and in duplicate by pairs of authors, using a standardized data collection form. Synthetic results are reported as meta-analytic means and proportions, based on random effects models. RESULTS: Thirty-nine studies (14,637 patients, mean age 43) were selected. Cervical lesions were predominant (12,717 patients had cervical lesions only, 1843 in association with other levels' lesions). Twenty-five studies were conducted in intensive care units (ICUs), 14 in rehabilitative settings. In ICU, the mean time from injury to hospitalization was 8 h [95% CI 7-9], mean duration of mechanical ventilation 27 days [20-34], probability of weaning success 63% [45-78] and mortality 8% [5-11]. Patients hospitalized in rehabilitation centres had a greater number of high-level lesions (C3 or above), were at 40 days [29-51] from injury and were ventilated for a mean of 97 days [65-128]; 82% [70-90] of them were successfully weaned, while mortality was 1% [0-19]. CONCLUSIONS: Although our study highlights the lack of uniform definition of weaning success, of clear factors associated with weaning outcomes, and of high-level evidence to guide optimal weaning in patients with SCI, it shows that around two-thirds of mechanically ventilated patients can be weaned in ICU after SCI. A substantial gain in weaning success can be obtained during rehabilitation, with additional duration of stay but minimal increase in mortality. The study is registered with PROSPERO (CRD42020156788).

Reducing antibiotic treatment duration for ventilator-associated pneumonia (REGARD-VAP): a trial protocol for a randomised clinical trial.

INTRODUCTION: Ventilator-associated pneumonia (VAP) is the most common nosocomial infection in intensive care units (ICUs). Using short-course antibiotics to treat VAP caused by Gram-negative non-fermenting bacteria has been reported to be associated with excess pneumonia recurrences. The "REducinG Antibiotic tReatment Duration for Ventilator-Associated Pneumonia" (REGARD-VAP) trial aims to provide evidence for using a set of reproducible clinical criteria to shorten antibiotic duration for individualised treatment duration of VAP. METHODS AND ANALYSIS: This is a randomised controlled hierarchical non-inferiority-superiority trial being conducted in ICUs across Nepal, Thailand and Singapore. The primary outcome is a composite endpoint of death and pneumonia recurrence at day 60. Secondary outcomes include ventilator-associated events, multidrug-resistant organism infection or colonisation, total duration of antibiotic exposure, mechanical ventilation and hospitalisation. Adult patients who satisfy the US Centers for Disease Control and Prevention National Healthcare Safety Network VAP diagnostic criteria are enrolled. Participants are assessed daily until fever subsides for >48 hours and have stable blood pressure, then randomised to a short duration treatment strategy or a standard-of-care duration arm. Antibiotics may be stopped as early as day 3 if respiratory cultures are negative, and day 5 if respiratory cultures are positive in the short-course arm. Participants receiving standard-of-care will receive antibiotics for at least 8 days. Study participants are followed for 60 days after enrolment. An estimated 460 patients will be required to achieve 80% power to determine non-inferiority with a margin of 12%. All outcomes are compared by absolute risk differences. The conclusion of non-inferiority, and subsequently superiority, will be based on unadjusted and adjusted analyses in both the intention-to-treat and per-protocol populations. ETHICS AND DISSEMINATION: The study has received approvals from the Oxford Tropical Research Ethics Committee and the respective study sites. Results will be disseminated to patients, their caregivers, physicians, the funders, the critical care societies and other researchers. TRIAL REGISTRATION NUMBER: NCT03382548.

Point-of-Care Ultrasound Training Among Intensivists in Singapore: A Multicentre Survey.

INTRODUCTION: Point of care ultrasound (POCUS) has become essential in the management of critically ill patients. Multiple POCUS training courses exist, but are not widely adopted in Singapore. Given the discordance between training supply and demand, we aimed to uncover the learning needs and barriers among intensive care medicine (ICM) doctors locally. MATERIALS AND METHODS: An anonymous online survey was carried out from January to April 2019 among ICM doctors from 6 major teaching hospitals in Singapore. RESULTS: 66 out of 160 ICM specialists and trainees responded (41.3%). Although only 6% of respondents had current formal POCUS accreditation, the majority were already using critical care echocardiography (CCE) and pleural/ lung ultrasound. 93% supported having a local training programme. More than 50% of trainees wanted training in CCE, diaphragm/muscle ultrasound, airway ultrasound and ultrasound for neurological disease. More than 50% of specialists wanted training in diaphragm/muscle ultrasound, with mixed interests in other topics. The top 2 obstacles hindering POCUS training were lack of supervisors and locally based programmes. CONCLUSIONS: ICM doctors who responded were supportive of a local POCUS training programme. The programme's curriculum should address the learning needs of the majority of learners, with diaphragm/muscle ultrasound being the top unmet need. The programme would need to develop supervisors and be as affordable as possible.