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 Of the former, 80.8% had no limitation of LST, 13.0% had LST withheld, and 6.2% had LST withdrawn.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.

Blood Pressure Targets for Out-of-Hospital Cardiac Arrest: A Systematic Review and Meta-Analysis.

BACKGROUND: With ideal mean arterial pressure (MAP) targets in resuscitated out-of-hospital cardiac arrest (OHCA) patients unknown, we performed a meta-analysis of randomised controlled trials (RCTs) to compare the effects of higher versus lower MAP targets. METHODS: We searched four databases until 1 May 2023 for RCTs reporting the effects of higher MAP targets (>70 mmHg) in resuscitated OHCA patients and conducted random-effects meta-analyses. The primary outcome was mortality while secondary outcomes were neurological evaluations, arrhythmias, acute kidney injury, and durations of mechanical ventilation and ICU stay. We conducted inverse-variance weighted strata-level meta-regression against a proportion of non-survivors to assess differences between reported MAPs. We also conducted a trial sequential analysis of RCTs. RESULTS: Four RCTs were included. Higher MAP was not associated with reduced mortality (OR: 1.09, 95%-CI: 0.84 to 1.42, p = 0.51), or improved neurological outcomes (OR: 0.99, 95%-CI: 0.77 to 1.27, p = 0.92). Such findings were consistent despite additional sensitivity analyses. Our robust variance strata-level meta-regression revealed no significant associations between mean MAP and the proportion of non-survivors (B: 0.029, 95%-CI: -0.023 to 0.081, p = 0.162), and trial sequential analysis revealed no meaningful survival benefit for higher MAPs. CONCLUSIONS: A higher MAP target was not significantly associated with improved mortality and neurological outcomes in resuscitated OHCA patients.

Mild Hypercapnia or Normocapnia after Out-of-Hospital Cardiac Arrest.

BACKGROUND: Guidelines recommend normocapnia for adults with coma who are resuscitated after out-of-hospital cardiac arrest. However, mild hypercapnia increases cerebral blood flow and may improve neurologic outcomes. METHODS: We randomly assigned adults with coma who had been resuscitated after out-of-hospital cardiac arrest of presumed cardiac or unknown cause and admitted to the intensive care unit (ICU) in a 1:1 ratio to either 24 hours of mild hypercapnia (target partial pressure of arterial carbon dioxide [Paco2], 50 to 55 mm Hg) or normocapnia (target Paco2, 35 to 45 mm Hg). The primary outcome was a favorable neurologic outcome, defined as a score of 5 (indicating lower moderate disability) or higher, as assessed with the use of the Glasgow Outcome Scale-Extended (range, 1 [death] to 8, with higher scores indicating better neurologic outcome) at 6 months. Secondary outcomes included death within 6 months. RESULTS: A total of 1700 patients from 63 ICUs in 17 countries were recruited, with 847 patients assigned to targeted mild hypercapnia and 853 to targeted normocapnia. A favorable neurologic outcome at 6 months occurred in 332 of 764 patients (43.5%) in the mild hypercapnia group and in 350 of 784 (44.6%) in the normocapnia group (relative risk, 0.98; 95% confidence interval [CI], 0.87 to 1.11; P = 0.76). Death within 6 months after randomization occurred in 393 of 816 patients (48.2%) in the mild hypercapnia group and in 382 of 832 (45.9%) in the normocapnia group (relative risk, 1.05; 95% CI, 0.94 to 1.16). The incidence of adverse events did not differ significantly between groups. CONCLUSIONS: In patients with coma who were resuscitated after out-of-hospital cardiac arrest, targeted mild hypercapnia did not lead to better neurologic outcomes at 6 months than targeted normocapnia. (Funded by the National Health and Medical Research Council of Australia and others; TAME ClinicalTrials.gov number, NCT03114033.).

Hemorrhage, Disseminated Intravascular Coagulopathy, and Thrombosis Complications Among Critically Ill Patients with COVID-19: An International COVID-19 Critical Care Consortium Study.

OBJECTIVES: To determine the prevalence and outcomes associated with hemorrhage, disseminated intravascular coagulopathy, and thrombosis (HECTOR) complications in ICU patients with COVID-19. DESIGN: Prospective, observational study. SETTING: Two hundred twenty-nine ICUs across 32 countries. PATIENTS: Adult patients (≥ 16 yr) admitted to participating ICUs for severe COVID-19 from January 1, 2020, to December 31, 2021. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: HECTOR complications occurred in 1,732 of 11,969 study eligible patients (14%). Acute thrombosis occurred in 1,249 patients (10%), including 712 (57%) with pulmonary embolism, 413 (33%) with myocardial ischemia, 93 (7.4%) with deep vein thrombosis, and 49 (3.9%) with ischemic strokes. Hemorrhagic complications were reported in 579 patients (4.8%), including 276 (48%) with gastrointestinal hemorrhage, 83 (14%) with hemorrhagic stroke, 77 (13%) with pulmonary hemorrhage, and 68 (12%) with hemorrhage associated with extracorporeal membrane oxygenation (ECMO) cannula site. Disseminated intravascular coagulation occurred in 11 patients (0.09%). Univariate analysis showed that diabetes, cardiac and kidney diseases, and ECMO use were risk factors for HECTOR. Among survivors, ICU stay was longer (median days 19 vs 12; p < 0.001) for patients with versus without HECTOR, but the hazard of ICU mortality was similar (hazard ratio [HR] 1.01; 95% CI 0.92-1.12; p = 0.784) overall, although this hazard was identified when non-ECMO patients were considered (HR 1.13; 95% CI 1.02-1.25; p = 0.015). Hemorrhagic complications were associated with an increased hazard of ICU mortality compared to patients without HECTOR complications (HR 1.26; 95% CI 1.09-1.45; p = 0.002), whereas thrombosis complications were associated with reduced hazard (HR 0.88; 95% CI 0.79-0.99, p = 0.03). CONCLUSIONS: HECTOR events are frequent complications of severe COVID-19 in ICU patients. Patients receiving ECMO are at particular risk of hemorrhagic complications. Hemorrhagic, but not thrombotic complications, are associated with increased ICU mortality.

Correction: Expanding the utility of the ROX index among patients with acute hypoxemic respiratory failure.

[This corrects the article DOI: 10.1371/journal.pone.0261234.].

The Intersection Between Heart Failure and Critical Care Cardiology: An International Perspective on Structure, Staffing, and Design Considerations.

The overall patient population in contemporary cardiac intensive care units (CICUs) has only increased with respect to patient acuity, complexity, and illness severity. The current population has more cardiac and noncardiac comorbidities, a higher prevalence of multiorgan injury, and consumes more critical care resources than previously. Patients with heart failure (HF) now occupy a large portion of contemporary tertiary or quaternary care CICU beds around the world. In this review, we discuss the core issues that relate to the care of critically ill patients with HF, including global perspectives on the organization, designation, and collaboration of CICUs regionally and across institutions, as well as unique models for provisioning care for patients with HF within a health care setting. The latter includes a discussion of traditional and emerging models, specialized HF units, the makeup and implementation of multidisciplinary team-based decision-making, and cardiac critical care admission and triage practices. This article illustrates the ways in which critically ill patients with HF have helped to shape contemporary CICUs throughout the world and explores how these very patients will similarly help to inform the future maturation of these specialized critical care units. Finally, we will critically examine broad, contemporary, international models of HF and cardiac critical care delivery in North America, Europe, South America, and Asia, and conclude with opportunities for the further investigation and generation of evidence for care delivery.

Hypercoagulability, endotheliopathy, and inflammation approximating 1 year after recovery: Assessing the long-term outcomes in COVID-19 patients.

Sustained hypercoagulability and endotheliopathy are present in convalescent COVID-19 patients for up to 4 months from recovery. The hemostatic, endothelial, and inflammatory profiles of 39 recovered COVID-19 patients were evaluated up to 16 months after recovery from COVID-19. These values were compared with a control group of healthy volunteers (n = 124). 39 patients (71.8% males, median age 43 years) were reviewed at a mean of 12.7 ± 3.6 months following recovery. One patient without cardiovascular risk factors had post COVID-19 acute ischaemic limb. Elevated D-dimer and Factor VIII levels above normal ranges were noted in 17.9% (7/39) and 48.7% (19/39) of patients respectively, with a higher median D-dimer 0.34 FEU µg/mL (IQR 0.28, 0.46) (p < .001) and Factor VIII 150% (IQR 171, 203) (p = .004), versus controls. Thrombin generation (Thromboscreen) showed a higher median endogenous thrombin potential (ETP) of 1352 nM*min (IQR 1152, 1490) (p = .002) and a higher median peak height of 221.4 nM (IQR 170.2, 280.4) (p = 0.01) and delayed lag time 2.4 min (1.42-2.97) (p = 0.0002) versus controls. Raised vWF:Ag and ICAM-1 levels were observed in 17.9% (7/39) and 7.7% (3/39) of patients respectively, with a higher median VWF:Ag 117% (IQR 86, 154) (p = 0.02) and ICAM-1 54.1 ng/mL (IQR 43.8, 64.1) (p = .004) than controls. IL-6 was noted to be raised in 35.9% (14/39) of patients, with a higher median IL-6 of 1.5 pg/mL (IQR 0.6, 3.0) (p = 0.004) versus controls. Subgroup analysis stratifying patients by COVID-19 severity and COVID-19 vaccination preceding SARS-CoV-2 infection did not show statistically significant differences. Hypercoagulability, endothelial dysfunction, and inflammation are still detectable in some patients approximately 1 year after recovery from COVID-19.

Expanding the utility of the ROX index among patients with acute hypoxemic respiratory failure.

BACKGROUND: Delaying intubation in patients who fail high-flow nasal cannula (HFNC) may result in increased mortality. The ROX index has been validated to predict HFNC failure among pneumonia patients with acute hypoxemic respiratory failure (AHRF), but little information is available for non-pneumonia causes. In this study, we validate the ROX index among AHRF patients due to both pneumonia or non-pneumonia causes, focusing on early prediction. METHODS: This was a retrospective observational study in eight Singapore intensive care units from 1 January 2015 to 30 September 2017. All patients >18 years who were treated with HFNC for AHRF were eligible and recruited. Clinical parameters and arterial blood gas values at HFNC initiation and one hour were recorded. HFNC failure was defined as requiring intubation post-HFNC initiation. RESULTS: HFNC was used in 483 patients with 185 (38.3%) failing HFNC. Among pneumonia patients, the ROX index was most discriminatory in pneumonia patients one hour after HFNC initiation [AUC 0.71 (95% CI 0.64-0.79)], with a threshold value of <6.06 at one hour predicting HFNC failure (sensitivity 51%, specificity 80%, positive predictive value 61%, negative predictive value 73%). The discriminatory power remained moderate among pneumonia patients upon HFNC initiation [AUC 0.65 (95% CI 0.57-0.72)], non-pneumonia patients at HFNC initiation [AUC 0.62 (95% CI 0.55-0.69)] and one hour later [AUC 0.63 (95% CI 0.56-0.70)]. CONCLUSION: The ROX index demonstrated moderate discriminatory power among patients with either pneumonia or non-pneumonia-related AHRF at HFNC initiation and one hour later.

Pericarditis and myocarditis after COVID-19 mRNA vaccination in a nationwide setting.

INTRODUCTION: Despite reports suggesting an association between COVID-19 mRNA vaccination and pericarditis and myocarditis, detailed nationwide population-based data are sparsely available. We describe the incidence of pericarditis and myocarditis by age categories and sex after COVID-19 mRNA vaccination from a nationwide mass vaccination programme in Singapore. METHODS: The incidence of adjudicated cases of pericarditis and myocarditis following COVID-19 mRNA vaccination that were reported to the vaccine safety committee between January to July 2021 was compared with the background incidence of myocarditis in Singapore. RESULTS: As of end July 2021, a total of 34 cases were reported (9 pericarditis only, 14 myocarditis only, and 11 concomitant pericarditis and myocarditis) with 7,183,889 doses of COVID-19 mRNA vaccine administered. Of the 9 cases of pericarditis only, all were male except one. The highest incidence of pericarditis was in males aged 12-19 years with an incidence of 1.11 cases per 100,000 doses. Of the 25 cases of myocarditis, 80% (20 cases) were male and the median age was 23 years (range 12-55 years) with 16 cases after the second dose. A higher-than-expected number of cases were seen in males aged 12-19 and 20-29 years, with incidence rates of 3.72 and 0.98 case per 100,000 doses, respectively. CONCLUSION: Data from the national registry in Singapore indicate an increased incidence of pericarditis and myocarditis in younger men after COVID-19 mRNA vaccination.

Global haemostatic tests demonstrate the absence of parameters of hypercoagulability in non-hypoxic mild COVID-19 patients: a prospective matched study.

Severe COVID-19 patients demonstrate hypercoagulability, necessitating thromboprophylaxis. However, less is known about the haemostatic profile in mild COVID-19 patients. We performed an age and gender-matched prospective study of 10 severe and 10 mild COVID-19 patients. Comprehensive coagulation profiling together with Thromboelastography and Clot Waveform Analysis were performed. FBC, PT, APTT, D-dimer, fibrinogen and CWA were repeated every 3 days for both groups and repeat TEG was performed for severe patients up till 15 days. On recruitment, severe patients had markers reflecting hypercoagulability including raised median D-dimer 1.0 µg/mL (IQR 0.6, 1.4) (p = 0.0004), fibrinogen 5.6 g/L (IQR 4.9, 6.6) (p = 0.002), Factor VIII 206% (IQR 171, 203) and vWF levels 265.5% (IQR 206, 321). Mild patients had normal values of PT, aPTT, fibrinogen and D-dimer, and slightly elevated median Factor VIII and von Willebrand factor (vWF) levels. Repeated 3-day assessments for both groups showed declining trends in D-dimer and Fibrinogen. CWA of severe COVID-19 group demonstrated hypercoagulability with an elevated median values of aPTT delta change 78.8% (IQR 69.8, 85.2) (p = 0.001), aPTT clot velocity (min1) 7.8%/s (IQR 6.7, 8.3) (p = 0.001), PT delta change 22.4% (IQR 19.4, 29.5) (p = 0.004), PT min1 7.1%/s (IQR 6.3, 9.0) (p = 0.02), PT clot acceleration (min 2) 3.6%/s2 (IQR 3.2, 4.5) (p = 0.02) and PT clot deceleration (max2) 2.9%/s2 (IQR 2.5, 3.5) (p = 0.02). TEG of severe patients reflected hypercoagulability with significant increases in the median values of CFF MA 34.6 mm (IQR 27.4,38.6) (p = 0.003), CRT Angle 78.9° (IQR 78.3, 80.0) (p = 0.0006), CRT A10 67.6 mm (IQR 65.8, 69.6) (p = 0.007) and CFF A10 32.0 mm (IQR 26.8, 34.0) (p = 0.003). Mild COVID-19 patients had absent hypercoagulability in both CWA and TEG. 2 severe patients developed thromboembolic events while none occurred in the mild COVID-19 group. Mild COVID-19 patients show absent parameters of hypercoagulability in global haemostatic tests while those with severe COVID-19 demonstrated parameters associated with hypercoagulability on the global haemostatic tests together with raised D-Dimer, fibrinogen, Factor VIII and vWF levels.

Impact of Cardiac Arrest Centers on the Survival of Patients With Nontraumatic Out-of-Hospital Cardiac Arrest: A Systematic Review and Meta-Analysis.

Background The role of cardiac arrest centers (CACs) in out-of-hospital cardiac arrest care systems is continuously evolving. Interpretation of existing literature is limited by heterogeneity in CAC characteristics and types of patients transported to CACs. This study assesses the impact of CACs on survival in out-of-hospital cardiac arrest according to varying definitions of CAC and prespecified subgroups. Methods and Results Electronic databases were searched from inception to March 9, 2021 for relevant studies. Centers were considered CACs if self-declared by study authors and capable of relevant interventions. Main outcomes were survival and neurologically favorable survival at hospital discharge or 30 days. Meta-analyses were performed for adjusted odds ratio (aOR) and crude odds ratios. Thirty-six studies were analyzed. Survival with favorable neurological outcome significantly improved with treatment at CACs (aOR, 1.85 [95% CI, 1.52-2.26]), even when including high-volume centers (aOR, 1.50 [95% CI, 1.18-1.91]) or including improved-care centers (aOR, 2.13 [95% CI, 1.75-2.59]) as CACs. Survival significantly increased with treatment at CACs (aOR, 1.92 [95% CI, 1.59-2.32]), even when including high-volume centers (aOR, 1.74 [95% CI, 1.38-2.18]) or when including improved-care centers (aOR, 1.97 [95% CI, 1.71-2.26]) as CACs. The treatment effect was more pronounced among patients with shockable rhythm (P=0.006) and without prehospital return of spontaneous circulation (P=0.005). Conclusions were robust to sensitivity analyses, with no publication bias detected. Conclusions Care at CACs was associated with improved survival and neurological outcomes for patients with nontraumatic out-of-hospital cardiac arrest regardless of varying CAC definitions. Patients with shockable rhythms and those without prehospital return of spontaneous circulation benefited more from CACs. Evidence for bypassing hospitals or interhospital transfer remains inconclusive.

High-flow nasal cannula therapy: A multicentred survey of the practices among physicians and respiratory therapists in Singapore.

BACKGROUND: Use of high-flow nasal cannula (HFNC) has become a regular intervention in the intensive care units especially in patients coming in with hypoxaemic respiratory failure. Clinical practices may differ from published literature. OBJECTIVES: The objective of this study was to determine the clinical practices of physicians and respiratory therapists (RTs) on the use of HFNC. METHODS: A retrospective observational study looking at medical records on HFNC usage from January 2015 to September 2017 was performed and was followed by a series of questions related to HFNC practices. The survey involved physicians and RTs in intensive care units from multiple centres in Singapore from January to April 2018. Indications and thresholds for HFNC usage with titration and weaning practices were compared with the retrospective observational study data. RESULTS: One hundred twenty-three recipients (69.9%) responded to the survey and reported postextubation (87.8%), pneumonia in nonimmunocompromised (65.9%), and pneumonia in immunocompromised (61.8%) patients as the top three indications for HFNC. Of all, 39.8% of respondents wanted to use HFNC for palliative intent. Similar practices were observed in the retrospective study with the large cohort of 63% patients (483 of the total 768 patients) where HFNC was used for acute hypoxaemic respiratory failure and 274 (35.7%) patients to facilitate extubation. The survey suggested that respondents would initiate HFNC at a lower fraction of inspired oxygen (FiO2), higher partial pressure of oxygen to FiO2 ratio, and higher oxygen saturation to FiO2 ratio for nonpneumonia patients than patients with pneumonia. RTs were less likely to start HFNC for patients suffering from pneumonia and interstitial lung disease than physicians. RTs also preferred adjustment of FiO2 to improve oxygen saturations and noninvasive ventilation for rescue. CONCLUSIONS: Among the different intensive care units surveyed, the indications and thresholds for the initiation of HFNC differed in the clinical practices of physicians and RTs.

Predictors and outcomes of high-flow nasal cannula failure following extubation: A multicentre observational study.

INTRODUCTION: Despite adhering to criteria for extubation, up to 20% of intensive care patients require re-intubation, even with use of post-extubation high-flow nasal cannula (HFNC). This study aims to identify independent predictors and outcomes of extubation failure in patients who failed post-extubation HFNC. METHODS: We conducted a multicentre observational study involving 9 adult intensive care units (ICUs) across 5 public hospitals in Singapore. We included patients extubated to HFNC following spontaneous breathing trials. We compared patients who were successfully weaned off HFNC with those who failed HFNC (defined as re-intubation ≤7 days following extubation). Generalised additive logistic regression analysis was used to identify independent risk factors for failed HFNC. RESULTS: Among 244 patients (mean age: 63.92±15.51 years, 65.2% male, median APACHE II score 23.55±7.35), 41 (16.8%) failed HFNC; hypoxia, hypercapnia and excessive secretions were primary reasons. Stroke was an independent predictor of HFNC failure (odds ratio 2.48, 95% confidence interval 1.83-3.37). Failed HFNC, as compared to successful HFNC, was associated with increased median ICU length of stay (14 versus 7 days, P<0.001), ICU mortality (14.6% versus 2.0%, P<0.001) and hospital mortality (29.3% versus 12.3%, P=0.006). CONCLUSION: Post-extubation HFNC failure, especially in patients with stroke as a comorbidity, remains a clinical challenge and predicts poorer clinical outcomes. Our observational study highlights the need for future prospective trials to better identify patients at high risk of post-extubation HFNC failure.