Publications by authors named "Ryan Ruiyang Ling"

10 Publications

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Convalescent Plasma for Patients Hospitalized With Coronavirus Disease 2019: A Meta-Analysis With Trial Sequential Analysis of Randomized Controlled Trials.

Transfus Med Rev 2021 Oct 10. Epub 2021 Oct 10.

Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore; Cardiothoracic Intensive Care Unit, National University Heart Centre, National University Hospital, Singapore. Electronic address:

Current evidence from randomized controlled trials (RCTs) and systematic reviews on the utility of convalescent plasma (CP) in patients with coronavirus disease 2019 (COVID-19) suggests a lack of benefit. We conducted an updated meta-analysis of RCTs with trial sequential analysis to investigate whether convalescent plasma is futile in reducing mortality in patients hospitalized with COVID-19. We searched 6 databases from December 1, 2019 to August 1, 2021 for RCTs comparing the use of CP with standard of care or transfusion of non-CP standard plasma in patients with COVID-19. The risk of bias was assessed using the Cochrane Risk-of-Bias 2 Tool. Random effects (DerSimonian and Laird) meta-analyses were conducted. The primary outcome was the aggregate risk for in-hospital mortality between both arms. We conducted a trial sequential analysis (TSA) based on the pooled relative risks (RRs) for in-hospital mortality. Secondary outcomes included the pooled RR for receipt of mechanical ventilation and mean difference in hospital length of stay. We included 18 RCTs (8702 CP, 7906 control). CP was not associated with a significant mortality benefit (RR: 0.95, 95%-CI: 0.86-1.04, P = .27, high certainty). Subgroup analysis did not find any significant differences (p = 0.30) between patients who received CP within 8 days of symptom onset (RR: 0.97, 95%-CI: 0.79-1.19, P = .80), or after 8 days (RR: 0.79, 95%-CI: 0.57-1.10, P = .16). TSA based on a RR reduction of 10% from a baseline mortality of 20% found that CP was not effective, with the pooled effect within the boundary for futility. CP did not significantly reduce the requirement for mechanical ventilation (RR: 1.00, 95%-CI: 0.91-1.10, P = .99, moderate certainty) or hospital length of stay (+1.32, 95%-CI: -1.86 to +4.52, P = .42, low certainty). CP does not improve relevant clinical outcomes in patients with COVID-19, especially in severe disease. The pooled effect of mortality was within the boundary of futility, suggesting the lack of benefit of CP in patients hospitalized with COVID-19.
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October 2021

Prone positioning during venovenous extracorporeal membrane oxygenation for acute respiratory distress syndrome: a systematic review and meta-analysis.

Crit Care 2021 08 12;25(1):292. Epub 2021 Aug 12.

Adult Intensive Care Services, Prince Charles Hospital, Brisbane, QLD, Australia.

Background: Prone positioning (PP) improves oxygenation and respiratory mechanics and is associated with lower mortality in patients with moderate to severe acute respiratory distress syndrome (ARDS). Despite this, some patients develop refractory hypoxemia and hypercapnia requiring venovenous extracorporeal membrane oxygenation (VV ECMO) support and are usually cared for in supine position. The physiologic and outcome benefits of routine PP of patients during VV ECMO remains unclear. Hence, we conducted the systematic review and meta-analysis to evaluate the outcome benefits of PP for patients with ARDS being treated with VV ECMO.

Methods: After registration with PROSPERO (CRD42020199723), MEDLINE, EMBASE, Scopus and Cochrane databases were searched for relevant studies that reported PP in more than 10 adult patients supported with VV ECMO from origin to 1 March 2021. Studies were reviewed for quality using appropriate Joanna Briggs Institute (JBI) checklists, and certainty of evidence was assessed using the GRADE approach. The random-effects model (DerSimonian and Laird) was used. The primary outcome of interest was cumulative survival. Secondary outcomes were intensive care unit length of stay (ICU LOS) and ECMO duration. Changes in arterial blood gas (ABG) values, ventilator mechanics and complication rates were also studied.

Results: Of 812 potentially relevant publications, 12 studies (640 patients) met our inclusion criteria. Due to overlapping study populations, 11 studies were included in the final meta-analysis. Cumulative survival in patients that underwent PP was 57% (95% CI 41.9-71.4, high certainty). Patients that underwent PP had longer ICU LOS (+ 14.5 days, 95% CI 3.4-25.7, p = 0.01) and ECMO duration (+ 9.6 days, 95% CI 5.5-13.7, p < 0.0001). After PP, patients had significantly higher PaO/FiO ratio, lower PaCO and reduced ventilator driving pressure, and no major complications were reported.

Conclusions: PP during VV ECMO appears safe with a cumulative survival of 57% and may result in longer ECMO runs and ICU LOS. However, evidence from appropriately designed randomized trials is needed prior to widespread adoption of PP on VV ECMO.
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August 2021

Venoarterial extracorporeal membrane oxygenation as mechanical circulatory support in adult septic shock: a systematic review and meta-analysis with individual participant data meta-regression analysis.

Crit Care 2021 07 14;25(1):246. Epub 2021 Jul 14.

Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.

Background: While recommended by international societal guidelines in the paediatric population, the use of venoarterial extracorporeal membrane oxygenation (VA ECMO) as mechanical circulatory support for refractory septic shock in adults is controversial. We aimed to characterise the outcomes of adults with septic shock requiring VA ECMO, and identify factors associated with survival.

Methods: We searched Pubmed, Embase, Scopus and Cochrane databases from inception until 1st June 2021, and included all relevant publications reporting on > 5 adult patients requiring VA ECMO for septic shock. Study quality and certainty in evidence were assessed using the appropriate Joanna Briggs Institute checklist, and the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach, respectively. The primary outcome was survival to hospital discharge, and secondary outcomes included intensive care unit length of stay, duration of ECMO support, complications while on ECMO, and sources of sepsis. Random-effects meta-analysis (DerSimonian and Laird) were conducted.

Data Synthesis: We included 14 observational studies with 468 patients in the meta-analysis. Pooled survival was 36.4% (95% confidence interval [CI]: 23.6%-50.1%). Survival among patients with left ventricular ejection fraction (LVEF) < 20% (62.0%, 95%-CI: 51.6%-72.0%) was significantly higher than those with LVEF > 35% (32.1%, 95%-CI: 8.69%-60.7%, p = 0.05). Survival reported in studies from Asia (19.5%, 95%-CI: 13.0%-26.8%) was notably lower than those from Europe (61.0%, 95%-CI: 48.4%-73.0%) and North America (45.5%, 95%-CI: 16.7%-75.8%). GRADE assessment indicated high certainty of evidence for pooled survival.

Conclusions: When treated with VA ECMO, the majority of patients with septic shock and severe sepsis-induced myocardial depression survive. However, VA ECMO has poor outcomes in adults with septic shock without severe left ventricular depression. VA ECMO may be a viable treatment option in carefully selected adult patients with refractory septic shock.
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July 2021

Extracorporeal membrane oxygenation for COVID-19: a systematic review and meta-analysis.

Crit Care 2021 06 14;25(1):211. Epub 2021 Jun 14.

Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USA.

Background: There are several reports of extracorporeal membrane oxygenation (ECMO) use in patients with coronavirus disease 2019 (COVID-19) who develop severe acute respiratory distress syndrome (ARDS). We conducted a systematic review and meta-analysis to guide clinical decision-making and future research.

Methods: We searched MEDLINE, Embase, Cochrane and Scopus databases from 1 December 2019 to 10 January 2021 for observational studies or randomised clinical trials examining ECMO in adults with COVID-19 ARDS. We performed random-effects meta-analyses and meta-regression, assessed risk of bias using the Joanna Briggs Institute checklist and rated the certainty of evidence using the GRADE approach. Survival outcomes were presented as pooled proportions while continuous outcomes were presented as pooled means, both with corresponding 95% confidence intervals [CIs]. The primary outcome was in-hospital mortality. Secondary outcomes were duration of ECMO therapy and mechanical ventilation, weaning rate from ECMO and complications during ECMO.

Results: We included twenty-two observational studies with 1896 patients in the meta-analysis. Venovenous ECMO was the predominant mode used (98.6%). The pooled in-hospital mortality in COVID-19 patients (22 studies, 1896 patients) supported with ECMO was 37.1% (95% CI 32.3-42.0%, high certainty). Pooled mortality in the venovenous ECMO group was 35.7% (95% CI 30.7-40.7%, high certainty). Meta-regression found that age and ECMO duration were associated with increased mortality. Duration of ECMO support (18 studies, 1844 patients) was 15.1 days (95% CI 13.4-18.7). Weaning from ECMO (17 studies, 1412 patients) was accomplished in 67.6% (95% CI 50.5-82.7%) of patients. There were a total of 1583 ECMO complications reported (18 studies, 1721 patients) and renal complications were the most common.

Conclusion: The majority of patients received venovenous ECMO support for COVID-19-related ARDS. In-hospital mortality in patients receiving ECMO support for COVID-19 was 37.1% during the first year of the pandemic, similar to those with non-COVID-19-related ARDS. Increasing age was a risk factor for death. Venovenous ECMO appears to be an effective intervention in selected patients with COVID-19-related ARDS. PROSPERO CRD42020192627.
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June 2021

Severe COVID-19 and coagulopathy: A systematic review and meta-analysis.

Ann Acad Med Singap 2021 04;50(4):325-335

Cardiothoracic Intensive Care Unit, National University Heart Centre, National University Hospital, Singapore.

Introduction: Coronavirus disease 2019 (COVID-19)-induced coagulopathy (CIC) has been widely reported in the literature. However, the spectrum of abnormalities associated with CIC has been highly variable.

Methods: We conducted a systematic review of the literature (until 1 June 2020) to assess CIC and disease severity during the early COVID-19 pandemic. Primary outcomes were pooled mean differences in platelet count, D-dimer level, prothrombin time, activated partial thromboplastin time (aPTT) and fibrinogen level between non-severe and severe patients, stratified by degree of hypoxaemia or those who died. The risk factors for CIC were analysed. Random-effects meta-analyses and meta-regression were performed using R version 3.6.1, and certainty of evidence was rated using the Grading of Recommendation, Assessment, Development, and Evaluation approach.

Results: Of the included 5,243 adult COVID-19 patients, patients with severe COVID-19 had a significantly lower platelet count, and higher D-dimer level, prothrombin time and fibrinogen level than non-severe patients. Pooled mean differences in platelet count (-19.7×109/L, 95% confidence interval [CI] -31.7 to -7.6), D-dimer level (0.8μg/mL, 95% CI 0.5-1.1), prothrombin time (0.4 second, 95% CI 0.2-0.6) and fibrinogen level (0.6g/L, 95% CI 0.3-0.8) were significant between the groups. Platelet count and D-dimer level were significant predictors of disease severity on meta-regression analysis. Older men had higher risks of severe coagulopathic disease.

Conclusion: Significant variability in CIC exists between non-severe and severe patients, with platelet count and D-dimer level correlating with disease severity. Routine monitoring of all coagulation parameters may help to assess CIC and decide on the appropriate management.
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April 2021

Outcomes of Pediatric Extracorporeal Cardiopulmonary Resuscitation: A Systematic Review and Meta-Analysis.

Crit Care Med 2021 04;49(4):682-692

University of Texas Southwestern Medical Center, Dallas, TX.

Objective: The goal of this work is to provide insight into survival and neurologic outcomes of pediatric patients supported with extracorporeal cardiopulmonary resuscitation.

Data Sources: A systematic search of Embase, PubMed, Cochrane, Scopus, Google Scholar, and Web of Science was performed from January 1990 to May 2020.

Study Selection: A comprehensive list of nonregistry studies with pediatric patients managed with extracorporeal cardiopulmonary resuscitation was included.

Data Extraction: Study characteristics and outcome estimates were extracted from each article.

Data Synthesis: Estimates were pooled using random-effects meta-analysis. Differences were estimated using subgroup meta-analysis and meta-regression. The Meta-analyses Of Observational Studies in Epidemiology guideline was followed and the certainty of evidence was assessed using Grading of Recommendations Assessment, Development and Evaluation system. Twenty-eight studies (1,348 patients) were included. There was a steady increase in extracorporeal cardiopulmonary resuscitation occurrence rate from the 1990s until 2020. There were 32, 338, and 1,094 patients' articles published between 1990 and 2000, 2001 and 2010, and 2010 and 2020, respectively. More than 70% were cannulated for a primary cardiac arrest. Pediatric extracorporeal cardiopulmonary resuscitation patients had a 46% (CI 95% = 43-48%; p < 0.01) overall survival rate. The rate of survival with favorable neurologic outcome was 30% (CI 95% = 27-33%; p < 0.01).

Conclusions: The use of extracorporeal cardiopulmonary resuscitation is rapidly expanding, particularly for children with underlying cardiac disease. An overall survival of 46% and favorable neurologic outcomes add credence to this emerging therapy.
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April 2021

Concurrent Use of Renal Replacement Therapy during Extracorporeal Membrane Oxygenation Support: A Systematic Review and Meta-Analysis.

J Clin Med 2021 Jan 11;10(2). Epub 2021 Jan 11.

Cardiothoracic Intensive Care Unit, National University Heart Centre, National University Hospital, Singapore 119228, Singapore.

Patients supported with extracorporeal membrane oxygenation (ECMO) often receive renal replacement therapy (RRT). We conducted this systematic review and meta-analysis (between January 2000 and September 2020) to assess outcomes in patients who received RRT on ECMO. Random-effects meta-analyses were performed using R 3.6.1 and certainty of evidence was rated using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach. The primary outcome was pooled mortality. The duration of ECMO support and ICU/hospital lengths of stay were also investigated. Meta-regression analyses identified factors associated with mortality. A total of 5896 adult patients (from 24 observational studies and 1 randomised controlled trial) were included in this review. Overall pooled mortality due to concurrent use of RRT while on ECMO from observational studies was 63.0% (95% CI: 56.0-69.6%). In patients receiving RRT, mortality decreased by 20% in the last five years; the mean duration of ECMO support and ICU and hospital lengths of stay were 9.33 days (95% CI: 7.74-10.92), 15.76 days (95% CI: 12.83-18.69) and 28.47 days (95% CI: 22.13-34.81), respectively, with an 81% increased risk of death (RR: 1.81, 95% CI: 1.56-2.08, < 0.001). RRT on ECMO was associated with higher mortality rates and a longer ICU/hospital stay compared to those without RRT. Future research should focus on minimizing renal dysfunction in ECMO patients and define the optimal timing of RRT initiation.
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January 2021

Vascular Complications of Extracorporeal Membrane Oxygenation: A Systematic Review and Meta-Regression Analysis.

Crit Care Med 2020 12;48(12):e1269-e1277

Cardiothoracic Intensive Care Unit, Department of Cardiothoracic and Vascular Surgery, National University Heart Centre, National University Hospital, Singapore.

Objectives: Perform a systematic review and meta-analysis of vascular complications associated with extracorporeal membrane oxygenation and identify prognostic and predictive factors.

Data Sources: Systematic search for publications reporting vascular complications on extracorporeal membrane oxygenation, published from 1972 to January 31, 2020, was conducted via PubMed, Scopus, and Embase.

Study Selection: Of 4,076 references screened, 47 studies with 6,583 patients were included in final analyses. Studies with fewer than 10 patients were excluded.

Data Extraction: Relevant data, including demographics, comorbidities, extracorporeal membrane oxygenation and cannulation characteristics, occurrence rates of early and late vascular complications, patient outcomes, and use of distal perfusion cannula, were extracted from selected articles into an excel sheet specifically designed for this review.

Data Synthesis: Random-effects meta-analyses and meta-regression analyses were undertaken. Overall pooled estimate of vascular complications in our meta-analysis was 29.5% (95% CI, 23.6-35.9%). Two-thousand three-hundred forty-seven vascular complications in 6,124 venoarterial extracorporeal membrane oxygenation patients compared with 95 in 459 venovenous extracorporeal membrane oxygenation patients (odds ratio, 2.35; 95% CI, 1.87-2.96; p < 0.0001) were analyzed. Successful weaning off extracorporeal membrane oxygenation occurred in 60.6% of pooled patients; 46.2% were eventually discharged. Pooled prevalences of vascular complications like significant bleeding, limb ischemia, and cannula site bleeding were 15.4% (95% CI, 8.6-23.7%), 12.6% (95% CI, 10.0-15.5%), and 12.6% (95% CI, 9.6-18.5%), respectively. Meta-analysis showed that the use of distal perfusion cannula was associated with lower odds of limb ischemia (odds ratio, 1.93; 95% CI, 1.17-2.47; p = 0.03) Meta-regression showed that male sex, smoking, advanced age, and comorbidities contributed to higher in-hospital mortality, while distal perfusion cannula was protective.

Conclusions: Nearly a third of patients on extracorporeal membrane oxygenation develop vascular complications; elderly males with comorbidities appear vulnerable. The use of distal perfusion cannulas caused significant reduction in limb ischemia and mortality.
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December 2020