Publications by authors named "Jan Hau Lee"

129 Publications

Large scale cytokine profiling uncovers elevated IL12-p70 and IL-17A in severe pediatric acute respiratory distress syndrome.

Sci Rep 2021 Jul 8;11(1):14158. Epub 2021 Jul 8.

KK Research Centre, KK Women's and Children's Hospital, 100 Bukit Timah Road, Singapore, 229899, Singapore.

The specific cytokines that regulate pediatric acute respiratory distress syndrome (PARDS) pathophysiology remains unclear. Here, we evaluated the respiratory cytokine profile in PARDS to identify the molecular signatures associated with severe disease. A multiplex suspension immunoassay was used to profile 45 cytokines, chemokines and growth factors. Cytokine concentrations were compared between severe and non-severe PARDS, and correlated with oxygenation index (OI). Partial least squares regression modelling and regression coefficient plots were used to identify a composite of key mediators that differentially segregated severe from non-severe disease. The mean (standard deviation) age and OI of this cohort was 5.2 (4.9) years and 17.8 (11.3), respectively. Early PARDS patients with severe disease exhibited a cytokine signature that was up-regulated for IL-12p70, IL-17A, MCP-1, IL-4, IL-1β, IL-6, MIP-1β, SCF, EGF and HGF. In particular, pro-inflammatory cytokines (IL-6, MCP-1, IP-10, IL-17A, IL-12p70) positively correlated with OI early in the disease. Whereas late PARDS was characterized by a differential lung cytokine signature consisting of both up-regulated (IL-8, IL-12p70, VEGF-D, IL-4, GM-CSF) and down-regulated (IL-1β, EGF, Eotaxin, IL-1RA, and PDGF-BB) profiles segregating non-severe and severe groups. This cytokine signature was associated with increased transcription, T cell activation and proliferation as well as activation of mitogen-activated protein kinase pathway that underpin PARDS severity.
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http://dx.doi.org/10.1038/s41598-021-93705-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8266860PMC
July 2021

Comparative Analysis of Pediatric COVID-19 Infection in Southeast Asia, South Asia, Japan, and China.

Am J Trop Med Hyg 2021 Jun 15. Epub 2021 Jun 15.

Duke-NUS Medical School, Singapore.

There is a scarcity of data regarding coronavirus disease 2019 (COVID-19) infection in children from southeast and south Asia. This study aims to identify risk factors for severe COVID-19 disease among children in the region. This is an observational study of children with COVID-19 infection in hospitals contributing data to the Pediatric Acute and Critical Care COVID-19 Registry of Asia. Laboratory-confirmed COVID-19 cases were included in this registry. The primary outcome was severity of COVID-19 infection as defined by the World Health Organization (WHO) (mild, moderate, severe, or critical). Epidemiology, clinical and laboratory features, and outcomes of children with COVID-19 are described. Univariate and multivariable logistic regression models were used to identify risk factors for severe/critical disease. A total of 260 COVID-19 cases from eight hospitals across seven countries (China, Japan, Singapore, Malaysia, Indonesia, India, and Pakistan) were included. The common clinical manifestations were similar across countries: fever (64%), cough (39%), and coryza (23%). Approximately 40% of children were asymptomatic, and overall mortality was 2.3%, with all deaths reported from India and Pakistan. Using the multivariable model, the infant age group, presence of comorbidities, and cough on presentation were associated with severe/critical COVID-19. This epidemiological study of pediatric COVID-19 infection demonstrated similar clinical presentations of COVID-19 in children across Asia. Risk factors for severe disease in children were age younger than 12 months, presence of comorbidities, and cough at presentation. Further studies are needed to determine whether differences in mortality are the result of genetic factors, cultural practices, or environmental exposures.
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http://dx.doi.org/10.4269/ajtmh.21-0299DOI Listing
June 2021

A narrative review of diaphragmatic ultrasound in pediatric critical care.

Pediatr Pulmonol 2021 Aug 3;56(8):2471-2483. Epub 2021 Jun 3.

Children's Intensive Care Unit, Department of Pediatric Subspecialties, KK Women's and Children's Hospital, Singapore, Singapore.

The use of point of care ultrasound (POCUS) at the bedside has increased dramatically within emergency medicine and in critical care. Applications of POCUS have spread to include diaphragmatic assessments in both adults and children. Diaphragm POCUS can be used to assess for diaphragm dysfunction (DD) and atrophy or to guide ventilator titration and weaning. Quantitative, semi-quantitative and qualitative measurements of diaphragm thickness, diaphragm excursion, and diaphragm thickening fraction provide objective data related to DD and atrophy. The potential for quick, noninvasive, and repeatable bedside diaphragm assessments has led to a growing amount of literature on diaphragm POCUS. To date, there are no reviews of the current state of diaphragm POCUS in pediatric critical care. The aims of this narrative review are to summarize the current literature regarding techniques, reference values, applications, and future innovations of diaphragm POCUS in critically ill children. A summary of current practice and future directions will be discussed.
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http://dx.doi.org/10.1002/ppul.25518DOI Listing
August 2021

Singapore's health outcomes after critical illness in kids: A study protocol exploring health outcomes of families 6 months after critical illness.

J Adv Nurs 2021 Aug 3;77(8):3531-3541. Epub 2021 Jun 3.

University of Plymouth, Plymouth, UK.

Aim: To explore and understand the impact of paediatric intensive care unit (PICU) admission on longitudinal health outcomes, experiences and support needs of children and their parents in the first 6 months after PICU discharge and to examine the role of ethnicity.

Design: This study uses a prospective, longitudinal design.

Methods: The sample will include children (N = 110) and at least one parent (N = 110) admitted to the PICU (KKH-AM start-up fund, October 2020). Quantitative study: Participants will be recruited at PICU admission. Data will be collected at five time points: during PICU admission (T0), at PICU discharge (T1), 1 month (T2), 3 months (T3) and 6 months (T4) after PICU discharge. Questionnaires will assess physical and cognitive outcomes of the child survivor. Emotional and social health outcomes will be assessed for both the child and the parents. Qualitative study: At least 12 parents will take part in a semi-structured interview conducted at both 1 and 6 months after PICU to explore their experiences and support needs after PICU discharge. All interviews will be audio-recorded with verbatim transcription. We will use framework analysis for qualitative data analysis.

Discussion: Understanding of Singapore health outcomes after critical illness in kids (SHACK) and their families is limited. There is an urgent need to comprehensively understand the health trajectory and consequences of the PICU child survivors and their families. This research will be the first to explore the health outcomes, needs and experiences after paediatric critical illness in Asia.

Impact: This study will provide an understanding of the health outcomes and trajectory of children and parents in the first 6 months after PICU discharge and examine the association between race and outcomes after PICU discharge. Identification of modifiable pre-disposing risk factors during the PICU admission will inform future interventions to improve long-term outcomes of children and parents following paediatric critical illness.

Trial Registration: Clinicaltrial.gov: ClinicalTrials.gov Identifier: NCT04637113.
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http://dx.doi.org/10.1111/jan.14911DOI Listing
August 2021

Statistical Note: Using Scoping and Systematic Reviews.

Pediatr Crit Care Med 2021 06;22(6):572-575

Department of Pediatric Subspecialties, Children's Intensive Care Unit, KK Women's and Children's Hospital, Singapore.

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http://dx.doi.org/10.1097/PCC.0000000000002738DOI Listing
June 2021

High burden of acquired morbidity in survivors of pediatric acute respiratory distress syndrome.

Pediatr Pulmonol 2021 Aug 8;56(8):2769-2775. Epub 2021 Jun 8.

Children's Intensive Care Unit, Department of Pediatric Subspecialties, KK Women's and Children's Hospital, Singapore, Singapore.

Introduction: With improving mortality rates in pediatric acute respiratory distress syndrome (PARDS), functional outcomes in survivors are increasingly important. We aim to describe the change in functional status score (FSS) from baseline to discharge and to identify risk factors associated with poor functional outcomes.

Methods: We examined clinical records of patients with PARDS admitted to our pediatric intensive care unit (PICU) from 2009 to 2016. Our primary outcome was acquired morbidity at PICU and hospital discharge (defined by an increase in FSS ≥3 points above baseline). We included severity of illness scores and severity of PARDS in our bivariate analysis for risk factors for acquired morbidity.

Results: There were 181 patients with PARDS, of which 90 (49.7%) survived. Median pediatric index of mortality 2 score was 4.05 (1.22, 8.70) and 21 (23.3%) survivors had severe PARDS. A total of 59 (65.6%) and 14 (15.6%) patients had acquired morbidity at PICU and hospital discharge, respectively. Median baseline FSS was 6.00 (6.00, 6.25), which increased to 11.00 (8.75, 12.00) at PICU discharge before decreasing to 7.50 (6.00, 9.25) at hospital discharge. All patients had significantly higher FSS at both PICU and hospital discharge median compared to baseline. Feeding and respiratory were the most affected domains. After adjusting for severity of illness, severity categories of PARDS were not a risk factor for acquired morbidity.

Conclusion: Acquired morbidity in respiratory and feeding domains was common in PARDS survivors. Specific attention should be given to these two domains of functional outcomes in these children.
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http://dx.doi.org/10.1002/ppul.25520DOI Listing
August 2021

Anti-N-Methyl-D-aspartate receptor encephalitis masquerading as fever of unknown origin.

Clin Case Rep 2021 Apr 4;9(4):2323-2327. Epub 2021 Mar 4.

Paediatric Neurology Service Department of Paediatric Medicine KK Women's and Children's Hospital Singapore City Singapore.

Fever of unknown origin (FUO) is a diagnostic challenge. Anti-N-methyl-D-aspartate receptor encephalitis should be considered in children with FUO and new-onset neurological symptoms without significant encephalopathy.
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http://dx.doi.org/10.1002/ccr3.4025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8077294PMC
April 2021

Association between admission body mass index and outcomes in critically ill children: A systematic review and meta-analysis.

Clin Nutr 2021 May 18;40(5):2772-2783. Epub 2021 Apr 18.

Duke-NUS Medical School, 8 College Rd, 169857, Singapore; Children's Intensive Care Unit, Department of Pediatric Subspecialties, KK Women's and Children's Hospital, 100 Bukit Timah Rd, 229899, Singapore. Electronic address:

Background & Aims: The association between nutritional status at pediatric intensive care unit (PICU) admission with clinical outcomes remains unclear. We conducted this systematic review to summarize the overall impact of PICU admission body mass index (BMI) on clinical outcomes.

Methods: We searched the following medical databases from inception through May 2020: PubMed, Excerpta Medica database (Embase), Cumulative Index of Nursing and Allied Health Literature (CINAHL), Cochrane Library, and Web of Science. We included studies on patients ≤18 years old admitted to a PICU that investigated the effect of BMI on mortality, PICU or hospital length of stay (LOS), or duration of mechanical ventilation (MV). Classification of underweight, overweight, and obese were based on each study's criteria.

Results: There was a total of 21,558 patients from 20 included studies. 12,936 (60.0%), 2965 (13.8%), 2182 (10.1%), 3348 (15.5%) were normal weight, underweight, overweight, and obese patients, respectively. Relative to normal weight patients, underweight (OR 1.32, 95% CI 0.89-1.98; p = 0.171) and overweight/obese patients (OR 1.10, 95% CI 0.86-1.42; p = 0.446) did not have an increase risk in mortality. There was also no difference in duration of MV, PICU and hospital LOS between all three weight categories. Included studies were heterogeneous and lacked standardized nutritional categorization. Sensitivity analysis including only studies that used BMI z-scores as nutritional classification (n = 5) revealed that underweight patients had higher odds of mortality compared to patients with normal weight (OR 1.61, 95% CI 1.35-1.92; p < 0.001); studies that used percentiles as classification did not reveal any differences in mortality. Sensitivity analysis including only studies containing mixed PICU cohorts (i.e., excluding specialized cohorts e.g., congenital heart surgeries, burns) revealed higher mortality odds in underweight patients (OR 1.53, 95% CI 1.25-1.87; p < 0.001) and overweight/obese patients (OR 1.51, 95% CI 1.14-2.01; p = 0.004) relative to normal weight patients.

Conclusions: Our systematic review did not reveal any association between PICU admission BMI status and outcomes in critically ill children. Further investigation with standardized nutrition status classification on admission, stratified by patient subgroups, is needed to clarify the association between nutritional status and clinical outcomes of PICU patients.
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http://dx.doi.org/10.1016/j.clnu.2021.04.010DOI Listing
May 2021

Early Coagulopathy in Pediatric Traumatic Brain Injury: A Pediatric Acute and Critical Care Medicine Asian Network (PACCMAN) Retrospective Study.

Neurosurgery 2021 Jul;89(2):283-290

Duke-NUS Medical School, Singapore.

Background: Although early coagulopathy increases mortality in adults with traumatic brain injury (TBI), less is known about pediatric TBI.

Objective: To describe the prothrombin time (PT), activated partial thromboplastin time (APTT), and platelet levels of children with moderate to severe TBI to identify predictors of early coagulopathy and study the association with clinical outcomes.

Methods: Using the Pediatric Acute and Critical Care Medicine Asian Network (PACCMAN) TBI retrospective cohort, we identified patients <16 yr old with a Glasgow Coma Scale (GCS) ≤13. We compared PT, APTT, platelets, and outcomes between children with isolated TBI and multiple trauma with TBI. We performed logistic regressions to identify predictors of early coagulopathy and study the association with mortality and poor functional outcomes.

Results: Among 370 children analyzed, 53/370 (14.3%) died and 127/370 (34.3%) had poor functional outcomes. PT was commonly deranged in both isolated TBI (53/173, 30.6%) and multiple trauma (101/197, 51.3%). Predictors for early coagulopathy were young age (adjusted odds ratio [aOR] 0.94, 95% CI 0.88-0.99, P = .023), GCS < 8 (aOR 1.96, 95% CI 1.26-3.06, P = .003), and presence of multiple trauma (aOR 2.21, 95% confidence interval [CI] 1.37-3.60, P = .001). After adjusting for age, gender, GCS, multiple traumas, and presence of intracranial bleed, children with early coagulopathy were more likely to die (aOR 7.56, 95% CI 3.04-23.06, P < .001) and have poor functional outcomes (aOR 2.16, 95% CI 1.26-3.76, P = .006).

Conclusion: Early coagulopathy is common and independently associated with death and poor functional outcomes among children with TBI.
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http://dx.doi.org/10.1093/neuros/nyab157DOI Listing
July 2021

Early prediction of serious infections in febrile infants incorporating heart rate variability in an emergency department: a pilot study.

Emerg Med J 2021 Apr 16. Epub 2021 Apr 16.

Department of Emergency Medicine, Singapore General Hospital, Singapore.

Background: Early differentiation of febrile young infants with from those without serious infections (SIs) remains a diagnostic challenge. We sought to (1) compare vital signs and heart rate variability (HRV) parameters between febrile infants with versus without SIs, (2) assess the performance of HRV and vital signs with reference to current triage tools and (3) compare HRV and vital signs to HRV, vital signs and blood biomarkers, when predicting for the presence of SIs.

Methods: Using a prospective observational design, we recruited patients <3 months old presenting to a tertiary paediatric ED in Singapore from December 2018 through November 2019. We obtained patient demographic characteristics, triage assessment (including the Severity Index Score (SIS)), HRV parameters (time, frequency and non-linear domains) and laboratory results. We performed multivariable logistic regression analyses to predict the presence of an SI, using area under the curve (AUC) with the corresponding 95% CI to assess predictive capability.

Results: Among 203 infants with a mean age of 38.4 days (SD 27.6), 67 infants (33.0%) had an SI. There were significant differences in the time, frequency and non-linear domains of HRV parameters between infants with versus without SIs. In predicting SIs, gender, temperature and the HRV non-linear parameter Poincaré plot SD2 (AUC 0.78, 95% CI 0.71 to 0.84) performed better than SIS alone (AUC 0.61, 95% CI 0.53 to 0.68). Model performance improved with the addition of absolute neutrophil count and C reactive protein (AUC 0.82, 95% CI 0.76 to 0.89).

Conclusion: An exploratory prediction model incorporating HRV and biomarkers improved prediction of SIs. Further research is needed to assess if HRV can identify which young febrile infants have an SI at ED triage.

Trial Registration Number: NCT04103151.
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http://dx.doi.org/10.1136/emermed-2020-210675DOI Listing
April 2021

Skeletal Muscle Changes, Function, and Health-Related Quality of Life in Survivors of Pediatric Critical Illness.

Crit Care Med 2021 Apr 2. Epub 2021 Apr 2.

1 Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. 2 Department of Nutrition and Dietetics, KK Women's and Children's Hospital, Singapore. 3 Children's Intensive Care Unit, KK Women's Children's Hospital, Singapore. 4 Duke-NUS Medical School, Singapore. 5 Clinical Nutrition Research Center, Agency for Science, Technology and Research, Singapore. 6 Department of Endocrinology, Tan Tock Seng Hospital, Singapore. 7 Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore. 8 William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom. 9 Adult Critical Care Unit, Royal London Hospital, London, United Kingdom.

Objectives: To describe functional and skeletal muscle changes observed during pediatric critical illness and recovery and their association with health-related quality of life.

Design: Prospective cohort study.

Setting: Single multidisciplinary PICU.

Patients: Children with greater than or equal to 1 organ dysfunction, expected PICU stay greater than or equal to 48 hours, expected survival to discharge, and without progressive neuromuscular disease or malignancies were followed from admission to approximately 6.7 months postdischarge.

Interventions: None.

Measurements And Main Results: Functional status was measured using the Functional Status Scale score and Pediatric Evaluation of Disability Inventory-Computer Adaptive Test. Patient and parental health-related quality of life were measured using the Pediatric Quality of Life Inventory and Short Form-36 questionnaires, respectively. Quadriceps muscle size, echogenicity, and fat thickness were measured using ultrasonography during PICU stay, at hospital discharge, and follow-up. Factors affecting change in muscle were explored. Associations between functional, muscle, and health-related quality of life changes were compared using regression analysis. Seventy-three survivors were recruited, of which 44 completed follow-ups. Functional impairment persisted in four of 44 (9.1%) at 6.7 months (interquartile range, 6-7.7 mo) after discharge. Muscle size decreased during PICU stay and was associated with inadequate energy intake (adjusted β, 0.15; 95% CI, 0.02-0.28; p = 0.030). No change in echogenicity or fat thickness was observed. Muscle growth postdischarge correlated with mobility function scores (adjusted β, 0.05; 95% CI, 0.01-0.09; p = 0.046). Improvements in mobility scores were associated with improved physical health-related quality of life at follow-up (adjusted β, 1.02; 95% CI, 0.23-1.81; p = 0.013). Child physical health-related quality of life at hospital discharge was associated with parental physical health-related quality of life (adjusted β, 0.09; 95% CI, 0.01-0.17; p = 0.027).

Conclusions: Muscle decreased in critically ill children, which was associated with energy inadequacy and impaired muscle growth postdischarge. Muscle changes correlated with change in mobility, which was associated with child health-related quality of life. Mobility, child health-related quality of life, and parental health-related quality of life appeared to be interlinked.
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http://dx.doi.org/10.1097/CCM.0000000000004970DOI Listing
April 2021

Psychosocial impact of the COVID-19 pandemic on paediatric healthcare workers.

Ann Acad Med Singap 2021 03;50(3):203-211

Children's Intensive Care Unit, Division of Nursing, KK Women's and Children's Hospital, Singapore.

Introduction: Frontline healthcare workers (HCWs) exposed to coronavirus disease 2019 (COVID-19) are at risk of psychological distress. This study evaluates the psychological impact of COVID-19 pandemic on HCWs in a national paediatric referral centre.

Methods: This was a survey-based study that collected demographic, work environment and mental health data from paediatric HCWs in the emergency, intensive care and infectious disease units. Psychological impact was measured using the Depression, Anxiety, Stress Scale-21. Multivariate regression analysis was performed to identify risk factors associated with psychological distress.

Results: The survey achieved a response rate of 93.9% (430 of 458). Of the 430 respondents, symptoms of depression, anxiety and stress were reported in 168 (39.1%), 205 (47.7%) and 106 (24.7%), respectively. Depression was reported in the mild (47, 10.9%), moderate (76, 17.7%), severe (23, 5.3%) and extremely severe (22, 5.1%) categories. Anxiety (205, 47.7%) and stress (106, 24.7%) were reported in the mild category only. Collectively, regression analysis identified female sex, a perceived lack of choice in work scope/environment, lack of protection from COVID-19, lack of access to physical activities and rest, the need to perform additional tasks, and the experience of stigma from the community as risk factors for poor psychological outcome.

Conclusion: A high prevalence of depression, anxiety and stress was reported among frontline paediatric HCWs during the COVID-19 pandemic. Personal psychoneuroimmunity and organisational prevention measures can be implemented to lessen psychiatric symptoms. At the national level, involving mental health professionals to plan and coordinate psychological intervention for the country should be considered.
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March 2021

A Cross-Sectional Study of the Clinical Metrics of Functional Status Tools in Pediatric Critical Illness.

Pediatr Crit Care Med 2021 Apr 2. Epub 2021 Apr 2.

Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. Department of Nutrition and Dietetics, KK Women's and Children's Hospital, Singapore. Children's Intensive Care Unit, KK Women's Children's Hospital, Singapore. Duke-NUS Medical School, Singapore. Department of Physiotherapy, KK Women's and Children's Hospital, Singapore. Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore. Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research, Singapore. Department of Endocrinology, Tan Tock Seng Hospital, Singapore. William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom. Adult Critical Care Unit, Royal London Hospital, London, United Kingdom.

Objectives: To determine the clinical metrics of functional assessments in pediatric critical illness survivors.

Design: Cross-sectional observational study.

Setting: PICU follow-up clinic.

Patients: Forty-four PICU survivors 6-12 months post PICU stay, and 52 healthy controls 0-18 years old.

Interventions: Nil.

Measurements And Main Results: Function was assessed using the Pediatric Quality of Life Inventory 4.0 generic scales and infant scales, the Pediatric Evaluation of Disability Inventory-Computer Adaptive Test, and the Functional Status Scale. Muscle strength was assessed by hand grip strength in children greater than or equal to 6 years. Clinical metrics assessed included floor and ceiling effects, known-group, and convergent validity. Floor and ceiling effects were present if the participants achieving the worst or best scores exceeded 15%, respectively. Known-group validity was assessed by comparing scores between those with and without complex chronic conditions and abnormal versus good baseline function. Convergent validity was assessed using partial correlation between two tools. Functional Status Scale and Pediatric Quality of Life Inventory physical domain scores showed significant ceiling effects in PICU survivors (69.2% and 15.4%, respectively, achieved the highest possible score). Functional scores were not significantly different between children with or without complex chronic conditions or children with good versus abnormal baseline function. In healthy children, Pediatric Quality of Life Inventory physical correlated moderately with hand grip strength (partial r = 0.66; p < 0.001), whereas Pediatric Quality of Life Inventory psychosocial correlated moderately with Pediatric Evaluation of Disability Inventory-Computer Adaptive Test social/cognitive score (partial r = 0.53; p < 0.001). In PICU survivors, only Pediatric Quality of Life Inventory physical and Pediatric Evaluation of Disability Inventory-Computer Adaptive Test mobility scores were correlated (partial r = 0.55; p < 0.001).

Conclusions: PICU functional assessment tools have varying clinical metrics. Considering ceiling effects, Pediatric Evaluation of Disability Inventory-Computer Adaptive Test may be more suitable in survivors than Functional Status Scale. Differences in scores between children with or without complex chronic conditions, and with or without baseline functional impairment, were not observed. Functional assessments likely require a combination of tools to measure the spectrum of pediatric critical illness and recovery.
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http://dx.doi.org/10.1097/PCC.0000000000002722DOI Listing
April 2021

The Impact of Traumatic Brain Injury on Neurocognitive Outcomes in Children: a Systematic Review and Meta-Analysis.

J Neurol Neurosurg Psychiatry 2021 Mar 31. Epub 2021 Mar 31.

Duke-NUS Medical School, Singapore

Objective: To assess the burden of paediatric traumatic brain injury (TBI) on neurocognition via a systematic review and meta-analysis.

Methods: Studies that compared neurocognitive outcomes of paediatric patients with TBI and controls were searched using Medline, Embase, PsycINFO and Cochrane Central Register of Controlled Trials, between January 1988 and August 2019. We presented a random-effects model, stratified by TBI severity, time of assessment post injury and age.

Results: Of 5919 studies, 41 (patients=3717) and 33 (patients=3118) studies were included for the systematic review and meta-analysis, respectively. Studies mostly measured mild TBI (n=26, patients=2888) at 0-3 months postinjury (n=17, patients=2502). At 0-3 months postinjury, standardised mean differences between TBI and controls for executive function were -0.04 (95% CI -0.14 to 0.07; I=0.00%), -0.18 (95% CI -0.29 to -0.06; I=26.1%) and -0.95 (95% CI -1.12 to -0.77; I=10.1%) for mild, moderate and severe TBI, respectively; a similar effect was demonstrated for learning and memory. Severe TBI had the worst outcomes across all domains and persisted >24 months postinjury. Commonly used domains differed largely from workgroup recommendations. Risk of bias was acceptable for all included studies.

Conclusion: A dose-dependent relationship between TBI severity and neurocognitive outcomes was evident in executive function and in learning and memory. Cognitive deficits were present for TBIs of all severity but persisted among children with severe TBI. The heterogeneity of neurocognitive scales makes direct comparison between studies difficult. Future research into lesser explored domains and a more detailed assessment of neurocognitive deficits in young children are required to better understand the true burden of paediatric TBI.
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http://dx.doi.org/10.1136/jnnp-2020-325066DOI Listing
March 2021

Alternating hemiplegia of childhood presenting as recurrent apnoea in a term newborn infant.

Ann Acad Med Singap 2021 Feb;50(2):174-176

Department of Paediatrics, KK Women's and Children's Hospital, Singapore.

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February 2021

Pediatric Severe Sepsis and Shock in Three Asian Countries: A Retrospective Study of Outcomes in Nine PICUs.

Pediatr Crit Care Med 2021 Mar 1. Epub 2021 Mar 1.

1 Division of Pediatric Critical Care, Department of Pediatrics, King Chulalongkorn Memorial Hospital, Bangkok, Thailand. 2 Department of Pediatrics, KK Women's and Children's Hospital, Singapore. 3 Hat Yai Medical Center, Division of Pediatric Pulmonary & Critical care, Department of Pediatrics, Songkhla Province, Thailand. 4 Pediatric Critical Care Division, Department of Pediatrics, Ramathibodi Hospital, Bangkok, Thailand. 5 Division of Pulmonary and Critical Care Unit, Department of Pediatrics, Chiang Mai University, Chiang Mai, Thailand. 6 Pediatric Critical Care Division, Department of Pediatrics, National University, Singapore. 7 Pediatric Intensive Care Unit, Department of Pediatrics, Sarawak General Hospital, Sarawak, Malaysia. 8 Pediatric Intensive Care Unit, Department of Pediatrics, National University of Malaysia, Selangor, Malaysia. 9 Pediatric Critical Care Division, Department of Pediatrics, Siriraj Hospital, Bangkok, Thailand.

Objectives: Pediatric sepsis remains a major health problem and is a leading cause of death and long-term disability worldwide. This study aims to characterize epidemiologic, therapeutic, and outcome features of pediatric severe sepsis and septic shock in three Asian countries.

Design: A multicenter retrospective study with longitudinal clinical data over 1, 6, 24, 48, and 72 hours of PICU admission. The primary outcome was PICU mortality. Multivariable logistic regression analysis was used to identify factors at PICU admission that were associated with mortality SETTING:: Nine multidisciplinary PICUs in three Asian countries.

Patients: Children with severe sepsis or septic shock admitted to the PICU from January to December 2017.

Intervention: None.

Measurement And Main Results: A total of 271 children were included in this study. Median (interquartile range) age was 4.2 years (1.3-10.8 yr). Pneumonia (77/271 [28.4%]) was the most common source of infection. Majority of patients (243/271 [90%]) were resuscitated within the first hour, with fluid bolus (199/271 [73.4%]) or vasopressors (162/271 [59.8%]). Fluid resuscitation commonly took the form of normal saline (147/199 [74.2%]) (20 mL/kg [10-20 mL/kg] over 20 min [15-30 min]). The most common inotrope used was norepinephrine 81 of 162 (50.0%). Overall PICU mortality was 52 of 271 (19.2%). Improved hemodynamic variables (e.g., heart rate, blood pressure, and arterial lactate) were seen in survivors within 6 hours of admission as compared to nonsurvivors. In the multivariable model, admission severity score was associated with PICU mortality.

Conclusions: Mortality from pediatric severe sepsis and septic shock remains high in Asia. Consistent with current guidelines, most of the children admitted to these PICUs received fluid therapy and inotropic support as recommended.
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http://dx.doi.org/10.1097/PCC.0000000000002680DOI Listing
March 2021

Pediatric Emergency and Critical Care Resources and Infrastructure in Resource-Limited Settings: A Multicountry Survey.

Crit Care Med 2021 04;49(4):671-681

Centre for Global Child Health, Hospital for Sick Children, Toronto, ON, Canada.

Objectives: To describe the infrastructure and resources for pediatric emergency and critical care delivery in resource-limited settings worldwide.

Design: Cross-sectional survey with survey items developed through literature review and revised following piloting.

Setting: The electronic survey was disseminated internationally in November 2019 via e-mail directories of pediatric intensive care societies and networks and using social media.

Patients: Healthcare providers who self-identified as working in resource-limited settings.

Interventions: None.

Measurements And Main Results: Results were summarized using descriptive statistics and resource availability was compared across World Bank country income groups. We received 328 responses (238 hospitals, 60 countries), predominantly in Latin America and Sub-Saharan Africa (n = 161, 67.4%). Hospitals were in low-income (28, 11.7%), middle-income (166, 69.5%), and high-income (44, 18.4%) countries. Across 174 PICU and adult ICU admitting children, there were statistically significant differences in the proportion of hospitals reporting consistent resource availability ("often" or "always") between country income groups (p < 0·05). Resources with limited availability in lower income countries included advanced ventilatory support, invasive and noninvasive monitoring, central venous access, renal replacement therapy, advanced imaging, microbiology, biochemistry, blood products, antibiotics, parenteral nutrition, and analgesic/sedative drugs. Seventy-seven ICUs (52.7%) were staffed 24/7 by a pediatric intensivist or anesthetist. The nurse-to-patient ratio was less than 1:2 in 71 ICUs (49.7%).

Conclusions: Contemporary data demonstrate significant disparity in the availability of essential and advanced human and material resources for the care of critically ill children in resource-limited settings. Minimum standards for essential pediatric emergency and critical care in resource-limited settings are needed.
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http://dx.doi.org/10.1097/CCM.0000000000004769DOI Listing
April 2021

COVID-19 and Children: Many Questions Yet To Be Answered.

Ann Acad Med Singap 2020 08;49(8):527-529

Children's Intensive Care Unit, KK Women's and Children's Hospital, Singapore.

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August 2020

Critically Ill Patients with COVID-19: A Narrative Review on Prone Position.

Pulm Ther 2020 Dec 21;6(2):233-246. Epub 2020 Oct 21.

Children's Intensive Care Unit, Department of Pediatric Subspecialties, KK Women's and Children's Hospital, 100 Bukit Timah Road, Singapore, 229899, Singapore.

Introduction: Prone position is known to improve mortality in patients with acute respiratory distress syndrome (ARDS). The impact of prone position in critically ill patients with coronavirus disease of 2019 (COVID-19) remains to be determined. In this review, we describe the mechanisms of action of prone position, systematically appraise the current experience of prone position in COVID-19 patients, and highlight unique considerations for prone position practices during this pandemic.

Methods: For our systematic review, we searched PubMed, Scopus and EMBASE from January 1, 2020, to April 16, 2020. After completion of our search, we became aware of four relevant publications during article preparation that were published in May and June 2020, and these studies were reviewed for eligibility and inclusion. We included all studies reporting clinical characteristics of patients admitted to the hospital with COVID-19 disease who received respiratory support with high-flow nasal cannula, or noninvasive or mechanical ventilation and reported the use of prone position. The full text of eligible articles was reviewed, and data regarding study design, patient characteristics, interventions and outcomes were extracted.

Results: We found seven studies (total 1899 patients) describing prone position in COVID-19. Prone position has been increasingly used in non-intubated patients with COVID-19; studies show high tolerance and improvement in oxygenation and lung recruitment. Published studies lacked a description of important clinical outcomes (e.g., mortality, duration of mechanical ventilation).

Conclusions: Based on the findings of our review, we recommend prone position in patients with moderate to severe COVID-19 ARDS as per existing guidelines. A trial of prone position should be considered for non-intubated COVID-19 patients with hypoxemic respiratory failure, as long as this does not result in a delay in intubation.
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http://dx.doi.org/10.1007/s41030-020-00135-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7575418PMC
December 2020

A Core Outcome Set for Pediatric Critical Care.

Crit Care Med 2020 12;48(12):1819-1828

Children and Young People Health Research, School of Health Sciences, University of Nottingham and Nottingham Children's Hospital, Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom.

Objectives: More children are surviving critical illness but are at risk of residual or new health conditions. An evidence-informed and stakeholder-recommended core outcome set is lacking for pediatric critical care outcomes. Our objective was to create a multinational, multistakeholder-recommended pediatric critical care core outcome set for inclusion in clinical and research programs.

Design: A two-round modified Delphi electronic survey was conducted with 333 invited research, clinical, and family/advocate stakeholders. Stakeholders completing the first round were invited to participate in the second. Outcomes scoring greater than 69% "critical" and less than 15% "not important" advanced to round 2 with write-in outcomes considered. The Steering Committee held a virtual consensus conference to determine the final components.

Setting: Multinational survey.

Patients: Stakeholder participants from six continents representing clinicians, researchers, and family/advocates.

Measurements And Main Results: Overall response rates were 75% and 82% for each round. Participants voted on seven Global Domains and 45 Specific Outcomes in round 1, and six Global Domains and 30 Specific Outcomes in round 2. Using overall (three stakeholder groups combined) results, consensus was defined as outcomes scoring greater than 90% "critical" and less than 15% "not important" and were included in the final PICU core outcome set: four Global Domains (Cognitive, Emotional, Physical, and Overall Health) and four Specific Outcomes (Child Health-Related Quality of Life, Pain, Survival, and Communication). Families (n = 21) suggested additional critically important outcomes that did not meet consensus, which were included in the PICU core outcome set-extended.

Conclusions: The PICU core outcome set and PICU core outcome set-extended are multistakeholder-recommended resources for clinical and research programs that seek to improve outcomes for children with critical illness and their families.
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http://dx.doi.org/10.1097/CCM.0000000000004660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785252PMC
December 2020

Traumatic Brain Injury Outcomes in 10 Asian Pediatric ICUs: A Pediatric Acute and Critical Care Medicine Asian Network Retrospective Study.

Pediatr Crit Care Med 2021 04;22(4):401-411

Duke-NUS Medical School, Singapore.

Objectives: Traumatic brain injury remains an important cause of death and disability. We aim to report the epidemiology and management of moderate to severe traumatic brain injury in Asian PICUs and identify risk factors for mortality and poor functional outcomes.

Design: A retrospective study of the Pediatric Acute and Critical Care Medicine Asian Network moderate to severe traumatic brain injury dataset collected between 2014 and 2017.

Setting: Patients were from the participating PICUs of Pediatric Acute and Critical Care Medicine Asian Network.

Patients: We included children less than 16 years old with a Glasgow Coma Scale less than or equal to 13.

Interventions: None.

Measurements And Main Results: We obtained data on patient demographics, injury circumstances, and PICU management. We performed a multivariate logistic regression predicting for mortality and poor functional outcomes. We analyzed 380 children with moderate to severe traumatic brain injury. Most injuries were a result of road traffic injuries (174 [45.8%]) and falls (160 [42.1%]). There were important differences in temperature control, use of antiepileptic drugs, and hyperosmolar agents between the sites. Fifty-six children died (14.7%), and 104 of 324 survivors (32.1%) had poor functional outcomes. Poor functional outcomes were associated with non-high-income sites (adjusted odds ratio, 1.90; 95% CI, 1.11-3.29), Glasgow Coma Scale less than 8 (adjusted odds ratio, 4.24; 95% CI, 2.44-7.63), involvement in a road traffic collision (adjusted odds ratio, 1.83; 95% CI, 1.04-3.26), and presence of child abuse (adjusted odds ratio, 2.75; 95% CI, 1.01-7.46).

Conclusions: Poor functional outcomes are prevalent after pediatric traumatic brain injury in Asia. There is an urgent need for further research in these high-risk groups.
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http://dx.doi.org/10.1097/PCC.0000000000002575DOI Listing
April 2021

Reassessing the Use of Proton Pump Inhibitors and Histamine-2 Antagonists in Critically Ill Children: A Systematic Review and Meta-Analysis.

J Pediatr 2021 01 9;228:164-176.e7. Epub 2020 Sep 9.

Duke-NUS Medical School, Singapore; Children's Intensive Care Unit, KK Women's and Children's Hospital, Singapore.

Objective: To determine the associations of stress ulcer prophylaxis with gastrointestinal (GI) bleeding, nosocomial pneumonia (NP), mortality, and length of stay in the pediatric intensive care unit (PICU).

Study Design: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) and observational studies in the English language assessing the effects of proton pump inhibitors and histamine-2 receptor antagonists on patients in the PICU published before October 2018 from the PubMed, Embase, CINAHL, and Cochrane Central Register of Controlled Trials databases. A random-effects Mantel-Haenszel risk difference (MHRD) model was used to pool all the selected studies for meta-analysis. Primary outcomes were the incidences of GI bleeding and NP. Secondary outcomes included mortality and length of PICU stay.

Results: Seventeen studies (4 RCTs and 13 observational studies) with a total of 340 763 patients were included. The overall incidence of GI bleeding was 15.2%. There was no difference in the risk of GI bleeding based on stress ulcer prophylaxis status (MHRD, 5.0%; 95% CI, -1.0% to 11.0%; I = 62%). There was an increased risk of NP in patients who received stress ulcer prophylaxis compared with those who did not (MHRD, 5.3%; 95% CI, 3.5%-7.0%; I = 0%). An increased risk of mortality was seen in patients receiving stress ulcer prophylaxis (MHRD, 2.1%; 95% CI, 2.0%-2.2%; I = 0%), although this association was no longer found when 1 large study was removed in a sensitivity analysis. There was no statistically significant difference in length of PICU stay between the groups (standardized mean difference, 0.42 days; 95% CI, -0.16 to 1.01 days; I = 89.8%).

Conclusions: Stress ulcer prophylaxis does not show a clear benefit in reducing GI bleeding or length of PICU stay. Observational studies suggest an increased risk of NP and mortality with stress ulcer prophylaxis, which remains to be validated in clinical trials.
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http://dx.doi.org/10.1016/j.jpeds.2020.09.011DOI Listing
January 2021

The authors reply.

Pediatr Crit Care Med 2020 09;21(9):855-856

Children's Intensive Care Unit, KK Women's and Children's Hospital, Singapore.

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http://dx.doi.org/10.1097/PCC.0000000000002446DOI Listing
September 2020

The Interplay Between Coagulation and Inflammation Pathways in COVID-19-Associated Respiratory Failure: A Narrative Review.

Pulm Ther 2020 Dec 25;6(2):215-231. Epub 2020 Aug 25.

Duke-NUS Medical School, Singapore, Singapore.

The novel coronavirus disease (COVID-19) pandemic has caused an unprecedented worldwide socio-economic and health impact. There is increasing evidence that a combination of inflammation and hypercoagulable state are the main mechanisms of respiratory failure in these patients. This narrative review aims to summarize currently available evidence on the complex interplay of immune dysregulation, hypercoagulability, and thrombosis in the pathogenesis of respiratory failure in COVID-19 disease. In addition, we will describe the experience of anticoagulation and anti-inflammatory strategies that have been tested. Profound suppression of the adaptive and hyperactivity of innate immune systems with macrophage activation appears to be a prominent feature in this infection. Immune dysregulation together with endotheliitis and severe hypercoagulability results in thromboinflammation and microvascular thrombosis in the pulmonary vasculature leading to severe respiratory distress. Currently, some guidelines recommend the use of prophylactic low molecular weight heparin in all hospitalized patients, with intermediate dose prophylaxis in those needing intensive care, and the use of therapeutic anticoagulation in patients with proven or suspected thrombosis. Strong recommendations cannot be made until this approach is validated by trial results. To target the inflammatory cascade, low-dose dexamethasone appears to be helpful in moderate to severe cases and trials with anti-interleukin agents (e.g., tocilizumab, anakinra, siltuximab) and non-steroidal anti-inflammatory drugs are showing early promising results. Potential newer agents (e.g., Janus kinase inhibitor such as ruxolitinib, baricitinib, fedratinib) are likely to be investigated in clinical trials. Unfortunately, current trials are mostly examining these agents in isolation and there may be a significant delay before evidence-based practice can be implemented. It is plausible that a combination of anti-viral drugs together with anti-inflammatory and anti-coagulation medicines will be the most successful strategy in managing severely affected patients with COVID-19.
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http://dx.doi.org/10.1007/s41030-020-00126-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446744PMC
December 2020

Timing of tracheal intubation on mortality and duration of mechanical ventilation in critically ill children: A propensity score analysis.

Pediatr Pulmonol 2020 11 20;55(11):3126-3133. Epub 2020 Aug 20.

Saw Swee Hock School of Public Health, National University Health System, National University of Singapore, Singapore.

Objective: We aimed to investigate whether early tracheal intubation (TI) is associated with a reduced risk of mortality and increased ventilator-free days (VFD).

Methods: We performed a retrospective cohort study of children 0 to 18 years old in a pediatric intensive care unit (PICU), between 2008 and 2017. Patient demographics, vital signs, and laboratory findings were extracted. Using a time-dependent propensity score-matched algorithm, each patient was matched with another equally likely to be intubated within the same hour but was actually intubated with ≤2 hours, 2 to 4 hours, and 4 to 6 hours delays. Outcomes were mortality and VFD.

Results: Among 333 patients, the median age was 1.72 years (interquartile range [IQR] 0.17-7.75). Thirty children died (9.0%) and the median PICU length of stay was 6.7 days (IQR 3.9-13.2). Early TI did not decrease mortality significantly when compared to a ≤2 hour delay (odds ratios [OR] 0.86; 95% CI, 0.40-1.85), a 2 to 4 hour delay (OR, 0.81; 95% CI, 0.39-1.69), or a 4 to 6 hour delay (OR, 0.87; 95% CI, 0.43-1.79). Similarly, early TI did not significantly increase VFD. Patients with early TI had 0.09 more VFD (95% CI -1.83 to 2.01) when compared to a delay within 2 hours, 0.23 more VFD (95% CI -1.66 to 2.13) when compared to a 2 to 4-hour delay and 0.56 more VFD (95% CI -1.49-2.61) when compared to a 4 to 6-hour delay.

Conclusions: We did not find a significant association between the timing of TI and mortality or VFD in critically ill children.
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http://dx.doi.org/10.1002/ppul.25026DOI Listing
November 2020

Use of an Electronic Feeds Calorie Calculator in the Pediatric Intensive Care Unit.

Pediatr Qual Saf 2020 Jan-Feb;5(1):e249. Epub 2020 Jan 12.

Children's Intensive Care Unit, Department of Pediatric Subspecialties, KK Women's and Children's Hospital, Singapore.

Strategies to improve nutritional management are associated with better outcomes in pediatric intensive care units. We implemented a calorie-based protocol that integrated an electronic feeds calculator and stepwise feeds increment algorithm.

Methods: Using a pretest-posttest design, we compared the effectiveness of the calorie-based protocol with an existing fluid-based protocol in a quality improvement project. The main outcome measure was the proportion of patients prescribed with the appropriate amount of calories (defined as 90%-110% of calculated energy requirements). Nurses were surveyed on their satisfaction with the new calorie-based protocol. We compared consecutive patients enrolled in the calorie-based protocol over 21 months with retrospective data of patients in the fluid-based protocol. and Mann-Whitney U tests were used to compare categorical and continuous variables, respectively.

Results: We enrolled 75 and 92 patients in the fluid-based (pre) and calorie-based (post) protocols, respectively. Both groups did not differ in their age, reasons for pediatric intensive care units admissions, length of stay, duration of mechanical ventilation, and risks of mortality. The frequency of appropriate feeds prescription increased (16.0% versus 33.7%, = 0.002). The new protocol significantly reduced the time from protocol initiation to full feeds (median: 18.0 hours, interquartile range = 18.0-27.5 versus median: 12.8 hours, interquartile range = 12.0-16.0, < 0.001). The satisfaction surveys (n = 63) revealed favorable nursing perceptions.

Conclusions: The use of a calorie-based protocol with an electronic calculator led to an improvement in the accuracy of the prescribed feeds and the time required to attain full enteral feeding. Nursing perceptions regarding the protocol were positive.
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http://dx.doi.org/10.1097/pq9.0000000000000249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7056286PMC
January 2020

Contemporary trends in global mortality of sepsis among young infants less than 90 days old: protocol for a systematic review and meta-analysis.

BMJ Open 2020 07 31;10(7):e038815. Epub 2020 Jul 31.

Department of Emergency Medicine, KK Women's and Children's Hospital, Singapore

Introduction: Neonatal sepsis has a high mortality rate that varies across different populations. We aim to perform a contemporary global evidence synthesis to determine the case fatality rates of neonatal sepsis, in order to better delineate this public health urgency and inform strategies to reduce fatality in this high-risk population.

Methods And Analysis: We will search PubMed, Cochrane Central, Embase and Web of Science for articles in English language published between January 2010 and December 2019. All clinical trials and observational studies involving infants less than 90 days old with a clinical diagnosis of sepsis and reported case fatality rate will be included. Two independent reviewers will screen the studies and extract data on study variables chosen a priori. Quality of evidence and risk of bias will be assessed using Cochrane Collaboration's tool and ROBINS-I. Results will be synthesised qualitatively and pooled for meta-analysis.

Ethics And Dissemination: No formal ethical approval is required as there is no collection of primary data. This systematic review and meta-analysis will be disseminated through conference meetings and peer-reviewed publications.

Prospero Registration Number: CRD42020164321.
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http://dx.doi.org/10.1136/bmjopen-2020-038815DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7398098PMC
July 2020

Impact of Failure of Noninvasive Ventilation on the Safety of Pediatric Tracheal Intubation.

Crit Care Med 2020 10;48(10):1503-1512

Department of Anesthesiology and Critical Care Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA.

Objectives: Noninvasive ventilation is widely used to avoid tracheal intubation in critically ill children. The objective of this study was to assess whether noninvasive ventilation failure was associated with severe tracheal intubation-associated events and severe oxygen desaturation during tracheal intubation.

Design: Prospective multicenter cohort study of consecutive intubated patients using the National Emergency Airway Registry for Children registry.

Setting: Thirteen PICUs (in 12 institutions) in the United States and Canada.

Patients: All patients undergoing tracheal intubation in participating sites were included. Noninvasive ventilation failure group included children with any use of high-flow nasal cannula, continuous positive airway pressure, or bilevel noninvasive ventilation in the 6 hours prior to tracheal intubation. Primary tracheal intubation group included children without exposure to noninvasive ventilation within 6 hours before tracheal intubation.

Interventions: None.

Measurements And Main Results: Severe tracheal intubation-associated events (cardiac arrest, esophageal intubation with delayed recognition, emesis with aspiration, hypotension requiring intervention, laryngospasm, pneumothorax, pneumomediastinum) and severe oxygen desaturation (< 70%) were recorded prospectively. The study included 956 tracheal intubation encounters; 424 tracheal intubations (44%) occurred after noninvasive ventilation failure, with a median of 13 hours (interquartile range, 4-38 hr) of noninvasive ventilation. Noninvasive ventilation failure group included more infants (47% vs 33%; p < 0.001) and patients with a respiratory diagnosis (56% vs 30%; p < 0.001). Noninvasive ventilation failure was not associated with severe tracheal intubation-associated events (5% vs 5% without noninvasive ventilation; p = 0.96) but was associated with severe desaturation (15% vs 9% without noninvasive ventilation; p = 0.005). After controlling for baseline differences, noninvasive ventilation failure was not independently associated with severe tracheal intubation-associated events (p = 0.35) or severe desaturation (p = 0.08). In the noninvasive ventilation failure group, higher FIO2 before tracheal intubation (≥ 70%) was associated with severe tracheal intubation-associated events.

Conclusions: Critically ill children are frequently exposed to noninvasive ventilation before intubation. Noninvasive ventilation failure was not independently associated with severe tracheal intubation-associated events or severe oxygen desaturation compared to primary tracheal intubation.
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http://dx.doi.org/10.1097/CCM.0000000000004500DOI Listing
October 2020

Pharmacokinetics Alterations in Critically Ill Pediatric Patients on Extracorporeal Membrane Oxygenation: A Systematic Review.

Front Pediatr 2020 26;8:260. Epub 2020 Jun 26.

Duke-NUS Medical School, Singapore, Singapore.

This study aimed to identify alterations in pharmacokinetics in children on extracorporeal membrane oxygenation (ECMO), identify knowledge gaps, and inform future pharmacology studies. We systematically searched the databases MEDLINE, CINAHL, and Embase from earliest publication until November 2018 using a controlled vocabulary and keywords related to "ECMO" and "pharmacokinetics," "pharmacology," "drug disposition," "dosing," and "pediatrics." Inclusion criteria were as follows: study population aged <18 years, supported on ECMO for any indications, received any medications while on ECMO, and reported pharmacokinetic data. Clearance and/or volume of distribution values were extracted from included studies. Forty-one studies (total patients = 574) evaluating 23 drugs met the inclusion criteria. The most common drugs studied were antimicrobials ( = 13) and anticonvulsants ( = 3). Twenty-eight studies (68%) were conducted in children <1 year of age. Thirty-three studies (80%) were conducted without intra-study comparisons to non-ECMO controls. Increase in volume of distribution attributable to ECMO was demonstrated for nine (56%) drugs: cefotaxime, gentamicin, piperacillin/tazobactam, fluconazole, micafungin, levetiracetam, clonidine, midazolam, and sildenafil (range: 23-345% increase relative to non-ECMO controls), which may suggest the need for higher initial dosing. Decreased volume of distribution was reported for two drugs: acyclovir and ribavirin (50 and 69%, respectively). Decreased clearance was reported for gentamicin, ticarcillin/clavulanate, bumetanide, and ranitidine (range: 26-95% decrease relative to non-ECMO controls). Increased clearance was reported for caspofungin, micafungin, clonidine, midazolam, morphine, and sildenafil (range: 25-455% increase relative to non-ECMO controls). There were substantial pharmacokinetic alterations in 70% of drugs studied in children on ECMO. However, studies evaluating pharmacokinetic changes of many drug classes and those that allow direct comparisons between ECMO and non-ECMO patients are still lacking. Systematic evaluations of pharmacokinetic alterations of drugs on ECMO that incorporate multidrug opportunistic trials, physiologically based pharmacokinetic modeling, and other methods are necessary for definitive dose recommendations. : CRD42019114881.
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http://dx.doi.org/10.3389/fped.2020.00260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332755PMC
June 2020

A narrative review of heart rate and variability in sepsis.

Ann Transl Med 2020 Jun;8(12):768

Duke-NUS Medical School, Singapore, Singapore.

Clinicians face challenges in the timely diagnosis and management of pediatric sepsis. Pediatric heart rate has been incorporated into early warning systems and studied as a predictor for critical illness. We aim to review: (I) the role of heart rate in pediatric warning systems and (II) the role of heart rate variability (HRV) in adult and neonatal sepsis, with a focus on its potential applications in pediatrics. We conducted a literature search for papers published up to December 2019 on the utility of heart rate and HRV analysis in the diagnosis and management of sepsis, using four medical databases: PubMed, Google Scholar, EMBASE and Web of Science. This review demonstrates that the clinical utility of pediatric heart rate in predicting clinical deterioration is limited by the lack of consensus among warning systems, consensus-based guidelines, and evidence-based studies as to what constitutes abnormal heart rate in the pediatric age group. Current studies demonstrate that abnormal heart rate itself does not adequately discriminate children with sepsis from those without. HRV analysis provides a quick and non-invasive method of assessment and can provide more information than traditional heart rate. HRV analysis has the potential to add value in identification and prognostication of adult and neonatal sepsis. With further studies to explore its role, HRV analysis has the potential to add to current tools in the diagnosis and prognosis of pediatric sepsis.
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http://dx.doi.org/10.21037/atm-20-148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7333166PMC
June 2020
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