Lung-Protective Ventilation for Pediatric Acute Respiratory Distress Syndrome: A Nonrandomized Controlled Trial.

OBJECTIVES: Despite the recommendation for lung-protective mechanical ventilation (LPMV) in pediatric acute respiratory distress syndrome (PARDS), there is a lack of robust supporting data and variable adherence in clinical practice. This study evaluates the impact of an LPMV protocol vs. standard care and adherence to LPMV elements on mortality. We hypothesized that LPMV strategies deployed as a pragmatic protocol reduces mortality in PARDS. DESIGN: Multicenter prospective before-and-after comparison design study. SETTING: Twenty-one PICUs. PATIENTS: Patients fulfilled the Pediatric Acute Lung Injury Consensus Conference 2015 definition of PARDS and were on invasive mechanical ventilation. INTERVENTIONS: The LPMV protocol included a limit on peak inspiratory pressure (PIP), delta/driving pressure (DP), tidal volume, positive end-expiratory pressure (PEEP) to Fio2 combinations of the low PEEP acute respiratory distress syndrome network table, permissive hypercarbia, and conservative oxygen targets. MEASUREMENTS AND MAIN RESULTS: There were 285 of 693 (41·1%) and 408 of 693 (58·9%) patients treated with and without the LPMV protocol, respectively. Median age and oxygenation index was 1.5 years (0.4-5.3 yr) and 10.9 years (7.0-18.6 yr), respectively. There was no difference in 60-day mortality between LPMV and non-LPMV protocol groups (65/285 [22.8%] vs. 115/406 [28.3%]; p = 0.104). However, total adherence score did improve in the LPMV compared to non-LPMV group (57.1 [40.0-66.7] vs. 47.6 [31.0-58.3]; p < 0·001). After adjusting for confounders, adherence to LPMV strategies (adjusted hazard ratio, 0.98; 95% CI, 0.97-0.99; p = 0.004) but not the LPMV protocol itself was associated with a reduced risk of 60-day mortality. Adherence to PIP, DP, and PEEP/Fio2 combinations were associated with reduced mortality. CONCLUSIONS: Adherence to LPMV elements over the first week of PARDS was associated with reduced mortality. Future work is needed to improve implementation of LPMV in order to improve adherence.

Severe Pneumonia in PICU Admissions: The Pediatric Acute and Critical Care Medicine Asian Network (PACCMAN) Observational Cohort Study, 2020-2022.

OBJECTIVES: Mortality from pneumonia is three times higher in Asia compared with industrialized countries. We aimed to determine the epidemiology, microbiology, and outcome of severe pneumonia in PICUs across the Pediatric Acute and Critical Care Medicine Asian Network (PACCMAN). DESIGN: Prospective multicenter observational study from June 2020 to September 2022. SETTING: Fifteen PICUs in PACCMAN. PATIENTS: All children younger than 18 years old diagnosed with pneumonia and admitted to the PICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Clinical, microbiologic, and outcome data were recorded. The primary outcome was PICU mortality. Univariate and multivariable logistic regression was performed to investigate associations between PICU mortality and explanatory risk factors on presentation to the PICU. Among patients screened, 846 of 11,778 PICU patients (7.2%) with a median age of 1.2 years (interquartile range, 0.4-3.7 yr) had pneumonia. Respiratory syncytial virus was detected in 111 of 846 cases (13.1%). The most common bacteria were Staphylococcus species (71/846 [8.4%]) followed by Pseudomonas species (60/846 [7.1%]). Second-generation cephalosporins (322/846 [38.1%]) were the most common broad-spectrum antibiotics prescribed, followed by carbapenems (174/846 [20.6%]). Invasive mechanical ventilation and noninvasive respiratory support was provided in 438 of 846 (51.8%) and 500 of 846 (59.1%) patients, respectively. PICU mortality was 65 of 846 (7.7%). In the multivariable logistic regression model, age (adjusted odds ratio [aOR], 1.08; 95% CI, 1.00-1.16), Pediatric Index of Mortality 3 score (aOR, 1.03; 95% CI, 1.02-1.05), and drowsiness (aOR, 2.73; 95% CI, 1.24-6.00) were associated with greater odds of mortality. CONCLUSIONS: In the PACCMAN contributing PICUs, pneumonia is a frequent cause for admission (7%) and is associated with a greater odds of mortality.

Copper-Catalyzed Oxidative Coupling of Quinazoline-3-Oxides: Synthesis of O-Quinazolinic Carbamates.

Organic carbamates represent a kind of privileged structures in both organic chemistry and industry. Despite the fact that the synthesis of alcohol-based carbamates has been well studied, an efficient access to hydroxamic acid-based carbamates is less explored due to the nucleophilicity of both O and N atoms in hydroxamic acids. Herein, we report a copper-catalyzed oxidative coupling of quinazoline-3-oxides and formamides for the synthesis of O-quinazolinic carbamates. This protocol is featured with practicability, simple starting materials, and operational simplicity.

Special considerations for the management of COVID-19 pediatric patients in the operating room and pediatric intensive care unit in a tertiary hospital in Singapore.

COVID-19 was first identified in Wuhan, China and is caused by the novel coronavirus SARS-CoV 2. It has now spread rapidly to over 190 countries and territories around the world and has been declared a global pandemic by the World Health Organization. The virus is spread through droplet transmission and currently has a mortality rate of over 4% globally. The pediatric population has been found to be less susceptible to the disease with the majority of children having milder symptoms and only one pediatric death being reported globally so far. Despite this, strategies need to be put in place to prevent further spread of the virus. We present a summary of the general measures implemented at a large adult and pediatric tertiary hospital in Singapore (National University Hospital) as well as the specific strategies in place for the operating room and pediatric intensive care unit.

Early metabolic derangements and unfavorable outcomes in pediatric traumatic brain injury: a retrospective multi-center cohort study.

Background: To study the association in moderate and severe pediatric traumatic brain injury (TBI) between hyperglycemia, hyperlactatemia, acidosis and unfavorable outcome, as assessed by Pediatric Cerebral Performance Category (PCPC) on discharge from the pediatric intensive care unit (PICU). Methods: Children <16 years old with TBI and Glasgow Coma Scale (GCS) ≤13 in an Asian multi-center PICU TBI cohort from January 2014 to October 2017 were included in this study. We defined unfavorable outcome as PCPC ≥3-moderate disability, severe disability, vegetative state, and death. We performed logistic regression to investigate the association between metabolic changes with unfavorable outcome. We divided hyperglycemia (glucose >11.1 mmol/L) during PICU admission into early-onset (within 24 h), late-onset (beyond 48 h) and persistent (throughout first 72 h). Results: Among the 305 children analyzed, 136 (44.6%) had unfavorable outcome. Children with unfavorable outcome were more likely to have early hyperglycemia (75/136, 55.1% vs. 33/169, 19.5%; P<0.001), high lactate levels >2.0 mmol/L (74/136, 54.4% vs. 56/169, 32.5%; P<0.001) and initial acidosis (85/136, 62.5% vs. 78/169, 56.1%; P=0.003) compared to those with favorable outcome. After adjusting for gender, GCS ≤8 and presence of polytrauma, early hyperglycemia [adjusted odds ratio (aOR) =3.68, 95% CI: 2.12-6.39, P<0.001] and late hyperglycemia (aOR =13.30, 95% CI: 1.64-107.8, P=0.015] were independently associated with unfavorable outcome. All children with persistent hyperglycemia died. Conclusions: We described unfavorable outcome in pediatric TBI especially with persistent hyperglycemia. Future trials should investigate the causal relationship between glycemic trends, early intervention and outcome in this cohort.

Protein supplementation versus standard feeds in underweight critically ill children: a pilot dual-centre randomised controlled trial protocol.

INTRODUCTION: Protein-energy malnutrition, increased catabolism and inadequate nutritional support leads to loss of lean body mass with muscle wasting and delayed recovery in critical illness. However, there remains clinical equipoise regarding the risks and benefits of protein supplementation. This pilot trial will determine the feasibility of performing a larger multicentre trial to determine if a strategy of protein supplementation in critically ill children with body mass index (BMI) z-score ≤-2 is superior to standard enteral nutrition in reducing the length of stay in the paediatric intensive care unit (PICU). METHODS AND ANALYSIS: This is a randomised controlled trial of 70 children in two PICUs in Singapore. Children with BMI z-score ≤-2 on PICU admission, who are expected to require invasive mechanical ventilation for more than 48 hours, will be randomised (1:1 allocation) to protein supplementation of ≥1.5 g/kg/day in addition to standard nutrition, or standard nutrition alone for 7 days after enrolment or until PICU discharge, whichever is earlier. Feasibility outcomes for the trial include effective screening, satisfactory enrolment rate, timely protocol implementation (within first 72 hours) and protocol adherence. Secondary outcomes include mortality, PICU length of stay, muscle mass, anthropometric measurements and functional outcomes. ETHICS AND DISSEMINATION: The trial protocol was approved by the institutional review board of both participating centres (Singhealth Centralised Institutional Review Board and National Healthcare Group Domain Specific Review Board) under the reference number 2020/2742. Findings of the trial will be disseminated through peer-reviewed journals and scientific conferences. TRIAL REGISTRATION NUMBER: NCT04565613.

Life-threatening infections during treatment for acute lymphoblastic leukemia on the Malaysia-Singapore 2003 and 2010 clinical trials: A risk prediction model.

AIM: Life-threatening infections significantly impact the care of children undergoing therapy for acute lymphoblastic leukemia (ALL) who are at risk of severe sepsis due to both host and treatment factors. Our aim was to develop a life-threatening infection risk prediction model that would allow remote rapid triage of patients to reduce time to first dose of antibiotics and sepsis-related mortality. METHODS: A retrospective analysis of 2068 fever episodes during ALL therapy was used for model building and subsequent internal validation. RESULTS: Three hundred and seventy-seven patients were treated for ALL in two institutions with comparable critical and supportive care resources. A total of 55 patients accounted for 71 admissions to the critical care unit for sepsis that led to eight septic deaths during a 16-year study period. A retrospective analysis of risk factors for sepsis enabled us to build a model focused on 13 variables that discriminated admissions requiring critical care well: area under the receiver operating characteristic curve of .82; 95% CI .76-.87, p<.001, and Brier score of .033. Significant univariate predictors included neutropenia, presence of symptoms of abdominal pain, diarrhea, fever during induction or steroid-based phases, and the lack of any localizing source of infection at time of presentation. CONCLUSION: We have developed a risk prediction model that can reliably identify ALL patients undergoing treatment who are at a higher risk of life-threatening sepsis. Clinical applicability can potentially be extended to low-middle income settings, and its utility should be further studied in real-world settings.

Enteral feeding and the microbiome in critically ill children: a narrative review.

OBJECTIVE: This narrative review summarizes our current knowledge on the interplay between enteral nutrition (EN) and gut microbiota in critically ill children, using examples from two commonly encountered diagnoses in the pediatric intensive care unit (PICU): severe sepsis and acute respiratory distress syndrome (ARDS). This review will also highlight potential areas of therapeutic interventions that should be explored in future studies. BACKGROUND: Critically ill children display extreme dysbiosis in their gut microbiome. Factors within the PICU that are often associated with dysbiosis include the use of broad-spectrum antibiotics, proton-pump inhibitors (PPIs), intravenous morphine, and fasting. Dysbiosis can potentially lead to adverse clinical outcomes (e.g., nosocomial infection, and prolonged hospitalization). EN may modulate dysbiosis. The gut microbiota is involved in the breaking down of macronutrients, mainly carbohydrates and proteins. Fermentation of undigestible carbohydrate (e.g., inulin and oligosaccharides), and amino acids by large intestine microbiota produces short chain fatty acids (SCFAs). SCFAs serve as the main fuel source for enterocytes and help to maintain healthy gut lining. Changes to selected components of macronutrients can result in alterations in gut microbiome and have potentially beneficial effects in patients in the PICU. METHODS: A comprehensive search of the MEDLINE, Cochrane Library and Google Scholar databases was conducted using appropriate MESH terms and keywords. In this narrative review, we provide a summary of current knowledge on effect of EN on gut microbiota in pediatric studies, but also describes animal- and lab-based, as well as adult studies where relevant. CONCLUSIONS: The gut microbiome can be altered by dietary modifications and common PICU practices and treatment. Although there are strong associations in restoring eubiosis and improvement in clinical outcomes, proving causality remains challenging. Further microbiome research is needed to provide mechanistic insights into the impact of the ever changing gut microbiome. In the future, new microbiota targeted therapies could potentially be the treatment of challenging PICU conditions and restore homeostasis in these children.

Factors affecting successful use of intranasal dexmedetomidine: a cohort study from a national paediatrics tertiary centre.

BACKGROUND: Use of intranasal (IN) dexmedetomidine for procedural sedation has been reported in recent years. Good patient selection is important to ensure high success rates. We aimed to identify factors that influence the successful use of IN dexmedetomidine in non-invasive investigations. METHODS: All paediatric patients who received IN dexmedetomidine for investigations between 01 July 2019 to 01 July 2020 were included. Baseline demographics, time to reach adequate sedation level, duration of sedation, dose, indications for sedation and need for rescue sedatives were recorded. Procedures were classified into "long" or "short" according to completion time. Successful sedation was defined by completion of investigations by IN dexmedetomidine alone. RESULTS: Of 105 patients included, median age was 20.0 months, and median weight 11.0 kg. Magnetic resonance imaging (56, 53.3%) was the most common indication. Sixty (57.1%) were successfully sedated using IN dexmedetomidine alone. Automated auditory brainstem response, computerised tomography and mercaptoacetyltriglycine-3 renogram scans had the highest success rate (83.3%, 83.3%, and 100% respectively). On multivariate analysis, short procedures had an adjusted odds ratio of 5.30 (95% CI: 1.69-16.61; P=0.004) compared to long procedures. CONCLUSIONS: IN dexmedetomidine is effective for procedural sedation for paediatric patients. The most important predictor for sedation success was indication of sedation and duration of procedures.

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

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.

Plasmodium knowlesi infection: a diagnostic challenge.

Plasmodium knowlesi malaria is an uncommon, but highly prevalent parasitic infection in parts of Malaysia. This is the case of a 14-year-old Singaporean boy presenting to our emergency department with an 11-day history of fever following a school trip to Malaysia. Hepatosplenomegaly was the only clinical finding; laboratory tests showed thrombocytopaenia, lymphopaenia, mild anaemia and liver transaminitis. Specific malaria antigen tests were negative, but the peripheral blood film showed plasmodia with atypical features, with a parasite load of 0.5%. PCR confirmed the diagnosis of P knowlesi. The patient was successfully treated with chloroquine. The clinical course of P knowlesi malaria is indistinguishable from that of Plasmodium falciparum. This case highlights the importance of taking detailed travel history, careful examination of malaria blood films and judicious use of molecular techniques. Antigen tests alone may have missed a malaria diagnosis altogether, while blood film examination may wrongly identify the species as Plasmodium malariae or P falciparum. Third-generation PCR assays can be used to reliably identify P knowlesi.