Paediatric dengue shock syndrome and acute respiratory failure: a single-centre retrospective study.

OBJECTIVE: Dengue shock syndrome (DSS) is a serious health condition leading to paediatric intensive care unit (PICU) admissions and deaths in tropical countries. Acute respiratory failure (ARF) is associated with DSS and is a major cause of dengue deaths. We aimed to identify risk factors associated with ARF in children with DSS. METHODS: We retrospectively reviewed children with DSS admitted to a PICU from 2010 to 2020 at a tertiary level hospital in Bangkok, Thailand. Patient characteristics, clinical parameters and laboratory data were collected. Multivariable logistic regression analysis was used to identify factors associated with ARF. RESULTS: Twenty-six (43.3%) of 60 children with DSS developed ARF and 6 did not survive to day 28. The median (IQR) age was 8.1 years (IQR 4.0-11.0). Fluid accumulation during the first 72 hours of PICU admission was greater in the ARF group compared with the non-ARF group (12.2% (IQR 7.6-21.7) vs 8.3% (IQR 4.4-13.3), p=0.009). In a multivariate analysis at 72 hours post PICU admission, the presence of ˃15% fluid accumulation was independently associated with ARF (adjusted OR 5.67, 95% CI 1.24 to 25.89, p=0.025). CONCLUSION: ARF is an important complication in children with DSS. A close assessment of patient fluid status is essential to identify patients at risk of ARF. Once the patient is haemodynamically stable and leakage slows, judicious fluid management is required to prevent ARF.

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

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.

Acute kidney injury without previous renal disease in critical care unit.

BACKGROUND: Acute kidney injury (AKI) is common in hospitalized and critically ill children. Apart from primary kidney disease, etiologies of AKI are usually related to systemic disease and nephrotoxic insult. This study examines the incidence, characteristics, and mortality risks of AKI in critically ill children without primary renal disease or previously known chronic kidney disease. METHODS: A retrospective cohort study was conducted of patients aged 1-18 years, diagnosed with AKI (excluding severe glomerulonephritis and previously known chronic kidney disease) in pediatric intensive care units between 2013 and 2016. Acute kidney injury was defined according to the Kidney Disease Improving Global Outcomes classifications. Cox proportional hazards regression analysis was employed to assess the relationship between the risk factors and mortality. RESULTS: Of 1,377 pediatric intensive care unit patients, 253 (18.4%) developed AKI and only 169 (12.3%) who did not have previously known renal disease were included. Of these 169 AKI patients, the mean age was 8.1 ± 4.7 years; 88 (52.1%) patients were male; and 60 (35.5%) patients had AKI stage 3. The most common etiologies of AKI were sepsis (76.9%) and shock (64.5%). Fifty-three (31.4%) of those patients died during admission. The risk factors for death were the need for mechanical ventilation (adjusted hazard ratio, 17.82; 95% CI, 2.41-132.06) and AKI stage 3 (adjusted hazard ratio, 2.32; 95% CI, 1.07-5.00). CONCLUSIONS: Acute kidney injury in critically ill children without previously known renal disease was approximately two-thirds of the overall incidence. The risk factors of in-hospital death were the use of mechanical ventilation, and AKI stage 3.

The impact of high frequency oscillatory ventilation on mortality in paediatric acute respiratory distress syndrome.

BACKGROUND: High-frequency oscillatory ventilation (HFOV) use was associated with greater mortality in adult acute respiratory distress syndrome (ARDS). Nevertheless, HFOV is still frequently used as rescue therapy in paediatric acute respiratory distress syndrome (PARDS). In view of the limited evidence for HFOV in PARDS and evidence demonstrating harm in adult patients with ARDS, we hypothesized that HFOV use compared to other modes of mechanical ventilation is associated with increased mortality in PARDS. METHODS: Patients with PARDS from 10 paediatric intensive care units across Asia from 2009 to 2015 were identified. Data on epidemiology and clinical outcomes were collected. Patients on HFOV were compared to patients on other modes of ventilation. The primary outcome was 28-day mortality and secondary outcomes were 28-day ventilator- (VFD) and intensive care unit- (IFD) free days. Genetic matching (GM) method was used to analyse the association between HFOV treatment with the primary outcome. Additionally, we performed a sensitivity analysis, including propensity score (PS) matching, inverse probability of treatment weighting (IPTW) and marginal structural modelling (MSM) to estimate the treatment effect. RESULTS: A total of 328 patients were included. In the first 7 days of PARDS, 122/328 (37.2%) patients were supported with HFOV. There were significant differences in baseline oxygenation index (OI) between the HFOV and non-HFOV groups (18.8 [12.0, 30.2] vs. 7.7 [5.1, 13.1] respectively; p < 0.001). A total of 118 pairs were matched in the GM method which found a significant association between HFOV with 28-day mortality in PARDS [odds ratio 2.3, 95% confidence interval (CI) 1.3, 4.4, p value 0.01]. VFD was indifferent between the HFOV and non-HFOV group [mean difference - 1.3 (95%CI - 3.4, 0.9); p = 0.29] but IFD was significantly lower in the HFOV group [- 2.5 (95%CI - 4.9, - 0.5); p = 0.03]. From the sensitivity analysis, PS matching, IPTW and MSM all showed consistent direction of HFOV treatment effect in PARDS. CONCLUSION: The use of HFOV was associated with increased 28-day mortality in PARDS. This study suggests caution but does not eliminate equivocality and a randomized controlled trial is justified to examine the true association.

Non-Invasive Ventilation in Children with Paediatric Acute Respiratory Distress Syndrome.

INTRODUCTION: Evidence supporting non-invasive ventilation (NIV) in paediatric acute respiratory distress syndrome (PARDS) remains sparse. We aimed to describe characteristics of patients with PARDS supported with NIV and risk factors for NIV failure. MATERIALS AND METHODS: This is a multicentre retrospective study. Only patients supported on NIV with PARDS were included. Data on epidemiology and clinical outcomes were collected. Primary outcome was NIV failure which was defined as escalation to invasive mechanical ventilation within the first 7 days of PARDS. Patients in the NIV success and failure groups were compared. RESULTS: There were 303 patients with PARDS; 53/303 (17.5%) patients were supported with NIV. The median age was 50.7 (interquartile range: 15.7-111.9) months. The Paediatric Logistic Organ Dysfunction score and oxygen saturation/fraction of inspired oxygen (SF) ratio were 2.0 (1.0-10.0) and 155.0 (119.4- 187.3), respectively. Indications for NIV use were increased work of breathing (26/53 [49.1%]) and hypoxia (22/53 [41.5%]). Overall NIV failure rate was 77.4% (41/53). All patients with sepsis who developed PARDS experienced NIV failure. NIV failure was associated with an increased median paediatric intensive care unit stay (15.0 [9.5-26.5] vs 4.5 [3.0-6.8] days; P <0.001) and hospital length of stay (26.0 [17.0-39.0] days vs 10.5 [5.5-22.3] days; P = 0.004). Overall mortality rate was 32.1% (17/53). CONCLUSION: The use of NIV in children with PARDS was associated with high failure rate. As such, future studies should examine the optimal selection criteria for NIV use in these children.

Differences Between Pulmonary and Extrapulmonary Pediatric Acute Respiratory Distress Syndrome: A Multicenter Analysis.

OBJECTIVES: Extrapulmonary pediatric acute respiratory distress syndrome and pulmonary pediatric acute respiratory distress syndrome are poorly described in the literature. We aimed to describe and compare the epidemiology, risk factors for mortality, and outcomes in extrapulmonary pediatric acute respiratory distress syndrome and pulmonary pediatric acute respiratory distress syndrome. DESIGN: This is a secondary analysis of a multicenter, retrospective, cohort study. Data on epidemiology, ventilation, therapies, and outcomes were collected and analyzed. Patients were classified into two mutually exclusive groups (extrapulmonary pediatric acute respiratory distress syndrome and pulmonary pediatric acute respiratory distress syndrome) based on etiologies. Primary outcome was PICU mortality. Cox proportional hazard regression was used to identify risk factors for mortality. SETTING: Ten multidisciplinary PICUs in Asia. PATIENTS: Mechanically ventilated children meeting the Pediatric Acute Lung Injury Consensus Conference criteria for pediatric acute respiratory distress syndrome between 2009 and 2015. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Forty-one of 307 patients (13.4%) and 266 of 307 patients (86.6%) were classified into extrapulmonary pediatric acute respiratory distress syndrome and pulmonary pediatric acute respiratory distress syndrome groups, respectively. The most common causes for extrapulmonary pediatric acute respiratory distress syndrome and pulmonary pediatric acute respiratory distress syndrome were sepsis (82.9%) and pneumonia (91.7%), respectively. Children with extrapulmonary pediatric acute respiratory distress syndrome were older, had higher admission severity scores, and had a greater proportion of organ dysfunction compared with pulmonary pediatric acute respiratory distress syndrome group. Patients in the extrapulmonary pediatric acute respiratory distress syndrome group had higher mortality (48.8% vs 24.8%; p = 0.002) and reduced ventilator-free days (median 2.0 d [interquartile range 0.0-18.0 d] vs 19.0 d [0.5-24.0 d]; p = 0.001) compared with the pulmonary pediatric acute respiratory distress syndrome group. After adjusting for site, severity of illness, comorbidities, multiple organ dysfunction, and severity of acute respiratory distress syndrome, extrapulmonary pediatric acute respiratory distress syndrome etiology was not associated with mortality (adjusted hazard ratio, 1.56 [95% CI, 0.90-2.71]). CONCLUSIONS: Patients with extrapulmonary pediatric acute respiratory distress syndrome were sicker and had poorer clinical outcomes. However, after adjusting for confounders, it was not an independent risk factor for mortality.

Risk Stratification in Pediatric Acute Respiratory Distress Syndrome: A Multicenter Observational Study.

OBJECTIVES: The Pediatric Acute Lung Injury Consensus Conference developed a pediatric specific definition for acute respiratory distress syndrome (PARDS). In this definition, severity of lung disease is stratified into mild, moderate, and severe groups. We aim to describe the epidemiology of patients with PARDS across Asia and evaluate whether the Pediatric Acute Lung Injury Consensus Conference risk stratification accurately predicts outcome in PARDS. DESIGN: A multicenter, retrospective, descriptive cohort study. SETTING: Ten multidisciplinary PICUs in Asia. PATIENTS: All mechanically ventilated children meeting the Pediatric Acute Lung Injury Consensus Conference criteria for PARDS between 2009 and 2015. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Data on epidemiology, ventilation, adjunct therapies, and clinical outcomes were collected. Patients were followed for 100 days post diagnosis of PARDS. A total of 373 patients were included. There were 89 (23.9%), 149 (39.9%), and 135 (36.2%) patients with mild, moderate, and severe PARDS, respectively. The most common risk factor for PARDS was pneumonia/lower respiratory tract infection (309 [82.8%]). Higher category of severity of PARDS was associated with lower ventilator-free days (22 [17-25], 16 [0-23], 6 [0-19]; p < 0.001 for mild, moderate, and severe, respectively) and PICU free days (19 [11-24], 15 [0-22], 5 [0-20]; p < 0.001 for mild, moderate, and severe, respectively). Overall PICU mortality for PARDS was 113 of 373 (30.3%), and 100-day mortality was 126 of 317 (39.7%). After adjusting for site, presence of comorbidities and severity of illness in the multivariate Cox proportional hazard regression model, patients with moderate (hazard ratio, 1.88 [95% CI, 1.03-3.45]; p = 0.039) and severe PARDS (hazard ratio, 3.18 [95% CI, 1.68, 6.02]; p < 0.001) had higher risk of mortality compared with those with mild PARDS. CONCLUSIONS: Mortality from PARDS is high in Asia. The Pediatric Acute Lung Injury Consensus Conference definition of PARDS is a useful tool for risk stratification.

Close correlation between arterial and central venous lactate concentrations of children in shock: A cross-sectional study.

BACKGROUND: Arterial lactate (aLact) has been widely used to guide therapeutic decisions in children with shock. We evaluated the feasibility of central venous lactate (cvLact) in assessing aLact among children with shock. METHODS: Pairs of arterial and central venous samples for lactate concentrations were collected simultaneously during the shock and hemodynamically stable states. The results were analyzed by using a Cobas 8000 analyzer. RESULTS: Sixty-four blood paired samples were collected from 48 patients. The overall correlation between central venous and arterial lactate concentrations was r=0.962, p<0.0001, r2=0.965. The regression equation was aLact=(0.978×cvLact)-0.137. A similar correlation was found between central venous and arterial lactate concentrations during the states of shock and stable hemodynamics (r=0.970, p<0.0001, r2=0.966 and r=0.935, p<0.0001, r2=0.962, respectively). The mean difference between central venous and arterial lactate concentrations was 0.20mmol/l (95% CI: 0.08 to 0.32) and the limits of agreement were -0.74mmol/l (95% CI: -0.94 to -0.53) and 1.13 (95% CI: 0.93 to 1.34). CONCLUSIONS: In situations of shock where a central venous catheter is required, samples from a central vein present an acceptable and timely alternative to arterial samples for quantitating lactate concentrations.

Effect of high-dose continuous albuterol nebulization on clinical variables in children with status asthmaticus.

OBJECTIVES: Continuous albuterol nebulization is generally administered at 2.5-20 mg/hr at most centers. We examined the effect of high-dose (75 or 150 mg/hr) albuterol on clinical variables in children with status asthmaticus. DESIGN: Retrospective analysis of inpatient medical records and prospectively collected computerized PICU respiratory therapy database. SETTING: Twenty-five-bed multidisciplinary PICU in a tertiary care children's hospital. PATIENTS: Children admitted to the PICU between January 2006 and December 2007 with status asthmaticus receiving high-dose continuous albuterol nebulization. (Those with cerebral palsy, cardiac pathology, and ventilator dependence were excluded.) INTERVENTIONS: : Chart review for PICU length of stay, albuterol dose, duration of nebulization, occurrence of chest pain, vomiting, tremors, hypokalemia (serum potassium < 3.0 mEq/L), and cardiac arrhythmia. Maximal heart rate, lowest diastolic blood pressure, and mean arterial pressure were compared to the variables at initiation of therapy and at hospital discharge. MEASUREMENTS AND MAIN RESULTS: Forty-two patients (22 boys and 20 girls) received high-dose continuous albuterol nebulization. Twenty-three received 75 mg/hr and 19 received 150 mg/hr (3.7 mg/kg/hr [interquartile range, 2.4-5.8 mg/kg/hr]) for a duration of 22.3 hours (interquartile range, 6.6-31.7 hr). Heart rate increased and diastolic blood pressure and mean arterial pressure were significantly lower during nebulization compared to initiation of therapy or at hospital discharge (p < 0.05). No patient required fluid resuscitation or inotropic support, and one had self-limited premature ventricular contractions. Hypokalemia occurred in five of 33 patients who had serum electrolytes measured but did not require supplementation. One patient required endotracheal intubation after initiation of nebulization, and seven patients (16.7%) received noninvasive ventilation. PICU length of stay was 2.3 ± 1.7 days; there were no deaths. CONCLUSIONS: High-dose continuous albuterol nebulization is associated with a low rate of subsequent mechanical ventilation and fairly short PICU length of stay without significant toxicity. Prospective studies comparing conventional and high-dose albuterol nebulization are needed to determine the optimum dose providing maximum efficacy with the least adverse effects.

Detection of inflammation and oxidative lung injury in exhaled breath condensate of rats with acute lung injury due to Staphylococcal enterotoxin B.

The objectives were to determine if tumor necrosis factor (TNF)-α, leukotriene (LT)B4 and 8-isoprostane (IP) were present in the exhaled breath condensate (EBC) and total lung lavage (TLL) of mechanically ventilated rats, 4 and 24 h after administration of Staphylococcal entertoxin (SEB) and to find out if these mediators in the EBC correlate with the concentration in the TLL. Rats were assigned to control (n = 8); 4 h (n = 8) or 24 h (n = 8) groups after SEB. The rats were mechanically ventilated and EBC and TLL were collected for TNF-α, LTB4 and 8-IP. TNF-α was higher in the EBC of rats at 24 h after SEB when compared to control [34.5 (16-62 versus 2 (14-30) pg ml⁻¹, p < 0.05] and also in the TLL [113.5 (70-460) versus 59 (35-79) pg ml⁻¹, p < 0.04]. LTB4 was higher in the EBC of 24 h SEB rats, when compared to control [42 (28-50) versus 36 (29-37) pg ml⁻¹, p < 0.01] and also in the TLL [179 (116-232) versus 114 (80-187) pg ml⁻¹, p < 0.05). 8-IP was similar among the groups. No correlation was observed between TNF-α, LTB4 or 8-IP in the EBC compared to the TLL. TNF-α and LTB4 may be indicators of inflammation and oxidative lung injury but the EBC does not correlate with TLL concentrations.

Genetic association study of tumor necrosis factor-alpha with sepsis and septic shock in Thai pediatric patients.

OBJECTIVES: To evaluate the association between the genetic polymorphism of the tumor necrosis factor-alpha (TNF-α) gene and the development of sepsis and septic shock in Thai pediatric patients and to investigate the clinical impacts of TNF-α polymorphisms in this population. METHODS: To perform this genetic association study, a prospective analysis of pediatric patients (age < 18 years) with clinical sepsis/septic shock was conducted. All clinical data were collected by pediatric intensive care experts, and genetic analyses were performed at a central laboratory. A single nucleotide polymorphism (SNP) located in the 5'-promoter region at position -308 was genotyped and the results were associated with clinical phenotypes. RESULTS: A total of 167 Thai individuals were investigated, 66 of which were pediatric patients with sepsis/septic shock and 101 were healthy controls. Interestingly, we could not identify an association between sepsis and -308 (G/A) polymorphism, which have previously been demonstrated to be a major SNP associated with sepsis in several Caucasian populations, since there was no frequency difference between cases and controls. CONCLUSIONS: In this report, the major TNF-α polymorphism (-308) was not associated with clinical sepsis/septic shock in Thais. This information will be important for future analyses to identify the role of TNF-α as a genetic risk for the development of immunopathology underlying several diseases in Asia.

Estudo de associação genética entre fator de necrose tumoral alfa e sepse e choque séptico em pacientes pediátricos tailandeses / Genetic association study of tumor necrosis factor-alpha with sepsis and septic shock in Thai pediatric patients

OBJETIVOS: Avaliar a associação entre o polimorfismo genético do fator de necrose tumoral alfa (TNF-α) e o desenvolvimento de sepse e choque séptico em pacientes pediátricos tailandeses e investigar o impacto clínico de polimorfismos do TNF-α nessa população. MÉTODOS: Para a realização deste estudo de associação genética, foram analisados prospectivamente pacientes pediátricos (idade < 18 anos) com sepse clínica/choque séptico. Todos os dados foram coletados por especialistas em terapia intensiva pediátrica e as análises genéticas foram realizadas em um laboratório central. Um polimorfismo de nucleotídeo único [single nucleotide polymorphism (SNP)], localizado na região promotora 5' na posição -308, foi genotipado e os resultados foram associados a fenótipos clínicos. RESULTADOS: Foram investigados 167 indivíduos tailandeses, dos quais 66 eram pacientes pediátricos com sepse/choque séptico e 101 eram controles saudáveis. Curiosamente, não foi possível identificar associação entre sepse e o polimorfismo -308 (G→A), um dos principais SNPs anteriormente associado à sepse em várias populações caucasianas, visto que não houve diferença de frequência entre casos e controles. CONCLUSÕES: Neste estudo, o principal polimorfismo do TNF-α -308 não esteve associado à sepse clínica/choque séptico na população tailandesa. Essa informação é importante para futuras análises que busquem identificar a função do TNF-α como risco genético para o desenvolvimento de imunopatologia subjacente a várias doenças no continente asiático.

OBJECTIVES: To evaluate the association between the genetic polymorphism of the tumor necrosis factor-alpha (TNF-α) gene and the development of sepsis and septic shock in Thai pediatric patients and to investigate the clinical impacts of TNF-α polymorphisms in this population. METHODS: To perform this genetic association study, a prospective analysis of pediatric patients (age < 18 years) with clinical sepsis/septic shock was conducted. All clinical data were collected by pediatric intensive care experts, and genetic analyses were performed at a central laboratory. A single nucleotide polymorphism (SNP) located in the 5'-promoter region at position -308 was genotyped and the results were associated with clinical phenotypes. RESULTS: A total of 167 Thai individuals were investigated, 66 of which were pediatric patients with sepsis/septic shock and 101 were healthy controls. Interestingly, we could not identify an association between sepsis and -308 (G→A) polymorphism, which have previously been demonstrated to be a major SNP associated with sepsis in several Caucasian populations, since there was no frequency difference between cases and controls. CONCLUSIONS: In this report, the major TNF-α polymorphism (-308) was not associated with clinical sepsis/septic shock in Thais. This information will be important for future analyses to identify the role of TNF-α as a genetic risk for the development of immunopathology underlying several diseases in Asia.

Detection of tumor necrosis factor-α and interleukin-6 in exhaled breath condensate of rats with pneumonia due to staphylococcal enterotoxin B.

Exhaled breath condensate (EBC) may contain mediators of acute lung injury. The objectives were to determine if EBC could be collected in a mechanically ventilated rat, to measure tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in the EBC after staphylococcal enterotoxin B administration (SEB) and to find out if the concentrations of TNF-α and IL-6 correlated with those in lung lavage. Four hours after SEB instillation, rats were placed on mechanical ventilation and EBC was collected over 90 minutes. Lung lavage was collected and white cell count was determined. TNF-α and IL-6 were measured in the EBC and lavage. EBC was available in a sufficient quantity (250-400 µL) for the measurement of cytokines. The rats that received SEB had an inflammatory response when compared to control rats as shown by an increase in white cell count. TNF-α and IL-6 were detected in the EBC. Concentration of TNF-α correlated with that in the lavage (r = .497, P = .021), whereas IL-6 did not. EBC can be collected in rats in sufficient quantities to study acute lung injury. TNF-α and IL-6 can be measured in the EBC. Correlation between TNF-α in the EBC and lavage was demonstrated in this rat model of lung injury.