Deciphering the TLR transcriptome and downstream signaling pathway in cerebrospinal fluid in pediatric meningitis.

OBJECTIVE/DESIGN: Pediatric meningitis is characterized by a colossal inflammatory response to the pathogen in the central nervous system (CNS). This unabated inflammatory response persists even after the removal of the pathogen by antibiotics/steroids causing collateral damage to CNS tissue. Toll-like receptors (TLRs) are the key players in the recognition and elicitation of innate-immune response against bacterial/viral components in cerebrospinal fluid (CSF). Till date, the precise understanding of TLR-triggered inflammatory response in pediatric meningitis is lacking. The present study was designed to delineate the role of TLR transcriptome and downstream signaling pathways in CSF of pediatric meningitis. METHODS: Children in the age group of > 3 months to 12 years with pediatric meningitis were included. A total of 249 cases of pediatric meningitis (bacterial = 89, viral = 160) were included. In addition, 71 children who tested negative to the pathogen in CSF tap and did not have signs of infection clinically constituted the controls. RNA was extracted from the CSF samples of both cases and controls. The relative gene expression profile of 42 TLR signaling pathway genes was performed. For the analysis of secretory cytokines and chemokines in CSF, Luminex assay was performed. RESULTS: We report global upregulation of TLR genes in patients with acute bacterial meningitis (ABM). The downstream signaling molecules were upregulated as well. The CSF of pediatric ABM patients revealed a predominant pro-inflammatory milieu marked by increased levels of pro-inflammatory cytokines. A significant correlation between poor clinical outcomes of patients and an increased expression of TLR/pro-inflammatory cytokine genes was observed. CONCLUSION: Our findings provide support for future studies exploring TLR-based adjunct therapy to limit the neurological sequelae, owing to persistent inflammation in pediatric ABM patients.

Clinical Features Associated With Need for Mechanical Ventilation in Children With Guillain-Barré Syndrome: Retrospective Cohort From India.

OBJECTIVES: To analyze the clinical features associated with the need for mechanical ventilation (MV) in children with Guillain-Barré syndrome (GBS). DESIGN: Retrospective cohort study, 2010-2019. SETTING: PICU. PATIENTS: All children, 1 month to 12 years old, diagnosed with GBS in our single-center PICU. INTERVENTION: Retrospective chart and data review. MEASUREMENTS AND MAIN RESULTS: Out of 189 children identified with a diagnosis of GBS, 130 were boys (69%). The median (interquartile range [IQR]) age was 6 years (3-9 yr). At admission, the Hughes disability score was 5 (4-5), and cranial nerve palsies were present in 81 children (42%). Autonomic instability subsequently occurred in a total of 97 children (51%). In the 159 children with nerve conduction studies, the axonal variant of GBS (102/159; 64%) predominated, followed by the demyelinating variant (38/189; 24%). All children received IV immunoglobulins as first-line therapy at the time of admission. The median (IQR) length of PICU stay was 12 days (3-30.5 d). Ninety-nine children (52%) underwent invasive MV, and median duration of MV was 25 days (19-37 d). At admission, upper limb power less than or equal to 3 (p = 0.037; odds ratio (OR), 3.5 [1.1-11.5]), lower limb power less than or equal to 2 (p = 0.008; OR, 3.5 [1.4-8.9]), and cranial nerve palsy (p = 0.001; OR, 3.2 [1.6-6.1]) were associated with subsequent need for MV. Prolonged (> 21 d) MV was associated with more severe examination findings at admission: upper limb power less than or equal to 2 (p < 0.0001; OR, 4.2 [2.5-6.9]) and lower limb power less than or equal to 1 (p < 0.0001; OR, 4.5 [2.6-7.9]). CONCLUSIONS: In children with GBS, referred to our center in North India, severe neuromuscular weakness at admission was associated with the need for MV. Furthermore, greater severity of this examination was associated with need for prolonged (> 21 d) MV. Identification of these signs may help in prioritizing critical care needs and early PICU transfer.

Cytokine Levels in Critically Ill Children With Severe Sepsis and Their Relation With the Severity of Illness and Mortality.

OBJECTIVE: To study the baseline cytokine levels and their relation with the severity of illness and mortality in critically ill children with severe sepsis. DESIGN: Subgroup analysis of a randomized, double-blind, placebo-controlled trial. SETTING: Pediatric intensive care unit of a tertiary level teaching hospital in India. PATIENTS: Fifty children with severe sepsis aged 3 months to 12 years. MATERIAL AND METHODS: Blood was collected at admission for estimation of pro-inflammatory (interleukin 6 [IL-6], IL-12p70, IL-17, and tumor necrotic factor α [TNF-α]) and anti-inflammatory (IL-10 and transforming growth factor ß1 [TGF-ß1]) cytokines. PRIMARY OUTCOME: To find out correlation between cytokine levels and severity of illness scores (Pediatric Risk of Mortality [PRISM] III score, Sequential Organ Failure Assessment [SOFA], and Vasoactive-Inotropic Score [VIS]). SECONDARY OUTCOMES: To compare cytokine levels among survivors and nonsurvivors. RESULTS: Baseline pro-inflammatory cytokine levels (median [interquartile range]) were IL-6: 189 (35-285) pg/mL, IL-12p: 48 (28-98) pg/mL, IL-17: 240 (133-345) pg/mL, and TNF-α: 296 (198-430) pg/mL; anti-inflammatory cytokine levels were IL-10: 185 (62-395) pg/mL and TGF-ß1: 204 (92-290) ng/mL. Pro-inflammatory cytokines showed positive correlation with PRISM III score: IL-6 (Spearman correlation coefficient, ρ = 0.273, P = .06), IL-12 (ρ = 0.367, P = .01), IL-17 (ρ = 0.197, P = .17), and TNF-α (ρ = 0.284, P = .05), and anti-inflammatory cytokines showed negative correlation: IL-10 (ρ = -0.257, P = .09) and TGF-ß (ρ = -0.238, P = .11). Both SOFA and VIS also showed weak positive correlation with IL-12 (ρ = 0.32, P = .03 and ρ = 0.31, P = .03, respectively). Among nonsurvivors (n = 5), the levels of all the measured pro-inflammatory cytokines were significantly higher as compared to survivors, IL-6: 359 (251-499) pg/mL versus 157 (97-223) pg/mL, P < .0001, IL-12p70: 167 (133-196) pg/mL versus 66 (30-100) pg/mL, P < .0001, IL-17: 400 (333-563) pg/mL versus 237 (122-318) pg/mL, P = .009, and TNF-α: 409 (355-503) pg/mL versus 330 (198-415) pg/mL, P = .002, respectively. CONCLUSION: In critically ill children with severe sepsis, pro-inflammatory cytokines (especially IL-12p70) showed a weak positive correlation with severity of illness and were significantly higher among nonsurvivors.

Risk Factors for Cerebral Edema and Acute Kidney Injury in Children with Diabetic Ketoacidosis.

OBJECTIVES: To study the clinical profile and risk factors of cerebral edema and acute kidney injury in children with diabetic ketoacidosis. DESIGN: Retrospective review of medical records. PATIENTS: Fifty consecutive patients (age <18 years) admitted to our pediatric intensive care unit with a diagnosis of diabetic ketoacidosis over 5 years. MATERIALS AND METHODS: Retrospective analysis of medical records was done, and data including patients' age, sex, presenting features, biochemical profile including blood glucose, osmolality, urea, creatinine, and venous blood gas, electrolytes were recorded at admission, at 12 and 24 hours. Treatment details including fluid administration, rate of fall of glucose, time to resolution of diabetic ketoacidosis were noted. Complications such as cerebral edema and acute kidney injury were recorded. Patients with and without cerebral edema and acute kidney injury were compared. Variables that were significant on univariate analysis were entered in a multiple logistic regression analysis to determine the independent predictors for cerebral edema and acute kidney injury. Odds ratio and 95% confidence interval were calculated using SPSS version 22. MEASUREMENTS AND MAIN RESULTS: Between November 2015 and 2020, 48 patients were admitted for a total of 50 episodes of diabetic ketoacidosis. Two patients had recurrent diabetic ketoacidosis. Median age was 9.5 years (range 1-17). Thirty-one patients (62%) had new-onset type I diabetes mellitus. Twenty-two patients (44%) presented with severe diabetic ketoacidosis. Cerebral edema and acute kidney injury were seen in 11 (22%) and 15 (30%) patients, respectively. On multiple logistic regression analysis, higher blood urea level, lower serum bicarbonate level, and higher corrected sodium levels at admission were identified to be variables independently associated with risk of cerebral edema. CONCLUSIONS: Higher corrected sodium, higher urea level, and lower serum bicarbonate levels at admission are predictive of cerebral edema in patients presenting with diabetic ketoacidosis. The severity of dehydration and acidosis in DKA appears to be a common factor responsible for the development of dysfunction of both brain and kidney. HOW TO CITE THIS ARTICLE: Raghunathan V, Jevalikar G, Dhaliwal M, Singh D, Sethi SK, Kaur P, et al. Risk Factors for Cerebral Edema and Acute Kidney Injury in Children with Diabetic Ketoacidosis. Indian J Crit Care Med 2021;25(12):1446-1451.

Randomized Clinical Trial of 20% Mannitol Versus 3% Hypertonic Saline in Children With Raised Intracranial Pressure Due to Acute CNS Infections.

OBJECTIVES: Mannitol is a commonly used osmotherapy agent in raised intracranial pressure. However, the side effects of mannitol are significant. In traumatic brain injury (adult and pediatric), hypertonic saline (3%) shows varied results in comparison with 20% mannitol. We compared the effect of 3% hypertonic saline versus 20% mannitol (using common dosing strategies) on raised intracranial pressure in pediatric acute CNS infections. DESIGN: Open-label randomized controlled trial. SETTING: PICU of a quaternary care academic institute. PATIENTS: Children 1-12 years old, with raised intracranial pressure and modified-Glasgow Coma Scale scores less than or equal to 8, were enrolled. INTERVENTIONS: Patients were randomly assigned to 20%-mannitol (n = 28), 0.5 gram/kg/dose versus 3%-hypertonic saline (n = 29), 10 mL/kg loading followed by 0.5-1 mL/kg/hr infusion. An intraparenchymal catheter was used to monitor the intracranial pressure. The primary outcome was the proportion of patients achieved target average intracranial pressure less than 20 mm Hg during 72 hours. Secondary outcomes were interventions, morbidity, and mortality. MEASUREMENTS AND MAIN RESULTS: The proportion of patients with target average intracranial pressure (< 20 mm Hg) was higher in hypertonic saline-group as compared to mannitol-group (79.3% vs 53.6%; adjusted hazard ratio 2.63; 95% CI: 1.23-5.61). Mean (± SE) reduction of intracranial pressure (-14.3 ± 1.7 vs -5.4 ± 1.7 mm Hg; p ≤ 0.001) and elevation of cerebral perfusion pressure (15.4 ± 2.4 vs 6 ± 2.4 mm Hg; p = 0.007) from baseline were significant in hypertonic saline-group. Mean (± SE) intracranial pressure over 72 hours was lower (14 ± 2 vs 22 ± 2 mm Hg; p = 0.009), and cerebral perfusion pressure was higher (65 ± 2.2 vs 58 ± 2.2; p = 0.032) in hypertonic saline-group. Hypertonic saline-group had higher modified-Glasgow Coma Scale score at 72 hours (median, interquartile range 10; 7-11 vs 7; 3-9; p = 0.003), lower mortality (20.7% vs 35.7%; p = 0.21), shorter duration of mechanical ventilation (5 vs 15 d; p = 0.002), and PICU stay (11 vs 19 d; p = 0.016) and less severe neurodisability at discharge (31% vs 61%; p = 0.049). CONCLUSIONS: In pediatric acute CNS infections, 3%-hypertonic saline was associated with a greater reduction of intracranial pressure as compared to 20% mannitol.

Decompressive craniectomy in pediatric non-traumatic intracranial hypertension: a single center experience.

Purpose: To study the clinical profile and predictors of outcome in children undergoing decompressive craniectomy (DC) for non-traumatic intracranial hypertension (ICH).Materials and methods: Mixed observational study of children, aged 1 month-12 years, who underwent DC for non-traumatic ICH in a tertiary care pediatric intensive care unit from 2012 to 2017. Data on clinical profile and outcome were retrieved retrospectively and survivors were assessed prospectively. The primary outcome was neurological outcome using Glasgow Outcome Scale-Extended (GOS-E) at minimum 6 months' post-discharge. GOS-E of 1-4 were classified as a poor and 5-8 as a good outcome.Results: Thirty children, median (IQR) age of 6.5 (2, 50) months, underwent DC; of which 26 (86.7%) were boys. Altered sensorium (n = 26, 86.7%), seizures (n = 25, 83.3%), pallor (n = 19, 63.3%) and anisocoria (n = 14, 46.7%) were common signs and symptoms. Median (IQR) Glasgow Coma Scale at admission was 9 (6,11). Commonest etiology was intracranial bleed (n = 24; 80%). Median (IQR) time to DC was 24 (24,72) h. Eight (26.7%) children died; 2 during PICU stay and 6 during follow-up. Neurological sequelae at discharge (n = 28) were seizures (n = 25; 89.2%) and hemiparesis (n = 16; 57.1%). Twenty-one children were followed-up at median (IQR) duration of 12 (6,54) months. Good neurological outcome was seen in 14/29 (48.2%) and hemiparesis in 10/21 (47.6%) patients. On regression analysis, anisocoria at admission was an independent predictor of poor outcome [OR 7.33; 95%CI: 1.38-38.87; p = 0.019].Conclusions: DC is beneficial in children with non-traumatic ICH due to a focal pathology and midline shift. Evidence on indications and timing of DC in NTC is still evolving.

Airway Pressure Release Ventilation in Pediatric Acute Respiratory Distress Syndrome. A Randomized Controlled Trial.

RATIONALE: Although case series describe benefits of airway pressure release ventilation (APRV), this mode of ventilation has not been evaluated against the conventional low-tidal volume ventilation (LoTV) in children with acute respiratory distress syndrome (ARDS). OBJECTIVES: To compare the effect of APRV and conventional LoTV on ventilator-free days in children with ARDS. METHODS: This open-label, parallel-design randomized controlled trial was conducted in a 15-bed ICU. Children aged 1 month to 12 years satisfying the modified Berlin definition were included. We excluded children with air leaks, increased intracranial pressure, poor spontaneous breathing efforts, chronic lung disease, and beyond 24 hours of ARDS diagnosis or 72 hours of ventilation. Children were randomized using unstratified, variable-sized block technique. A priori interim analysis was planned at 50% enrollment. All enrolled children were followed up until 180 days after enrollment or death, whichever was earlier. MEASUREMENTS AND MAIN RESULTS: The trial was terminated after 50% enrollment (52 children) when analysis revealed higher mortality in the intervention arm. Ventilator-free days were statistically similar in both arms (P = 0.23). The 28-day all-cause mortality was 53.8% in APRV as compared with 26.9% among control subjects (risk ratio, 2.0; 95% confidence interval, 0.97-4.1; Fisher exact P = 0.089). The multivariate-adjusted risk ratio of death for APRV compared with LoTV was 2.02 (95% confidence interval, 0.99-4.12; P = 0.05). Higher mean airway pressures, greater spontaneous breathing, and early improvement in oxygenation were seen in the intervention arm. CONCLUSIONS: APRV, as a primary ventilation strategy in children with ARDS, was associated with a trend toward higher mortality compared with the conventional LoTV. Limitations should be considered while interpreting these results. Clinical trial registered with www.clinicaltrials.gov (NCT02167698) and Clinical Trials Registry of India (CTRI/2014/06/004677).

Spontaneous intracranial haemorrhage in children-intensive care needs and predictors of in-hospital mortality: a 10-year single-centre experience.

PURPOSE: Spontaneous intracranial haemorrhage (SICH) in children, although uncommon, is associated with significant mortality and morbidity. Paediatric data is however limited. MATERIAL AND METHODS: Case records of 105 children with SICH, > 1 month to 12 years, admitted to a tertiary level PICU of a teaching and referral hospital between January 2009 and May 2018 were analysed retrospectively. In-hospital mortality was the primary outcome. Variables between survivors and non-survivors were compared to  determine predictors of mortality. RESULTS: The median (IQR) age of subjects was 6 (2.25, 70) months. Common clinical features were altered sensorium (n = 87, 82.9%), seizures (n = 73, 69.5%), pallor (n = 66, 62.9%) and bulging anterior fontanelle (n = 52, 49.5%). Median (IQR) Glasgow Coma Scale (GCS) at admission was 10 (6, 13) with herniation noted in 27 (25.7%) children. Vitamin K deficiency bleeding (VKDB) and arteriovenous malformation (AVM) were the most common etiology for bleeding among infants and older children respectively. The most common site of bleeding was intracerebral (n = 47, 44.8%) followed by subdural (n = 26; 24.8%). Sixteen (15.2%) children died during hospital stay. On univariate analysis, GCS < 8, Pediatric Risk of Mortality score (PRISM III) > 20, need for intubation, thiopentone coma for refractory intracranial pressure (ICP) and progression to shock and acute kidney injury (AKI) predicted mortality. Seizures were favourably associated with survival. Age, site of bleeding, etiology or type of management for raised ICP (conservative versus decompressive craniectomy) did not affect the outcome. On multivariable analysis, progression to AKI (OR 5.86; 95% CI, 1.53-22.4; p 0.01) predicted poor outcome. Seizures, however, were associated with better odds for survival (OR 0.12; 95% CI, 0.03-0.47; p 0.002). CONCLUSIONS: VKDB and AVM were the common etiologies among infants and older children respectively. Age, site, etiology of bleeding and type of management did not affect outcome. Severe decompensation at presentation, thiopentone for refractory ICP and progression to multiorgan dysfunction determined mortality.

Pediatric empyema thoracis: What has changed over a decade?

OBJECTIVES: The purposes of this paper are to study clinicobacteriological profile, treatment modalities and outcome of pediatric empyema thoracis and to identify changes over a decade. DESIGN: This is a retrospective study. SETTING: Department of Pediatrics of a tertiary care hospital in North India. PATIENTS: We enrolled 205 patients (1 month-12 years) of empyema thoracis admitted over 5 years (2007-11) and compared the profile with that of a previous study from our institute (1989-98). RESULTS: Pleural fluid cultures were positive in 40% (n = 82) cases from whom 87 isolates were obtained. Staphylococcus aureus was the most common isolate (66.7%). Methicillin-sensitive S. aureus accounted for 56%, Methicillin-resistant S. aureus (MRSA) 10% and gram-negative organisms 18.3% of isolates. Intercostal drainage tube (ICDT) was inserted in 97.5%, intrapleural streptokinase was administered in 33.6%, and decortication performed in 27.8% cases. Duration of hospital stay was 17.2 (±6.3) days, duration of antibiotic (intravenous and oral) administration was 23.8 (±7.2) days and mortality rate was 4%. In the index study (compared with a previous study), higher proportion of cases received parenteral antibiotics (51.7% vs. 23.4%) and ICDT insertion (20.5% vs. 7%) before referral and had disseminated disease (20.5% vs. 14%) and septic shock (11.2% vs. 1.6%), less culture positivity (40% vs. 48%), more MRSA (10.3% vs. 2.5%) and gram-negative organisms (18.4% vs. 11.6%), increased use of intrapleural streptokinase and surgical interventions (27.8% vs. 19.7%), shorter hospital stay (17 vs. 25 days) and higher mortality (3.9% vs. 1.6%). CONCLUSIONS: Over a decade, an increase in the incidence of empyema caused by MRSA has been noticed, with increased use of intrapleural streptokinase and higher number of surgical interventions.

End-of-Life Milieu of Critically Sick Children Admitted to a Pediatric Hospital: A Comparative Study of Survivors versus Nonsurvivors.

OBJECTIVE: The aim of this study was to describe end-of-life (EOL) milieu among caregivers of children who died in the hospital and to compare their psychosocial, spiritual, and financial concerns with caregivers of children who survived. MATERIALS AND METHODS: Sixty caregivers of children (30 survivors and 30 nonsurvivors), admitted in the pediatric intensive care unit and general pediatric unit, were recruited over a period of 1 year. Mixed qualitative methods were used to collect information from parents on EOL care perspectives. RESULTS: Demographic, disease, and treatment-related characteristics were not significantly different between nonsurvivor and survivor groups. The caregivers of nonsurvivors versus survivors showed no significant differences as regards optimal care (76.67% vs. 56.67%), social support (76.6% vs. 66.67%), and frequent recitation of scriptures (30.77% vs. 45.83%). Mean medical expenditure among children receiving EOL care was Rs. 40,883 (range: Rs. 800-5 lakhs). Regression results revealed that for every 1 day of increase in hospital stay, cost of hospitalization for dying children increased by Rs. 3000 (P = 0.0001). Medical insurance was reported by only minority of the cases (5%). Several themes emerged in the focus group discussions with care providers which highlighted the importance of communication and need for emotional, social, and financial support. EOL decision was taken in only two of the nonsurviving children. CONCLUSIONS: The study offers useful insight about social, financial, and religious "end-of-life" needs among terminally sick children and thereby sensitizes the health-care providers to optimize their care at this niche period.

Evaluation of Effect of Probiotics on Cytokine Levels in Critically Ill Children With Severe Sepsis: A Double-Blind, Placebo-Controlled Trial.

OBJECTIVES: To evaluate the effect of probiotics on cytokines in children with severe sepsis. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: ICU of a tertiary care teaching hospital in North India. PATIENTS: Children 3 months to 12 years old with severe sepsis. INTERVENTIONS: Enrolled children were randomized to probiotic (n = 50) and placebo (n = 50) groups. Probiotic group received VSL#3 (Danisco-Dupont USA, Madison, WI) (Lactobacillus paracasei, L. plantarum, L. acidophilus, L. delbrueckii, Bifidobacterium longum, B. infantis, B. breve, Streptococcus salivarius; maltose and silicon dioxide), and placebo group received maltose and silicon dioxide. Dose was 1 sachet twice daily for 7 days. Blood was collected on days 1 and 7 for estimation of interleukin-6, interleukin-12p70, interleukin-17, tumor necrosis factor-α, interleukin-10, and transforming growth factor -ß1. "Primary outcome": Change in cytokine levels in probiotic and placebo groups from day 1 to 7. "Secondary outcomes": Sequential Organ Failure Assessment score, healthcare-associated infections, ICU stay, and mortality. MEASUREMENTS AND MAIN RESULTS: On day 7, probiotic group had significantly lower levels of proinflammatory cytokines (interleukin-6 [80 vs 186 pg/mL, p = 0.001]; interleukin-12p70 [44 vs 79 pg/mL, p = 0.001]; interleukin-17 [217 vs 293 pg/mL, p = 0.01]; and tumor necrosis factor-α [192 vs 348 pg/mL, p = 0.01]) and higher levels of antiinflammatory cytokines (interleukin-10 [320 vs 240 pg/mL, p = 0.02] and transforming growth factor-ß1 [311 vs 221 ng/mL, p = 0.01]) than placebo group. From day 1 to 7, probiotic group showed significant decrease in proinflammatory cytokines (interleukin-6 [196-80 pg/mL, p = 0.001]; interleukin-12p70 [71-44 pg/mL, p = 0.01]; interleukin-17 [258-217 pg/mL, p = 0.01]; and tumor necrosis factor-α [347-192 pg/mL, p = 0.001]) and increase in antiinflammatory cytokines (interleukin-10 [198-320 pg/mL, p = 0.001] and transforming growth factor-ß1 [216-311 ng/mL, p = 0.001]) as compared to placebo group. Sequential Organ Failure Assessment score on day 7 was significantly less in probiotic group (1 vs 3). There was a nonsignificant trend toward lower incidence of healthcare-associated infections (14% vs 20%) and duration of ICU stay (6.5 vs 9 d) in probiotic group. Mortality was similar in two groups. CONCLUSIONS: Probiotics supplementation for 7 days resulted in significant decrease in proinflammatory and increase in antiinflammatory cytokines in children with severe sepsis.

Pulmonary Functions in Children Ventilated for Acute Hypoxemic Respiratory Failure.

OBJECTIVE: To assess pulmonary functions of children who received mechanical ventilation for acute hypoxemic respiratory failure. DESIGN: Longitudinal study. SETTING: PICU and Pediatric Pulmonology Clinic of a tertiary care teaching hospital in North India. PATIENTS: All children, 5-12 years old, ventilated for acute hypoxemic respiratory failure in PICU from July 2012 to June 2013 and survived. INTERVENTIONS: The baseline admission variables recorded were as follows: age, sex, duration of illness, primary diagnosis at admission, Pediatric Risk of Mortality III score, lung injury score, mechanical ventilation parameters, oxygenation indices, and duration of PICU stay. The children were followed up twice, at 3 and 9-12 months, after discharge from PICU and evaluated for any residual respiratory symptoms and signs, pulse oximetry, chest radiograph, 6-minute walk test, peak expiratory flow rate, and spirometry. Age, sex, duration of illness, primary diagnosis, Pediatric Risk of Mortality III score, lung injury score, mechanical ventilation parameters, oxygenation indices (PaO2/FIO2 ratio and oxygenation index), and duration of PICU stay were recorded from patient records. MEASUREMENTS AND MAIN RESULTS: Twenty-nine children (25 boys and four girls; mean [SD] age, 8.4 [2.4] yr) were followed up at 3.5 (± 1.2) and 10.6 (± 2.7) months after discharge from PICU. Recurrent respiratory symptoms were noted in 37.9% patients (11/29) during first and in none during second follow-up. None had limitation of physical activity or need of supplemental oxygen. Chest examination was normal in all, except one during first follow-up, but 13.8% (4/29) had abnormal chest radiograph during first follow-up. Nearly all children could perform 6-minute walk test although mean distance walked increased significantly from first (352 ± 66.7 m) to second follow-up (401 ± 60.7 m; p = 0.002). Abnormal spirometry was seen in 82.7% (24/29) versus 18.5% (5/27) children during first and second follow-up visits, respectively (p = 0.0001). Most cases had restrictive abnormality (58.6% vs 11.1%; p = 0.002) during first and second follow-up, respectively. There was no correlation between pulmonary functions and lung injury scores, oxygenation indices (PaO2/FIO2 ratio and oxygenation index), and mechanical ventilation parameters. CONCLUSIONS: Significant number of children ventilated for acute hypoxemic respiratory failure had subclinical pulmonary function abnormality, without limiting physical activity, which improved over time. Further research on this topic with a larger sample size and patient categorization according to recent pediatric acute respiratory distress syndrome definition is needed.

Intrapleural streptokinase is effective and safe for children with multi-loculated empyema regardless of the time from disease onset.

AIM: This study compared the efficacy of administering intrapleural streptokinase to children with multi-loculated empyema within 14 days or at any time after disease onset. METHODS: We studied children under 12 years with multi-loculated empyema who were admitted to a teaching hospital in Chandigarh, India, from July 2013 to June 2017. They received antibiotics, pleural drainage and intrapleural streptokinase. The first group received three doses within 14 days of disease onset, the second received three doses regardless of time after onset and the third group received four to six doses regardless of time after onset. The three phases lasted 18, 18 and 12 months, respectively. RESULTS: Of 195 children, 133 (68%) received streptokinase within 14 days, 46 (24%) beyond 14 days and 16 (8%) did not receive it. There was no difference in surgical decortication (14/133 versus 7/46, p > 0.05) and median hospitalisation duration (15 versus 14 days, p > 0.05) between administration before versus after 14 days. Median hospitalisation was shorter with four to six doses than three doses (11 versus 16 days, p < 0.01). CONCLUSION: Intrapleural streptokinase was effective for multi-loculated empyema even when it was administered more than 14 days after disease onset and four to six doses were superior to three doses.

Post-neonatal Tetanus in a PICU of a Developing Economy: Intensive Care Needs, Outcome and Predictors of Mortality.

Objectives: To evaluate pediatric intensive care unit (PICU) needs, outcome and predictors of mortality in post-neonatal tetanus. Materials and methods: Review of 30 consecutive post-neonatal tetanus cases aged 1 months to 12 years admitted to a PICU in north India over a period of 10 years (January 2006 to December 2015). Results: Chronic suppurative otitis media was the commonest portal of entry. All received tetanus toxoid, human tetanus immunoglobulin (HTIG) and appropriate antibiotics; 7 (23.3%) received intrathecal HTIG. Common complications were respiratory failure, rhabdomyolysis, autonomic dysfunction, acute kidney injury and healthcare-associated infections. PICU needs were as follows: ventilation; benzodiazepine, morphine and magnesium sulfate infusion; neuromuscular blockers, inotropes, tracheostomy and renal replacement therapy. Mortality rate was 40%; severity Grade IIIb, autonomic dysfunction, use of vasoactive drugs and those who did not receive intrathecal HTIG were significantly associated with mortality. Conclusion: Post-neonatal tetanus is associated with high mortality, and PICU needs include management of spasms, autonomic dysfunction and complications and cardiorespiratory support.

Tropical Fevers in Indian Intensive Care Units: A Prospective Multicenter Study.

BACKGROUND AND AIMS: Infections in tropics often present as undifferentiated fevers with organ failures. We conducted this nationwide study to identify the prevalence, profile, resource utilization, and outcome of tropical fevers in Indian Intensive Care Units (ICUs). MATERIALS AND METHODS: This was a multicenter prospective observational study done in 34 ICUs across India (July 2013-September 2014). Critically ill adults and children with nonlocalizing fever >48 h and onset < 14 days with any of the following: thrombocytopenia/rash, respiratory distress, renal failure, encephalopathy, jaundice, or multiorgan failure were enrolled consecutively. RESULTS: Of 456 cases enrolled, 173 were children <12 years. More than half of the participants (58.7%) presented in postmonsoon months (August-October). Thrombocytopenia/rash was the most common presentation (60%) followed by respiratory distress (46%), encephalopathy (28.5%), renal failure (23.5%), jaundice (20%), and multiorgan failure (19%). An etiology could be established in 365 (80.5%) cases. Dengue (n = 105.23%) was the most common followed by scrub typhus (n = 83.18%), encephalitis/meningitis (n = 44.9.6%), malaria (n = 37.8%), and bacterial sepsis (n = 32.7%). Nearly, half (35% invasive; 12% noninvasive) received mechanical ventilation, a quarter (23.4%) required vasoactive therapy in first 24 h and 9% received renal replacement therapy. Median (interquartile range) ICU and hospital length of stay were 4 (3-7) and 7 (5-11.3) days. At 28 days, 76.2% survived without disability, 4.4% had some disability, and 18.4% died. Mortality was higher (27% vs. 15%) in patients with undiagnosed etiology (P < 0.01). On multivariate analysis, multiorgan dysfunction syndrome at admission (odds ratio [95% confidence interval]-2.8 [1.8-6.6]), day 1 Sequential Organ Failure Assessment score (1.2 [1.0-1.3]), and the need for invasive ventilation (8.3 [3.4-20]) were the only independent predictors of unfavorable outcome. CONCLUSIONS: Dengue, scrub typhus, encephalitis, and malaria are the major tropical fevers in Indian ICUs. The data support a syndromic approach, point of care tests, and empiric antimicrobial therapy recommended by Indian Society of Critical Care Medicine in 2014.

Double-Blind Randomized Clinical Trial Comparing Dopamine and Epinephrine in Pediatric Fluid-Refractory Hypotensive Septic Shock.

OBJECTIVE: We compared efficacy of dopamine and epinephrine as first-line vasoactive therapy in achieving resolution of shock in fluid-refractory hypotensive cold septic shock. DESIGN: Double-blind, pilot, randomized controlled study. SETTING: Pediatric emergency and ICU of a tertiary care teaching hospital. PATIENTS: Consecutive children 3 months to 12 years old, with fluid-refractory hypotensive septic shock, were enrolled between July 2013 and December 2014. INTERVENTION: Enrolled children were randomized to receive either dopamine (in incremental doses, 10 to 15 to 20 µg/kg/min) or epinephrine (0.1 to 0.2 to 0.3 µg/kg/min) till end points of resolution of shock were achieved. After reaching maximum doses of test drugs, open-label vasoactive was started as per discretion of treating team. Primary outcome was resolution of shock within first hour of resuscitation. The study was registered (CTRI/2014/02/004393) and was approved by institute ethics committee. MEASUREMENTS AND MAIN RESULTS: We enrolled 29 children in epinephrine group and 31 in dopamine group. Resolution of shock within first hour was achieved in greater proportion of children receiving epinephrine (n = 12; 41%) than dopamine (n = 4; 13%) (odds ratio, 4.8; 95% CI, 1.3-17.2; p = 0.019); the trend persisted even at 6 hours (48.3% vs 29%; p = 0.184). Children in epinephrine group had lower Sequential Organ Function Assessment score on day 3 (8 vs 12; p = 0.05) and more organ failure-free days (24 vs 20 d; p = 0.022). No significant difference in adverse events (16.1% vs 13.8%; p = 0.80) and mortality (58.1% vs 48.3%; p = 0.605) was observed between the two groups. CONCLUSION: Epinephrine is more effective than dopamine in achieving resolution of fluid-refractory hypotensive cold shock within the first hour of resuscitation and improving organ functions.

Global epidemiology of pediatric severe sepsis: the sepsis prevalence, outcomes, and therapies study.

RATIONALE: Limited data exist about the international burden of severe sepsis in critically ill children. OBJECTIVES: To characterize the global prevalence, therapies, and outcomes of severe sepsis in pediatric intensive care units to better inform interventional trials. METHODS: A point prevalence study was conducted on 5 days throughout 2013-2014 at 128 sites in 26 countries. Patients younger than 18 years of age with severe sepsis as defined by consensus criteria were included. Outcomes were severe sepsis point prevalence, therapies used, new or progressive multiorgan dysfunction, ventilator- and vasoactive-free days at Day 28, functional status, and mortality. MEASUREMENTS AND MAIN RESULTS: Of 6,925 patients screened, 569 had severe sepsis (prevalence, 8.2%; 95% confidence interval, 7.6-8.9%). The patients' median age was 3.0 (interquartile range [IQR], 0.7-11.0) years. The most frequent sites of infection were respiratory (40%) and bloodstream (19%). Common therapies included mechanical ventilation (74% of patients), vasoactive infusions (55%), and corticosteroids (45%). Hospital mortality was 25% and did not differ by age or between developed and resource-limited countries. Median ventilator-free days were 16 (IQR, 0-25), and vasoactive-free days were 23 (IQR, 12-28). Sixty-seven percent of patients had multiorgan dysfunction at sepsis recognition, with 30% subsequently developing new or progressive multiorgan dysfunction. Among survivors, 17% developed at least moderate disability. Sample sizes needed to detect a 5-10% absolute risk reduction in outcomes within interventional trials are estimated between 165 and 1,471 [corrected] patients per group. CONCLUSIONS: Pediatric severe sepsis remains a burdensome public health problem, with prevalence, morbidity, and mortality rates similar to those reported in critically ill adult populations. International clinical trials targeting children with severe sepsis are warranted.

Use of Nasal Bubble CPAP in Children with Hypoxemic Clinical Pneumonia-Report from a Resource Limited Set-Up.

OBJECTIVE: Nasal bubble continuous positive airway pressure (bCPAP) is preferred in developing economies for easy applicability and low cost. Because its use in older children is unexplored, we sought to evaluate its utility in hypoxemic clinical pneumonia. METHODS: Of 330 children (1 month-12 years) with clinical pneumonia enrolled prospectively over 1 year, those with increased work of breathing and/or SpO2 <92% received bCPAP delivered via an underwater 'T' tube through nasal prongs. Proportion requiring intubation despite bCPAP constituted primary outcome. Incidence of complications, duration of bCPAP and emergency stay were secondary outcomes. RESULTS: Oxygen was initiated by nasal prongs (NPO2) in 204 (61.8%), and by bCPAP in 110 (33.3%). Sixteen (4.8%) were intubated at the outset. Fifty-three (25.9%) on NPO2 were shifted to bCPAP for worsening distress and hypoxemia. Only three (1.8%) from bCPAP group required intubation, of which one died. Failure rate and complications were negligent. The median emergency stay was 4 days. CONCLUSIONS: Nasal bCPAP was safe and effective in children with hypoxemic clinical pneumonia.

Bedside burr hole for intracranial pressure monitoring performed by pediatric intensivists in children with CNS infections in a resource-limited setting: 10-year experience at a single center.

OBJECTIVE: Intracranial pressure monitoring can help in early identification of raised intracranial pressure and in setting more informed goals for treatment. We describe our 10-year experience of bedside burr holes performed by pediatric intensivists to establish intracranial pressure monitoring in children with CNS infections in a resource-limited setting and the technical difficulties and complications encountered. DESIGN: Descriptive study of prospectively recorded data. SETTING: PICU of a tertiary care academic institute. PATIENTS: Consecutive comatose patients with raised intracranial pressure who underwent intracranial pressure monitoring from 2004 to 2013. INTERVENTION: An intraparenchymal (1.2 mm) or an intraventricular transducer (3.4 mm) (Codman) was placed by a pediatric intensivist through a micro burr hole using a standard protocol. Technical difficulties during the procedure and complications were recorded. MEASUREMENTS AND MAIN RESULTS: Over 10 years, 265 intracranial pressure catheters were placed in 259 patients, mainly for acute CNS infections (n = 242, 93.4%). Median age of patients was 4.8 years, youngest being 6 weeks; 21 patients (8.1%) were younger than 1 year. Intraparenchymal transducer was used in 252 patients (97.3%). Median (interquartile range) duration of intracranial pressure monitoring was 96 hours (72-144 hr). Complications were seen in 3.5% of patients (n = 9/259); the incidence was 0.28 per 1,000 hours of intracranial pressure monitoring. Procedure-related ventriculitis occurred in three of seven patients (42.8%) with intraventricular catheter, in contrast to none in patients with intraparenchymal transducer. Overall mortality was 32.8% (n = 85). On Cox-regression analysis, "blood component therapy" was an independent predictor of poor outcome defined as death or severe neurodisability (adjusted hazard ratio, 1.58; 95% CI, 1.16-2.16; p = 0.004). CONCLUSIONS: In a resource-limited setting, pediatric intensivists can safely and successfully perform burr holes at bedside for establishing intraparenchymal intracranial pressure monitoring in children with acute CNS infections. However, our data do not support placement of ventriculostomy catheters by pediatric intensivists in similar settings.

High-dose Oral Ambroxol for Early Treatment of Pulmonary Acute Respiratory Distress Syndrome: an Exploratory, Randomized, Controlled Pilot Trial.

OBJECTIVE: To evaluate efficacy of high-dose oral ambroxol in acute respiratory distress syndrome (ARDS) with respect to ventilator-free days (VFD). DESIGN: Prospective, randomized, placebo-controlled, blinded pilot trial. PATIENTS: Sixty-six mechanically ventilated patients (1 month to 12 years) with ARDS who were hand-ventilated for <24 hr before pediatric intensive care unit admission. INTERVENTIONS: Patients randomized to oral ambroxol (40 mg/kg/day, in four divided doses) (n = 32) or placebo (n = 34) until 10 days, extubation or death whichever is earlier. MEASUREMENTS AND MAIN RESULTS: Majority (91%) had pneumonia and bronchiolitis. Two study groups were similar in baseline characteristics. Mean partial pressure of arterial oxygen/fraction of inspired oxygen and oxygenation index were >175 and <10, respectively, with no difference in the two study groups. VFD were similar in the two study groups. Overall mortality was 26%. No adverse events were noted with ambroxol. CONCLUSIONS: Among ventilated pulmonary ARDS patients with oxygenation index of <10, mortality was 26%. Ambroxol did not improve VFD. Study with higher and more frequently administered doses of ambroxol in larger sample is suggested after having generated relevant pharmacokinetic data among critically ill children.