Furosemide stress test to predict acute kidney injury progression in critically ill children.

BACKGROUND: Furosemide stress test (FST) is a novel functional biomarker for predicting severe acute kidney injury (AKI); however, pediatric studies are limited. METHODS: Children 3 months to 18 years of age admitted to the intensive care unit (ICU) of a tertiary care hospital from Nov 2019 to July 2021 were screened and those who developed AKI stage 1 or 2 within 7 days of admission underwent FST (intravenous furosemide 1 mg/kg). Urine output was measured hourly for the next 6 h; a value > 2 ml/kg within the first 2 h was deemed furosemide responsive. Other biomarkers like plasma neutrophil gelatinase-associated lipocalin (NGAL) and proenkephalin (PENK) were also evaluated. RESULTS: Of the 480 admitted patients, 51 developed AKI stage 1 or 2 within 7 days of admission and underwent FST. Nine of these patients were furosemide non-responsive. Thirteen (25.5%) patients (eight of nine from FST non-responsive group) developed stage 3 AKI within 7 days of FST, nine (17.6%) of whom (seven from non-responsive group) required kidney support therapy (KST). FST emerged as a good biomarker for predicting stage 3 AKI and need for KST with area-under-the-curve (AUC) being 0.93 ± 0.05 (95% CI 0.84-1.0) and 0.96 ± 0.03 (95% CI 0.9-1.0), respectively. FST outperformed NGAL and PENK in predicting AKI stage 3 and KST; however, the combination did not improve the diagnostic accuracy. CONCLUSIONS: Furosemide stress test is a simple, inexpensive, and robust biomarker for predicting stage 3 AKI and KST need in critically ill children. Further research is required to identify the best FST cut-off in children.

Infant Pulmonary Function Tests in Children with Airway Anomalies and Correlation with Bronchoscopy Findings.

OBJECTIVES: To evaluate the role infant pulmonary function tests (Tidal Breathing Flow Volume Loops, TBFVL) in children with airway anomalies and to correlate the TBFVL so obtained with bronchoscopy findings. METHODS: In this prospective cohort study, we enrolled children aged 0-2 years with airway anomalies and performed TBFVL and bronchoscopy. The primary outcome measure was graphic pattern of TBFVL in laryngomalacia. Secondary outcome measures were types of TBFVL results in various airway anomalies and controls. RESULTS: Out of 53 children enrolled, 28 (52.3%) had laryngomalacia. Pattern 3 (fluttering of inspiratory limb) was commonest TBFVL pattern in laryngomalacia. Among TBFVL parameters, the ratio of inspiratory time to expiratory time (Ti/Te) and tPTEF/tE was significantly high in children with isolated laryngomalacia compared to controls. At six months of follow-up, TBFVL pattern 1 (normal) became the commonest pattern. CONCLUSION: A particular type of airway anomaly may have a characteristic graphic pattern in TBFVL and TBFVL pattern may indicate improvement in airway anomalies in follow-up.

Pediatric Sepsis Phenotypes and Outcome: 5-Year Retrospective Cohort Study in a Single Center in India (2017-2022).

OBJECTIVES: To describe mortality associated with different clinical phenotypes of sepsis in children. DESIGN: Retrospective study. SETTING: PICU of a tertiary care center in India from 2017 to 2022. PATIENTS: Six hundred twelve children (from 2 mo to 17 yr old) with a retrospectively applied diagnosis of sepsis using 2020 guidance. METHODS: The main outcome was mortality associated with sepsis subtypes. Other analyses included assessment of risk factors, requirement for organ support, and PICU resources used by sepsis phenotype. Clinical data were recorded on a predesigned proforma. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Of the 612 children identified, there were 382 (62%) with sepsis but no multiple organ failure (NoMOF), 48 (8%) with thrombocytopenia-associated MOF (TAMOF), 140 (23%) with MOF without thrombocytopenia, and 40 (6.5%) with sequential MOF (SMOF). Mortality was higher in the SMOF (20/40 [50%]), MOF (62/140 [44%]) and TAMOF (20/48 [42%]) groups, compared with NoMOF group (82/382 [21%] [ p < 0.001]). The requirement for organ support and PICU resources was higher in all phenotypes with MOF as compared with those without MOF. On multivariable analysis elevated lactate and having MOF were associated with greater odds of mortality. CONCLUSIONS: In this single-center experience of sepsis in India, we found that sepsis phenotypes having MOF were associated with mortality and the requirement of PICU resources. Prospective studies in different regions of the world will help identify a classification of pediatric sepsis that is more widely applicable.

Long-Term Outcomes of Survivors of COVID-19 with Moderate to Severe Infection and Children with Multisystem Inflammatory Syndrome or MIS-C.

The study aims to evaluate the long-term outcomes - functional, pulmonary and non-pulmonary (other organs) - in children hospitalized with COVID-19 infection or with Multisystem inflammatory syndrome (MIS-C) after 1-2 y of discharge. All children with moderate or severe COVID-19 or MIS-C were enrolled. Out of 45 enrolled subjects, 19.8% had COVID-19 infection and 82% had MIS-C. Four children (8.9%) had abnormal baseline echocardiography; two each with cardiac dysfunction and coronary dilatation. At baseline, 44% had moderate disability and 24% had mild disability as per Pediatric Cerebral Performance Category (PCPC). On follow-up, only 8.9% (n = 4) had mild and 2.2% (n = 1) had moderate disability as per the PCPC score. One child developed new onset tuberculosis of the bone. None had any pulmonary morbidities. Follow-up echocardiogram was also within normal limits for children with abnormal findings. Further studies in different populations (settings) are required to draw meaningful conclusions about long-term effects of COVID-19 on children.

Development and Validation of a Weight Estimation Tool for Acutely Ill Children Who Cannot be Weighed.

OBJECTIVES: To develop and validate weight estimation tools using mid upper arm circumference (MUAC) and body length, and determine accuracy and precision of Broselow tape in children 6 mo to 15 y of age. METHODS: Data of 18,456 children aged 6 mo to 5 y and 1420 children aged 5 to 15 y were used to develop linear regression equations using length and MUAC to estimate weight. These were validated on prospectively enrolled populations of 276 and 312 children, respectively. Accuracy was measured by Bland-Altman bias, median percentage errors, and percentage of predicted weight within 10% of true weight. Broselow tape was tested on the validation population. RESULTS: Gender specific equations were developed which estimated weight within 10% of true weight in 69.9% (64.1-75.2%) and 65.7% (60.1-70.9%) of children aged 6 mo to 5 y, and 5 to 15 y, respectively. Broselow tape predicted weight within 10% of the true weight in 40.5% (34.7-46.6%) and 32.5% (26.7-38.7%) of children aged 6 mo to 5 y and 5 to 15 y, respectively. CONCLUSIONS: The model developed from MUAC and length accurately estimated weight in children aged 6 mo to 15 y, and is potentially useful during emergencies. The Broselow tape frequently overestimated weight in authors' setting.

Validation of a Clinical Tool to Predict Neurological Outcomes in Critically Ill Children-A Prospective Observational Study.

OBJECTIVES: To evaluate the performance of the empiric tool by Gupta et al. in predicting neurological outcomes in children admitted to the pediatric intensive care unit (PICU) and to evaluate the association of biomarkers S100B and NSE with neurological outcomes. METHODS: This prospective observational study was conducted in 163 critically ill children aged 2 mo to 17 y admitted to the PICU from June 2020 to July 2021. The authors used the prediction tool developed by Gupta et al.; the tool was applied at admission and at PICU discharge/death. Samples for NSE and S100B were collected at admission and discharge. The performance of the new tool was assessed through discrimination and calibration. Risk factors for "unfavorable outcomes" (decline in PCPC score by > 1) were evaluated by multivariate analysis. RESULTS: The PICU mortality was 28% (n = 45). When the tool developed by Gupta et al. was used at the time of admission, favorable neurological outcomes were predicted for 69% (112) children. The area under the curve for the new tool at admission was 0.72 and at discharge/death it was 0.99, and the calibration was excellent at both time points. Independent factors associated with unfavorable neurological outcomes were higher PCPC scores and organ failure. As the number of samples processed for NSE and S100B was less, statistical analysis was not attempted. CONCLUSIONS: The new tool by Gupta et al. has good discrimination, calibration, sensitivity, and specificity and can be used as a prediction tool. NSE and S100B are promising biomarkers and need further evaluation.

The Microbiome and Metabolome of the Gut of Children with Sepsis and Septic Shock.

BACKGROUND: There is limited understanding of alteration of gut microbiota and metabolome in children with sepsis/septic shock. METHODS: In this prospective observational study carried out in a pediatric intensive care unit of a tertiary care center from 2020 to 2022, patients aged <17 years with sepsis/septic shock and healthy children (HC) were enrolled. We characterized the gut bacterial compositions by metagenome sequencing and metabolomes by untargeted gas chromatography-mass spectrometry. The primary outcome was to compare the gut microbiota and metabolome of children with sepsis/septic shock with that of HC. The Firmicutes/Bacteroidetes (F/B) ratio was compared between children with sepsis/septic shock and HC. Key secondary outcomes were to evaluate association of factors associated with a low F/B ratio in children with sepsis/septic shock. RESULTS: A total of 40 children (63% boys) (15 children with sepsis and septic shock and 10 healthy children) with a median (IQR) age of 5.5 (1.5, 10) years were enrolled. In the fecal microbiota, the α-diversity index including Shannon and Simpson indices of the sepsis/septic shock groups was significantly lower than that of the HC. The samples lacked beneficial Bifidobacterium spp. and were dominated by Bacteroides, Enterobacteriaceae, and Enterococcaceae. There was reduction in short-chain fatty acids (SCFAs) in patients with sepsis/septic shock as compared to healthy children. A lower F/B ratio (≤1.57) of the gut microbiota discriminated well between children with sepsis/septic shock and HC. Factors associated with lower F/B ratio were male gender, clinical GI dysfunction, elevated inflammatory markers, and higher organ failure scores. CONCLUSION: There were significant alterations in the gut microbiota and metabolome in children with sepsis/septic shock as compared to healthy children. Larger study is needed to confirm these exploratory findings and develop potential therapeutic targets that will improve outcomes in children with sepsis/septic shock.

Comparison of Protocol-Based Continuous and Intermittent Tube Feeding in Mechanically Ventilated Critically Ill Children - An Open Label Randomized Controlled Trial.

OBJECTIVES: To compare the time taken to reach the target calories and proteins by protocol based "continuous tube feeding (CTF)" and "intermittent tube feeding (ITF)" in critically ill children. METHODS: This trial was conducted in the Pediatric Intensive Care Unit (PICU) of a tertiary care institute. Eligible children were randomized to receive CTF or ITF. Target calories were defined as 70% of calorie amount as per the WHO formula and target protein was defined as 1.5 g/kg as per the American Society of Parenteral and Enteral Nutrition (ASPEN) criteria. The primary outcome was time taken to reach target calories, the secondary outcomes were time taken to reach target protein, incidence of feed intolerance, PICU mortality, duration of ventilation, and outcome on 28th day. RESULTS: Fifty-eight children were randomized; 29 in each group. The baseline characters were comparable. The median (IQR) times for reaching target calories were 1.7 (1.4, 2.5) d and 1.8 (1.4, 4.4) d in the CTF and ITF groups, respectively [Hazards ratio (HR) 0.89 (95% CI 0.5, 1.5); p = 0.69]. For the target protein intake, the median times were comparable in the 2 groups [HR 0.82 (95% CI 0.4-1.5); p = 0.55]. The other outcomes were not significantly different between the groups. CONCLUSIONS: The authors did not observe any difference in the time taken to reach target calories and protein between the two different modes of delivery of enteral nutrition.

Utility of Inferior Vena Cava Distensibility and Respiratory Variation in Peak Aortic Blood Flow Velocity to Predict Fluid Responsiveness in Children with Shock.

OBJECTIVES: To evaluate the sensitivity and specificity of inferior vena cava (IVC) distensibility index (∆IVC) and respiratory variation in peak aortic blood flow velocity (∆Vpeak) to predict fluid responsiveness in ventilated children with shock and to find out the best cut-off values for predicting fluid responsiveness. METHODS: In this prospective observational study, conducted in a pediatric ICU from January 2019 through May 2020, consecutive children aged 2 mo to 17 y with shock requiring fluid bolus were included. ∆IVC and ∆Vpeak were measured before and immediately after 10 ml/kg fluid bolus administration. ∆IVC and ∆Vpeak were compared between responders and non-responders, defined by a change in stroke volume index (SVI) of ≥10%. RESULTS: Thirty-seven ventilated children [26 (70.4%) boys] with median age of 60 (36, 108) mo were included. The median (IQR) ∆IVC was 21.7% (14.3, 30.9) and the median (IQR) ΔVpeak was 11.3% (7.2, 15.2). Twenty-three (62%) children were fluid responsive. The median (IQR) ∆IVC was higher in responders compared to non-responders [26% (16.9, 36.5) vs. 17.2% (8.4, 21.9); p = 0.018] and mean (SD) ΔVpeak was higher in responders [13.9% (6.1) vs. 8.4% (3.9), p = 0.004]. The prediction of fluid responsiveness with ΔIVC [ROC curve area 0.73 (0.56-0.9), p = 0.01] and ΔVpeak [ROC curve area 0.78 (0.63-0.94), p = 0.002] was similar. The best cut-off of ∆IVC to predict fluid responsiveness was 23% (sensitivity, 60.8%; specificity, 85.7%) and ΔVpeak was 11.3% (sensitivity, 74%; specificity, 86%). CONCLUSIONS: In this study, authors found that ∆IVC and ΔVpeak were good predictors of fluid responsiveness in ventilated children with shock.

Haemodynamic support for paediatric septic shock: a global perspective.

Septic shock is a leading cause of hospitalisation, morbidity, and mortality for children worldwide. In 2020, the paediatric Surviving Sepsis Campaign (SSC) issued evidence-based recommendations for clinicians caring for children with septic shock and sepsis-associated organ dysfunction based on the evidence available at the time. There are now more trials from multiple settings, including low-income and middle-income countries (LMICs), addressing optimal fluid choice and amount, selection and timing of vasoactive infusions, and optimal monitoring and therapeutic endpoints. In response to developments in adult critical care to trial personalised haemodynamic management algorithms, it is timely to critically reassess the current state of applying SSC guidelines in LMIC settings. In this Viewpoint, we briefly outline the challenges to improve sepsis care in LMICs and then discuss three key concepts that are relevant to management of children with septic shock around the world, especially in LMICs. These concepts include uncertainties surrounding the early recognition of paediatric septic shock, choices for initial haemodynamic support, and titration of ongoing resuscitation to therapeutic endpoints. Specifically, given the evolving understanding of clinical phenotypes, we focus on the controversies surrounding the concepts of early fluid resuscitation and vasoactive agent use, including insights gained from experience in LMICs and high-income countries. We outline the key components of sepsis management that are both globally relevant and translatable to low-resource settings, with a view to open the conversation to the large variety of treatment pathways, especially in LMICs. We emphasise the role of simple and easily available monitoring tools to apply the SSC guidelines and to tailor individualised support to the patient's cardiovascular physiology.

Multiple Electrolytes Solution Versus Saline as Bolus Fluid for Resuscitation in Pediatric Septic Shock: A Multicenter Randomized Clinical Trial.

OBJECTIVE: To determine if initial fluid resuscitation with balanced crystalloid (e.g., multiple electrolytes solution [MES]) or 0.9% saline adversely affects kidney function in children with septic shock. DESIGN: Parallel-group, blinded multicenter trial. SETTING: PICUs of four tertiary care centers in India from 2017 to 2020. PATIENTS: Children up to 15 years of age with septic shock. METHODS: Children were randomized to receive fluid boluses of either MES (PlasmaLyte A) or 0.9% saline at the time of identification of shock. All children were managed as per standard protocols and monitored until discharge/death. The primary outcome was new and/or progressive acute kidney injury (AKI), at any time within the first 7 days of fluid resuscitation. Key secondary outcomes included hyperchloremia, any adverse event (AE), at 24, 48, and 72 hours, and all-cause ICU mortality. INTERVENTIONS: MES solution ( n = 351) versus 0.9% saline ( n = 357) for bolus fluid resuscitation during the first 7 days. MEASUREMENTS AND MAIN RESULTS: The median age was 5 years (interquartile range, 1.3-9); 302 (43%) were girls. The relative risk (RR) for meeting the criteria for new and/or progressive AKI was 0.62 (95% CI, 0.49-0.80; p < 0.001), favoring the MES (21%) versus the saline (33%) group. The proportions of children with hyperchloremia were lower in the MES versus the saline group at 24, 48, and 72 hours. There was no difference in the ICU mortality (33% in the MES vs 34% in the saline group). There was no difference with regard to infusion-related AEs such as fever, thrombophlebitis, or fluid overload between the groups. CONCLUSIONS: Among children presenting with septic shock, fluid resuscitation with MES (balanced crystalloid) as compared with 0.9% saline resulted in a significantly lower incidence of new and/or progressive AKI during the first 7 days of hospitalization.

A Randomized Controlled Trial of Norepinephrine Plus Dobutamine Versus Epinephrine As First-Line Vasoactive Agents in Children With Fluid Refractory Cold Septic Shock.

Our objective was to compare norepinephrine plus dobutamine versus epinephrine as the first-line agent in children with fluid refractory cold septic shock. DESIGN: Open-label randomized controlled study. SETTING: A single-center PICU from North India. PATIENTS: Children 2 months to less than 18 years old with fluid refractory cold septic shock. INTERVENTIONS: In the intervention group, norepinephrine and dobutamine were started and in the control group, epinephrine was started as the first-line vasoactive agent. The primary outcome was the proportion attaining shock resolution (attaining all the therapeutic endpoints) at 1 hour of therapy. MEASUREMENTS AND MAIN RESULTS: We enrolled 67 children: 34 in the norepinephrine plus dobutamine group (intervention) and 33 in the epinephrine group (control). There was no difference in shock resolution at 1 hour (17.6% vs 9%; risk ratio [RR], 2.0; 95% CI, 0.54-7.35; p = 0.25), 6 hours (76.4% vs 54.5%; RR, 1.69; 95% CI, 0.92-3.13; p = 0.06), and 24 hours between the intervention and control groups, respectively. Children in the norepinephrine plus dobutamine group attained shock resolution earlier (measured from starting of vasoactive agents to attaining all the therapeutic endpoints) (hazard ratio, 1.84 [1.1-3.08]). The difference in 28-day mortality was not significant (23.5% vs 39.3% in the intervention and control groups, respectively [RR, 0.59; 95% CI, 0.28-1.25]). CONCLUSIONS: In children with fluid refractory cold septic shock, with use of norepinephrine plus dobutamine as first-line agents, the difference in the proportion of children attaining shock resolution at 1 hour between the groups was inconclusive. However, the time to shock resolution was earlier in the norepinephrine plus dobutamine group. Also, fewer children in the intervention group were refractory to treatment. Further studies powered to detect (or exclude) an important difference would be required to test this intervention.

Advances in Shock Management and Fluid Resuscitation in Children.

Shock in children is associated with significant mortality and morbidity, particularly in resource-limited settings. The principles of management include early recognition, fluid resuscitation, appropriate inotropes, antibiotic therapy in sepsis, supportive therapy for organ dysfunction, and regular hemodynamic monitoring. During the past decade, each step has undergone several changes and evolved as evidence that has been translated into recommendations and practice. There is a paradigm shift from protocolized-based care to personalized management, from liberal strategies to restrictive strategies in terms of fluids, blood transfusion, ventilation, and antibiotics, and from clinical monitoring to multimodal monitoring using bedside technologies. However, uncertainties are still prevailing in terms of the volume of fluids, use of steroids, and use of extracorporeal and newer therapies while managing shock. These changes have been summarized along with evidence in this article with the aim of adopting an evidence-based approach while managing children with shock.

Feasibility and Efficacy of Sustained Low-Efficiency Dialysis in Critically Ill Children with Severe Acute Kidney Injury.

OBJECTIVES: To examine the feasibility, efficacy, and safety of sustained low-efficiency dialysis (SLED) in hemodynamically unstable, critically ill children. METHODS: Critically ill patients, 1-18 y old with hemodynamic instability (≥ 1 vasoactive drugs) and severe acute kidney injury (AKI) requiring kidney replacement therapy (KRT) in a tertiary care pediatric intensive care unit were prospectively enrolled. Patients weighing ≤ 8 kg or with mean arterial pressure < 5th percentile despite > 3 vasoactive drugs, were excluded. Patients underwent SLED until hemodynamically stable and off vasoactive drugs, or lack of need for dialysis. The primary outcome was the proportion of patients in whom the first session of SLED was initiated within 12 h of its indication and completed without premature (< 6 h) termination. Efficacy was estimated by ultrafiltration, urea reduction ratio (URR), and equilibrated Kt/V. Other outcomes included: changes in hemodynamic scores, circuit clotting, adverse events, and changes in indices on point-of-care ultrasonography and echocardiography. RESULTS: Between November 2018 and March 2020, 18 patients with median age 8.6 y and vasopressor dependency index of 83.2, underwent 41 sessions of SLED. In 16 patients, SLED was feasible within 12 h of indication. No session was terminated prematurely. Ultrafiltration achieved was 4.0 ± 2.2 mL/kg/h, while URR was 57.7 ± 16.2% and eKt/V 1.17 ± 0.56. Hemodynamic scores did not change significantly. Asymptomatic hypokalemia was the chief adverse effect. Sessions were associated with a significant improvement in indices on ultrasound and left ventricular function. Fourteen patients died. CONCLUSIONS: SLED is feasible, safe, and effective in enabling KRT in hemodynamically unstable children with severe AKI.

Evaluation of Changes in Quadriceps Femoris Muscle in Critically III Children Using Ultrasonography.

OBJECTIVE: To measure changes in muscle thickness and echogenicity, reflecting muscle bulk and quality, respectively, of quadriceps femoris (QF), in critically ill children. METHODS: This study was done on 58 children aged 1-18 y requiring mechanical ventilation, admitted in a pediatric intensive care unit (PICU) of a tertiary care hospital from January 2018 to June 2019. QF thickness was measured twice in longitudinal plane and twice in transverse plane, and an average of these four measurements was used. Muscle quality was assessed using ImageJ software to determine the mean echogenicity, and was calculated separately for vastus intermedius and rectus femoris. These observations were repeated on day 3 and day 7 of the ICU stay. RESULTS: The median muscle thickness of QF was 1.58 cm, and vastus intermedius and rectus femoris echogenicity was 35.5 and 25.88 units, respectively in the present cohort, with median age of 6 y. Only 36 of the 58 patients underwent day 7 ultrasonography, as the remainder were either extubated or died. There was no significant change in the muscle thickness over 7 d. Rectus femoris echogenicity increased significantly over 7 d by 16.1% (p = 0.03). Baseline vastus intermedius echogenicity was significantly higher in patients who subsequently died during the course of their illness (p = 0.026). CONCLUSION: There was a significant change in rectus femoris echogenicity, but not in QF thickness. Echogenicity rather than muscle thickness may be a more sensitive marker for changes in muscle properties.

Role of high-sensitivity C-reactive protein (hs-CRP) in assessment of asthma control in children.

INTRODUCTION: Data are scarce on hs-CRP as a biomarker for airway inflammation in pediatric asthma. We aimed to examine correlation between hs-CRP and asthma control levels. METHODS: Children with physician-diagnosed asthma, ages 6-15 years, were enrolled. GINA-2016 criteria were used to assess the level of asthma control. The relationships between serum hs-CRP and each of asthma control measures (asthma control criteria, spirometry, impulse oscillometry, eosinophil counts and fractional exhaled nitric oxide (FeNO) were assessed. RESULTS: 150 asthmatic children were enrolled; 52 (35%) had well controlled asthma, 76 (51%), and 22 (14%) children had partly controlled and uncontrolled asthma, respectively. Median (IQR) values of hs-CRP were 0.47 (0.1, 1.67) mg/L in well controlled, 0.30 (0.1, 1.83) mg/L in partly controlled, and 2.74 (0.55, 3.74) mg/L in uncontrolled asthma (p = 0.029). Using receiver operator characteristic (ROC) curve analysis, area under the curve for hs-CRP (mg/L) to discriminate between uncontrolled and (controlled + partly controlled) asthma was 0.67 (95% CI 0.55, 0.80) and a cutoff 1.1 mg/L of serum hs-CRP level had a sensitivity of 68.1% with specificity of 67.97%. In two groups of hs-CRP (<3 mg/L) and hs-CRP (≥3 mg/L), high hs-CRP group had higher proportion of uncontrolled asthmatic children (p = 0.03). CONCLUSION: We observed higher serum hs-CRP values in children with uncontrolled asthma, suggesting its potential role as a biomarker of asthma control.