Saptharishi L G, Jayashree M, Singhi S, Bansal A Airway Pressure Release Ventilation (APRV) in Pediatric Acute Respiratory Distress Syndrome (P-ARDS): An Open-label, Parallel-design Randomized Controlled Trial Saptharishi L G, Jayashree M, Singhi S, Bansal A Advanced Pediatrics Center, Post Graduate Institute of Medical Education & Research (PGIMER), Chandigarh, INDIA Background Materials & Methods Results Table 3: Safety and Efficacy outcomes of the trial Pediatric Acute Respiratory Distress Syndrome (ARDS) is one of the major causes of mortality across ICUs around the world Despite use of Low-Tidal Volume (LoTV) ventilation, no appreciable improvement in mortality in pediatric population Airway Pressure Release Ventilation (APRV): Time-triggered, pressure-limited, inverse-ratio mode Provides continuous distending airway pressure, with intermittent release phase Allows spontaneous breathing throughout Maximizes alveolar recruitment and stability This pilot trial is the first to evaluate APRV in comparison to conventional low-tidal volume ventilation in pediatric ARDS Sample Size Calculation: Assuming alpha of 5%, power of 80% with non-inferiority limit of 4 days (SD of VFDs = 8.2 days)  Sample size of 52 per group (104 in total) Inclusion criteria: Children meeting ARDS Berlin criteria and requiring invasive mechanical ventilation Exclusion criteria: Raised intracranial pressure, poor spontaneous breathing efforts, air-leaks, airway obstruction, known heart disease, ventilated > 72 hours and >24 hours since ARDS diagnosis Computer-generated randomization with variable block sizes Opaque, sealed envelopes used to conceal allocation Ventilation and supportive care protocols: standardized Followed up till 180 days after PICU discharge or death Interim intention-to-treat analysis planned at 50% enrolment Chi-square and Mann-Whitney U tests used to compare proportions and non-parametric continuous variables respectively Log-rank: Mantel Cox test and Kaplan Meier analysis was used to compare differences in length of mechanical ventilation and survival times between the two groups Table 1: Baseline Characteristics of the study cohort (n=52) Outcomes Control Group APRV Group RR [95% CI] P value Nosocomial infections, n (%) 7 (26.9%) 1.0[0.3 -3.4] 1.000 Adverse events, n (%) Pneumothorax Pneumo-mediastinum Hemodynamic instability (new) Cardiac arrest Pulmonary Hemorrhage 9 (34.6)  4 (15.4%) 1 (3.8%) 3 (11.5%) 0 (0%) 5 (19.2%)  3 (11.5%) 0.450 [0.13- 1.6] 0.349 Treatment failure, n (%) 4 (15.4%) 1.3 [0.3-5.6] Contamination, n (%) 4 [1.0-15.0] 0.110 P:F ratio Change: First 24 hours 59 [39, 91] 81 [24,152] - 0.297 Change in OI- First 24 hours 2.7 [1.9, 4.8] 2.6 [1.6, 4.7] 0.949 Characteristics Control group n=26 APRV group Age (months) 65.5 [12.8, 127] 36 [9.75, 84] Gender (Male), n (%) 9 (34.6%) 17 (65.4%) Duration of respiratory complaints 4 [2, 10] days 6.5 [3, 9.3] days Interval: illness onset & fulfillment of ARDS criteria 3 [1.9, 4.5] days 3.5 [1, 7] days Interval: admission & fulfillment of ARDS criteria 6 [2, 39] hours 5.5 [0, 26.5] hours Children with co-morbidities 8 (30.8%) Children with Wasting, n (%) Stunting, n (%)   4 (15.4%) Children with compromised immune status, n (%) 5 (19.2%) Children with sepsis at admission, n (%) 24 (92.3%) 21 (80.8%) PRISM III-24 Score 18 [15, 27] 20 [17.5, 25.3] Number of non-pulmonary organ-dysfunctions 2 [1, 2.3] 2 [1,4] Cause of lung injury/ARDS Primary, n (%) Secondary, n (%) 14 (53.8%) 12 (46.2%) Severity of ARDS at enrolment Mild, n (%) Moderate, n (%) Severe, n (%) 7 (26.9%) 1 (3.8%) 16 (61.5%) PaO2: FiO2 ratio (P:F ratio) 159.5 [107, 212] 116.5 [98.4, 178.8] Oxygenation Index (OI) 9 [5.2, 16] 11.9 [7.9, 21.1] Figure 2: Probability of cumulative survival for the study cohort Kaplan Meier Analysis: Median [95%CI] Survival Time APRV – 13 [3.9- 22] days LoTV – 19 [13.3 – 24.7] days Objectives PRIMARY: To evaluate the impact of APRV on 28-day ventilator-free days in comparison to conventional LoTV SECONDARY: To compare the aforementioned groups for All-cause 28-day and 180-day mortality Length of PICU and hospital stay Organ-failure-free days Adverse events & Treatment failure Long-term neurocognitive outcomes On Cox Proportional Hazards Analysis, Independent predictors of mortality in the cohort after adjustment for age, comorbidities and mode of ventilation were: PRISM-III-24 Score P:F Ratio at Enrolment Results All baseline characteristics including markers of respiratory dysfunction (P:F ratio and OI) were comparable, except gender distribution across the two groups (Table 1) Discussion Strengths: First RCT on APRV in Pediatric ARDS Rigorous methodology & follow up of 6 months Intention to Treat Analysis Adequate mix of primary and secondary ARDS Materials & Methods Table 2: Major outcomes of the trial (n=52) Limitations: Small sample size Single center trial Early stoppage of trial Resource-limitation Outcomes Control group n=26 APRV group Relative risk [95% CI] P value Ventilator-free days (28-day) Median [IQR] Mean ± SD 20 [0,23] 14.2 ± 10.4 0 [0, 22.5] 9.7 ± 11.1 - 0.230 28-day All-cause mortality, n (%) 7 (26.9%) 14 (53.8%) 3.2 [1-10.1] 0.044 180-day All-cause mortality, n (%) Length of PICU stay, days 8 [6.8, 11] 7 [3.8, 13.3] 0.244 Length of hospital stay, days 13.5 [9,23.5] 9.5 [5.8, 20.5] 0.073 Organ-failure-free days, days 18 [0, 20] 0 [0,20] 0.286 Design: Open-label, parallel-design, non-inferiority trial Setting: 15-bed PICU of a multi-specialty, tertiary referral and teaching hospital in Northern India Enrolment period: January 2014 to December 2015 Study was approved by Ethics Committee and registered a priori with CTRI (CTRI/2014/06/004677) and International clinical trials registry (NCT02167698) Informed consent obtained from parents/legal guardian Conclusion Airway Pressure Release Ventilation is comparable to conventional low-tidal volume ventilation in terms of ventilator-free days but may have significantly higher 180-day all-cause mortality in children with Acute Respiratory Distress Syndrome (P-ARDS). Trial had to be terminated prematurely due to higher mortality in intervention arm.