1. 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[ ]
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
[ ]
0.349
Treatment failure, n (%)
4 (15.4%)
1.3 [ ]
Contamination, n (%)
4 [ ]
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 [ ] 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 (NCT )
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.