Study design and setting
This study was designed as a retrospective review of prospectively collected data between January 2013 and December 2015.
Patients
Included were all children younger than 18 years of age managed with HFOV for acute respiratory failure originating from any cause, defined by acute onset, presence of ≥ 1 infiltrate on chest radiograph, PaO2/FIO2 < 300 mmHg and PEEP ≥ 5 cm H2O. Patients with status asthmaticus, upper airway disorders, and underlying (congenital) cardiac anomalies were excluded. All patients had body weight within appropriate for age.
Data collection
Demographic, physiological, laboratory and ventilator parameters were manually extracted from the patient’s medical record. Disease severity was assessed by the Pediatric RIsk of Mortality (PRISM) III 24-h score. We applied the paediatric ARDS (PARDS) definition to identify patients with ARDS [15]. All consecutive PICU chest radiograph images were reviewed by a paediatric radiologist to determine the presence or absence of pulmonary infiltrates.
Variable definition and calculation
Physiological and laboratory data included heart rate, invasively measured arterial systolic, mean and diastolic blood pressure (mABP), central venous pressure (if a central line was in situ), and transcutaneous measured oxygen saturation (SpO2). These variables were continuously monitored using a Philips MP70 Intellivue monitor (Philips Medical Systems, Best, the Netherlands) and documented hourly by the bedside nurse. Although the frequency of arterial blood sampling was completed at the discretion of the attending physician, typically, arterial blood gases and lactate are measured at least every 6 h daily in the early phase of the oscillatory trajectory unless the clinical condition of the patient warranted more frequent analysis (Radiometer, Brønshøj, Denmark). Ventilator parameters for conventional mechanical ventilation (CMV) included PIP, mean airway pressure (mPaw), positive end-expiratory pressure (PEEP), expiratory tidal volume (Vte), and FiO2; for HFOV, these included mPaw, F, ∆P and FiO2. Vte was measured near the Y-piece of the endotracheal tube in patients < 10 kg (VarFlex™, Vyaire, Yorba Linda, CA, USA). These data were documented hourly. The PF ratio and oxygenation index (OI: mPaw * FiO2 * 100)/PaO2) were computed using concurrent blood gas and ventilator data.
To study haemodynamics, we analysed the daily cumulative fluid intake and number of fluid boluses administered. A daily vasoactive inotrope score (VIS) was calculated to describe the need for vasoactive support [16]. The non-respiratory Pediatric Logistic Organ Dysfunction (PELOD) 2 score was calculated daily to describe organ dysfunction [17]. The use of neuromuscular blocking agents (NMBAs) was noted as well as total daily cumulative dosage of sedatives and analgesic drugs. The use of NMBA, sedation and analgesia were managed using a unit-based clinical algorithm.
CMV protocol
Patients were managed per a unit-based algorithm. This algorithm prescribes the use of a time-cycled, pressure-limited ventilation mode (pressure control (PC)/assist control (AC) in children < 12 months or PC/synchronized intermittent mandatory ventilation (SIMV) in children ≥ 12 months) in children with acute lung injury. Expiratory tidal volume (Vte) is measured near the Y-piece of the endotracheal tube (ETT) in children < 10 kg (VarFlex™, Vyaire, Mettawa, Ill, USA). We target PIP < 30–32 cm H2O and maximum Vte 5–8 mL/kg actual bodyweight in all patients. Initial PEEP at the start of CMV is 4–6 cm H2O in all patients, adjustments are dictated by the FiO2 at the discretion of the attending physician. We do not use the ARDS Network PEEP/FiO2 grid or lung volume optimization manoeuvres such as staircase PEEP titration or sustained inflation during CMV [18]. Mandatory breath rate is dictated by underlying respiratory mechanics and age to maintain pH within target range; the flow-time scalar is carefully observed to prevent auto-PEEP. The maximum I/E ratio is 1:1. The amount of pressure support in the PC/SIMV mode is calculated by PIP minus PEEP.
HFOV protocol
Patients are oscillated per a unit-based algorithm that defines HFOV criteria, recruitment manoeuvre (RM), and titration of HFOV settings according to the evolving physiologic needs of each patient (SensorMedics 3100; Vyaire, Yorba Linda, CA, USA). Transitioning to HFOV is performed when peak inspiratory pressure (PIP) > 28–32 cm H2O, PEEP > 8 cm H2O, FiO2 > 0.60, and oxygenation index (OI) increases on three consecutive 1-hour measurements despite increasing PEEP and using neuromuscular blockade. A specific OI or mPaw threshold is not used to initiate HFOV. Vt was not measured when the patient was on HFOV.
The following starting HFOV settings are used: F 12 Hz, mPaw 3 cm H2O above mPaw on CMV, ∆Pproximal 70–90 cm H2O, inspiratory time 33%, and bias flow 20–40 L/min, irrespective of age or bodyweight. Immediately after switching to HFOV, we perform an individualized staircase incremental–decremental mPaw titration to find the optimal initial mPaw on the deflation limb of the pressure–volume relation (Figs. 1, 2). In brief, immediately after transitioning to HFOV, we perform an individualized staircase incremental–decremental mPaw titration to find the optimal initial mPaw on the deflation limb of the pressure–volume relation (Fig. 1). First, we increase the mPaw 2 cm H2O every 3–5 min while simultaneously observing the SpO2 (as proxy for lung volume) and mean ABP until no further improvement in SpO2 and/or decrease in mean ABP occurs during two consecutive increments. This allows us to identify the onset of lung recruitment (i.e. increase in SpO2, mPawrecruitment) and the onset of lung overdistension (mPawhyperinflation). If during the RM the SpO2 exceeds 97%, we reduce FiO2 and continue the RM. Next, we decrease the mPaw by 2 cm H2O every 3–5 min until SpO2 decreases (mPawderecruitment) during two consecutive decrements. The RM is repeated to mPawhyperinflation with setting the “optimal” mPaw + 2 cm H2O above mPawderecruitment. During the RM, oscillations are continued.
The RM is discontinued in the event of bradycardia and/or refractory hypotension (i.e. > 20% decrease in mABP for > 5 min). Chest radiographs are not routinely taken after the RM. During ongoing support, the mPaw is actively decreased by 2 cm H2O if FiO2 < 0.40–0.50 and SpO2 is within target range. F is decreased by 0.5–1.0 Hz (min 8 Hz) when the pH is below target range and increased by 0.5–1 Hz if the pH rises above target range. We decrease the power by 10% if hypocapnia occurs at F 15 Hz. The ETT cuff is routinely inflated.
Failure of HFOV is defined by the inability to wean either the mPaw or the FiO2 over the first 24 h following start of HFOV or if there is a worsening of the oxygenation index despite “maximum” HFOV settings. If a patient meets these criteria, he will be cannulated for extra-corporeal life support (ECLS).
Targets of oxygenation and ventilation in all patients
FiO2 is adjusted to maintain SpO2 88–92%. Unless dictated by the clinical condition, permissive hypercapnia is allowed targeting pH ≥ 7.20 irrespective of PaCO2. Transcutaneous CO2 monitoring is not used.
Supportive care in all ventilated patients
All patients were ventilated in the supine position and received continuous intravenous infusion of analgesic-sedative drugs, including midazolam and morphine. The bedside nurse titrated the analgesic-sedative drugs guided by the heart rate and pupils (for patients on neuromuscular blockade) or by the Comfort B score (for non-paralyzed patients) [19]. Hemodynamic management of ventilated patients included targeting a fluid nil balance via fluid restriction (± 75% of normal fluid intake) and intravenous diuretic therapy (continuous intravenous administration of furosemide). The decision to prone a patient is at the discretion of the attending physician.
Study endpoints
The primary endpoint of this study was feasibility of our protocol (in each patient, defined as maintaining F ≥ 8 Hz and ∆Pproximal 70–90 cmH2O as function of disease severity. Secondary endpoints included the level and trajectory of metrics for oxygenation and ventilation as function of disease severity and the level and trajectory of hemodynamic parameters, occurrence of new air leak, daily cumulative dosage of sedative-analgesic drugs and use of NMBA, and level and time course of the non-respiratory PELOD-2 as function of age. The latter was chosen because the current approach to HFOV calls for oscillator settings dictated by age and/or weight.
Statistical analysis
Continuous data are presented as median and 25–75 interquartile range (IQR) since assumptions of normality were not always satisfied. Categorical data are presented as percentage (%) of total. When comparisons between groups were made, continuous data were analysed using the Kruskal–Wallis test, and the Chi-square test with Yates continuity correction was used to analyse categorical data. Generalized linear model analyses were performed to analyse the effects of PARDS severity, age, survival status and time as well as the interaction between time and age or PARDS severity on all study endpoints as these parameters are repeated measurements. All statistical analyses were performed using SPSS for Mac (IBM, Chicago, Ill, USA). p values below 0.05 were considered statistically significant.