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Neurally Adjusted Ventilatory Assist in preterm neonates with acute respiratory failure
Electronic Supplementary Material
Patients
We considered eligible all preterm infants (<37 weeks gestation) ventilated for respiratory
failure who fulfilled the following inclusion criteria: 1) postnatal age <30 days; 2) presence of
spontaneous breathing effort able to trigger the ventilator; 3) mechanical ventilation initiated at least
12 hours prior to the enrolment; 4) arterial oxygen saturation (SatO2) ≥90% with an inspiratory
oxygen fraction (FiO2) <0.5. Exclusion criteria were: 1) contraindications for an EAdi catheter
placement, as previously described [1]; 2) hemodynamic instability after adequate volume
replacement, defined as need for epinephrine and norepinephrine at any dosage, or need for
dopamine infusion >5 µg∙kg-1∙min-1, or need for dobutamine infusion >10 µg∙kg-1∙min-1; 3)
congenital heart disease; 4) neuromuscular disorders; 5) esophageal reflux; 7) complex congenital
malformations; 8) intraventricular haemorrhage (grade III or higher); 9) inclusion in other research
protocols. Criteria for study discontinuation were: 1) need for FiO2 > 0.6 to maintain SatO2 ≥90%;
2) capillary carbon dioxide pressure (PcCO2) >60 mmHg and/or pH ≤7.25 in spite of a progressive
increase of ventilatory support; 3) heart rate >180 beats/min for more than 15 minutes; 4)
respiratory rate >80 breaths/min for more than 15 minutes.
Equipment
Both PRVC and NAVA were applied using a Servo-I ventilator (Maquet Critical Care, Solna,
Sweden). EAdi was obtained by means of a 6-Fr esophageal catheter with a multiple array of
electrodes placed at its distal end (EAdi catheter, Maquet Critical Care, Solna, Sweden). The EAdi
catheter ends in the stomach and can be also used for enteral feeding. Correct positioning of the
EAdi catheter was assured using a dedicated function of the ventilator, as previously described [2].
Study protocol
The standard oro-gastric tube was replaced with the EAdi catheter before the study initiation.
All patients first received PRVC, set to achieve a VT of approximately 5 ml/kg with a Pawpeak limit
of 25 cmH2O. The ventilator rate of cycling, i.e., mechanical respiratory rate (RRmec), was set at 35
breaths/min and increased, if needed, targeted to obtain a capillary pH ≥ 7.25. Inspiratory time
duration was set between 0.33 and 0.35 seconds. The inspiratory flow-trigger was set at the lowest
possible level without auto-triggering. Positive end-expiratory pressure (PEEP) was applied in all
patients (4 to 6 cmH2O) and inspiratory oxygen fraction (FiO2) was titrated to achieve an arterial
oxygen saturation (SatO2) between 90% and 95% [3].
After 12 consecutive hours of PRVC, the ventilator was switched to NAVA for another 12-hour
period. The level of assistance (NAVA level) was set to achieve a Pawpeak equal to the average
value observed during the last 5 minutes in PRVC, by means of a dedicated function of the
ventilator, as previously described [2]. The ventilator default setting of the neural inspiratory trigger
(0.5 V) and expiratory trigger threshold (EAdi fall to 70% of its peak) remained unmodified
throughout the NAVA trial; PEEP was maintained as in the previous PRVC trial, while FiO2 was
titrated according to the criteria already described for PRVC. During both PRVC and NAVA, the
Pawpeak limit was set at 25 cmH2O. PRVC or NAVA settings were never modified throughout the
whole study period. While during PRVC the mandatory breaths assured ventilation when neural
apnea occurred, in NAVA the apnea alarm was set at 20 seconds (i.e.; the mandatory breaths started
after 20 seconds of absence of EAdi signal, which in NAVA means absence of ventilator assistance).
Antenatal steroid prophylaxis was administered as 12 mg intramuscular betamethasone followed
by a second dose 24h apart. Stabilization at birth was provided according to the American Academy
of Pediatrics/American Heart Association guidelines by certified NICU physicians [4]. Surfactant
administration was decided according to the 2010 European guidelines [5].
Sedation was administered using fentanyl according to the routine NICU protocol, based on
recommendations [6]. Fentanyl was administered to reduce pain and stress in continuous i.v.
infusion starting from 0.5 mcg∙kg/h, and titrated to achieve a good comfort, up to 2 mcg∙kg/h. SatO2,
heart rate (HR) and non-invasive blood pressure were continuously monitored throughout the study
period. A physician not involved in the study was always present in the NICU.
Data acquisition and analysis
Airflow, airway pressure and EAdi signals were acquired from the ventilator through a RS232
interface at a sampling rate of 100 Hz, recorded by means of dedicated software (NAVA Tracker®
rel.3.0, Maquet Critical Care, Solna, Sweden), and displayed and analyzed using a customized
program during all the study period (24 hours).
For both modes, each 12-hour period was divided into three 4-hour epochs (E1, from enrolment to
the end of the 4th hour; E2, from 5th to 8th hour; E3, from 9th to 12th hour). Data were real time
acquired on a dedicated laptop and stored for subsequent analysis. Along the entire recording, the
following parameters were computed in a breath-by-breath analysis, and expressed for the overall
12-hour period and separately for the three 4-hour epochs: VT, RRmec, patient’s own (neural)
respiratory rate (RRneu), as assessed from the EAdi tracing, Pawpeak and the amplitude of the swing
in EAdi (EAdiswing), this latter calculated subtracting baseline EAdi from peak EAdi and
representing the patient’s neural inspiratory effort [7]. The infant-ventilator synchrony was
evaluated using the mechanical-to-neural respiratory rate ratio (MNR, calculated as RRmec/RRneu)
and the asynchrony index (AI). This latter was calculated along the entire study period as the
number of asynchronous breaths (wasted efforts plus double triggered breaths plus short cycled
breaths plus prolonged cycled breaths plus auto-triggered breaths) divided by the total number of
breaths and expressed in percent. Asynchronies were recognized according to predefined criteria
[2,8]. We also considered, throughout the overall 24-hours study period, number and duration of the
episodes of neural apneas, defined as absence of EAdi for a period ≥ 15 seconds [9].
With both modes, blood was sampled for capillary arterialized blood gas analysis. Capillary pH,
and partial pressure of oxygen (PcO2) and capillary carbon dioxide pressure (PcCO2) were
determined after 1 (PRVC1 and NAVA1), 6 (PRVC6 and NAVA6) and 12 (PRVC12 and NAVA12)
hours; PcO2/FiO2 and the oxygenation index (OI), i.e, mean airway pressure x FiO2/PcO2, were also
calculated. Mean airway pressure was individually calculated for 10 consecutive breaths using a
customized software based on Microsoft Excel, as previously described [10]. The 10 values
obtained were then averaged. SatO2, HR and mean arterial pressure (MAP) were also registered
hourly from the bedside monitoring system.
We recorded in each epoch the number of patients who did not require fentanyl during both
PRVC and NAVA. Finally, we reviewed nurses’ notes regarding any problem of routine care in
terms of bradicardic and hypotensive events, desaturations or other difficulties in nursing cares.
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