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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. References 1 Lee J, Kim HS, Sohn JA, Lee JA, Choi CW, Kim EK, Kim BI, Choi JH: Randomized crossover study of neurally adjusted ventilatory assist in preterm infants. J Pediatr 2012;161:808813. 2 Colombo D, Cammarota G, Bergamaschi V, De Lucia M, Corte FD, Navalesi P: Physiologic response to varying levels of pressure support and neurally adjusted ventilatory assist in patients with acute respiratory failure. Intensive Care Med 2008;34:2010-2018. 3 Sweet DG, Carnielli V, Greisen G, Hallman M, Ozek E, Plavka R, Saugstad OD, Simeoni U, Speer CP, Vento M, Halliday HL: European consensus guidelines on the management of neonatal respiratory distress syndrome in preterm infants--2013 update. Neonatology 2013;103:353-368. 4 Kattwinkel J, Perlman JM, Aziz K, Colby C, Fairchild K, Gallagher J, Hazinski MF, Halamek LP, Kumar P, Little G, McGowan JE, Nightengale B, Ramirez MM, Ringer S, Simon WM, Weiner GM, Wyckoff M, Zaichkin J: Part 15: Neonatal resuscitation: 2010 american heart association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation 2010;122:S909-919. 5 Sweet DG, Carnielli V, Greisen G, Hallman M, Ozek E, Plavka R, Saugstad OD, Simeoni U, Speer CP, Halliday HL: European consensus guidelines on the management of neonatal respiratory distress syndrome in preterm infants - 2010 update. Neonatology 2010;97:402-417. 6 Batton DG, Barrington KJ, Wallman C: Prevention and management of pain in the neonate: An update. Pediatrics 2006;118:2231-2241. 7 Grasselli G, Beck J, Mirabella L, Pesenti A, Slutsky AS, Sinderby C: Assessment of patient- ventilator breath contribution during neurally adjusted ventilatory assist. Intensive Care Med 2012;38:1224-1232. 8 Thille AW, Rodriguez P, Cabello B, Lellouche F, Brochard L: Patient-ventilator asynchrony during assisted mechanical ventilation. Intensive Care Med 2006;32:1515-1522. 9 Nock ML, Difiore JM, Arko MK, Martin RJ: Relationship of the ventilatory response to hypoxia with neonatal apnea in preterm infants. J Pediatr 2004;144:291-295. 10 Schulze A, Rieger-Fackeldey E, Gerhardt T, Claure N, Everett R, Bancalari E: Randomized crossover comparison of proportional assist ventilation and patient-triggered ventilation in extremely low birth weight infants with evolving chronic lung disease. Neonatology 2007;92:1-7.