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R Sindelar FOT Protocol 1 Clinical trial of premature newborn infants with ventilatory assistance and different levels of PEEP measured by FOT Background: Preterm newborn infants are at risk of developing lung diseases such as transient tachypnoea of the newborn (TTN i.e. “wet lung”) or respiratory distress syndrome (RDS), which usually necessitates ventilatory support/assistance such as nasal continuous positive airway pressure (CPAP) or intermittent mandatory ventilation (IMV), surfactant treatment and supplementary oxygen (FiO2). The lung mechanics in term, and foremost preterm infants, are characterized by low functional respiratory capacity (FRC), low tidal volumes (VT), low lung compliance (CL) and high airflow resistance (R). To estimate and optimize the right level of positive end expiratory pressure (PEEP) is difficult and might lead to either overextension (barotrauma) or collapse (atelectasis; atelectrauma) of the lung. Barotrauma and atelectrauma in addition to exposure to high FiO2 predispose for developing chronic lung disease (CLD) / bronchopulmonary dysplasia (BPD) with increased long term morbidity and mortality. The factors identified with decreased risk of developing BPD in preterm infants have been mainly reduced time on mechanical ventilation i.e. early weaning, and low tidal volume ventilation. It’s still unclear, though, how to maintain an adequate ventilation and oxygenation without invasive ventilation, and the correct level of tidal volume to be set. In some studies, high frequency oscillatory ventilation (HFOV) have shown short term benefits on lung inflammatory response but no difference has been seen in long term follow up in the incidence of BPD, time on mechanical ventilation or neurological outcome. Different recruitment maneuvers have been applied to achieve an adequate level of FRC, the most commonly used being PEEP in preterm newborns, with less evident effects of increased peak inspiratory pressure (PIP) and prolongation of inspiratory time or higher ventilatory rates, all with the aim of increasing mean airway pressure (MAP) without overextending the lungs. The tools to set the adequate PEEP level during IMV and nCPAP or MAP during HFOV are arbitrary, as no objective ventilatory measurement is sufficient in preterm infants with small tidal volumes and FRC, non-cuffed tubes with leakage and variable lung mechanical changes depending on stage of lung development and thoracic cage instability. The forced oscillatory technique (FOT) is a method to measure the reactance of the lung and thereby the oscillatory compliance (Cx5). In animal models, FOT has been shown to be both a reliable and a non-invasive method in estimating the correct airway R Sindelar FOT Protocol 2 opening pressure i.e. the correct level of FRC, by setting the correct level of PEEP. FOT has also been shown to be able to separate non-homogenous lung injury form unilateral lung collapse. Also, FOT can be applied both invasively and non-invasively and during spontaneous breathing. Aim: Observational study of lung mechanics (oscillatory compliance) by FOT in preterm newborn infants during different stages of lung development and lung injury related to different clinical settings of PEEP both during invasive and non-invasive ventilatory assistance Purpose: Obtain optimal PEEP levels and thereby optimal ventilation without overdistension or derecruitment of the lung Inclusion: Preterm newborn infants with need of invasive and non-invasive ventilatory assistance Exclusion: Major congenital anomalies, hemodynamic instability, seizures, or ongoing sepsis or meningitis Protocol: A. Daily sequential FOT measurements during mechanical ventilation at different PEEP levels over 14 days (or until weaning off ventilatory assistance) in extremely premature newborn infants in need of mechanical ventilation from day 1 in order to estimate the optimal recruitment level and lung mechanics changes over the first 2 weeks of postnatal age. No other intervention should be made during the registration. During ventilatory settings made by the attending physician Independent of invasive or non-invasive ventilatory assistance PEEP will be changed within the range of 3 to 7 cm H2O, in any case no more than ±2 cm H2O from the original clinical settings FOT frequencies 5, 10 and 15 Hz will used 1. Connect external FOT monitoring device to 3 analogue ports for air flow, pressure or signal of choice on Stephanie Ventilator 2. Calibrate pressure transducer 3. Connect pressure transducer at Y-piece of patient??? 4. Position patient in supine 5. Apply tcPCO2 and tcPO2, besides SaO2 and ECG R Sindelar FOT Protocol 3 6. Patient on ex. A/C=23/5 cm H2O, freq=60/min, Tinsp=0.33, Texp=0.67 7. Set fHFOV sinusoidal 50% and set HFOV P-P range to 1:3 instead of 1:1 (decreased scaling of amplitude=P-P knob: 1-6 scaling will be 0.3-2 scaling). Be aware that PEEP must be adjusted during the different fHFOV frequencies 8. Increase PEEP up to 7 cmH2O 9. Stabilize for 5 minutes 10. Set fHFOV at 10 Hz and P-P at 1 (equals ±2 cm H2O) and apply HFOV 11. Stabilize 2-4 ventilatory breaths 12. Registration for 10-20 breaths 13. Increase fHFOV to 15 Hz (same P-P and ventilatory settings) 14. Stabilize 2-4 ventilatory breaths 15. Register 10-20 breaths 16. Decrease fHFOV to 5 Hz (same P-P and ventilatory settings) 17. Stabilize 2-4 ventilatory breaths 18. Register 10-20 breaths 19. Increase expiratory time from 0.67 s to 0.8 s (Tinsp=0.33, RR=53 bmp) 20. Stabilize 2-4 ventilatory breaths 21. Register 10-20 breaths 22. Decrease PEEP to 6 cmH2O 23. follow from 9 to 21 24. Decrease PEEP to 5 cmH2O 25. follow from 9 to 21 26. Decrease PEEP to 4 cmH2O 27. follow from 9 to 21 28. Decrease PEEP to 3 cmH2O?? 29. Go back to the starting settings 30. Switch off HFOV R Sindelar FOT Protocol 4 If patient is on nasal CPAP put the pneumotachograph in place trying to avoid leaks hopefully with the mouth closed, then a continuous registration from 8. with increases of fHFOV 5 – 10 – 15 Hz, 2-4 breaths stabilization per fHFOV and 10-20 breaths per registration If the patient is triggering more than 60 bpm during A/C, then necessary to switch to S-IMV with the same settings as during A/C. If too large clinical changes during manipulations with PEEP, might be necessary to go back to baseline in between changes in Same procedure can be made on nasal CPAP and PAV B. To validate differences in FOT measurements between invasive and nasal CPAP Invasive CPAP prior to extubation and then during nasal CPAP (5 patients) HFOV frequencies 5, 10 and15 Hz 1. 1. to 7. as in A. 2. Set fHFOV at 10 Hz and P-P at 1 (equals ±2 cm H2O) and apply HFOV 3. Compute the resistance of the ETT and unload the patient from the tube unless it has an ETT with a diameter > 3.0 mm 4. Set CPAP 5 cm H2O (same PEEP level as during A/C) or the supposed set CPAP after extubation which is usually PEEP +1-2 cm H2O 5. Stabilize 2-4 ventilatory breaths 6. Registration for 5 breaths 7. Set back A/C as previously 8. Increase fHFOV to 15 Hz (same P-P and ventilatory settings) 9. Set CPAP 5 cm H2O (same PEEP level as during A/C) 10. Stabilize 2-4 ventilatory breaths 11. Register 5 breaths 12. Set back A/C as previously 13. Decrease fHFOV to 5 Hz (same P-P and ventilatory settings) 14. Stabilize 2-4 ventilatory breaths R Sindelar FOT Protocol 5 15. Register 5 breaths 16. Set back A/C as previously 17. Switch off HFOV 18. Extubation to nasal CPAP 19. After stabilization of the patient on nasal CPAP set by the clinician (usually PEEP +1-2 cm H2O), a continuous registration with increases of fHFOV 5 – 10 – 15 Hz, 2-4 breaths stabilization and registration of 5 breaths per fHFOV setting 20. Switch off If patient is stable during invasive CPAP, then a continuous registration with increases of fHFOV 5 – 10 – 15 Hz, 2-4 breaths stabilization and registration of 5 breaths per fHFOV Measurements: FOT – 5 / 10 / 15 Hz – HFOV sinusoidal 50% superimposed on A/C, S-IMV, nCPAP or short duration during PAV on CPAP only – HFOV with P-P 4 or 2 cm H2O (if lower see “Scale” and then 1:1 HFOV, button represents 0-2 instead of 1-6 for P-P) – Connect pressure sensor to Y-piece; calibration – During 5 Hz FOT, at least 0.8 s expiratory time during 15 seconds; other FOT frequencies according to ventilatory rate i.e. 60/min Supine position with head straight forward tcPCO2 and tcPO2 (infants < 25 GA with immature skin will start tc measurements after 3rd day of life), SaO2, heart rate (ECG), episodes of apnea and bradycardia registered by attending physician Arterial blood gases at the beginning of the daily measurements Ventilatory settings; PAV, nCPAP, PIP/PEEP, ventilatory frequency, MAP, FiO2 Tidal volume (exp/insp) as provided from Stephanie BW, APGAR, GA, day of age, sedatives, other medications vital for breathing or lung mechanical changes, present weight R Sindelar FOT Protocol tube size and length Electrical diaphragm (Edi) activity as measured by feeding gavages electrodes to assess influence of different PEEP levels on breathing activity 6 Collaborators Raffaele Dellaca PhD Richard Sindelar MD PhD Peter Frykholm MD PhD Emanuela Zannin PhD Linda Wallström MD PhD student Ilaria Milesi PhD student Chiara Veneroni PhD student References 1. Dellaca R, Andersson Olerud M, Zannin E, Kostic P, Pompilio P, Hedenstierna G, Pedotti A, and Frykholm P. Lung recruitment assessed by total respiratory system input reactance. Intensive Care Med (2009) 35:2164–2172 2. Dinger J, Töpfer A, Schaller P, and Schwarze R. Effect of positive end-expiratory pressure on functional residual capacity and compliance in surfactant-treated preterm infants. J. Perinat. Med. 29 (2001) 137-143 3. Thome U, Töpfer A, Schaller P, and Pohlandt F. The effect of positive end-expiratory pressure, peak inspiratory pressure, and inspiratory time on functional residual capacity in mechanically ventilated preterm infants. Eur J Pediatr (1998) 157: 831-837 4. Alegria X, Claure N, Wada Y, Esquer C, D’Ugard C, and Bancalari E. Acute effects of PEEP on tidal volume and respiratory center output during synchronized ventilation in preterm infants. Pediatric Pulmonology (2006) 41:759–764