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• Response to the letter to the editor by Zhu et al regarding “Non-invasive high-frequency oscillatory ventilation in preterm infants”
  Daniel Klotz, Hans Fuchs
  Published on: 24 September 2018
• Non-invasive high-frequency oscillatory ventilation in preterm infants
  Xingwang Zhu, Yuan Shi
  Published on: 1 August 2018

• Published on: 24 September 2018

  Response to the letter to the editor by Zhu et al regarding “Non-invasive high-frequency oscillatory ventilation in preterm infants”

  • Daniel Klotz, Consultant Neonatology Center for Pediatrics, Department of Neonatology, Medical Center/Faculty of Medicine - University of Freiburg, Germany
  • Other Contributors:
    • Hans Fuchs, Consultant Neonatology

  Dear Editor

  We appreciate the comments of Zhu and Shi on our crossover trial comparing nHFOV (nasal high frequency oscillatory ventilation) and nCPAP (nasal continuous positive airway pressure) in preterm infants <32 weeks gestational age after extubation from invasive ventilation for respiratory distress syndrome or after less invasive surfactant therapy.1

  The aim of our study was to evaluate the efficacy of an oscillatory pressure waveform superposed to CPAP in spontaneously breathing preterm infants suffering from hypercarbia. In our trial, patients received a CPAP of 5 – 8 cmH2O, which represents standard of care in our unit and is in line with the clinical practice within many neonatal centers.2 Individual CPAP levels were the same before (adjusted according to standard of care) and within the study periods.
  We agree with Zhu et al that increasing the CPAP level in addition to oscillations may enhance lung recruitment and ventilation. However, the effect of oscillations can hardly be differentiated from elevated CPAP levels in this scenario. Other factors than increased lung recruitment might contribute to increased CO2 clearance (e.g. increased leak flow, increased pharyngeal washout or the infants’ respiratory response). In conclusion, we cannot speculate on the effect of increased CPAP levels when testing nHFOV in our trial, but we would advise against testing differing opening pressures when comparing nHFOV to CPAP respiratory support.

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  Dear Editor

  We appreciate the comments of Zhu and Shi on our crossover trial comparing nHFOV (nasal high frequency oscillatory ventilation) and nCPAP (nasal continuous positive airway pressure) in preterm infants <32 weeks gestational age after extubation from invasive ventilation for respiratory distress syndrome or after less invasive surfactant therapy.1

  The aim of our study was to evaluate the efficacy of an oscillatory pressure waveform superposed to CPAP in spontaneously breathing preterm infants suffering from hypercarbia. In our trial, patients received a CPAP of 5 – 8 cmH2O, which represents standard of care in our unit and is in line with the clinical practice within many neonatal centers.2 Individual CPAP levels were the same before (adjusted according to standard of care) and within the study periods.
  We agree with Zhu et al that increasing the CPAP level in addition to oscillations may enhance lung recruitment and ventilation. However, the effect of oscillations can hardly be differentiated from elevated CPAP levels in this scenario. Other factors than increased lung recruitment might contribute to increased CO2 clearance (e.g. increased leak flow, increased pharyngeal washout or the infants’ respiratory response). In conclusion, we cannot speculate on the effect of increased CPAP levels when testing nHFOV in our trial, but we would advise against testing differing opening pressures when comparing nHFOV to CPAP respiratory support.

  We furthermore agree with Zhu et al. that careful consideration has to be given to the individual significance of an intervention free interval in between study periods when planning a cross-over trial.3 However, there is an incongruence across cross-over trials on the use of washout phases and the issue of carry-over effects.4 As detailed in the manuscript, there was no washout phase between both study periods since a wash out in the classical meaning (omission of respiratory support) was not feasible in our trial. Even so, we calculated the carry-over effect for any outcome parameter and found none (table 2).1

  We thank Zhu et al for their comments and hope our reply clarified those important aspects to the reader.

  References:
  1 Klotz D, Schneider H, Schumann S, et al. Non-invasive high-frequency oscillatory ventilation in preterm infants: a randomised controlled cross-over trial. Arch Dis Child Fetal Neonatal Ed 2018;103:F1–F5 . doi: 10.1136/archdischild-2017-313190

  2 Beltempo M, Isayama T, Vento M, et al. Respiratory Management of Extremely Preterm Infants: An International Survey. Neonatology 2018;114:28–36 . doi: 10.1159/000487987

  3 Wellek S, Blettner M. On the proper use of the crossover design in clinical trials: part 18 of a series on evaluation of scientific publications. Dtsch Arztebl Int 2012; 109:276–281. doi: 10.3238/arztebl.2012.0276

  4 Mills EJ, Chan A-W, Wu P, et al. Design, analysis, and presentation of crossover trials. Trials 2009;10:27. doi: 10.1186/1745-6215-10-27

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  Conflict of Interest:
  None declared.

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• Published on: 1 August 2018

  Non-invasive high-frequency oscillatory ventilation in preterm infants

  • Xingwang Zhu, neonatologist Department of Neonatology JiulongpoPeople's Hospital
  • Other Contributors:
    • Yuan Shi, neonatologist

  To the editor:
  We appreciate the work by Klotz et al., published in this journal1, who presented a randomized controlled cross-over trial to determine whether noninvasive high-frequency oscillatory ventilation (nHFOV) decreases CO2 partial pressure(pCO2) in premature infants more effectively than non-invasive continuous positive airway pressure(nCPAP). In this trial, they assigned 26 premature infants of less than 28 weeks’gestational age (GA) to receive either nHFOV or nasal continuous positive airway pressure (nCPAP) immediately after extubation or non-invasive
  surfactant treatment. The authors could not etablish an increased
  carbon dioxide clearance applying nHFOV compared with
  nCPAP in this cohort of preterm infants. The result is in contrast
  to previous reports where nHFOV was applied at higher airway
  levels compared with nCPAP. Although the author provided brief information about the trial in the paper, we have the following questions about the details of the trial.
  1. How was the mean airway pressure (MAP) titrated in the two sequences?
  According to the paper, the range of MAPs applied in the two sequences were (5-8cmH2O)and (5-7cmH2O)respectively. The authors emphasized that the MAPs applied to nHFOV and nCPAP are equal, but it is not clear how was the MAP titrated (within the range) in the two sequences. Similar to what is done in invasive high frequency oscillatory ventilation, The MAP applied in nHFOV should be tit...

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  To the editor:
  We appreciate the work by Klotz et al., published in this journal1, who presented a randomized controlled cross-over trial to determine whether noninvasive high-frequency oscillatory ventilation (nHFOV) decreases CO2 partial pressure(pCO2) in premature infants more effectively than non-invasive continuous positive airway pressure(nCPAP). In this trial, they assigned 26 premature infants of less than 28 weeks’gestational age (GA) to receive either nHFOV or nasal continuous positive airway pressure (nCPAP) immediately after extubation or non-invasive
  surfactant treatment. The authors could not etablish an increased
  carbon dioxide clearance applying nHFOV compared with
  nCPAP in this cohort of preterm infants. The result is in contrast
  to previous reports where nHFOV was applied at higher airway
  levels compared with nCPAP. Although the author provided brief information about the trial in the paper, we have the following questions about the details of the trial.
  1. How was the mean airway pressure (MAP) titrated in the two sequences?
  According to the paper, the range of MAPs applied in the two sequences were (5-8cmH2O)and (5-7cmH2O)respectively. The authors emphasized that the MAPs applied to nHFOV and nCPAP are equal, but it is not clear how was the MAP titrated (within the range) in the two sequences. Similar to what is done in invasive high frequency oscillatory ventilation, The MAP applied in nHFOV should be titrated according to open lung strategy, performing alveolar recruitment, as published elsewhere2. Open lung strategy is the key to the application of nHFOV, however, it is rarely applied in nCPAP. The most commonly pressure range of CPAP is 3-10cmH2O. In fact, the MAP of higher than 10 cmH2O was often applied in some premature infants with severe respiratory distress syndrome(RDS) or the high risk of developing bronchopulmonary dysplasia(BPD) to perform alveolar recruitment. If MAP used in the nHFOV sequence was not based on open lung strategy but according to nCPAP setting, then the effect of nHFOV and the impact of the oscillations may be greatly dampened due to alveolar collapse. Therefore, providing more details about the adjustments of MAP over time both in the nHFOV and the nCPAP sequence would be extremely helpful to the reader and for future study protocols.
  2. How long is the washout period in their trial?
  According to the paper, the authors did not describe the length of the washout period. In the design of cross-over trial, the length of washout period should be considered. A recent randomized crossover trial by Ruegger et al.3, the washout period is thirty minutes. If there is no washout period preceded on the assigned therapy in their trial, the statistical results may be affected.
  While answers to the above-mentioned questions will enhance our understanding of the promising data presented by Klotz et al. Given the increasing interest in avoiding invasive mechanical ventilation in very preterm infants, it may be time to embark on the first multicenter randomized controlled trial that investigates the effects of nHFOV in very preterm infants.

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  Conflict of Interest:
  None declared.

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