American Journal of Respiratory and Critical Care Medicine

To the Editor:

Respiratory movements cause motion artifacts during image acquisition of the thorax and upper abdomen, which limit the clinical use of magnetic resonance imaging in the visualization of lung parenchyma and thoracic vascular structures (1, 2), reduce the accuracy of positron emission tomography (3, 4), and increase the toxicity of radiation therapy, directly influencing the amount of normal tissue included in the irradiated volumes (5, 6).

Suppressing respiratory movements during imaging acquisition and radiation therapy may, therefore, improve image quality and reduce healthy tissue irradiation while maximizing radiation dose to the tumor. The suppression of thoracic movement has been previously obtained in invasively ventilated subjects under general anesthesia using high-frequency ventilation (HFV), which ensures oxygen delivery and carbon dioxide (CO2) clearance (79).

We performed an interventional, crossover, randomized, open-label study, applying for the first time HFV using a noninvasive interface (HF-NIV) to obtain prolonged apnea (absence of thoracoabdominal respiratory movements) in 10 nonsedated healthy adults with normal spirometry and no known cardiopulmonary disease (median age, 30 yr; range, 26–56 yr; 6/10 men). The study was conducted in accordance with the Declaration of Helsinki and the local ethics committee (Protocol 225/14 CHUV-DO-PART).

HF-NIV was performed using a Monsoon III ventilator (Acutronic Medical Systems, Hirzel, Switzerland) and a noninvasive patient interface (Phasitron; Percussionaire, Sagle, ID). This setting allowed constant monitoring of airway pressures and the application of ventilation with an open airway, protecting against overpressure, and allowing the resumption of spontaneous breathing at any moment during HFV. Each participant performed three breath hold attempts after 1 minute of self-induced hyperventilation: a maximal spontaneous (unassisted) apnea and two HF-NIV–assisted attempts with respiratory rate (RR) of 250/min and 500/min, in a randomized sequence. The working pressure of the ventilator was set to obtain a lung volume between the end-inspiratory lung volume and the total lung capacity, and a mean airway pressure of 15 to 20 cm H2O, adapted according to volunteers’ comfort. To minimize the risk of barotraumas, the ventilator safety pressure relief valve was set at 40 cm H2O. Inspired oxygen fraction was 100%. The test was interrupted on resumption of spontaneous breathing or after 20 minutes of apnea. Chest and abdominal motion bands were applied to obtain respiratory inductive plethysmography, and a pneumotachograph and a pressure transducer were inserted in the ventilator circuit (Embla N7000; Embla Systems, Reykjavik, Iceland) to record ventilator’s flow and pressure. Continuous transcutaneous capnography (TcCO2) and oxygen saturation (SpO2) were recorded using a Digital Monitoring System (SenTec, Therwil, Switzerland).

The duration of apnea was considered as the primary end point, defined as a reduction of the respiratory inductive plethysmography–derived flow (X flow) by 90% or more compared with spontaneous breathing. Artifacts secondary to swallowing movements, which briefly interrupt the ventilation delivery, were excluded from the analysis. We used paired Wilcoxon tests to compare measurements. The amplitude of the thoracic and abdominal movements during each test were assessed computing the coefficient of variation—defined as the ratio of the SD to the mean—of the values measured by the thoracoabdominal motion bands.

HF-NIV with an RR of 250/min resulted in a median apnea duration of 20:00 minutes (interquartile range [IQR], 11:16–20:00 min; in 7/10 participants the attempt was interrupted after 20:00 minutes according to the study protocol), which was significantly longer than the value obtained during unassisted apnea (median, 2:16 min; IQR, 1:41–2:45 min; P = 0.002) and using HF-NIV with RR 500/min (median, 5:16 min; IQR, 3:57–6:48 min; P = 0.002) (Figure 1). The efficacy of HF-NIV at 250/min was explained by an effective CO2 clearance, with median TcCO2 at the end of the RR 250/min apnea trial being 0.8 mm Hg (IQR, −1.1 to 4.4 mm Hg) higher than the baseline value during spontaneous breathing (P = 0.232). In fact, the delivered tidal volume of HFV depends on the respiratory rate and was 54 ml (IQR, 52–57 ml) for the RR 250/min trial. Contrarily, the tidal volume was 26 ml (IQR, 26–27 ml) during the RR 500/min test, and TcCO2 increased by 6.2 mm Hg (IQR, 5.4–9.0 mm Hg; P < 0.01 compared with the baseline value during spontaneous breathing), leading to respiration resumption by the participant. SpO2 remained greater than or equal to 97% during all the HF-NIV tests. The very small tidal volumes resulted in a significant reduction of the thoracic and abdominal movements compared with spontaneous breathing (Figure 2).

In this pilot study, the application of HFV using a noninvasive interface allowed a significant prolongation of apnea time in awake healthy subjects compared with spontaneous apnea, while preserving normal oxygen and carbon dioxide levels. The technique was safe and well tolerated by all the study participants, with dryness of the upper airways being the main reported discomfort.

This present work, a systematic efficacy and safety evaluation of the technique, enriches our group’s experience showing some potential important clinical applications of HF-NIV in the fields of thoracic magnetic resonance imaging and radiotherapy (3, 5). The main finding is the relationship between Pco2 control and apnea duration, both influenced by the set respiratory rate and the resulting tidal volume. According to the HFV characteristics, decreasing the RR resulted in an increase in tidal volume, which increased the efficiency of ventilation. In fact, HF-NIV with an RR of 250/min allowed us to obtain an apnea and a stable Pco2 lasting 20 minutes in 7 of 10 participants, whereas the remaining 3 participants showed an increasing Pco2 during the test and resumed spontaneous breathing after 5:26 to 8:22 minutes. We found no clinical characteristics allowing us to identify these subjects in advance. An individual titration of the RR would probably result in a better Pco2 control, but this was not planned in our protocol.

Although very promising, our data should be considered as preliminary, because we selected healthy subjects in this pilot study. Furthermore, the use of HF-NIV is time consuming and needs a team experienced with the technique, although the participants did not require prior training to use the technique. The use of HF-NIV in patients suffering from lung diseases and its application during thoracic imaging and radiotherapy require further research.

In conclusion, we demonstrate the safety, feasibility, and good tolerability of HF-NIV to suppress respiratory motion in nonsedated subjects. This work represents the basis for subsequent studies, which should define its potential benefits in the different thoracic imaging and treatment application fields.

We thank Jean-William Fitting and Kathleen Grant for their scientific support and constructive feedback.

1. Ciet P, Serra G, Bertolo S, Spronk S, Ros M, Fraioli F, Quattrucci S, Assael MB, Catalano C, Pomerri F, et al. Assessment of CF lung disease using motion corrected PROPELLER MRI: a comparison with CT. Eur Radiol 2016;26:780787.
2. Higano NS, Hahn AD, Tkach JA, Cao X, Walkup LL, Thomen RP, Merhar SL, Kingma PS, Fain SB, Woods JC. Retrospective respiratory self-gating and removal of bulk motion in pulmonary UTE MRI of neonates and adults. Magn Reson Med 2017;77:12841295.
3. Prior JO, Péguret N, Pomoni A, Pappon M, Zeverino M, Belmondo B, Lovis A, Ozsahin M, Vienne M, Bourhis J. Reduction of respiratory motion during PET/CT by pulsatile-flow ventilation: a first clinical evaluation. J Nucl Med 2016;57:416419.
4. Dasari P, Johnson K, Dey J, Lindsay C, Shazeeb MS, Mukherjee JM, Zheng S, King MA. MRI investigation of the linkage between respiratory motion of the heart and markers on patient’s abdomen and chest: implications for respiratory amplitude binning list-mode PET and SPECT studies. IEEE Trans Nucl Sci 2014;61:192201.
5. Péguret N, Ozsahin M, Zeverino M, Belmondo B, Durham AD, Lovis A, Simons J, Long O, Duclos F, Prior J, et al. Apnea-like suppression of respiratory motion: first evaluation in radiotherapy. Radiother Oncol 2016;118:220226.
6. Timmerman R, McGarry R, Yiannoutsos C, Papiez L, Tudor K, DeLuca J, Ewing M, Abdulrahman R, DesRosiers C, Williams M, et al. Excessive toxicity when treating central tumors in a phase II study of stereotactic body radiation therapy for medically inoperable early-stage lung cancer. J Clin Oncol 2006;24:48334839.
7. Fritz P, Kraus HJ, Mühlnickel W, Sassmann V, Hering W, Strauch K. High-frequency jet ventilation for complete target immobilization and reduction of planning target volume in stereotactic high single-dose irradiation of stage I non-small cell lung cancer and lung metastases. Int J Radiat Oncol Biol Phys 2010;78:136142.
8. Biro P, Spahn DR, Pfammatter T. High-frequency jet ventilation for minimizing breathing-related liver motion during percutaneous radiofrequency ablation of multiple hepatic tumours. Br J Anaesth 2009;102:650653.
9. Denys A, Lachenal Y, Duran R, Chollet-Rivier M, Bize P. Use of high-frequency jet ventilation for percutaneous tumor ablation. Cardiovasc Intervent Radiol 2014;37:140146.

Author disclosures are available with the text of this letter at www.atsjournals.org.

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American Journal of Respiratory and Critical Care Medicine
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