This is a single-center, nonblinded, nonrandomized prospective study. As the use of oscillation is obvious, this study cannot be performed blindly. The study will be performed in the Department of Pediatrics, Kobe University Hospital, in Kobe, Japan. The study implementation period is from March 27, 2018, to January 31, 2022 (enrollment period: 3 years; follow-up period: 4 months from enrollment of the last subject).
This study is conducted in patients who fulfill the following inclusion criteria and who do not meet any of the following exclusion criteria.
The inclusion criteria are as follows: patients with NMDs hospitalized in Kobe University Hospital owing to respiratory tract infection, who have already used MI-E without HFO or have started MI-E use in this study in addition to noninvasive ventilation, tracheostomy ventilation, and home oxygen therapy, and who provide written voluntary consent (or whose parents provide written voluntary consent) to participate in this study.
The exclusion criteria are as follows: patients with severe acute respiratory failure who have a very low SpO2 level (<90%) for more than 1 hour, albeit adequate ventilation or oxygen therapy; those who do not have tracheostomy and require intubation; those who refuse to participate in the study; and those for whom it is deemed inappropriate to participate in this study in the opinion of the investigator. These exclusion criteria are set to target patients with NMDs who have mild-to-moderate respiratory infection and to secure the safety of the subjects.
The Cough Assist E70 (Philips Respironics) is employed in this study. The device is used according to the manufacturer’s recommendation. The Cough Assist E70 is applied via an oronasal mask or the tracheostomy opening by trained parents, nurses, or doctors. It is used at least 3 times a day, as well as whenever SpO2 decreases, heart rate increases, or the patients have an increase in dyspnea or sense of retained secretions, in addition to the standard treatment, including oxygen supplementation and increased oxygen. It is set at 20 to 40 cm H2O for insufflation and −20 to −40 cm H2O for exsufflation pressure, with an insufflation and exsufflation time ratio of 1.5 to 2.5 and 0.8 to 1.5 seconds, respectively, and a pause of 0.5 to 2.0 seconds between each cycle. A total of 3 to 5 cycles are applied in every session. The frequency setting of oscillation is 15 Hz and the amplitude setting is 5 cm H2O. This oscillation frequency was derived from a similar previous study [
The principal subinvestigator will obtain written informed assent or consent from patients or from their parents. After informed consent is obtained, the principal investigator or subinvestigator will determine the subject’s eligibility for enrollment. Enrollment should be done within 2 days after obtaining written consent, and protocol treatment should be started within 1 day after enrollment.
For the patients currently using MI-E, they will continue to use it with their existing settings. For new MI-E users, the setting described above will be used.
The following subject information will be recorded in the case report form (CRF) at the time of obtaining informed consent: date of informed consent; subject identification code; and subject’s baseline characteristics, including sex, birth date, height, body weight, medical history, concurrent diseases, and original setting of MI-E.
HFO will be added to MI-E in every subject on every other day, for 6 days. The addition of HFO on day 1 or day 2 will be determined in a random manner. When the subject is randomly selected to start the protocol with HFO on, the subject will receive MI-E with HFO treatment on days 1, 3, and 5 (
Outline of the study. Subjects will receive high frequency oscillation (HFO) every other day for 6 days. This shows the study schedule when the subject is randomized to start the protocol with HFO-on.
When continuation with the study is judged to be impossible for any of the following reasons, the principal investigator or subinvestigator will terminate the subject’s participation in the study and specify the date and time of discontinuation or dropout, reason for discontinuation, and clinical course in the medical records and CRF. The reasons for discontinuation include the following: when the subject or their parents request to withdraw from the study; when the subject’s respiratory status worsens and continuation of the study treatment is judged to be undesirable; when an adverse event, including pneumothorax, occurs and further continuation with the study is difficult; when the subject is discharged from the hospital; and when discontinuation from the study is appropriate for other reasons in the opinion of the principal investigator or subinvestigator.
When subjects who have already used MI-E have completed the protocol, MI-E will be set at the original setting. For subjects who commence use of MI-E for the first time in this study, MI-E will be set at a clinically favorable setting. HFO will be added if requested by the subject. For each subject, the observation period will end on the day when the subject visits the outpatient clinic of Kobe University Hospital for follow-up at 2 to 4 weeks after discharge.
Oxygenation change (SpO2) is the primary outcome in this study. Data will be obtained at every MI-E use during the study protocol. SpO2 values will be recorded at any point within 15 min before MI-E treatment and at 3 min after treatment.
To evaluate the efficacy of the treatment, changes in heart rate will be obtained at the same time point used for SpO2. Additionally, the amount of mucus removed will be assessed subjectively, according to 3 grades (little, moderate, and abundant). As it was recommended by an external reviewer, peak cough flow was added to the secondary outcomes at the midpoint of the study. As safety end points, adverse events and the incidence of complications during the observation period will be obtained. The worst grade of the event will be considered the severity grade of each observed adverse event.
The primary endpoint of this study is the change in SpO2 (ΔSpO2) between MI-E with and without HFO. As no previous study has elucidated HFO efficacy in patients with NMDs, it is difficult to estimate how much change will be achieved. We assumed that the ratio of the average ΔSpO2 difference between HFO-on and HFO-off to the standard deviation would be about 1.1 to 1.2. To test the null hypothesis that there would be a mean change of 0 in the SpO2 between MI-E with and without HFO, using a paired
This study will evaluate weather MI-E with HFO is significantly superior to MI-E without HFO in terms of the change in SpO2 as the primary endpoint of this study. If the protocol treatment with HFO is found to be statistically significantly superior to the treatment without HFO, the study will conclude that the addition of HFO to MI-E is more efficacious than not adding HFO.
The ΔSpO2 is calculated by subtracting the SpO2 value of pre-MI-E from the SpO2 value of post-MI-E. For every subject, the average of ΔSpO2 with or without HFO will be obtained. Then, a statistical analysis will be performed using a paired
The safety endpoint of this study is the frequency of adverse events and complications. A summary table will be prepared for this endpoint. For estimation of the proportion, the exact 2-sided 95% CI for binomial distribution will be calculated by group. As necessary, Fisher exact test will be used for intergroup comparison. The final analysis will be performed after data from the subjects have been obtained and locked after the end of the follow-up period. The full analysis dataset and safety analysis dataset will consist of all subjects enrolled in this study, who performed at least one protocol treatment and for whom efficacy data are available.
The statistical analysis will be performed using GraphPad PRISM 7.02 (GraphPad Software).
The study protocol was approved by the ethics committee of the Graduate School of Medicine, Kobe University (approval #290090).