A parallel-group, superiority randomised controlled trial, with concealed allocation and blinded assessments (single blinded), will be conducted according to the CONSORT recommendations [28,29]. A trained researcher, blinded to group allocation, will obtain signed written informed consent and measure outcome measures at baseline and post-intervention (until weaning) (Figure 1). The examiner will be blinded to group allocation, and participants and the treating physiotherapist will be asked not to share any information about the intervention with the examiner. Participants will be randomly assigned to either (1) IMT combined with routine physical therapy (training group [TG]) or (2) routine physical therapy alone (control group [CG]) (Figure 2). The protocol for this trial was registered in the database for randomised clinical trials, ClinicalTrials.gov (NCT03758573) version 1.0, 29th November 2018. There is no plan for further trial modifications. The clinical trial protocol also follows the SPIRIT 2013 checklist .
The research will be conducted in the ICU of universitary hospital (Hospital Universitário da Universidade Federal do Vale do São Francisco - HU-UNIVASF; Petrolina/PE, Brazil).
Ethics approval has been obtained from the Research Ethics Committee of the UNIVASF (REC-UNIVASF; N. 2.680.771), was gained on 12 July 2018. Written informed consent will be obtained from the participants or their relatives/responsible at the time of recruitment, including consent for evaluation and intervention procedures adopted in the research. Personal information will be coded to maintain and protect participants’ confidentiality. At any time, the trial may be independently audited by the ethics committees.
Study population and eligibility criteria
The sample will consist of individuals of both sexes who meet the following inclusion criteria: (1) age ≥18 years; (2) intubated; (3) on MV for at least 24 hours; (4) in spontaneous modes of ventilatory flow; (5) without sedation for >12 hours; (6) functional level ≤3; (7) maximum inspiratory pressure (PImax) ≥20 cmH2O; (8) mean arterial pressure ≥60 cmH2O and ≤130 cmH2O; (9) fraction of inspired oxygen ≤60 cmH2O; (10) positive end-expiratory pressure ≤10 cmH2O; (11) heart rate (HR) ≥60 bpm and ≤130 bpm; (12) respiratory rate (RR) ≤30 ipm; (13) peripheral oxygen saturation ≥90% and (14) temperature <38°C.
Participants with the following characteristics will be excluded: (1) under sedation, (2) administered vasoactive drugs, (3) spinal cord trauma, (4) progressive neuromuscular diseases, (5) previous tracheostomy, (6) terminal state, (7) pneumothorax, (8) unstable chest, (9) diaphragmatic injury, (10) ruptured eardrum and (11) postoperative pulmonary and abdominal surgeries. In addition, patients who cannot perform for IMT for two consecutive or four alternate days will be excluded from the trial.
Sample size and power calculations
The sample size was calculated using the G*Power V. 126.96.36.199 program , based on the F test, analysis of variance of repeated measures between independent groups. A type I error of 5%, power of 80% and effect size equal to 0.48, calculated from the means and standard deviations of a similar study that analysed weaning time from MV , gave a required number of 38 in total, with 19 participants in each group. Assuming an expected dropout rate of 10%, a target of 42 participants was set (21 participants per group).
When analysing the sample size of studies included in a recent systematic review , 23 (82%) studies had <50 patients and only five (18%) studies had ≥50 (mean sample size 34; standard deviation 23; minimum 6 and maximum 92). In view of this analysis, this feasibility study will hopefully contribute to decision-making around the clinical application of early IMT in critical patients.
Although this study is underpowered to detect the outcome measures, one may argue that including this outcome measure (weaning time from MV) will provide important feasibility data for future studies.
Participant identification, recruitment and informed consent
The main investigator will examine all ICU patients daily for study eligibility (Figure 2). Recruitment will be facilitated by the use of the evaluation form completed daily by physiotherapists, and this registration will allow the identification of eligible patients according to the pre-established criteria. During the screening visit, those responsible for eligible participants will be informed of the procedures for evaluations and interventions to be adopted in the research, all questions will be answered, and participants will be invited to sign the informed consent form.
The following information will be included in the informed consent form: “Ethical guarantees: To participate in this study you will not have any cost, nor will you receive any financial advantage; however, all expenses that may occur with the research will be repaired (refunded). Your right to compensation is also guaranteed (repair or compensation for any loss that may occur). You will receive full and immediate assistance, free of charge, for as long as necessary in case of damages resulting from the research and you can to refuse to participate and still refuse to continue participating in any phase of the research, without any prejudice”.
Randomisation, allocation concealment and blinding
Patients will be randomly assigned to receive either routine physical therapy (CG) or routine physical therapy with IMT (TG). A randomisation sequence will be created using the website www.random.org, with a 1:1 allocation ratio using blocks of 10 participants. Allocation concealment will be achieved by means of sequentially numbered, opaque and sealed envelopes.
The randomisation sequence will be computer generated prior to study commencement by a trained research assistant, who will be not involved in the study, and maintained in randomised blocks in sequentially numbered sealed opaque envelopes. Eligible participants will be randomly allocated to either the control or experimental group, after the baseline measurements. The training therapist will be responsible for revealing the contents of the sealed opaque envelopes and, therefore, for revealing the allocation.
After blinded assignment to interventions, outcome assessors and data analysts will also be blinded. They will not have access to the information of either the control or experimental group. Participants will be prohibited from saying anything about their treatment. Allocation will be revealed to the outcome assessors after the post-intervention evaluations and to data analysts after the statistical analysis. Data referring to the groups will be coded for blinding of the researcher who will perform the statistical analysis.
Plans for assessment and outcome collection will be prepared in which the assessors (blinded to the interventions) will perform assessments pre- and post-intervention, will be well trained for evaluation procedures and will be checked at the baseline for all outcomes. The data collection forms will remain with the main researcher.
The primary outcome is weaning time from MV (days) from baseline to the end-point. Secondary outcomes will be respiratory muscle strength (mmHg) (baseline and end-point), mortality (n) (end-point), length of stay in the ICU (days) (end-point) and successful weaning (n) (end-point). Respiratory muscle strength will be measured as PEF, PImax and PEmax. Successful extubation will be defined as maintaining spontaneous ventilation for at least 48 hours after the interruption of artificial ventilation .
This article provides a detailed description of the background, target population and methodology of the IMT study, a randomised controlled trial investigating the effects of early IMT in critically ill patients undergoing MV using the POWERbreath® combined with routine physical therapy (TG) versus routine physical therapy alone (CG) on weaning time, inspiratory muscle strength, length of stay in the ICU and weaning success rate.
The study participants included will be assessed daily until discharge through routine ICU monitoring. The following haemodynamic parameters will be recorded at each session: HR, RR, peripheral oxygen saturation and systolic and diastolic blood pressure. As for ventilation parameters, the following markers will be observed: ventilation mode, volume, pressure, respiratory frequency, inspiratory time, positive end-expiratory pressure, inspired oxygen fraction and presence of acid/basic and/or oxygenation disorders by collecting arterial blood for gas analysis performed daily. To assess the level of consciousness, the Glasgow Coma Scale will be used .
IMT will occur in the TG using POWERbreathe® equipment (Medic, London, United Kingdom), according to the following parameters: load adjusted daily at 50% of PImax, three sets of ten repetitions with one-minute rests on the mechanical ventilator between each series, twice a day, with patients in bed at the bedside angle of 45°, while on MV. Adjustments in the IMT load will occur according to PImax values evaluated daily by the interventional physiotherapist . Supplemental oxygen will be administered during IMT , and the endotracheal cuff pressure will be maintained at 30 mmHg during training . If necessary, airway aspiration will be performed before the procedure.
Routine ICU care (common interventions to the both groups)
Both groups will remain under routine ICU physical therapy, consisting of respiratory and motor physiotherapy. Such routine care will include an individualised and supervised intervention programme, consisting of any of the following procedures: bronchial hygiene manoeuvers and pulmonary expansion therapy. Passive, assisted, active or resisted mobilisation and sedation will depend on the functional level of the patients . There will be 10 joint mobilisations, prioritising diagonal and combined movements that favour patient functionality, in addition to a lower limb cycle ergometer for 30 minutes and functional positioning according to the protocol adopted at the institution.
The protocol will be discontinued if the patient has two or more of the following signs of respiratory failure or adverse events: RR >35 incursions per min; peripheral oxygen saturation <90%; HR >130 bpm; systolic blood pressure >180 mmHg or <90 mmHg and signs and symptoms such as agitation, sweating, altered level of consciousness and thoraco-abdominal asynchrony . We do not anticipate problems with regard to adherence because the patients are hospitalised. Other relevant details of concomitant care is that the protocol will recommended not to use too much sedative in these patients, although use of sedatives will not be prohibited.
Oversight and monitoring
The trial will be overseen and monitored by co-investigators involved in the day-to-day running of the trial, who will meet weekly throughout the project. In addition, independent experts with relevant clinical research and statistical experience from HU-UNIVASF and Research Ethics Committee of the UNIVASF (REC-UNIVASF) will meet twice yearly to ensure data integrity and participant safety.
Despite the short duration of this trial, any modifications to the protocol that may impact the conduct of the study, the potential benefits for the patient or patient safety, including changes of study objectives, study design, patient population, sample sizes, study procedures or significant administrative aspects will require a formal amendment to the protocol. Such amendments will be approved by the Research Ethics Committee. The plans to communicate the trial results involve dissemination to the hospital and university and publication in journals and conferences.
All essential documentation and trial records will be stored in accordance with the applicable regulatory requirements, and access restricted to authorised personnel at HU-UNIVASF and the research group (Research Group on Evidence-Based Practice). Trial documentation and data will be archived in an online repository.
Dissemination of information
The trial will be reported in line with the Consolidated Standards of Reporting Trials (CONSORT) checklist, and results will be disseminated in peer-review scientific journals. Important modifications to the trial protocol will be communicated to the funder, study investigators, HU-UNIVASF, REC-UNIVASF and trial registries.
At the time of initial manuscript submission, recruitment had already started for the trial. The study started in March 2019. The trial is recruiting participants but is paused due to COVID-19.
To verify the normality of the distribution, the Shapiro–Wilk test will be used. For comparisons of means between and within outcome groups, generalised estimating equations will be used, with its own syntax and linear distribution and when necessary, multiple comparisons will be performed using the Bonferroni test to identify differences. Categorical variables will be compared using the chi-square (χ2) or Fisher’s exact test where appropriate. Statistics such as difference of means (95% CI) and effect size (Cohen’s d) will be calculated. Multiple imputation will be used in case of missing data. The intention-to-treat principle will be used in the final analyses. The statistical significance adopted will be 5%, and analyses will be performed using the statistical programme SPSS 22.0 (Statistical Package for the Social Sciences, Chicago, IL, USA).