Trial design and setting
This is an investigator-initiated, multicenter, superiority, randomized controlled trial that will include 132 participants in intervention arm. Six large tertiary hospitals in China will be involved in this trial. This study was prospectively registered with Chictr.org.cn on February 29, 2020 (identifier: ChiCTR 2000030349).The Ethics Committee of Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College in Beijing has approved the trial protocol. The schedule of enrollment, intervention, data collection and assessment follows the Standardized Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines (see Figure 1 for checklist and Additional File 1 for more details).
Study population
Patients will be eligible for inclusion if they are aged 18-80 years, admitted into the Emergency Department(ED) and intubated emergently for one of the following conditions: (1)severe traumatic injury, (2)Glasgow Coma Scale (GCS) score<8, (3)hypoventilation, (4)persistent hypoxemia (SaO2≤ 90%) despite supplemental oxygen, (5)persistent hypotension despite vasopressor treatment, or (6)cardiac arrest. Since most participants in our study will have no capacity to make decisions, written informed consent will be acquired from each patient’s next of kin prior to inclusion. Patients or their next of kin will be informed of the purpose, procedures, potential risks, and benefits of the study. Participants will be allowed to withdraw from the trial at any time without consequence.
Patients will be excluded if they meet at least one of the following criteria: pregnant or breastfeeding, chronically treated with corticosteroids or other anti-inflammatory drugs, extubated for patient comfort or on family request, unplanned or self-extubation, vocal cord dysfunction, deep sedation (defined as a Richmond Agitation-Sedation Scale (RASS) score≤-4), or those diagnosed with gastrointestinal hemorrhage within the past three months.
There will be a research coordinator at each hospital to promote and monitor the trial.
Intervention, control and observation groups
Once eligible patients successfully pass a spontaneous breathing trial (SBT), a CLT will be performed to evaluate their risk for developing PES. Patients who had a cuff-leak volume(CLV) less than 24% of vital volume will be included in the intervention arm, where they will be randomly allocated to either the corticosteroid group or the placebo group. The planned extubation will be implemented within six hours after allocation. Patients in the corticosteroid group and placebo group will be treated with an intravenous injection of methylprednisolone 40mg (corticosteroid) or an equivalent volume of isotonic saline (placebo) four hours prior to extubation. Patients with a CLV >24% of tidal volume will serve as a control group, where extubation will be performed within two hours after CLT completion.
All other standard precautions or treatments will be implemented in all patients.
Precautions include gentle extubation to avoid laryngotracheal mucosal injury, strict endotracheal tube (EET) fixation to avoid repeated friction between the EET and laryngotracheal mucosa, EET nursing to reduce contamination risk. Any treatments for PES will be applied in accordance with each patient’s condition, including: oxygen therapy with inhaled corticosteroid for mild airway edema, intravenous administration of hydrocortisone (100mg) for moderate airway edema. Non-invasive ventilation or re-intubation will be carried out as clinically indicated if the above treatments are ineffective.
Study endpoints
The primary endpoint is the occurrence of PES within the first 48 hours after extubation. Secondary endpoints include oxygen therapy after extubation, respiratory support requirements, reintubation secondary to PES within 48 hours after extubation , adverse effects (glycemic change, gastrointestinal bleeding or neuropsychiatric events). Clinical assessments will be done at 5, 15, 30, and 60 minutes, and then at 3, 6, 12, 24, 36 and 48 hours after extubation. Hospital length of stay and hospital mortality will also serve as secondary endpoints. (see Figure 2 for study flow chart).
Sample size calculation
We used a Chi-Squared statistical analysis of minimum sample size required to evaluate the effect of corticosteroids on our study outcomes. Cheng[9] showed that either a single or multiple doses of methylprednisolone six hours before extubation reduced the incidence of PES compared to placebo (11.6%/7.1% vs 30.2%,). Cheng[10] later reported that a single dose of methylprednisolone four hours before extubation significantly reduced the incidence of PES from 39.4% to 15.8%. Other studies treating with prophylactic dexamethasone showed that it decreased the incidence of PES from 27.5-30.2% to 8.8-11.5% [11, 12].We therefore anticipate an incidence of PES of 10% in the treatment group and 30% in the placebo group. With an 80% power to detect a difference and a two-sided alpha of 0.05, we anticipate needing 59 subjects in each group. Assuming a drop-out rate of 10%, we calculate a total minimum sample size of 132 subjects.
Randomization and blinding
As female sex has been reported to be an independent risk factor for stridor and extubation failure [5,6, 9,16,17], a gender-stratified block randomization will be performed in a 1:1 ratio. Within each stratum, a random block size of four will be used. After completion of the pre-extubation assessment and obtaining written informed consent, participants will be randomly assigned to either the intervention group or the control group. Staff not assigned to patient therapy or assessment will be responsible for injecting the intervention, thus both patients and therapists involved will be blinded to treatment allocation. All analyses will be performed on an intention-to-treat basis.
Data collection and management
For each participant, anthropometric data (gender, age, body mass index (BMI)) and baseline characteristics such as GCS score, Acute Physiology and Chronic Health II (APACHE II) score, vital signs (blood pressure, heart rate, respiratory rate, blood oxygen saturation and temperature) and arterial blood gases (ABGs) will be recorded as long as the patients are in-hospital. Arterial blood oxygen saturation (SaO2), as well as end tidal carbon dioxide (PETCO2) if available, will be continuously recorded. In order not to cause unnecessary pain to patients, ABGs will be collected when deemed clinically necessary during follow-up, while other baseline characteristics will be recorded at set times.
We will also record incidence of the following for each enrolled patient:
- PES, defined as a presence of an audible high-pitched sound with respiration
- Oxygen therapy after extubation (e.g. nasal catheter, reservoir mask or venturi mask)
- Requiring a respiratory support , as defined by:
- Presence of respiratory acidosis (an arterial pH of less than 7.35 with a partial pressure of arterial carbon dioxide of more than 45mmHg)
- Clinical signs of increased respiratory effort (use of accessory muscles, intercostal retractions, or paradoxical motion of the abdomen)
- Respiratory rate >30 breaths/min for two consecutive hours
- Hypoxemia (SaO2 of <90% with an FiO2 >50%)
- Reintubation secondary to PES
- Adverse effects due to corticosteroids
- Hospital length of stay
- Hospital mortality.
Clinical data will be collected locally via the Research Electronic Data Capture (REDCap) system, an Internet-based electronic case report form (CRF). The research coordinators at each hospital will form a steering committee, which provides training and reviews study processes, to improve adherence to the protocol and resolve problems. In addition, they will regularly audit CRFs and contact responsible medical staff members every three months to ensure data quality and accuracy. All data use will be limited to study analysis only, and no individuals’ personal information will be published. Data confidentiality will be under the supervision of the study coordinators and the Ethics Committee of Peking Union Medical College Hospital.
Statistical methods
The primary endpoint will be analyzed on an intention-to-treat basis, regardless of whether subjects complete their originally allocated treatment study protocol. Any reasons for protocol violations will be recorded and described. All p-values will be two-tailed, and significance will be a p-value <0.05. Data will be presented as frequencies and percentages for categorical variables. Continuous variables will be expressed as means with standard deviations (when normally distributed) or as medians with interquartile ranges (for skewed distribution). Student’s t-test (normal distribution) or Mann-Whitney U test (skewed distribution) will be used for group comparisons. Categorical variables will be compared using Pearson’s chi-squared test or Fisher’s exact test as appropriate. Statistical uncertainty will be expressed in terms of a relative risk and 95% confidence intervals.