Trial design and setting
This is an investigator-initiated, multicenter, parallel-group, non-inferiority, randomized controlled trial that will include 232 participants from 6 large tertiary hospitals in China. The 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 & Peking Union Medical College in Beijing have also approved the trial protocol. The schedule of enrollment, intervention data collection and assessment follows the Standardized Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines and checklist is presented in Fig. 1 (also see Additional File 1 for more detail).
Study Population
Previous studies have found several risk factors for post-extubation stridor and extubation failure, including: female sex, intubation duration > 36 hours, age ≥ 80 years, short stature, intubation with a larger internal diameter sized-tube (males > 8 mm, females > 7 mm), ETT to laryngeal size ratio (> 45%), patients intubated after traumatic injury, GCS score < 8, a higher APACHE II score, an asthma history, presence of a nasogastric tube, and excessive tube mobility due to insufficient fixation[4, 8, 15, 24, 31–34]. Epstein[33] believed that the focus of using steroids should continue be on patients at greater risk, so our study population will be restricted to patients with at least one of the above risk factors for developing stridor. Some studies recommended a cuff-leak test (CLT) as an efficient way of identifying patients with the highest risks, with a threshold volume less than 110 ml-130 ml or 12% of inspiratory VTs[6, 11, 17]. The sensitivity and specificity of the CLT is suboptimal[6, 7, 10, 11], as the volume amount is also influenced by other factors such as inspiratory flow rates, and system compliance or resistance[7]. In addition, CLT may even lead to unnecessary prolongation of intubation time[33]. Therefore, we will not use CLT in our inclusion criteria.
The inclusion criteria and exclusion criteria are as follows.
Inclusion criteria
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Age ≥ 18 years old
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Patients receiving mechanical ventilation for at least 24 hours
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Patients with confirmed consent
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Patients undergoing extubation from mechanical ventilation within the next 12 hours
- 18.5 ≤ BMI༜27
*6. Age ≥ 80 years old
*7. Patients receiving mechanical ventilation for at least 36 hours
*8. Patients intubated with a larger tube (male > 8 mm, female > 7 mm)
*9. Patients intubated after traumatic injury
*10. Patients with a medical history of asthma
*11. Patients with a GCS < 8 or a higher APACHE II score
Note
Patients should meet all items of 1–5 and at least one items of *6–11.
Exclusion criteria
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1. Patients with a prior history of laryngotracheal disease, surgery or tracheostomy
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2. Pregnant or breastfeeding patients
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3. Patients with a history of post-extubation UAO
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4. Unplanned or self-extubation, where immediate reintubation is deemed necessary
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5. Patients chronically using anti-inflammatory drugs or corticosteroids
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6. Patients has been treated with corticosteroids within a week prior to extubation
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7. Patients being extubated for comfort measures or family request
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8. Patients or family refusing extubation
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9. Patients with vocal cord dysfunction
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10. Patients in deep sedation (RASS score≤-4)
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11. Patients suffered gastrointestinal hemorrhage within 3 months
There will be a research coordinator at each hospital to promote and monitor the trial. Patients and their guardians will be informed of the purpose, procedures, potential risks and benefits of the study. The participants’ written consent will be obtained. Participants will be allowed to withdraw from the trial at any time without consequence.
Treatment Arms And Co-interventions
Once the registered patients meet the extubation standards (Table 1), they will be allocated to either the corticosteroid group or the placebo group, and the planned extubation will be implemented within 12 hours after allocation. Patients from the corticosteroid group and placebo group will be treated with an intravenous injection of methylprednisolone 40 mg or an equivalent volume of isotonic saline (placebo), respectively, four hours prior to the planned extubation.
Table 1
Successfully complete a spontaneous breathing trial (SBT)
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* No or mild amount of endotracheal secretions (last suctioning > 2.5 hours prior)
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* Cough strength (grades 3–5)[21]
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* Cough peak expiratory flow (PCEF) > 35 L/min[26]
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* Positive white card test (WCT) result[21]
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Patients ready for extubation should meet the first item (SBT) along with at least one *item. |
General treatment measures include precautions and countermeasures to increase the UAO risk and guarantee the safety of all patients as could as possible. The precautions include gentle extubation to avoid laryngotracheal mucosal injury; strict EET fixation to avoid repeated friction between EET and laryngotracheal mucosal; emphasizing EET disinfection to reduce contamination rick. The countermeasures to UAO are applied in accordance to the patient’s condition, including oxygen therapy with corticosteroid inhalation for mild airway edema; same as mild with intravenous infusion of hydrocortisone 100 mg for moderate airway edema; NIV implementation and re-intubation assessment will be carried out when the above treatments are invalid. |
Study Endpoints
The primary endpoint is the occurrence of laryngeal stridor within the first 48 hours after extubation. Secondary end-points include: the need for respiratory support (both invasive and non-invasive ventilation, NIV) and reintubation secondary to post-extubation stridor within 48 hours after extubation, 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. Any side-effects, hospital length of stay and 30-day mortality will also serve as secondary endpoints.
Sample Size Calculation
We reviewed the international critical care literature concerning the incidence of post-extubation stridor and extubation failure. We sought to estimate using a Chi-Squared statistical analysis the minimum sample size required to evaluate the effect of corticosteroids on our study outcomes. François[8] in 2007 performed a randomized double-blind single-center trial of methylprednisolone 12 hours prior to extubation in 698 patients (343 placebo, 355 steroid). They found methylprednisolone significantly reduced the incidence of post-extubation laryngeal edema from 22–3%, reduced reintubations from 8–4% and the proportion of reintubations secondary to edema from 54–8%. Cheng[15] found in 2006 that both single- and four-dose regimens of methylprednisolone reduced rates of post-extubation stridor compared to placebo (11.6% vs. 7.1% vs. 30.2%, respectively). Lee, Peng and Wu[25] in 2007 reported decreased post-extubation stridor of 10% vs. 27.5% after dexamethasone was given 24 hours prior to extubation.
We therefore anticipate a post-extubation stridor rate of 10% in the treatment group and 25% in the control group. With an 80% power to detect a difference and an alpha of 0.05(two-sided), we anticipate requiring 97 subjects in each group. Assuming a drop-out rate of 20%, this gives a total minimum sample size of 232 subjects.
Randomization And Blinding
As female sex has been reported to be an independent risk factor for stridor and extubation failure[4, 8, 15], a gender-stratified block randomization will be performed. Within each stratum, a random block size of 4 will be used. After completion of the pre-extubation assessment and written informed consent is obtained, participants will be randomly assigned to either the intervention group or control group. Patients and medical staff involved will both be blinded to treatment allocation. All analyses will be performed in an un-blinded fashion.
Data Collection And Management
For each participant, anthropometric data (gender, age, body mass index) and baseline characteristics such as GCS score, 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. Blood oxygen saturation (SaO2), as well as end tidal carbon dioxide tension (PETCO2) if available, will be in continuous record. In order not to cause unnecessary pain to patients, ABGs will be collected only for necessity during the follow-up operation, while the baseline characteristics will be recorded at set times.
We will also record rates of the following for each enrolled patient:
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laryngeal stridor
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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 45 mmHg)
clinical signs of increased respiratory effort (use of accessory muscles, intercostal retractions, or paradoxical motion of the abdomen)
respiratory rate > 30 breath/min for two consecutive hours
hypoxemia (an arterial oxygen saturation of < 90% with an FiO2 > 50%)
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reintubations, noting which are secondary to post-extubation stridor
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reported side-effects due to corticosteroids
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hospital length of stay
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30-day 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 process, to improve adherence to the protocol and resolve problems. In addition, they will regularly check CRFs and contact responsible medical staff members every 3 months to ensure data quality and accuracy.
Statistical Methods
The primary endpoint will be analyzed on an intention-to-treat basis, regardless of whether they complete the originally allocated treatment study protocol. Any reasons for protocol violations will be recorded and described. All p-values are two-tailed, and the significance level 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 and standard deviations (normal distribution) or median with interquartile range (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.