Efficacy of prophylactic methylprednisolone on reducing the risk of post-extubation stridor in patients after an emergency intubation: study protocol for a randomized controlled trial

Background Post-extubation stridor (PES) is one of the most common complications of invasive respiratory support, with severe cases leading to possible extubation failure (reintubation within 48 h) and increased mortality. Previous studies confirmed that prophylactic corticosteroids play an important role in reducing the risk of PES and extubation failure. However, few studies have looked at the efficacy of corticosteroids on preventing PES in patients after an emergency intubation. Aim To evaluate whether a single dose of methylprednisolone given over a set timeframe before extubation is effective in preventing PES in patients after an emergency intubation. Methods A multicenter, randomized, placebo-controlled trial will be performed in an emergency department (ED) setting. The trial will include 132 patients who fail a cuff-leak test (CLT) prior to the intervention. Patients will be randomly assigned to either intravenous methylprednisolone (40 mg) or placebo 4 h prior to extubation. Other eligible patients who pass the CLT will be included in a non-intervention (observation) group. The primary endpoint is the incidence of PES within 48 h after extubation. Secondary endpoints include oxygen therapy, respiratory support requirements, reintubation secondary to PES, adverse effects within 48 h after extubation, hospital length of stay, and hospital mortality. Discussion Patients who are intubated on an emergency basis have a higher risk of intubation-related complications. Previous studies have examined treatment regimens involving more than 10 different variations on corticosteroid treatments for PES prevention, while for ED therapy, only a simple and effective treatment would be appropriate. Corticosteroid administration is usually accompanied by adverse effects; thus, this study will be important for further risk stratification among intubated ED patients. Trial registration Chictr.org.cn ChiCTR2000030349. Registered on 29 February 2020. Supplementary Information The online version contains supplementary material available at 10.1186/s13063-020-04994-9.

Methods: A multicenter, randomized, placebo-controlled trial will be performed in an 33 emergency department (ED) setting. The trial will include 132 patients who fail a 34 cuff-leak test (CLT) prior to the intervention. Patients will be randomly assigned to 35 either intravenous methylprednisolone (40mg) or placebo four hours prior to 36 extubation. Other eligible patients who pass the CLT will be included in a    We conceived the present protocol in order to evaluate whether a single dose of 100 methylprednisolone given over a set timeframe before extubation is effective in 101 reducing the incidence of PES in patients who had been intubated on an emergency 102 basis and were approaching extubation. We hope to answer this question through a 103 multicenter, double-blind, randomized controlled trial. This is an investigator-initiated, multicenter, superiority, randomized controlled trial 108 that will include 132 participants in intervention arm. Six large tertiary hospitals in 109 China will be involved in this trial. This study was prospectively registered with   Since most participants in our study will have no capacity to make decisions, written 123 informed consent will be acquired from each patient's next of kin prior to inclusion.

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Patients or their next of kin will be informed of the purpose, procedures, potential 125 risks, and benefits of the study. Participants will be allowed to withdraw from the trial 126 at any time without consequence.

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Patients will be excluded if they meet at least one of the following criteria: pregnant 128 or breastfeeding, chronically treated with corticosteroids or other anti-inflammatory 129 drugs, extubated for patient comfort or on family request, unplanned or There will be a research coordinator at each hospital to promote and monitor the trial.

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Intervention, control and observation groups 135 Once eligible patients successfully pass a spontaneous breathing trial (SBT), a CLT 136 will be performed to evaluate their risk for developing PES. Patients who had a 137 cuff-leak volume(CLV) less than 24% of vital volume will be included in the 138 intervention arm, where they will be randomly allocated to either the corticosteroid 139 group or the placebo group. The planned extubation will be implemented within six 140 hours after allocation. Patients in the corticosteroid group and placebo group will be 141 treated with an intravenous injection of methylprednisolone 40mg (corticosteroid) or 142 an equivalent volume of isotonic saline (placebo) four hours prior to extubation.

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Patients with a CLV >24% of tidal volume will serve as a control group, where 144 extubation will be performed within two hours after CLT completion.

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All other standard precautions or treatments will be implemented in all patients.

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Precautions include gentle extubation to avoid laryngotracheal mucosal injury, strict 147 endotracheal tube (EET) fixation to avoid repeated friction between the EET and 148 laryngotracheal mucosa, EET nursing to reduce contamination risk. Any treatments 149 for PES will be applied in accordance with each patient's condition, including:   Sample size calculation 163 We used a Chi-Squared statistical analysis of minimum sample size required to 164 evaluate the effect of corticosteroids on our study outcomes. Cheng[9] showed that 165 either a single or multiple doses of methylprednisolone six hours before extubation 166 reduced the incidence of PES compared to placebo (11.6%/7.1% vs 30.2%,). As female sex has been reported to be an independent risk factor for stridor and 177 extubation failure [5,6, 9,16,17], a gender-stratified block randomization will be 178 performed in a 1:1 ratio. Within each stratum, a random block size of four will be 179 used. After completion of the pre-extubation assessment and obtaining written 180 informed consent, participants will be randomly assigned to either the intervention 181 group or the control group. Staff not assigned to patient therapy or assessment will be 182 responsible for injecting the intervention, thus both patients and therapists involved 183 will be blinded to treatment allocation. All analyses will be performed on an 184 intention-to-treat basis. 186 For each participant, anthropometric data (gender, age, body mass index (BMI)) and 187 baseline characteristics such as GCS score, Acute Physiology and Chronic Health II 188 (APACHE II) score, vital signs (blood pressure, heart rate, respiratory rate, blood 189 oxygen saturation and temperature) and arterial blood gases (ABGs) will be recorded 190 as long as the patients are in-hospital. Arterial blood oxygen saturation (SaO 2 ), as well 191 as end tidal carbon dioxide (PETCO 2 ) if available, will be continuously recorded. In 192 order not to cause unnecessary pain to patients, ABGs will be collected when deemed 193 clinically necessary during follow-up, while other baseline characteristics will be 194 recorded at set times. 195 We will also record incidence of the following for each enrolled patient: problems. In addition, they will regularly audit CRFs and contact responsible medical 215 staff members every three months to ensure data quality and accuracy. All data use 216 will be limited to study analysis only, and no individuals' personal information will be  The primary endpoint will be analyzed on an intention-to-treat basis, regardless of 221 whether subjects complete their originally allocated treatment study protocol. Any 222 reasons for protocol violations will be recorded and described. All p-values will be 223 two-tailed, and significance will be a p-value <0.05. Data will be presented as 224 frequencies and percentages for categorical variables. Continuous variables will be 225 expressed as means with standard deviations (when normally distributed) or as 226 medians with interquartile ranges (for skewed distribution). Student's t-test (normal 227 distribution) or Mann-Whitney U test (skewed distribution) will be used for group 228 comparisons. Categorical variables will be compared using Pearson's chi-squared test 229 or Fisher's exact test as appropriate. Statistical uncertainty will be expressed in terms 230 of a relative risk and 95% confidence intervals. Although several studies found a multiple dose 248 strategy may be more efficient than a single dose strategy [1,17,22,23], this is not 249 optimal for ED use due to relative complexity over a single-dose. In addition, a 250 multiple dose strategy requires a longer pre-extubation period, which may cause 251 unnecessary delays and increase the risk of complications in the ED setting.   Recruitment is expected to be finished within 10 months.