Aerosolized L-epinephrine vs Budesonide for Post-extubation Stridor: A Randomized Controlled Trial

Received: August 8, 2008;
 Initial review: August 29, 2008;
Accepted: April 24, 2009.
 Published online: 2009 September 3.

PII:S097475590800491-1
 

Objective: To compare the efficacy and adverse effects of aerosolized L-epinephrine vs budesonide in the treatment of post-extubation stridor.

Study design: Randomized controlled trial.

Setting: Pediatric intensive care unit (PICU) of a tertiary teaching and referral hospital.

Subjects: Sixty two patients with a stridor score ³4 following extubation.

Intervention: Patients were randomized to receive either aerosolized L-epinephrine (n=32) or budesonide (n =30). Respiratory rate, heart rate, stridor score, blood pressure and oxygen saturation were recorded from 0 min to 24 hours.

Outcome measures: Stridor score remaining at ³4, need for re-nebulization and re-intubation between 20 min –24 hours were primary outcome measures. Tachycardia (HR > normal for age), hypertension (BP >95th centile for age) and hypoxia (SpO2 <92% for 5 min) were secondary outcome measures.

Results: Both drugs showed a significant and comparable decline in the median (95% CI) stridor scores from baseline to 60 min [4 (4.10-4.50) to 2.00 (1.46-2.67) for budesonide vs 4 (4.12-5.00) to 2.00 (1.31 -2.75) for epinephrine]. At 2 hours, the stridor scores were significantly lower in the epinephrine as compared to budesonide group [0.00 (0.69-1.81) vs 3.00(1.75-3.32); P =0.02)]. However, the proportion of patients with stridor score ³4 at any time between 20min-24 hrs (53.3% vs 53.1%; P=0.99), need for renebulization (40 % vs 43.8 %; P=0.76) and re-intubation (20% vs 25%, P=0.638), and adverse effects were similar in both groups.

Conclusions: Both aerosolized L-epinephrine and budesonide were equally effective in their initial therapeutic response in post-extubation stridor. However, epinephrine showed a more sustained effect.

Key words: Budesonide, Epinephrine, Extubation, Stridor.

The most serious and immediate complication of extubation in young children is laryngeal edema; the incidence of post extubation stridor in the Pediatric intensive care unit (PICU) is described to be between 2-25%(1-5). Aerosolized epinephrine has been found to be an effective therapy in both infective and postextubation stridor(6,7). The action of epinephrine, however, is transient and there is a potential risk of rebound laryngeal edema, which may limit the repeated use of this drug(7). Treatment with steroids provides a sustained effect due to their anti-inflammatory action. Intravenous dexamethasone was found to be effective in pre-extubation and post- extubation states thus decreasing the risk of post-extubation stridor by around 40%(8). Theoretically, inhaled steroids with a similar mechanism of action as systemic steroids should be more advantageous due to direct delivery at the site of action, lesser dose needed and fewer side effects. Thus, aerosolized budesonide when used in the treatment of croup was found to reduce edema without any side effects(9,10). Trials comparing aerosolized epinephrine and budesonide in the treatment of infective croup have shown similar efficacy and safety of both the drugs(11). However, there are no studies comparing these two drugs in the treatment of post-extubation stridor.

Patients demonstrating hoarseness of voice, barking cough and/or inspiratory stridor with a stridor score ³4 (Table I) after extubation, were enrolled after obtaining a written informed consent from parents or guardians. The demographic details, admission diagnosis, indication for PICU admission, Pediatric risk of mortality (PRISM) III scores, duration of mechanical ventilation and indication, type and duration of intubation were recorded at the time of inclusion.

TABLE I



Stridor Scoring System 

After randomization, Group I(E) received L- epinephrine 1% solution 0.25mL in 2mL normal saline, nebulized over 15-20 min with face mask and 6L/min of oxygen flow. Group II (B) received budesonide 1000µg (2mL) nebulized over 15-20 min with face mask and 6L/min of O₂ flow. Respiratory rate (RR), stridor score, heart rate (HR), blood pressure (BP) and oxygen saturation (SpO₂) were recorded for each patient immediately before aerosol administration (time 0) and at 20, 40 and 60 mins; and at 2, 4, 8, 12 and 24 hours. Stridor score remaining at ³4, need for re-nebulisation, and/or re-intubation at any time between 20 min-24 h were identified as primary outcome variables.

Children in whom the stridor score remained ³4 or worsened after receiving therapy, were re-nebulized with L-epinephrine (conventional protocol). The need for reintubation was decided by the treating physician based on combination of variables i.e. HR, RR, stridor score and SpO₂.

Sample size: Assuming a failure rate of 40% in L-epinephrine group and a desired reduction of failure rate to 10% in the budesonide group, with an a error of 5% and power of 80%, we calculated that approximately 30 subjects would be required in each group.

Statistical analysis: Data are presented as mean±SD, median and percentages wherever applicable. Parametric data were analyzed using the Student’s‘t’ test and non-parametric data with Mann- Whitney U test. Categorical data were analyzed with Chi-sqaure or Fisher’s exact test. Continuous variables measured at different time intervals between the groups were compared using the repeated measures ANOVA. The linear trend in proportion between the groups was analyzed with Chi-square. The statistical packages used in the study were SPSS (version 10.0) and Epi Info 2000 (version 6.0).

Results

Of the 370 patients admitted to the PICU during the study period, 196 (52.9%) were intubated for various reasons. Sixty-two (31.6%) of the intubated patients fulfilled the inclusion criteria and were randomized (Fig.1). Their baseline characteristics are summarized in Table II.

Fig. 1 Study flow chart.

 

TABLE II



Baseline Characteristics of the Study Subjects 

*Student’s ‘t’ test, **Mann Whitney U test, ***Chi Square test.

The median (95% CI) stridor scores from baseline (0min) to 24 hours and corresponding proportion of subjects with stridor score ³4 at different time intervals is depicted in Table III. The proportion of patients with stridor score ³4 at any time between 20min-24 hrs between budesonide and epinephrine group was 53.3% and 53.1%, respectively (P=0.99).

TABLE III



Stridor Score ≥4 at Different Time Intervals 

The trends in RR, HR, systolic and diastolic BP and SpO₂ in both groups were not significantly different when assessed over time. Frequency of sinus tachycardia within 2 hours of aerosolized therapy was similar in both the groups [10 (31.3%) in epinephrine vs 7 (23.3%) in budesonide group]. Transient hypertension was noted in 4 patients (12.5%) in epinephrine as compared to 2 (6.7%) in budesonide group.

The incidence of post-extubation stridor in our patients was 31.6%, similar to that reported previously(12,13). Both aerosolized epinephrine and budesonide were similar with respect to their rapid therapeutic action. Epinephrine, however, showed a statistically significant sustained effect at 2 hours post-nebulization. The proportion of patients with stridor score ³4, need for re-intubation and re-nebulization were similar in both the groups. The frequency of adverse effects in both the groups were also similar.

The rapid onset of action of aerosolized epinephrine and budesonide postulated due to local vasoconstrictor effect mediated by a-adrenergic receptors has been observed by several authors(6,7, 9,11,15). Our findings in the epinephrine group are in concordance with observations of Westley, et al.(7) and Waisman, et al.(15) who had shown a similar change in croup score at 30 min post nebulization lasting for 60-90 min. Rapid response with budesonide observed by us was also similar to the findings of Husby, et al.(9) and Fitzgerald, et al.(11), who reported a significant change in the mean croup scores from baseline to 30 min post-nebulization(9, 11). The trend of response observed by us at 2 hours post nebulization was different in that epinephrine showed a significant and sustained improvement as compared to budesonide. Majority of the published reviews have, however, reported a trend to the contrary – supporting the contention that the response to nebulized epinephrine is rapid and transitory and that to budesonide more sustained(7, 10,16). Klassen, et al.(16) and Godden, et al.(10) found a significant reduction in croup scores at 4 hours and 2 hours with aerosolized budesonide in the treatment of children with croup, thus reiterating the sustained nature of the drug effect. The sustained effect of steroids is attributed to their anti-inflammatory effects, which are usually not apparent until 6 hours after treatment(9). The statistically significant difference in the therapeutic response between epinephrine and budesonide observed by us at 2 hours was possibly not clinically meaningful as the proportion of patients with a stridor score of ³4 in both groups was similar at that point. Additionally, the subsequent rate of re-nebulization and re-intubation was also similar in both the groups. Since there were more patients with raised intracranial pressure in the latter, it is possible that the poor outcomes in the form of worsening stridor scores were related to the effects of raised ICP causing aggravation of airway problems and not to the direct drug effect per se.

17. Fogel JM, Berg IJ, Gerber MA, Sherter CB. Racemic epinephrine in the treatment of croup: nebulization alone versus nebulization with intermittent positive pressure breathing. J Pediatr 1982; 25: 1028-1031.