Efficacy of Nebulised Hypertonic Saline (3%) Among Children With Bronchiolitis.
Condition: Bronchiolitis
MeSH terms: Bronchiolitis
Study type: Interventional
Phase: Phase 4

Summary: 
      To assess the efficacy of nebulized 3% hypertonic saline in improving clinical severity
      scores among children aged 6 weeks to 24 months with bronchiolitis.
    

Detailed description: 
      Introduction and Rationale:

      Bronchiolitis is a common problem with significant morbidity, and occasional mortality among
      young infants. Diagnostic testing, indications for hospitalization, eligibility criteria for
      discharge and therefore, the length of hospital stay for bronchiolitis vary globally,
      suggesting a lack of consensus and an opportunity to improve care for this common disorder.
      Likewise, despite the frequency of this condition there is no single, widely practiced,
      evidence-driven and universally accepted therapeutic guidelines other than supportive care.
      Recent studies have shown promising results regarding the role of nebulised 3% hypertonic
      saline in the treatment of bronchiolitis.

      This therapy might obviate the need for hospital admission and reduce the length of hospital
      stay, if found effective. The implications of this would be that children return home early
      and parents return to work earlier, resulting in reduction of the morbidity and cost
      associated with the disease.

      Trial Design This study was a prospective, interventional, parallel-assigned, double-blind,
      (subject,caregiver, investigator, outcome assessor) randomized controlled trial.

      Ethical Clearance The study was approved by Institutional Review Board and Ethics Committee,
      Tribhuvan University Teaching Hospital, Institute of Medicine as well as The Institutional
      Review Board of Kanti Children's Hospital.

      Study Participants Subjects were recruited from previously healthy children aged 6 weeks to
      24 months visiting the Emergency Room and Out-Patient Department of Kanti Children Hospital
      with first episode of bronchiolitis.

      Bronchiolitis was clinically defined as per the AAP consensus guidelines as the first episode
      of acute wheezing in children less than two years of age, starting as a viral upper
      respiratory infection (coryza, cough or fever).

      Study setting The study was carried out in the Emergency Room, Observation and Out-Patient
      Department of Kanti Children Hospital, Kathmandu, Nepal. Recruitment occurred at the peak of
      bronchiolitis season in between January 15th to April 15th for duration of 4 months.

      Interventions Patient enrollment occurred on weekdays (Sunday to Friday) between
      approximately 08.00 and 17.00 hr when, after the initial assessment, the attending
      pediatrician (non-study physician) called the investigator. The investigator assessed the
      children for eligibility, examined the children and assigned a clinical severity score
      described by Wang et al.

      Children meeting inclusion criteria were invited to participate in the study and written
      informed consent was obtained from a parent or guardian.

      General condition, weight, temperature, respiratory rate, heart rate, SpO2 and
      presence/absence of clinical dehydration were assessed in all patients and Clinical Severity
      score was calculated as described by Wang et al. Patients determined to be in life
      threatening condition were immediately managed for same and were not further considered for
      study.

      Preparation of study drugs was done by a faculty appointed by the Department of Child Health
      and administration was done by an ER/OPD nurse or the investigator, and compliance with
      medication administration was assured by the investigator's direct observation of each
      nebulization.

      All eligible patients were randomly assigned to one of the two groups:

        1. Group 1 (n = 50) received inhalation of L-Epinephrine 1.5 mg, diluted to 4ml with 3%
           Hypertonic Saline (HS) solution;

        2. Group 2 (n=50) received inhalation of L-Epinephrine, 1.5 mg, diluted to 4ml with 0.9%
           Normal Saline solution.

      The study drug was administered at 0 and 30 min by jet nebulizers using a face mask. Prior to
      each drug administration and at 30, 60 and 120 min, the investigator assessed the children's
      general condition and recorded the CS score, SpO2 in room air, respiratory rate 60 and heart
      rate. All patients received the first dose of nebulization within 15- 30 minutes depending
      upon the time required for preparation and enrollment.

      Adverse events were defined as heart rate >200, tremor, withdrawal from the study due to
      worsening clinical status, or discontinuation of any study medications due to side effects.

      Patients were excluded from the study if the administration of the 2 courses of nebulisation
      was not delivered, the study drug was delayed by 10 min or more (protocol deviation) or if
      clinical deterioration mandated escalation of therapy and/or support.

      At the end of the observation period, the attending pediatrician determined the need for
      hospital admission.

      The parents of the patients enrolled in the study were asked to follow up after 24 hours in
      the OPD for repeat assessment. If the parents were not available for follow up, the
      investigator contacted the parents or guardians via telephone 24 hours after their ED/OPD
      discharge to determine the need for any unscheduled hospital visit within the next 24 hours
      of OPD/ ER visit: their readmission (relapse) rate.In addition, they were reassessed at the
      end of 1 week by telephone contact . A single investigator participated in the measurement of
      observations to minimize inter observer variability. All calls were made from the Hospital
      reception Office at appropriate times 10:00a.m. - 14:00p.m NST. Patient were labeled as
      Lost-to-Follow up if there was failure to communicate for 3 consecutive attempts for 2
      consecutive days at their 7th and 8th day of initial presentation to the OPD/ER.

      Sample Size Estimation:

      Sample size was determined by the following formula :

        -  n = [(z1 +z2)² (Ó1² + Ó2²) ] / (û1 - û2)²

        -  Allowing a Type1 error of 5% (α :0.05), z1 score : 1.96.

        -  For a Power of 95%, z2=1.64.

        -  Standard deviation of the Clinical Severity Score : 1.3

        -  Mean Change in Clinical Severity Score between the two interventions to consider
           clinically significant : Change in Clinical Severity Score of 1

        -  The study proposed that a difference of 1 point in the Clinical Severity Score between
           the two intervention groups would be considered Clinically Significant.

        -  To detect this mean difference of 1 unit in the Clinical severity score, with a Power of
           95%, a Sample size of 44 in each intervention group were required.This made a total of
           88 patients to be enrolled in the study.Considering the drop out/ lost to follow up to
           be approximately 10%, 100 patients were enrolled, allowing 50 in each group.

        -  Standard deviation of the Change in clinical severity score was derived from previous
           studies and taken as 1.3 .

      Randomization

        1. Sequence Generation A Random Allocation Software generated by computer, identified
           patients by a triple digit mixed numeric code was used by the study coordinator to
           allocate patients to treatment groups, and the study coordinator was the only person
           with access to the randomization.

        2. Type of Randomization Block Randomization method was used to stratify patients into
           blocks of 10 each, each comprising of 10 patients.

      Allocation Concealment After preparation, the study solutions were labeled with the codes and
      wrapped in an envelope with the respective codes and attached with the proforma bearing the
      respective codes.Study solutions were identical in appearance and odor. The identity of the
      study solutions was blinded to all participants, care providers, and investigators and
      outcome assessor.

      Implementation The randomization process was done by the study coordinator (not involved in
      the study) and he was the only person to have access to the codes.

      The study solutions were stored in the non-freezer compartment of the refrigerator at a
      temperature of 2-8*C and were discarded if not used within 72 hours of preparation.

      Blinding The study was a Double Blind Randomized Controlled Trial with the investigator, the
      participants, the nurses who delivered the drug, and the outcome assessor being blinded to
      the therapeutic option.

      Statistical Methods The primary outcome was to detect the difference in mean change in
      Clinical Severity score between the two intervention groups. A power analysis revealed that,
      for detection of the difference of 1 unit in CS score between the 2 treatment groups, with α
      of 0.05 and power of 95%, we required 88 patients (44 per group).

      A sample size of 100 patients was therefore chosen, with 50 patients in each group
      considering the possibility of loss to follow up.

      Statistical analysis was performed using SPSS for Windows, Release 16.0 (SPSS Inc., Chicago,
      IL). Dichotomous events were analyzed by using the Chi-Square test.Dependent variables were
      compared by Student t-test. Statistical significance was defined as p-value < 0.05.
    

Intervention name(s): L-Epinephrine and Normal Saline (0.9%); L-Epinephrine and Hypertonic Saline (3%)
Intervention type(s): Drug; Drug
Intervention description(s): 1.5ml of 1:1,000 L-Epinephrine and 4 ml of 0.9% Normal Saline; 1.5ml of 1:1,000 L-Epinephrine and 4 ml of 3% Hypertonic Saline
Other intervention name(s): Nebulised Epinephrine in 0.9% Normal saline; Nebulised Epinephrine in 3% Hypertonic Saline
Intervention MeSH terms: Epinephrine; Racepinephrine; Epinephryl borate
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Bronchiolitis; L-Epinephrine; 3% Hypertonic Saline; Clinical Severity Score