Efficacy and Safety of Increasing Doses of Inhaled Albuterol in Children With Acute Wheezing Episodes

Efficacy and Safety of Increasing Doses of Inhaled Albuterol Administered by Metered Dose Inhalers in Children With Acute Wheezing Episodes

Metered dose inhalers with spacers are devices capable of providing higher rates of lung deposition of drugs such as beta agonists when compared to conventional nebulizers, but there is no consensus about the optimal dose when this is the device of choice and there is evidence that younger children need proportionally higher doses of albuterol (in μg/kg) when compared to older children. Other factors that may interfere with response to albuterol treatment include the genetics of the beta adrenergic receptor (ADRβ2) and infectious etiology of the wheezing attack. This study will assess the effectiveness of a dose regimen that prioritizes higher doses of albuterol, with doses in μg/kg higher for younger children. Security of this new dosing regimen will be assessed by monitoring clinical side effects and serum levels of albuterol, but the investigators will also examine the presence of 12 different respiratory viruses in these patients and evaluate the influence of ADRβ2 receptor genetics in the response to albuterol. The primary outcome measure will be the need for hospitalization. Secondary outcomes will include a change in clinical score, respiratory rate and forced expiratory volume in the first second, the need for additional treatments and length of stay in the emergency room for those not hospitalized.

Study Overview

• Status: Completed
• Conditions: Asthma; Children
• Intervention / Treatment: Drug: Albuterol - Experimental; Drug: Albuterol - Control

Detailed Description

This is a prospective, randomized, double blinded, controlled study. The patients will be randomly assigned to one of the treatment groups (experimental or control groups).

The patients will be assessed 1 hour later and every 30 minutes thereafter until discharge. Following 4 hours in the emergency room, any patient who do not meet the discharge criteria (PRAM score ≤ 3 and SpO2 ≥ 92%) will be admitted to the hospital. Each patient's attending physician will determine the need for additional therapies following the first hour.

Identification of respiratory viruses in the nasal lavage samples wil be performed using the CLART PneumoVir® kit.

Albuterol plasmatic levels will be analyzed via HPLC (High Performance Liquid Chromatography).

To genotype the ADBR2 receptor (blood samples), the gene regions encompassing the Arg16Gly, Gln27Glu, and Arg19Cys Thr164Ile polymorphisms will be amplified via PCR. The resultant amplimers were then sequenced.

A sample of 124 patients (62 in each group) was calculated to provide an 80% power with which to detect a significant difference of at least 30 minutes in the lengths of stay between the groups. The chi-square test will be used to compare hospital admission rates and tremor rates. For all other outcomes, t-tests for mean comparisons (variables with a normal distribution), a Mann Whitney test (nonparametric data) and ANOVA with repeated measures will be used.

• Study Type: Interventional
• Enrollment (Actual): 119
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Brazil
  • Sao Paulo, Brazil, 05403-010
    • Instituto Da Crianca HCFMUSP

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Aged 2 to 18 years;
2. History of two or more previous episodes of wheezing treated with bronchodilators in the last year;
3. Wheezing attacks characterized by coughing, difficulty breathing and auscultation of expiratory wheezing or prolonged expiration;
4. Intensity of wheezing attacks defined by PRAM score as moderate or severe (PRAM ≥ 5).

Exclusion Criteria:

1. Pre-existing chronic diseases such as bronchopulmonary dysplasia, cystic fibrosis, bronchiolitis obliterans or other chronic pulmonary or cardiovascular disease;
2. Initial clinical status indicating immediate ventilatory support, need for subcutaneous or intravenous bronchodilators;
3. Decreased level of consciousness;
4. Using a β-agonist in the four hours prior to arrival.
5. Use of corticosteroids in the last 24h.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Albuterol - Experimental; Albuterol dosages during the first hour include 900 mcg (up to 15 kg), 1200 mcg (> 15 to 20 kg), 1500 mcg (> 20 to 25 kg) and 1800 mcg (> 25 kg).	Drug: Albuterol - Experimental; The Experimental group will receive higher doses of albuterol in the first hour: 900 mcg (up to 15 kg), 1200 mcg (> 15 to 20 kg), 1500 mcg (> 20 to 25 kg) and 1800 mcg (> 25 kg).; Other Names: Ventolin
Active Comparator: Albuterol - Control; Albuterol dosages during the first hour include either 600 mcg (up to 25 kg) or 1200 mcg (> 25 kg).	Drug: Albuterol - Control; The Control group will receive the following doses of albuterol in the first hour 600 mcg (up to 25 kg) or 1200 mcg (> 25 kg); Other Names: Ventolin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hospital Admission	Hospital admission was defined as the need to stay in the emergency room for more than 4 hours, due to the failure to meet the discharge criteria (PRAM score ≤ 3 and pulse oximetry, ≥ 92%)	Starting at 4 hours post-treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Forced Expiratory Volume in the First Second	Change in FEV1 one hour post-treatment in comparison with baseline. Spirometry was performed only in subjects older than 6 years and who could perform the maneuver properly.	One hour post-treatment in comparison with baseline
Change in PRAM Score After One Hour	Change in the Pediatric Respiratory Assessment Measure (PRAM) score one hour post-treatment in comparison with baseline. The PRAM score is used to assess the severity of asthma attacks, it ranges from 0 to 15, and the higher the score, the greater the severity of the attack. We calculated the difference between the PRAM score measured one hour post treatment and the PRAM score at baseline (PRAM score 1 hour - PRAM score baseline). The larger the absolute value of the difference, the better the outcome (e.g., a difference of -4 indicates a better outcome that a difference of -2). minimum value of the difference (Albuterol - Higher Dose, experimental group): -8 maximum value of the difference (Albuterol - Higher Dose, experimental group): 0 minimum value of the difference (Albuterol - Lower Dose, control group): -8 maximum value of the difference (Albuterol - Lower Dose, control group): 0	One hour post-treatment
Albuterol Determination in the Plasma	Albuterol determination in the plasma was carried out at at discharge or hospital admission (up to 4 hours post treatment), dosage was accomplished by High Performance Liquid Chromatography.	at discharge or admission (up to 4 hours post treatment, minimum 1 hour, maximum 4 hours post treatment)
Changes in Glucose Serum Levels	Changes in glucose serum levels at discharge or hospital admission (up to 4 hours post treatment) in comparison with baseline.	at discharge or admission (up to 4 hours post treatment, minimum 1 hour, maximum 4 hours post treatment) in comparison with baseline.
Electrocardiogram at Baseline	Electrocardiogram performed at baseline	at baseline
Changes in Respiratory Rate After One Hour	Change in respiratory rate one hour post-treatment in comparison with baseline.	One hour post-treatment in comparison with baseline
Need for Additional Therapies	The need for additional therapies such as magnesium sulphate or intravenous albuterol were recorded	at discharge or admission (up to 4 hours post treatment, minimum 1 hour, maximum 4 hours post treatment)
Changes in PRAM Score at Discharge or Hospital Admission	Change in the Pediatric Respiratory Assessment Measure (PRAM) score at discharge or hospital admission (up to 4 hours post treatment) in comparison with baseline. The PRAM score is used to assess the severity of asthma attacks, it ranges from 0 to 15, and the higher the score, the greater the severity of the attack. We calculated the difference between the PRAM score measured at discharge or admission and the PRAM score at baseline (PRAM score discharge or admission - PRAM score baseline). The larger the absolute value of the difference, the better the outcome (e.g., a difference of -4 indicates a better outcome that a difference of -2). minimum value of the difference (Albuterol - Higher Dose, experimental group): -9 maximum value of the difference (Albuterol - Higher Dose, experimental group): 0 minimum value of the difference (Albuterol - Lower Dose, control group): -9 maximum value of the difference (Albuterol - Lower Dose, control group): 1	at discharge or admission (up to 4 hours post treatment, minimum 1 hour, maximum 4 hours post treatment) in comparison with baseline.
Changes in Potassium Serum Levels	Changes in potassium serum levels at discharge or hospital admission (up to 4 hours post treatment) in comparison with baseline.	at discharge or admission (up to 4 hours post treatment, minimum 1 hour, maximum 4 hours post treatment) in comparison with baseline.
Changes in Bicarbonate Serum Levels	Changes in bicarbonate serum levels at discharge or hospital admission (up to 4 hours post treatment) in comparison with baseline.	at discharge or admission (up to 4 hours post treatment, minimum 1 hour, maximum 4 hours post treatment) in comparison with baseline.
Changes in Respiratory Rate at at Discharge or Hospital Admission.	Changes in respiratory rate at discharge or hospital admission (up to 4 hours post treatment) in comparison with baseline.	at discharge or admission (up to 4 hours post treatment, minimum 1 hour, maximum 4 hours post treatment) in comparison with baseline.
Change in Pulse Oximetry One Hour Post-treatment	Change in pulse oximetry one hour post-treatment in comparison with baseline	One hour post-treatment in comparison with baseline
Changes in Pulse Oximetry at Discharge or Hospital Admission.	Changes in pulse oximetry at discharge or hospital admission (up to 4 hours post treatment) in comparison with baseline.	at discharge or admission (up to 4 hours post treatment, minimum 1 hour, maximum 4 hours post treatment) in comparison with baseline.
Changes in Heart Rate After One Hour	Change in heart rate one hour post-treatment in comparison with baseline.	One hour post-treatment in comparison with baseline
Changes in Heart Rate at Discharge or Hospital Admission	Changes in heart rate at discharge or hospital admission (up to 4 hours post treatment) in comparison with baseline.	at discharge or admission (up to 4 hours post treatment, minimum 1 hour, maximum 4 hours post treatment)
Electrocardiogram One Hour Post-treatment.	Electrocardiogram one hour post-treatment to identify possible rhythm disturbances.	One hour post-treatment
Electrocardiogram at Discharge or Hospital Admission	Electrocardiogram at discharge or hospital admission to identify possible rhythm disturbances.	at discharge or admission (up to 4 hours post treatment, minimum 1 hour, maximum 4 hours post treatment)
Lengths of Stay in the Emergency Room	lengths of stay in the emergency room for discharged patients	one to four hours
Admission Rates in Patients With and Without Any Virus Detected	Admission rates in patients with and without any of the following viruses detected by PCR in nasal lavage samples: Adenovirus; Bocavirus; Coronavirus; Enterovirus (Echovirus); Influenza (A H3N2, A H1N1/2009, B and C); Metapneumovirus (subtypes A and B); Parainfluenza 1, 2, 3 and 4 (subtypes A and B); Rhinovirus; Respiratory Syncytial Virus type A and Respiratory Syncytial Virus type B.	at discharge or admission (up to 4 hours post treatment, minimum 1 hour, maximum 4 hours post treatment)
Admission Rates in Patients With and Without Rhinovirus Detect	Admission rates in patients with and without rhinovirus detected by PCR in nasal lavage samples.	at discharge or admission (up to 4 hours post treatment, minimum 1 hour, maximum 4 hours post treatment)
Admission Rates in Patients With the Arg16Gly Polymorphisms	Admission rates in patients with the Arg16Gly polymorphisms of the beta-2 adrenergic receptor (Arg16Gly, Arg16Arg and Gly16Gly genotypes).	at discharge or admission (up to 4 hours post treatment, minimum 1 hour, maximum 4 hours post treatment)

Collaborators and Investigators

• Sponsor: University of Sao Paulo
• Collaborators: Fundação de Amparo à Pesquisa do Estado de São Paulo
• Investigators: Principal Investigator: Luiz Vicente RF Silva Filho, MD, University of Sao Paulo

Publications and helpful links

General Publications

• Muchao FP, Souza AV, Souza JME, Silva Filho LVRFD. Association between beta-2 adrenergic receptor variants and clinical outcomes in children and adolescents with acute asthma. Einstein (Sao Paulo). 2022 Mar 25;20:eAO6412. doi: 10.31744/einstein_journal/2022AO6412. eCollection 2022.
• Muchao FP, Souza JM, Torres HC, De Lalibera IB, de Souza AV, Rodrigues JC, Schvartsman C, da Silva Filho LV. Albuterol via metered-dose inhaler in children: Lower doses are effective, and higher doses are safe. Pediatr Pulmonol. 2016 Nov;51(11):1122-1130. doi: 10.1002/ppul.23469. Epub 2016 May 12.

Study record dates

Study Major Dates

• Study Start: September 1, 2011
• Primary Completion (Actual): December 1, 2013
• Study Completion (Actual): April 1, 2014

Study Registration Dates

• First Submitted: March 24, 2011
• First Submitted That Met QC Criteria: March 24, 2011
• First Posted (Estimate): March 25, 2011

Study Record Updates

• Last Update Posted (Estimate): March 14, 2016
• Last Update Submitted That Met QC Criteria: February 15, 2016
• Last Verified: February 1, 2016

More Information

Terms related to this study

• Keywords: asthma; albuterol; metered dose inhalers
• Additional Relevant MeSH Terms: Signs and Symptoms, Respiratory; Respiratory Sounds; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Adrenergic Agonists; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Reproductive Control Agents; Adrenergic beta-2 Receptor Agonists; Adrenergic beta-Agonists; Tocolytic Agents; Albuterol
• Other Study ID Numbers: Hidalba