Is there any data supporting the safety and efficacy of continuous infusion terbutaline for pediatric status asthmatics?

Is there any data supporting the safety and efficacy of continuous infusion terbutaline for pediatric status asthmatics?

Comment by InpharmD Researcher

Limited data supports the safety and efficacy of continuous infusion terbutaline for pediatric status asthmaticus. While terbutaline has been investigated for this use, studies have not demonstrated statistically significant outcome measures, though a trend toward improvement was observed in some studies. Further research is needed to determine the safety and efficacy of intravenous terbutaline for acute severe asthma in children before recommending its routine use.

Background

Terbutaline is a β2-selective agonist that has been investigated for use in the management of status asthmaticus. The oral form of terbutaline is not commonly used due to its slow onset of action and potential for more adverse effects. The subcutaneous route can be advantageous in patients with limited airflow and no intravenous (IV) access. The typical subcutaneous dose is 0.1 mg/kg with a maximum of 0.3 mg, which can be repeated every 15-20 minutes for up to 3 doses if needed. [1, 2]

For IV administration, terbutaline is typically given as a loading dose of 10 mcg/kg, followed by a continuous infusion starting at 0.1-0.5 mcg/kg/min and titrated up based on clinical response and adverse effects. Potential side effects of terbutaline include tremors, skeletal muscle twitches, hypokalemia, tachycardia, hypotension (particularly diastolic), and, very rarely, ventricular tachyarrhythmias. However, IV terbutaline has not been found to be more effective than other agents like methylxanthines or aminophylline. Continuous monitoring of telemetry is recommended for patients receiving IV terbutaline. [1, 2]

A 2022 retrospective cohort study aimed to determine if adding a single dose of parenteral terbutaline to the asthma protocol resulted in fewer pediatric intensive care unit (PICU) admissions. Patients aged 2 to 18 years with a diagnosis of severe asthma exacerbation, defined by an initial Respiratory Clinical Score (RCS) of 9 or higher, were included in the analysis. The results showed that patients who received terbutaline had an increased risk of admission to the PICU (p<0.001), but the association was lost after controlling for age, sex, continuous albuterol use, and intramuscular epinephrine use. Additionally, patients receiving terbutaline in the emergency department had a higher risk of admission to the hospital (odds ratio [OR] 1.55; 95% CI 1.08 to 2.22; p= 0.020). Overall, the study found that terbutaline administration was not associated with decreased PICU or general hospital floor admission in pediatric patients experiencing severe asthma exacerbations. [3]

Literature Review

A search of the published medical literature revealed 3 studies investigating the researchable question:

Is there any data supporting the safety and efficacy of continuous infusion terbutaline for pediatric status asthmatics?

Level of evidence

C - Multiple studies with limitations or conflicting results Read more→

Please see Tables 1-3 for your response.

Comparison of Intravenous Terbutaline Versus Normal Saline in Pediatric Patients on Continuous High-Dose Nebulized Albuterol for Status Asthmaticus
Design	Prospective, randomized, double-blind, placebo-controlled trial N= 49
Objective	To determine if the addition of intravenous terbutaline provides any clinical benefit to children with acute severe asthma already on continuous high-dose nebulized albuterol
Study Groups	Treatment (n= 25) Placebo (n= 21)
Inclusion Criteria	Children aged 2-17 years with moderate to severe asthma exacerbation, failed to improve after at least 3 consecutive nebulized albuterol/ipratropium bromide treatments, and required ICU admission.
Exclusion Criteria	Known allergy to terbutaline, history of cardiac dysrhythmia, intubation before initial therapy, pregnancy, previous enrollment, transfer due to lack of PICU bed, fixed obstructive cardiopulmonary lesions.
Methods	Patients received continuous nebulized albuterol, ipratropium bromide, systemic corticosteroids, and were randomized to receive either intravenous terbutaline or normal saline. Outcome measures included clinical asthma severity score, hours on continuous nebulized albuterol, and PICU stay duration. The doses were as followed: Continuous nebulized albuterol at a weight-based dose of 10 mg/h for children <20 kg, 15 mg/h for children 20-40 kg, and 20 mg/h for children >40 kg, with the dose allowed to be increased up to 20 mg/h for children <40 kg. Nebulized ipratropium bromide at 250 mg every 6 hours for children ≤10 kg, and 500 mg every 6 hours for children ≥11 kg. Methylprednisolone 2 mg/kg loading dose followed by 1 mg/kg every 6 hours. IV terbutaline given as a 10 μg/kg per minute loading dose over 10-20 minutes, followed by a 1 μg/kg per minute continuous infusion, which could be increased to 2 μg/kg per minute and then up to 4 μg/kg per minute if needed.
Duration	24 hours of treatment and monitoring.
Outcome Measures	Primary: Clinical asthma severity score (CASS; subjective method of determining level of asthma severity and change in condition) Secondary: Hours on continuous nebulized albuterol, duration of PICU stay
Baseline Characteristics		Treatment (n= 25)	Placebo (n= 21)
	Age, years	7.6	7.8
	Female	36%	43%
	Race/ethnicity White Hispanic African American	16% 28% 56%	10% 19% 71%
	Historical asthma severity Mild Moderate Severe	32% 60% 8%	62% 29% 10%
Results	Endpoint	Treatment (n= 25)	Placebo (n= 21)	p-Value
	Mean improvement in CASS	6.5	4.8	0.073
	Hours on continuous nebulized albuterol	38.19	51.93	-
	PICU length of stay	43.9	56.85	-
Adverse Events	One patient in the terbutaline group experienced a significant cardiac dysrhythmia. Elevated troponin I values were noted in 6 patients in the terbutaline group. Hypotension was documented in 17 patients, chest pain in 1 patient in the terbutaline group.
Study Author Conclusions	No outcome measures demonstrated statistical significance. Outcome measures revealed a trend toward improvement in the terbutaline group. Before recommending routine use of intravenous terbutaline for acute severe asthma, further study to determine safety and efficacy is necessary
InpharmD Researcher Critique	The study was well-designed as a double-blind, placebo-controlled trial, but the small sample size limits the power to detect significant differences. The lack of objective pulmonary function measurements is a limitation. Variability in pre-enrollment treatments and incomplete data collection also pose challenges.

References:

Bogie AL, Towne D, Luckett PM, Abramo TJ, Wiebe RA. Comparison of intravenous terbutaline versus normal saline in pediatric patients on continuous high-dose nebulized albuterol for status asthmaticus. Pediatr Emerg Care. 2007;23(6):355-361. doi:10.1097/01.pec.0000278397.63246.33

Safety of Terbutaline for Treatment of Acute Severe Pediatric Asthma
Design	Retrospective study N= 124
Objective	To provide a descriptive report on the largest cohort of severe pediatric asthma patients treated with terbutaline
Study Groups	0-6 years (n= 59) 7-12 years (n= 47) 13-18 years (n= 18)
Inclusion Criteria	Pediatric patients (8 months to 18 years old) admitted with the diagnosis of acute severe asthma, did not respond to initial therapy with albuterol, atrovent nebulizers, IV steroids, and IV magnesium
Exclusion Criteria	Patients with pneumonia, acute respiratory distress syndrome, cardiac conditions, or renal conditions with respiratory distress
Methods	Pediatric patients received IV terbutaline during treatment for acute severe asthma in a pediatric intensive care unit (PICU). Patients received a bolus of IV terbutaline at a dose of 4-6 μg/kg followed by an infusion starting at 0.4 μg/kg per minute and titrated up to a maximum of 3 μg/kg per minute. Other medications used included ipratropium bromide nebulization, methylprednisolone, and magnesium sulfate. Patients were divided into 3 age groups (0-6 years, 7-12 years, 13-18 years) for analysis.
Duration	Data collection: January 2007 to January 2012
Outcome Measures	Systolic and diastolic blood pressure changes up to 1 hour after discontinuation, heart rate changes,
Baseline Characteristics		0-6 years (n= 59)	7-12 years (n= 47)	13-18 years (n= 18)
	Female	22	19	3
	Race Black White Hispanic Asian	31 17 6 5	26 8 8 5	9 6 1 2
Results	Endpoint	0-6 years (n= 59)	7-12 years (n= 47)	13-18 years (n= 18)
	Systolic blood pressure, mmHg Baseline 1 hour 4 hours 1 hour after discontinuation	111.43 101.70 95.23 103.39	112.96 104.42 104.11 112.22	123.57 111.41 108.52 115.02
	Diastolic blood pressure, mmHg Baseline 1 hour 4 hours 1 hour after discontinuation	64.4 47.71 49.9 60.8	64.21 48.77 53.77 65.87	65.45 45.19 56.56 71.07
	Heart rate, BPM Baseline 1 hour 4 hours 1 hour after discontinuation	149.68 164.03 156.18 123.85	135.93 15451 141.24 108.18	130.10 146.23 133.71 93.27
Adverse Events	All patients developed sinus tachycardia compared to baseline after initiation of the drip. No patient developed seizure while on terbutaline infusion.
Study Author Conclusions	Terbutaline infusion is a safe treatment option for children with severe asthma requiring escalation of bronchodilator therapy. Although it is associated with the development of decreased blood pressure and increased HR as well as decreased levels of serum potassium, hemodynamic support or electrolyte replacement is infrequently required.
InpharmD Researcher Critique	The study was retrospective and conducted within a single center, limiting the generalizability of the results to other settings and populations.

References:

Doymaz S, Schneider J. Safety of Terbutaline for Treatment of Acute Severe Pediatric Asthma. Pediatr Emerg Care. 2018;34(5):299-302. doi:10.1097/PEC.0000000000000677

Early administration of terbutaline in severe pediatric asthma may reduce incidence of acute respiratory failure
Design	Retrospective chart review N= 120
Objective	To investigate the influence of early initiation of IV terbutaline on the incidence of acute respiratory failure requiring mechanical ventilation in severe pediatric asthma
Study Groups	Outlying hospital (n= 35) Author's hospital (n= 85)
Inclusion Criteria	Patients admitted to the PICU with severe asthma treated with continuous IV terbutaline.
Exclusion Criteria	N/A
Methods	Patients received 3 doses of albuterol nebulizer treatment, IV steroids, and 1 dose of IV magnesium before initiation of terbutaline infusion. Terbutaline was administered as a continuous IV infusion.
Duration	Data collection: 2007-2010
Outcome Measures	Incidence of acute respiratory failure requiring mechanical ventilation, duration of pre-PICU terbutaline infusion
Baseline Characteristics		Outlying hospital (n= 35)	Author's hospital (n= 85)
	Age, years	8.43	6.26
	Loading dose, mcg/kg	4.2	4.4
	Maximum IV drip dose, mcg/kg/min	0.8	0.7
	Respiratory rate before IV terbutaline	39.4	40.2
	Heart rate before IV terbutaline	139.9	143.8
	Duration of pre-PICU terbutaline	0.69	2.91
Results	Endpoint	Outlying hospital (n= 35)	Author's hospital (n= 85)
	Incidence of acute respiratory failure requiring mechanical ventilation	0.69 ± 1.38	2.91 ± 2.47
	Duration of pre-PICU terbutaline, h	21 (60%)	23 (27%)
Adverse Events	N/A
Study Author Conclusions	Early administration of continuous terbutaline in the ED may decrease acute respiratory failure and the need for mechanical respiratory support in severe pediatric asthma.
InpharmD Researcher Critique	The study is retrospective, which limits causal inference. The lack of detailed adverse event reporting and additional severity measures (e.g., arterial blood gas data) are limitations.

References:

Doymaz S, Schneider J, Sagy M. Early administration of terbutaline in severe pediatric asthma may reduce incidence of acute respiratory failure. Ann Allergy Asthma Immunol. 2014;112(3):207-210. doi:10.1016/j.anai.2014.01.003