Intravenous Terbutaline in Severe Status Asthmaticus
Terbutaline is a medication that is used to treat serious asthma attacks (status asthmaticus). The purpose of this study is to determine if terbutaline is effective and safe when given as a continuous intravenous infusion to children ages 2 years to 18 years of age. Children participating in this study are inpatients in the Intensive Care Unit with a diagnosis of status asthmaticus and are receiving terbutaline as part of their routine care. Blood samples and physiological assessments will be used to determine how the body is using terbutaline and how well it is working.
1. Background: Asthma remains a significant source of morbidity and mortality in children. In the United States, more than 11 million people reported having an asthma attack in the year 2000, and more than 5 percent of all children younger than age 18 reported having asthma attacks. The trend of increasing asthma-associated morbidity and mortality that occurred during 1980-1995 has not continued for all measures. During 1995-1998, the rate of emergency department visits for asthma increased, while the rate of hospitalization and death decreased for all age groups, except children younger than age 15. Asthma remains a significant problem despite scientific advances that generated greater understanding of the mechanisms of asthma and the development of therapeutic approaches that can reduce morbidity.
Status asthmaticus is a common diagnosis for admission to pediatric intensive care units (PICUs). Widely accepted treatment for status asthmaticus includes inhaled beta-2 agonists, systemic corticosteroids, and inhaled anticholinergic agents. The intravenous and/or subcutaneous administration of beta-2 agonists has been advocated in the treatment of severe asthma and is prescribed in current practice. Additional treatment regimens may include magnesium, theophylline, and/or heliox with some patients still requiring mechanical ventilation, anesthetic agents or extracorporeal membrane oxygenation.
Beta-adrenergic receptor agonists are critical in the treatment of asthma. Their use frequently results in effective bronchodilation. Commonly used beta-adrenergic agonists are epinephrine, albuterol and terbutaline, with albuterol and terbutaline having an increased selectivity for beta-2 receptors. These agents can be given by inhaled, IV, subcutaneous or oral routes. In the United States inhaled albuterol is the drug and route of choice in a majority of circumstances. Regarding efficacy when administering medications via the inhaled route, one must take into account many factors including inhalation technique, inspiratory flow rate, inspiratory volume and mode of delivery. Several characteristic pathophysiological changes that occur during a severe asthma attack (near complete airway obstruction, low tidal volumes, mucus plugging) may preclude the delivery of inhaled particles to the area of the lung that is most affected. In these instances, intravenous beta-agonists should be considered. Because of cardiac related side effects that are more pronounced in non-selective beta-agonist therapy, a beta-2 receptor agonist should be administered. In the United States, terbutaline is the only approved intravenous beta-2 receptor agonist.
Terbutaline is a sympathomimetic amine synthesized in the mid-1960's that has been shown by in vitro and in vivo pharmacologic studies in animals to exert a preferential effect on beta 2-adrenergic receptors (beta2-AR), such as those located in bronchial smooth muscle. It has been available for clinical use since the 1970's and has been approved by the FDA for use in the treatment of asthma in children. Terbutaline binds to the beta-2 adrenergic receptor resulting in Gs-protein stimulation which in turn activates adenylyl cyclase increasing intracellular levels of 3'-5' cyclic adenosine monophosphate (cAMP). cAMP then activates protein kinase A (PKA) that phosphorylates several proteins that contribute to smooth muscle relaxation and resultant bronchodilation.
2. Hypothesis and Primary Objectives: Intravenous terbutaline by continuous infusion is effective in decreasing the severity of an acute asthma attack and is safe to use in children 2 years to 18 years old. Terbutaline has different pharmacokinetics when given by continuous infusion versus single dose administration.
3. Study Design: Phase 2 clinical pharmacokinetic/pharmacodynamic trial in pediatric patients aged 2-18 years old who are receiving intravenous terbutaline for a severe asthma attack. Three groups of 12 children will be examined based on age for a total N of 36. The first group will be 2-6 years, the second group will be 6-12 years old and the third will be adolescents 12-18 years old. Treatment efficacy will be gauged by comparing scores of the modified pulmonary index (MPIS) as well as utilization of the rescue medication protocol (see below). Pharmacokinetics and pharmacodynamics will be determined by serum samples collected in 1-2 ml aliquots prior to infusion and at 20 minutes, 2, 4, 6, 8, 10, and 12 hours post infusion, or until clinical improvement necessitates discontinuation of the infusion if less than 12 hours.
4. Study Components:
- Modified Pulmonary Index Score (MPIS): Children will be assessed for clinical changes during therapy by utilizing the modified pulmonary index score (MPIS) which is a combination of 6 physiologic parameters, each graded 0-3, the sum of which reflects pulmonary status. The MPIS was assessed for reproducibility and validity and was shown to be highly reproducible across groups of health care providers (nurses, physicians, respiratory therapists) and was a valid indicator of asthma severity in children.
- Terbutaline levels as determined by HPLC at designated times stated previously.
Observational Model: Cohort, Time Perspective: Prospective
Kosair Children's Hospital
Enrolling by invitation
Wayne State University
Results (where available)
- Source: http://clinicaltrials.gov/show/NCT00750568
- Information obtained from ClinicalTrials.gov on July 15, 2010
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Medical and Biotech [MESH] Definitions
A sudden intense and continuous aggravation of a state of asthma, marked by dyspnea to the point of exhaustion and collapse and not responding to the usual therapeutic efforts.
A prolonged seizure or seizures repeated frequently enough to prevent recovery between episodes occurring over a period of 20-30 minutes. The most common subtype is generalized tonic-clonic status epilepticus, a potentially fatal condition associated with neuronal injury and respiratory and metabolic dysfunction. Nonconvulsive forms include petit mal status and complex partial status, which may manifest as behavioral disturbances. Simple partial status epilepticus consists of persistent motor, sensory, or autonomic seizures that do not impair cognition (see also EPILEPSIA PARTIALIS CONTINUA). Subclinical status epilepticus generally refers to seizures occurring in an unresponsive or comatose individual in the absence of overt signs of seizure activity. (From N Engl J Med 1998 Apr 2;338(14):970-6; Neurologia 1997 Dec;12 Suppl 6:25-30)
A demographic parameter indicating a person's status with respect to marriage, divorce, widowhood, singleness, etc.
A quality-of-life scale developed in the United States in 1972 as a measure of health status or dysfunction generated by a disease. It is a behaviorally based questionnaire for patients and addresses activities such as sleep and rest, mobility, recreation, home management, emotional behavior, social interaction, and the like. It measures the patient's perceived health status and is sensitive enough to detect changes or differences in health status occurring over time or between groups. (From Medical Care, vol.xix, no.8, August 1981, p.787-805)
The measurement of the health status for a given population using a variety of indices, including morbidity, mortality, and available health resources.