Bronchodilators to Treat Asthma May Worsen Youngsters’ SCD, Study Suggests

Bronchodilators used to treat asthma could worsen sickle cell disease (SCD) in children and teens, and contribute to a greater risk of vaso-occlusive crisis (VOC), a study suggests.

The study, “Salbutamol Worsens the Autonomic Nervous System Dysfunction of Children With Sickle Cell Disease” was published in the journal Frontiers in Physiology

People with SCD who also have asthma have an increased rate of complications and premature death when compared to those without asthma.

Complications include VOCs — blockage of small blood vessels causing injury and acute pain — and acute chest syndrome, a lung disease characterized by chest pain, cough, fever, and hypoxia (low oxygen level).

One of the difficulties in diagnosing asthma in SCD patients is the overlap of signs and symptoms that may be caused either by the blood disorder or by asthma. Asthma medications also may be a confounding factor as they, too, may worsen SCD.

Short-acting beta-agonists, including salbutamol (also known as albuterol, marketed as Ventolin, Proventil, and others), are common quick-relief medications for treating or preventing asthma attacks.

Long-term control medications, which are taken regularly to control asthma symptoms and prevent attacks, include long-acting beta-agonists (LABAs), inhaled corticosteroids, and leukotriene modifiers.

These bronchodilators relax muscles in the airways and increase airflow to the lungs. However, they also may alter the functioning of the body’s autonomic nervous system (ANS) — the part of the nervous system that controls bodily functions such as heart rate, digestion, and respiratory rate, in an automatic and unconscious manner.

The autonomic nervous system is divided into two parts: the parasympathetic system, which controls several organs when the body is at rest (e.g., reduces heartbeats, narrows the airways); and the sympathetic system, which directs the rapid and involuntary response to dangerous or stressful situations, including increases in heart rate and opening of the airways.

Asthma and the bronchodilators used to treat it might aggravate SCD by altering the balance in these two autonomic functions. Which of the two could have a greater impact remains unknown.

To address that knowledge gap, researchers at Hôpital Robert Debré and the Université de Paris, in France, conducted a clinical trial (NCT04062409) in which they compared autonomic function in three groups of children and teens: those with SCD who did not have asthma (30 patients); participants with SCD but without asthma (also 30); and patients with asthma but without the blood disorder (a control group with 29 participants).

Patients with SCD had a mean age of 12 years, all within the 8 to 16 age range. All participants were of Sub-Saharan African or Caribbean ethnicity.

For assessing autonomic function, the researchers measured heart rate variability, which reflects the beat-to-beat variations in heart rate.

Heartbeats have a natural rhythm that fluctuates with breathing; they accelerate during inspiration, and slow during expiration. Analysis of these fluctuations (e.g., low-to-high frequency ratio, LF/HF) can help doctors understand which parts of the autonomic function are more active — the parasympathetic or the sympathetic.

Participants underwent an electrocardiogram to assess cardiac function and pulmonary tests, including a spirometry test, after patients had taken an inhaled dose of salbutamol.

SCD patients with asthma were treated more often by a short-acting bronchodilator than participants with asthma but without SCD, who took inhaled corticosteroids combined with long-acting beta-agonists more commonly.

Compared to SCD patients without asthma, those with asthma had mildly lower breathing function as determined by FEV₁/FVC ratio (0.84 versus 0.89) — a measure of the amount of air one can forcefully exhale from the lungs.

They also had an increased bronchodilator response, and a greater incidence of VOCs (27 vs. 22 patients) and acute chest syndrome (14 vs. five patients), when compared to children with SCD but without asthma.

Patients with SCD also had reduced heart rate variability, consistent with impaired parasympathetic control and sympathetic overactivity, as compared to children with asthma but not the blood disorder.

Notably, such impairments were worsened by salbutamol administration. Salbutamol actually aggravated heart rate variability in all patients, raising heart rate (95 vs. 88 beats/min) and increasing the LF/HF ratio (1.57 vs 1.17).

However, there were no differences in heart rate variability between SCD children with and without asthma “suggesting that asthma diagnosis per se did not modify ANS functions,” the researchers wrote.

Overall, the results indicate that bronchodilator medications aggravate SCD by modifying patients’ autonomic function, while SCD patients with asthma have more vaso-occlusive events. “As a consequence, these events may have been precipitated by salbutamol administration, which warrants further clinical demonstration,” the team concluded.