Explainer: Salbutamol, asthma, and what comes next for Froome

When it was revealed that Chris Froome had returned an adverse analytical finding at the Vuelta a España, exceeding the limit for asthma drug Salbutamol, it set off a wave of alarm through the cycling world. Was he cheating? Was he not? How can an elite athlete have asthma? Can he prove his innocence?

VeloNews reached out to Dr. John Dickinson, a leading expert on asthma in sport and head of the respiratory clinic at the University of Kent’s School of Sport and Exercise Science for help in understanding the science of exercise-induced asthma (EIA). In 2014, Dickinson led a study that revealed more than 70 percent of Britain’s top swimmers and nearly one-third of Team Sky riders were afflicted by EIA. Furthermore, the British physician has objectively tested Froome and confirms the four-time Tour de France champion has asthma. Due to doctor/patient confidentiality, he is not able to divulge how severe Froome’s asthma is.

Let’s turn to the science.

What is exercise-induced asthma?

In exercise-induced asthma (EIA), rapid and heavy breathing causes the same symptoms as asthma, in which a person’s airways become inflamed, narrow, and swollen, producing extra mucus, making it difficult to breathe.

The effect can be exacerbated by atmospheric conditions, particularly cold, dry air. It is thought that because elite athletes are pushing themselves to their limits, they tend to use lung capacities that normal people never use.

Dickinson said that it probably isn’t fair to call those with EIA full-blown asthmatics.

“It basically means they have an asthma response to doing high-intensity exercise,” Dickinson said. “It’s not necessarily the exercise that’s the problem, but rather the volume of air that they breathe and the amount of time that they stay at that level.”

He explained that most of the air elite cyclists breathe travels through their mouth rather than their nose, meaning the lungs are having to constantly condition the air by warming and humidifying it in the lower airways with every breath. Typically the nose would do that. This high air volume drives an inflammatory response. Some athletes are more sensitive than others and will develop extreme muscle constriction around their airwaves.

“That’s asthma, in a nutshell. EIA is a form of asthma, but it is possible that it might be the only form of asthma that an elite athlete has,” Dickinson said.

Dickinson and his research team are focused on trying to objectively test for asthma in athletes. First, they measure baseline lung function when an athlete is breathing as hard and as fast as possible to determine how open the airways are (or not). To test this (known as FEV1), doctors measure the volume of air that a subject can exhale in one second. This determines a baseline level of performance. Next comes something called a eucapnic voluntary hyperpnoea challenge, which replicates breathing rates during a hard effort for six minutes. Finally, lung function is measured again, at three, five, 10, and 15 minutes after performing the challenge. If FEV1 drops by 10 percent or more at two of those time points, an athlete can be diagnosed with some form of EIA.

“What that means in terms of exercise detriment, we don’t know,” Dickinson said. “There’s very little research that has looked at the impact of EIA on performance.”

What does Salbutamol do?

Salbutamol is the most common form of so-called bronchodilator drugs. In someone with EIA, it is used to prevent asthma symptoms and bring that athlete back to a baseline level of lung function.

“When someone takes Salbutamol, it won’t give them super-lungs, but rather maintain function as if they didn’t have asthma,” Dickinson said.

For a WorldTour cyclist, WADA permits Salbutamol to be taken through inhalation only, in limited amounts. Through an inhaler, athletes with asthma can take up to 1,600 micrograms every 24 hours but cannot exceed 800 micrograms within 12 hours. The permitted concentration of Salbutamol allowed in a urine sample cannot exceed 1,000 nanograms per milliliter. (The sample in question, given by Froome at the Vuelta, contained 2,000 nanograms per milliliter.)

How does an athlete secure a TUE to use Salbutamol or other treatments for asthma?

According to WADA’s TUE physician guidelines for asthma, it is recommended that all athletes who may be prescribed asthma medications seek a clear diagnosis from a respiratory specialist. They should also undergo the appropriate tests to optimize management and to exclude other possible diagnoses. This is mandatory if a TUE is being sought to prescribe a systemic glucocorticoid (GC) in-competition or a prohibited inhaled beta-2 agonist (such as Salbutamol) in- and out-of-competition.

The medical file required to support an application for an asthma TUE must include the following details:

– A complete medical history as described and clinical examination with specific focus on the respiratory system;

– A spirometry report with flow volume curve;

– If airway obstruction is present, the spirometry will be repeated after inhalation of a short-acting beta-2 agonist to demonstrate the reversibility of bronchoconstriction;

– In the absence of reversible airway obstruction, a bronchial provocation test is required to establish the presence of airway hyperresponsiveness;

– Exact name, speciality and contact details of examining physician;

– If the athlete reapplies for a TUE that has expired, the application should include the documents that confirm the initial diagnosis as well as the reports and pulmonary function tests from regular asthma follow-up visit.

What happens in the case of an adverse analytical finding?

The presence of Salbutamol in the urine in excess of 1,000 ng/mL is presumed not to be a therapeutic use of the substance and will be considered an adverse analytical finding. The athlete would then need to document the details of his/her medical condition and medication use. The athlete may then be required to prove, by a controlled pharmacokinetic study (see below), that the abnormal test result was the consequence of the use of a therapeutic dose of inhaled salbutamol.

In this particular case, according to Dickinson, Froome and Team Sky will collect evidence from the team doctor and others to try and demonstrate what he did on the day he returned the adverse finding. This would include details on his hydration status and the amount of salbutamol he presumably inhaled.

Research indicates that intense effort, fatigue, and dehydration can affect urine concentrations of Salbutamol in doping tests. Everyone excretes and metabolizes Salbutamol in different ways. Some individuals may have a greater metabolism and excretion rate that may cause the Salbutamol concentration to be increased.

Interestingly, WADA does not correct for an athlete’s state of hydration when measuring for a concentration of a substance. However, an athlete’s hydration status can be determined from the initial urine sample, which could inform the conditions that would need to be recreated during the pharmacokinetic test.

What is involved in a pharmacokinetic study?

WADA lays out exactly what is involved for a controlled pharmacokinetic study as follows:

  1. The study shall be conducted in a controlled setting allowing a strict and independent supervision of the drug administration (route, dose, frequency, etc.) and sample collection (matrix, volume, frequency) protocol.
  2. A wash-out period should be established in order to collect baseline urine or blood samples just prior to the administration of the drug, i.e. the athlete should not be taking the medication before the test. Necessity of the drug for health reasons as well as the known pharmacokinetics of the product will need to be taken into account, if necessary.
  3. Collection of urine samples shall occur whenever that athlete wishes to deliver samples but no less than every two hours during the monitoring period. Sampling periods should be adjusted to the known pharmacokinetic of the product (e.g. every 30 min. or night collections might be considered, if justified).
  4. The athlete shall take the drug in accordance with the treatment course (dose, frequency, route of administration) declared in the doping control form or, alternatively, following the therapeutic regime indicated on a granted TUE, if any. The administered dose shall never exceed the maximal dose/frequency recommended by the drug manufacturer or a safe level prescribed by the athlete’s physician.
  5. The samples shall be analyzed in a WADA accredited laboratory with the validated relevant anti-doping method. Correction for specific gravity shall be applied in accordance with the provisions of the International Standard for Laboratories and related Technical Documents.
  6. The WADA accredited laboratory will issue a comprehensive report indicating the results of the analyses and interpretation, if needed. If deemed necessary, review of the results by an independent expert can be sought by the Testing Authority.

“If he were able to recreate the findings on the day in a study setting, there’s a chance he wouldn’t receive a doping violation,” Dickinson said. “But it can be quite difficult to demonstrate that that is what happened.”

Furthermore, there could have been other issues that on the day exacerbated the problem — a chest infection, for example — that would be extremely difficult to reproduce for the study.

“It’s a bit of a risk, really,” Dickinson said. “Because if he can’t reproduce what he’s hoping to reproduce, there’s not much to back up his story, really. It weakens his evidence and his story quite substantially.”

Could Froome have taken an oral dose of salbutamol?

From limited research, it has been shown that an oral dose of salbutamol may produce gains in strength and power, not endurance. It does this by improving the efficiency of muscle contractions.

“If we’re speculating, it doesn’t necessarily scream out why he would choose to take an oral dose of this,” Dickinson said.

Secondly, WADA can actually differentiate between an oral and inhaled dose of salbutamol through analyzing metabolites in the urine sample.

So, in Dr. Dickinson’s opinion, what is the most plausible explanation for what happened?

“In a best-case scenario — and I always like to think in those terms — a lot of this could be put down to a mismanagement of the [EIA],” Dickinson said.

“Now, if you’re symptomatic with asthma, asthma is a dangerous condition. We want asthmatics, at the first sign of symptoms, to take their inhaler — that should help improve the symptoms. And if it doesn’t improve the symptoms, take it again.

“In an elite athlete, you want them to follow that protocol because you don’t want them to have a catastrophic event. Now, if that’s happened on day one, there are certain things that could be put in place for day two that could involve improving the level of preventative therapy. For example, he could have taken more of an inhaled corticosteroid, or a longer-acting beta-2 agonist. That would have meant the use of Salbutamol would have been reduced on the second day, and reduced the risk or providing this adverse analytical.

“The last thing to consider is, if his asthma is that bad and he keeps having to use that level of Salbutamol, then you’ve got to look at it from a health point of view and go, ‘Actually, are we endangering this athlete’s health by allowing him to compete if he’s continuing at that level of Salbutamol.’ That is, is there a point at which the team physician needs to step in and say, ‘Look, your asthma is not under control for the last three days, that’s not healthy. Maybe we need to withdraw you from the race.’

“If you’re an elite athlete, that’s probably not what you want to hear. And if you’re a doctor, that’s an awful big call to be making when your star rider is in the leader’s jersey.

“The situation with Bradley Wiggins last year doesn’t help. Because the next step after inhalers is to get a TUE to use a stronger form of medication, like an oral corticosteroid. But because of all the issues that came up with Wiggins last year, there could potentially have been some hesitation to go down that road as well.

“All of that leads me to believe this is a case of a mismanagement of an athlete with asthma.”

Listen to our discussion of the Froome case on the VeloNews podcast: