After a couple years of waiting for the new methacholine standards to be released “any day now”, they were finally published in this month’s issue of the European Respiratory Journal. The standard is an open access article and can be downloaded by anyone.
The length of time taken to develop the standard was acknowledged and although active ATS participation was withdrawn because the original timeline was not met, for the most part the original ATS participants continued with the task group and the standard has been officially endorsed by the ATS.
The biggest difference between the 1999 standards and those from 2017 is the change from PC20 (provocative concentration causing a 20% decline in FEV) to PD20 (the provocative dose causing a 20% decline in FEV1) as the primary endpoint and this alone will make a difference in how methacholine challenges are performed and calculated.
The 1999 standard included both tidal volume and dosimeter protocols. The dosimeter protocol consisted of 5 breaths to TLC. The 2017 standards state that a dosimeter may be used but that this is primarily to make counting breaths and calculating the cumulative dose easier and that inhalations to TLC are specifically contraindicated due to “the bronchodilating or bronchoprotective effect of a maximal inspiratory manoeuvre with a breathhold at TLC”.
Other differences include:
- The 1999 standard had both absolute and relative contraindications. There are only contraindications in the 2017 standard.
- Absolute contraindications in the 1999 standards included an FEV1 < 50% of predicted (or < 1.0 L, age group unspecified) and for the 2017 standard it is an FEV1 < 60% of predicted (or 1.5 L, adults) which were relative contraindications in 1999.
While reading a recently published article I found they had performed response to hypoxia and hyperoxia testing as part of the study. At one time or another in the past I’ve read about response to hypoxia testing but I’d never heard about hyperoxia testing before. I had some difficulty understanding their interpretation of the study’s results and for this reason I’ve spent some time reading up on the subject. I’m not sure this helped because there appears to be a lack of consensus not in only how to perform these tests but also in how they are interpreted, except perhaps in the most simplistic sense. Hypoxia and hyperoxia testing has been performed primarily to gain a deeper understanding of the way in which the peripheral (carotid) and central chemoreceptors function. There are a variety of sensor-feedback network models and results are often presented in terms of one model or another and this makes comparing results from different studies difficult. Interpretation and comparison is further complicated by the fact that results depend not only on the length of time that hypoxia or hyperoxia is maintained but whether the subject was exposed to hypoxia, hyperoxia or hypercapnia previously.
The ventilatory response to hypoxia tends to have three phases. First, once a subject begins breathing a hypoxic gas mixture within several seconds there is a rapid increase in minute ventilation known as the Acute Hypoxic Ventilatory Response (AHVR). Second, after several minutes there is a decrease in ventilation and this is usually called the Hypoxic Ventilatory Depression (HVD). Third, there is a progressive rise in ventilation after several hours which is related to acclimatization to altitude. It is the first phase, AHVR, that is most commonly measured during a hypoxic ventilatory response test. The actual length of time that is spent in any of these phases is widely variable between individuals and there is also a relatively large day-to-day variability within the same individual.
Airway hyper-responsiveness is a primary feature of asthma. There are a number of bronchial challenge tests designed to evoke and measure this factor, the most common of which require the inhalation of one or another bronchoconstrictive agent such as methacholine, histamine, mannitol or hypertonic saline.
An elevated ventilation can cause many asthmatics to bronchoconstrict and this is often the cause of Exercise-Induced Bronchospasm (EIB). There are two competing theories as to why this happens. A number of researchers have suggested that the mechanism is a drying of the airway mucosa which changes the osmolarity of the respiratory tract fluid which in turn causes some cells to releases mediators that cause bronchoconstriction. Other researchers assert that it is the cooling of the airways during hyperventilation and an increased blood flow and edema during subsequent re-warming that causes the bronchoconstriction. There is evidence to support both interpretations and it is likely that both mechanisms coexist, with one or the other being more predominant in any given individual.
Although the inhalation challenge tests are reasonably sensitive not all patients with EIB have a positive reaction. When a patient’s primary complaint is exercise-related or when they have had a negative inhalation challenge test and are still symptomatic, a ventilatory challenge test should be considered. There are several ventilatory challenge tests that are specifically oriented towards evoking and characterizing EIB. These are the Cold Air challenge, Eucapnic Voluntary Hyperventilation and Exercise Challenge. There are a number of similarities between these tests.
Cold Air Challenge
A Cold Air Challenge (CACh) test consists of having a patient hyperventilate while breathing air that has been cooled to a temperature of between -10°C and -20°C. It is usually performed using a mixture of 5% CO2, 21% O2, 74% N2 in order to prevent dizziness from hypocapnia.