Inhalers are among the most commonly used devices for treating respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD). With each inhalation through the inhaler, the device delivers a specific amount of medication to the lungs. However, it is commonly misused because patients often have problems adopting the correct inhaler technique and thus receive insufficient medication. This leads to poor disease control and increased healthcare costs.
Global annual costs associated with asthma and COPD management are substantial from both the healthcare payer and the societal perspectives. Research findings show that healthcare spending for an uncontrolled patient is more than double that of a controlled patient. 1 Studies have also found that most patients make at least one mistake during inhaler drug intake, resulting in only 7% to 40% of the drug being delivered to the lungs. The two biggest and most serious errors when using metered dose inhalers (MDIs) are both related to patient inhalation. The first error is related to the coordination between inhalation and triggering the dose release of the inhaler. Even a short delay can result in only 20% of the medication being delivered to the lungs. The second most significant error is not breathing deeply enough, which can cause another 10% less medication to reach the lungs.
To address these problems, Sensirion AG (Stäfa, Switzerland) has developed a prototype that can be clipped on to the inhaler to measure patient inhalation airflow and determine when during the inhalation the inhaler is actuated.
Why Measure the Inhalation Flow Profile?
Since the two biggest and most serious errors in using inhalers are related to patient inhalation, it is important to measure the airflow through the inhaler, and for MDIs also the point in time when the drug is dispensed. That provides information on whether the drug was released within the optimal window of the inhalation cycle (see Figure 1). This dose-trigger timing versus flow correlation is one critical parameter for understanding whether the drug-carrying flow reached deep into the bronchia and achieved the desired high lung deposition.
The second critical parameter is the inhaled airflow profile. Similar to using a spirometer, several parameters can be derived from the inhalation airflow profile that provide insights into each patient’s inhalation:
Depth and length of inhalation
Entire exhalation before inhaling
Slow inhalation according to instructions
Lung function and its development over time (change in inhalation flow characteristics)
Accurate and calibrated real-time recordings of the inhalation flow profile provide this information, from which it can be determined whether the patient carried out the inhalation correctly.
Other parameters of interest include the inhaled volume (IV) and peak inspired flow rate (PIF), along with the full inhalation airflow characteristic as shown in Figure 2.
Subsets of parameters such as the airway resistance (RAW) can also be determined from the inhalation airflow profile. The derivation of RAW is shown in Figure 3. When the inhaler is used as a spirometer-like device, all parameters are derived during the regular inhalation, so there is nothing further the patient must do compared to taking their medication the way they are used to. At the same time the device will also register if the patient did not take the medication, which can be used to remind the patient to adhere to the prescribed therapy.
In addition to monitoring every inhalation, the important parameters can be followed over time, providing feedback on the correct use of the inhaler, the effectiveness of the medication, and the course of the disease. This information can be sent to the healthcare provider and to also help motivate the user. This combination of drug delivery and diagnostic unit in a single device is a powerful tool for improving patient outcomes.
Figure 4 shows the schematic behavior of PIF, IV, and RAW versus time. It visualizes the positive effect of starting the treatment, the stable treatment phase during regular dosage, and the negative effect of interrupting the treatment.
How to Measure the Inhalation Flow Profile
In the past, accurate measurement of the flow through the inhaler was challenging due to the lack of sufficiently robust and yet sensitive devices capable of measuring the smallest flows. To avoid having to revalidate the inhaler with the FDA and maintain approval, the key regulatory requirement for inhaler clip-ons demands that the flow path of the inhaler remains unaltered in order to ensure that it does not interfere with the existing inhaler device function. The Sensirion clip-on inhaler does just that.
Figure 5 shows the 3D-printed inhaler clip-on containing the Sensirion flow sensor SDP3x as well as a Bluetooth low energy communications chip and a battery power source. The inhaler housing has not been altered.
The Bernoulli/Venturi effect explains that the acceleration of the air flow entering the inhaler caused by the patient inhaling creates a negative pressure at the inhaler top opening, around the cannister and the opening of the attached clip-on. The magnitude of the negative pressure is directly related to the magnitude of the flow rate of the air flow through the inhaler to the patient and is measured by the flow-sensor.
A more graphic way of understanding the principal is to consider the flow setup to be a by-pass main-pass system (See Figure 6). As the patient inhales, the negative pressure around the inhaler opening draws a small amount of clean ambient air through the by-pass path of the sensor and into the mainpass of the inhaler. By measuring the by-pass airflow and knowing the by-pass/ main-pass ratio, which is provided by the inhaler/clip-on geometry, the total amount of airflow to the patient can be determined.
A MEMS-Based Flow Sensor
There are many different methods of measuring gas flow: mechanical volumetric, float-type, differential pressure, ultrasonic, Coriolis, magnetic inductive, and thermal flow metering, to name but a few. Metering techniques without contact between gas and sensor require relatively expensive technology and are thus out of the question for many applications. In the classic differential pressure method, hysteresis effects and membrane fatigue can lead to drift problems and a lack of zero-point accuracy as well as low flow sensitivity because the mechanical deflection of a sensor membrane over an orifice is used to gauge the pressure drop.
Measuring techniques based on thermal principles are therefore a good solution. In the simplest of these — the hot-wire anemometer — gas flow is determined via the rate of cooling of an electrically heated wire with a temperature-dependent resistance. Advanced methods use a heating element and two temperature sensors, which measure the transport of heat through the gas. Sensirion refers to the term “microthermal flow sensors” because in the MEMS-based flow chip solution utilized in their SDP3x flow sensor series, the sensor components are integrated into a millimeter-scale silicon microchip.
The calibrated inhaler airflow shows excellent agreement in a lab setup against a calibrated spirometer syringe or against an external flow reference.
Outlook for Flow Measurement in Smart Inhalers
Adding a diagnostic unit to the drug delivery device that the patient is already familiar with is a powerful tool in asthma and COPD disease management. Improper inhalation technique leads to decreased efficacy because of reduced deposition of medication in the lungs, which in turn leads to increased disease severity. The solution of guiding the patient and providing direct feedback, as well as supporting the patient in controlling the disease and increasing adherence, have already been shown to improve patient outcomes by currently used connected drug delivery devices.
The high percentage of patients suffering from asthma or COPD and misusing their inhaler, when a life free of complaints would generally be possible with proper disease management, will continue to drive innovation for connected drug delivery. Supporting the patient with the optimal treatment of their disease, not solely as a simple medical tool but as a companion device to remind, coach, and provide relevant insight into the treatment and the course of the disease, is the direction in which the industry is advancing.
- S. Sullivan, “The burden of uncontrolled asthma on the US health care system,” Managed Care, vol. 14, no. 8, pp. 4-7, 2005.