Pulmonary Delivery of Therapeutic and Diagnostic Gases

Abstract

The 21st Congress for the International Society for Aerosols in Medicine included, for the first time, a session on Pulmonary Delivery of Therapeutic and Diagnostic Gases. The rationale for such a session within ISAM is that the pulmonary delivery of gaseous drugs in many cases targets the same therapeutic areas as aerosol drug delivery, and is in many scientific and technical aspects similar to aerosol drug delivery. This article serves as a report on the recent ISAM congress session providing a synopsis of each of the presentations. The topics covered are the conception, testing, and development of the use of nitric oxide to treat pulmonary hypertension; the use of realistic adult nasal replicas to evaluate the performance of pulsed oxygen delivery devices; an overview of several diagnostic gas modalities; and the use of inhaled oxygen as a proton magnetic resonance imaging (MRI) contrast agent for imaging temporal changes in the distribution of specific ventilation during recovery from bronchoconstriction. Themes common to these diverse applications of inhaled gases in medicine are discussed, along with future perspectives on development of therapeutic and diagnostic gases.

Keywords: in vitro upper airway model; lung imaging; magnetic resonance imaging (MRI); nitric oxide; oxygen; pulmonary hypertension.

FIG. 1.

Producing NO by pulsed electrical discharge.⁽⁴³⁾ NO, nitric oxide.

FIG. 2.

Experimental apparatus used to evaluate oxygen delivery using realistic nasal airway replicas. Arrows indicate direction of gas flow. Adapted from Chen et al.⁽⁵²⁾

FIG. 3.

Functional lung images from a subject with COPD. Each of the frames shows one slice from a 3D image obtained during a single deep breath-hold. The images are obtained using an approach of three tidal breaths followed by the single deep breath-hold and this is repeated several times until a steady state is obtained. The time frame from image to image is generally 30–45 seconds depending on the subject's respiration rate. Much like hyperpolarized gas Magnetic Resonance Imaging (hpMRI), the early frames show areas that have been described in the hpMRI literature as “ventilation defects” or areas of no or poor ventilation. As is evident in the time axis (left to right), these actually describe “slow filling” compartments of the lung. Since the gaseous agent does not reach these areas in a single breath, it is likely the distribution of inhaled agent would be similar. 3D, three dimensional; COPD, chronic obstructive pulmonary disease.

FIG. 4.

Parametric images calculated pixelwise from the time series data show the distribution of “slow filling” compartments of the lung, and the fraction of lung volume that has such poor ventilation can easily be determined.

FIG. 5.

A possible evaluation strategy for pharmacokinetic/pharmacodynamic evaluation of inhaled therapeutic agents.

FIG. 6.

Left panel: specific ventilation maps in a sagittal slice of the right lung in a healthy control (top row) and a mild asthmatic (bottom row) at baseline, and following methacholine-induced bronchoconstriction. In these sagittal images, the head is to the right, and the dorsal lung is toward the bottom of the images. Administration of the predetermined methacholine PC20 dose altered the pattern of specific ventilation, mostly in the dependent lung. Right panel: fraction of constricted lung in the dependent, middle, and nondependent lung thirds, constriction defined as a decrease in specific ventilation of ≥50%, for the two healthy (circles, blue lines) and two asthmatics studied (square, orange line).

FIG. 7.

Specific ventilation maps of a 15 mm sagittal slice of the right lung (same as in Fig. 6, mild asthmatic, bottom row), showing the time course of recovery following methacholine-induced bronchoconstriction (1 mg/mL) in a mild asthmatic. A 7-minute overlapping sliding window approach, centered at 15, 20, and 25 minutes after methacholine was applied, opening a window into the dynamics of the recovery from an induced asthma challenge.