The Treatment of Adrenal Crisis With Inhaled Prednisolone

The prevalence of adrenal insufficiency is approximately 30-50 individuals per 100.0001. Patients with adrenal insufficiency rely on glucocorticoid substitution therapy (hydrocortisone or cortisone acetate). In case of an acute stressful situation, e.g. illness, trauma, or psychological stress, the standard substitution dose falls short and patients need to increase their glucocorticoid dose to prevent a cortisol deficiency which could ultimately lead to an adrenal crisis. The incidence of an adrenal crisis is about 5-10 cases per year 100 patient-years and is characterized by hypotension, nausea, hyponatremia, hyperkalemia, hypoglycemia, and a circulatory shock with the risk of a fatal outcome2,3. Acute glucocorticoid administration in case of an adrenal crisis is a life-saving procedure.

Currently, patients have to inject themselves with an intramuscular injection of hydrocortisone sodium succinate, corresponding with 100 mg hydrocortisone. This mode of self-treatment has several disadvantages. Hydrocortisone sodium succinate is an unstable product in solution, it is therefore available as Solu-cortef Act-O-Vial in two-chamber vials containing hydrocortisone powder and diluent solution separately. The patient should first prepare the solution and then self-administer the hydrocortisone solution by an intramuscular injection. This is a multistep procedure (Supplement 1). If the injected dose is insufficient, a second injection might be necessary.

In addition, patients with an (imminent) adrenal crisis often experience confusion, drowsiness, dizziness, and nausea with vomiting. As a result, patients may be incapacitated to self-administer intramuscular hydrocortisone. Moreover, needle phobia might hamper self-injection of hydrocortisone. Furthermore, patients are advised to always carry the Solu-Cortef® Act-O-vial, syringe, and needles with them. This is, however, often not very practical and many patients do not follow up on this recommendation. These disadvantages of self-injection of hydrocortisone create a barrier for optimal emergency treatment. It is therefore logical that this method of drug administration is often not sufficiently used and easily leads to errors. Notably, we recently published data about adrenal crises in our own UMCG population and concluded that less than half of the patients who experienced an adrenal crisis used their emergency medication4.

A small inhalation device containing micronized prednisone seems a promising alternative for the replacement of the hydrocortisone injection. It is known that several drugs have a similar time from administration to effect after inhalation as after injection. Examples are adrenaline, levodopa, morphine, and insulin5. Based on its physicochemical properties, prednisone is expected to be as rapidly distributed into the bloodstream after inhalation compared to an intramuscular injection. In addition, previous application of inhaled prednisone for patients with asthma and COPD has demonstrated that the inhalation of prednisone is safe6.

A major advantage to prednisone inhalation compared to the Solu-Cortef® injection is that difficult reconstitution procedures are no longer necessary. In addition, the prednisone powder within the inhalator is very stable and easy to carry along as it fits inside a small pocket. Moreover, in contrast to intramuscular self-injection, inhalation treatment is pain-free and is expected to be acceptable for the majority of patients The patient's resistance against inhalation is much less than against the injection.

As the first step in the development of this prednisone inhaler we will investigate if therapeutic plasma concentrations of prednisolone can be reached by nebulizing prednisolone. In this study, we administer nebulized prednisolone in two different dosages to healthy volunteers.