Liposomal adrenaline for cardiopulmonary resuscitation: microfluidic production and pharmacokinetic analysis

Cardiopulmonary resuscitation of patients in cardiac arrest includes procedures such as chest compression and defibrillation, as well as the intravenous or intraosseus administration of adrenaline. The use of adrenaline increases the chances of return of spontaneous circulation, leading to reperfusion of the brain and myocardium. However, the safety of adrenaline has been questioned by recent clinical trials, that have linked its use to a higher incidence of neurological impairment in cardiac arrest survivors. The necessity for repeated injections due to the quick metabolism of adrenaline, with the consequent oscillation in plasmatic concentration, was suggested as a possible culprit of severe neurological damage. We have previously designed a liposomal formulation for the sustained release of adrenaline, providing proof-of-concept in vitro and optimizing a lab-scale production process. In this work, we aimed at moving the technology forward by developing a microfluidic process for scaled-up production and exploring the pharmacokinetics of the formulation in swine. Regarding the first aim, three liposomal formulations containing different PEGylated lipids were produced, achieving uniform (PDI < 0.2), negatively charged and stable vesicles for encapsulation and controlled release of adrenaline in vitro. The lead formulation used for in vivo studies consisted mainly of bilamellar vesicles, as observed by cryo-TEM. The pharmacokinetic profile of liposomal adrenaline showed an increased mean residence time (p < 0.02), and plasmatic half-life (p < 0.05) compared to the clinical standard, as well as a less pronounced rise in heart rate and milder hemodynamic alterations. These results support the development of liposomal adrenaline in further preclinical studies on a model of cardiac arrest and resuscitation.