Respiratory stimulant drugs in the post-operative setting

Abstract

Drug-induced respiratory depression (DIRD) is a common problem encountered post-operatively and can persist for days after surgery. It is not always possible to predict the timing or severity of DIRD due to the number of contributing factors. A safe and effective respiratory stimulant could improve patient care by avoiding the use of reversal agents (e.g., naloxone, which reverses analgesia as well as respiratory depression) thereby permitting better pain management by enabling the use of higher doses of analgesics, facilitate weaning from prolonged ventilation, and ameliorate sleep-disordered breathing peri-operatively. The purpose of this review is to discuss the current pharmaceutical armamentarium of drugs (doxapram and almitrine) that are licensed for use in humans as respiratory stimulants and that could be used to reverse drug-induced respiratory depression in the post-operative period. We also discuss new chemical entities (AMPAkines and GAL-021) that have been recently evaluated in Phase 1 clinical trials and where the initial regulatory registration would be as a respiratory stimulant.

Low cost of pulmonary ventilation in American alligators (Alligator mississippiensis) stimulated with doxapram

“…Doxapram was synthesised in the 1960s (Ward and Franko, 1962) and quickly gained wide usage in human as well as veterinary medicine to stimulate ventilation post-operatively in patients with ventilatory depression (Yost, 2006;Golder et al, 2013). In mammals, doxapram predominantly stimulates tidal volume, and while it was originally described to act on the central nervous system, most of the ventilatory response is now believed to stem from direct stimulation of peripheral chemoreceptors in the aortic and carotid bodies (Yost, 2006;Golder et al, 2013). Regardless of the exact mechanism, doxapram causes hyperventilation without changes in the inspired gases.…”

Oxidative stress in severe pulmonary trauma in critical ill patients. Antioxidant therapy in patients with multiple trauma — a review

“…Most often, patients with multiple traumas develop serious lung problems due to several complications arising from injury, infections or from mechanical ventilation. The management of the respiratory system has a special importance [3], due to the constant and critical need of tissue oxygenation of the body [3−6]. Recorded data in Trauma Register DGU (Germany) [6], and presented by Huber et al [6], highlight a high mortality rate with pulmonary trauma patients: 17.5% (16.5% male and 20.5% female).…”

Blockade of phosphodiesterase 4 reverses morphine-induced ventilatory disturbance without loss of analgesia

“…On the other hand, agents such as doxapram, GAL-021 and almitrine that block potassium channels in the carotid bodies are also useful approaches for offsetting opioid-induced respiratory depression without loss of analgesia [10,45]. Since the reversal of opioid-induced respiratory depression by caffeine and rolipram occurred in in vitro preparations [33], the present study focused on their central effects.…”