P-009 - The role of the carotid body for reversal of opioid-induced respiratory depression

Abstract Title: The role of the carotid body for reversal of opioid-induced respiratory depression


Background: Exposure to inhaled anesthetics, opioids, and other central depressants during the peri-operative period can lead to atelectasis and loss of air-exchange surface in the lungs. Several of these medications can produce respiratory depression, either alone or in additive or synergistic manner. Further, it has been recently recognized that in addition to the in-hospital post-operative period, there are 30-, 60-, and even 90-day sequelae and onset of serious morbidity and mortality (Miskovic & Lumb, 2017). Opioids used for postsurgical analgesia exacerbate the problem by decreasing respiratory drive and minute ventilation. Reversal attempts commonly use the opioid receptor antagonist naloxone. Unfortunately, such antagonists reverse not only respiratory depression but also analgesia, and are not as effective against non-opioid depressants. Recent research seeks an ‘agnostic’ reversal agent – and leads to exploration of the carotid body as a target.

Purpose/Objectives: The extent and magnitude of the negative impact of intra- and post-operative respiratory depression goes under-recognized and under-reported. With the large – and increasing – number of surgical procedures performed each year, even a small percentage of postoperative respiratory complications translates into a large number of affected patients. We present a succinct overview of the problem, and the historic and investigative novel future therapy. Past approaches (‘analeptics’) have primarily targeted, directly or indirectly, the brain or sympathetic subdivision of the autonomic nervous system (e.g., cocaine, ephedrine, atropine, amphetamines, strychnine, picrotoxin, tetrazoles, caffeine, ampakines). We summarize a recent novel physiologic target – the carotid bodies – which are located outside the central nervous system (CNS), thus offering potential respiratory efficacy without CNS adverse effects.

Methods: Data from published reviews and primary sources (in English) on the topics of postoperative respiratory depression and the carotid-body as target for respiratory stimulants were reviewed and summarized. We present a succinct overview of the problem, and the historic and investigative novel future therapy. Past approaches (‘analeptics’) have primarily targeted, directly or indirectly, the brain or sympathetic subdivision of the autonomic nervous system (e.g., cocaine, ephedrine, atropine, amphetamines, strychnine, picrotoxin, tetrazoles, caffeine, ampakines).

Results: K⁺-channel chemoreceptors in the carotids are sensitive to changes in pO₂, pCO₂, and pH. The primary sensors for hypoxia are the type I glomus cells in the carotids, which send afferent impulses via the carotid sinus nerve to the nucleus tractus solitarius (NTS) in the brainstem (Grönblad, 1983). The NTS, via links through the pontine respiratory group, connects to the pre-Bötzinger complex. These nuclei function as a pacemaker for normal respiration. Doxapram is an agonist at homodimeric and heterodimeric TASK-1/TASK-3 potassium channels. In contrast, ENA-001 represents a new mechanism, antagonism of large-conductance Ca²⁺ and voltage-activated K⁺ (BK) channels.

Conclusions/Implications for future research and/or clinical care: When it is administered to rats or Cynomolgus monkeys, ENA-001 elicits dose-dependent increases in minute ventilation and the reversal of opioid-induced respiratory depression. But unlike opioid receptor antagonists, it does not compromise opioid analgesia. Thus, ENA-001 is ‘agnostic’, in that it also reverses respiratory depression evoked by non-opioids, including benzodiazepines and propofol.

References: Miskovic A and Lumb AB: Postoperative pulmonary complications. Brit J Anaesth 118:317-334, 2017 [doi: 10.1093/bja/aex002. PMID: 28186222]

Grönblad M: Function and structure of the carotid body. Med Biol 61:229-248, 1983 [PMID: 6323893]