Ketamine: yay or neigh? Implications for cardiovascular regulation and considerations for field use

Abstract

In a prehospital setting, pain management following traumatic injury is an important consideration in both military and civilian contexts. Traditionally, opioids (e.g. fentanyl) are administered to help manage pain; however, their use may result in altered cardiovascular and neural function. Furthermore, development of opioid addiction following analgesic use may contribute to an increasing incidence of opioid abuse, overdose, and death in North America. Ketamine, an NMDA receptor antagonist, has emerged as a promising alternative treatment. Previous work in humans has shown that, in anaesthetic doses, ketamine does not negatively affect the neural response to acute hypotension induced via sodium nitroprusside injection (Kienbaum et al. 2000). Furthermore, low (i.e. subanaesthetic) dose ketamine has been shown to be effective at reducing acute pain sensation during a cold pressor test (CPT) (Watso et al. 2020). Collectively, these two studies indicate that sympathetic reactivity to both hypotension (Kienbaum et al. 2000) and hypertension (Watso et al. 2020) remains intact with ketamine administration. However, the effects of lowdose ketamine on tolerance to haemorrhage remain unclear, and this has important implications for pain management and ultimately survival following trauma in a field setting. The recent paper by Huang et al. (2020) in The Journal of Physiology provides novel insights on the effects of low-dose ketamine on the cardiovascular and neural response to experimentally induced central hypovolaemia. Huang et al. (2020) employed lower body negative pressure (LBNP) as an experimental model to simulate haemorrhage. Lower body negative pressure induces central hypovolaemia via fluid redistribution from the upper limbs and abdominal region to the lower extremities, resulting in decreased venous return, and an increase in baroreflex-mediated sympathetic nerve activity to maintain blood pressure. Huang et al. (2020) collected measurements of mean arterial pressure (MAP), heart rate and radial nerve muscle sympathetic nerve activity (MSNA) and also obtained blood samples to analyse for circulating catecholamines under: (i) control conditions (saline injection) and (ii) following ketamine injection. Over these two independent and randomized trials, participants completed a ramped LBNP protocol, starting at 40 mmHg of LBNP, and increased the severity of LBNP by 10 mmHg every 3 min until reaching a maximum LBNP of 100 mmHg or until participant reached presyncope. Maximal LBNP tolerance was determined experimentally using a cumulative stress index and compared between control and ketamine conditions. Despite a similar tolerance and MSNA response to LBNP between control and ketamine conditions, MAP and heart rate were generally elevated during the ketamine trial, indicating an uncoupling between sympathetic outflow and the cardiovascular response. Although this elegant study by Huang et al. (2020) will undoubtedly serve as a solid foundation for future studies in this research area, there are some experimental and methodological considerations that warrant further discussion.