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 low-dose 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. Although broadly used as an experimental model to study haemorrhage, there are some limitations in the translation of responses from LBNP to actual blood loss. Studies involving removal of blood volume are invasive and logistically difficult to perform in humans but provide the most applicable insight into the mechanism(s) involved in defending against cardiovascular collapse during haemorrhage. Johnson et al. (2014) conducted an impressive study assessing the response trajectory between progressive LBNP and progressive blood removal (up to 1000 mL) in humans. Overall, their results showed a strong correlation between cardiovascular responses to both protocols, substantiating that there is a similar engagement of compensatory hemodynamic responses between both stimuli. However, during blood removal, some notable differences were reported, which included an attenuated heart rate, lower circulating noradrenaline and lower total peripheral resistance (Johnson et al. 2014). Taken together, these highlighted cardiovascular differences between LBNP and blood removal suggest that sympathetic nerve activation might be lower following blood removal compared to LBNP, although this has not been experimentally confirmed in humans. Although LBNP is a proven non-invasive tool for investigating the impact of central hypovolaemia on cardiovascular and neural regulation, it may not be entirely applicable in the context of haemorrhage as a result of field trauma (i.e. blood loss) and a worthwhile future direction is to replicate this study during blood removal as opposed to LBNP. Huang et al. (2020) found no differences in MSNA burst frequency or incidence during rest or progressive LBNP following ketamine administration, despite an elevation in MAP and heart rate. This finding indicates that systemic neurovascular transduction or, more specifically, the ability of sympathetic nerve activity to alter the vasculature, is potentially elevated. Mechanism(s) of altered neurovascular transduction are difficult to elucidate but could be attributable to either: (i) changes in sympathetic neural recruitment and/or neurotransmitter release and reuptake and/or (ii) changes in sensitivity of vascular adrenergic, peptidergic or purinergic receptors. It has been previously recognized that the sympathomimetic effects of ketamine may be mediated through inhibition of the noradrenaline transporter (Liebe et al. 2017), which would result in decreased removal of noradrenaline from the synaptic cleft, prolonging its action. Intriguingly, Huang et al. (2020) reported no differences in the circulating noradrenaline concentration between control and ketamine trials, suggesting that neurovascular transduction may be altered through an alternative mechanism. However, it is difficult to assess noradrenaline re-uptake based solely on its concentration in venous blood, and thus future studies should consider tritiated noradrenaline to calculate hormone extraction. Noradrenaline release or reuptake may also be different between LBNP and blood loss, (as suggested in Johnson et al. 2014), which remains an important consideration for interpretation of the sympathetic effects of low-dose ketamine in this context. Despite unchanged MSNA burst frequency or incidence between control and ketamine trials, Huang et al. (2020) did not report metrics of burst amplitude or mean burst area, which may have provided important information regarding the neural response to LBNP. As comprehensively reviewed by Klassen and Shoemaker (2021), MSNA burst frequency may remain unchanged, whereas mean burst area, amplitude and/or burst latency (i.e. conduction velocity) could be altered. Sympathetic burst size (i.e. amplitude) is reflective of the proximity of the recording electrode to the postganglionic fibres (Klassen & Shoemaker 2021); however, changes in burst size (amplitude or area), although in the same recording site, can represent physiological differences in action potential recruitment (i.e. burst ‘content’). Evaluation of changes in burst amplitude or area following ketamine administration at rest (pre-LBNP) may have offered insight into whether there is a shift in neural recruitment and hence a shift in neurovascular transduction. Because ketamine exerts its effects on NMDA receptors located throughout the central nervous system, it should also be considered that there may be effects that act independently of autonomic control. The nuances of blood pressure regulation and sympathetic nervous system function following low-dose ketamine remains an area of interest for future research. In a similar study the same research group examining the effects of low-dose ketamine on pain perception, Watso et al. (2020) found that, during a sympathetic stressor (CPT), low-dose ketamine attenuated the increase in blood pressure but did not alter MSNA burst frequency. These results suggest that there is a blunting of neurovascular transduction in response to noxious stimuli (e.g. pain) following ketamine administration, although the precise mechanism(s) underlying this observation remains unclear. However, without analysis of burst amplitude or area to characterize ‘total MSNA’, it is difficult to determine whether neurovascular transduction was blunted with low-dose ketamine, or whether total MSNA was simply reduced. Also notable in the study by Watso et al. (2020) is the blunting of cardiac output during CPT following ketamine administration, which probably primarily contributes to the attenuation of increases in MAP. Importantly, the findings by Watso et al. (2020) and Huang et al. (2020) support the notion that the neural response to changes in blood pressure are relatively maintained following low-dose ketamine, and thus it appears to be a promising treatment option for pain management. Lastly, the homogeneity of the sample was appropriately justified to be representative of a military population involved in battlefield injury, trauma injuries are not limited to military settings, and research in this area should be expanded to the broader population. It has been previously reported that age, sex, ethnicity and or training status can affect neurovascular transduction. Although it is unclear whether there would be different pharmacokinetic or pharmacodynamic responses to ketamine administration in different populations, it is important to consider how differential cardiovascular regulation can independently influence tolerance to central hypovolaemia and or low-dose ketamine. The findings of Huang et al. (2020) indicate that the cardiovascular and neural response to LBNP after administration of low-dose ketamine remains largely unaltered, and thus highlights ketamine as a promising alternative to opioids for acute pain management in prehospital settings. This landmark investigation adds to the growing body of human-based literature related to ketamine administration and provides an excellent foundation for future research. Extending these findings to more diverse populations, and using various experimental approaches, will help to enrich our understanding of the potential utilities of low-dose ketamine. No competing interests declared. Sole author. Lindsey Berthelsen is funded by an NSERC CGS-M grant. I thank Dr Michael Tymko for his help in editing the final version of this manuscript submitted for publication.
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Jan 18, 2024
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