VUTSKITS, Laszlo, SNEYD, J R. Quest for new drugs: a way to solve anaesthesia neurotoxicity? British Journal of Anaesthesia , 2018, vol. 120, no. 4, p. 619-621

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Quest for new drugs: a way to solve anaesthesia neurotoxicity?


VUTSKITS, Laszlo, SNEYD, J R. Quest for new drugs: a way to solve anaesthesia neurotoxicity? British Journal of Anaesthesia , 2018, vol. 120, no. 4, p. 619-621

DOI : 10.1016/j.bja.2018.01.024 PMID : 29576101

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17. Noguchi KK, Johnson SA, Dissen GA, et al. Isoflurane exposure for three hours triggers apoptotic cell death in neonatal macaque brain.Br J Anaesth2017;119: 524e31 18. Schino G, Perretta G, Taglioni AM, Monaco V, Troisi A.

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British Journal of Anaesthesia,120 (4): 619e621 (2018) doi:10.1016/j.bja.2018.01.024

Advance Access Publication Date: 24 February 2018

©2018 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.

Quest for new drugs: a way to solve anaesthesia neurotoxicity?

L. Vutskits


and J. R. Sneyd



Department of Anesthesiology, Pharmacology and Intensive Care, University Hospitals of Geneva, Geneva, Switzerland and


Department of Anaesthesia, Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth, UK

*Corresponding author.

All contemporary general anaesthetics have been convincingly shown to produce neurotoxic effects in at least some experi- mental animal models, and many of the underlying mecha- nisms have been identified.1Whilst the human relevance of these observations is still under intense scrutiny, the elabora- tion of protective strategies along with the development of new

‘non-toxic’anaesthetic drug regimens have been identified as rational research directions to alleviate potential neurotox- icity.2In this edition of theBritish Journal of Anaesthesia, Atluri and colleagues3report preliminary animal experiments for a novel neurosteroid hypnotic. They describe the compound as

‘safe’in comparison to ketamine, and suggest that this new class of hypnotic represents ‘a distinct panselective T-type Ca channel blocker devoid of GABAergic or NMDA antagonistic properties at hypnotically-relevant brain concentrations’that provides a rational route of drug development that might lead to effective anaesthesia without paediatric neurotoxicity.

This work deserves particular attention, as it provides us with the detailed laboratory neurotoxicity profile of a drug, called (3b,5b,17b)-3-hydroxyandrostane-17-carbonitrile (3b- OH), which can induce anaesthesia/sedation comparable with that of ketamine in rats. Focusing on 7-day-old neonatal rat pups, the authors first showed that 3b-OH is virtually devoid of pro-apoptotic effects when compared with ketamine at equi- potent concentrations. In line with these observations, they then provide data showing that, unlike ketamine, the neonatal administration of 3b-OH does not lead to impaired spatial learning at later stages of life in this experimental model. In parallel, the authors also performed serial measurements of 3b- OH concentrations both in plasma and in brain to obtain the pharmacokinetic profiles of this drug. Finally, they performed a series of electrophysiological recordings to identify potential targets and show that 3b-OH is a potent T-type Cachannel blocker, but lacks direct effects on both gamma-aminobutyric- acid- and N-methyl-D-aspartate-activated currents.

What do these new and interesting data teach us? Can we consider, as the authors suggest, that this ‘novel class of anaesthetic agents with different cellular targets might be safe and promising alternatives to the traditional general anaes- thetics currently used in paediatric medicine’? Whilst this hypothesis is plausible, there is still a long way to go to reach such a conclusion with certainty.

From the preclinical perspective, the major question is:

what criteria should be fulfilled in order to declare drug safety as far as the neurotoxicity issue is concerned? There is obvi- ously no appropriate answer to this question. By performing a variety of experimental approaches, Atluri and colleagues3 clearly raise the standards for how to define the neurotox- icity potential of novel anaesthetic compounds. Based on their observations, we have a reasonable set of data to consider that 3b-OH is less toxic than ketamine in the experimental model studied. However, we cannot exclude that 3b-OH induces a variety of other morpho-functional effects at this particular or at another developmental stage, which, in turn, could induce neurocognitive deficits in distinct cognitive domains that were not tested with the behavioural paradigm applied in this study. To push this idea further towards translational rele- vance, future experiments on the neurotoxicity profile of this drug are needed in the context of surgery and analgesia.

Should further experiments be performed with the goal of moving 3b-OH towards clinical trials? It should be kept in mind that none of the currently used anaesthetic drugs have un- dergone such detailed testing protocols. Knowing the costs associated with such experiments, especially in light of as yet questionable clinical relevance, it is difficult to envisage that such detailed preclinical work will ever be conducted on currently used anaesthetics. Last, but not least, the results obtained by one research group should be reproduced by other laboratories before taking observations for granted. This latter point is important to emphasise especially when considering





two recent studies where performing the very same experi- mental protocol to evaluate the neurotoxic potential of dex- medetomidine yielded largely divergent results.4,5

From the clinical perspective, all contemporary general an- aesthetics produce neurotoxic effects in at least some animal or model system. This rather than convincing human data have precipitated precautionary comments by regulators.6Anaes- thesia providers are currently confronted by a ‘problem’: alleged neurotoxicity risk to paediatric recipients of general anaes- thesia, whilst not having any robust basis on which to choose one anaesthetic against another. Nevertheless, research in this area has been identified as an international priority, and out- comes from human studies are eagerly awaited. Anaesthetic effects on cancer outcomes, paediatric neurotoxicity, and pro- pensity to postoperative cognitive dysfunction in adult patients have all been recommended as new development targets for hypnotic development programmes.7It is against this back- ground that we should consider the neuroactive steroid, 3b-OH.

Are preclinical studies a useful guide to neurotoxic pro- pensity in children and neonates? Quite clearly, the answer is that we currently have no idea. Given the uncertain relevance of preclinical data to humans, the conduct of additional ani- mal experiments is unlikely to take us forward. What we need to know is whether a drug is safe in humans. Easy to say, but difficult to do. If the only valid model for demonstration of anaesthetic neurotoxicity in humans is the demonstration of anaesthetic neurotoxicity in humans, we are not going to make much progress, except through lengthy, expensive, and hard-to-conduct randomised controlled trials.

From a practical standpoint, the ‘elephant in the room’

affecting the development of new hypnotics is the ubiquitous availability of low-cost and safe i.v. anaesthesia using generic propofol formulations. Although there are well-known issues with propofol (the lipid formulation, risks of bacterial contam- ination and subsequent sepsis, pain on injection, and cardio- respiratory depression), the reality is that virtually every patient can be safely anaesthetised using propofol subject to judicious choice of dosing and appropriate use of fluid and pressors.8Any new hypnotic, therefore, has its business case substantially undermined by the presence in the marketplace of an excellent low-cost generic competitor. For a development project to make progress in the harsh commercial world, the compound con- cerned will need to have a distinct ‘edge’over its competitors.

In order for a putative non-neurotoxic hypnotic to complete development and approval followed by successful commerci- alisation and deployment, several conditions need to be satis- fied. Firstly, the clinical community needs to be convinced that paediatric-anaesthetic-induced neurotoxicity is a reality.9At present, the data appear to suggest the opposite.10Whilst his- toric data offer some signals that early exposure to general anaesthesia might be associated with neurodevelopmental delay or other markers of impaired brain function, the evidence can best be summarised as equivocal, and all parties stress the importance of prospective randomised controlled trials.11 To date, the non-randomised Pediatric Anesthesia Neuro- development Assessment (PANDA) trial12 has a negative outcome, and we await the 5 yr data from the randomised General Anesthesia Compared to Spinal Anesthesia (GAS) study knowing, as we wait, that the 2 yr planned interim analysis showed no difference between patients receiving general anaesthesiavsspinal anaesthesia.13Other high-quality clinical data can be anticipated, including the Toxicity of Remifentanil and Dexmedetomine (TREX) trial comparing sevoflurane anaesthesia with a technique based mainly upon

dexmedetomidine and remifentanil (albeit with a small amount of sevoflurane; identifier: NCT02353182).

Nevertheless, it now seems very likely that none of the current limited portfolios of prospective clinical trials are going to show a convincing anaesthetic effect.

What do we do then? Would we propose to continue using agents known to be neurotoxic in a range of animal models? In the absence of an alternative, the answer can easily become

‘yes’. Once we have identified a convincingly non-neurotoxic (at least in animals) hypnotic, the dialogue may change, possibly in an irrational manner. As scientists, we could argue that it is logical to continue using hypnotics that are known to be neurotoxic in animal models, but appear to be harmless in humans. As parents, we might think about it differently, preferring compounds that are not neurotoxic even if the known neurotoxicity either does not matter to humans or does not exist in them. Good luck to the anaesthesiologist attempting to have that conversation with anxious parents shortly before taking their child to the operating room!

Authors ’ contributions

Writing paper: both authors.

Declaration of interest

The authors are not supported by, nor maintain any financial interest in, any commercial activity that may be associated with the topic of this article.


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3. Atluri N, Joksimovic SM, Oklopcic A, et al. A neurosteroid analogue with T-type calcium channel blocking properties is an effective hypnotic, but is not harmful to neonatal rat brain.Br J Anaesth2018;120: 768e78

4. Lee JR, Lin EP, Hofacer RD, et al. Alternative technique or mitigating strategy for sevoflurane-induced neuro- degeneration: a randomized controlled dose-escalation study of dexmedetomidine in neonatal rats.Br J Anaesth 2017;119: 492e505

5. Perez-Zoghbi JF, Zhu W, Grafe MR, Brambrink AM. Dexme- detomidine-mediated neuroprotection against sevoflurane- induced neurotoxicity extends to several brain regions in neonatal rats.Br J Anaesth2017;119: 506e16

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British Journal of Anaesthesia,120 (4): 621e623 (2018) doi:10.1016/j.bja.2018.01.002

Advance Access Publication Date: 14 February 2018

©2018 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.

Mode of anaesthesia for Caesarean delivery and maternal morbidity: can we overcome confounding by indication?

A. J. Butwick


and A. Palanisamy



Department of Anesthesiology, Perioperative, and Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA and


Department of Anesthesiology, Washington University School of Medicine, St Louis, MO, USA

*Corresponding author.

Rates of Caesarean delivery worldwide have reached unprece- dented levels. The global average Caesarean rate increased from 6.7% in 1990 to 19.1% in 2014, a 12.4% absolute increase over time,1with rates exceeding 30% in Latin America and the Caribbean, North America, and Oceania.1The escalating global rate of Caesarean delivery puts increasing demands on obstetric anaesthesiologists to deliver high-quality surgical anaesthesia.

For women undergoing Caesarean delivery, the anaesthesia type has an important influence on maternal outcomes. One of the main advantages of neuraxial anaesthesia is the lower rate of maternal mortality compared with general anaesthesia. Be- tween 1997 and 2002, case-fatality rates in the United States were lower for neuraxial anaesthesia compared with general anaes- thesia (3.8vs6.5 deaths per million live births, respectively).2 Unfortunately, in low- and middle-income countries, the rates of anaesthetic-related maternal death are substantially higher (1200vs5900 deaths per million women undergoing obstetric procedures with neuraxialvsgeneral anaesthesia, respectively), with anaesthetic complications accounting for a staggering 14%

of maternal deaths amongst those undergoing Caesarean de- livery.3In order to reduce the rates of anaesthetic-related deaths in under-resourced countries, there is a pressing need to identify causative factors and apply this information to improve anaes- thetic training, resources, and quality-measurement platforms.

Although maternal deaths are tragic events that we should strive to prevent, epidemiological data from the United States indicate that 52 000 women per year incur severe maternal morbidity, an event rate 100 times greater than maternal

death.4Of additional concern, severe maternal morbidity rates in the United States have increased from 73 per 10 000 delivery hospitalisations between 1998 and 1999 to 129 per 10 000 de- livery hospitalisations between 2008 and 2009, a 75% increase.4 As a consequence, leaders in obstetrics have called for more research to identify determinants of severe maternal morbidity.5These determinants include patient-level factors [such as advanced maternal age, race/ethnicity, obesity, and pre-existing medical conditions (heart disease and hyperten- sion)] and hospital system-level factors (such as delayed referral to higher levels of care, poor team communication, and lack of equipment or education).6

Less well studied is whether anaesthesia type influences the risk of severe maternal morbidity. Because general anaesthesia is typically considered for women who have contraindications to neuraxial anaesthesia or emergent indications for delivery, it would be unethical to consider a prospective trial where women are randomised to receive either general or neuraxial anaes- thesia. The next best options are observational studies using large, population-wide cohorts. Several studies suggest that, compared with general anaesthesia, neuraxial anaesthesia is associated with a lower risk of maternal morbidity, specifically postpartum haemorrhage, wound infection, and postoperative pain.7e9However, a key limitation of observational studies is disentangling any effect of anaesthesia type mode on morbidity from the myriad of confounders, especially those related to the clinical indication for Caesarean delivery (confounding by indication) or the severity of the indication (confounding by






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