Novel anesthetics in pediatric practice: is it time?

Abstract

Purpose of review

Steadily mounting evidence of anesthesia-induced developmental neurotoxicity has been a challenge in pediatric anesthesiology. Considering that presently used anesthetics have, in different animal models, been shown to cause lasting behavioral impairments when administered at the peak of brain development, the nagging question, ‘Is it time for the development of a new anesthetic’ must be pondered.

Recent findings

The emerging ‘soft analogs’ of intravenous anesthetics aim to overcome the shortcomings of currently available clinical drugs. Remimazolam, a novel ester-analog of midazolam, is a well tolerated intravenous drug with beneficial pharmacological properties. Two novel etomidate analogs currently in development are causing less adrenocortical suppression while maintaining equally favorable hemodynamic stability and rapid metabolism. Quaternary lidocaine derivatives are explored as more potent and longer lasting alternatives to currently available local anesthetics. Xenon, a noble gas with anesthetic properties, is being considered as an anesthetic-sparing adjuvant in pediatric population. Finally, alphaxalone is being reevaluated in a new drug formulation because of its favorable pharmacological properties.

Summary

Although a number of exciting anesthetic drugs are under development, there is currently no clear evidence to suggest their lack of neurotoxic properties in young brain. Well designed preclinical studies are needed to evaluate their neurotoxic potential.

INTRODUCTION

The requirement for adequate and readily controlled depth of anesthesia during surgical procedures and the foremost importance of patient safety have shifted the anesthetic drug development paradigm. The recent trend towards a ‘soft drug’ design, defined by rapid onset of action and recovery, increased therapeutic index and predictable metabolism to inactive metabolites [1,2], aims to provide the anesthesiologist with a very powerful tool. As the chemical structure of a given drug is intimately linked to its pharmacokinetic properties, this is often achieved via introduction of an ester bond, making the molecule prone to metabolism by nonspecific tissue esterases. On the other hand, the need for long-lasting nerve blocks and effective postoperative pain control call for more potent drugs with longer duration of action with less local and/or systemic toxicity [3].

On the basis of extensive body of preclinical [4–13] and growing clinical [14–19] evidence that early-in-life anesthesia causes widespread and long-lasting neurological damage because of unphysiological activation of neuroapoptosis resulting in permanent reduction in neuronal densities [5] and long-term behavioral impairments [4], novel general and local anesthetics should be designed with anesthesia-induced developmental neurotoxicity in mind. We have recently published a summary of the most promising neuroprotective strategies that may enable well tolerated use of currently available anesthetics [20]. Here, we highlight the recent advances in anesthetic drug development and evaluate their potential for clinical use in children.

REMIMAZOLAM: A NOVEL ULTRA-SHORTACTING BENZODIAZEPINE

The intravenous anesthesia and sedation in the current practice are predominantly achieved with propofol and/or midazolam. The slow onset of action and presence of active metabolite along with certain controversies about the quality and depth of midazolam-induced anesthesia [21,22] have diminished its use in favor of propofol, which provides faster onset of hypnosis, rapid recovery, antiemetic properties and enables target-controlled infusion (TCI). Notwithstanding these advantages, the narrow therapeutic index, systemic hypotension and central apnea, pain on injection site, phlebitis, and lipid accumulation associated with prolonged use of propofol have brought up a consideration for the development of potentially better intravenous anesthetics.

Remimazolam (CNS7056) is a novel ultra-short acting benzodiazepine [23]. The structure of remimazolam is almost identical to midazolam with the addition of an ester bond in the side chain. As a result, remimazolam undergoes metabolism by nonspecific tissue esterases, making it a useful drug in hepatic or renal failure. Remimazolam was approved for use as a general anesthetic in Japan in 2020 and for procedural anesthesia in the USA in 2021.

The ultra-rapid pharmacokinetics of remimazolam [23] have triggered several clinical trials aiming to revisit the concept of benzodiazepine-based general anesthesia. Recently, two large multicenter randomized controlled trials have been conducted to evaluate the feasibility of remimazolam versus propofol-based anesthesia in low-risk [24^■■] and high-risk patients [25^■■]. Both studies concluded that remimazolam has excellent ability to both induce and maintain anesthesia with fewer hypotensive episodes compared with propofol. Although remimazolam-based anesthesia resulted in slightly longer overall duration of a procedure because of longer latency to loss of consciousness and longer time to extubation [24^■■], as well as delayed time to discharge from the operating room compared with propofol, this could be because of technical difficulties rather than the intrinsic properties of the drug. Of note, flumazenil administration to two patients with delayed recovery resulted in the immediate return of consciousness [25^■■].

The intrinsic hemodynamic stability of remimazolam could be of particular value in patients with reduced cardiovascular reserve. In patients undergoing valve replacement surgery, induction of with remimazolam resulted in significantly fewer hypotensive episodes and a decreased use of vasopressors [26]. Remimazolam was also suitable for induction in elderly patients with severe aortic stenosis with no serious adverse effects [27^■], suggesting that remimazolam could be beneficial in patients with compromised cardiovascular function.

In the United States, remimazolam is registered as a sedative for procedural anesthesia. Sedation with remimazolam versus midazolam or placebo led to superior procedural success rates in bronchoscopy and gastrointestinal endoscopy [28–30] cases with shorter length of procedure and faster and more complete return to preprocedure cognitive functions. Recently, it has been reported that female patients undergoing hysteroscopy exhibited fewer adverse effects and less respiratory depression with remimazolam compared with propofol sedation with improved overall recovery [31^■].

Currently, the preclinical literature involving remimazolam administration is scarce. Through TLR4 receptor downregulation, remimazolam was shown to interfere with lipopolysaccharide (LPS)-induced endotoxemia via blockade of NF-kB signaling pathway and reversal of LPS-induced phosphorylation of Akt and Erk protein kinases essential for neuronal survival [32^■■]. The interaction with NF-kB was also beneficial in promoting glioma cell apoptosis in vitro [33] and in alleviating neuropathic pain in adult rats [34].

Remimazolam, like midazolam, is a potent GABA_A receptor agonist [23], which is the hallmark property of many neurotoxic anesthetics [4,35–39]. Interestingly, there is a report suggesting that remimazolam may negatively affect cognition in the elderly [40^■]. On the basis of the pharmacodynamic properties of remimazolam, there is currently no evidence to suggest it may be any different than other GABA_A-agonists with regard to anesthesia-induced neurotoxicity. However, the rapid conversion to completely inactive metabolites [23], easier dose titration and a potential for pharmacological reversal might reduce the cumulative neurotoxicity compared with other clinically available anesthetics. Of note, remimazolam was safely applied in 3-year-old Cynomolgus monkeys [41] and in a 4-year-old child with Duchenne muscular dystrophy undergoing inguinal herniorrhaphy [42^■]. Therefore, we believe that well designed preclinical studies in young animals aiming to compare the neurotoxic potential of remimazolam versus commonly used anesthetics, such as propofol or midazolam, would be a valuable addition to the current literature.

ETOMIDATE ANALOGS: A QUEST FOR CARDIOVASCULAR AND ADRENAL SAFEGUARD

The original enthusiasm towards etomidate as a rapidly acting anesthetic with wide therapeutic index and excellent cardiovascular stability had significantly diminished when increased mortality following etomidate-based anesthesia was observed [43]. As a potent inhibitor of 11β-hydroxylase [44,45], a rate-limiting step in steroid synthesis, etomidate use can lead to adrenocortical suppression for over a day even after routine application, resulting in almost complete abandonment of its clinical use.

The interest for etomidate was renewed after significant efforts were made to develop analog that would result in less adrenocortical suppression while preserving the rapid kinetics and hemodynamic stability. Cyclopropyl-methoxycarbonylmetomidate (CPMM) has emerged among many candidate drugs as a new ‘soft’ etomidate ester-analog. In contrast with etomidate, anesthesia with CPMM in LPS-induced sepsis model in rats was associated with less adrenocortical suppression, lower proinflammatory cytokine levels and less mortality [46] suggesting that CPMM might be the superior anesthetic for use in critically ill patients. Although relatively few, studies on healthy volunteers suggest that CPMM is well tolerated with few mild side effects [47,48]. Of note, involuntary muscle movements were present in a dose-dependent fashion, but they were not ictal in origin [49] and were effectively treated with midazolam or fentanyl [47,48].

A different line of research developed ET-26 hydrochloride (ET-26HCl), another etomidate analog currently approved for clinical trials in China. Early research showed that ET-26HCl preserved the rapid onset and hemodynamic stability of parent compound etomidate with very little adrenocortical suppression, which was comparable to that of CPMM [50,51]. The hemodynamic and adrenal stability together with superior myocardial performance following ET-26HCl administration [52] were demonstrated in rat models of hemorrhagic shock [53] and LPS-induced sepsis [54] resulting in overall better survival rates compared with etomidate parent compound. Recently completed studies in rats and beagle dogs have provided preclinical evidence about ET-26HCl safety profile [55^■,56,57], thus setting the stage for further testing in clinical trials.

The controversial findings and surprisingly few studies describing the effects of etomidate on the developing brain necessitate further investigation. Although earlier studies reported etomidate to be seemingly innocuous to immature brains, a recent study highlighted the proapoptotic effects of etomidate on hippocampal neurons in adult rats [58^■]. The development of novel etomidate analogs with fewer side effects, such as CPMM and ET-26HCl might reignite the interest and trigger new research of its potential applicability in pediatric anesthesia.

QUATERNARY LIDOCAINE DERIVATIVES: NOVEL DEVELOPMENTS IN REGIONAL ANESTHESIA

In contrast to the recent trends in general anesthetic development where the focus is on quick ‘on’ and ‘off’ effects and rapid metabolism, which allows for greater anesthesia control and easier titration, recent advances in the development of local anesthetics have focused on increasing the duration of action while keeping the systemic adverse effects to a minimum [3]. The short duration of action remains the major shortcoming of lidocaine, limiting its use in certain clinical scenarios. Although the discovery of bupivacaine seemed to solve this problem, the pronounced cardiotoxicity with difficult resuscitation remains a concern in the clinical setting [59^■■].

A novel class of local anesthetics known as quaternary lidocaine derivatives (QLD) has recently gained significant research interest with high hopes that they might solve some of the issues described with current local anesthetics [59^■■]. Although the mechanism of action of QLD is identical to other local anesthetics [60], the hydrophilic nature and permanent positive charge requires substantial time and concentration gradient to penetrate the neuronal and axonal membrane, which accounts for both the slow onset and prolonged duration of action of QLD.

QX-314, the QLD prototype, applied in three different animal models produced between 6-fold and 12-fold longer duration of anesthesia compared with equimolar lidocaine concentration [61]. Unfortunately, the significant tissue inflammation and systemic toxicity associated with QX-314 [62–64] precluded its clinical applicability. The substitution of one hydrogen group (-H) for hydroxyl group (-OH) yielded the newest QLD compound named QX-OH. When three concentrations of QX-OH were compared with equimolar QX-314 and bupivacaine using well established in vivo models, it was shown that QX-OH provided even longer duration of anesthesia and significantly less inflammation; however, because of the permanent charge and hydrophilicity of QX-OH, the rate of onset remains a major issue [65].

Ultimately, it was suggested that transient receptor potential vanilloid 1 (TRPV1) receptors could provide an aqueous route for QLD entry into the neurons [59^■■]. As local anesthetics are known to open TRPV1 receptors [66,67], combining QX-OH with levobupivacaine not only dramatically shortened the latency of local anesthetic effect but also prolonged its duration compared with QX-OH alone with minimal local tissue inflammation [68,69]. Furthermore, the preferential location of TRPV1 on nociceptor neurons might provide better pain control with less motor nerve paralysis [70].

Regional anesthesia provides better hemodynamic and respiratory stability with fewer gastrointestinal complications compared with general anesthesia. Although recent evidence suggests that lidocaine causes significant neuroapoptosis both in vivo and in vitro [71], it remains unclear whether local anesthetics are damaging to the developing neurons [20,72]. Nonetheless, the permanent charge of QLD and increased hydrophilicity of QX-OH could help prevent theblood–brain barrier crossing of these novel drugs, and therefore, may minimize the neurotoxic potential. For this reason, further studies are needed to establish whether QLD-based regional anesthesia could serve as a valuable alternative to general anesthesia in childhood, whenever applicable.

XENON: AN ANESTHETIC-SPARING AGENT

Although xenon has been known for its anesthetic properties for some years now, it has not received much attention as an anesthetic for widespread use [73]. In addition to excellent cardiovascular stability [73], preclinical evidence suggests xenon might be neuroprotective especially when used as an adjuvant to other commonly used anesthetics [74–77].

Recent warnings about clinical use of anesthetics in young children issued by Food and Drud Administration (FDA) [78] and xenon’s ability to protect against general anesthetics’ developmental neurotoxicity [74–77] brought its clinical potential to the forefront. The feasibility of combined xenon and sevoflurane anesthesia was first demonstrated in 2017 on children under the age of 4 undergoing cardiac catheterization [79]. Along with the satisfactory depth of anesthesia, the addition of xenon decreased the requirement for vasopressors and improved cerebral oxygenation. In the latest study comparing the effects of xenon and sevoflurane anesthesia on postoperative neural injury biomarkers, xenon was at least as effective as sevoflurane but the neuroprotective properties could not be confirmed possibly because of overall low incidence of postoperative cognitive dysfunction in the study group [80^■■].

Although the xenon production is especially costly [73], the favorable cardiovascular profile and potential neuroprotective properties could mean that the use of xenon as an adjuvant anesthetic might increase in the upcoming years. Although further human studies are needed, the technical feasibility of xenon anesthesia and substantial preclinical evidence might bring this almost forgotten anesthetic back in the operating rooms.

NEUROACTIVE STEROIDS: ANESTHESIA REVISITED FOR THE 21ST CENTURY

Almost 50 years ago, Gyermek and Soyka Lester [81] published an extensive review of a contemporary anesthetic, Alphadione (Althesin), which was a mixture of neuroactive steroid alphaxalone and its 21-acetoxy ester and concluded that alphaxalone, the carrier of the anesthetic effect, was a nearly ideal general anesthetic. In addition to rapid onset of action, alphaxalone had impressively high therapeutic index and hypnotic potency, offered good cardiovascular and respiratory stability, minimal cumulative effects, no injection-site injuries and few drug interactions [81]. Unfortunately, the Althesin formulation contained Cremophor EL, which was likely the culprit for unacceptably high rate of anaphylactic reactions associated with its use [82] leading to its withdrawal from the market in 1984.

The interest towards alphaxalone has recently reemerged and a new formulation with 7-sulfobutyl-ether-β-cyclodextrin as the vehicle was formulated under the name Phaxan. One preclinical study sought to compare the pharmacological properties of Phaxan versus Althesin and propofol in rats [83]. In addition to comparable anesthetic potency and rapid onset and offset of anesthesia, Phaxan had significantly less adverse reactions and higher therapeutic index compared with the other two drugs tested in this study. Alongside similar findings of hypnotic potency and fewer side effects when compared with propofol in humans [84,85], these findings suggest that alphaxalone might, once again, find its place in clinical setting.

We have recently published an extensive summary on mechanism of action of neuroactive steroids and the lack of observable neuronal injury even after prolonged exposures in young animals [86], thus making them a potentially viable alternative to currently used general anesthetics [20]. Briefly, alphaxalone and similar neuroactive steroids, such as investigational drugs, CDNC24 [(3α,5α)-3-hydroxy-13,24-cyclo-18,21-dinorchol-22-en-24-ol) and 3β-OH ((3β,5β,17β)-3-hydroxyandrostane-17-carbonitrile], unlike propofol or ketamine, lack the neuroapoptogenic properties in rat pups [87,88^■]. Hence, the novel formulation of alphaxalone devoid of its anaphylactogenic properties might be a valuable addition to the anesthetic drug arsenal for children undergoing general anesthesia.

Published studies on the novel anesthetics discussed in this review are summarized in Table 1.

Table 1.

Summary of published clinical and preclinical studies of novel general and local anesthetics

Study type	Study		Study group			Regimen				Comparator	Endpoints	Conclusions
Remimazolam
Clinical	Doi et al., 2020 [24■■]		More than 20 years old, less than 100 kg ASA-PS I and II, n = 375			6–12mg/kg/h induction, i.v., 1 mg/kg/h maintenance, i.v.				Propofol	Efficacy, time to LoC, recovery	Well tolerated, noninferior
	Doi et al., 2020 [25■■]		More than 20 years old; more than 100 kg ASA-PS >III, n = 67			6–12 mg/kg/h induction, i.v. 1–2 mg/kg/h maintenance, i.v.				None	Efficacy, time to LoC, recovery, control of anesthesia	Safe and efficacious
	Liu et al., 2021 [26]		35–65 years old SAVR NYHA II or III, n = 60			1.8 mg/kg/h, i.v.				Propofol	Induction only, ΔHR, ΔMAP, vasopressor use, BIS, Lac, Glu	ΔMAP lower in remimazolam, less need for vasopressors
	Nakanishi et al., 2021 [27■]		More than 65 years old TAVR or SAVR severe aortic stenosis ASA-PS IV, n = 20			6 mg/kg/h				None	vasopressor use, ΔHR, ΔMAP, BIS, time to LoC, time to intubation	safe and efficacious with timely vasopressor use
	Pastis et al., 2019 [28]		More than 18 years old bronchoscopy ASA-PS I, II, III, n = 420			5 mg, i.v. bolus				Midazolam, placebo	Procedural success, latency to onset and recovery, safety parameters	Safe and efficacious, rapid onset and recovery
	Borkett et al., 2015 [30]		18–65 years old upper GI endoscopy 60–120 kg, BMI 18–29 ASA-PS I or II n = 100			0.10, 0.15 or 0.20 mg/kg				Midazolam	Procedural success, latency to onset and recovery, safety parameters	Safe and efficacious, rapid onset and recovery at all doses tested
	Zhang et al., 2022 [31■]		Female, 18–55 years old hysteroscopy BMI 18–30 ASA-PS I or II, n = 90			0.25 mg/kg i.v. bolus, 0.48 or 0.6 mg/kg/h, i.V.				Propofol	Procedural success, latency to onset and recovery, safety parameters	Safe and efficacious, less adverse effects
	Tan et al., 2022 [40■]		More than 60 years old, upper GI endoscopy ASA-PS I or II, n = 99			0.1 or 0.2 mg/kg				Propofol	Cognitive outcomes in elderly patients, success rates, onset and recovery	Cognitive impairment, 0.2>0.1 mg/kg less hypotension in 0.1 mg/kg
	Horikoshi et al, 2021 [42■]		4-year-old boy Duchenne muscular dystrophy, inguinal herniorrhaphy			3 mg i.v. bolus induction, 15 mg/h i.v. maintenance				None	Efficacy, feasibility, recovery	Safe and effective
Preclinical	Liu et al., 2021 [32■■]		Mice, 8 weeks old 20 mg/kg LPS primary BMDM			16 mg/kg i.p., 30 min before LPS 8 mg/kg i.p., 30 min after LPS				None	IHC, IF, ELISA, qPCR, WB, flow cytometry	↓LPS-induced cell death ↓TNFα, IL-1β, IL-6 ↓tissue inflammation and necrosis ↓TLR4, NF-kB signaling ↓pAkt, ↓pERKl/2
	Xu et al., 2021 [33]		Primary astrocytes, U-11 8MG and U87MG glioma cell lines	2–20 μmol/l RFMSP (remimazolam derivative)						None	Viability, IF, WB, flow cytometry	↓glioma cell viability ↑glioma apoptosis (caspase-3) ↓NF-kB, ↓survivin ↓Bcl-2 and ↑Bax
	Xie et al., 2021 [34]		Rats, adult CFA 20 μl paw BV2 microglial cells LPS 1 mg/ml	2.5 mg/kg in vivo 200 μg/ml in vitro						None	ELISA, WB, TEM, IF	↓bradykinin receptor ↓pain and Inflammation ↓NF-kB, ↓autophagy
	Kops et al., 2021 [41]		Cynomolgus monkeys, 3 years old	5–50 mg/kg/h, i.v.						Midazolam, propofol	Sedation behavior	Rapid and potent sedation dose-dependent synergism with remifentanil
CPMM
Clinical	Valk et al., 2018 [47]		18–45 years old, healthy nonsmoking, ASA-PS I, n = 40	30–60 μg/kg/min for 30 min						Propofol, placebo	Safety and efficacy, hemodynamic and adrenal	Rapid onset and recovery, mild ↑HR and ↑MAP dose-dependent IMM
	Struys et al., 2017 [48]		18–45 years old, healthy nonsmoking, BMI 17.5–30, ASA-PS I or II, n = 60	0.03–1 mg/kg, i.v. bolus						Placebo	Safety and efficacy, dose optimization, onset and recovery	Rapid onset and recovery, dose-dependent IMM
Preclinical	Santer et al., 2015 [46]		Rats, adult 1 mg/kg LPS	71 mg/kg total, 1 h i.v. infusion						Etomidate	ELISA (corticosterone and cytokines)	Less adrenal suppresion than etomidate ↓IL-1β, IL-6, IL-10 ↓mortality
	Valk et al., 2019 [49]		Beagle dogs, 8–9 months, n = 14	6 mg/kg i.v. bolus induction 1, 1.5 or 2.3 mg/kg/min maintenance for 2 h						None	GABAA electrophysiology and toxicology	IMM upon use not of ictal origin GABAA and glycin mediated
ET-26HCI
Preclinical	Wang et al., 2017 [50]		Rats, adult	1.3–4.5 mg/kg, i.v.						Etomidate, propofol	ELISA, behavior, pharmacokinetics, onset and recovery	Rapid onset and recovery less adrenal suppression than etomidate less ΔMAP than propofol IMM with use
	Yang et al., 2017 [51]		Beagle dogs, adult	Dose range not specified						Etomidate, CPMM	Onset and recovery, pharmacokinetics, pharmacodynamics	Less adrenal suppression than etomidate
	Liu et al., 2017 [52]		Rats, adult beagle dogs, adult Langendorff rat heart	1, 2, 4 × ED50						Etomidate	echocardiography, ECG, electrophysiology	↑myocardial performance similar to etomidate
	Wang et al., 2017 [53]		Rats, adult uncontrolled hemorrhagic shock model	1.33–3 mg/kg, i.v. bolus						Etomidate, propofol	Pharmacokinetics, pharmacodynamics, hemodynamics	↑hemodynamic stability ↓lactate
	Wang et al, 2017 [54]	Rats, adult 1 mg/kg LPS			2 × ED50, i.v. bolus			Etomidate, saline			IHC (lungs, kidneys) ELISA (plasma cytokines, corticosterone)	↑survival compared to etomidate less adrenal suppression ↓IL-1β, ↓IL-6
	Zhang et al., 2021 [55■]	Rats, adult beagle dogs, 1–2 years old			4, 8, 16 mg/kg, rat, i.v. 8, 12, 16 mg/kg, dog, i.v.			Vehicle (propylene glycol)			Cardiovascular, respiratory, central nervous system function	Mild and reversible adverse effects
	Zhang et al., 2020 [56]	Beagle dogs, 6–8 months			4–16 mg/kg, i.v., single 8–16 mg/kg, i.v., repeated for 14 days			Vehicle (propylene glycol)			Toxicology: heart, blood, vital organs	No observable side effects at any timepoint
	Zhang et al., 2020 [57]	Rats, adult			8, 16, 20 mg/kg, i.v., single 8, 12, 16 mg/kg, i.v., repeated for 14 days			Vehicle (propylene glycol)			Toxicology: urine, blood, vital organs	↑Mortality with repeated doses no serious adverse effects with single doses
QX-314
Preclinical	Lim et al., 2007 [61]	Mice, adult, n = 45 guinea pigs, adult, n = 8			10, 30, 70 mmol/l			Lidocaine, saline			Intradermal (guinea pigs) tail flick and sciatic nerve block (mice)	↑↑Duration slow onset
	Shankarappa et al, 2012 [62]	Rats, adult males			25 mmol/l			QX-222			Sciatic nerve block IHC (myotoxicity)	↑↑Duration severe myotoxicity
	Schwarz et al, 2010 [63]	Mice, adult female			0.5–10 mmol/l, it			Saline			Efficacy (lumbosacral block) toxicity (irritation and death)	↑↑Duration severe adverse effects
	Cheung et al, 2011 [64]	Mice, adult			7.5–30 mg/kg, i.v.			Lidocaine			Toxic and lethal dose CNS and cardiac toxicity	Severe cardiac and CNS toxicity
QX-OH
Preclinical	Zhang et al, 2017 [65]		Rats, adult		25, 35, 45 mmol/l			QX-314 bupivacaine saline			IHC (local inflammation) sciatic nerve block cutaneous trunci pinprick	↑↑↑Duration compared with QX-314 and bupivacaine less local toxicity slow onset
	Zhao et al, 2018 [68]		Rats, adult mice, adult total knee arthroplasty		35 mmol/l + 10 mmol/l levobupivacaine			Liposome bupivacaine, saline			IHC (local inflammation) behavior (open field, thermal nociception, autonomic activity)	↑↑↑Duration of block minimal local toxicity when combined
	Yin et al, 2019 [69]		Rats, adult subcutaneous infiltration sciatic nerve block		35 mmol/l + 10 mmol/l levobupivacaine			QX-OH levobupivacaine saline			Onset and recovery duration of effect local and systemic toxicity	Faster onset ↑↑↑duration ↓local and systemic toxicity when combined
Xenon
Clinical	Devroe et al, 2017 [79]		Less than 4 years old elective cardiac catheterization n = 40		50–65% + sevoflurane			Sevoflurane			Hemodynamic stability feasibility, efficacy and recovery safety	Safe and efficacious ↓vasopressor use
	McGuigan et al., 2022 [80■■]		More than 50 years old ESWL, ASA-PS I and II n = 23				60% end-tidal, 6 ml/kg		Sevoflurane		Neural injury biomarkers cognitive assessment	No change in injury biomarkers no difference in cognitive assessment
Preclinical	Cattano et al., 2008 [74]		Mice, 7 days old				70%±0.75% isoflurane for 4 h		Isoflurane		IHC (neuroapoptosis)	↓Caspase-3 in caudate/putamen when combined with isoflurane
	Gill et al., 2020 [75]		Rats, 8 days old				35% + 1.8% sevoflurane 70% + 0.9% sevoflurane for 6 h		Sevoflurane		IHC (neuroapoptosis)	↓Caspase-3 in cortex and caudate/putamen (70% only)
	Ma et al., 2007 [76]		Rats, 7 days old				30, 60, 75%±0.75% isoflurane for 6 h		Isoflurane		IHC and WB (neuroapoptosis)	↓Caspase-3, caspase-9 ↓cytochrome c
	Shu et al., 2010 [77]		Rats, 7 days old				70%, pretreatment for 2 h		Nitrous oxide and isoflurane		IHC and WB (neuroapoptosis) fear conditioning (memory)	↓Neuroapoptosis in cortex and hippocampus ↑memory
Neuroactive steroids
Clinical	Monagle et al., 2015 [84]		18–40 years old males BMI 18–25, ASA-PS I, healthy volunteers n = 24				0.42–0.55 mg/kg (Phaxan) dose titration to BIS<50		Propofol		Onset and recovery cardiovascular and respiratory effects adverse effects cognitive function	Rapid onset and recovery ↓cardiovascular and respiratory depression ↓adverse effects normal cognitive performance
Preclinical	Goodchild et al., 2015 [83]		Rats, adult				1.2–15 mg/kg, i.v. (Phaxan)		Propofol althesin		Effective and lethal dose cardiovascular effects lethality	Rapid onset and recovery equipotent to Althesin higher therapeutic index less cardiovascular depression
	Atluri et al., 2018 [87]		Rats, 7 days old				5–10 mg/kg, i.p. every 2 h for 12 h (3β-OH)		Ketamine		Effective and lethal dose, IHC (neuroapoptosis) behavior (radial arm maze) electrophysiology	↓Neuroapoptosis subiculum, thalamus and cortex ↑memory T-type calcium channel block, ↓spontaneous GABA release
	Tesic et al., 2020 [88■]		Rats, 7 days old				10 mg/kg, i.p. every hour for 6h (alphaxalone and CDNC24)		Propofol		Effective and lethal dose, IHC (neuroapoptosis) electrophysiology	↓Neuroapoptosis subiculum and medial prefrontal cortex GABA-potentiating effect

ASA-PS, American Society of Anesthesiologists Physical Status; BIS, bispectral index; BMDM, bone marrow-derived macrophages; CFA, complete Freund’s adjuvant; CNS, central nervous system; ESWL, extracorporeal shock wave lithotripsy; GABA, gamma-amino butyric acid; GI, gastrointestinal; Glu, glucose; HR, heart rate; IF, immunofluorescence; IHC, immunohistochemistry; IL, interleukin; IMM, involuntary muscle movement; i.p., intraperitoneally; i.v., intravenously; Lac, lactose; LoC, loss of consciousness; LPS, lipopolysaccharide; MAP, mean arterial pressure; NF-kB, nuclear factor kappa b; NYHA, New York Heart association; qPCR, quantitative PCR; SAVR, surgical aortic valve replacement; TAVR, transcatheter aortic valve replacement; TEM, transmission electron microscopy; TLR4, toll-like receptor 4; TNFα, tumor necrosis factor alpha; WB, western blot.

CONCLUSION

Despite established preclinical and growing clinical evidence indicating the neurotoxic properties of virtually all commonly used general anesthetics with long-lasting consequences on normal behavioral development, the best path forward remains unclear. As the evidence in this field continues to mount (over 1000 publications around the world in a variety of animal species – from nematodes to nonhuman primates and humans), we have seen an interesting spectrum of corollaries ranging from minimizing it, to being sceptical but willing to consider it, to actually contemplating the phenomenon as important and relevant. Although the field is pondering the best course of action, we believe the need for the development of new and safer anesthetics cannot be underestimated especially in view of the fact that many therapeutic interventions have tried and failed to conclusively convey any neuroprotection against anesthesia-induced developmental neurotoxicity [20], leaving us perplexed as to how to proceed. Perhaps it is time to question the entrenched fondness for our current anesthetics and embrace the new pharmacotherapeutics for the sake of the youngest, sickest and most vulnerable members of our community.

KEY POINTS.

• Remimazolam is a ‘soft’ analog of midazolam with safety and applicability comparable to propofol causing benzodiazepine-based anesthesia to be revisited.

• Two of the etomidate analogs, CPMM and ET-26HCl, are currently being investigated as intravenous anesthetics with less adrenocortical suppression while maintaining hemodynamic stability.

• Quaternary lidocaine derivatives are being developed as more potent, longer lasting regional anesthetics with unique pharmacological features.

• Xenon and alphaxalone are being revisited as potential general anesthetics in humans with potentially important safety benefits in children.

• Further preclinical evidence is necessary to establish the neurotoxic profile of these novel anesthetic compounds.