A systematic review and narrative synthesis on the histological and neurobehavioral long‐term effects of dexmedetomidine

Abstract

SummaryBackgroundRecent experimental studies suggest that currently used anesthetics have neurotoxic effects on young animals. Clinical studies are increasingly publishing about the effects of anesthesia on the long‐term outcome, providing contradictory results. The selective alpha‐2 adrenergic receptor agonist dexmedetomidine has been suggested as an alternative nontoxic sedative agent.AimsThe aim of this systematic review was to assess the potential neuroprotective and neurobehavioral effects of dexmedetomidine in young animals and children.MethodsSystematic searches separately for preclinical and clinical studies were performed in Medline Ovid and Embase on February 14, 2018.ResultsThe initial search found preclinical (n = 661) and clinical (n = 240) studies. A total of 20 preclinical studies were included. None of the clinical studies met the predefined eligibility criteria. Histologic injury by dexmedetomidine was evaluated in 11 studies, and was confirmed in three of these studies (caspase‐3 activation or apoptosis). Decrease of injury caused by another anesthetic was evaluated in 16 studies and confirmed in 13 of these. Neurobehavioral tests were performed in seven out of the 20 studies. Of these seven rodent studies, three studies tested the effects of dexmedetomidine alone on neurobehavioral outcome in animals (younger than P21). All three studies found no negative effect of dexmedetomidine on the outcome. In six studies, outcome was evaluated when dexmedetomidine was administered following another anesthetic. Dexmedetomidine was found to lessen the negative effects of the anesthetic.ConclusionIn animals, dexmedetomidine was found not to induce histologic injury and to show a beneficial effect when administered with another anesthetic. No clinical results on the long‐term effects in children have been identified yet.

Is Perioperative Dexmedetomidine Associated With a Reduced Risk of Perioperative Neurocognitive Disorders Following Cardiac Surgery? A Systematic Review and Meta-Analysis With Trial Sequential Analysis of Randomized Controlled Trials

“…In recent years, a great deal of research confirmed that dexmedetomidine had a protective effect on multiple organ systems, namely, the heart, lungs, kidneys, liver, and the central nervous system. The reported neuroprotective mechanisms of dexmedetomidine included (1) inhibiting the excitability of sympathetic nerves and regulating the release of catecholamines; (2) regulating the release of central glutamate; (3) inhibiting cell apoptosis and release of inflammatory cytokines; (4) antioxidant stress; and (5) regulating synaptic plasticity and reducing neurotoxicity of anesthetics ( 40 , 41 ). Our study showed a decreased risk of POD following dexmedetomidine administration in cardiac surgery.…”

Quantitative Behavioural Phenotyping to Investigate Anaesthesia-Induced Neurobehavioural Impairment

“…In this, the effect is similar to that seen in vertebrates, where the most robust and consistent findings of neurobehavioural impairment also come in experiments with multiple agents and stronger exposures 9,37,38 . We have also seen that morphine and dexmedetomidine, both agents which have been shown not to cause neuroapoptosis or behavioural change in vertebrates 31,32 , do not appear to cause lasting behavioural change in C. elegans . Although there are 2 hits for morphine and 1 for dexmedetomidine, the pattern of these, with hits in lower concentrations not being reproduced for higher concentrations, suggests that they are outliers.…”

“…This timepoint was chosen because it is a period of extensive neurogenesis and neural rewiring (Fig 1a); exposure to isoflurane at this stage has previously been showed to result in defective behaviour 26 . Agents were chosen because of previous vertebrate literature suggesting a neurotoxic effect (ketamine 8 , isoflurane 9 ), lack of effect (morphine 31 , dexmedetomidine 32 ) or potential to rescue the neurotoxic deficit (lithium 33 ).…”

Quantitative behavioural phenotyping to investigate anaesthesia induced neurobehavioural impairment

“…1a); exposure to isoflurane at this stage has previously been showed to result in defective behaviour 26,28 . Agents were chosen because of previous vertebrate literature suggesting a neurotoxic effect (ketamine 8 , isoflurane 9 ), lack of effect (morphine 33 , dexmedetomidine 34 ) or potential to rescue the neurotoxic deficit (lithium 35 ).…”