Anesthesia, the developing brain, and dexmedetomidine for neuroprotection

Balkan Medical Journal, 2013

Alpha 2 agonists contribute to pain control at the level of the medulla spinalis via descendant neuroadrenergic systems originating from the brain. Neuroadrenergic neurons stemming from the locus coeruleus and subcoeruleus nuclei send projections to the posterior horn of the medulla spinalis. Stimulation of this pathway provides antinociception, apparently dependent on noradrenaline discharge (1). Alpha 2 agonists are frequently added to local anaesthetic agents in order to prolong the duration of spinal or epidural anesthesia. An alpha 2 agonist drug, clonidine, extends the duration of analgesia in patients receiving spinal or epidural anaesthesia when given in combination with local anaesthetics, opioids, or both (2, 3). In studies performed on rats, sedative effects of alpha 2 agonists were suggestively related to the alpha 2A subtype, which involved the region of the locus coeruleus (4, 5). Compared with other alpha 2 agonists, dexmedetomidine has a higher affinity for receptors, and its spinal antinociceptive efficacy has been demonstrated in animal studies (6, 7). It was reported that long-term intrathecal drug application could induce permanent neuronal damage especially following spinal anaesthesia (8, 9). However, the neurotoxic effects of intrathecal or intracerebroventricular dexmedetomidine application are not known. In this study, we applied dexmedetomidine via the intracerebroventricular route for 5 days using a different catheterisation technique, with the intention to investigate its antinociceptive, sedative, and neurotoxic effects on the spinal cord. Material and Methods This study was performed on 32 16-week-old Wistar strain male rats weighing 250-300 g after obtaining the approval of

Journal of Neuroanaesthesiology and Critical Care, 2016

There is an increasing concern regarding the risk of anesthetic-induced developmental neurotoxicity (AIDN) in children. Evidence has shown that exposure to most of the commonly used anaesthetic and sedatives can cause neurodegeneration in the developing brain. Anesthetic effects on the brain during its growth spurt can initiate a cascade of alterations in neurodevelopment, which can be detected structurally or functionally. Anesthetic exposure induces apoptosis and neurodegeneration in a dose and time-dependent fashion consistent with the pattern of N-methyl D-aspartate antagonism and gamma-amino butyric acid type A activation by these drugs. Understanding the cellular and molecular mechanisms of AIDN may help in developing methods that are safe and do not interfere with the beneficial properties of anaesthetic drugs and yet inactivate the intracellular signals that trigger neuroapoptosis.

Translational Perioperative and Pain Medicine, 2018

Since its approval by US Food and Drug Administration in 1999 the clinical use of dexmedetomidine has been gaining in popularity. The indications and clinical applications of this drug have been expanded significantly. In this paper we reviewed its pharmacokinetics, pharmacodynamics, mechanisms of action and mainly focused on its clinical uses and outcomes. Common clinical uses of dexmedetomidine include pre-operative anxiolysis, heart rate control during intubation, treatment of bronchospasm, prevention of laryngospasm and avoiding opioid-induced post-operative respiratory depression and nausea and vomiting. Avoiding opioid induced respiratory depression has been especially beneficial in patients with sleep apnea syndrome. Other problems that can be prevented with dexmedetomidine are tachydysrhythmias, myocardial ischemia, delirium and acute kidney injury. Dexmedetomidine is an excellent sedative drug for intubated patients and it greatly facilitates neurological evaluation. It has been used successfully as a patient-controlled anesthesia drug and to prevent shivering. It is also used as an adjuvant to local anesthetics. It has been suggested that dexmedetomidine is a drug that has many beneficial effects and should be used more frequently by anesthesia care providers to prevent common problems in the peri-operative period. With judicious titration to effect during the intravenous administration of this drug the occurrence of side effects can be minimized. It is very likely that this drug will ascend to take a much more prominent role in future anesthesia practice.

Anesthesia & Analgesia, 2007

BACKGROUND: The alpha2-receptor agonist, dexmedetomidine, provides sedation with facilitated arousal and analgesia with no respiratory depression. These properties render it potentially useful for anesthesia premedication, although parenteral administration is not practical in this setting. We designed this study to evaluate the sedative, anxiolytic, analgesic, and hemodynamic effects of dexmedetomidine administered intranasally in healthy volunteers. METHODS: Koch's design for crossover trials (three-treatment and two-period design) was adopted. The study was double-blind and there were three treatment groups: A (placebo), B (intranasal dexmedetomidine 1 g/kg) and C (intranasal dexmedetomidine 1.5 g/kg). Each of the 18 subjects participated in two study periods. The study drug was administered intranasally after baseline observations of modified Observer Assessment of Alertness/Sedation Scale, visual analog scale of sedation, bispectral index, visual analog scale of anxiety, pain pressure threshold measured by an electronic algometer, systolic blood pressure (SBP) and diastolic blood pressure, heart rate, respiratory rate, and oxygen saturation. These were repeated during the course of the study. RESULTS: Intranasal dexmedetomidine was well tolerated. Both 1 and 1.5 g/kg doses equally produced significant sedation and decreases in bispectral index, SBP, diastolic blood pressure, and heart rate when compared with placebo (P Ͻ 0.05). The onset of sedation occurred at 45 min with a peak effect at 90 -150 min. The maximum reduction in SBP was 6%, 23%, and 21% for Groups A, B, and C respectively. There was no effect on pain pressure threshold, oxygen saturation or respiratory rate. Anxiolysis could not be evaluated as no subjects were anxious at baseline. CONCLUSION: The intranasal route is effective, well tolerated, and convenient for the administration of dexmedetomidine. Future studies are required to evaluate the possible role of the noninvasive route of administration of dexmedetomidine in various clinical settings, including its role as premedication prior to induction of anesthesia.

Anesthesiology, 2018

Postoperative delirium is associated with poor long-term outcomes and increased mortality. General anesthetic drugs may contribute to delirium because they increase cell-surface expression and function of α5 subunit-containing γ-aminobutyric acid type A receptors, an effect that persists long after the drugs have been eliminated. Dexmedetomidine, an α2 adrenergic receptor agonist, prevents delirium in patients and reduces cognitive deficits in animals. Thus, it was postulated that dexmedetomidine prevents excessive function of α5 γ-aminobutyric acid type A receptors. Injectable (etomidate) and inhaled (sevoflurane) anesthetic drugs were studied using cultured murine hippocampal neurons, cultured murine and human cortical astrocytes, and ex vivo murine hippocampal slices. γ-Aminobutyric acid type A receptor function and cell-signaling pathways were studied using electrophysiologic and biochemical methods. Memory and problem-solving behaviors were also studied. The etomidate-induced s...

Paediatric anaesthesia, 2015

A multitude of animal studies have shown that virtually all general anesthetics used in clinical practice possibly during a vulnerable period of brain development (i.e., brain growth spurt, peak of synaptogenesis) may lead to neurodegeneration (particularly apoptosis) and abnormal synaptic development with functional deficits in learning and behavior later in life. Initial studies were mainly performed in immature rodent pups, but more recent studies have included nonhumans primates (rhesus monkeys). Given the number of neonates, infants, and young children anesthetized annually worldwide, these findings could have significant public health implications. So far, relatively few human (cohort) studies focusing on this topic have been published with inconsistent results. While some studies have indicated an association between exposure to anesthesia and surgery, other studies have indicated no such association. Prospective studies are underway, but the result will not be available for ...

2014

The practices of anaesthesiology and intensive therapy are difficult to imagine without sedation or general anaesthesia , regardless of whether the patient is a newborn, baby, child or adult. The relevant concerns for children are distinct from those for adults, primarily due to the effects of anatomical, physiological and pharmacokinetic-phar-macodynamic (PK/PD) differences, which become increasingly important in the brains of children as they develop. The process of central nervous system maturation in humans lasts for years, but its greatest activity (myelination and synaptogenesis) occurs during the fetal period and the first two years of life. Many experimental studies have demonstrated that exposure to anaesthetic drugs during this period can induce neurodegenerative changes in the central nervous systems of animals. The extrapolation of these results directly to humans must be performed with great caution, but anaesthesiologists around the world must begin to debate the safet...

Current Anesthesiology Reports, 2013

A multitude of animal studies have shown that virtually all general anesthetics used in clinical practice exert detrimental effects on the developing brain, notably enhanced neuroapoptosis. Some studies have also indicated that animals exposed to general anesthesia may experience long term neurobehavioral deficits later in life. The neurotoxic effects seem to be dose-dependent and have been suspected to occur at certain early developmental stages. Initially, the animal studies comprised primarily rodents but recently they have been confirmed in non-human primates. Recently, a number of (mainly retrospective) human cohort studies have been published with inconsistent results. While some studies have indicated an association between anesthesia and surgery and adverse neurobehavioral outcome, other studies have indicated no association. The cohort studies have many constraints and shortcomings. While prospective studies are underway, they will not provide any answers for several more years. The aim of this review is to provide the reader with a summary of recent human cohort studies and discuss their limitations and weaknesses. Although disturbing, the animal data lacks verification in humans. To date there are no data to support any change in clinical pediatric anesthetic practice. Any such change will be premature and potentially dangerous until we have evidence as to if and how general anesthesia impairs neurocognition and behaviour in infants and young children.

PLOS ONE

Dexmedetomidine (DEX) is a highly selective agonist of α2-receptors with sedative, anxiolytic, and analgesic properties. Neuroprotective effects of dexmedetomidine have been reported in various brain injury models. In the present study, we investigated the effects of dexmedetomidine on hippocampal neurogenesis, specifically the proliferation capacity and maturation of neurons and neuronal plasticity following the induction of hyperoxia in neonatal rats. Six-day old sex-matched Wistar rats were exposed to 80% oxygen or room air for 24 h and treated with 1, 5 or 10 μg/kg of dexmedetomidine or normal saline. A single pretreatment with DEX attenuated the hyperoxia-induced injury in terms of neurogenesis and plasticity. In detail, both the proliferation capacity (PCNA+ cells) as well as the expression of neuronal markers (Nestin+, PSA-NCAM+, NeuN+ cells) and transcription factors (SOX2, Tbr1/2, Prox1) were significantly reduced under hyperoxia compared to control. Furthermore, regulators of neuronal plasticity (Nrp1, Nrg1, Syp, and Sema3a/f) were also drastically decreased. A single administration of dexmedetomidine prior to oxygen exposure resulted in a significant up-regulation of expression-profiles compared to hyperoxia. Our results suggest that dexmedetomidine may have neuroprotective effects in an acute hyperoxic model of the neonatal rat.

Journal of Pregnancy and Child Health, 2015

Advances in neonatal and pediatric surgery and intensive care demanded for increasing general anesthesia requirements in small infants, as well as the need for prolonged infusions for sedation. General anesthesia results from a complex pharmacological interaction of different drugs, many with still incompletely known mechanisms . Consequently, their immediate and long-term effects are not completely understood. Traditionally, anesthetic drugs' effects were thought to dissipate as early as the end of their administration, without prospective effects on children development . Since fifties, a concern about anesthetic consequences in the developing brain started to rise due to studies that have showed that vinyl ether, cyclopropane or ethyl chloride administration to young children could cause long-term personality changes . During the past three decades, strong evidence from animal studies have questioned the anesthetic safety profile on central nervous system development, and inflamed debate surrounds the negative effects of anesthesia in the developing brain. In fact, animal studies to date reveal very robust and consistent data concerning anesthesia-induced neurotoxicity in immature mammals and rodents. Considering the universal and serious possible impact of this issue in pediatric health care, the Food and Drug Administration (FDA) established a partnership with the International Anesthesia Research Society (IARS), called SmartTots (Strategies for Mitigating Anesthesia-Related Neurotoxicity in Tots), to specifically address and make recommendations on this matter.