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      Nalbuphine pretreatment for prevention of etomidate induced myoclonus: A prospective, randomized and double-blind study

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          Abstract

          Background and Aims:

          Etomidate induced myoclonus (EM) is a common and hazardous sequel. Premedication with a number of opioids has been shown to effectively attenuate EM. However, there is no reported literature evaluating the effect of nalbuphine pretreatment on EM. The present study was designed to evaluate the efficacy of 0.2 mg/kg nalbuphine intravenous (IV) pretreatment for prevention of EM.

          Material and Methods:

          This prospective randomized double-blind and placebo controlled study was conducted in a medical college associated tertiary hospital. One hundred patients undergoing elective surgeries under general anesthesia were randomly allocated to one of two groups to receive: 10 ml of normal saline (Group I) or 0.2 mg/kg nalbuphine in 10 ml of normal saline (Group II) 150 s before injection etomidate 0.3 mg/kg administered IV over 20 s. The patients were assessed for the presence and severity of etomidate induced vascular pain (EP) and EM while injecting etomidate and for the next 2 min, respectively. The patients were monitored for sedation, nausea/vomiting, headache, dizziness, and respiratory depression for 24 h postoperatively. Student's t-test, Chi-square test, or Fisher exact test were used wherever appropriate and P < 0.05 was considered statistically significant.

          Results and Conclusion:

          Both the groups were comparable with respect to demographic characteristics. Nalbuphine pretreatment significantly reduced the incidence (20% vs. 72%; respiratory rate = 0.294, 95% confidence interval: 0.160–0.496, P < 0.01) and severity of EM without any significant increase in the incidence of adverse effects. Nalbuphine 0.2 mg/kg IV pretreatment significantly reduces the incidence and severity of EM with side-effect profile comparable to saline placebo.

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          Most cited references23

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          Reducing myoclonus after etomidate.

          The authors hypothesized that myoclonus after etomidate is dose-related, could be suppressed when small doses of etomidate were administered before induction, and is unassociated with seizure-like activity on electroencephalogram (EEG). Three studies were performed. In the first study, 36 men were randomly assigned to receive 0.025, 0.050, 0.075, 0.100, 0.200, or 0.300 mg/kg of etomidate. In a second crossover study, eight men were randomly allocated to receive either a pretreatment dose of 0.050 mg/kg etomidate or placebo 50 s before 0.300 mg/kg etomidate was injected. EEG was recorded for subjects in the first two studies. In a third study, 60 patients were randomly allocated to one of three pretreatment doses of etomidate: 0.030, 0.050, or 0.075 mg/kg before 0.300 mg/kg was given. In Study 1, myoclonus was not observed after 0.025 or 0.050 mg/kg etomidate. One volunteer had myoclonus after 0.075 mg/kg and another after 0.100 mg/kg etomidate; three had myoclonus after 0.200 mg/kg; and five after 0.300 mg/kg. Incidence of myoclonus was dose-related (P < or = 0.01). In Study 2, two volunteers (25%) with etomidate pretreatment had mild myoclonus compared to six (75%) with placebo pretreatment (P < or = 0.05). EEG changes, other than delta waves, were not seen during myoclonic epochs. In Study 3, myoclonus was less likely after the small pretreatment doses (0.030 or 0.050 mg/kg) than after the large dose (0.075 mg/kg, P < or = 0.01). Incidence and intensity of myoclonus after induction with etomidate are dose-related, suppressed by pretreatment, and unassociated with seizure-like EEG activity.
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            The howling cortex: seizures and general anesthetic drugs.

            The true incidence of seizures caused by general anesthetic drugs is unknown. Abnormal movements are common during induction of anesthesia, but they may not be indicative of true seizures. Conversely, epileptiform electrocortical activity is commonly induced by enflurane, etomidate, sevoflurane and, to a lesser extent, propofol, but it rarely progresses to generalized tonic-clonic seizures. Even "nonconvulsant" anesthetic drugs occasionally cause seizures in subjects with preexisting epilepsy. These seizures most commonly occur during induction or emergence from anesthesia, when the anesthetic drug concentration is relatively low. There is no unifying neural mechanism of anesthetic drug-related seizurogenesis. However, there is a growing body of experimental work suggesting that seizures are not caused simply by "too much excitation," but rather by excitation applied to a mass of neurons which are primed to react to the excitation by going into an oscillatory seizure state. Increased gamma-amino-butyric acid (GABA)ergic inhibition can sensitize the cortex so that only a small amount of excitation is required to cause seizures. This has been postulated to occur 1) at the network level by increasing the propensity for reverberation (e.g., by prolongation of the "inhibitory lag"), or 2) via different effects on subpopulations of interneurons ("inhibiting-the-inhibitors") or 3) at the synaptic level by changing the chloride reversal potential ("excitatory GABA"). On the basis of applied neuropharmacology, prevention of anesthetic-drug related seizures would include 1) avoiding sevoflurane and etomidate, 2) considering prophylaxis with adjunctive benzodiazepines (alpha-subunit GABA(A) agonists), or drugs that impair calcium entry into neurons, and 3) using electroencephalogram monitoring to detect early signs of cortical instability and epileptiform activity. Seizures may falsely elevate electroencephalogram indices of depth of anesthesia.
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              Endogenous dynorphin in epileptogenesis and epilepsy: anticonvulsant net effect via kappa opioid receptors.

              Neuropsychiatric disorders are one of the main challenges of human medicine with epilepsy being one of the most common serious disorders of the brain. Increasing evidence suggest neuropeptides, particularly the opioids, play an important role in epilepsy. However, little is known about the mechanisms of the endogenous opioid system in epileptogenesis and epilepsy. Therefore, we investigated the role of endogenous prodynorphin-derived peptides in epileptogenesis, acute seizure behaviour and epilepsy in prodynorphin-deficient mice. Compared with wild-type littermates, prodynorphin knockout mice displayed a significantly reduced seizure threshold as assessed by tail-vein infusion of the GABA(A) antagonist pentylenetetrazole. This phenotype could be entirely rescued by the kappa receptor-specific agonist U-50488, but not by the mu receptor-specific agonist DAMGO. The delta-specific agonist SNC80 decreased seizure threshold in both genotypes, wild-type and knockout. Pre-treatment with the kappa selective antagonist GNTI completely blocked the rescue effect of U-50488. Consistent with the reduced seizure threshold, prodynorphin knockout mice showed faster seizure onset and a prolonged time of seizure activity after intracisternal injection of kainic acid. Three weeks after local injection of kainic acid into the stratum radiatum CA1 of the dorsal hippocampus, prodynorphin knockout mice displayed an increased extent of granule cell layer dispersion and neuronal loss along the rostrocaudal axis of the ipsi- and partially also of the contralateral hippocampus. In the classical pentylenetetrazole kindling model, dynorphin-deficient mice showed significantly faster kindling progression with six out of eight animals displaying clonic seizures, while none of the nine wild-types exceeded rating 3 (forelimb clonus). Taken together, our data strongly support a critical role for dynorphin in the regulation of hippocampal excitability, indicating an anticonvulsant role of kappa opioid receptors, thereby providing a potential target for antiepileptic drugs.
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                Author and article information

                Journal
                J Anaesthesiol Clin Pharmacol
                J Anaesthesiol Clin Pharmacol
                JOACP
                Journal of Anaesthesiology, Clinical Pharmacology
                Medknow Publications & Media Pvt Ltd (India )
                0970-9185
                2231-2730
                Apr-Jun 2018
                : 34
                : 2
                : 200-204
                Affiliations
                [1]Department of Anaesthesia, ICU and Pain, Shri Guru Ram Rai Institute of Medical and Health Sciences, Shri Mahant Indresh Hospital, Dehradun, Uttarakhand, India
                Author notes
                Address for correspondence: Dr. Mayank Gupta, Flat No. 9, G Block, College Campus, Shri Guru Ram Rai Institute of Medical and Health Sciences, Shri Mahant Indresh Hospital, Dehradun - 248 001, Uttarakhand, India. E-mail: drm_gupta@ 123456yahoo.co.in
                Article
                JOACP-34-200
                10.4103/joacp.JOACP_210_16
                6066906
                30104829
                16739499-63ed-4ec8-a8a7-bf1caafd0789
                Copyright: © 2018 Journal of Anaesthesiology Clinical Pharmacology

                This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.

                History
                Categories
                Original Article

                Anesthesiology & Pain management
                anesthesia,etomidate,mixed agonist-antagonists,myoclonus,nalbuphine,opioid

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