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      Effect of butorphanol on etomidate-induced myoclonus: a systematic review and meta-analysis

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          Objective: To evaluate the effect of butorphanol on the prevention of myoclonus induced by etomidate.

          Materials and methods: We searched the PubMed, Embase, Cochrane Library, and China National Knowledge Infrastructure databases to collect relevant randomized controlled trials (RCTs) evaluating the effect of butorphanol on etomidate-induced myoclonus in January 2019 without any language restrictions. The primary outcome was the incidence of etomidate-induced myoclonus. Secondary outcomes included the incidence of myoclonus at various degrees and the incidence of adverse effects. Risk ratios (RRs) were calculated for binary outcomes. All statistical analysis were performed by using RevMan 5.3 software.

          Results: We identified 6 RCTs involving a total of 608 patients who reported the incidence of etomidate-induced myoclonus. In pooled analyses, the incidence of etomidate-induced myoclonus in the butorphanol group was significantly lower than that in the control group (RR =0.15, 95% CI [0.10, 0.22], P<0.00001). Subgroup analyses showed that butorphanol significantly decreased the numbers of patients with mild myoclonus (RR =0.41, 95% CI [0.25, 0.68], P=0.0005), moderate myoclonus (RR =0.18, 95% CI [0.09, 0.34], P<0.00001), and severe myoclonus (RR =0.04, 95% CI [0.01, 0.10], P<0.00001). Additionally, butorphanol did not increase the incidence of postoperative nausea/vomiting (RR =3.0, 95% CI [0.32, 28.42], P=0.34) or dizziness (RR =6.79, 95% CI [0.84, 54.84], P=0.07) associated with etomidate.

          Conclusion: Our findings suggest that butorphanol can effectively prevent the incidence of etomidate-induced myoclonus and alleviate the intensity of etomidate-induced myoclonus, without inducing postoperative nausea/vomiting and dizziness.

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          Most cited references 23

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          Assessing the quality of randomized trials: reliability of the Jadad scale.

          An instrument was developed and validated by Jadad, et al. to assess the quality of clinical trials using studies from the pain literature. Our study determined the reliability of the Jadad scale and the effect of blinding on interrater agreement in another group of primary studies. Four raters independently assessed blinded and unblinded versions of 76 randomized trials. Interrater agreement was calculated among combinations of four raters for blinded and unblinded versions of the studies. A 4 x 2 x 2 repeated measures design was employed to evaluate the effect of blinding. The interrater agreement for the Jadad scale was poor (kappa 0.37 to 0.39), but agreement improved substantially (kappa 0.53 to 0.59) with removal of the third item (an explanation of withdrawals). Blinding did not significantly affect the Jadad scale scores. A more precise description of how to score the withdrawal item and careful conduct of a practice set of articles might improve interrater agreement. In contrast with the conclusions reached by Jadad, we were unable to demonstrate a significant effect of blinding on the quality scores.
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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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              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.

                Author and article information

                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                16 April 2019
                : 13
                : 1213-1220
                [1 ]Department of Anesthesiology, The 101 Hospital of Chinese People’s Libration Army , Wuxi, Jiangsu, People’s Republic of China
                [2 ]Department of Anesthesiology, The Affiliated Hospital of XuZhou Medical University , Xuzhou, Jiangsu, People’s Republic of China
                [3 ]Department of Anesthesiology, Tangshan People‘s Hospital, North China University of Science and Technology , Tangshan, Hebei, People’s Republic of China
                Author notes
                Correspondence: Jianhui GanDepartment of Anesthesiology, Tangshan People’s Hospital, North China University of Science and Technology , Tangshan, 063000Hebei, People’s Republic of ChinaEmail msci666@ 123456163.com

                These authors contributed equally to this work

                © 2019 Hua et al.

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                Page count
                Figures: 7, Tables: 2, References: 25, Pages: 8
                Original Research

                Pharmacology & Pharmaceutical medicine

                butorphanol, etomidate, myoclonus


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