|Year : 2021 | Volume
| Issue : 1 | Page : 73-78
Comparison of ketofol (ketamine and propofol) and etomidate in electro convulsive therapy: A double-blinded randomized controlled trial
Chhaya P Joshi1, Thapisrija1, Basavaraja Ayyanagouda1, Narayan Mutalik2, Shivanand Y Hulakund1, Harini Jalapati1
1 Department of Anaesthesiology, S Nijalingappa Medical College and HSK Hospital Research Center, Navanagar, Bagalkot, Karnataka, India
2 Department of Psychiatry, S Nijalingappa Medical College and HSK Hospital Research Center, Navanagar, Bagalkot, Karnataka, India
|Date of Submission||02-Jul-2020|
|Date of Acceptance||04-Aug-2020|
|Date of Web Publication||22-Feb-2021|
Dr. Basavaraja Ayyanagouda
Department of Anaesthesiology, S N Medical College and HSK Hospital, Nava Nagar, Bagalkot - 587 102, Karnataka
Source of Support: None, Conflict of Interest: None
Background and Aims: Electroconvulsive therapy (ECT) is the most effective treatment modality for severe and medication-resistant psychiatric disorders. ECT provokes generalized tonic-clonic seizures. Induction of optimal seizures (duration of motor seizures >15 s) is considered as an important goal during the ECT procedure. We compared ketofol and etomidate as induction agents in ECT with respect to the seizure duration and seizure threshold as there is less information available in the literature.
Methods: One hundred and twenty patients posted for ECT were randomized into two groups. Group A received ketofol 1:1 (ketamine 0.5 mg/kg + propofol 0.5 mg/kg), while as Group B received etomidate 0.2 mg/kg. After administration of the muscle relaxant (succinylcholine 0.5 mg/kg) ECT was delivered. The primary outcome was seizure duration, and secondary outcomes such as seizure threshold, hemodynamic parameters, recovery profile, and any complications were noted. Motor seizure duration was recorded as the time interval between starting of the seizure episode until the cessation of tonic-clonic motor activity in the isolated upper limb. Data were entered in MS-Excel and analyzed in SPSS V22. Descriptive statistics were represented with percentages, and parametric data were represented with mean with standard deviation. The statistical analysis was carried out using the Chi-square test, independent t-test. A Probability (P) value <0.05 was considered statistically significant.
Results: There was a statistically significant difference in seizure duration between two groups with Group A having less meantime 38 ± 14.9 s compared to Group B 45.3 ± 17.5 s with P = 0.014. Seizure threshold, hemodynamic parameters, recovery profile, and complications except myoclonus were not statistically significant between the two groups.
Conclusion: Etomidate has the definite advantage of longer seizure duration compared to ketofol, and hence, etomidate is a better induction agent in patients with psychiatric disorders undergoing ECT.
Keywords: Electroconvulsive therapy, etomidate, induction agents, ketofol
|How to cite this article:|
Joshi CP, Thapisrija, Ayyanagouda B, Mutalik N, Hulakund SY, Jalapati H. Comparison of ketofol (ketamine and propofol) and etomidate in electro convulsive therapy: A double-blinded randomized controlled trial. Indian Anaesth Forum 2021;22:73-8
|How to cite this URL:|
Joshi CP, Thapisrija, Ayyanagouda B, Mutalik N, Hulakund SY, Jalapati H. Comparison of ketofol (ketamine and propofol) and etomidate in electro convulsive therapy: A double-blinded randomized controlled trial. Indian Anaesth Forum [serial online] 2021 [cited 2021 May 9];22:73-8. Available from: http://www.theiaforum.org/text.asp?2021/22/1/73/309842
| Introduction|| |
Electroconvulsive therapy (ECT) generates generalized clonic and tonic seizures by applying electrical stimulus to either one or both the cerebral hemispheres. Previously, ECT was done on an awake patient without anesthesia which was named as the unmodified technique, which leads to several musculoskeletal complications. Later this technique was modified and named as a modified technique where the patient was provided with anesthesia and muscle relaxant. This technique improved patient's safety and was easily accepted by both patients and society. Recently, there have been few indications for ECT such as drug-resistant disorders, suicidal tendencies, manias in bipolar disorders, severe depressive disorders. In an initial 10–15 s of ECT an increase in parasympathetic activity occurs, which is followed by an increase in sympathetic activity, which resolves in 5–10 min after clonic phase. Due to the increase in cerebral metabolic rate, there will be increase in cerebral blood flow and intracranial pressures. An anesthetic agent and muscle relaxant are administered during ECT to optimize the hemodynamic variations and other associated complications. An ideal anesthetic induction agent should cause rapid unconsciousness which does not affect the seizure duration and seizure threshold, maintain adequate depth of anesthesia, minimal hemodynamic effects and a rapid recovery Methohexital was considered as the most effective induction agent during ECT because it increases the seizure duration but has more cardiac side effects. Similarly, thiopental, propofol, ketamine, and etomidate were used with different dosages in order to attain ideal anesthetic properties. Almost all short-acting anesthetic agents used in ECT exhibit antiepileptic properties. Therefore, general anesthesia might compromise the induction of adequate ictal activity and impact the clinical outcome. Induction of optimal seizures was considered an important goal during the ECT procedure. However, currently used induction agents such as propofol and thiopental have produced them inconsistently. Hence, in this study, we compared ketofol with etomidate as induction agents in ECT. The primary objective was seizure duration and secondary objectives such as seizure threshold, hemodynamic parameters, recovery profile, and any complications were compared between the groups.
| Methods|| |
This was a prospective randomized double-blinded controlled trial. After approval by the institutional ethical committee (SNMC/IECHSR/2017-18/A-41/1.1) and written informed consent from patient's attendants/guardian, the study was conducted. After obtaining institutional ethical clearance, a pilot study was conducted on ten patients posted for ECT using ketofol 1 mg/kg (0.5 mg/kg propofol plus 0.5 mg/kg ketamine) 1:1 combination to know seizure duration and threshold, hemodynamic data, recovery parameters, and patient safety. The pilot study showed seizure duration of 35.5 ± 2.0 s, seizure threshold 120 ± 60.0 mc without much variations in hemodynamic parameters from baseline and good recovery profile. After obtaining results from pilot study, 120 patients between 18 and 60 years of age American Society of Anesthesiology physical status I–II suffering from various psychiatric disorders (depressive disorder, schizophrenia, obsessive-compulsive disorders, mania, catatonia, and any other psychotic disorders) scheduled for ECT from December 2017 to June 2019 were included in the study. Patients who refused to participate in the study, cardiovascular diseases before 6 months before ECT, previous history of stroke, raised ICT, pacemakers, history of uncontrolled seizures on antiepileptics were excluded from the study. A detailed pre-anesthetic evaluation was done. All antipsychotics and antiepileptics were skipped on the day before ECT. Patients were kept fasting overnight. Number of patients taken for this study was randomly divided by using computerized randomization. Random group allocations were concealed in the sealed opaque envelope by anesthesiologist and divided into two groups of 60 each. Patients in Group A received ketofol and Group B received etomidate. Baseline heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), and SpO2 were registered. HR, SBP, DBP, and SpO2 were recorded every 3 min after induction for 12 min (3 min, 6 min, 9 min, and 12 min). The procedure was carried out in the ECT room. An intravenous cannula was inserted. All patients were pre oxygenated with 100% O (2) at 6 l/min flow rate for 3 min. Glycopyrrolate 0.2 mg was given intravenously as premedicant. Double blinding was done. The patient and the observer were blinded to the drug. The anesthesiologist who prepared the drugs also induced the patients. The anesthesiologist (observer) who recorded study parameters was unaware of the study drug given by fellow anesthesiologist. Group A was given ketofol 1:1 (ketamine 0.5 mg/kg + propofol 0.5 mg/kg) as induction agent and Group B was given etomidate 0.2 mg/kg as an induction agent. Ten ml syringe was loaded with ketamine and propofol (Group A) and etomidate (Group B). The dosage was calculated according to patient's weight and diluted to 10 ml with normal saline. Loss of responsiveness to verbal commands was considered as endpoint for dosage in both groups and, if not achieved within 30 s ketofol 20 mg and etomidate 3 mg was given as incremental dose. After that blood pressure (BP) cuff was tied around the left arm and inflated to 50 mmHg above the SBP to isolate the forearm muscles from the effect of intravenous succinylcholine. After induction, succinylcholine 0.5 mg/kg was given intravenously. Ventilation was accomplished with 100% oxygen through bag and mask at the rate of 12 breaths/min. Muscle twitch appears immediately and after the complete disappearance of muscle twitch, which indicates complete muscle relaxation, adequate sized bite block was inserted just before ECT. Electrodes were placed in bitemporal region and pulse stimulus was given by NIVIQURE ECT machine (ISO 13485: 2003 and ISO 9001: 2008 NIMHANS and NIVIQUIRE hold the joint patent for instrumentation software design Bengaluru India). Initially, energy starting from 60 millicoulombs (mc) was used to produce a seizure and observed for a minimum 20 s for eliciting motor seizures as recommended by the company. If seizures were not obtained, the energy given was doubled, and seizure duration was measured. If again, seizure activity does not occur, and if patients' vital parameters remain stable, another trial with higher energy (180 mc) was given. If vital parameters became unstable such as desaturation (<90%), bradycardia (<60 beats/min) or hypotension (20% reduction in the basal value of systolic BP or mean BP) such patients were excluded from the study. Motor seizure duration was recorded as the time interval between starting of the seizure episode till the cessation of tonic-clonic motor activity in the isolated upper limb. After cessation of seizure, bite block was removed, and ventilation was done with 100% oxygen through bag and mask until adequate spontaneous ventilation was returned. Seizure threshold was measured as the lowest dose of stimulation, which could elicit seizure activity clinically. Recovery profile was assessed in terms of return to spontaneous breathing, the mean time for eye-opening (eye-opening to verbal commands) and meantime for responding to verbal commands. The time from the end of succinylcholine administration to the above responses was recorded separately. Seizure duration, seizure threshold, hemodynamic changes, recovery profile, and any adverse events during the procedure were recorded. Adverse events such as pain on injection, allergic drug reactions, myoclonus, abnormal prolonged seizure duration, brady or tachycardia, and hypo or hypertension were noted. Immediate treatment was carried out with midazoloam 3 mg intravenously if seizure duration was >2 min, atropine 0.6 mg intravenously for bradycardia (HR <60/min) associated with hypotension, ephedrine 6 mg intravenously for hypotension (20% reduction in the basal value of systolic BP or mean BP).
The sample size calculation was done using open epi software version 2.3.1. At 95% confidence level and 80% power of study seizure duration following ketofol (pilot study) was 35.5 s, seizure duration following etomidate according to study done by Tan and Lee was 43.4 s. The difference in mean was used for calculating sample size and calculated to be 52, which was rounded off to 60 in each group. Data were entered in MS-Excel and analyzed in SPSS (Statistical package for social sciences, IBM, SPSS statistics USA) V22. Descriptive statistics were represented with percentages, and parametric data were represented with mean with standard deviation. Chi-square test, independent t-test were applied to find significance. P < 0.05 was considered statistically significant.
| Results|| |
One hundred and twenty patients were enrolled for the study, and all the patients were included for statistical analysis [Figure 1]. Demographic variables such as age, sex, and weight were comparable between groups [Table 1]. Seizure duration with Group A showed less meantime (38 ± 14.9 s) compared to Group B (45.3 ± 17.5 s), with P = 0.014, which was statistically significant [Graph 1]. Seizure threshold with Group A showed (130 ± 60.7 mc) compared to Group B (118 ± 46.8 mc), with value of P = 0.23 [Graph 2]. There was no significant difference between the two groups. Hemodynamic variables such as HR, blood pressure, and Spo2 were comparable between groups. Recovery profile assessed in terms of spontaneous breathing, meantime of eye opening, and meantime of responding to verbal commands was comparable in both the groups [Table 2]. Complications such as pain during injection, myoclonus, and prolonged seizure duration were more in Group B compared to Group A [Table 3]. Other complications such as tachycardia, bradycardia, episodes of desaturation, hypotension, hypertension, nausea, and vomiting were not seen in any patients.
| Discussion|| |
In the present study, we have demonstrated that Group B (Etomidate group) has a definite advantage of longer seizure duration compared to Group A (Ketofol group), which increases the clinical efficacy of ECT. In regard to the seizure threshold, hemodynamic variations, recovery profile, and complications, both the drugs were comparable. However, pain during injection, myoclonus, and abnormally prolonged seizure duration were observed more frequently in the etomidate group. The ideal induction agent is the one which causes rapid unconsciousness with less hemodynamic changes, especially which does not affect the seizure duration, seizure threshold and also has a rapid recovery., It was proved by Toprak et al. and
Jadeja C et al. that propofol 1.5 and 1 mg/kg respectively caused less seizure duration compared to sevoflurane and thiopentone. As propofol acts on GABA receptors, which has anticonvulsant properties, it affects seizure duration. Hence, there was a growing interest on agent, which does not affect seizure duration. In a study done by Zavorotnyy et al. it was proved that S-Ketamine at a dose of 1 mg/kg did not have much effect on increasing seizure duration, but seizure threshold was decreased, and it did not cause any dissociation states or psychotomimetic effects as its effect might be dose related. However. ketamine increases mean arterial pressures, HR and induces nausea vomiting. Hence, this agent needs to be cautiously used. Recovery due to propofol was early in the study done by Toprak et al. and recovery due to S-ketamine was slow in the study done by Zavorotnyy et al. Hence in view of their opposite actions, there appeared an increase in usage of ketofol mixing ketamine and propofol in the same syringe with different dosages such as 1:1, 1:2, 1:3 for short-duration procedures. Due to their nullifying actions, there seemed to be an increase in seizure duration and decrease in hemodynamic changes caused by the individual agents. In a study done by Erdogan et al. he compared ketofol (0.5 mg/kg ketamine + 0.5 mg/kg propofol) with propofol 1 mg/kg and he concluded that electroencephalography (EEG) seizure duration and seizure quality was good with ketofol. In our study, we have taken ketofol in the same dosage and there were four cases where we required an additional dosage of 20 mg mixture. A similar requirement of additional dosage was also seen in the study done by Erdogan et al. In a study done by Tan and Lee he compared etomidate at 0.3 mg/kg with propofol at 1.5 mg/kg and proved that etomidate has better motor seizure duration compared to propofol during ECT. In patients with a high seizure threshold, etomidate was recommended as first-line medication. Based on the above studies, we have assumed both ketofol (0.5 mg/kg ketamine + propofol 0.5 mg/kg) and etomidate 0.2 mg/kg are better induction agents till date for ECT. As there was no study done till date comparing both these drugs, we chose them as induction agents in our study. In a study done by Tan and Lee they have taken repeat ECT in consideration and formed four groups as first ECT 1A was given etomidate 0.3 mg/kg, s session ECT 1B was given propofol 1.5 mg/kg, first ECT 2A was given propofol 1.5 mg/kg, s session ECT 2B was given etomidate 0.3 mg/kg, but they did not find any significant difference in these groups as the washout period of 2–3 days between the procedures was there and the agents used were short-acting; hence, we did not take repeat ECT into consideration and treated every patient as a fresh patient. In this study, we measured only motor seizure duration as the measurement through EEG did not show much difference in a study done by Tan and Lee. In our study, the etomidate group had longer motor seizure duration compared to ketofol group. In a study done by Abdollahi et al. and Zavorotnyy et al., mean seizure duration in the etomidate group was similar to this study, which was 41.9 s and 45.1 s, respectively. In a study done by Tan and Lee and Mir AH et al. motor seizure duration in the etomidate group was 61.9 s and 56.5 s, respectively, which is more than our study. In a study done by Erdogan et al. in ketofol group motor seizure duration was 29 s, which was lesser than our results. However, motor seizure duration was 34 s in a study done by Yalcin et al., which is similar to our study. The results which 8 we obtained are similar to our pilot study also. Seizure threshold between the two groups was statistically not significant in our study. In a study done by Zavorotnyy et al., seizure threshold in the etomidate group was 104.2 mc compared with S-ketamine group 72.3 mc and were statistically significant, which is not comparable with our study. S-ketamine causes a decrease in seizure threshold, but due to the mixture of propofol and ketamine, the effect of ketamine on the seizure threshold is not manifested, leading to this statistical insignificance due to nullifying actions of ketamine and propofol. There were no statistically significant hemodynamic changes observed in both groups. In the studies done by Jadeja et al. Tan and Lee, and Zavorotnyy et al., similar results were obtained. There were no complications such as bradycardia, tachycardia, premature ventricular and atrial contractions, asystole events after 3 min in both the groups. Within 3 min of desaturation, it was managed with an oxygen mask at 6 l/min flow rate. There was an incidence of myoclonus observed immediately after injecting etomidate, which subsided without any treatment. There was pain during injection seen in both the groups. Similar complications were also noted by Tan and Lee and Abdollahi et al. There was one incidence of prolonged seizure duration of 128 s seen in a patient after induction with etomidate, which was treated with injection midazolam 3 mg intravenously. There was no incidence of nausea and vomiting in both groups. Recovery profiles of our study were similar to a study done by Erdogan et al.
Limitations of the study are cost-efficacy of the drug etomidate. It is five times more than the regular drugs (propofol, thiopental, ketamine), which makes its usage restricted to patients with very low seizure durations. The severity of the disease is not considered in our study, which may affect the seizure duration. The future scope of this study is that its outcome can be utilized in meta-analysis studies and systemic reviews. The varying dose of the above drugs for subsequent ECT sessions needs to be evaluated. The same study may be conducted on seizure resistant patients.
| Conclusion|| |
We conclude that both the agents ketofol and etimodate enhance the seizure duration and clinical efficacy of ECT. Etomidate has the definite advantage of longer seizure duration compared to ketofol, so etomidate is a better induction agent in patients with psychiatric disorders undergoing ECT.
The authors would like to thank Dr. Manjula Associate Professor Department of Community Medicine S N Medical College Bagalkot.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3]