Ket Mid Study comparing between ketamine alone with ketamine and midazolam

Study Journal

1. Combined Ketamine and Midazolam Versus Midazolam Alone for Initial Treatment of Pediatric Generalized Convulsive Status Epilepticus (Ket-Mid Study) : A Randomized Controlled Trial Sohag University, Sohag, Egypt Othman AA, Sadek AA, Ahmed EA, Abdelkreem E. Combined Ketamine and Midazolam Versus Midazolam Alone for Initial Treatment of Pediatric Generalized Convulsive Status Epilepticus (Ket-Mid Study): A Randomized Controlled Trial. Pediatr Neurol. 2025 Jun;167:24-32. doi : 10.1016/j.pediatrneurol.2025.03.011. Epub 2025 Mar 22. PMID: 40186980. Alyssa Cheah, Journal Read 13.06.25

2. background Generalized convulsive status epilepticus (GCSE): most frequent pediatric neurological emergency worldwide Benzodiazepines ( first-line ASM) fail to end seizures in 1/3 of cases . About half of BDZ-refractory GCSE are not aborted by second-line ASMs ( eg levetiracetam, valproate, phenytoin) Longer GCSE persists  more resistant to control  progressive brain damage with increased risk of death, chronic epilepsy, long-lasting neurocognitive deficits Earlier GCSE termination= better patient outcome

3. Evolving Status epilepticus definition (ILAE) 1970: seizure that persists for a sufficient length of time or is repeated frequently enough to produce a fixed and enduring condition 1993: a single epileptic seizure of >30 minutes duration or a series of epileptic seizures during which function is not regained between ictal events in a 30-minute period 2015: Status epilepticus : condition resulting either from FAILURE of mechanisms responsible for seizure termination or from initiation of mechanisms , which lead to abnormally, prolonged seizures ( after time point t1 ). It is a condition, which can have long-term consequences ( after time point t2 ), including neuronal death, neuronal injury, and alteration of neuronal networks , depending on type & duration of seizures T1: 5mins T2: 30 mins = continuous seizure activity = risk of long term consequences ● Treatment should be considered/started ● determines how aggressively treatment should be implemented to prevent long-term consequences

4. Status epilepticus is a serious epileptic condition associated with significant morbidity and mortality. It can be divided into four stages: developing (seizures leading up to status epilepticus), established (>5 minutes convulsive status epilepticus, nonconvulsive/focal status epilepticus >10 min), refractory (failure of two adequately dosed antiseizure medications in different drug classes), and super-refractory (persisting despite >24 hours of anesthesia)

5. Is 2 better than 1?? B enzodiazepines + another ASM by different pathway  ??= rapid control??? Levetiracetam : broad spectrum ASM with a high safety profile Add on levetiracetam to midazolam offers no significant advantage over midazolam alone as first line in controlling seizures at 20-min, 40-min, and 24-hour of presentation as first line 2023

6. promising option: anticonvulsive and neuroprotective effects as well as availability, affordability, and high safety profile. BDZs allosteric agonist for g-aminobutyric acid (GABA)A receptors Ketamine noncompetitive glutamate antagonist acting on N-methyl-d-aspartate (NMDA) receptors. Ongoing seizure activity  rapidly progressive downregulation of inhibitory GABAA receptors and upregulation of excitatory NMDA receptors  more resistant to GABAergic agents but remaining responsive to NMDA antagonists. Ketamine+ BDZs  target enhanced NMDA-mediated neuroexcitation and remaining functionally active GABAA receptors. No RCT available yet for ketamine- BDZ combination in paediatric GCSE management The study hypothesis is that in children with GCSE ketamine plus midazolam , compared with midazolam alone , as first-line ASMs would be more successful in terminating clinical seizures at five minutes following drug administration. KETAMINE

7. Methods Randomized, two-group, parallel, 1:1, superiority, double blind, placebo-controlled trial Between March 2023 - August 2024 Pediatric Emergency room of Sohag University Hospital (southern Egypt) Eligibility Criteria: C hildren aged between 6 months & 16 years who presented with GCSE GCSE defined as clinically detectable generalized tonic- clonic convulsions that persist or recur without complete regaining of consciousness for longer than 5 minutes Seizure duration before hospital arrival was parent-reported . Emergency oral informed consent obtained from parents/legal guardian, followed by written informed consent Registered on ClinicalTrials.gov, Approved by Medical Research Ethics Committee of their institute.

8. Exclusion criteria Previous treatment with any ASMs for the presenting seizure episode, traumatic brain injury (TBI), conditions associated with increased intracranial pressure (e.g., hydrocephalus, central nervous system [CNS] mass lesions), hypertension, glaucoma, hyperthyroidism, pheochromocytoma, end-stage kidney or liver diseases, cardiac disease (arrhythmia, severe heart disease, or pulmonary hypertension) history of alcohol intake, hypoglycemia or hyperglycemia, inborn errors of metabolism known allergy or contraindication to any of the study drugs known or suspected psychiatric disorder failure to secure intravenous access in first five minutes of stabilization phase cessation of seizures during the stabilization phase (0-5 minutes) failure to obtain informed consent.

9. Sample size calculation S uperiority trial A ssumed 50% efficacy of midazolam in stopping clinically observed seizures at five-minute study timepoint (primary outcome) & an additional 25% efficacy for add-on ketamine over placebo, keeping two-sided type I error ( α ) = 0.05 and type II error ( β ) = 0.2. This calculation resulted in 58 individuals per group, which was raised to 72 subjects per group to account for possible 20% dropouts I ntention-to-treat principle , using Stata/BE 17 to analyze data Binary outcomes were compared between the study and comparison groups using chi-square test or Fisher exact test C onducted subgroup analysis to compare treatment effect on primary outcome among different age categoriesm , seizure etiologies & seizure durations at hospital arrival using Mantel- Haenszel (M-H) method. Further examined the homogeneity of the intervention effect on the primary outcome measure across age, seizure etiology, and seizure duration at hospital arrival through logistic regression models that contained terms for intervention, age/etiology/duration, and intervention-age/etiology/ duration interaction investigated the possible factors affecting primary outcome measure through univariate logistic regression analysis, followed by multivariate model that included variables demonstrating statistically significant associations in univariate analysis. P- value (two-tailed) <0.05 was deemed statistically significant. No multiple comparison adjustment was planned ex ante or performed posthoc . Statistical analysis

10. D ouble-blind, randomized, placebo-controlled trial Participants/parents, treating physicians/paramedical staff, investigators were unaware of the ketamine/placebo assignment. C omputer-generated random numbers in permuted blocks of four Person NOT from research team secured these random numbers into serially ordered opaque envelopes For every participant - E nvelope in turn opened & allocated medication given Ketamine 5mg/mL solution (Dilute IV ketamine 50mg/mL with NS to 1:10 concentration) Isotonic saline (placebo) Fill into identical 12 -mL containers with sealed identification codes Pharmacy prepare Enrolled children randomized equally : ketamine & midazolam (Ket-Mid group) or placebo & midazolam (Pla-Mid group)

11. Time point 35 mins Time points & Medication given Time point 0 min =moment of administration of randomly allocated study drug PICU care IV midazolam 0.2 mg/kg (2mg/min) load then 0.05-2 mg/kg/h IV Phenytoin 20mg/kg over 20 mins 0.4mL/kg = ketamine 2mg/kg [max 60mg] Time point 15 mins IV LEV 60mg/kg over 5 mins Standard GCSE emergency measures: - first-aid measures - vital signs - airway management - O2 by nasal cannula/mask - intubation (if required) - Dxt & treat any hypoglycemia - intravenous access - blood sampling s S tudy timeframe was limited to 24 hours from T0 Stabilization Beyond 5 minute stabilization >5 mins after complete 1 st dose IV Midazolam 0.2mg/kg over 2 minutes concurrent with 0.4mL/kg (max 12ml) study drug over 2 minutes via 2 separate IV line Second IV midazolam dose Time point 55 mins All participants: provision of proper fluids and electrolytes, fever control, maintaining adequate oxygenation and ventilation through oxygen and noninvasive or invasive ventilation, hemodynamic support by fluids and vasopressors, and specific treatment of any identifiable cause. Ongoing seizures

12. Secondary Outcomes need for repeat midazolam during the first 15 minutes of study timepoint cessation of clinical seizures at 15-,35- & 55-min timepoints seizure control (no recurrence of clinically seizures after initial cessation) hypotension; hypertension; arrhythmia; emergence phenomenon (one or more of hallucination, delirium, vivid dreams, blurred/double vision, nausea/vomiting, and hypersalivation); skin rash; need for endotracheal intubation mortality Primary Outcome proportion of participants attained seizure cessation at T=5min

13. Study participants flow chart

14. Baseline Characteristics of Study Participants 32% <1 yo 37% 1-5 yo 31% >5 yo None of the study participants received ASMs for their acute seizure episodes before hospital arrival more than half (58%) had seizures lasting >30 minutes upon hospital presentation

15. Adjunct ketamine exerts significantly higher efficacy in stopping clinical seizures at T=5-mins among children with GCSE >30 minutes at hospital presentation compared with <30 mins Subgroup Analysis for Primary Outcome P<0.001 N o significant difference in add-on ketamine effect on primary outcome among different age categories and seizure etiologies P=0.495 P=0.777

16. univariate logistic regression for factors significantly associated with primary outcome multivariate model for independent predictors for primary outcome add-on ketamine shorter duration from GCSE onset to hospital arrival known epilepsy etiology prior ASM therapy nonfebrile seizure etiology lower body temperature. add-on ketamine therapy ( P < 0.001) shorter seizure duration at hospital presentation (P 0.001) epileptic seizure etiology (P= 0.004)

17. discussion First RCT for efficacy of adjunct ketamine to midazolam as first-line ASM combination for pediatric GCSE. Ketamine plus midazolam more effective than midazolam alone in terminating clinical seizures at 5, 15, 35 and 55 minutes following drug administration, particularly for GCSE >30 minutes , and significantly reduced the need for endotracheal intubation. Findings consistent with: experimental different animal SE models which demonstrated adjuvant NMDA receptor antagonists (e.g., ketamine, dizocilpine) work synergistically with BDZs  ket -mid combi more effective in reducing seizure severity than double dose midazolam or ketamine monotherapies or midazolam-valproate or ketamine-valproate combinations in a lithium/pilocarpine induced-SE rat model Numerous cohorts & case series in adults/children with RSE & SRSE with seizure cessation/reduction after ketamine infusion (most with midazolam co-administration) in 40-90% cases

18. inhibitory/excitatory imbalance  vicious cycle  circuit overactivity and neuronal injury  further neuroplastic changes  enhance self-sustained seizures. endocytosis and trafficking of BDZ-sensitive γ 2 subunit containing GABA A receptors away from synapse  time-dependent reduction in synaptic inhibition and responsiveness to BDZs. progressive increase in surface expression of glutamate-sensitive N2B subunit-containing NMDA receptors at synaptic and extrasynaptic sites  glutamatergic overexcitation. midazolam target remaining functionally active GABA A receptors ketamine antagonize enhanced NMDA receptor-mediated neuroexcitation Ketamine + BDZ Synergy

19. progressive loss of GABA A receptor-mediated synaptic inhibition enhancement of NMDA receptor-mediated excitation triggers enzymes (calcineurin, protein phosphatase 2A) Reduced GABAergic inhibition enhances circuit hyperactivity, membrane depolarization, removal of magnesium block reciprocal interaction NMDA receptor-mediated glutamatergic overexcitation + Ca 2+ influx induce dephosphorylation of GABAA receptors GABAA receptors desensitization, internalization, and trafficking away from synapses. progressive loss of GABAergic inhibition and diminished responsiveness to BDZs. Even in prolonged SE: BDZs may potentiate ketamine effect Ketamine could maintain/restore responsiveness to BDZs Ketamine + BDZ Synergy

20. Ketamine + BDZ = Synergy Neuroprotective effects against epileptogenesis , neuronal injury, and functional impairment Seizure cessation ketamine Immunomodulatory effects : reducing inflammatory mediators  attenuate neuroinflammation, seizure severity, neuronal injury. Ketamine anti-inflammatory effects  may mitigate resistance to other ASMs. BDZs could inhibit hepatic cytochrome P450 enzyme-mediated N-demethylation of ketamine  may increase biological half-life & therapeutic effects.

21. Safety outcomes Ket-Mid Ket Properties significantly reduced need for endotracheal intubation maintaining protective airway reflexes and spontaneous respiratory drive May decrease likelihood of hypotension. inhibiting catecholamine reuptake, which may counteract hypotensive effects of BDZs. No significant adverse effect (including arrhythmia & emergence reaction) BDZ coadministration mitigate several ketamine-related side effects, such as hypertension, psychomimetic effects, and intracranial hypertension

22. Midazolam monotherapy terminate seizures in only 23.6% of children  latency to midazolam administration due to delayed hospital arrival by median of 34 minutes  pronounced time-dependent increase in resistance to BDZs ??? anticonvulsive efficacy of add-on ketamine therapy may be quite low during very early seizures (e.g., 1 st 5-10 minutes) when BDZs’ responsiveness is high However, animal data indicate NMDA receptor antagonists could enhance BDZs’ responsiveness to a greater extent when administered during early than the late phase of SE. ?Add on ketamine in very early seizures?  ???ketamine-midazolam as a first-line ASM combination has specific time window of maximum anticonvulsive efficacy outside very early and late seizure phases  r equires validation in future research.

23. several studies also reported marked delay to first-line BDZ administration  median times from SE to first-line ASM/ hosp arrival = 42 and 56 minutes, respectively. ??? current stepwise protocols with first-line BDZ monotherapy are suboptimal in prolonged naïve GCSE argue for starting with synergistic ASM polytherapy for prolonged GCSE (stage 1 plus) Therefore, ket -mid as first-line ASMs could be more useful in rapidly terminating seizures through early correction of excitatory/inhibitory imbalance and restoration of BDZs’ responsiveness rather than its late use for RSE and SRSE when extensive neuronal damage has already occurred. “The definition of Stage 1 plus is suggested, as a stage requiring combined therapy from the start, which includes prolonged SE with seizure activity going on for >10 min, the time that marks the disruption of receptor homeostasis, with increased internalization. ”

24. no significant interaction of SE etiology and participant's age on primary outcome ?may be subpowered for definitive subgroup analysis  may need more adequately powered and inclusive studies Prior studies indicate that acute primary CNS etiology (e.g., cerebrovascular diseases, CNS infection, TBI) is associated with worse clinical outcome and poor response to BZDs. Late presentation of participants with GCSE (stage 1 plus; probably BDZ resistant) and the exclusion of those with TBI and CNS mass lesions may also contribute to the lack of statistically significant difference among different SE etiologies Other Observational studies: higher ketamine effectiveness in RSE and SRSE secondary to epilepsy than other causes.  may stem from molecular changes during epilepsy development with reduced expression of BDZ-sensitive α 1 γ 2 subunits containing GABA receptors coupled with upregulated NMDA receptor-mediated neurotransmission. study did not include newborns who may be more responsive to ketamine due to higher expression of N2B subunit containing NMDA receptors.  some studies showed efficacy of ketamine in neonatal refractory SE, but concerns on possible ketamine-related neurotoxicity in this age group.

25. Primary outcome of T=5 mins chose Pragmatic: Since guidelines recommend 2nd BDZ dose for seizures >5 minutes after 1 st dose. Ketamine: fast-acting drug with high lipid solubility & low plasma protein binding capacity  rapidly crosses BBB with onset of action in <1 minute and typical duration of 5-10 minutes. Short duration of action may explain reduced extra-efficacy of ketamine when evaluated at later at 24-hour seizure control Need further studies for possibly more beneficial with higher or repeated ketamine doses IV Ketamine dose 2mg/kg dose range typically used in pediatric procedural sedation (1- 4 mg/kg) prior observational studies on pediatric SRSE (bolus 1- 3 mg/kg) Besides intravenous route, intramuscular and intranasal routes are clinically important for use in prehospital settings.

26. No confirmatory electroencephalography (EEG) for seizure cessation  use of EEG in future studies for electrographic response to ketamine particularly important since prior studies on SRSE described that ketamine response is associated with appearance of characteristic background of superimposed beta rhythm in EEG rather than classic burst suppression pattern following traditional anesthetic ASMs. limitations restricted 24-hour study time frame  possible neuroprotective or neurotoxic effects of ketamine not investigated lack of advanced investigations : future studies  serial assessment of neuroinjury biomarkers in CSF and plasma, neuroimaging scans, electrophysiological studies, and neuropsychologic tests in Egypt, low middle- income country , included children who presented late without prior ASM  may not be generalizable to high-resource settings where EMS routinely provide BDZs during hospital transport A US emergency medical service study reported ketamine could terminate seizures in all 47 adults and 13 of 16 children with BDZ-refractory SE during the prehospital and emergency ward phases  ? future RCTs for prehospital management Further replication studies are warranted among specific category of children with SE secondary to surgical causes . (TBI and surgical causes, eg CNS mass lesions)

27. Conclusion Add-on ketamine may present extra-efficacy over midazolam alone as first-line ASMs for children with GCSE, particularly for GCSE longer than 30 minutes. Future research is warranted to confirm our findings and to investigate different ketamine doses, formulations, and routes of administration as well as electrographic validation of seizure control, long-term efficacy and safety outcomes, larger sample size, and more inclusive study population

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