Rescue medications. What are rescue medications? Ideal rescue medication. Why use rescue medications?

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1 Rescue medications Out-of-hospital treatment of prolonged seizures or acute repetitive seizures What are rescue medications? Medicines used to terminate a prolonged seizure or acute repetitive seizures Tina Shih, MD UCSF Epilepsy Center May 22, 2009 Why use rescue medications? Time to treatment directly correlated with outcome Avoid ER visits Reclaim lost days due to seizures Ideal rescue medication 1. Stops 100% of seizures immediately and protects patient during time when he/she is likely to have another seizure 2. Can be administered easily and quickly 3. Enters the brain quickly 4. Has no side effects (sleepiness, breathing problems) 1

2 Rescue medications can be delivered by self or caregiver 1. (Diastat AcuDial) 2. Buccal/intranasal midazolam 3. Oral/sublingual lorazepam (Ativan) 4. Oral diazepam Only FDA approved medication for athome treatment of repetitive seizures Diazepam gel in prefilled syringes Diastat AcuDial properties High lipid solubility: rapid CNS penetration Peak serum plasma concentrations: 5-45 High bioavailability (80-100%) Two multi-center studies Randomized, double-blind, placebo-controlled, parallelgroup Total of 239 adults and children (age 2-60) (Dreifuss, N Engl J Med 1998; Cereghino, Neurology 1998) 2

3 vs. placebo Outcome measures: Seizure frequency Global assessment of treatment outcome by caregiver Time-to seizure recurrence Percentage Seizure-free Hours since First Dose Dreifuss, N Engl J Med 1998 Administration of rectal diazepam Weight-based dosing Physician writes prescription with dose amount, pharmacist dials in correct dose 3

4 Intranasal/buccal midazolam As of 5/14/2004: >1.5 million syringes used Nine reports of respiratory adverse effects Three deaths reported Many mitigating circumstances Water soluble prior to injection, lipid soluble in physiological ph Persistant brain levels Not FDA approved for this indication or administration Limited studies in outpatient setting Buccal midazolam: results (12) Randomized, controlled multicenter trial Children >6 months, febrile or afebrile seizures (219 episodes, 177 patients) Primary outcome measure: termination of seizure activity within 10 of delivering medication, w/o respiratory depression, no seizures for next hour Buccal midazolam (109 episodes) Therapeutic success (%) Initial episodes Rectal diazepam (110 episodes) Percentage difference (95% CI) 61 (56%) 30(27%) 29% (16-41) All episodes 49 (53%) 24 (28%) 25% (11-39) Time () to stop seizure after treatment (median, IQR) Initial episodes 8 (5-20) 15 (5-31) All episodes 10 (5-22) 15 (6-32) 4

5 Other studies of midazolam Administration of midazolam Study Medicine Population Outcome Scott et al, Epilepsia 1998 IN midazolam vs. rectal diazepam Adults in long term care facility Equally effective Glass vials (5 mg/ml) Draw up with syringe Cost: $40-75 Lahat et al, BMJ 2000 IN midazolam vs IV diazepam ER: children 6 mos to 5 yrs, febrile seizures Equally effective Squirt liquid between cheek and gums Scheepers et al, Seizure 2000 IN midazolam Adults in residential epilepsy center Effective in 79/84 trials Squirt liquid into each nostril Compounding lab Metered dose inhaler 0.1 ml/spray Cost: ~$100 Rectal Diazepam Buccal/ intranasal midazolam Oral/ sublingual lorazepam Rapid Anticonvulsant Medication Prior to Arrival Trial (RAMPART) Part of Neurological Emergencies Treatment Trial Network (NETT) Time to therapeutic levels Time to max blood levels 5-15 Brain levels Fall by 2/3 within 1 hr High for hours ~ hours High for hours 5

6 RAMPART investigators Rapid Anticonvulsant Medication Prior to Arrival Trial (RAMPART) San Francisco General Hospital (SFGH)= hub Stanford= hub Participating ERs=all San Francisco county hospitals and 19 community hospitals in San Mateo/Santa Clara counties Claude Hemphill, MD Associate Professor of Neurology & Neurosurgery UCSF James Quinn, MD Associate Professor of Emergency Medicine Stanford University Who What When Person >13 kg (~28 lbs) Continuous or repetitive convulsive seizure activity for>5 and still in midst of seizure when paramedics arrive Randomized to receive either intramuscular midazolam OR intravenous lorazepam After paramedics evaluate and determine study criteria are met Where At scene RAMPART intervention Medics arrive on scene and evaluate patient Ask bystanders duration of seizure and trauma Look for medic alert jewelry Check blood sugar and vital signs For small children, check estimated weight If criteria are met, study box is opened to enroll (voice recordings will be made) Select dose bundle Give intramuscular medication and announce on voice recorder Continued. RAMPART intervention Start IV, give IV medication and announce on voice recorder Monitor vital signs and transport Announce if convulsions stop At 10 minute after treatment, provide rescue meds per local protocol if still in midst of seizure en route, announce on voice recorder that medication was given At ED arrival, announce whether patient is still in midst of seizure or not 6

7 RAMPART: special considerations Exception from informed consent Life threatening? Available therapy inadequate or unproven? Informed consent not feasible? Prospect of direct benefit? Trial couldn t be carried out without exception from informed consent? Patients can opt out : wearing a red silicone bracelet RAMPART DECLINED (obtain for free from researchers) NETT(6388) 7