First Line Therapy in Acute Seizure Management

William C. Dalsey, MD, MBA, FACEPWilliam C. Dalsey, MD, MBA, FACEPDepartment of Emergency MedicineDepartment of Emergency Medicine

Robert Wood Johnson University HospitalRobert Wood Johnson University HospitalNew JerseyNew Jersey

William Dalsey, MD

CaseCase

• A seven year old with spina bifida and arnold chiari fell and hit her head. She has intermittent generalized tonic clonic seizures without return to baseline. IV access can’t be obtained.

William Dalsey, MD

CaseCase

• A twenty-seven year old male presents with five minutes of generalized tonic clonic seizures. What is the best choice for initial treatment?

William Dalsey, MD

What is the best initial treatment for seizure?What is the best initial treatment for seizure?

• Benzodiazepines–Lorazepam–Diazepam–Midazolam

• Phenytoin• Phenobarbital

William Dalsey, MD

VA Cooperative StudyVA Cooperative Study

• Compared lorazepam to diazepam + phenytoin to phenytoin to phenobarbital

• 12 hour and 30 day outcomes were the same in all groups

• Lorazepam recommended as the drug of choice because of efficacy and ease of administration

Treiman. NEJM 1998; 339:792-798Treiman. NEJM 1998; 339:792-798

William Dalsey, MD

Which benzodiazepine is the best?Which benzodiazepine is the best?

• Rate of Success

• Duration

• Side effects/Complications

William Dalsey, MD

BenzodiazepinesBenzodiazepines

• Review of 47 clinical trials involving 1346 patients

• 79% control rate of seizure – Higher rate than the VA Cooperative Study

probably because of selection bias

• No superiority of one benzo over the other in terminating seizures

Treiman. Epilepsia 1989:30;4-10Treiman. Epilepsia 1989:30;4-10

William Dalsey, MD

BenzodiazepinesBenzodiazepines

• Lorazepam .1 mg / kg vs diazepam .2 mg / kg• Lorazepam has a smaller volume of distribution =

longer duration of anticonvulsant action• 12 hours for lorazepam vs 20 minutes for diazepam• Seizure recurrence 50% with diazepam vs 20% with lorazepam • If diazepam used, second AED must be started

• Lorazepam may have less respiratory depression

Prensky. NEJM 1967; 276:779-784Prensky. NEJM 1967; 276:779-784Leppik. JAMA 1983; 249:1452-1454Leppik. JAMA 1983; 249:1452-1454

William Dalsey, MD

If you have no IV access, are there alternatives If you have no IV access, are there alternatives

routes for benzodiazepines administration?routes for benzodiazepines administration?

• Intranasal (Midazolam)

• Buccal (Midazolam)

• IM (Lorazepam, Midazolam)

• Rectal (Diazepam, Midazolam)

• ET (Diazepam)

William Dalsey, MD

Intramuscular MidazolamIntramuscular Midazolam

• Water soluble; well absorbed

• Adult dose 10 - 15 mg

• Case reports

Jawad. J Neurol Neurosurg Psych 1986; 49:1050-1054Jawad. J Neurol Neurosurg Psych 1986; 49:1050-1054Chamberlain. Pediatr Emerg Care 1997; 13:92-94Chamberlain. Pediatr Emerg Care 1997; 13:92-94

William Dalsey, MD

Rectal DiazepamRectal Diazepam

• Diazepam well absorbed rectally: gel or solution better than suppositories

• Tmax 17 minutes with therapeutic effect earlier

• May provide longer acting anticonvulsant effect than intravenous administration due to slower absorption rate

• Has been used effectively by EMS

Dieckmann. Ann Emerg Med 1994; 23:216-224Dieckmann. Ann Emerg Med 1994; 23:216-224

William Dalsey, MD

Rectal DiazepamRectal Diazepam

• Diazepam get (Diastat)

• Indicated for children with acute repetitive seizures

• Double blind placebo controlled studies have demonstrated its effectiveness

• Main side effect: Somnolence

Cereghino. Neurology 1998;51:1274-1282Cereghino. Neurology 1998;51:1274-1282

William Dalsey, MD

Rectal DiazepamRectal Diazepam

• Dosing is age dependent:• 2 -5 years: .5 mg / kg• 6 - 11 years: .3 mg / kg• > 11 years: .2 mg /kg

• Prepackaged commercial syringes available in 2.5, 5, 10, 20 mg

William Dalsey, MD

Alternative treatments when IV Alternative treatments when IV access is not availableaccess is not available

• Fosphenytoin (IM)

• Paraldehyde (Rectal, IM)

William Dalsey, MD

Intramuscular FosphenytoinIntramuscular Fosphenytoin

• 100 % bioavailable

• 20 PE /kg: 20 cc intragluteal

• Therapeutic levels at 1 hours

• Pruritis and paresthesias most common side effects

• Cardiac monitoring not necessary

DeToledo. Emerg Med 1996; supplement:26-31DeToledo. Emerg Med 1996; supplement:26-31

William Dalsey, MD

ParaldehydeParaldehyde

• Can be given IM or PR: parenteral preparation no longer available in the US

• Old literature reports effectiveness but was used before availability of phenytoin or benzodiazepines

• Can cause heart failure, hypotension, pulmonary hemorrhage, tissue necrosis

• 80% bioavailable when given rectallyRamsay. Epilepsia 1989;30(suppl):S1-S3Ramsay. Epilepsia 1989;30(suppl):S1-S3

William Dalsey, MD

ConclusionsConclusions

• Lorazepam is the preferred first line agent for seizure control due to its long lasting anticonvulsant properties.

• Diazepam is equally effective but requires that a concomitant, long acting AED be administered.

• When the IV access is unavailable:– IM midazolam– Rectal diazepam– IM fosphenytoin