Introduction References Annotated BibliographyWhat
Are the Optimal Routes of Antiepileptic Drug Administration in Seizing
Patients Without IV Access?
Case Presentation A 32-year old male intravenous drug user was brought to the ED having had a witnessed generalized tonic-clonic seizure 10 minutes prior to presentation. The patient arrived post-ictal but responsive. No other medial history was available. On exam the blood pressure was 130/80 mm Hg, heart rate 88, respirations 14, and oxygen saturation of 98% on room air. The head was atraumatic, the pupils were 4 mm and reactive, cardiopulmonary exam was normal. Neurologically, the patient was oriented to person only; had no facial asymmetry, moved all four extremities, deep tendon reflexes were +4 symmetrically and no Babinski reflexes were present. A stat blood sugar was 110 meq/dl. While looking for venous access over the patients scarred extremities the patient began a second generalized tonic clonic seizure.
2. What options are available when intravenous access is not available? 3. What are the role of rectal benzodiazepines and intramuscular fosphenytoin?
1. Use a benzodiazepine as the first-line therapy. 2. If there is no IV access consider IM versed or posphenytoin, or rectal valium. 3. Lorazepam is the preferred first line agent for seizure control due to its long lasting anticonvulsant properties. 4. Diazepam is equally effective but requires that a concomitant, long acting AED be administered (ie Dilantin). 5. When the IV access is unavailable, alternate routes such as IM injections of midazolam, rectal solutions of diazepam, and IM fosphenytoin should be considered; of the three, IM midazolam is probably the fastest and easiest to use.
What
Are the Optimal Routes of Antiepileptic Drug Administration in Seizing
Patients Without IV Access? Introduction What
is the best first line therapy for acute seizure management?
Benzodiazepines are considered the best first line drugs in managing status epilepticus and have been shown to be equal or superior to phenobarbital alone and superior to using phenytoin alone. (Treiman 1989) Treiman reviewed 47 clinical studies involving 1346 patients treated with either diazepam, lorazepam, or clonzaepam. (Treiman 1989) A composite seizure control rate of 79% was reported without one benzodizepine demonstrating superiority in seizure control over another. Diazepam, 0.2 mg/kg at 5 mg/min, and lorazepam, 0.1 mg/kg at 2 mg/min are equally effective in terminating seizures however lorazepam has the advantage of a much smaller volume of distribution. Lorazepam’s small volume of distribution results in anticonvulsant activity that lasts up to 12 hours versus 20 minutes for diazepam that rapidly redistributes in lipid stores throughout the body (Treiman 1988). Diazepam’s short duration of action places the patient at risk for seizure recurrence unless a longer acting AED is administered. Prensky et al reported that only nine of 20 patients treated with diazepam remained seizure free two hours after treatment (Prensky); while in another study, only 16% of patients treated with lorazepam had a recurrent seizure in twenty four hours (Treiman). When diazepam is used as the initial AED, intravenous phenytoin loading, 18-20 mg/kg, should also be started to prevent recurrent seizures. In
a randomized double blind study by Treiman et al, lorazepam was recommended
as the best first line AED because of its efficacy and its ease of
administration. An additional advantage of lorazepam may be that it
is associated in a few studies with a slightly lower incidence of
respiratory depression than diazepam. In a retrospective review by
Chiulli et al, intravenous lorazepam was associated with a 37% incidence
of intubation compared to 73% with diazepam; however, this finding
needs confirmation with a prospective study. (Chiulli) Other studies
have demonstrated no significant difference in adverse events between
the two benzodiazepines. (Leppik)
What
options are available when intravenous access is not available?
When
intravenous access is unattainable intranasal, buccal, rectal, IM,
and intraosseous routes have all been used to administer antiepileptic
medications. In the ED, each route has certain advantages and disadvantages.
Optimal drugs for intramuscular delivery are water soluble with a
neutral pH. For example, phenytoin cannot be given intramuscularly
because its alkaline pH will result is significant tissue necrosis.
Optimal drugs for rectal delivery are lipid-soluble and non-ionized,
with solutions providing faster results than suppositories. Drugs
are absorbed passively through lipid membranes. Although some drugs
may have a cathartic effect, the advantage of rectal administration
is that the route bypasses the portal circulation and first-pass hepatic
elimination. (Woody)
Intramuscular
or intranasal midazolam is an excellent option when intravenous access
is not available since it is water soluble, nonirritating, and rapidly
absorbed. (Orebaugh, Kendall, Chamberlain) In a study by Jawad and
colleagues, (Jawad) intramuscular midazolam was effective as quickly
as IV diazepam. Midazolam, 10 to 15 mg, given intramuscularly reduced
the mean number of spikes on an EEG within 5 to 15 minutes, similar
to an intravenous administration of diazepam (10 or 20 mg). Kendall
reported two cases of status epilepticus, one in a 2 year old child
and one in an adult, that were successfully terminated with intranasal
midazolam, 1.6 mg and 10 mg respectively. (Kendall) Midazolam may
also be used buccally (10 mg dose for children over the age of 5 years),
and nasally, with a recommend dose of 0.2 mg/kg. (Richens) Several
randomized trials in children have demonstrated the efficacy of intranasal
midazolam or buccal midazolam in comparison to IV diazepam in pediatric
patients. When you compare the overall time to seizure ablation the
midazolam groups had faster seizure control because of the additional
time needed to start an IV. Diazepam may be administered intravenously or rectally. Intramuscular diazepam is not absorbed consistently. In a study by Moolenaar and colleagues (Moolenaar), 10 adult volunteers were given a 10-mg dose of diazepam by various routes, with maximum serum concentrations (Cmax) and the time to peak serum concentration (Tmax) measured and averaged between individuals. Intravenous diazepam reached its maximum serum concentration in 6 minutes. A rectal solution of diazepam had a time to peak serum concentration of 17 minutes. Orally administered diazepam had a Tmax of 52 minutes, rectal suppositories took 82 minutes, and intramuscularly administered diazepam took 95 minutes to attain maximum serum concentrations. Of note, anticonvulsant efforts usually begin before Cmax is reached. Studies in young children suggest that a single rectal dose of 0.5 mg/kg diazepam solution provides effective anticonvulsant levels of AED in 3 minutes. (Dooley, Kriel) In a prehospital study, Dieckmann reported that 13 of 16 children who received rectal diazepam stopped seizing after a single dose; seizures recurred in 4 of the children before ED arrival. (Dieckmann) None of the children suffered complications from the rectal diazepam. Unfortunately there was no control group to ascertain whether it was the diazepam or the natural course of the seizures that resulted in termination. Children with serial seizures had fewer seizures over time when given diazepam solution versus placebo. (Kriel, Cereghino) In a double blind placebo controlled study, rectal diazepam gel was reported to significantly reduce the median seizure frequency in children predisposed to repetitive seizure. (Cereghino). The most frequently reported complication was somnolence. Rectal doses of diazepam solution range from 0.5 mg/kg for children between the ages of 2 and 5 years of age, 0.3mg/kg for children between the ages of 6 and 11 years of age, and 0.2 mg/kg for children of 12 years of age and older. Prepackaged commercial syringes with adult and pediatric-sized tips are available in doses of 2.5, 5, 10, and 20 mg. Multiple syringes may be used; for instance, a child needing a 7.5 mg dose would receive a 2.5- and a 5-mg dose. Fosphenytoin,
a phosphate ester of phenytoin, became available in 1995 and has a
safety profile that makes it preferable to phenytoin in certain situations.
Fosphenytoin is water soluble obviating the need for the propylene
glycol vehicle. It can be given intramuscularly or intravenously with
100% bioavailability. Fosphenytoin is less of a tissue irritant than
the phenytoin/propylene glycol preparation, with pruritis and paresthesias
the most common side effects. There are minimal cardiotoxic effects
though hypotension has been reported with rapid intravenous infusions.
(Leppik) Blood pressure should be carefully monitored, especially
in patients with underlying cardiovascular disease, when given intravenously,
while monitoring is not necessary when it is given intramuscularly.
While fosphenytoin works fastest when given intravenously, it is well
absorbed by the IM route with 100% bioavailability. It should reach
therapeutic serum levels within one hour of administration though
its therapeutic benefit may be seen much earlier. Other standard AEDs
given orally or rectally, such as valproic acid or carbamazepine,
take too long to achieve therapeutic serum levels and thus are inappropriate
for emergency use.
1. Use a benzodiazepine as the first-line therapy.
2. If there is no IV access consider intranasal, buccal or IM versed, or IM Fosphenytoin, or rectal valium. Seizure management in the ED requires a risk benefit analysis that balances the patient’s needs with the urgency of the situation. 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 (ie Dilantin). When the IV access is unavailable, alternate routes such as intranasal or buccal midazolam, IM injections of midazolam, rectal solutions of diazepam, and IM fosphenytoin should be considered; of these intrasal midazolam may be the fastest and easiest to use.
Other
Information in the Literature
Alternative
agents for therapy include valproate, lidocaine and propofol as well
as brabituate coma.Lidocaine can be administered via the ETT as can
valium. Valium may cause pneumonitis. The definition of Status Epilepticus
can vary from 5, to 20 to 30 minutes. The most commonly misunderstood
aspect of status is that the patient must return to his baseline to
not be in status. Though brain damage is theoretically possible and
may occur with brief seizures, significant brain injury is unlikely
unless a patient has prolonged seizures. Brain injury and refractory
status can occur from hypoxia and hypoglycemia so these must be avoided.
In refractory status each subsequent AED provides only modestly greater
effect on seizure cessation. Very large doses of medications may be
necessary to stop refractory status epilepticus. Phenytoins have been
administered at up to 30 mg/kg to effectively control seizures.
There are insufficient prospective randomized clinical trials to determine the best treatments for status, prevention of brain injury, recurrent seizure and minimizing complications to provide the best overall outcomes.
What Are the Optimal Routes of Antiepileptic Drug Administration in Seizing Patients Without IV Access?Reference
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What
Are the Optimal Routes of Antiepileptic Drug Administration in Seizing
Patients Without IV Access?
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