Vol. 22, No. 8August 2000
Refereed Peer Review
FOCAL POINTKEY FACTS
#
Because status epilepticus (SE)frequently occurs outside thehospital, prompt prehospitaltreatment, including rectal andintranasal administration ofdrugs, can improve patientmanagement.
Status Epilepticus:Managing Refractory Cases and TreatingOut-of-HospitalPatients
*
University of Georgia
Simon R. Platt, BVM&S, MRCVS John J. McDonnell, DVM, MS
ABSTRACT:
Status epilepticus (SE) is an emergency medical situation that may not respondto benzodiazepine or phenobarbital treatment. This situation is termed
refractory SE
and re-quires more aggressive treatment such as anesthesia. SE may also occur in the home environ-ment where facilities are limited. The time that passes before treatment is instituted is crucialin the prevention of permanent cerebral damage and may be important in saving the patient’slife. For such patients, the efficacy of rectally delivered diazepam has been established. In-tranasal delivery of anticonvulsants is being evaluated in dogs and may represent a futuremethod of at-home seizure control.
S
tatus epilepticus (SE) is a medical emergency that requires prompt treatmentto avoid appreciable neurologic morbidity.
1–5
The proper management strat-egy involves prompt control of seizures.
3
Benzodiazepines (i.e., diazepam, lor-azepam, midazolam, and clonazepam) are potent, fast-acting anticonvulsants thatform the cornerstone of early SE therapy.
1-4
In animal screening tests, benzodi-azepines have shown a broad spectrum of anticonvulsant activity and may at lowdoses effectively inhibit seizure activity.
6
However, there are situations in whichthese drugs do not arrest continuous seizure activity and other treatments shouldbe employed. The companion articles in this series discussed the manifestations,pathophysiology, and treatment of patients with SE. This paper explores thetreatment of refractory SE by veterinarians and at-home seizures by owners.
CE
V
I
SE that does not respond to abenzodiazepine or phenobarbitalrequires more aggressivetreatment; potential reasons forrefractory seizure activity includeinadequate anticonvulsant doses,an uncorrected metabolicabnormality, intoxication,or tumor.
I
Adequate doses of thiopental andpentobarbital will usually controlthe physical manifestations ofseizures, but severe hypotensionlimits their safety.
I
The resources neededto manage the potentialcomplications of intravenoustherapy in seizuring patients areoften inadequate, and may resultin severe systemic and cerebraldamage or death.
I
Rectal administration ofanticonvulsants is relatively easyto carry out in the home and,therefore, is useful inemergencies.
*A companion article entitled “Status Epilepticus: Clinical Features and Pathophysiology”appeared in the July 2000 (Vol. 22 No. 7) issue of
Compendium
. The second installment,entitled “Status Epilepticus: Patient Management and Pharmacologic Therapy,” can befound in this issue. This is the final article in the series.
REFRACTORY STATUS EPILEPTICUS
Status epilepticus that does not respond to a benzodi-azepine or phenobarbital is considered refractory andrequires more aggressive treatment
5,7,8
(Figure 1). Poten-tial reasons for resistant seizure activity include inade-quate anticonvulsant doses, an uncorrected metabolicabnormality, or the presence of intracranial disease(e.g., a tumor).
3,9
These patients are often difficult totreat. Short-acting anesthetic drugs are commonly usedto treat resistant SE because these agents have a rapidonset of action and short half-lives and reduce cerebralmetabolic rates.
3
These drugs should be used only in anintensive care setting because blood pressure and cen-tral venous pressure should be monitored continuously.General anesthesia prevents tonic–clonic movementsand allows control of respirations.
Continuous Benzodiazepine Infusion
Continuous benzodiazepine infusion has been shownto be effective for treating refractory SE in humans andanimals.
5,10
Continuous intravenous (IV) infu-sions of diazepam were administered to 124 of 186 (66.8%) dogs with severe seizures,
10
butthe efficacy of this treatment could not be de-termined. The authors reported that continu-ous diazepam infusions may be underused inthe management of dogs with seizures.
10
Thedose should be calculated hourly (0.1 to 0.5mg/kg [0.23 mg/lb]) and is usually diluted in5% dextrose in water, with the volume used be-ing equal to the maintenance fluid requirementover the hour (Figure 1).
5,10,11
The dose can bedelivered with an infusion pump. The infusionof diazepam should be used with caution be-cause of its poor aqueous solubility, tendency to crystallize in solution, and adsorption ontopolyvinyl chloride tubings.
5
Midazolam, whichis completely water soluble, has been used as asafe, effective therapy for pediatric patients with SE but is more expensive to administer.
8
Propofol
In humans with refractory SE, IV infusionsof anesthetic doses of propofol (2,6-diisopropyl-phenol) have become standard.
3,7,12–14
This ap-proach has recently been evaluated in animals.
15
Propofol has shown barbiturate- and benzodi-azepine-like effects on the
γ
-aminobutyric acid
A
(GABA
A
) receptor and can suppress central ner-vous system metabolic activity.
12,13
Propofol canbe administered by IV bolus or by constant-rateinfusion (0.1 to 0.6 mg/kg/minute).
3,14,15
Theadvantages of propofol over the barbiturates areits rapid clearance, chiefly eliminated by hepatic conju-gation to inactive metabolites, and less profound hy-potensive effects.
2,3,13
However, propofol should be used with caution and preferably in settings in which defini-tive airway control and hemodynamic support are possi-ble because hypoxemia secondary to apnea as well asmyocardial depression are primary side effects.
2
When using propofol, seizures have been observedduring the induction of and emergence from anesthe-sia, but the importance of these proconvulsant effectsin SE management is unknown.
3,7
Whether the convul-sive phenomena occasionally seen with the use of thisdrug represent seizures, excitatory events, and/or a dis-order of muscle tone is controversial.
2
Experimental an-imal models have documented the anticonvulsant ef-fects of propofol.
2
This drug has been shown to raisethe lidocaine seizure threshold in rats, arrest bupiva-caine-induced seizures as effectively as thiopental at 10-mg/kg doses, and be as potent as is diazepam at pre-venting pentylenetetrazol-induced seizures in rabbits.
2
Compendium
August 2000Small Animal/Exotics
ANESTHETIC DRUGS
I
INFUSION PUMP
I
HYPOTENSIVE EFFECTS
I
AIRWAY CONTROL
Seizures persist despite treatmentwith diazepam and phenobarbitalConsider cause and institutemaintenance therapyMedical team andowner decide to useaggressive treatmentSignificanthypotension/bradycardia?Seizuresstop?Consider:1)
Intubation/ventilation2)
Arterial line for blood
gas evaluation3)
Urethral catheter 4)
Continuous
electrocardiogram
Phenobarbitalinfusion maximum24 mg/kg/dayOptions are:1)
Additional low-dose
boluses of diazepam2)
Continuous IV diazepam
infusion 0.1 mg/kg/hour
in 2.5% dextrose/0.9%
sodium chloride drip at
maintenance rate
3)
No further treatment
except to optimize
phenobarbital serum
levelIV pentobarbital1)
3–15 mg/kg to effect2)
Dopamine to maintain
blood pressureSeveredecreasedblood pressureSeizuresstopIV pentobarbitalinfusion 1 mg/kg/hour up to 6 hoursPoor prognosis consider:1)
Isoflurane anesthesia2)
Propofol infusion
0.1–0.6 mg/kg/minute3)
IV mannitol 1 g/kg bolus4)
IV furosemide 0.7 mg/kgIV dopamine infusion2–10 µg/kg/min and/or IV dobutamine 2–10µg/kg/minNoYesNoNoNoYesYesYesYesNo
Figure 1—
Patients in status epilepticus that fail to respond to diazepamand phenobarbital are considered to be refractory. This algorithm depictstreatment options for these patients.
IV
= intravenous.
Several reports have documented the anticonvulsant ac-tivity of propofol in humans.
12
Stecker and colleaguesrecently reported that propofol can control refractory SE more quickly in humans than can high-dose barbi-turates.
12
Because of the pharmacokinetics of propofol,it is believed that even if this drug failed to controlseizures and high-dose barbiturates were required, littletime would be lost and there would be no long-terminterference with other treatments.
12
Heldmann andcolleagues recently studied the use of propofol in infour cats and one dog with naturally occurring seizuresfollowing the surgical attenuation of single extrahepaticportosystemic shunts.
15
All of the patients, two of which had seizures that were unresponsive to other an-ticonvulsants, responded to propofol.
15
All five animalshad regular indirect blood pressure measurements andremained hemodynamically stable when the drug wasappropriately administered.
15
All of the animals sur-vived to discharge.
Barbiturates
Thiopental and pentobarbital have shown potential,although unproven, cerebral protective effects in themanagement of SE. Adequate doses of these drugs usu-ally control the physical manifestations of seizures, butsevere hypotension limits their safety.
4,7,8
Pentobarbitalsodium (Nembutal
®
; Abbott), used at standard safedoses, is a general anesthetic with negligible anticonvul-sant properties.
4
Thiopental has been associated with ahigher degree of cardiac toxicity than has pentobarb-ital.
13
In one study, Roesch and colleagues reported moreventricular arrhythmias in animals treated with thio-pental than in those treated with pentobarbital at doseslower than those required to cause a flat electroen-cephalogram (EEG).
13
At higher doses than those re-quired to produce a flat EEG, only two of seven dogstreated with thiopental survived whereas all 17 dogstreated with pentobarbital survived.
13
Pentobarbitalshould be given to effect and not as a specific dose (3 to15 mg/kg IV) because response varies widely among pa-tients (Figure 1).Patients treated with “barbiturate coma” commonly require an extended period of mechanical ventilation inan intensive care setting.
5,8,12
In general, the side effectsof barbiturate coma include depression of myocardialmetabolism, vasodilation with a decrease in venous re-turn, and decreased cardiac perfusion.
16
These effectscan be minimized by using saline infusion and smalldoses of dopamine. Patients can develop poikilothermiaand decreased urinary output during myocardial de-pression and hypotension. Neurologic evaluation is dif-ficult because spontaneous respiratory responses andmovements cease. We recommend reserving the use of these anesthetics for patients in which benzodiazepinesand phenobarbital fail.
Etomidate
Etomidate,which has shown GABA-ergic activity inthe brain, is a short-acting drug. The anticonvulsant ef-fects of this agent in dogs and cats have not yet beendocumented.
4
Lidocaine
In 1955, IV lidocaine was first reported as a treat-ment for SE in humans.
17
Since that time, a number of studies, mostly in Europe, have reported the efficacy of lidocaine in refractory SE,
9
although no large, double-blind, placebo-controlled studies have proven the drug’sefficacy in humans with SE.
17
The exact mechanism by which lidocaine terminates seizures is unknown at pres-ent. Lidocaine decreases neuronal excitability by block-ing voltage-dependent sodium channels in the cellmembrane.
17
In addition, it reduces potassium effluxinto the extracellular space and decreases neuronal mi-tochondrial metabolism and cerebral oxygen consump-tion.
17
Increased extracellular potassium increases theconcentration of the excitatory neurotransmitter gluta-mate and may increase the recruitment of other neu-rons into the seizure activity.
17
Most reports on the useof lidocaine in humans recommend a maintenance in-fusion after initial termination of SE.
17
Lidocaine hasbeen reported to cause seizures as well as myocardialdepression and cardiac conduction abnormalities.
17
However, the signs attributable to lidocaine toxicity arerare clinically when the drug is used specifically for itsanticonvulsant properties. The optimal anticonvulsantdose of lidocaine in humans and animals is unknown; we do not recommend its use in SE until further inves-tigations have been pursued.
Inhalational Anesthesia
Inhalational anesthetics have been recommended as atreatment of last resort for patients with resistant SE.The equipment and personnel necessary to administerinhalational anesthesia may not be readily available andthe equipment can be cumbersome. Isoflurane, an in-halational general anesthetic agent, may be efficaciousin the treatment of resistant SE.
3
Not all of the volatileanesthetic agents have antiepileptic potential; however;enflurane may actually increase seizure activity.
3
Isoflu-rane, which has been studied extensively, does not un-dergo hepatic metabolism and has a rapid onset of ac-tion.
3
Obviously, isoflurane therapy requires ventilationand intensive care monitoring; hypotension may occurduring therapy.
3
Small Animal/Exotics
Compendium
August 2000
CARDIAC TOXICITY
I
SALINE INFUSION
I
POTASSIUM EFFLUX
I
ISOFLURANE
of 00
Status Epilepticus-Managing Refractory Cases and Treating Out-Of-hospital Patients
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