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Vol. 22, No. 8August 2000
Refereed Peer Review
FOCAL POINTKEY FACTS
5
The ideal pharmacologictreatment of status epilepticus(SE) requires the use of anintravenous lipid-solubleanticonvulsant to rapidly attainand then maintain a therapeuticdrug concentration in the brain.
Status Epilepticus:Patient Managementand PharmacologicTherapy 
*
University of Georgia
Simon R. Platt, BVM&S, MRCVS John J. McDonnell, DVM, MS
ABSTRACT:
Status epilepticus (SE) requires immediate treatment of the seizure activity to pre-vent the possibility of permanent brain damage. Intravenous drug therapy, most commonlyachieved using diazepam, should be instituted without delay. Intravenous or intramuscularphenobarbital, often used in addition to a diazepam protocol, affords a longer period of seizurecontrol. The use of multiple drugs in SE patients is limited by the onset of hypotension. Pa-tients that do not respond to this pharmacologic approach are considered to be refractory; amore aggressive protocol involving intensive care will be required and, depending on thecause, may not be successful. This article addresses the systemic and pharmacologic man-agement of SE.
S
tatus epilepticus (SE) is a medical emergency that requires immediate ther-apy to prevent severe cerebral damage.
1–5
The management of SE involvesprompt control of seizures as well as treatment of the systemic effects andunderlying causes
3
(Figure 1). The side effects of aggressive pharmacologic treat-ment should be recognized when determining a treatment plan. The first articlein this series addressed the features and pathophysiology of SE. This paper dis-cusses the antiepileptic drug (AED) therapies used to treat SE. A final article (seepage 732) will discuss therapies for refractory patients and potential at-hometreatment.
PATIENT MANAGEMENT
Status epilepticus can be a danger to patients and can provide a treatmentchallenge for clinicians. Treatment can be divided into acute emergency manage-ment and rational drug administration. Emergency care is designed to prevent
CE
V
s
Vital functions such as glucosemetabolism, oxygenation, andtemperature regulation should bemonitored in patients with SE toprevent significant neurologicmorbidity.
s
The drug used to treat SE shouldbe determined by its ease ofadministration, time of onset,duration of effect, and extentof effects on cardiorespiratoryfunction and level ofconsciousness.
s
A dangerous error that iscommonly made when managingSE is to treat consecutiveseizures with repeated doses ofintravenous diazepam withouttreating the precipitating factorsand without administering anadequate loading dose of alonger-acting antiepilepticdrug.
*A companion article entitled
“
Status Epilepticus: Clinical Features and Pathophysiology 
”
appeared in the July 2000 (Vol. 22 No. 7) issue of 
Compendium 
. A final installment inthe series, entitled
“
Status Epilepticus: Managing Refractory Cases and Out-of-HospitalPatients,
”
can be found in this issue.
 
patient injury, whereas drugtreatment is guided by itsability to limit morbidity re-sultingfrom systemic changesor from seizure-induced neu-ronal damage.
6
The goal of immediate treatment is tostop the abnormal cerebralelectrical activity associated with SE.
3
The overall objec-tives in managing SE are tomaintain vital functions atall times, identify and treatprecipitating factors of SE,and administer an AED.
7
MAINTAINING VITALFUNCTIONS
Treatment must sometimesbe initiated before a diagnos-tic evaluation can be made.Medical and neurologic ex-aminations should be per-formed concomitant withpatient management. Theinitial care of patients withSE requires basic medicalemergency measures, other- wise known as the ABCs of life support (i.e., airway,breathing, circulation).
3,8
Oxygenation, Airway, and Acid–Base Status
Hypoxia may cause SE
6
and must be corrected beforerecovery can occur. Likewise, SE can also induce hypox-ia.
6
 Airway management and respiratory monitoring inpatients with SE can be difficult. If possible, airway pa-tency should be maintained while the patient remainsunresponsive. Oxygen may be administered by using anonrebreathing mask or an intranasal delivery system. Arterial blood gas monitoring is extremely useful inpatients with SE because marked metabolic acidosis canbe prevalent during the convulsive episodes. Respirato-ry acidosis or hypoxia detected on the blood gas analy-sis should be treated immediately, whereas metabolicacidosis may resolve after the physical manifestations of the convulsions subside. In experimental animal stud-ies, the severity of brain damage correlated best withhypoxia, hypotension, and pyrexia as well as the dura-tion of the convulsive status.
2,3,8
Intravenous Access
 A large intravenous (IV) catheter should be insertedfor fluid and drug adminis-tration. Maintenance admin-istration of IV isotonic saline,supplemented with potassi-um chloride, may be initiat-ed. Other secondary meta-bolic complications (e.g.,electrolyte imbalance) mustbe corrected.
2,8
Glucose Metabolism
Patients presenting withaltered consciousness shouldbe administered a bolus of IV glucose as soon as hypo-glycemia is confirmed by routine blood tests. Thi-amine (vitamin B
1
) shouldbe administered immediately before the glucose (25 to 50mg per animal IM) becauseit is an important cofactorin the aerobic metabolism of glucose.
9
Temperature Regulation
Hyperthermia, which canbe life threatening, can oc-cur frequently during SE andeven in humans represents amanifestation of the seizures rather than evidence of aninfection.
4,10
Hyperthermia should be treated promptly  with passive cooling, especially if the body temperatureexceeds 40
˚
C (104
˚
F).
9
In some patients, temperatureshould be monitored rectally, particularly if coolingtechniques are used. Passive cooling should be stopped when body temperature reaches 102
˚
F to prevent re-bound hypothermia.
9
PRINCIPLES OF DRUG TREATMENT
The drug used in SE treatment can be determined by its ease of administration, time of onset, duration of ef-fect, and minimal effects on cardiorespiratory functionand level of consciousness.
11
–
13
Unfortunately, no singledrug is ideal.
3,12
The rate of brain entry of a drug is di-rectly proportional to the non
–
protein-bound drugserum concentration, lipid solubility, and cerebralblood flow.
13
Therefore, SE can be treated by IV infu-sion (to obtain high serum concentration) of lipid-solu-ble AEDs. Drug volume of distribution increases withlipid solubility, and lipid-soluble drugs tend to redis-tribute out of the brain and serum and into body fat.
13
To rapidly attain and then maintain a therapeutic
Compendium 
August 2000Small Animal/Exotics
HYPOXIA
s
METABOLIC ACIDOSIS
s
HYPERTHERMIA
s
PASSIVE COOLING
1)IV isotonic saline ata maintenance rate2)Complete blood count,chemistry, electrolytesplus toxicity screen Administer 1)Intramuscular thiamine(vitamin B
1
), 50 mg2)IV dextrose 50%, 500mg/kg over 15 minutesNeurologic examinationSignificant impairmentof airway,breathing, or circulationIV glucoseassessmentUrgent medical therapy1)Intubate if necessary2)Adequate venous access3)IV glucose assessment4)Temperature assessment5)Pressors if necessaryGlucose <60 mg/dLStatus Epilepticus
NoYesYesNo
Figure 1
—
Patients that present in status epilepticus shouldbe considered to be in systemic crisis. Immediate assessmentand stabilization are essential, as depicted in this flow dia-gram. (
IV 
= intravenous)
 
serum and brain concentration of drug, a loading dosesufficient to attain the desired concentration through-out the volume of distribution must be administered.The loading dose of a drug can be computed usingthe following equation:Loading dose (mg/kg) = Desired concentration(mg/L)
×
Volume of distribution (L/kg)Drug loading is therefore a passive process determinedby volume of distribution and is independent of drugelimination kinetics.Intravenous drug treatment for SE should be initiat-ed without delay 
11
based on the relationship betweenduration of SE and the extent of neurologic morbidity 
2
;experimental animal models suggest that SE becomesprogressively less responsive to treatment with diaze-pam.
11,14
 Anticonvulsants prevent the synchronizationof related neurons and can be more effective when they act at more than one biochemical site.
4
PHARMACOLOGIC THERAPYBenzodiazepines
Because the benzodiazepines (diazepam, lorazepam,midazolam, and clonazepam) are potent, fast-acting AEDs, these drugs (particularly diazepam) are the pre-ferred initial therapy in SE.
3,4,11,15
However, none of thebenzodiazepines are effective for long-term control of SE.
15
This widely used class of sedative/tranquilizer andanxiolytic agents differs greatly in course of timing andcentral effects.
15
These differences may be related totheir pharmacokinetics,
15
especially their central ner-vous system (CNS) distribution, which has been relatedto the drugs
’
lipophilicity and plasma protein binding.
15
The lipophilicity of these compounds determines theirrapid brain penetration after IV administration.
15
 Al-though penetration is rapid, distribution equilibriumamong all regions takes longer.
15
Their primary pharmacologic actions are probably related to a benzodiazepine-receptor
–
mediated en-hancement of 
γ 
-aminobutyric acid (GABA) -ergictransmission, both pre- and postsynaptically.
4,5,11,16,17
Benzodiazepines do not seem to alter the synthesis, re-lease, or metabolism of GABA but rather potentiate itsaction at the receptor.
17
The resultant augmented flow of chloride ions into cells decreases the cell
’
s ability toinitiate an action potential.
17
 At higher concentrations,benzodiazepines also limit sustained repetitive neuronalfiring in a manner similar to that of carbamazepine andphenytoin; this effect may be relevant to their mecha-nism of action in SE.
11
Benzodiazepines seem to pre-vent the spread of seizure rather than suppress the fo-cus.
16
In animal screening tests, benzodiazepines haveshown a broad spectrum of anticonvulsant activity.
16
These AEDs, which can be effective at low doses, in-hibit seizure activity induced by pentylenetetrazol andpicrotoxin in animal models.
16
 Adverse effects of IV benzodiazepines include respira-tory depression, hypotension, and impaired conscious-ness.
3,16
However, it is believed that a low incidence of respiratory depression with benzodiazepines occurs be-cause of the low density of binding sites in the brainstem.
17
The dose of diazepam that causes respiratory ar-rest in patients may be difficult to determine.
3,5
Diazepam 
Classified as a Schedule IV drug under the 1970Controlled Substances Act, diazepam is not approvedfor animal use by the FDA 
4
; however, it remains thedrug of choice for the treatment of SE in dogs andcats.
4
The major metabolites of diazepam, nordiazepam(desmethyldiazepam) and oxazepam, have up to 33%of the activity of the parent drug.
4
 Although the half-life of diazepam is 3.2 hours in dogs, the half-lives of the metabolites (up to 5.2 hours in the case of oxaze-pam) are slightly longer.
18
 With its relatively brief duration of action, diazepamis not a definitive therapy for SE. Because IV diazepamproduces transiently high serum and brain concentra-tions, however, the drug can be useful in therapy. Be-cause SE may end spontaneously, IV diazepam shouldnot be administered to patients presenting in a postictalstate unless another seizure occurs.In treating dogs and cats, diazepam has been recom-mended at a dose of 0.5 to 1.0 mg/kg IV, up to a maxi-mum dose of 20 mg.
4,19
This dose can be repeated to ef-fect or twice within 2 hours.
4
Constant-rate infusionsof diazepam have been advocated in human and veteri-nary patients.
4
The recommended dose is 2 to 5 mg/hour in 5% dextrose in water.
4
Continuous diazepaminfusions have been shown to be an effective modality to control refractory SE in children and have been asso-ciated with a reduced need for ventilatory and vasopres-sor support.
5
If diazepam does not control the seizures,the use of phenobarbital should be considered. Probably the most dangerous error commonly made in SE man-agement is to treat consecutive seizures with repeateddoses of IV diazepam without administering an ade-quate loading dose of a longer-acting AED. Patients willcontinue to have seizures, toxic concentrations of di-azepam or diazepam metabolites will accumulate, andserious morbidity may result from diazepam overdosage.In some patients, administration of IV diazepam may not be possible. The drug can be given intramuscularly (IM), although absorption is not predictable.
4
Rectaladministration of diazepam may be considered initially at a dose of 0.5 to 2.0 mg/kg depending on whether
Small Animal/Exotics
Compendium 
August 2000
NEUROLOGIC MORBIDITY
s
POSTICTAL STATE
s
CONSTANT-RATE INFUSIONS
of 00

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