V Vol. 22, No.
8 August 2000
CE Refereed Peer Review
FOCAL POINT
★The ideal pharmacologic
treatment of status epilepticus
(SE) requires the use of an
intravenous lipid-soluble
anticonvulsant to rapidly attain
and then maintain a therapeutic
drug concentration in the brain.
KEY FACTS
■ Vital functions such as glucose
metabolism, oxygenation, and
temperature regulation should be
monitored in patients with SE to
prevent significant neurologic
morbidity.
■ The drug used to treat SE should
be determined by its ease of
administration, time of onset,
duration of effect, and extent
of effects on cardiorespiratory
function and level of
consciousness.
■ A dangerous error that is
commonly made when managing
SE is to treat consecutive
seizures with repeated doses of
intravenous diazepam without
treating the precipitating factors
and without administering an
adequate loading dose of a
longer-acting antiepileptic
drug.
Status Epilepticus:
Patient Management
and Pharmacologic
Therapy*
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 commonly
achieved using diazepam, should be instituted without delay. Intravenous or intramuscular
phenobarbital, often used in addition to a diazepam protocol, affords a longer period of seizure
control. 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; a
more aggressive protocol involving intensive care will be required and, depending on the
cause, 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 involves
prompt control of seizures as well as treatment of the systemic effects and
underlying causes3 (Figure 1). The side effects of aggressive pharmacologic treat-
ment should be recognized when determining a treatment plan. The first article
in 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 (see
page 732) will discuss therapies for refractory patients and potential at-home
treatment.
PATIENT MANAGEMENT
Status epilepticus can be a danger to patients and can provide a treatment
challenge for clinicians. Treatment can be divided into acute emergency manage-
ment and rational drug administration. Emergency care is designed to prevent
*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 in
the series, entitled “Status Epilepticus: Managing Refractory Cases and Out-of-Hospital
Patients,” can be found in this issue.
Compendium August 2000 Small Animal/Exotics

patient injury, whereas drug Status Epilepticus

for fluid and drug adminis-
treatment is guided by its tration. Maintenance admin-
ability to limit morbidity re- istration of IV isotonic saline,
sulting from systemic changes supplemented with potassi-
Significant impairment
or from seizure-induced neu- of airway, um chloride, may be initiat-
breathing, or
ronal damage.6 The goal of No circulation Yes
ed. Other secondary meta-
immediate treatment is to bolic complications (e.g.,
stop the abnormal cerebral electrolyte imbalance) must
electrical activity associated Urgent medical therapy be corrected.2,8
1) Intubate if necessary
with SE.3 The overall objec- IV glucose
assessment
2) Adequate venous access
3) IV glucose assessment
tives in managing SE are to 4) Temperature assessment Glucose Metabolism
maintain vital functions at 5) Pressors if necessary
Patients presenting with
all times, identify and treat altered consciousness should
precipitating factors of SE, Glucose <60 mg/dL be administered a bolus of
and administer an AED.7 IV glucose as soon as hypo-
Yes No
glycemia is confirmed by
MAINTAINING VITAL routine blood tests. Thi-
FUNCTIONS Administer 1) IV isotonic saline at amine (vitamin B1) should
1) Intramuscular thiamine a maintenance rate
Treatment must sometimes (vitamin B ), 50 mg
1 2) Complete blood count, be administered immediately
2) IV dextrose 50%, 500 chemistry, electrolytes
be initiated before a diagnos- mg/kg over 15 minutes plus toxicity screen before the glucose (25 to 50
tic evaluation can be made. mg per animal IM) because
Medical and neurologic ex- it is an important cofactor
aminations should be per- in the aerobic metabolism of
Neurologic examination
formed concomitant with glucose.9
patient management. The Figure 1—Patients that present in status epilepticus should
initial care of patients with be considered to be in systemic crisis. Immediate assessment Temperature Regulation
SE requires basic medical and stabilization are essential, as depicted in this flow dia- Hyperthermia, which can
emergency measures, other- gram. (IV = intravenous) be life threatening, can oc-
wise known as the ABCs of cur frequently during SE and
life support (i.e., airway, even in humans represents a
breathing, circulation).3,8 manifestation of the seizures rather than evidence of an
infection.4,10 Hyperthermia should be treated promptly
Oxygenation, Airway, and Acid–Base Status with passive cooling, especially if the body temperature
Hypoxia may cause SE6 and must be corrected before exceeds 40˚C (104˚F).9 In some patients, temperature
recovery can occur. Likewise, SE can also induce hypox- should be monitored rectally, particularly if cooling
ia.6 Airway management and respiratory monitoring in techniques are used. Passive cooling should be stopped
patients with SE can be difficult. If possible, airway pa- when body temperature reaches 102˚F to prevent re-
tency should be maintained while the patient remains bound hypothermia.9
unresponsive. Oxygen may be administered by using a
nonrebreathing mask or an intranasal delivery system. PRINCIPLES OF DRUG TREATMENT
Arterial blood gas monitoring is extremely useful in The drug used in SE treatment can be determined by
patients with SE because marked metabolic acidosis can its ease of administration, time of onset, duration of ef-
be prevalent during the convulsive episodes. Respirato- fect, and minimal effects on cardiorespiratory function
ry acidosis or hypoxia detected on the blood gas analy- and level of consciousness.11–13 Unfortunately, no single
sis should be treated immediately, whereas metabolic drug is ideal.3,12 The rate of brain entry of a drug is di-
acidosis may resolve after the physical manifestations of rectly proportional to the non–protein-bound drug
the convulsions subside. In experimental animal stud- serum concentration, lipid solubility, and cerebral
ies, the severity of brain damage correlated best with blood flow.13 Therefore, SE can be treated by IV infu-
hypoxia, hypotension, and pyrexia as well as the dura- sion (to obtain high serum concentration) of lipid-solu-
tion of the convulsive status.2,3,8 ble AEDs. Drug volume of distribution increases with
lipid solubility, and lipid-soluble drugs tend to redis-
Intravenous Access tribute out of the brain and serum and into body fat.13
A large intravenous (IV) catheter should be inserted To rapidly attain and then maintain a therapeutic

HYPOXIA ■ METABOLIC ACIDOSIS ■ HYPERTHERMIA ■ PASSIVE COOLING

Small Animal/Exotics
serum and brain concentration of drug, a loading dose
sufficient to attain the desired concentration through-
out the volume of distribution must be administered.
The loading dose of a drug can be computed using
the following equation:
Loading dose (mg/kg) = Desired concentration
(mg/L) × Volume of distribution (L/kg)
Drug loading is therefore a passive process determined
by volume of distribution and is independent of drug
elimination kinetics.
Intravenous drug treatment for SE should be initiat-
ed without delay11 based on the relationship between
duration of SE and the extent of neurologic morbidity2;
experimental animal models suggest that SE becomes
progressively less responsive to treatment with diaze-
pam.11,14 Anticonvulsants prevent the synchronization
of related neurons and can be more effective when they
act at more than one biochemical site.4
PHARMACOLOGIC THERAPY
Benzodiazepines
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 the
benzodiazepines are effective for long-term control of
SE.15 This widely used class of sedative/tranquilizer and
anxiolytic agents differs greatly in course of timing and
central effects.15 These differences may be related to
their pharmacokinetics,15 especially their central ner-
vous system (CNS) distribution, which has been related
to the drugs’ lipophilicity and plasma protein binding.15
The lipophilicity of these compounds determines their
rapid brain penetration after IV administration.15 Al-
though penetration is rapid, distribution equilibrium
among all regions takes longer.15
Their primary pharmacologic actions are probably
related to a benzodiazepine-receptor–mediated en-
hancement of γ-aminobutyric acid (GABA) -ergic
transmission, 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 its
action at the receptor.17 The resultant augmented flow
of chloride ions into cells decreases the cell’s ability to
initiate an action potential.17 At higher concentrations,
benzodiazepines also limit sustained repetitive neuronal
firing in a manner similar to that of carbamazepine and
phenytoin; 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 have
shown a broad spectrum of anticonvulsant activity.16
NEUROLOGIC MORBIDITY ■ POSTICTAL STATE ■ CONSTANT-RATE INFUSIONS
Compendium August 2000
These AEDs, which can be effective at low doses, in-
hibit seizure activity induced by pentylenetetrazol and
picrotoxin 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 brain
stem.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 1970
Controlled Substances Act, diazepam is not approved
for animal use by the FDA4; however, it remains the
drug of choice for the treatment of SE in dogs and
cats.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, diazepam
is not a definitive therapy for SE. Because IV diazepam
produces transiently high serum and brain concentra-
tions, however, the drug can be useful in therapy. Be-
cause SE may end spontaneously, IV diazepam should
not be administered to patients presenting in a postictal
state 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 infusions
of 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 diazepam
infusions 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 repeated
doses of IV diazepam without administering an ade-
quate loading dose of a longer-acting AED. Patients will
continue to have seizures, toxic concentrations of di-
azepam or diazepam metabolites will accumulate, and
serious 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 Rectal
administration of diazepam may be considered initially
at a dose of 0.5 to 2.0 mg/kg depending on whether
Compendium August 2000 Small Animal/Exotics

the animal was being treated with phenobarbital before

Share Your
the onset of SE.4,9 The higher dose may be necessary in
dogs receiving long-term phenobarbital therapy.20 In
Knowledge
untreated dogs, a per-rectum (PR) diazepam dose of 1
mg/kg resulted in a mean time to peak plasma concen- We invite you to impart your clinical knowledge
tration of 14.3 minutes.9 The peak concentration was
474 µg/L; plasma benzodiazepine concentrations by discussing your interesting cases, unusual
greater than 300 µg/L were needed to provide anticon-
vulsant action in the dog’s brain.9 presentations, or procedures for clinical solutions

Midazolam
for the following features:
Midazolam is a recently developed water-soluble ben- DIAGNOST
IC CHALLENG
E

isoning
rn on a Rat Po
zodiazepine of the group of 1,2-annelated benzodi- Unexpected Tu

azepines.21 The water solubility allows midazolam to be DIAGNOSTIC CHALLENGE By Marjory

Brooks, D.V.M
and Jeff Jacobs
on, D.V.M
.
., Dipl. A.C.V.
I.M.,

d male Beagle,
was exam-
r-old, neutere Con-
ugsy, a four-yea n of the rat poison
M ined within one
hour of ingestio l placement

packaged without the use of such diluents as propylene A detailed account of a clini- trac® . Initial
of apomorphine
vomiting. In
treatment consiste
and 30 mL of
response to this
amount of green-b
lue material
d of subconjunctiva
oral hydrogen
therapy, Mugsy
identified as
peroxide to induce
vomited a large
the rat bait.
d charcoal by
Addi-
gas-
nt included 200 mL of activate (SC).
neously

glycol, thus decreasing venous and IM irritation.17 At

tional treatme 2.5 mg/kg subcuta

cal dilemma takes readers from

and vitamin K1 supply of
tric intubation with a 10-day
ed to his owners
Mugsy was discharg hours orally.
K 50 mg every 24
vitamin 1

ry

physiologic pH, midazolam becomes extremely

SEALING
NS BY LES
blood chemist
nation. All
ILLUSTRATIO

for PT determi PT at recheck

specific patient presentation

hours later limits. The
d for 48 hours within normal because cor-
tion was schedule values were ted finding
A recheck examina vitamin K regimen to
confirm , an unexpec K deficiency
was 65.9 seconds al PT due to vitamin
ion of the owners report- initiating an
after complet Although his rection of abnorm 48 hours of
coagulopathy. and Mugsy within 24 to
resolution of K1 as directed should resolve K1. of
had given vitamin re to rat poison, clotting

lipophilic, enabling a rapid onset of action.17 Like other

dose of vitamin persistent prolongation
ed that they appropriate
nity for reexposu was markedl
y the cause of additional vitamin
had no opportu time (PT) assay To determine and whether
prothrom bin
: 9.5-12.5). This
finding
clotting time
in the PT sent for more
time in the a sample was

through the steps leading to the 57 seconds (normal d that his early pre- was needed, was drawn
prolonged at it appeare ed K therapy analyses . Whole blood
ted because prevent ion 3.8 percent
was unexpec vomiting had detailed coagulat anticoagulant (one part
productive Contrac, how- citrate ged, and the
sentation with dose of rodenticide. poison.
directly into blood) and centrifu
to a vet-
parts

benzodiazepines, midazolam is biotransformed by hep-

a toxic a long-acting cold packs
absorption of citrate to nine shipped on
s bromadiolone, at the same vitamin K1 plasma was Coagulation
ever, contain supernatant (Comparative
therefore resumed e laboratory University,
Treatment was two weeks.
erinary referenc
tic Laborat
ory, Cornell
completion
dosage for another recheck, 48 hours after Section, Diagnos

ultimate diagnosis in 1000-1500

ed and d
At Mugsy’s next was still markedly prolong York). d of activate
Ithaca, New ion panel consiste
, the PT sample. A thrombin
of vitamin K1 from the previous The initial coagulattime (aPTT), PT, and g
unchanged al vita- plastin TCT screenin

atic microsomal oxidation followed by glucuronide

essentially submitted, parenter were partial thrombo aPTT and
ry profile was owners (TCT). The
blood chemist 50 mg SC, and the 48 clotting time
min K1 was
given and recheck
vitamin K1 August 2000
resume oral
instructed to
ed
Peer Review

conjugation.17 Alpha-hydroxy-midazolam, the primary words. 76 Veterinary

Forum

metabolite after hydroxylation, is pharmacologically ac- THERAPEUTIC

CHALLENGE

tive and has sedative properties equivalent to those of THERAPEUTIC CHALLENGE

KAREN WILSON
midazolam in humans, although only low levels of this Intussuscep
tio
In a Yearlin n
While the course of therapy is of- g
metabolite could be detected after IV or IM adminis- By Linnea Lentz,
D.V.M.

tration of midazolam to dogs.17,22 All the metabolites ten clear-cut, some patients pre-
B eau, a 15-mont
when the owners
h-old colt, had been
colicky for about

sent true challenges to medical

called the referring four hours

are rapidly excreted in human urine, but in dogs a

veterinarian. The and no other
described as mild, colic was
abnormali-
and Beau was treated ties. An initial
IV injection
nixine) administe with 10 cc Banamin ® of xylazine appeared
red intravenously e (flu- to
approximately 1 (IV), 10 cc of control the pain
⁄2 gallon of mineral dipyrone IV, and for only 20
oil administered minutes before
tube. Within the via nasogastric a second
hour, Beau was dose was necessary.
University of Minneso again colicky and Rectal
was referred to the

more predominant extrarenal excretion is suggested,

palpation revealed

skills. In 1000-1500 words, these

ta. many
distended loops
of small
testine. After placemen in-
Initial Treatme t of
nt on Referra a nasogastric
Clinical signs l reflux were obtained. tube, 6-7 L of
on presentation Abdominocen-
included profuse tesis results were
sweating, numerous normal.
attempts to lie Because of the

probably through the bile.22 In dogs, the elimination

down, and a distended severity of the
abdomen. Physical colic, the small
examination re- intestinal distention

cases describe the steps that

vealed a pulse and nasogastr ,
of 84 beats per ic reflux, we
decreased gastrointe minute, mended explorato recom-
stinal motility ry laparotomy
all four quadrants in diagnose the cause to
, slightly toxic of the colt’s colic.
cous membran mu- The owners quickly
es, a capillary agreed, and pre-
time of 2.5 seconds refill operative antibiotic

half-life of these metabolites is 11 minutes.22

(normal: 1-2),
and a normal
temperature. potassium penicillin s, including
work revealed Blood 22,000 units/kg
a packed cell IV and Gentocin
volume (gentamicin) 6.6

eventually lead to case resolu-

of 48 percent mg/kg IV, were
(normal: 32-48), administered before
protein of 7.2 g/dL total preparing the colt
(normal: 5.7-7.9), for surgery. During
surgery, a jejunocec
August 2000 al intussuscep-➔

Midazolam has been shown to have a wide margin of

Peer Reviewed
Veterinary Forum
73

tion.
safety and a broad therapeutic index12; therefore, it can
diffuse rapidly across the capillary wall into the CNS CASE OF THE
MONTH

is
and can be mixed with saline or glucose solutions.21 Canine Hemipares , D.V.M.

CASE OF THE MONTH

By Donivan Hudgins

The mean plasma elimination half-life in dogs was 53 Some case presentations are so had been normal,

J old, 29- activity levels

to 77 minutes following IV administration.22 Midazo-

were current
asmine, a four-year- and vaccinations
kg, spayed Golden
Retriev- hepatitis, lep-
for distemper, nza, par-
to the clinic
er, was presented tosporosis, parainflue
of lameness. irus, Lyme
for sudden onset vovirus, coronoav

confounding that both diagnosis

found a stray
The owner had and sus- disease, and rabies.
given Solu
goat in the backyard have The patient was
may (prednisolone)

lam has a significant antiepileptic effect in humans

goat ®
pected that the Delta Cortef
On presenta- usly (IV) and
butted Jasmine. ry 100 mg intraveno 2.5 cc in-
was ambulato
tion, the dog amoxicillin injectable
uncoordinated, The owner was
but obviously tramuscularly.
n revealed the provide cage rest
and observatio instructed to

and therapy are perplexing. Often,

deficit was in and return
primary walking over the weekend
dog’s condition

proven to be caused by GABAA receptor stimulation3,23

the right rear leg. ion re- Monday if the
Physical examinat .
had not improved
re of 101.6˚F, week, Jas-
vealed a temperatu The following
es, capil- to improve, and
pink mucous membran (normal:
CORBIS

mine appeared
of 1 sec she did have
lary refill time whatever problems
heart and Over the next
1-2 sec), normal seemed subtle.

a patient may return again and

sign of pain. The weeks, her prob-

and has been shown to be more effective and safer for

lungs, and no two to three
did knuckle over, but not as pro-
right rear foot proprio- lems recurred the
indicating decreased indicat- before, and
nounced as
pinch that the dog
ception, but toe owner reported
were intact. to her deficits.
ed sensory nerves seemed to adjust
of the affected next few weeks,
Temperatures Then, over the
no different of coördination
foot and leg were

the control of seizures than comparable doses of di-

Jasmine’s lack

again with continuously changing

other three feet
than that of the flexion seemed to worsen. Jasmine
and 21,
and legs. Extension On October
hip joints were for examina-
of the stifle and reflex on was re-presented
on a leash
normal, but patellar tion. When followed appeared
exaggerated,
the right was in the lawn, Jasmine
upper motor ated, with

azepam.17,21 A recent study in humans demonstrated the

which suggested to be very uncoördin
Appetite and
neuron disease.

signs. Word count: 1000-2000. 66 Veterinary Forum

Peer Reviewed
August 2000

beneficial effects of an IV midazolam infusion in 11 of

12 patients with refractory SE.21 Data that relate con-
centrations of venous midazolam to anticonvulsant ef-
fects in humans or in animals are not yet available, al-
though the anticonvulsant effect of midazolam has
been documented in experimental animal models.17,21 SEND YOUR ARTICLES TO:
Unlike diazepam, with erratic and incomplete IM ab- Editor, Veterinary Forum
sorption, midazolam is rapidly absorbed following IM 275 Phillips Blvd.
injection, with a high bioavailability, an early onset of
sedation, and early clinical effects.17 Peak plasma con- Trenton, NJ 08618
centration in dogs after IM administration occurred Fax: (609) 882-6357
within 15 minutes, and a mean elimination half-life of E-mail: lmiller.vls@medimedia.com

METABOLITE ■ BIOAVAILABILITY
Small Animal/Exotics Compendium August 2000

56 minutes was demonstrated Generalized Tonic—Clonic Status Epilepticus

the active extrusion of sodi-
with a bioavailability of more um from neurons and the
than 90%.22 These properties decrease of the spread of
may support the use of IM nerve impulses to other
midazolam for the treatment Diazepam 0.5 mg/kg neurons.4 As this drug de-
IV/PR
of SE. presses motor areas of the
A human-approved midazo- cortex without affecting
lam injectable product (Versed; No the sensory areas, a stabi-
Wait 20—60 seconds
Roche Laboratories, Nutley, lizing effect occurs without
NJ) is available, but at present causing general CNS de-
there are no approved veteri- pression.25
Yes
nary midazolam preparations. Seizures More than 1—2 mg/kg Go to refractory Although phenytoin is
persist diazepam given? status protocol
A poorly documented dose for used to treat SE in humans,
cats and dogs is 0.066 to 0.22 Yes
IV injection can cause se-
mg/kg IM or IV.19 No Yes vere hypotension in dogs
Repeated Yes
No
twice and IM absorption is ex-
Lorazepam tremely variable. IM injec-
Lorazepam is not as lipid- tion of phenytoin can also
Start phenobarbital load Wait 15—30 Seizures
soluble as is diazepam; in ani- 2 mg/kg IV/IM minutes persist? result in adverse local reac-
mals, brain and cerebrospinal tions caused by precipita-
fluid concentrations of lor- tion at the site, including
azepam rise at a slower rate (i) Consider the cause
(ii) Assess the need for No
soft tissue sloughing.4,15
than do those of diazepam af- maintenance of The half-life of pheny-
anticonvulsant treatment
ter IV injection.11 Pilot studies toin in dogs is variable and
on the use of lorazepam 0.2 Figure 2—Initial pharmacologic treatment of patients in gen- can be as short as 3.65
mg/kg IV and 0.5 to 1.0 mg/ eralized tonic–clonic status epilepticus. (IM = intramuscular; hours after an 11 mg/kg IV
kg PR in normal dogs suggest- IV = intravenous; PR = per rectum) dose.26 In cats, phenytoin
ed that the drug may not be can have an effective dura-
acceptable for PR administra- tion of up to 108 hours,
tion because of an extensive first-pass effect.24 However, whereby this may be related to the decreased ability to
lorazepam can reach therapeutic blood concentrations conjugate the compound to glucuronic acid.4
24
when administered IV. Lorazepam is being evaluated
in normal dogs by one of the authors (S. P.) for its po- Fosphenytoin
tential use in an intranasal dosing regimen. At present, Fosphenytoin sodium (Cerebyx®; Parke-Davis) is a
there are no data on the use of lorazepam in clinical phospate ester prodrug of phenytoin developed as a re-
studies. finement of parenteral phenytoin. After administration,
phenytoin is cleaved from the prodrug by phosphatases
Clonazepam in the bloodstream and several other organs.27 However,
Compared with diazepam, tolerance to the IV ad- fosphenytoin is freely soluble in aqueous solutions and
ministration of clonazepam develops more slowly.4 An rapidly absorbed by the IM route.27 Fosphenytoin has
IV dose of 0.05 to 0.2 mg/kg may have a comparably no known antiepileptic action before conversion.27 To
longer-lasting effect than that of diazepam, but no IV the authors’ knowledge, there are no veterinary studies
preparation is available in the United States. using this drug clinically as an AED.

Phenytoin Sodium (Diphenylhydantoin) Barbiturates

Although approved by the FDA to treat seizure activ-
ity in dogs, phenytoin (Dilantin®; Parke-Davis) is not
very efficacious. 4 This AED, which is a hydantoin
derivative, is a five-membered ring structure lacking a
C=O group in comparison with the barbiturates.4 Syn-
aptic junctions that normally allow nerve impulses to
be transmitted at lower thresholds are stabilized by phe-
nytoin.4 The effect of this drug seems to be caused by
Phenobarbital is a safe, inexpensive drug that may be
administered orally, IV, or IM. Like diazepam, pheno-
barbital is classified as a Schedule IV drug. Phenobarbi-
tal increases the threshold required for seizure discharge
and acts to decrease the spread of the discharge to
neighboring neurons.4 The actions of this drug are pri-
marily caused by the enhancement of the inhibitory ef-
fects of GABA postsynaptically.8 Some inhibition of

LIPID SOLUBLE ■ FIRST-PASS EFFECT ■ PHOSPHATASES ■ PHENOBARBITAL

Compendium August 2000 Small Animal/Exotics

Your comprehensive
glutamate activity and the flux of calcium across the
neuronal membranes also occurs.25 guide to diagnostic
Distribution of phenobarbital to the CNS may take
up to 30 minutes because of weaker lipophilicity com- ultrasonography
pared with diazepam.4 Practitioners must consider the
time of onset when treating animals that are still ex- Nautrup and Tobias
hibiting generalized seizure activity. The recommended
loading dose is 12 to 24 mg/kg IV if immediate thera-
peutic concentrations are desired.4 Alternatively, the
initial dose can be 2 mg/kg IV, repeated every 20 to 30
minutes to effect and to a maximum 24-hour dose of
24 mg/kg4 (Figure 2). The serum concentrations of
phenobarbital will rise by approximately 5 µg/ml for
each 3 mg/kg administered IV.4 The parenteral form
can also be given IM, which is recommended if di-
azepam has already been administered, thereby avoid-
ing the potentiation of profound respiratory and car-
diovascular depression. 4
Phenobarbital, especially when administered after a
benzodiazepine, may have depressant effects on respira-
tory drive, level of consciousness, and blood pressure, New
which may complicate management of SE patients.8
For these reasons, tracheal intubation may be necessary
during IV administration of phenobarbital.

Potassium bromide
Potassium bromide (KBr) is a recommended mainte-
nance AED in dogs.4 The half-life of KBr after oral ad-
$
149
Robert E. Cartee, Editor
ministration is approximately 25 days, which has pre-
cluded its use in SE.4 Recent studies have established
400 pages, hard cover
that KBr is well absorbed after PR administration, with 1597 illustrations
an estimated bioavailability of 57.7% and a mean half-
life of 20.4 days.28 For a more rapid effect than that ob- ■ Sonographic diagnosis in dogs and cats,
tained with oral maintenance dosing regimens, a PR including ultrasound, M-mode, pulsed
loading protocol has been devised.28 Intrarectal admin-
and color Doppler echography
istration may be preferred in patients that are heavily
sedated from prior diazepam and phenobarbital admin- ■ Echocardiography, abdominal and pelvic
istration. A loading dose for KBr (600 mg/kg) can be sonography, and fetal ultrasonography
administered over a 24-hour period as 6 PR boluses
(100 mg/kg every 4 hours).28 The side effects from this ■ Case illustrations using conventional
regimen may be transient diarrhea and sedation. radiography, computed microfocal
tomography, specimen photography,
SUMMARY
The goal of treatment for patients exhibiting SE is and line drawings
rapid cessation of the seizure activity. Practitioners must ■ Recognition of the disease process and
have a knowledge and understanding of the available
AED therapies and a step-wise plan for their use. Misuse courses of treatment
of these drugs in an already cerebrally compromised pa-
tient can create management problems and may be fatal.
AEDs administered in emergent situations, even if used CALL OR FAX TODAY TO ORDER
correctly, will suppress the patient’s respiratory and car- 800-426-9119 • Fax: 800-556-3288
diovascular systems, necessitating constant and close
Price valid only in the US, Canada, Mexico, and
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the Caribbean. Request international pricing.
Email: books.vls@medimedia.com

HALF-LIFE ■ LOADING DOSE

Small Animal/Exotics
ACKNOWLEDGMENT
The authors thank Ms. Emily Pritchard, Department
of Educational Resources, University of Georgia,
Athens, for providing the artistic content.
REFERENCES
1. Maytal J, Shinnar S, Moshe SL, et al: Low morbidity and
mortality of status epilepticus in children. Pediatrics 83(3):
323–331, 1989.
2. Harrison AM, Lugo RA, Schunk JE: Treatment of convul-
sive status epilepticus with propofol: Case report. Pediatr
Emerg Care 13(6):420–422, 1997.
3. Cascino GD: Generalized convulsive status epilepticus.
Mayo Clin Proc 71:787–792, 1996.
4. Boothe DM: Anticonvulsant therapy in small animals. Vet
Clin North Am Small Anim Pract 28(2):411–448, 1998.
5. Singhi S: Refractory status epilepticus in children: Role of con-
tinuous diazepam infusion. J Child Neurol 13(1):23–26, 1998.
6. Singhal PC, Chugh KS, Gulati DR: Myoglobinuria and renal
failure after status epilepticus. Neurology 28(2):200–201, 1978.
7. Kiessling M, Hossman KA, Kleihues P: Pulmonary edema
during bicuculline-induced seizures in rats. Exp Neurol 74(2):
430–438, 1981.
8. Cruz J: Neurologic and Neurosurgical Emergencies. Philadel-
phia, WB Saunders Co, 1998, pp 51–88.
9. Podell M: Seizures in dogs. Vet Clin North Am Small Anim
Pract 26(4):779–809, 1996.
10. Hauser WA: Status epilepticus: Epidemiologic considera-
tions. Neurology 40(Suppl 2):9–13, 1990.
11. Lowenstein DH, Alldredge BK: Status epilepticus. N Engl J
Med 338 (14):970–976, 1998.
12. Walsh GO, Delgado-Escueta AV: Status epilepticus. Neurol
Clin 11(4):835–853, 1993.
13. Ropper AH: Neurological and Neurosurgical Intensive Care.
New York, Raven Press, 1993, pp 383–410.
14. Treiman DM: Generalized convulsive status epilepticus, in
Engel J, Pedley TA (eds): Epilepsy: A Comprehensive Text-
book. Philadelphia, Lippincott-Raven, 1997, pp 669–680.
15. Van der Kleijn E, Baars AM, Vree TB, et al: Clinical phar-
macokinetics of drugs used in the treatment of status epilep-
ticus. Adv Neurol 34(2):421–430, 1983.
16. Trieman DM: Pharmacokinetics and clinical use of benzodi-
azepines in the management of status epilepticus. Epilepsia
30(Suppl 2):4–10, 1989.
17. Nordt SP, Clark RF: Midazolam: A review of therapeutic
uses and toxicity. J Emerg Med 15(3):357–365, 1997.
18. Klotz U, Antonin KH, Bieck PR: Pharmacokinetic profiles
of diazepam in man, dog, rabbit, guinea pig and rat. J Phar-
Compendium August 2000
macol Exp Ther 199(1):67–73, 1976.
19. Plumb DC: Veterinary Drug Handbook, ed 3. White Bear Lake,
MN, Pharma Vet Publishing, 1999.
20. Wagner SO, Sams RA, Podell M: Chronic phenobarbital
therapy reduces plasma benzodiazepine concentrations after
intravenous and rectal administration of diazepam in the
dog. J Vet Pharmacol Ther 21(5):335–341, 1998.
21. Koul RL, Aithala GR, Chacko A, et al: Continuous midazo-
lam infusion as treatment of status epilepticus. Arch Dis
Child 76(5):445–448, 1997.
22. Court MH, Greenblatt DJ: Pharmacokinetics and prelimi-
nary observations of behavioral changes following adminis-
tration of midazolam to dogs. J Vet Pharmacol Ther 15(4):
343–350, 1992.
23. Scott RC, Besag FMC, Boyd SG: Buccal absorption of mi-
dazolam: Pharmacokinetics and EEG pharmacodynamics.
Epilepsia 39(3):290–294, 1998.
24. Podell M, Wagner SO, Sams RA: Lorazepam concentrations
in plasma following its intravenous and rectal administration
in dogs. J Vet Pharmacol Ther 21(2):158–160, 1998.
25. McNamara JD: Drugs effective in the therapy of epilepsies,
in Hardmoan JG, Limbird LE (eds): Goodman and Gilman’s
the Pharmacological Basis of Therapeutics. New York, Mc-
Graw-Hill, 1996, pp 461–485.
26. Sanders JE, Yeary RAL: Serum concentrations of orally ad-
ministered diphenylhydantoin in dogs. JAVMA 172(2):
153–155, 1978.
27. Morton LD, Rizkallah E, Pellock JM: New drug therapy for
acute seizure management. Semin Pediatr Neurol 4(4):51–
63, 1997.
28. Dewey CW, Ducote JM, Coates JR, et al: Intrarectally ad-
ministered potassium bromide loading in normal dogs. Proc
17th ACVIM Forum, Abstract 213:745, 1999.
About the Authors
When this article was submitted for publication, Drs. Platt
and McDonnell were affiliated with the Department of
Small Animal Medicine, College of Veterinary Medicine,
University of Georgia, Athens. Dr. Platt is now affiliated
with The Animal Health Trust, Centre for Small Animal
Studies, Suffolk, England. Dr. McDonnell is affiliated with
the Veterinary Medical Center, Tufts University, North
Grafton, Massachusetts. Both are Diplomates of the
American College of Veterinary Internal Medicine (Neu-
rology).