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V Vol. 22, No.

8 August 2000

CE Refereed Peer Review

Status Epilepticus:
FOCAL POINT Patient Management
★The ideal pharmacologic
treatment of status epilepticus
(SE) requires the use of an
and Pharmacologic
intravenous lipid-soluble
anticonvulsant to rapidly attain
and then maintain a therapeutic
Therapy*
drug concentration in the brain.
University of Georgia
Simon R. Platt, BVM&S, MRCVS
KEY FACTS John J. McDonnell, DVM, MS
■ Vital functions such as glucose
metabolism, oxygenation, and ABSTRACT: Status epilepticus (SE) requires immediate treatment of the seizure activity to pre-
temperature regulation should be vent the possibility of permanent brain damage. Intravenous drug therapy, most commonly
achieved using diazepam, should be instituted without delay. Intravenous or intramuscular
monitored in patients with SE to
phenobarbital, often used in addition to a diazepam protocol, affords a longer period of seizure
prevent significant neurologic
control. The use of multiple drugs in SE patients is limited by the onset of hypotension. Pa-
morbidity. 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
■ The drug used to treat SE should cause, may not be successful. This article addresses the systemic and pharmacologic man-
be determined by its ease of agement of SE.
administration, time of onset,
duration of effect, and extent

S
of effects on cardiorespiratory tatus epilepticus (SE) is a medical emergency that requires immediate ther-
function and level of apy to prevent severe cerebral damage.1–5 The management of SE involves
consciousness. prompt control of seizures as well as treatment of the systemic effects and
underlying causes3 (Figure 1). The side effects of aggressive pharmacologic treat-
■ A dangerous error that is ment should be recognized when determining a treatment plan. The first article
commonly made when managing in this series addressed the features and pathophysiology of SE. This paper dis-
SE is to treat consecutive cusses the antiepileptic drug (AED) therapies used to treat SE. A final article (see
seizures with repeated doses of page 732) will discuss therapies for refractory patients and potential at-home
intravenous diazepam without treatment.
treating the precipitating factors
and without administering an PATIENT MANAGEMENT
adequate loading dose of a Status epilepticus can be a danger to patients and can provide a treatment
longer-acting antiepileptic challenge for clinicians. Treatment can be divided into acute emergency manage-
drug. 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 Compendium August 2000

serum and brain concentration of drug, a loading dose These AEDs, which can be effective at low doses, in-
sufficient to attain the desired concentration through- hibit seizure activity induced by pentylenetetrazol and
out the volume of distribution must be administered. picrotoxin in animal models.16
The loading dose of a drug can be computed using Adverse effects of IV benzodiazepines include respira-
the following equation: tory depression, hypotension, and impaired conscious-
ness.3,16 However, it is believed that a low incidence of
Loading dose (mg/kg) = Desired concentration
respiratory depression with benzodiazepines occurs be-
(mg/L) × Volume of distribution (L/kg)
cause of the low density of binding sites in the brain
Drug loading is therefore a passive process determined stem.17 The dose of diazepam that causes respiratory ar-
by volume of distribution and is independent of drug rest in patients may be difficult to determine.3,5
elimination kinetics.
Intravenous drug treatment for SE should be initiat- Diazepam
ed without delay11 based on the relationship between Classified as a Schedule IV drug under the 1970
duration of SE and the extent of neurologic morbidity2; Controlled Substances Act, diazepam is not approved
experimental animal models suggest that SE becomes for animal use by the FDA4; however, it remains the
progressively less responsive to treatment with diaze- drug of choice for the treatment of SE in dogs and
pam.11,14 Anticonvulsants prevent the synchronization cats.4 The major metabolites of diazepam, nordiazepam
of related neurons and can be more effective when they (desmethyldiazepam) and oxazepam, have up to 33%
act at more than one biochemical site.4 of the activity of the parent drug.4 Although the half-
life of diazepam is 3.2 hours in dogs, the half-lives of
PHARMACOLOGIC THERAPY the metabolites (up to 5.2 hours in the case of oxaze-
Benzodiazepines pam) are slightly longer.18
Because the benzodiazepines (diazepam, lorazepam, With its relatively brief duration of action, diazepam
midazolam, and clonazepam) are potent, fast-acting is not a definitive therapy for SE. Because IV diazepam
AEDs, these drugs (particularly diazepam) are the pre- produces transiently high serum and brain concentra-
ferred initial therapy in SE.3,4,11,15 However, none of the tions, however, the drug can be useful in therapy. Be-
benzodiazepines are effective for long-term control of cause SE may end spontaneously, IV diazepam should
SE.15 This widely used class of sedative/tranquilizer and not be administered to patients presenting in a postictal
anxiolytic agents differs greatly in course of timing and state unless another seizure occurs.
central effects.15 These differences may be related to In treating dogs and cats, diazepam has been recom-
their pharmacokinetics,15 especially their central ner- mended at a dose of 0.5 to 1.0 mg/kg IV, up to a maxi-
vous system (CNS) distribution, which has been related mum dose of 20 mg.4,19 This dose can be repeated to ef-
to the drugs’ lipophilicity and plasma protein binding.15 fect or twice within 2 hours.4 Constant-rate infusions
The lipophilicity of these compounds determines their of diazepam have been advocated in human and veteri-
rapid brain penetration after IV administration.15 Al- nary patients.4 The recommended dose is 2 to 5 mg/
though penetration is rapid, distribution equilibrium hour in 5% dextrose in water.4 Continuous diazepam
among all regions takes longer.15 infusions have been shown to be an effective modality
Their primary pharmacologic actions are probably to control refractory SE in children and have been asso-
related to a benzodiazepine-receptor–mediated en- ciated with a reduced need for ventilatory and vasopres-
hancement of γ-aminobutyric acid (GABA) -ergic sor support.5 If diazepam does not control the seizures,
transmission, both pre- and postsynaptically.4,5,11,16,17 the use of phenobarbital should be considered. Probably
Benzodiazepines do not seem to alter the synthesis, re- the most dangerous error commonly made in SE man-
lease, or metabolism of GABA but rather potentiate its agement is to treat consecutive seizures with repeated
action at the receptor.17 The resultant augmented flow doses of IV diazepam without administering an ade-
of chloride ions into cells decreases the cell’s ability to quate loading dose of a longer-acting AED. Patients will
initiate an action potential.17 At higher concentrations, continue to have seizures, toxic concentrations of di-
benzodiazepines also limit sustained repetitive neuronal azepam or diazepam metabolites will accumulate, and
firing in a manner similar to that of carbamazepine and serious morbidity may result from diazepam overdosage.
phenytoin; this effect may be relevant to their mecha- In some patients, administration of IV diazepam may
nism of action in SE.11 Benzodiazepines seem to pre- not be possible. The drug can be given intramuscularly
vent the spread of seizure rather than suppress the fo- (IM), although absorption is not predictable.4 Rectal
cus.16 In animal screening tests, benzodiazepines have administration of diazepam may be considered initially
shown a broad spectrum of anticonvulsant activity.16 at a dose of 0.5 to 2.0 mg/kg depending on whether

NEUROLOGIC MORBIDITY ■ POSTICTAL STATE ■ CONSTANT-RATE INFUSIONS


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

HALF-LIFE ■ LOADING DOSE


Small Animal/Exotics Compendium August 2000

ACKNOWLEDGMENT macol Exp Ther 199(1):67–73, 1976.


The authors thank Ms. Emily Pritchard, Department 19. Plumb DC: Veterinary Drug Handbook, ed 3. White Bear Lake,
of Educational Resources, University of Georgia, MN, Pharma Vet Publishing, 1999.
20. Wagner SO, Sams RA, Podell M: Chronic phenobarbital
Athens, for providing the artistic content. therapy reduces plasma benzodiazepine concentrations after
intravenous and rectal administration of diazepam in the
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book. Philadelphia, Lippincott-Raven, 1997, pp 669–680. and McDonnell were affiliated with the Department of
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