Beruflich Dokumente
Kultur Dokumente
8 August 2000
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
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
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
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
ry
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
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
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.
The mean plasma elimination half-life in dogs was 53 Some case presentations are so had been normal,
mine appeared
of 1 sec she did have
lary refill time whatever problems
heart and Over the next
1-2 sec), normal seemed subtle.
METABOLITE ■ BIOAVAILABILITY
Small Animal/Exotics Compendium August 2000
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
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