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V Vol. 22, No.

8 August 2000

CE Refereed Peer Review

Status Epilepticus:
Managing Refractory
★ Because status epilepticus (SE)
frequently occurs outside the
hospital, prompt prehospital
treatment, including rectal and
Cases and Treating
intranasal administration of
drugs, can improve patient
■ SE that does not respond to a
benzodiazepine or phenobarbital University of Georgia
requires more aggressive Simon R. Platt, BVM&S, MRCVS
treatment; potential reasons for John J. McDonnell, DVM, MS
refractory seizure activity include
inadequate anticonvulsant doses,
an uncorrected metabolic ABSTRACT: Status epilepticus (SE) is an emergency medical situation that may not respond
abnormality, intoxication, to benzodiazepine or phenobarbital treatment. This situation is termed refractory SE and re-
quires more aggressive treatment such as anesthesia. SE may also occur in the home environ-
or tumor.
ment where facilities are limited. The time that passes before treatment is instituted is crucial
in the prevention of permanent cerebral damage and may be important in saving the patient’s
■ Adequate doses of thiopental and
life. For such patients, the efficacy of rectally delivered diazepam has been established. In-
pentobarbital will usually control tranasal delivery of anticonvulsants is being evaluated in dogs and may represent a future
the physical manifestations of method of at-home seizure control.
seizures, but severe hypotension
limits their safety.

tatus epilepticus (SE) is a medical emergency that requires prompt treatment
■ The resources needed to avoid appreciable neurologic morbidity.1–5 The proper management strat-
to manage the potential egy involves prompt control of seizures.3 Benzodiazepines (i.e., diazepam, lor-
complications of intravenous azepam, midazolam, and clonazepam) are potent, fast-acting anticonvulsants that
therapy in seizuring patients are form the cornerstone of early SE therapy.1-4 In animal screening tests, benzodi-
often inadequate, and may result azepines have shown a broad spectrum of anticonvulsant activity and may at low
in severe systemic and cerebral doses effectively inhibit seizure activity.6 However, there are situations in which
damage or death. these drugs do not arrest continuous seizure activity and other treatments should
be employed. The companion articles in this series discussed the manifestations,
■ Rectal administration of pathophysiology, and treatment of patients with SE. This paper explores the
anticonvulsants is relatively easy treatment of refractory SE by veterinarians and at-home seizures by owners.
to carry out in the home and, *A companion article entitled “Status Epilepticus: Clinical Features and Pathophysiology”
therefore, is useful in appeared in the July 2000 (Vol. 22 No. 7) issue of Compendium. The second installment,
emergencies. entitled “Status Epilepticus: Patient Management and Pharmacologic Therapy,” can be
found in this issue. This is the final article in the series.
Compendium August 2000 Small Animal/Exotics

REFRACTORY STATUS EPILEPTICUS its rapid clearance, chiefly eliminated by hepatic conju-
Status epilepticus that does not respond to a benzodi- gation to inactive metabolites, and less profound hy-
azepine or phenobarbital is considered refractory and potensive effects.2,3,13 However, propofol should be used
requires more aggressive treatment5,7,8 (Figure 1). Poten- with caution and preferably in settings in which defini-
tial reasons for resistant seizure activity include inade- tive airway control and hemodynamic support are possi-
quate anticonvulsant doses, an uncorrected metabolic ble because hypoxemia secondary to apnea as well as
abnormality, or the presence of intracranial disease myocardial depression are primary side effects.2
(e.g., a tumor).3,9 These patients are often difficult to When using propofol, seizures have been observed
treat. Short-acting anesthetic drugs are commonly used during the induction of and emergence from anesthe-
to treat resistant SE because these agents have a rapid sia, but the importance of these proconvulsant effects
onset of action and short half-lives and reduce cerebral in SE management is unknown.3,7 Whether the convul-
metabolic rates.3 These drugs should be used only in an sive phenomena occasionally seen with the use of this
intensive care setting because blood pressure and cen- drug represent seizures, excitatory events, and/or a dis-
tral venous pressure should be monitored continuously. order of muscle tone is controversial.2 Experimental an-
General anesthesia prevents tonic–clonic movements imal models have documented the anticonvulsant ef-
and allows control of respirations. fects of propofol.2 This drug has been shown to raise
the lidocaine seizure threshold in rats, arrest bupiva-
Continuous Benzodiazepine Infusion caine-induced seizures as effectively as thiopental at 10-
Continuous benzodiazepine infusion has been shown mg/kg doses, and be as potent as is diazepam at pre-
to be effective for treating refractory SE in humans and venting pentylenetetrazol-induced seizures in rabbits.2
animals.5,10 Continuous intravenous (IV) infu-
sions of diazepam were administered to 124 of Seizures persist despite treatment
186 (66.8%) dogs with severe seizures,10 but with diazepam and phenobarbital
the efficacy of this treatment could not be de-
termined. The authors reported that continu-
Medical team and
ous diazepam infusions may be underused in No
owner decide to use
the management of dogs with seizures. The aggressive treatment

dose should be calculated hourly (0.1 to 0.5 Options are: Consider:

1) Additional low-dose  1) Intubation/ventilation
mg/kg [0.23 mg/lb]) and is usually diluted in  boluses of diazepam 2) Arterial line for blood 
2) Continuous IV diazepam   gas evaluation
5% dextrose in water, with the volume used be-  infusion 0.1 mg/kg/hour 3) Urethral catheter
ing equal to the maintenance fluid requirement  in 2.5% dextrose/0.9%  4)  Continuous
 sodium chloride drip at   electrocardiogram
over the hour (Figure 1).5,10,11 The dose can be  maintenance rate 
delivered with an infusion pump. The infusion 3) No further treatment 
 except to optimize  Consider cause and institute
of diazepam should be used with caution be-  phenobarbital serum  maintenance therapy
cause of its poor aqueous solubility, tendency
IV pentobarbital Yes
to crystallize in solution, and adsorption onto 1) 3–15 mg/kg to effect Phenobarbital
polyvinyl chloride tubings. Midazolam, which Seizures
2) Dopamine to maintain  infusion maximum
 blood pressure 24 mg/kg/day
is completely water soluble, has been used as a
safe, effective therapy for pediatric patients No No

with SE but is more expensive to administer.8 No

IV dopamine infusion
Severe Significant Yes
Seizures 2–10 µg/kg/min and/or
decreased hypotension/
Propofol No
blood pressure
IV dobutamine 2–10
In humans with refractory SE, IV infusions
Yes Yes
of anesthetic doses of propofol (2,6-diisopropyl-
phenol) have become standard. This ap- Poor prognosis consider: IV pentobarbital
proach has recently been evaluated in animals.15 1) Isoflurane anesthesia infusion 1 mg/kg/hour
2) Propofol infusion up to 6 hours
Propofol has shown barbiturate- and benzodi-  0.1–0.6 mg/kg/minute
azepine-like effects on the γ-aminobutyric acidA 3) IV mannitol 1 g/kg bolus
4)  IV furosemide 0.7 mg/kg
(GABAA) receptor and can suppress central ner-
vous system metabolic activity.12,13 Propofol can
be administered by IV bolus or by constant-rate Figure 1—Patients in status epilepticus that fail to respond to diazepam
and phenobarbital are considered to be refractory. This algorithm depicts
infusion (0.1 to 0.6 mg/kg/minute).3,14,15 The treatment options for these patients. IV = intravenous.
advantages of propofol over the barbiturates are


Small Animal/Exotics Compendium August 2000

Several reports have documented the anticonvulsant ac- these anesthetics for patients in which benzodiazepines
tivity of propofol in humans.12 Stecker and colleagues and phenobarbital fail.
recently reported that propofol can control refractory
SE more quickly in humans than can high-dose barbi- Etomidate
turates.12 Because of the pharmacokinetics of propofol, Etomidate, which has shown GABA-ergic activity in
it is believed that even if this drug failed to control the brain, is a short-acting drug. The anticonvulsant ef-
seizures and high-dose barbiturates were required, little fects of this agent in dogs and cats have not yet been
time would be lost and there would be no long-term documented.4
interference with other treatments.12 Heldmann and
colleagues recently studied the use of propofol in in
four cats and one dog with naturally occurring seizures Lidocaine
following the surgical attenuation of single extrahepatic In 1955, IV lidocaine was first reported as a treat-
portosystemic shunts. 15 All of the patients, two of ment for SE in humans.17 Since that time, a number of
which had seizures that were unresponsive to other an- studies, mostly in Europe, have reported the efficacy of
ticonvulsants, responded to propofol.15 All five animals lidocaine in refractory SE,9 although no large, double-
had regular indirect blood pressure measurements and blind, placebo-controlled studies have proven the drug’s
remained hemodynamically stable when the drug was efficacy in humans with SE.17 The exact mechanism by
appropriately administered.15 All of the animals sur- which lidocaine terminates seizures is unknown at pres-
vived to discharge. ent. Lidocaine decreases neuronal excitability by block-
ing voltage-dependent sodium channels in the cell
Barbiturates membrane.17 In addition, it reduces potassium efflux
Thiopental and pentobarbital have shown potential, into the extracellular space and decreases neuronal mi-
although unproven, cerebral protective effects in the tochondrial metabolism and cerebral oxygen consump-
management of SE. Adequate doses of these drugs usu- tion.17 Increased extracellular potassium increases the
ally control the physical manifestations of seizures, but concentration of the excitatory neurotransmitter gluta-
severe hypotension limits their safety.4,7,8 Pentobarbital mate and may increase the recruitment of other neu-
sodium (Nembutal®; Abbott), used at standard safe rons into the seizure activity.17 Most reports on the use
doses, is a general anesthetic with negligible anticonvul- of lidocaine in humans recommend a maintenance in-
sant properties.4 Thiopental has been associated with a fusion after initial termination of SE.17 Lidocaine has
higher degree of cardiac toxicity than has pentobarb- been reported to cause seizures as well as myocardial
ital.13 In one study, Roesch and colleagues reported more depression and cardiac conduction abnormalities. 17
ventricular arrhythmias in animals treated with thio- However, the signs attributable to lidocaine toxicity are
pental than in those treated with pentobarbital at doses rare clinically when the drug is used specifically for its
lower than those required to cause a flat electroen- anticonvulsant properties. The optimal anticonvulsant
cephalogram (EEG).13 At higher doses than those re- dose of lidocaine in humans and animals is unknown;
quired to produce a flat EEG, only two of seven dogs we do not recommend its use in SE until further inves-
treated with thiopental survived whereas all 17 dogs tigations have been pursued.
treated with pentobarbital survived.13 Pentobarbital
should be given to effect and not as a specific dose (3 to Inhalational Anesthesia
15 mg/kg IV) because response varies widely among pa- Inhalational anesthetics have been recommended as a
tients (Figure 1). treatment of last resort for patients with resistant SE.
Patients treated with “barbiturate coma” commonly The equipment and personnel necessary to administer
require an extended period of mechanical ventilation in inhalational anesthesia may not be readily available and
an intensive care setting.5,8,12 In general, the side effects the equipment can be cumbersome. Isoflurane, an in-
of barbiturate coma include depression of myocardial halational general anesthetic agent, may be efficacious
metabolism, vasodilation with a decrease in venous re- in the treatment of resistant SE.3 Not all of the volatile
turn, and decreased cardiac perfusion.16 These effects anesthetic agents have antiepileptic potential; however;
can be minimized by using saline infusion and small enflurane may actually increase seizure activity.3 Isoflu-
doses of dopamine. Patients can develop poikilothermia rane, which has been studied extensively, does not un-
and decreased urinary output during myocardial de- dergo hepatic metabolism and has a rapid onset of ac-
pression and hypotension. Neurologic evaluation is dif- tion.3 Obviously, isoflurane therapy requires ventilation
ficult because spontaneous respiratory responses and and intensive care monitoring; hypotension may occur
movements cease. We recommend reserving the use of during therapy.3


Compendium August 2000 Small Animal/Exotics

Muscle Relaxants cant.11 The efficacy of diazepam delivered PR depends

Curarization, which allows control of respiration, on the time needed for the drug to reach the therapeu-
prevents tonic and clonic movements and physical in- tic concentration and how much of the agent is needed
jury9; however, it does not prevent ongoing cerebral for the individual dog. In humans, the therapeutic con-
seizure activity.9 Animal studies indicate that prolonged centration is estimated to be approximately 150 to 300
seizure activity—even in paralyzed, ventilated ani- ng/ml.22 If this is also true in dogs, several canine stud-
mals—results in irreversible cerebral damage.9 ies have demonstrated that this level can be reached
well within 30 minutes—the time before serious neuro-
OUT-OF-HOSPITAL STATUS EPILEPTICUS logic morbidity occurs.22 The actual therapeutic level in
Patients that present with SE demonstrate massive dogs has not been well documented and may range
uncontrolled muscle activity that often makes it diffi- from 300 to 1500 ng/ml.23
cult to administer essential anticonvulsant medications Podell and colleagues evaluated the use of PR di-
into the vein. In out-of-hospital situations, the re- azepam at home for cluster seizures in dogs.24 The au-
sources to manage potential complications of IV thera- thors reported fewer seizures per cluster, reduced owner
py are inadequate; therefore, severe systemic and cere- cost for emergency room visits, and good owner com-
bral damage may result and can lead to death in some pliance.24 In pharmacokinetic studies, 0.5 mg/kg of di-
dogs.18 However, if prompt prehospital seizure treat- azepam delivered PR produced a mean peak total ben-
ment can be given, fewer antiepileptic drugs (AEDs) zodiazepine concentration of approximately 500 ng/ml
are required and seizures tend to be shorter.1,19 Rectal in four healthy beagles.25 A separate study using six
(PR), intranasal (IN), and buccal/sublingual routes of healthy mixed-breed dogs found that the mean peak to-
administration may be useful in these settings, especial- tal concentration of benzodiazepines was 474 ng/ml
ly because the absorbed drug bypasses the liver (thereby with a dose of 1 mg/kg.23
avoiding the problem of first-pass metabolism).19 IV The effect of concurrent long-term oral phenobarbi-
and intramuscular (IM) injections during SE can pose tal administration on diazepam delivered PR has re-
risks to patients and caregivers and are often difficult to cently been evaluated.22 The mean peak concentrations
administer 20; therefore, PR and IN administration, of diazepam after PR administration in six dogs fell
which needs further study, will be used more routinely. from 629 to 274 ng/ml after the dogs were given phe-
IN anticonvulsants have been used successfully in treat- nobarbital (2.5 mg/kg every 12 hours for 30 days).22
ing humans with SE.20 These results demonstrated that dogs receiving chronic
Because administering benzodiazepines by these phenobarbital therapy may require a higher dose of PR
routes is not licensed, these methods must be used with diazepam than those dogs that have not been previously
caution. Benzodiazepines are also Schedule IV drugs treated with this drug. These phenomena resulted from
and are not approved for animal use by the FDA.4 Di- the increased activity of the hepatic microsomal enzyme
azepam, however, remains the drug of choice for treat- system caused by phenobarbital administration.
ing SE in dogs and cats.4 Clients should be instructed Pilot studies on the use of 0.2 mg/kg IV and 0.5 to
that at-home treatment of seizures must not replace im- 1.0 mg/kg PR lorazepam in normal dogs suggest that
mediate veterinary attention for systemic stabilization. lorazepam may not be acceptable for PR administration
Indications for immediate veterinary care may include because of an extensive first-pass effect.26 However, lor-
seizures that do not respond within 10 minutes to the azepam can reach therapeutic blood concentrations
at-home therapy prescribed; seizures that respond but when administered IV.26
recur within 24 hours; and systemic concerns such as Rectal administration of a parenteral solution of di-
depressed respiratory effort, obtundation, and blind- azepam (0.5 mg/kg) is approximately 80% effective in
ness. The dangers of being in close contact with a controlling prolonged seizures in children, usually
seizuring dog should also be emphasized to clients. within 15 minutes.27 European studies have emphasized
the safety and efficacy of at-home use of PR diazepam
Rectal Drug Administration in treating seizures.27 Previous canine studies have failed
Rectal AED administration, which is relatively easy to document any adverse cardiovascular or respiratory
to perform in the home environment, can be useful in effects when diazepam is administered PR.22,28
emergencies. The absorption of lipid-soluble drugs by A gel formulation of diazepam in a prefilled (5
the membranes of the colon and rectum is rapid and mg/ml) single-dose syringe for PR administration (Dia-
complete.21 Diazepam can be administered into the rec- stat®; Athena Neurosciences) has become available
tum using plastic administrators (e.g., teat infusion in the United States for the treatment of seizure clusters
cannulas, tomcat catheters) with a water-soluble lubri- in children and adults.29 In a randomized study, admin-


Small Animal/Exotics Compendium August 2000

istration of a single dose of Diastat® in

humans was significantly more effec-
tive than was placebo in reducing the
number of seizures.29 In addition, Dia-
stat® increased the probability that pa-
tients would remain seizure free for 12
hours after treatment compared with
patients who received the placebo. Re-
ported adverse effects of Diastat® (e.g.,
sedation) are consistent with the
known safety profile of diazepam. Dia-
stat® seems to have no observable de-
pressive effects on respiratory rate.29
PR administration of diazepam gel Figure 2—Intranasal administration of diazepam. Rapid uptake of the drug results in
may be useful for out-of-hospital man- part from the profuse vascular supply of the nasal turbinate mucous membranes.
agement of SE; however, its expense The close proximity of the cribriform plate and nasopharynx should also be noted.
may prohibit its use in animals.
In humans, the use of diazepam suppositories is of midazolam in humans has been shown to be safe and
limited value in the treatment of SE because therapeu- effective.33 After rectal instillation of a midazolam hy-
tic plasma concentration is not reached until after 20 drochloride solution (0.3 mg/kg) in healthy human
minutes.30 One author (S. P.) is now evaluating the mer- volunteers, a mean bioavailability of 52% was found.31
its of diazepam suppositories compared with parenteral Clinical effects, measured in terms of sedation and
diazepam administered PR. EEG activity, were comparable to those obtained with
Canine studies have previously demonstrated the im- IV administration.31
portance of the drug formulation and the vehicle used
in determining the bioavailability of PR diazepam.31 Intranasal Drug Administration
Parenteral diazepam is compounded with 40% propy- In recent years, IN drug administration for systemic
lene glycol and 10% ethyl alcohol. This commercially effects has received increased attention because of its
available formulation is not approved for use as a PR convenience and reliability (Figure 2).34 IN AEDs have
drug. When this formulation of diazepam solution been used successfully in humans with SE.35 Midazo-
was administered in high doses to rats, no significant lam, which has been shown to be quickly absorbed by
gross or microscopic changes in the rectal mucosa were the nasal mucosa, can reach levels that equal or sub-
observed.21 Although this provides evidence of its local stantially exceed the threshold for sedation in hu-
safety, a potential complication of the use of PR di- mans.35,36 The duration of action following IN adminis-
azepam in dogs may be the development of a perirectal tration is similar to that after oral dosing, although the
abscess, which was recorded in one dog.32 This compli- onset of action is earlier.32 Peak plasma concentrations
cation may be a technique-associated problem rather were reported 10 minutes after administration in hu-
than a direct reaction to the drug; therefore, PR admin- mans and plasma concentrations of midazolam exceed-
istration protocol should be reviewed thoroughly with ing therapeutic values were seen within 3 minutes after
owners. Requiring the use of a glass ampule, needle, IN administration in children.36,37 Maximum plasma
and syringe for dispensing and tubing for administra- concentration for IN midazolam, triazolam, and flu-
tion, this method of delivery not only has the potential razepam in dogs has been achieved within about 15
for dosing error but is awkward and may cause poten- minutes.34 The bioavailability of these drugs following
tial injuries to patients or caregivers.27
IN delivery was more than two times greater than after
Compounding pharmacies can help prepare diazepam oral absorption.34 The difference in bioavailability has
suppositories. Logistical problems created by the use of been postulated to be caused by a reduction in first-
syringes and the technical abilities required by the clients pass metabolism after IN dosing.34 This property may
in dosing their pets from a glass ampule can be avoided allow the use of lower doses of the IN drug. We have
by using suppositories. This practice may also reduce shown that the time needed to reach the maximum
concerns regarding scheduled drug misuse and abuse. benzodiazepine plasma concentration for IN diazepam
The dosages we use range from 0.5 mg/kg to 2.0 mg/kg. (0.5 mg/kg) in dogs was within 6 minutes.38 Lorazepam
With peak plasma concentrations occurring within and midazolam are currently being evaluated in normal
10 minutes after administration, PR administration of dogs by one of the authors (S. P.) for their potential use


Compendium August 2000 Small Animal/Exotics

in an IN dosing regimen. At present, no data exist on Buccal Administration

the use of lorazepam in clinical studies. A recent study on the buccal absorption of midazolam
The onset of the sedative effects of midazolam was in humans demonstrated a rapid increase in venous mi-
seen within 3 minutes after the drug was administered dazolam concentrations for the first 20 to 30 minutes
IN to rabbits.37 The fast response time may be an indi- after administration19; however, this study also revealed
cation of the previously described direct pathway from direct evidence of a more rapid cerebral effect identified
the nasal cavity to the brain.30 It has also been suggested by spectral analysis of EEG recordings.19 Rapid clear-
that drugs instilled into the nasal cavity may directly ance of the drug from the arterial circulation into the
reach the brain by the cribriform plate and that the brain and fat may be the mechanism that results in ini-
concentration in the central nervous system may be tial venous blood levels being lower than arterial levels.19
higher than that reflected by measurements of plasma To the authors’ knowledge, the buccal route of anticon-
concentrations.37 Radiographic studies performed on vulsant delivery has not been evaluated in animals.
rabbits using contrast dye showed that administered
liquid IN reaches the vomeronasal gland, which has a SUMMARY
rich vascular supply, and that some liquid, albeit a Generalized convulsive SE has been recognized for a
small amount, may be swallowed.37 Further studies to long time and characterized by recurrent or prolonged
better understand the uptake and absorption from the generalized seizure events and profound impairment of
nasal cavity are required. consciousness. Generalized SE must be treated early to
A problem identified with the use of IN diazepam achieve the greatest probability of success. Morbidity
has been the excessive volume that may be required in and mortality are largely determined by the underlying
large patients. Unfortunately, only a few formulation etiology, but inadequate treatment further worsens a
studies of solubility have been performed on diazepam poor prognosis. If treatment cannot be established ear-
in an attempt to administer larger doses of the drug in ly, the probability of permanent neurologic damage be-
smaller volumes.30 In a rabbit study, a comparison was comes more likely. Because SE often starts in the home,
made of the pharmacokinetic parameters after a single rapid treatment becomes a logistical problem. Dispens-
IN administration of diazepam in various formula- ing parenteral benzodiazepines for PR administration is
tions compared with a single IV injection.30 The au- one option at present, although the use of these drugs
thors reported that nasal application of diazepam in a is not licensed in veterinary patients and thus should be
water-free, low-molecular-weight glycol might be of carefully managed. The success of this therapy relies on
clinical importance.30 When midazolam was adminis- complete client education, a thorough knowledge of
tered as drops of aqueous solution, mean bioavailabili- the properties of the drugs and methods of delivery, as
ty was 55%.39 If the midazolam is given as an IN spray, well as careful documentation of all client communica-
the bioavailability is approximately 85%.39 The dis- tions and the drugs dispensed.
parity is caused by that portion of the drug that is
expelled out of the nostrils or swallowed and then ab- ACKNOWLEDGMENTS
sorbed by the gastrointestinal tract. The mean bio- The authors thank Ms. Allison Wright and Ms. Emily
availability of oral midazolam in children has been es- Pritchard, Department of Educational Resources, Univer-
timated to be 15% to 27%, depending on the dose.39 sity of Georgia, Athens, for the artistic content.
This low bioavailability is chiefly the result of exten-
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the American College of Veterinary Internal Medicine
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