SE treatment

Question 1

Tx - benzo, check BG, cool if necessary

brain autoreg. w CPP ranging from:

Answer 1

CPP ranging from 50 to 150 mm Hg

Question 2

hypoxemia of ___PaO2 causes:

Answer 2

<50 increased cerebral blood flow and increased ICP

Question 3

is bradycardia reliable with cushing’s reflex?

Answer 3

Reflex bradycardia is sometimes seen along with the systemic hypertension of the Cushing’s reflex, but is not reliable, particularly in animals with concurrent hypovolemia

Question 4

Mannitol - not CRI why

Answer 4

osmotic gradient responsible for removing water from the brain tissue is lost when the drug is given continuously

and more likely reverse osmosis occurs

Question 5

A meta‐analysis of 5 human trials comparing hypertonic saline and mannitol in the treatment of increased ICP found

Answer 5

mannitol to be more effective. This comparison has not been investigated in veterinary medicine.

Question 6

Benzo MoA:

Answer 6

enhancement pre‐ and postsynaptic γ‐aminobutyric acid (GABA)‐ergic transmission
-influx of chloride, which inhibits the transmission of nerve impulses by increasing the distance between depolarization threshold and resting membrane potential

-at higher doses, benzo limit sustained repetitive neuronal firing, similar to phenytoin and carbamazepine

Question 7

Diazepam is carried in:
Propylene glycol can cause:
other routes:

CRI can be delivered

Coadministration of

Answer 7

Propylene glycol
hypotension with rapid administration and rectal and intranasal

0.1–0.5 mg/kg/h. Coadministration of

levetiracetam enhances anticonvulsant effects of diazepam- allow lower doses of diazepam

Question 8

preferred benzo in ppl

benefits-

onset of action:
-ve:

Answer 8

Lorazepam

less lipid soluble
binds more tightly to GABA receptors

slightly delayed compared to diazepam
also propylene glycol vehicle

Question 9

Midazolam benefit:

Midazolam is water soluble and becomes more ____ at physiologic pH, allowing prompt diffusion into the CNS

routes:

Answer 9

decreased CNS and respiratory depression

lipophilic at physiologic pH

IM, buccally, or nasally

Question 10

Barbiturates MoA:

Answer 10

1. bind to GABA-A = increase Cl
2. block AMPA
3. decrease body temp/metabolism

Question 11

Humans and phenobarb.

Answer 11

first line - PB as effective as the combination of benzodiazepines and phenytoin, and superior to phenytoin alone

Question 12

Why does it take 20min to act?

Answer 12

decreased lipophilicty and long time to redistribute

Question 13

How to load:
1.

2.

Answer 13

16–20 mg/kg IV divided 4 q30min

load dose (mg) = body weight (kg) × 0.8 × desired serum concentration (μg/mL)

Question 14

PB -ve

Answer 14

IV significant hypotension & CV depression

PU/PD, ataxia, hepatotox. neutropenia, thrombocytopenia

Question 15

Phenytoin is commonly used in human medicine as a parenteral agent in SE

MoA:

Oral formulations also exist for maintenance therapy

In dogs, phenytoin has ____oral bioavail

-ve:

to minimize these risks, slow infusions are typically administered, which leads to delayed onset of action

Answer 15

blockage of voltage‐gated Na channels and calcium fluxes across neuronal membranes

poor, short T1/2

IV cardiac dysrhythmias and hypotension, likely related to the propylene glycol vehicle
phlebitis
tissue necrosis with extravasation

Question 16

Phenytoin and phenobarbital are frequently administered

both potent inducers of

dogs, therapeutic levels are difficult to achieve w combination therapy due to

Answer 16

together in human epileptics

hepatic microsomal enzymes

enzyme induction, and the formation of epoxide and other toxic metabolites may lead to cholestatic liver injury

Question 17

Fosphenytoin is a

developed to

dogs, ____% of fosphenytoin was converted to phenytoin within 30 minute

Answer 17

prodrug of phenytoin

limit complications of phenytoin

80%

expensive

Question 18

Levetiracetam is similar to piracetam, a racetam drug

MoA:

Binding of levetiracetam to synaptic vesicle protein 2A =

primary anticonvulsant effect of levetiracetam comes from

also shown to have:

Answer 18

that is thought to improve cognitive function

1.
-binds to the synaptic vesicle protein 2A
-a protein that governs amount of available secretory vesicles and enhances neurotransmission
= < NT release

2. presynaptic decrease in glutamate‐mediated excitatory transmission

neuroprotective properties, affects expression of genes that are upregulated in epilepsy and modulates excessive neuronal Ca release

Question 19

2008 study of epileptic dogs that were resistant to PB & Br therapy
addition of levetiracetam = ___%

another study of resistant epileptic dogs the addition of levetiracetam -

metab.:

concurrent phenobarbital use increases:

monitoring of:

Answer 19

77% decrease in seizure frequency in 8/14

did not significantly reduce seizure but owner‐perceived improvement in quality of

undergoes little hepatic metabolism, does not cause sedation, and interacts minimally with other drugs

levetiracetam clearance

serum levetiracetam concentrations and dose adjustments may be needed when the drugs are used together

Question 20

2012 prospective study of 19 dogs with SE or cluster seizures
-diazepam + either levetiracetam/ placebo:

2011 PSS study:

Answer 20

56% percent no additional seizure
vs. 10% of dogs that received placebo
not found to be statistically significant

retrospective study found a significantly decreased risk of postoperative seizures and death when dogs received levetiracetam for a minimum of 24 hours before PSS

Question 21

Propofol is an
MoA

vet med, propofol has been used to control seizure activity after

CRI:
How long:

Adverse effects

Repeated propofol infusions in cats

Propofol‐infusion syndrome in people -
not seen in veterinary patients

what causes seizure‐like phenomena associated with propofol administration?:

Answer 21

alkylphenol
GABA‐A agonist
reversibly NMDA
and modulates slow calcium ion channels

ligation of PSS
and SE when benzo & barbiturates have failed

loading dose of 2–6 mg/kg followed by a CRI of 0.15–0.4 mg/kg/min

at least 6 hours
if seizure activity returns, consider continuing the infusion for 24 hours

injection site pain
cardiovascular compromise
respiratory depression/apnea
loss of gag reflex

may lead to Heinz body

acidosis, rhabdomyolysis, hyperkalemia, and cardiac dysfunction, and is associated with high morbidity and mortality

glycine antagonism in the spinal cord

• most often observed during anesthetic induction or emergence and may be related to changes in propofol concentrations in the blood or brain
• some studies have demonstrated epileptic activity on EEG monitoring associated w seizure‐like phenomena, while others have demonstrated no cortical epileptic activity

Question 22

Fospropofol is a water‐soluble prodrug that is hydrolyzed by alkaline phosphatases to yield:

Fospropofol does not cause inject site pain conversion =delayed onset and longer duration of sedation

Potential advantages

Fospropofol is widely available and may be useful in treating status epilepticus, but veterinary experience is lacking

Answer 22

propofol, formaldehyde, and phosphate

lower dosing to achieve EEG changes representative of general anesthesia
-possibly longer duration of action

Question 23

Ketamine

MoA:

Answer 23

noncompetitive NMDA glutamate receptor antagonist

for refractory status epilepticus (RSE) use is controversial

Ketamine, along with other NMDA antagonists, has been shown to have neuroprotective effects in a rat model of SE, whether seizure activity was terminated or not

• for refractory SE, conflicting evidence
• ketamine should be avoided or used cautiously in patients with increased ICP or preexisting seizure disorder, and has been shown to cause seizure activity in dogs
• irreversible degenerative changes in pyramidal neurons
• toxicity has been explained by an indirect mechanism working through a trisynaptic circuit. Glutamate, when acting at an NDMA receptor on a GABAergic interneuron in a cingulate neuron, normally inhibits release of acetylcholine. Antagonism of the NDMA receptor leads to uncontrolled cholinergic stimulation, and this leads to cholinergic excitotoxicity in the cingulate neuron

In a 2003 case study, ketamine was administered to a man with refractory SE. Electroencephalographic evidence of seizure activity was controlled, but the patient developed diffuse cerebellar and cerebral atrophy and neurologic defects that persisted during 15 months of follow‐up

Question 24

Zonisamide
MoA:

most commonly used as:

Answer 24

• sulfonamide derivative, biochemically similar serotonin
• inhibits seizure activity through inhibition of neuronal voltage‐gated Na and T‐type calcium channels
• weak inhibition of carbonic anhydrase
• may also modulate GABA, dopamine, serotonin, Ach

add‐on drug when seizures are not well controlled with traditional anticonvulsants. The addition of zonisamide may allow reduced doses of other anticonvulsants, leading to decreased frequency of undesirable side effects

58% of dogs had decreased seizure frequency when zonisamide was added to phenobarbital and potassium bromide

Zonisamide may also be used alone for seizure control. A 2012 study of 10 dogs with idiopathic epilepsy found that 60% achieved good seizure control for at least 12 months with zonisamide therapy alone.94

Dose‐dependent ataxia, lethargy, vomiting, and keratoconjunctivitis sicca were noted after zonisamide therapy in 50% of dogs with idiopathic epilepsy in a 2004 study. Case reports of hepatic necrosis, hepatopathy, and renal tubular acidosis have also been published, as well as anecdotal reports of immune‐mediated hemolytic anemia and thrombocytopenia

Question 25

Etomidate

Answer 25

carboxylated imidazole anesthetic agent that has been used to treat RSE in people

Etomidate is a GABA‐A agonist that enhances postsynaptic binding of GABA‐A receptor agonists

also decreases the cerebral metabolic rate and oxygen consumption, and lowers ICP while maintaining normal arterial pressure

effect on cerebral metabolism has been suggested to improve the brain’s tolerance to ischemia

Etomidate inhibits cortisol synthesis by suppression of the adrenocortical response to ACTH, which has been associated with increased mortality in people

Etomidate may also cause involuntary myoclonic movements and has been associated with an increase in EEG epileptiform activity in human epileptic patients

has been used to induce seizure activity in people to guide surgical resection

Because of its adverse effects and proconvulsant properties, etomidate use in people with SE is reserved for cases that are refractory to conventional therapy.

Question 26

Inhalational anesthetic agents

Answer 26

Inhalational anesthetic (IA) agents enhance inhibitory GABA‐A receptor‐mediated currents and decrease thalamic neuronal membrane excitability

also increase cerebral blood flow and ICP while decreasing cerebral oxygen consumption

Isoflurane and desflurane produce dose‐dependent depression of spontaneous epileptiform discharges

reserved for the treatment of RSE. Halothane has previously been used in RSE but carries a risk of hepatotoxicity due to generation of toxic metabolites

Sevoflurane may also produce toxic metabolites and can have epileptogenic properties. Isoflurane and desflurane undergo less metabolism and therefore carry a reduced risk of organ damage, making them the preferred IA agents used in treatment of RSE

In a case series of 7 people with seizure activity that was resistant to midazolam, propofol, and pentobarbital, isoflurane and desflurane terminated seizure activity and produced a burst suppression EEG pattern. Inhalational agents were administered for an average of 11 days

Veterinary studies regarding the use of IA agents in status epilepticus are lacking. Some authors advocate the use of isoflurane as a treatment of last resort for patients with RSE.

Question 27

Vagal nerve stimulation

Answer 27

manual vagal maneuvers such as ocular compression and carotid message are potential helpful interventions that can be easily and simultaneously administered to the seizing patient while vascular access is being obtained

Objective data regarding manual maneuvers are lacking

Vagal nerve stimulation appears to reduce cerebral extracellular glutamate concentrations in a rodent migraine model

handheld, transcutaneous device has been developed that allows for nonpainful stimulation of the vagal nerve in animals.2 The device is currently being evaluated as treatment to abate seizures in multicenter veterinary clinical trial.

Question 28

Ultrasonic brain stimulation offers several significant clinical advantages

Answer 28

compact system size, rapid and noninvasive administration of pulses, and superior spatial resolution compared to other noninvasive methods such as transcranial magnetic stimulation. These advantages make ultrasonic brain stimulation attractive for use in the ICU

Question 29

In people, EEG has been indispensable in the diagnostic evaluation of seizures for nearly 90 years
essential tool in the differentiation of seizure disorders from other paroxysmal events that impair consciousness, since psychogenic events, metabolic/toxic events, and movement disorders can look similar to SE

Data from EEG studies can provide important prognostic information, guide the rational selection of antiepileptic medication, and assist the clinician in determining treatment end points

EEG examinations are not routinely performed during the evaluation of veterinary patients with seizures.127-129

early detection of changes in neurologic status associated with intracranial hypertension and brain ischemia, which is particularly useful in comatose patients in whom the clinical examination is limited

periodic and rhythmic EEG patterns are frequently identified in the critically ill that are of unknown significance

In veterinary medicine, few studies have investigated cEEG; however, existing reports highlight the diagnostic utility of cEEG.
-In a report of 10 veterinary patients with SE, cEEG monitoring identified nonconvulsive SE in all 10 animals. Nonconvulsive SE manifested as epileptiform EEG discharges that persisted after termination of gross motor seizures following administration of general anesthetics. In this study, epileptiform activity was also noted when attempting to wean anesthetic medications after 6 hours. A burst suppression pattern was noted in 5 of 10 patients.138 Recently, cEEG was used to diagnose nonconvulsive SE in a cat and guide successful, high‐dose phenobarbital treatment using a burst suppression EEG pattern as a therapeutic end point

Answer 29

In epileptic people, EEG provides important information about location of epileptogenic foci, and epileptiform discharges, and is necessary for the diagnosis of specific electroclinical syndromes

Continuous electroencephalographic monitoring (cEEG) is frequently used in critically ill people. The use of cEEG in ICUs has focused primarily on seizure detection and the potential significance of specific EEG patterns in particular patient populations. Studies have demonstrated that nonconvulsive seizures and nonconvulsive SE are common in critically ill people

Continuous EEG is commonly used for decision making and to define therapeutic end points; however, how cEEG results are used varies among neurologists. Some consider the elimination of ictal EEG patterns and clinical seizure activity to be the end point target, while others prefer

• burst‐suppression patterns or complete suppression of EEG background activity
• a burst suppression pattern has been defined as a pattern of delta and/or theta waves intermixed with faster waves and intervening periods of quiescence.
• Burst suppression results from the hyperpolarization of 95% of cortical neurons, and the presence of such a pattern is thought to be neuroprotective
• Further studies are needed to determine which cEEG treatment end points are most clinically relevant for improved patient outcomes

Newly developed implantable, ambulatory, telemetric cEEG microsystems have the potential to improve seizure monitoring and treatment in dogs and cats. The premise of these devices is that when the implanted cEEG detects impending seizure activity, either an alert is sent to the caretaker’s mobile device prompting a specific medical intervention, or the cEEG device activates another implanted device that delivers treatment. A prototype example of this technology was subdurally implanted in 6 dogs with epilepsy and was able to successfully record the cEEG

Question 30

true mortality rate of patients with SE is difficult to determine, as many patients are euthanized

retrospective study of 156 dogs with either SE or cluster seizures, approximately
Upon follow‐up

The prognosis was significantly and negatively associated with

In a 2012 study of 407 dogs with epilepsy, approximately two‐thirds were euthanized due to epilepsy

Dogs with epilepsy have a decreased lifespan when compared to the general population, and survival time is even lower in epileptics that experience SE

Answer 30

25% of dogs died or euthanized during hospitalization. 59% of dogs had died or were euthanized

granulomatous meningoencephalitis
loss of seizure control after 6 hours of hospitalization
development of partial SE

approximately two‐thirds were euthanized due to epilepsy

decreased lifespan when compared to the general population, and survival time is even lower in epileptics that experience SE