Emergency Treatment of Status Epilepticus and Cluster Seizures in Dogs and Cats
Cluster seizures (CS) and status epilepticus (SE), whether they are convulsive or non-convulsive, necessitate immediate and aggressive parenteral antiepileptic drug (AED) therapy. The primary goal of such therapy is to stop the ongoing seizures immediately. This requires the intravenous administration of an effective and fast-acting AED, at a dosage that will provide a therapeutic serum concentration. The secondary goal of treatment is to prevent the reoccurrence of seizures in the following hours by maintaining a therapeutic AED serum concentration for several hours. The third goal of treatment is to provide adequate protection against further seizures in the following days and weeks. This requires prompt initiation of maintenance oral AED therapy, ideally with the administration of a loading dose to rapidly provide a therapeutic AED serum concentration. Guidelines for the emergency treatment of CS and SE in dogs and cats are presented in the following table.
Emergency treatment of CS and SE in dogs and cats
I. The animal is not seizing at the time of presentation but had ≥ 2 seizures or a sustained seizure that lasted ≥ 15 minutes within the previous 12–24 hours.
A. Perform a complete physical and neurological examination
1. In the post-ictal period, only asymmetrical neurological deficits (e.g., menace, proprioceptive positioning, hopping and facial sensation) indicate the presence of a forebrain lesion likely underlying the seizure problem. Bilateral and symmetrical deficits may only be due to functional post-ictal cerebral disturbances and usually do not persist longer than for a few hours.
B. Obtain samples for laboratory analyses (hematology, biochemical profile, urinalysis and serum concentration of the AED already administered for maintenance oral AED therapy).
1. Increased serum ALT and other liver enzyme concentrations, as well as CK elevation, may be the result of hypoxia and violent muscular activity caused by convulsive seizures, especially those that are of longer duration (> 2 minutes); the abnormal values should then normalize within a few days.
C. In naive patients, initiate AED therapy with a loading dose of the first-line AED (AED1) and then continue with the maintenance oral dosage.
1. In dogs with no history of renal dysfunction, give potassium bromide (KBr) 450–600 mg/kg PO.
(1) Divide this loading dose into four sub-doses to be administered at 3–4 hour intervals with a small amount of food to minimize gastric irritation and vomiting (hypertonic solution); this should provide a low therapeutic serum bromide concentration ([Br]s) of 10-15 mmol/L (1.0–1.5 mg/ml) within 24 hours.
(2) Continue with 40–50 mg/kg q24h PO the next day.
(3) If excessive side effects are produced by the loading dose (e.g., marked sedation, difficulty walking with frequent falling), the maintenance daily dose may not be administered for a few days, until side effects subside enough for the animal to function more normally. It should be stressed to the owner that excessive side effects are temporary (for a few to several days) and less deleterious to the animal than high frequency seizures.
(4) Measure [Br]s on day two, then three weeks later, and adjust the maintenance dosage accordingly; increase the maintenance dosage if the [Br]s is sub-optimal (< 15–20 mmol/L or 1.5–2.0 mg/ml) at three weeks. Always calculate the new daily dosage using the formula: actual daily KBr dosage ÷ actual [Br]s x desired optimal [Br]s.
2. In cats with no history of liver disease, and in dogs that cannot be given KBr because of renal insufficiency, administer a phenobarbital (PB) 15–20 mg/kg slow IV bolus.
(1) This should provide a low therapeutic serum PB concentration ([PB]s) of 80–110 µmol/L (19–25 µg/ml) immediately; profound sedation with inability to ambulate often occurs but usually subsides within a few hours.
(2) An IV PB bolus will take 20–30 minutes before it can produce its maximal antiepileptic effects (delay for penetration of brain tissue); if another seizure occurs during that time, go to section II, phase 1—1.
(3) Continue with 2.0–2.5 mg/kg (cats) or 3.0–4.0 mg/kg (dogs) q12h PO, starting 12 hours after the IV loading dose was given (or even give the first oral dose just before the IV bolus is given).
(4) Measure the [PB]s two weeks (cats) or three weeks (dogs) later (or sooner if another seizure occurs before that time), and adjust the dosage to obtain an optimal therapeutic [PB]s of 100-130 µmol/L (23–30 µg/ml). Always calculate the new dosage using the formula: actual PB dosage ÷ actual [PB]s x desired optimal [PB]s.
D. In known epileptic patients already treated with maintenance oral AED monotherapy,
1. If the serum AED concentration ([AED]s) is documented to be sub-optimal (or is likely to be because the dosage is low), administer a mini-loading dose to reach an optimal [AED]s and also increase the maintenance oral dosage (calculate using formula).
(1) In dogs treated with KBr: administer 225–250 mg/kg PO for each desired 5 mmol/L (0.5 mg/ml) increment of the [Br]s.
(2) In dogs and cats treated with PB: administer 1 mg/kg IV for each desired 5 µmol/L (1.2 µg/ml) increment of the [PB]s.
b) If the [AED]s is documented to be optimal, add a second-line AED (AED2) to the maintenance therapy.
(1) In dogs treated with KBr, add PB; give an IV PB loading dose (see section I.C.2 of this table).
(2) In dogs treated with PB, add KBr: start with an oral loading dose (see section I.C.1 of this table).
(3) In cats treated with PB, add diazepam (DZ): give an IV loading dose of 0.5 mg/kg, then continue with a maintenance dosage of 0.5–1.0 mg/kg q12h PO.
(4) In cats treated with DZ, add PB: give an IV loading dose (see section I.C.2 of this table).
2. In animals already treated with two AED that provide optimal serum concentration, add a third-line AED (AED3) to the maintenance regimen
(1) In dogs treated with PB and KBr, consult a veterinary neurologist for the choice of the most appropriate drug, dosage, and recommendations for the medical follow-up.
(2) In cats treated with PB and DZ, add KBr (unless the cat has renal failure or feline asthma): give an oral loading dose (same as for dogs; see section I.C.1 of this table), then continue with a maintenance dosage of 20–30 mg/kg q 24h.
E. If the animal has ≥ 2 seizures or one prolonged seizure (> 2 minutes) less than 24 hours after it had its previous seizure, continue to section II, phase 1 of this table.
II. The animal is seizing at the time of presentation.
A. Phase 1. Immediately stop the ongoing seizures.
1. Administer a DZ IV bolus: 0.5–1.0 mg/kg in dogs and 0.5 mg/kg in cats
a) Never use the rectal route to administer DZ unless it is absolutely impossible to inject IV (e.g. violent convulsive SE in a very small patient); about 15 minutes is necessary for rectally injected DZ to be absorbed and a significant amount may be lost into the rectal content.
(1) Place an IV catheter as soon as the violent motor activity subsides and administer another DZ bolus IV if seizure activity has not yet been completely stopped.
b) If seizures stop, continue to phase 2.
c) If seizures continue for more than one to two minutes after an IV DZ bolus, or if another seizure occurs, administer a second IV DZ bolus (may be repeated safely once or twice without too much risk of cardiorespiratory depression), then continue to phase 2.
2. Take samples for laboratory analyses (see section I, B of this table).
3. If seizures have been severe (sustained SE or many CS over a short period of time), consider administering IV corticosteroids (methylprednisolone succinate [SoluMedrol®] 30 mg/kg or dexamethasone phosphate 0.25 mg/kg IV), unless an infectious cause for the seizures is likely (rare).
B. Phase 2. Prevent the reoccurrence of seizures.
1. If maintenance PB oral therapy is to be initiated (e.g., AED1 in cats, AED2 in dogs already on KBr and with an optimal [Br]s), a slow IV loading dose should be given (15–20 mg/kg); maintenance oral therapy should be initiated immediately or as soon as the animal can swallow safely.
a) Remember that an IV bolus of PB will take 20–30 minutes before it can produce its maximal antiepileptic effects; if another seizure occurs during that time, give another DZ IV bolus.
b) If another seizure occurs within the following 12–24 hours, continue to section II, phase 2–2.
c) If PB is not to be used as a maintenance oral AED (e.g. AED1 in dogs, dogs or cats with liver disease), go to section II, phase 2–2.
2. Administer a constant rate DZ IV infusion: 0.5-1.0 mg/kg/h in dogs and 0.5 mg/kg in cats.
a) If more than 20 minutes have elapsed since the last IV DZ bolus was given, administer another bolus at the time the IV perfusion is started.
b) Prepare the DZ solution by adding the drug to maintenance fluids in an on-line burette (not into the fluid bag); prepare only 1 or two hours of the DZ solution at a time (DZ is rapidly deactivated by light and adsorbed into the burette and tubing plastic).
c) Aim at a normal hydration status while avoiding overhydration (to restore or maintain normal perfusion pressure to the brain and avoid cerebral edema).
d) Avoid saline (NaCl 0.9%) for fluid therapy in patients treated with KBr (will rapidly increase the renal elimination of bromide and decrease the [Br]s which could allow more seizures to occur).
e) Use a fluid pump to insure precise and constant rate infusion.
f) When no seizures have been observed for more than four to six hours, slowly decrease the DZ infusion rate by 25% increments every four to six hours.
g) If another seizure occurs during the DZ infusion, continue to section II, phase 3.
3. Treat with repeated DZ IV boluses only if it is absolutely impossible to administer a constant rate infusion (e.g., owners electing euthanasia because of the cost of such treatment, insufficient amount of injectable DZ available in the hospital and impossibility to quickly get some more, impossibility to provide continuous monitoring for 12-24 consecutive hours at night or during week-ends, and impossibility to refer the patient due to financial or geographical constraints).
a) After an initial 1 mg/kg IV bolus is given (dogs and cats), administer 0.5 mg/kg IV boluses every 20 minutes until at least four to five boluses have been given, even if no other seizures have yet occurred. This should provide and maintain a therapeutic [BZ]s for several hours and hopefully prevent the reoccurrence of seizures.
b) Marked sedation may ensue (especially in cats) but should resolve within a few hours, usually enough for the animal to go home with the owners, if continuous monitoring cannot be provided in the hospital. DO NOT leave such a patient in the hospital if nobody is there to provide continuous monitoring and appropriate emergency care.
(1) If ≥ 2 other seizures occur within the following 12-24 hours, emergency hospital readmission and IV administration of DZ or of another AED will be necessary.
4. As soon as the animal can swallow safely, initiate or continue maintenance oral AED therapy.
a) When initiating therapy, administer a loading dose whenever it is possible (see section I.C for loading dose guidelines).
b) If the patient cannot swallow safely at the time an oral AED dose is scheduled, give the AED dose parenterally (give PB and DZ IM and give KBr rectally).
C. Phase 3. Control refractory or recurring seizures.
1. If another seizure occurs during the DZ infusion, give another DZ IV bolus and increase the DZ infusion rate (up to 1.5 mg/kg/h in dogs and up to 1.0 mg/kg/h in cats) for at least six to eight hours before attempting to decrease its rate.
a) If no further seizures are observed, slowly decrease the DZ infusion rate by 25% increments every four to six hours.
b) If two or more seizures are observed despite the DZ infusion rate increase, continue to section II, phase 3–2 or 3.
2. In patients naive to PB, administer a PB IV bolus if this has not yet been done (see section II, phase 2-1).
a) If the patient is already treated with oral PB therapy but its [PB]s is sub-therapeutic (< 100 µmol/L or 23 µg/ml), immediately increase its [PB]s to an optimal level (100-130 µmol/L or 23–30 µg/ml) by giving an IV PB bolus (see section I.D.1.(2) and also increase the PB maintenance dosage (calculate with formula).
b) Also administer a constant rate IV PB infusion at the rate of 0.25 mg/kg/h to maintain therapeutic [PB]s.
(1) Injectable PB (120 mg/ml) should be diluted with sterile saline (1 ml of PB into 19 ml of saline) to provide a 6 mg/ml PB solution that will be added to the DZ solution into the in-line burette.
c) If no further seizures occur afterwards, slowly decrease the DZ and PB infusion in alternation, by 25% increments every four to six hours.
3. If adding PB is not indicated (the patient is already treated with PB and has an optimal [PB]s) or if ≥ 2 additional seizures occur despite the DZ ± PB constant rate infusion, administer propofol
a) Give an IV bolus of 1.0–3.5 mg/kg (can be repeated, to effect).
b) Also start a constant rate infusion of 0.01–0.25 mg/kg/minute, or higher, to effect (to obtain an adequate seizure control without producing excessive cardiorespiratory depression and hypotension), for at least six to twelve hours before attempting to decrease the infusion rate, if no other seizures have occurred.
(1) Propofol infusion can be continued for up to 48 hours if seizures reoccur as soon as the infusion rate is decreased
(2) Be aware of the risk of Heinz body formation and hemolytic anemia in cats; use the lowest effective dosage for the shortest periods of time and perform frequent hematological evaluation (PCV and RBC morphology)
4. If seizures continue with a high frequency, proceed to general anesthesia (go to Phase 4).
D. Phase 4. General anesthesia.
1. Administer an IV pentobarbital bolus of 2–5 mg/kg, to effect (first give half of the dose and wait five to ten minutes to see the full effect before adding more drug).
a) Do not confuse paddling from anesthetic recovery (slow and rhythmic) with seizure recurrence.
b) If convulsive seizure activity reoccurs, start a continuous IV infusion at the rate of 5 mg/kg/hour, or proceed to gas anesthesia with isoflurane for at least two to three hours.
2. Insure adequate anesthetic monitoring and supportive care (intubate, ventilate/oxygenate if necessary, prevent or correct hypothermia and hypotension, etc.)
III. Restore and maintain homeostasis
1. Body temperature, heart rate, respiratory frequency, and if possible, blood pressure should be monitored continuously; appropriate intervention should be taken if necessary.
a) Systemic complications to be looked for and corrected immediately include neurogenic pulmonary edema, intravascular disseminated coagulation, cardiac arrhythmia.
2. Neurological status should be monitored carefully to detect any signs of seizure recurrence or of complications.
a) Persisting seizures are often subtle (e.g., facial twitching, sudden opening of the eyes with pupil dilation).
b) Neurological complications include brain edema with increased intracranial pressure (small pupils may only be due to drug administration), tentorial herniation (coma with dilated unresponsive pupils, decerebrate posture)
3. Supportive and tender loving care include eye lubrification, bladder emptying to prevent over-distention damage to the detrusor muscle, turning the stuporous animal every four hours to prevent dependent lung congestion and atelectasia, etc.
IV. Emergency home treatment with rectal diazepam for CS and SE.
1. At the occurrence of the second or third seizure, the owner should administer a 1.0 mg/kg bolus of DZ rectally (with a soft urinary catheter or teat canula) every 20 minutes for a total of four to five doses.
a) A higher dosage (1.5–2.0 mg/kg) may be necessary in dogs treated with PB and that have been repetitively administered DZ for the treatment of CS or SE (more efficient hepatic metabolism and tolerance to the antiepileptic effect of DZ).
b) If other seizures occur, emergency hospitalization for IV administration of more DZ or of another AED will be necessary.
2. Owners of dogs with history of prior SE may also be instructed to administer rectal DZ in their way to the hospital for emergency treatment.