Mr Ivan KempHighly Specialised Pharmacist for Critical CareUniversity Hospital Southampton

• A life-threatening neurological condition defined as 5 minutes, or more, of either continuousseizure activity or repetitive seizures without regaining consciousness.

• SE carries a high mortality rate if not promptly treated.

• Treatment therefore, must precede any thorough investigation and must be initiated as soon as SEis suspected.

‘Status Epilepticus’

Emergency AED therapy for convulsive Status Epilepticus(3 phases) 1

Early statusmanagement

Benzodiazepine• Lorazepam IV 0.1mg/kg (but usually a 4 mg bolus)• Diazepam rectal 10−20mg• Midazolam buccal 10mg

Established status management

Non-benzodiazepine• Phenytoin infusion at a dose of 15–20mg/kg• Maintenance 300mg/daily (then guided by TDM)

Refractory status management (Reached 60/90 minutes after the initial therapy)

General anaesthesia with one of:• Propofol• Midazolam• ThiopentalContinue for 12−24 hours after the last clinical or electrographic seizure before weaning dose.

1. NICE guidelines CG137 Epilepsies: diagnosis and management. Appendix F: Protocols for treating convulsive status epilepticus in adults and children.

Zero-order kinetics

(enzyme saturation)

TDM

(10-20mg/L)

Heavily protein bound

Correct for

low albumin /

CrCl <20mL/min

Stability

dilute precipitate risk

Drug/Drug interactions

Liver enzyme inducer

Drug/Enteral feed interaction

Reduced absorption

Formulation equivalents

(Sodium salt vs. Base)

Phenytoin“clinical pharmacy explained”

Mechanism of actionVoltage-sensitive sodium channel blockade

Mechanism of action1. Inhibition of GABA transaminase2. Increased GABA in synaptic cleft3. Enhance inhibitory effect of GABA

Sodium Valproate, as good as phenytoin?

Data suggest that valproate is at least as effective, if not possibly superior to phenytoin in the treatment of SE.

A 2014 systematic review concluded that valproate demonstrated control of SE in 50-90 percent of patients when used in the ‘status management phase’’.

The largest comparative trial between valproate and phenytoin demonstrated similar efficacy, but valproate was better tolerated .

In the second largest trial, valproate was more effective than phenytoin as first-line treatment (without benzodiazepines), and much more effective when used after failing the other medication.

Evidence suggests that a loading dose of 30 mg/kg can be infused safely at a rate of 10 mg/kg per minute in adults without adverse effects on blood pressure or heart rate. Loading doses in this range yield concentrations in typical therapeutic ranges and without significant sedation.

Valproate useful as a non-sedating option in patients with focal or myoclonic SE over phenytoin and better in patients with primary generalised epilepsies (but only a small proportion of those presenting with GCSE)

Sodium Valproate

The “admission on to ICU” equation

+

Static WCC/CRP after 24h ABx

Pip/Taz

Escalation to Meropenem

=

No bloody valproate!

Sodium Valproate

Impact on the Critical Care patient

Heavily protein bound; valproic acid displaces phenytoin from its plasma proteinbinding sites and reduces its hepatic catabolism increasing phenytoin free form -toxicity risk.

Liver enzyme inhibition

Clinically relevant drug/drug interactions

Multiple formulations/routes available for the intubated patient: IV, liquid

Bioequivalent dosing between formulations

TDM not essential

Bone marrow suppression

Hyponatraemia (SIADH)

Hyperammonaemia

LevetiracetamMechanism of action

1. Binds to the synaptic vesicle protein SV2A2. Binding to SV2A reduces the rate of vesicle release3. Neurotransmitter release from nerve-end-terminals inhibited

Levetiracetam, as good as phenytoin?

Support for the use of IV levetiracetam in patients with SE is drawn primarily from observational trials in patients with refractory SE, as well as two small randomised trials as first-line therapy.

A randomised trial with 50 patients in each arm; seizure control was similar when comparing levetiracetam (25 mg/kg), valproate(30 mg/kg), and phenytoin (20 mg/kg) given as first-line agents for GCSE in combination with IV lorazepam.

In a separate non-blinded trial, 44 consecutive adults with SE and persistent seizure activity after one dose of lorazepam (0.1 mg.kg) were randomised to receive either phenytoin (20 mg/kg) or levetiracetam (20 mg/kg). Rates of seizure resolution within 30 minutes of the start of the infusion were similar in both groups (68 versus 59 percent, p = 0.53).

By contrast one retrospective study found that levetiracetam was associated with a higher rate of failure to control seizures compared with valproate (48 versus 25 percent) when used as a second-line treatment for SE.One small randomised trial found no benefit of adding levetiracetam to clonazepam IV in the pre-hospital setting, compared with clonazepam alone.

Loading doses from the literature for IV levetiracetam SE guidelines are variable.Suggested doses range from:• 1000 to 3000 mg IV • 60 mg/kg IV (up to a maximum of 4500 mg)

Levetiracetam

Impact on the Critical Care patient

Few clinically relevant drug/drug interactions

Low protein-binding

No clinically relevant impact on liver enzyme inhibition/induction

Multiple formulations/routes available for the intubated patient: IV, liquid

Bioequivalent dosing between formulations

May need to adjust dose in renal impairment

AED Need for TDM

Significantly protein-bound

Liver enzyme impact

Drug/Drug interactions

Drug/Enteralfeed

considerations

Dosingconsideration

between formulations

Licenseduse for SE

Phenytoin Yes Yes Stronginducer

+++ Yes Yes Yes

Levetiracetam No No None + No No No

Sodium Valproate

Not necessary

Yes Inhibitor ++ No No No

So which AED would YOU choose?

A complicated case of NORSE

• New-onset refractory status epilepticus (NORSE) is defined as refractory status epilepticus without an obvious cause after initial investigations.

• Refractory status epilepticus is a condition in which patients suddenly experience continuous seizures that do not respond to standard AEDs.

• Affected individuals are most often treated for weeks in an ICU because they require prolonged anaesthesia with coma-inducing drugs to control their seizures.

• NORSE carries a high rate of complications and mortality.

A complicated case of NORSE

• HPC – Previously fit and well 22 year old lady admitted in to ED following twogeneralised self-limiting seizures.

• Originally presented to ED with a 10 day history of frontal headache with intermittentfever. Thought initially to be secondary to possible sinusitis and discharged home onCo-Amoxiclav

• Initial Tx• Empirical meningitis/encephalitis cover: Ceftriaxone and Aciclovir• CTB - nil intracranial pathology• Further generalised seizures with accompanying agitation.• Loaded with phenytoin and admitted to ICU; intubated and ventilated

A complicated case of NORSE

•Transferred to Wessex Neuro ICU May 18• 6 month stay on NICU• Treatment and diagnostics received

• AED++• PLEX x5• IVIG• Ketogenic Diet• Cannabidiol

• Despite multi-directional treatments EEG throughout reveals Status Epilepticus.• Working diagnosis NORSE or antibody negative autoimmune encephaltits.• AED induced pancytopenia; could wean but would be exchanging one life-threatening issue (pancytopenia) for another (status epilepticus).• RIP Dec 18; inconclusive post-mortem. Hypothesis: seizures initially driven by a viralmeningoencephalitis, which was cleared, but the seizures continued.

AED May 18 June 18 July 18 Aug 18 Sept 18 Oct 18 Nov 18 Dec 18

BRIVARACETAM

CANNABIDIOL

CLOBAZAM

CLONAZEPAM

KETAMINE

LACOSAMIDE

LEVETIRACETAM

MIDAZOLAM

OXCARBAZEPINE

PERMAPANEL

PHENOBARBITAL

PHENYTOIN

SODIUM VALPROATE

THIOPENTONE

TOPIRAMATE

KETOGENIC DIET

Treatment timeline

0

5

10

15

20

25

30

35

02

-May

09

-May

16

-May

23

-May

30

-May

06

-Ju

n

13

-Ju

n

20

-Ju

n

27

-Ju

n

04

-Ju

l

11

-Ju

l

18

-Ju

l

25

-Ju

l

01

-Au

g

08

-Au

g

15

-Au

g

22

-Au

g

29

-Au

g

05

-Se

p

12

-Se

p

19

-Se

p

26

-Se

p

03

-Oct

10

-Oct

17

-Oct

24

-Oct

31

-Oct

07

-No

v

14

-No

v

21

-No

v

28

-No

v

Albumin and Urea levels

Urea (mmol/L)

Albumin (g/L)

Impact of a Ketogenic Diet

Complexity/Calculations/Complications/Considerations

In summary

• “Well managed” phenytoin still first-line for SE.

• Valproate as good, if not better, but it’s side-effect/interaction profile often not desirable in theICU patient.

• Levetiracetam probably as good as phenytoin/valproate; good side-effect/interaction profile butlacking some clarity on the loading dose.

• Multiple AEDs add complication to risk/benefit of the individual agent.

• A Ketogenic Diet may complicate further; hypoalbuminaemia, glucose, propylene glycol.

• Clearly document your thoughts, rationales and concerns. This may include a lack ofinformation.