Case: Part 4

2 Hours

lorazepam phenytoin

Treatment of Seizures

in Critically Ill Children

December 5, 2011

James J. Riviello, Jr., M.D.

NYU Comprehensive Epilepsy Center

Director, Division of Pediatric Neurology

Professor of Neurology

NYU School of Medicine

American Epilepsy Society | Annual Meeting

Disclosure

Spouse, Section Editor, Up To Date

Most Treatments for Status Epilepticus are off-label

American Epilepsy Society | Annual Meeting

Learning Objectives

• Identify Seizure Treatment Goals

• Define the stages of Status Epilepticus and how staging guides treatment decisions

• Know how to treat Seizures and Status Epilepticus, from First-Line Therapy to the Treatment of Refractory Status Epilepticus

American Epilepsy Society | Annual Meeting

Steps in Treatment Process: 1) Identify Seizures

2) Treat Seizures. What are the Tx Goals?• 1) Immediately stop all seizure activity (clinical and

electrographic).

– Prolonged seizures may result in neuronal injury.

– Avoid complications of treatment.

• 2) Identify and treat the specific etiology, and the complications of seizures and SE.

• 3) Prevent seizure recurrence.

• NB: A standardized treatment guideline or protocol is best to achieve these goals.

Treatment of Seizures

• Guideline or Protocol

• Evidence-based medicine (EBM) is ideal

– Levels of evidence

– Literature, case reports, expert opinion

• However, few RCTs exist to recommend specific AED doses

Assess Intervention (treatment)

• Does the treatment work?

• Does the intervention improve outcome?

Yoong, Chin, Scott: Arch Dis Child 2009

Guideline Preparation, Texas Children’s Hospital:

This guideline was prepared by the Evidence-Based (EB) Clinical

Decision Support Team in collaboration with content experts at

Texas Children’s Hospital. Development of this guideline supports

the TCH Quality and Patient Safety Program initiative to promote

clinical guidelines and outcomes that build a culture of quality and

safety within the organization.

Status Epilepticus Content Expert Team:

22 members from Neurology, Critical care Medicine,

Emergency Medicine, Nursing, Care Management, Pharmacy,

Quality Outcomes Management, Respiratory Care,

Social Work

Problems with Protocols

• Pre-hospital treatment protocols and even inpatient protocols are NOT followed!

• Chin (2008): North London SE Surveillance Study, (Lancet Neuro 2008;7:696-703) re APLS guidelines:

– Pre-hospital treatment: 75% treated with a lower dose of diazepam

– 42/82 gave the 2nd-line AED and the dose was low

– 32/82 gave a low phenytoin dose, (mean 12.4 mg), which is 5.5 mg lower than recommended

Stages of Status EpilepticusGoodkin HP, Riviello JJ Jr. Status Epilepticus. Wyllie E, editor. The Treatment of Epilepsy: Principles

and Practice, 5th Edition, Lippincott Williams and Wilkins, 2011, pages 469-485.

Special Circumstances of Early StageGoodkin and Riviello

• Post-operative patients, especially after cardiac or neurosurgery

• Head trauma, increased intracranial pressure, brain tumor, intracranial hematoma, subarachnoid hemorrhage

• Stroke: ischemic and hemorrhagic• CNS Infections (meningitis or encephalitis) or sepsis-

encephalopathy syndrome• Organ failure, especially hepatic or multisystem failure• Hyperthermia; malignant hyperthermia, hyperthyroidism• Metabolic Disorders prone to develop increased

intracranial pressure (DKA, organic acid disorders)

When is SE Refractory ?

• Bleck TP: Refractory SE defined as failure to respond to a standard treatment regimen for SE.– The failure of 2 or 3 AEDs, including the first-line agent,

was required. – Duration: In SE stages, SE considered refractory when Sz

duration was 60 minutes.(Bleck TP; Refractory Status Epilepticus; CurrOpCritCare

2005;11:117-120).

• Refractory SE now diagnosed when patient has failed to respond to two AEDs, including first-line therapy.– Duration seizure activity after treatment no longer

considered as criteria for Refractory SE.

Supportive Measures: The ABCs

• Airway

– Stabilize and maintain the Airway; position head to avoid airway obstruction

• Breathing

– Establish Breathing (i.e., ventilation): administer oxygen by nasal cannula or mask

• Circulation

– Maintain the Circulation: start intravenous (IV) line

What other Studies Needed?To identify etiology or a complication

• CBC, electrolytes, glucose, calcium, phosphorous, magnesium, AED levels, toxicology

• Lumbar puncture, when stable and increased ICP excluded: – especially when febrile or refractory

• Neuroimaging, when stable: – Cranial CAT scan or MRI

• EEG, especially if diagnosis is in doubt, pseudo SE

• CEEG, exclude NCSE or guide ongoing therapy

Need for EEG after control CSE• Evaluate Therapeutic Interventions

– Monitor continuous IV (cIV) AED treatment for RSE– ? End point: elimination of clinical Sz, NCSz versus burst-

suppression• Monitor mental status after the control of CSE, if no

improvement must evaluate for subclinical seizure activity [NCSz, Non-CSE (NCSE)]– Failure to RTB after control CSE (30 minutes)

• After treatment:• Adults 14%, DeLorenzo (Epilepsia 1998;39:833-840)• Children 26%, Tay (Epilepsia 2006;47;1504-1509)

– Coma • Adults 10%, Towne (Neurology 2000;54:340-345)• Children, 10.5%, Tay (Epilepsia 2006;47;1504-1509)

Immediate Treatment: First-Line Tx

• Lorazepam, 0.1 mg/kg, IV, over 2-5 minutes

• Maximum dose:– 4 mg

– In reality, there is no maximum dose.

• Many protocols administer a second dose if seizures continue after 5 minutes. – Chin (2008): only 20% had seizure termination after

2nd dose

– A second benzodiazepine was associated with respiratory depression.

First-Line Treatment: Expert Opinion

US

• Lorazepam, for GTC, absence, CPS SE

(J Child Neuro 2005;20:S1-S56)

Europe

• Diazepam, IV for GTC, absence, CPS SE

(Epileptic Disord2007;9:353-412)

Subsequent TreatmentAKA: Second through Fifth-Line Tx

Sequence (2nd through 5th Line)

• 2) Fosphenytoin, 20 mg/kg– Consider repeat 10 mg/kg

• 3) Phenobarbital, 20 mg/kg

• 4) Midazolam, 0.2 mg/kg – Repeat 0.2 mg/kg in 5 min

– followed by cIV at 0.1 mg/kg/hr

– repeat X 2

• 5) Pentobarbital– 5 mg/kg/hr, then cIV at

1 mg/kg/hr

Continuous IV infusion (cIV)

• Midazolam:

– 0.2 mg/kg, then 0.1 mg/kg/hr

• Propofol:

– 1-2 mg/kg, then 2-3 mg/kg/hr

• Pentobarbital:

– 5-15 mg/kg, then 1-3 mg/kg/hr

• Thiopental:

– 2-7 mg/kg, then 0.5-5mg/kg/hr

• Ketamine:

– 2 ug/kg, then up to 7.5 ug/kg/hr

When To Change to cIV Therapy?

• Or move from a standard AED to an intravenous anesthetic?

Fosphenytoin

• Loading Dose: 20 mg/kg IV (or IM as water soluble, unlike phenytoin)– May give additional 5 – 10 mg/kg if seizure

continues

• Infusion Rate: No faster than 150 mg PE/min– 3 mg/kg/min in children

• AEs: hypotension, paresthesias, choreioformmovements

• Need to Know: Compatible in all solutions

Phenobarbital

• Loading Dose: 20 mg/kg IV

– May give an additional 5 to 10 mg/kg

• Infusion Rate: 1 mg/kg/min,

– maximum 30 – 50 mg/min

• AEs: Hypotension, Respiratory Depression

Valproic Acid

• Loading Dose: 20 – 40 mg/kg IV– May give an additional 20 mg/kg 10 minutes after

loading dose

• Infusion Rate: 1.5 to 3.0 mg/kg/min (< 20 mg/min)

• AEs: Hyperammonemia, hepatic and pancreatic dysfunction, thrombocytopenia (usually chronic)

• Need To Know: Are metabolic diseases a contraindication, especially POLG??

(Saneto RP, Seizure 2010;19:140-146).

Levetiracetam

• Loading Dose: 20 to 60 mg/kg (responders 30 mg/kg)– Depositario-Cabacar (N=9): high-dose defined

as > 150 mg/kg/day; Mean dose 228 mg/kg/day

(Epilepsia 2009;51:1319-1322)

• Infusion Rate: 2 – 5 mg/kg/min

• AEs: minimal drug interactions, not metabolized in liver

• Need To Know: very safe

Lacosamide

• Loading Dose: 200 to 400 mg

• Infusion Rate: Over 30 to 60 minutes– Biton V: 30 minutes versus 60 minutes

(Epilepsia 2008;49:418-424)

– In adults, 200 mg over 15 minutes suggested

• AEs: First-degree heart block, hypertension– Minimal drug interactions

• Need To Know: – NO PEDIATRIC DOSING YET ESTABLISHED

Treatment of Refractory Status Epilepticus

• If first cIV drug fails, switch to another

• Pentobarbital: may have higher success rate, but greater AEs (hypotension, decreased cardiac contractilty)

• Midazolam: less sedation, hypotension, but efficacy may be less

• Propofol: success rate is equal to pentobarbital, but causes hypotension, especially the– Propofol Infusion Syndrome (PIS), when the

rate > 65 mcg/kg/min, or when prolonged

If Non Convulsive SE

• IV Phenobarbital, fos-Phenytoin, Valproic Acid, Levetiracetam, Lacosamide

– Rather than a continuous IV infusion (cIV) with Pentobarbital, Midazolam, or Propofol

• Oral AEDs

– If stable hemodynamics and not intubated

Role Pyridoxine in SE

• Should there be an age recommendation?– British SE Working Party: children under age 3

years with previous epilepsy (Arch Dis Child 2000;83:415-419)

– Babl FE (PREDICT): under 18 to 24 months

(J Paed Child Health;2009;45:541-546)

• CHOP (Abend NS): 100 mg, IV push (no age)– (Ped Emerg Care 2008:24:705-721)

• Guideline CHB (2003): 200 mg IV, slow push

Treatment of RSE

• High-dose Phenobarbital: Levels > 150 mcg/ml

• Ketamine, avoid with increased ICP

• Etomidate, avoid continuous infusion, causes adrenal insufficiency

• Inhalational Anesthetics: Isoflourane

• Verapamil: effects calcium channels or is a known p-Glycoprotein inhibitor, which block AED transport

• Topiramate through NG tube

• Ketogenic Diet, especially for FIRES

• Immune Modulation:

– Corticosteroids, IVIG, PLEX (Pheresis)

• Hypothermia

• Neurostimulation: VNS, TMS, ECT

The Identification of Seizures

• The Clinical Manifestations– Seizure Semiology: The signs– Convulsive (Sz, CSE) versus Non-convulsive (NCSz, NCSE)

• The EEG findings: Non-convulsive seizures (NCSz)– Frequent in the critically ill with altered mental status– CHOP: 46/100 had Sz; 70% NCSz, 30% both convulsive, NCSz

(Abend NS; Neurocrit Care 2010;15:70-75)

• Differential Dx: Episodic non-epileptic events– Automatisms, tonic posturing, myoclonic movements, autonomic

instability (heart rate, blood pressure changes)• Melbourne (N=100): Clinical Sz proven in only 4/18 suspected Sz

(Shahwan A; Epilepsia 2010;51:1198-1204)• CHOP: non-epileptic events in 21/100

(Abend NS; Neurocrit Care 2010;15:70-75)

• Especially the newborn

Premonitory (Prodromal) Stage SE: Tx with Home Remedies

• The Prodromal Stage:

– Confusion, myoclonus, increasing Sz frequency

• Pre-hospital treatment of status epilepticus (home or first-responders)

– Rectal Diazepam revolutionized this approach

– San Francisco pre-hospital treatment study, (Alldredge B et al, NEngJMed 2001;345:631-637).

• LZP better than DZP

Points from History

Is there a past history of epilepsy? What is the epilepsy syndrome? [VPA might better for a primary generalized epilepsy (absence, JME)]

Characteristics of past seizures: is there a history of status epilepticus?

Has an AED been given (pre-hospital treatment or inpatient), is patient on any AEDs (consider bolus), or are there any allergies, or ever have Stevens-Johnson Syndrome?

Are treatable causes present (any acute precipitants)?

Fever or illness, possible electrolyte imbalance, head trauma; intoxications, toxin exposure (organophosphates, INH)?

Are chronic medical conditions present or is patient on steroid therapy? (if so, needs stress coverage)

Current Practice EEG/CEEG in ICU (2)

• Characterize Events in the ICU

– Non-epileptic paroxysmal events

– Identification Pseudostatus epilepticus

• Monitoring neurologic status

– Evaluation altered awareness, coma

– Neuromuscular paralysis

– Early detection neurological deterioration

• Prognosis

Steps in The Treatment Process

• The Identification of Seizures

• The Treatment of Seizures

Need for EEG after control CSE

• If patient does not show improvement in mental status after the control of CSE, must exclude NCSE