STATUS EPILEPTICUS UPDATE
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Transcript of STATUS EPILEPTICUS UPDATE
STATUS EPILEPTICUS UPDATE
Jo WilmshurstDepartment of Paediatric Neurology
Red Cross Children’s Hospital
What are the protocols? How should we monitor these children?
Definitions
Status epilepticus: Generalised convulsions > 30 minutes = brain damage / neuronal cell death
Refractory status: Generalised convulsions > 1hour, resistant to level 1-2/3 intervention – i.e. need PICU intervention
The longer it takes to gain control the worse the outcome and the harder it will be to terminate Sz
Outcome influenced by underlying aetiology – encephalitis worst result
Scott et al, ARCH 1998Holtkamp et al; JNNP 2005
Causes
Fever 36% Medication change 20% Unknown 9% Metabolic 8% Congenital 7% Anoxic 5% Other (trauma, vascular, infection, tumour, drugs) 15%
Haafiz et al; Ped Emerg Care 1999
Mortality
Adults 15-22% Children 3-32%
No figures for SA
Fountain et al; Epilepsia 2000
Lacroix et al; CCM 1994
Sahin et al; Epilepsia 2001
Optimal intervention times
Children > 5 years : typical GTCS seizure duration < 5 minutes
Younger children and infants: paucity of data. Suggested time frame for a typical GTCS is less than 10-15 minutes.
Mean age for status in children 3.4 years
Lowenstein DH, Bleck T, , Macdonald RL. Epilepsia 1999;40(1):120-2
Singh et al 2010 Neurology
Diagnostic assessment of the child with status epilepticus Blood glucose Anti-epileptic drug (AED) levels. Toxicology testing Blood cultures
Lumbar puncture (as clinically indicated & all children < 18 months)
Neuroimaging: Insufficient evidence for routine neuroimaging (8% yield)
Indications: When convulsive status is unexplained the patient remains unconscious, or new focal neurological signs become apparent.
Evidence- based quideline American Academy of Neurology (ANN) and Child Neurology Society (CNS)
Brain Monitoring
Continuous Non-invasive Highly sensitive to a variety of brain insults Reasonably specific User friendly Not too expensive!
Kurtz et al Curr Opin Crit Care 2009
Monitoring
cEEG (continuous EEG – full head montage) The Gold standard – not viable in most SA settings Non-convulsive seizures IschaemiaaEEG (Amplitude-integrated EEG) Assessing if burst suppression attained Non-convulsive seizures Potential artefact
Need to remember overall underlying cause usually the defining feature for the outcome of the child.
The future?
Basic external monitoring (BP, sats, HR) often underestimates true cerebral function
Cerebral Near-infrared spectroscopy (cNIRS) Non-invasive Used as a tool to assess regional brain
saturations (RSO2) Available in SA!
Comparison studies with serological markers (S100beta and NSE) – performed well (better infact)
Subbaswamy et al Neurocrit Care 2009
Treatment of Status Epilepticus Pre hospital treatment A&E treatment In-hospital treatment (Ward/High care) Anaesthesia (ICU)
What recommendations exist for managing Status
Epilepticus in Children?
Mayo Clinic
Boston Children’s hospital
European expert opinion 2007
European expert opinion 2007
Children’s Hospital of Philadelphia
Red Cross Guidelines
APLS guidelines (2005; The convulsing child)
ABCD↓
(Level 1) Lorazepam IV/IO or diazepam pr / midazolam buccal
↓Lorazepam IV / IO
↓Paraldehyde pr
(Level 2) ↓Phenytoin IV / IO / Phenobarbitone IV / IO
↓(Level 3) RSI with Thiopental
Level one
Arrival – First Hosp intervention Benzodiazepine
Diazepam PR/IV/IO Midazolam IN/SL/IV/IO Lorazepam IV/PR/IO
Repeat if necessary
Good specialist consistency, good study data
Scott et al;Lancet 1999Jeannet et al;Europ J Paed Neurol 1999
DeNegri et al; Pediatr Drugs 2001
Diazepam versus Lorazepam Both are equally effective at aborting status epilepticus.
IV lorazepam vs IV diazepam Rectal lorazepam might be more effective than rectal
diazepam
Lorazepam: Substantial longer duration of anti-seizure activity (lipid-
soluble) Less seizure recurrence and fever repeat doses required.
Appleton R et al Cochrane Database Syst Rev 2008 Jul 16;(3)
Transmucosal pharmacological therapy
Intranasal midazolam as effective as intravenous diazepam
Buccal midazolam as effective as rectal diazepam. Intravenous formulations of midazolam (given buccal
or intranasal routes) are relatively inexpensive. Caregivers prefer intranasal midazolam to rectal
diazepam.
Appleton R et al Cochrane Database Syst Rev 2008 Jul 16;(3)
Paraldehyde
Treatment with IV phenytoin as a second-line therapy was associated with a 9-times greater likelihood of seizure termination than was treatment with paraldehyde
Chin R, Neville B et al Lancet Neurol 2008;7:696-703
Level 2 intervention
Phenytoin IV over 20 mins, cardiac monitor, large vein, not mixed with
glucose Phenobarbitone IV/IM
Push, flush through, monitor for resp depression and hypotension
Both agents fairly accepted BUT studies becoming more limited
small numbers less children
Shanner et al;Neurol 1988
Prasad et al;Ann Neurol 2002
Phenytoin
Takes 30 minutes to administer Requires a syringe driver Requires a large IV (NOT central) line Requires cardiac monitoring for potential cardiac
toxicity Can only be given by IV route Cannot be repeated It not as effective as phenobarbitone
DeToledo & Ramsay; Drug Saf 2000Trieman et al; NEJM 1998
Fosphenytoin More favourable vehicle that does not contain proylene glycol
and pH 8.6-9 Administer in dextrose containing IV solutions at a more
rapid rate.
Equally effective: Time for conversion of pro-drug to active drug (8-15minutes) = therapeutic phenytoin concentrations reached at the same time.
Cost: Fosphenytoin 3 times equivalent dose of IV Phenytoin. Benefit: More favorable side effect profile (purple glove
syndrome)
Experimental Rescue therapy
NG phenobarbitone 20mg/kg given during level 2 intervention Provided good airway protection and ability for gastric absorption
…
Study at Red Cross (Wilmshurst et al J Paed Child Health 2009) Any child / infant entering established status (Level 2) 1-4 hours to therapeutic levels SAFE No need for repeat dosage for therapeutic levels but for control
of seizures could safely repeat Good viable addition to the protocol – especially where
parenteral access or supply lacking
Syed et al;Dev Pharmacol Ther 1986Yska et al;Pharm World Sci 2000
Yukuwa et al;J Clin Pharm Ther 2005
Level 3 intervention
Basically heading into refractory status Disastrous situation Resistant seizures –
prob exacerbated by underlying cause ( eg encephalitis),
secondary complications from drugs hypotension, respiratory depression
all affecting brain perfusion Sahin et al;Neurol 2003
Scott et al, ARCH 1998
Holtkamp et al; JNNP 2005
Level 3 intervention: Treatment of refractory SE
No prospective randomised trials comparing the effects of anesthetics in the treatment of RSE. Safety data lacking.
Options: Barbiturate anesthetics: Pentobarbital (US)
Thiopental (Europe Aus) Propofol Midazolam.
Evidence based medicine: No recommendations on data available.
Even in a large survey of neurologists in USA – little consensus for 3rd / 4th line intervention (J Neurol Sci 2003)
Rosenow et al;Epileptic Disord 2002
Midazolam infusion
Requires a syringe driver Greater risk of airway suppression (especially following
previous Benzo boluses) Takes long time to gain control (range 15 mins – 4.5
hours) Potential for children left with prolonged seizures and
irreversible neuronal cell death in centres without high care facilities
NOTE: Excluded from APLS guidelines
Rivera et al; CCM 1993Lal Koul et al; ARCH 1997
Ozdemir et al; Seizure 2005
CLONAZEPAM INFUSION
NO EVIDENCE
Thiopentone
Poor anticonvulsant Marked haemodynamic effects Prolonged drug effects if infusion used Local ICU capacity limited
Staffing Monitoring Anaesthetic experience
Very-high-dose Phenobarbitone Both barbiturates and benzodiazepines exert a primary effect on
the GABA receptor complex.
No antiepileptic ceiling effect ! No maximum dose beyond which further doses are likely to be ineffective >200mgkg!
Complications: Sedative and respiratory-depressant properties more likely in
combination with benzodiazepines. Hypotension unusual and related to the highest Phenobarbitone
levels and easily controllable. Complications usually related to underlying aetiology
Crawford et al; Neurol 1988
Intravenous Sodium Valproate FDA approved 1996. Not in APLS guidelines
No reports of respiratory depression or hypotension. Caution in children with underlying liver disease or suspected mitochondrial
disorder. Potential hepatic encephalopathy
Comparative studies: Intravenous Sodium Valproate vs Diazepam infusion Intravenous Sodium Valproate vs Phenytoin.
No large studies measuring efficacy Larger paediatric focused studies are needed
Still need syringe driver Very expensive
Drug of choice: Absence status
Limdi et al; Neurology 2005Rossetti & Bromfield; Neurology 2005
Limbdi N et al Epilepsia 2007 48(3):478-483 Morton L et al Pediatr Neurol 2007;36:81-83
Metha V et al J Child Neuro 2007; 22:1191
IV Levetiracetam
FDA approved adults over 16 yrs since 2006 Limited data in children (most retrospective
case reviews – n=10 and n=32) Loaded with 25-50mg/kg at level 3 Effective Safe Larger comparison studies needed
Kirmani et al Ped Neurol 2009Abend et al Pediatr Crit Care Med 2009
Gamez-Leyva et al CND Drugs 2009
Mx of status epilepticus in SA Most centres policy of repeated IV PB boluses
Resulted (anecdotally) dramatic reduction in admissions to PICU and complications of status epilepticus
IV Pb: WHO / IMCI guidelines first line for neonates; 2nd line for infants / children in Mx status
Why is IV phenobarbitone so good for resource poor countries? Highly effective at controlling status Safe Cheap It can be given by rapid IV bolus It can be repeated It can be given by IM route No need for syringe driver
If control not attained at 1 hour time to arrange transfer to tertiary unit – exceptional situation
Crawford et al; Neurol 1988; Wilmshurst & Newton; DMCN 2005
Lee et al;Pediatr Neurol 2005
Overall
Still do not have the ideal solution Still do not know what this is Need effective, rapidly acting, easy to
administer, cheap agent ..
Watch this space! Prospective comparison study underway
relevant for RLC
Final recommendations
2 targets Rapid identification of the underlying aetiology
Affects treatment Affects prognosis
Early initiation towards terminating SE Decreases morbidity and mortality
Recommend Level 1 – benzodiazepines Level 2 – phenytoin, phenobarbitone, sodium
valproate Level 3 – “other medications” e.g. levetiracetam and
pharmacologic coma induction Abend and Marsh. Curr Treat Options Neurol 2009