REFRACTORY STATUS EPILEPTICUS

USE OF ANAESTHETIC AGENTSR MAHARAJ

LECTURE OUTLINE

• CURRENT CONCEPTS ON DEFINITION AND MANAGEMENT

• DEFINITIONS

• ANEASTHETIC AGENTS USED

• THE IDEAL ANAESTHETIC AGENT

• SUMMARY

CURRENT THINKING??

• More aggressive and early treatment of seizures

• Hence change in definition of status epilepticus…

• Generalized convulsive status epilepticus in adults and older children (greater than 5years old) refers to greater than 5 minutes of a continuous seizure, or two or more discrete seizures between which there is incomplete recovery of consciousness. (Lowenstein et al, EPILEPSIA, 1999)

REFRACTORY STATUS EPILEPTICUS

• DEFINED AS:• SEIZURES NOT RESPONDING TO 1ST LINE (BENZODIAZAPINES) OR 2ND LINE ( PHENYTOIN/ VALPROATES/

PHENOBARBITONE) AGENTS.

• Occurs in ~ 20% patients in status epilepticus

• Mortality rate > 20%

CONVULSIVE VS NONCONVULSIVE STATUS EPILEPTICUS

• Based on clinical and electrical(EEG) changes.

• CONVULSIVE – characterised by prolonged tonic clonic muscle contractions, associated loss of consciousness.

• Prolonged convulsive status epilepticus can degenerate into a non convulsive state look for subtle mouth twitching, eye movements etc.

• NON CONVULSIVE – absence of overt muscle activity

• has continuous or near-continuous generalized electrical seizure activity for at least 30 minutes without physical convulsions.

• Diagnosis can be difficult - physical signs: agitation or confusion, nystagmus, or bizarre behaviors such as lip smacking or picking at items in the air.

• NB!! DO NOT LABEL ALL STRANGE BEHAVIOUR AS PSYCHIATRIC.

• NCSE is categorized into absence or complex partial SE based on EEG criteria

• Absence SE - benign form of SE that does not cause serious brain damage.

• Complex partial SE is associated with neuronal injury and high morbidity and mortality ~ 3 times higher.

• aggressive treatment advocated

THE FINER POINTS OF ANAESTHETIC INFUSIONS USED IN REFRACTORY STATUS

EPILEPTICUS

AGENTS USED…

• MIDAZOLAM

• THIOPENTONE

• PROPOFOL

• KETAMINE

• INHALATIONAL AGENTS

• MAGNESIUM

• LIGNOCAINE

MIDAZOLAM

• a short-acting benzodiazepine

• loading dose of 0.2 mg/kg

• maintained at a continuous infusion of 0.05 to 2.0 mg/kg per hour

• Induction is rapid and effective. • metabolized via hepatic mechanisms - may require dose adjustment.

• Hypotension less frequently ,lesser degree VS propofol or the barbiturates.

• usually regain consciousness within an hour of drug withdrawal

• may be prolonged with longer duration of treatment.

• main limitation- rapid development of tachyphylaxis - often requires the persistent escalation of dosing.

THIOPENTONE

• BOLUS - 75- to 125-mg IV boluses.

• INFUSION- 1 and 5mg/kg per hour.

• redistribute rapidly to body fat, hence rapid brain penetration

• prolonged elimination.

• Barbiturates are immunosuppressive -> increase in nosocomial infections. - some investigators tend to prescribe barbiturates only after midazolam

and propofol fail.

• MAJOR S/E: hypotension –requires close BP monitoring

PROPOFOL

PROPOFOL…

• short-acting non barbiturate hypnotic

• GABA A agonist similar to the benzodiazepines and barbiturates.

• loading dose of 3 to 5mg/kg

• infusion: 1 to 15mg/kg per hour.

• advantage VS Midazolam/Thiopentone - rapid induction and elimination.

• avoided in children - severe metabolic acidosis.

• seizures have been associated with both the induction and withdrawal of propofol.

? Clinical importance

• should be reduced slowly under continuous EEG monitoring.

• side effects: hypotension, due to fat emulsion – feeding regimes need to be adjusted in prolonged infusions

PROPOFOL INFUSION SYNDROME

• TRIAD - of profound hypotension, lipidemia, and metabolic acidosis

• MECHANISM:

KETAMINE

• effective in controlling recalcitrant seizures in some animal models

• used recently with some clinical success.

• neuroprotective - simultaneously controls seizures and blocks glycine-activated NMDA receptors. Sheth RD, Gidal BE. Refractory status epilepticus: response to ketamine. Neurology. 1998;51:1765-1766.

Fujikawa DG. Neuroprotective effect of ketamine administered after status epilepticus onset. Epilepsia. 1995;36:186-195.

• Caution in raised intracranial pressure.

INHALATIONAL AGENTS

• an alternative approach to the treatment of RSE.

• ADVANTAGES - rapid onset of action, ability to titrate the dose according to the effects

demonstrated on the electroencephalogram (EEG).

• isoflurane and desflurane usually used.

INHALATIONAL AGENTS …

• mechanism of action of IA - not well understood.

• the antiepileptic effects of isoflurane are likely due to potentiation of inhibitory postsynaptic GABAA receptor–mediated currents

• effects on thalamocortical pathways have also been implicated

Mirsattari SM, Sharpe MD, Young GB. Treatment of refractory status epilepticus with inhalational anesthetic agents isoflurane and desflurane. Arch Neurol 2004;61:1254-9

NEWER AGENTS

• Topiramate via nasogastric tube. Effective dosages ranged from 300 to 1,600 mg/d

• Levetiracetam (500-3000 mg/day) by nasogastric route.

• Well designed studies are needed to assess above.

WHEN IS REFRACTORY STATUS EPILEPTICUS CONTROLLED???

• EEG FEATURES:• BURST SUPPRESSION VS TOTAL EEG SUPPRESSION VS

SUPPRESSION OF EPILEPTIFORM ACTIVITY

• MOST AUTHORS ADVOCATE BURST SUPPRESSION AS ACCEPTABLE

• ALTHOUGH NO STUDIES TO PROVE THAT THIS GIVES MOST FAVOURABLE PATIENT OUTCOMES.

MONITORING IN REFRACTORY STATUS EPILEPTICUS

• depth and duration of anesthesia that should be used to treat SE are unknown.

• titration to a burst-suppression pattern on the EEG

• maintained for 12 to 48 hours

• slowly weaned while the patient is observed and the EEG is monitored for seizures.

• If seizures recur, the process is repeated at progressively longer intervals.

WHAT IS THE “HOLY GRAIL” FOR TREATMENT OF REFRACTORY STATUS EPILEPTICUS??

• NO CLEAR CONSENSUS

WHAT IS THE “HOLY GRAIL” FOR TREATMENT OF REFRACTORY STATUS…

• EFNS guidelines 2006 - No large randomised control trials comparing different agents.

• Claassen J, Hirsch LJ, Emerson RG, Mayer SA. Treatment of refractory status epilepticus with pentobarbital, propofol, or midazolam: a systematic review. Epilepsia 2002; 43: 146–153

Pentobarbital was more effective than either propofol or midazolam in preventing breakthrough seizures (12 vs. 42%).

• Propofol and Midazolam in the Treatment of Refractory Status Epilepticus Prasad A, Worrall BB, Bertram EH, Bleck TP, Epilepsia 2001;42:380–386

Retrospective review of a small sample size… both infusions have similar efficacy

• Propofol Treatment of Refractory Status Epilepticus: A Study of 31 Episodes, Rossetti AO, Reichhart MD, Schaller MD, Despland PA Bogousslavsky J, Epilepsia

2004;45:757–763[PubMed] Propofol administered with clonazepam found to be effective in

controlling refractory episodes.

ANAESTHETISING AGENT ALONE VS ANAESTHETISING AGENT PLUS CONVENTIAL ANTI-EPILEPTIC

• The management of refractory generalised convulsive and complex partial status epilepticus in three European countries: a survey among epileptologists and critical care neurologists, M Holtkamp, F Masuhr, L Harms, K M Einhäupl, H Meierkord, K Buchheim J Neurol Neurosurg Psychiatry 2003;74:1095–1099

• Most respondents- use another non-anaesthetising anticonvulsant for generalised convulsive (65%) and complex partial status epilepticus (64%).

• general anaesthetic - generalised convulsive VS in complex partial status epilepticus (35% v 16%) -if first line anticonvulsants failed to terminate the seizures.

• The non-anaesthetising drug of choice was phenobarbitone.

Time point of induction of general anaesthesia after failure of first line drugs, and preferred anaesthetic…

• All used general aneasthesia as part of their protocol

• In generalised CSE, half the respondents proceeded to general anaesthesia within 30 minutes of the onset of the condition.

• 61% withheld general anaesthesia complex partial status

epilepticus for more than one hour after seizure onset • 21% would wait > 1 hr in patients with generalised seizures.

• preferred first choice agents- barbiturates (58%), predominantly thiopentone.

• 29% used propofol. • Followed by IV midazolam, as the first anaesthetising

drug.

• Ketamine and isoflurane were chosen by only a few respondents

QUESTIONS/COMMENTS

TAKE HOME POINTS…

• Early administration of first line agents.

• Use of an accelerated algorithm – first and second line agents simultaneously.

• Look for reversible causes and correct.

• Prevent secondary insults.

• For refractory status – no consensus as to which drugs are superior, use local guidelines.

• Anaesthetic infusions should ideally be started in ICU with haemodynamic and EEG monitoring.

REFERENCES

• EFNS guideline on the management of status epilepticus, H. Meierkorda, P. Boonb, B. Engelsenc, K. Go¨cked, S. Shorvone, P. Tinuperf and M. Holtkamp; European Journal of Neurology 2006, 13: 445–450

• EmergencyTreatment of Status Epilepticus:Current Thinking, Dan Millikan, MD, Brian Rice, MD, Robert Silbergleit, MD*; Emerg Med Clin N Am 27 (2009) 101–113

• New Management Strategies in the Treatment of Status Epilepticus, EDWARD M. MANNO, MD; Mayo Clin Proc. 2003;78:508-518

• Treatment of Refractory Status Epilepticus With Inhalational Anesthetic Agents Isoflurane and Desflurane, Seyed M. Mirsattari, MD; Michael D. Sharpe, MD; G. Bryan Young, MD, FRCPC; Arch Neurol. 2004;61:1254-1259