REFRACTORY STATUS EPILEPTICUS

1. REFRACTORY STATUS EPILEPTICUS USE OF ANAESTHETIC AGENTS R MAHARAJ

2. LECTURE OUTLINE CURRENT CONCEPTS ON DEFINITION AND MANAGEMENT DEFINITIONS ANEASTHETIC AGENTS USED THE IDEAL ANAESTHETIC AGENT SUMMARY

3. 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)

4. 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%

5. 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.

6. 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.

7. 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

8. THE FINER POINTS OF ANAESTHETIC INFUSIONS USED IN REFRACTORY STATUS EPILEPTICUS

9. AGENTS USED… MIDAZOLAM THIOPENTONE PROPOFOL KETAMINE INHALATIONAL AGENTS MAGNESIUM LIGNOCAINE

10. 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.

11. 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.

12. 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

13. PROPOFOL

14. 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.

15. 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

16. PROPOFOL INFUSION SYNDROME TRIAD - of profound hypotension, lipidemia, and metabolic acidosis MECHANISM:

17. 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.

18. 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.

19. 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

20. 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.

21. 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.

22. 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.

23. WHAT IS THE “HOLY GRAIL” FOR TREATMENT OF REFRACTORY STATUS EPILEPTICUS?? NO CLEAR CONSENSUS

24. 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%).

25. 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.

26. 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.

27. 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.

28. 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

30. QUESTIONS/COMMENTS

31. 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.

32. 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