Duration of Therapeutic Coma and Outcome of Refractory Status Epilepticus. Wolfgang Muhlhofer, M.D. Assistant Professor at UAB Epilepsy Center

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1 Duration of Therapeutic Coma and Outcome of Refractory Status Epilepticus Wolfgang Muhlhofer, M.D. Assistant Professor at UAB Epilepsy Center

2 Status Epilepticus Escalation of Treatment 5 to 10 min 10 to 60 min 1 to 6 hours > 6 hours First Response: Generalized tonic clonic seizure >5min or seizure cluster without regaining consciousness 1 à First Aid and 911 EMS: Stabilization and 1 st Line Treatment (Tx) for SE: benzodiazepines (e.g. Lorazepam or Midazolam) 1 à Transport to ER ER: Evaluation for acutely reversible causes and 2 nd Line Tx for SE: IV anticonvulsants (e.g. Fosphenytoin, Valproate, Levetiracetam etc.) 1 ICU: Intubation, EEGmonitoring and Tx for subacute/chronic causes and 3 rd Line Tx for SE: IV anesthetics (e.g. Propfol, Midazolam etc.) 1 Potentially Irreversible Brain Damage 2 Refractory Status Epilepticus (RSE) 2 1 Brophy et al 2012 and Meierkord et al 2010 and Glauser et al 2016; 2 Trinka et al 2015

3 Refractory Status Epilepticus (RSE) Epidemiology Status Epilepticus (SE) 2 nd most common neurologic emergency with estimated incidence in the US of 102,000 to 152,000 cases per year and its incidence is on the rise 1, 2 31 to 44% of SE cases progress to RSE 3 RSE is associated with an in-hospital mortality of 23 to 61% (versus 9 to 21% non-rse); prolonged hospitalization/icu stays; moderate to severe disability (mrs 3) in >50% and post-se epilepsy in 37 to 88% of the cases 4 1 Sutter et al 2016; 2 Dham et al Brophy et al 2012; Delja et al 2016; 4 Jayalakshmi et al 2016

4 Current Treatment Guidelines for RSE Neurocritical Care Society Status Epilepticus Committee 2012 The intensity of treatment is usually dictated by ceeg findings, with the goal of treatment being cessation of electrographic seizures or burst suppression. [ ] The optimal duration of maintaining electrographic seizure control in patients with RSE is not known since there are few data to indicate what duration of treatment is needed to maintain control. Customarily, electrographic seizure control is maintained for h, followed by gradual withdrawal of the continuous infusion AED. 1 European Federation of Neurologic Societies (EFNS) 2010 Depending on the anaesthetic used in the individual in-house protocol, we recommend titration against an EEG burst suppression pattern with propofol and barbiturates. If midazolam is given, seizure suppression is recommended. This goal should be maintained for at least 24 h. 2 American Epilepsy Society (AES) 2016 There is no clear evidence to guide therapy in the 3 rd phase (40 to 60 min into SE). 3 1 Brophy et al 2012; 2 Meierkord et al 2010; 3 Glauser et al 2016

5 Therapeutic Coma for RSE Dose of Anesthetic (variable unit) EEG Therapeutic Coma (TC) Duration of Sedation in hours (h)

6 Studies on Treatment of RSE Mainly class 2a or class 2b focused on comparing the efficacy of different anesthetic agents and depth of coma on seizure control and functional outcomes 1-6 Conclusion: regardless of the anesthetic used, suppression of the EEG-background (i.e. burst- or complete suppression) and early treatment initiation provides the best chances for immediate and sustained seizure control 1-6 Duration of therapeutic coma in these studies vary from 24 to 96 hours; only one study showed that duration for >20 hrs was associated with poor functional outcomes and death 7 None of these studies looked at seizure control in relation to duration of therapeutic coma 1 Brophy et al 2012; 2 Claassen et al 2002; 3 Krishnamurthy et al 1999; 4 Prasad et al 2001; 5 Bellante et al 2016; 6 Rossetti et al 2011; 7 Power et al 2016

7 Therapeutic Coma Related to Poor Outcomes? Multiple, retrospective studies showed that patients with therapeutic coma had: - prolonged hospitalizations - 4-fold increased risk for infections fold increased risk for new disabilities upon discharge, and - 3 to 12-fold increased risk of death compared to RSE patients treated without anesthetics 1-3 More recent, multi-centered study: therapeutic coma associated with higher chance of intubation, prolonged hospitalization and ICU stays but not with increased mortality 4 1 Marchi et al 2016; 2 Kowalski et al 2012; 3 Sutter et al 2014; 4 Alvarez et al 2016

8 Therapeutic coma is an effective treatment for RSE but bears significant risks for inhospital mortality and morbidity Importance to optimize therapeutic coma in order to maximize benefits and minimize treatment-exposure related risks

9 Study Design, Predictor and Primary Outcome Study Design: retrospective, observational cohort-study Subjects: adult patients (> 18 years) admitted to the UCSF and UAB Medical Center from 1/2009 to 12/2016 for RSE; all forms of SE (excluding post-anoxic SE) refractory to 1 st and 2 nd line treatment requiring intubation/sedation with either a mono- or combination therapy of propofol, midazolam or pentobarbital Predictor: duration of therapeutic coma with duration of maximum steady dose of anesthetic as surrogate Primary Outcome: seizure recurrence (either clinical or electrographic on EEG) within the first 48 hours of lightening of sedation

10 Secondary Outcomes In-hospital Complications: - Urinary tract infection - Hospital acquired/ventilator associated pneumonia - Deep vein thrombosis/pulmonary embolism - Stroke (hemorrhagic or ischemic) - Myocardial infarction (STEMI or NSTEMI) - Sepsis from any source - Critical illness myopathy/neuropathy Functional Neurologic Outcome: - discharge home without any permanent neurologic deficit - discharge with disability and/or need for out- or inpatient rehab or need for long-term care Duration of ventilation, length of stay in ICU and hospital Mortality (death or discharge to hospice/comfort care)

11 Search for Study Cohort at UAB and UCSF UAB I2b2 Search: ICD-9/10 Codes for SE Exposure to commonly used anesthetics CPT Codes for longterm EEG monitoring (>1h) à List with individual ID numbers that were matched to MRN, DOB and name: 230 patients UAB Search assisted by IT department at CCTS: Anesthetics Long-term EEG notes Inpatient locations (ICUs and neurology floors) à List with MRN, DOB, FIN, DOA and DOD: 101 patients UCSF Search ICD-9 Codes for SE only: 384 distinct encounters

12 Study Cohort Screening Results 66 post-anoxic SE 63 SE patients with incomplete dataset 715 distinct hospital and emergency department encounters 619 distinct patients with admission/discharge diagnosis of SE 182 distinct patients with RSE included in analysis (29.4% of all SE patients) 30 multiple admission of the same patient 374 SE patients controlled with either 1 st /2 nd line Tx

13 Demographics and Comorbidities (Bivariate Analysis)

14 Clinical Presentation and Details of Treatment (Bivariate Analysis)

15 Seizure Recurrence (Multivariate Analysis)

16 In-hospital Complication (Multivariate Analysis)

17 Functional Outcomes (Multivariate Analysis)

18 Duration of Therapeutic Coma ROC Curve/Youden Index Sensitivity (0.232, 0.477) Sensitivity (0.288, 0.567) 0.2 AUC: (0.515, 0.716) 0.2 AUC: (0.556, 0.721) Specificity 1-Specificity Sustained Seizure Control (Seizure Recurrence) Cut-Off: 35 hours Sens: 48%; Spec: 77%; PPV: 40%; NPV: 82% Morbidity (In-Hospital Complications) Cut-Off: 20 hours Sens: 57%; Spec: 71%; PPV: 74%; NPV: 54%

19 Duration of Therapeutic Coma ROC Curve/Youden Index (0.564, 0.717) 0.8 (0.474, 0.679) Sensitivity Sensitivity AUC: (0.497, 0.687) 0.2 AUC: (0.449, 0.67) Specificity Functional Neurologic Outcome (Independent vs. Dependent Survivor) Cut-Off: 10 hours Sens: 71%; Spec: 43%; PPV: 40%; NPV: 74% Specificity Mortality (Survivor vs. Death/Hospice/Comfort Care) Cut-Off: 17 hours Sens: 68%; Spec: 53%; PPV: 21%; NPV: 90%

20 Defining a Window for Therapeutic Coma 10 h 17 h 20 h 24 h 35 h 48 h Uncomplicated Hospitalization Survival Good Functional Outcome Sustained Seizure Control Seizure Recurrence In-Hospital Complications Death Poor Functional Outcome Current Recommendation Optimal Therapeutic Window for this Cohort

21 Conclusions Therapeutic coma is an effective but risky treatment for RSE Duration of therapeutic coma is not an independent risk factor for seizure recurrence, mortality, poor functional outcome or inhospital complication Seizure Recurrence is an independent predictor for poor functional outcome à prompt and sustained seizure control is important Higher doses of anesthetic (i.e. deeper therapeutic coma) decreases the risk for in-hospital complications à more aggressive treatment to begin with? The most effective and safest window for duration of therapeutic coma in this cohort lies between 10 to 35 hours, which is shifted towards shorter treatment duration than currently recommended (24 to 48 hours) à current recs longer than necessary?

22 Study Limitations Retrospective study à only association and not causation; potential extraction bias Patients intubated and started on treatment prior to transfer to UCSF/UAB à underestimation of treatment duration Patients intubated for airway protection could have already achieved complete seizure control prior to start of therapeutic coma Duration of burst-suppression or suppression of ictal pattern was not confirmed by review of the actual EEG tracings ICD-9 code search primarily captured GCSE and might have led to a relative underrepresentation of NCSE patients

23 Future Perspectives A randomized, controlled trial with higher patient numbers and an exact documentation of treatment duration should be obtained in the future to identify an optimal duration of therapeutic coma for treatment of RSE. Clinical scoring system that predicts risk of seizure recurrence might help to guide treatment with nonsedating ASDs and the duration of therapeutic coma.

24 Acknowledgements Daniel Lowenstein, MD (mentor at UCSF) Jerzy Szaflarski, MD, PhD (mentor at UAB) Stephen Layfield (research assistant at UAB) Chee Paul Lin, MS (statistician at UAB CCTS) Robert Dale Johnson, MS (system analyst/informatics architect at UAB CCTS) Shalini Saini, MS (system analyst at DOM IT)

25 Questions?

26 REFERENCES 1. Brophy GM, Bell R, Claassen J, Alldredge B, Bleck TP, Glauser T, Laroche SM, Riviello JJ Jr, Shutter L, Sperling MR, Treiman DM, Vespa PM; Neurocritical Care Society Status Epilepticus Guideline Writing Committee. Guidelines for the evaluation and management of status epilepticus. Neurocrit Care Aug;17(1): Claassen J, Hirsch LJ, Emerson RG, Mayer SA. Treatment of refractory status epilepticus with pentobarbital, propofol, or midazolam: a systematic review. Epilepsia 2002;43: Dham BS, Hunter K, Rincon F; The Epidemiology of Status Epilepticus in the United States; Neurocrit Care (2014) 20: Krishnamurthy KB, Drislane FW. Depth of EEG suppression and outcome in barbiturate anesthetic treatment for refractory status epilepticus. Epilepsia 1999;40: Prasad A, Worrall BB, Bertram EH, Bleck TP. Propofol and midazolam in the treatment of refractory status epilepticus. Epilepsia 2001;42: Bellante F, Legros B, Depondt C, Créteur J, Taccone FS, Gaspard N. Midazolam and thiopental for the treatment of refractory status epilepticus: a retrospective comparison of efficacy and safety. J Neurol Apr;263(4): Rossetti AO, Milligan TA, Vulliémoz S, Michaelides C, Bertschi M, Lee JW. A randomized trial for the treatment of refractory status epilepticus. Neurocrit Care Feb;14(1): Power KN, Gramstad A, Gilhus NE, Engelsen BA. Prognostic factors of status epilepticus in adults. Epileptic Disord Sep 1;18(3): Parviainen I, Uusaro A, Kälviäinen R, Mervaala E, Ruokonen E. Propofol in the treatment of refractory status epilepticus. Intensive Care Med Jul;32(7): Marchi NA, Novy J, Faouzi M, Stähli C, Burnand B, Rossetti AO. Status epilepticus: impact of therapeutic coma on outcome. Crit Care Med May;43(5): Kowalski RG, Ziai WC, Rees RN, Werner JK Jr, Kim G, Goodwin H, Geocadin RG. Third-line antiepileptic therapy and outcome in status epilepticus: the impact of vasopressor use and prolonged mechanical ventilation. Crit Care Med Sep;40(9): Alvarez V, Lee JW, Westover MB, Drislane FW, Novy J, Faouzi M, Marchi NA, Dworetzky BA, Rossetti AO. Therapeutic coma for status epilepticus: Differing practices in a prospective multicenter study. Neurology Oct 18;87(16): Sutter R, Marsch S, Fuhr P, Kaplan PW, Rüegg S. Anesthetic drugs in status epilepticus: risk or rescue? A 6-year cohort study. Neurology Feb 25;82(8):

27 REFERENCES cont. 14. Eugen Trinka, Hannah Cock, Dale Hesdorffer, Andrea O. Rossetti, Ingrid E. Scheffer, Shlomo Shinnar, Simon Shorvon, and Daniel H. Lowenstein - A definition and classification of status epilepticus Report of the ILAE Task Force on Classification of Status Epilepticus Epilepsia, 56(10): , Delaj L, Novy J, Ryvlin P, Marchi NA, Rossetti AO. Refractory and super-refractory status epilepticus in adults: a 9-year cohort study. - Acta Neurol Scand Apr Jayalakshmi S, Vooturi S, Sahu S, Yada PK, Mohandas S. - Causes and outcomes of new onset status epilepticus and predictors of refractoriness to therapy. - J Clin Neurosci Apr;26: Claassen J, Hirsch LJ, Mayer SA. - Treatment of status epilepticus: a survey of neurologists. - J Neurol Sci Jul 15;211(1-2): Ferlisi M, Hocker S, Grade M, Trinka E, Shorvon S; International Steering Committee of the StEp Audit. - Preliminary results of the global audit of treatment of refractory status epilepticus. Epilepsy Behav Aug;49: Rossetti AO, Alvarez V, Januel JM, Burnand B. - Treatment deviating from guidelines does not influence status epilepticus prognosis. - J Neurol Feb;260(2): Meierkord H, Boon P, Engelsen B, Göcke K, Shorvon S, Tinuper P, Holtkamp M; European Federation of Neurological Societies. - EFNS guideline on the management of status epilepticus in adults. - Eur J Neurol Mar;17(3): Glauser T, Shinnar S, Gloss D, Alldredge B, Arya R, Bainbridge J, Bare M, Bleck T, Dodson WE, Garrity L, Jagoda A, Lowenstein D, Pellock J, Riviello J, Sloan E, Treiman DM. Evidence-Based Guideline: Treatment of Convulsive Status Epilepticus in Children and Adults: Report of the Guideline Committee of the American Epilepsy Society. Epilepsy Curr Jan-Feb;16(1): Porhomayon J, Joude P, Adlparvar G, El-Solh AA, Nader ND. The Impact of High Versus Low Sedation Dosing Strategy on Cognitive Dysfunction in Survivors of Intensive Care Units: A Systematic Review and Meta-Analysis. J Cardiovasc Thorac Res. 2015;7(2): Soehle M, Dittmann A, Ellerkmann RK, Baumgarten G, Putensen C, Guenther U Intraoperative burst suppression is associated with postoperative delirium following cardiac surgery: a prospective, observational study. BMC Anesthesiol Apr 28;15: Fritz BA, Kalarickal PL, Maybrier HR, Muench MR, Dearth D, Chen Y, Escallier KE, Ben Abdallah A, Lin N, Avidan MS. Intraoperative Electroencephalogram Suppression Predicts Postoperative Delirium. - Anesth Analg Jan;122(1):