Duration of Therapeutic Coma and Outcome of Refractory ... · • Therapeutic coma is an effective but risky treatment for RSE • Duration of therapeutic coma is not an independent

Duration of Therapeutic Coma and Outcome of Refractory Status Epilepticus

Wolfgang Muhlhofer, M.D.Assistant Professor at UAB Epilepsy Center

Status Epilepticus – Escalation of Treatment

First Response: Generalized tonic clonic seizure >5min or seizure cluster without regaining consciousness 1 àFirst Aid and 911

EMS: Stabilization and 1st

Line Treatment (Tx) for SE: benzodiazepines (e.g. Lorazepam or Midazolam) 1

à Transport to ER

ER: Evaluation for acutely reversible causes and 2nd

Line Tx for SE: IV anticonvulsants (e.g. Fosphenytoin, Valproate, Levetiracetam etc.) 1

ICU: Intubation, EEG-monitoring and Tx for subacute/chronic causes and 3rd Line Txfor SE: IV anesthetics (e.g. Propfol, Midazolam etc.) 1

5 to 10 min 10 to 60 min 1 to 6 hours > 6 hours

Refractory Status Epilepticus (RSE) 2Potentially Irreversible Brain Damage 2

1 Brophy et al 2012 and Meierkord et al 2010 and Glauser et al 2016; 2 Trinka et al 2015

Refractory Status Epilepticus (RSE) – Epidemiology

• Status Epilepticus (SE) 2nd 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 2014 3 Brophy et al 2012; Delja et al 2016; 4 Jayalakshmi et al 2016

Current Treatment Guidelines for RSENeurocritical 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 24–48 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 andbarbiturates. 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 3rd phase (40 to 60 min into SE).” 3

1 Brophy et al 2012; 2 Meierkord et al 2010; 3 Glauser et al 2016

Therapeutic Coma for RSEDo

se o

f Ane

sthe

tic (v

aria

ble

unit)

Duration of Sedation in hours (h)

Therapeutic Coma (TC)

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32

70

60

50

40

30

20

10

EEG

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 hrswas 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

Therapeutic Coma – Related to Poor Outcomes?

• Multiple, retrospective studies showed that patients with therapeutic coma had: - prolonged hospitalizations- 4-fold increased risk for infections- 5.6-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

Therapeutic coma is an effective treatment for RSE but bears significant risks for in-

hospital mortality and morbidity

Importance to optimize therapeutic coma in order to maximize benefits and minimize

treatment-exposure related risks

Study Design, Predictor and Primary OutcomeStudy 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 1st and 2nd 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

Secondary OutcomesIn-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)

Search for Study Cohort at UAB and UCSFUAB – I2b2 Search:• ICD-9/10 Codes for SE• Exposure to commonly

used anesthetics• CPT Codes for long-

term 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

Study Cohort – Screening Results

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 patient66 post-anoxic SE

374 SE patients controlled with

either 1st/2nd line Tx

63 SE patients with incomplete dataset

Demographics and Comorbidities (Bivariate Analysis)

Clinical Presentation and Details of Treatment (Bivariate Analysis)

Seizure Recurrence (Multivariate Analysis)

In-hospital Complication (Multivariate Analysis)

Functional Outcomes (Multivariate Analysis)

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%

0.0 0.2 0.4 0.6 0.8 1.00.0

0.2

0.4

0.6

0.8

1.0

ROC Curve. Criterion: Youden

1-Specificity

Sen

sitiv

ity

AUC: 0.616 (0.515, 0.716)

(0.232, 0.477)

0.0 0.2 0.4 0.6 0.8 1.0

0.0

0.2

0.4

0.6

0.8

1.0

ROC Curve. Criterion: Youden

1-Specificity

Sens

itivi

ty

AUC: 0.639 (0.556, 0.721)

(0.288, 0.567)

Duration of Therapeutic Coma – ROC Curve/Youden Index

Duration of Therapeutic Coma – ROC Curve/Youden Index

0.0 0.2 0.4 0.6 0.8 1.0

0.0

0.2

0.4

0.6

0.8

1.0

ROC Curve. Criterion: Youden

1-Specificity

Sens

itivi

ty

AUC: 0.559 (0.449, 0.67)

(0.474, 0.679)

Mortality(Survivor vs. Death/Hospice/Comfort Care)

Cut-Off: 17 hours Sens: 68%; Spec: 53%; PPV: 21%; NPV: 90%

0.0 0.2 0.4 0.6 0.8 1.00.0

0.2

0.4

0.6

0.8

1.0

ROC Curve. Criterion: Youden

1-Specificity

Sen

sitiv

ity

AUC: 0.592 (0.497, 0.687)

(0.564, 0.717)

Functional Neurologic Outcome(Independent vs. Dependent Survivor)

Cut-Off: 10 hours Sens: 71%; Spec: 43%; PPV: 40%; NPV: 74%

Defining a Window for Therapeutic Coma

10 h 17 h 20 h 35 h

Good Functional Outcome

Poor Functional Outcome

Survival Death

Sustained Seizure Control Seizure Recurrence

Uncomplicated Hospitalization In-Hospital Complications

24 h 48 h

Current Recommendation

Optimal Therapeutic Window for this Cohort

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 in-hospital 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?

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

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 non-sedating ASDs and the duration of therapeutic coma.

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)

Questions?

REFERENCES1. 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. 2012 Aug;17(1):3-23.

2. 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.

3. Dham BS, Hunter K, Rincon F; The Epidemiology of Status Epilepticus in the United States; Neurocrit Care (2014) 20:476–483.

4. Krishnamurthy KB, Drislane FW. Depth of EEG suppression and outcome in barbiturate anesthetic treatment for refractory status epilepticus. Epilepsia1999;40:759-762.

5. Prasad A, Worrall BB, Bertram EH, Bleck TP. Propofol and midazolam in the treatment of refractory status epilepticus. Epilepsia 2001;42:380-386.

6. 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. 2016 Apr;263(4):799-806.

7. Rossetti AO, Milligan TA, Vulliémoz S, Michaelides C, Bertschi M, Lee JW. A randomized trial for the treatment of refractory status epilepticus. NeurocritCare. 2011 Feb;14(1):4-10.

8. Power KN, Gramstad A, Gilhus NE, Engelsen BA. Prognostic factors of status epilepticus in adults. Epileptic Disord. 2016 Sep 1;18(3):297-304.

9. Parviainen I, Uusaro A, Kälviäinen R, Mervaala E, Ruokonen E. Propofol in the treatment of refractory status epilepticus. Intensive Care Med. 2006 Jul;32(7):1075-9. –

10. Marchi NA, Novy J, Faouzi M, Stähli C, Burnand B, Rossetti AO. Status epilepticus: impact of therapeutic coma on outcome. Crit Care Med. 2015 May;43(5):1003-9. –

11. 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. 2012 Sep;40(9):2677-84.

12. 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. 2016 Oct 18;87(16):1650-1659.

13. Sutter R, Marsch S, Fuhr P, Kaplan PW, Rüegg S. Anesthetic drugs in status epilepticus: risk or rescue? A 6-year cohort study. Neurology. 2014 Feb 25;82(8):656-64.

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):1515–1523, 2015

15. Delaj L, Novy J, Ryvlin P, Marchi NA, Rossetti AO. – Refractory and super-refractory status epilepticus in adults: a 9-year cohort study. - Acta NeurolScand. 2016 Apr 15.

16. 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. 2016 Apr;26:89-94.

17. Claassen J, Hirsch LJ, Mayer SA. - Treatment of status epilepticus: a survey of neurologists. - J Neurol Sci. 2003 Jul 15;211(1-2):37-41.

18. 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. 2015 Aug;49:318-24.

19. Rossetti AO, Alvarez V, Januel JM, Burnand B. - Treatment deviating from guidelines does not influence status epilepticus prognosis. - J Neurol. 2013 Feb;260(2):421-8.

20. 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. 2010 Mar;17(3):348-55.

21. 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. 2016 Jan-Feb;16(1):48-61.

22. 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):43-8.

23. 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. 2015 Apr 28;15:61.

24. 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. 2016 Jan;122(1):234-42.