Is It Time for a Status Update? Transitioning Treatment ... · ©2016 MFMER | slide-1 Is It Time...

$: Is It Time for a Status Update? Transitioning Treatment ... · ©2016 MFMER | slide-1 Is It Time for a Status Update? Transitioning Treatment from Status Epilepticus to Super Refractory$
©2016 MFMER | slide-1

Is It Time for a Status Update? Transitioning Treatment from Status Epilepticus to Super Refractory Status Epilepticus

David Roy, PharmD PGY1 Pharmacy Resident Pharmacy Grand Rounds May 17th, 2016


Objectives • Differentiate diagnosis of status epilepticus, refractory

status epilepticus, and super refractory status epilepticus

• Describe pathophysiology of pharmacoresistance in status epilepticus

• Discuss different treatment options as status epilepticus becomes more refractory


A Silent Epidemic • 8-19% of comatose ICU patients diagnosed with status

epilepticus (SE) on EEG do not have clinical signs of seizures

• Second most common neurological emergency with a risk of major morbidity and mortality

• Generalized Convulsive Status Epilepticus (GCSE) • Non-convulsive Status Epilepticus (NCSE)

• Negative symptoms • aphasia, catatonia, confusion, lethargy

• Positive symptoms • agitation, aggression, delirium, emesis,

psychosis

Brophy GM, et al. Neurocrit Care. 2012;17:3-23 Towne AR, et al. Neurology 2000;54:340-5

Claassen J, et al. Neurology 2004;62:1743-8

EEG: electroencephalogram


Incidence & Mortality

Hesdorffer DC, et al. Neurology. 1998;50(3):735-41 Dham BS, et al. Neurocrit Care. 2014;20(3):476-83

Kantanen, AM, et al. Epilepsy Behav. 2015;49:131-34

0

10

20

30

40

50

0

5

10

15

20

25

30

1 3 5 7 9

In-h

ospi

tal M

orta

lity

(%)

SE In

cide

nce

(per

100

,000

)

Decade of Life

Incidence In-hospital Mortality

22%

36%

0

10

20

30

40

50

RSE SRSE1-

yr M

orta

lity

(%)


Question #1 What is the minimum continual seizure duration required to diagnose GCSE?

A. 2 minutes B. 5 minutes C. 10 minutes D. 15 minutes


Classifications

Status Epilepticus (SE)

Refractory Status Epilepticus (RSE)

Super Refractory Status Epilepticus

(SRSE)

≥ 5 min of continual seizures without recovery

“Etat de mal”

“…persists for a sufficient time to produce a fixed condition”

30 min

20 min

10 min

5 min

Chen JW, et al. Lancet Neurol. 2006; 5:246-56 Brophy GM, et al. Neurocrit Care. 2012;17:3-23


Pathophysiology of SE

• Disruption in balance of excitatory and inhibitory neurotransmitters

• Excitatory: glutamate • Inhibitory: GABA

Ca2+

Na+ Cl-

GABA glutamate

GABA NMDA


0 min 5 min >24 hr

LZP: lorazepam MDL: midazolam DZP: diazepam

ABC’s LZP 0.1 mg/kg IV

Max 4 mg/dose

MDL 0.2 mg/kg IM

Max 10 mg/dose

or

DZP 0.15mg/kg IV

Max 10mg/dose

or

30 min Refractory SE Impending SE Established SE Super Refractory SE

Stage 1

Brophy GM, et al. Neurocrit Care. 2012;17:3-23 Betjemann JP, et al. Lancet Neurol 2015;14:615-24


Treiman DM, et al. – VA Coop Trial

Treiman DM, et al. NEJM 1998. 339(12):792-98

64.9%

58.2% 55.8%

43.6%

17.9%

24.2%

8.3% 7.7%

0

10

20

30

40

50

60

70

LZP PHB DZP+PHT PHT

Suc

cess

ful T

reat

men

t (%

)

Overt GCSESubtle GCSE

p = 0.002

LZP: lorazepam DZP: diazepam

PHB: phenobarbital PHT: phenytoin


Out-of-Hospital SE Control

59.1 %

42.6 %

21.1 %

0

10

20

30

40

50

60

IV LZP IV DZP Placebo

SE

term

inat

ed (%

)

Alldredge BK, et al. NEJM 2001. 345(9):631-7 Silbergleit R, et al. NEJM 2012. 366(7):591-600

73.4 %

63.4 %

0

20

40

60

80

IM MDL IV LZP

OR: 5.4 (2.3-13.2)

LZP: lorazepam DZP: diazepam

MDL: midazolam


Alternative Routes of Administration • Intranasal MDL

• Equally effective as IV DZP in terminating seizures in children

• Buccal MDL • More effective than rectal DZP in children

with convulsive febrile seizures • Rectal DZP

• FDA-approved as Diastat® - 0.2-0.5 mg/kg

Chamberlain JM, et al. JAMA 2014;311(16):1652-60 Thakker A, et al. J Neurol 2013. 260:470-74

Dreifuss FE, et al. NEJM 1998. 338:1869-75 LZP: lorazepam DZP: diazepam

MDL: midazolam


Case • 30 y/o male admitted to the ED for generalized

tonic-clonic seizures • Continues to seize for over 5 minutes despite

two 4mg doses of IV lorazepam



0 min 5 min

PHT 20mg/kg IV

fPHT 20mg/kg IV PE

or

VPA 20-30 mg/kg IV

LEV 20-60 mg/kg IV

or

or


PHT: phenytoin fPHT: fosphenytoin VPA: valproic acid

LEV: levetiracetam

30 min >24 hr Refractory SE Impending SE Established SE Super Refractory SE

Stage 2


Max 4 mg/dose

MDL 0.2 mg/kg IM

Max 10 mg/dose

or

DZP 0.15mg/kg IV

Max 10mg/dose

or

Stage 1


PHT, VPA or LEV? • Retrospective analysis (n=187)

• LEV higher risk of failure than VPA • OR 2.7, 95% CI 1.2-6.1

• No difference in PHT

• Largest prospective RCT, single-center comparison

Alvarez V, et al. Epilepsia 2011. 52:1292-96 Mundlamuri RC, et al. Epilepsy Res 2015. 114: 52-58

PHT: phenytoin VPA: valproic acid LEV: levetiracetam

AED # controlled

PHT 34/50 (68%)

VPA 34/50 (68%)

LEV 39/50 (78%)

71%

87% 92%

50

60

70

80

90

100

1 AED 2 AED 3 AED

% S

eizu

re C

ontr

ol


No Clear Favorite • Phenytoin/Fosphenytoin

• Liver disease, hypotension, QT prolongation, purple glove syndrome, drug interactions

• Valproic Acid • Liver disease, pregnancy, hyperammonemia,

pancreatitis, somnolence, drug interactions • Levetiracetam

• Psychiatric history, agitation, osteoporosis, kidney disease, headache

Hocker, SE. Continuum 2015. 21(5):1362-83




two 4mg doses of IV lorazepam • Continues to seize despite adequate load

with fosphenytoin


Can I give another AED?

Treiman DM, et al. NEJM 1998. 339(12):792-98 Hocker, SE. Continuum 2015. 21(5):1362-83

NCSE w/o coma GCSE

AED

BZD

Anesthetics

Try another AED AED


Definitions




(SRSE)


Seizure activity despite BZD and

one AED


0 min 5 min

MDL 0.2 mg/kg load 0.1-2 mg/kg/hr

PRO 1-2 mg/kg load 2-12 mg/kg/hr

or

PBT 5-15 mg/kg load 0.5-5 mg/kg/hr

or


Max 4 mg/dose

MDL 0.2 mg/kg IM Max 10 mg

or

DZP 0.15mg/kg IV

Max 10mg/dose

or

Stage 1

PHT 20mg/kg IV

fPHT 20mg/kg IV PE

or

VPA 20-30 mg/kg IV

LEV 20-60 mg/kg IV

or

or

Stage 2 Stage 3

Refractory SE Impending SE Established SE Super Refractory SE 30 min >24 hr



LEV: levetiracetam PRO: propofol PBT: pentobarbital



Midazolam or Propofol for RSE? • Retrospective chart review (n=20)

• No difference in seizure control • Propofol with APACHE II ≥ 20 had higher

mortality

Prasad A, et al. Epilepsia 2001. 42(3):380-86

Clinical Seizure Suppression (%) Overall Mortality

MDL (n=6) 4/6 (67%) 1/6 (17%)

PRO (n=14) 9/14 (64%) 8/14 (57%)

p=0.16

MDL: midazolam PRO: propofol


Pentobarbital • Prospective RCT (terminated)

• Longer ventilation days • No difference in seizure

activity compared to PRO

Claassen J, et al. Epilepsia 2002. 43(2):146-53 Rossetti AO, et al. Neurocrit Care 2011. 14:4-10

Trinka E, et al. Drugs 2015. 75:1499-1521

4

13.5

0

5

10

15

PRO (n=14) PBT (n=9)

Day

s, in

tuba

tion p=0.03

• Systematic Review of MDL vs. PRO vs. PBT • Less treatment failure (8 vs. 23%, p<0.01) • Less breakthrough seizures (12 vs. 42%, p<0.001) • More hypotension (77% vs. 34%, p<0.001)

PBT: pentobarbital MDL: midazolam PRO: propofol


Which anesthetic?

Drug Mechanism Metabolism Advantages Disadvantages

Midazolam GABA potentiator Hepatic; active

metabolites excreted renally

Short half-life Hypotension, tachyphylaxis, prolonged elimination half-

life in obesity

Propofol

GABA agonist, Na channel antagonist, NMDA inhibition, Ca channel modulator

Hepatic Short half-life Hypotension, PRIS*, hypertriglyceridemia,

pancreatitis

Pentobarbital GABA potentiator Hepatic Can be used for prolonged

periods

Hypotension, ileus, immunosuppression,

hepatotoxicity, metabolic acidosis (propylene glycol

toxicity), long half-life

• Insufficient data to support one agent over another

Iyer VN, et al. Crit Care Med 2009. 37(12):3024-30 Hocker, SE. Continuum 2015. 21(5):1362-83

*Propofol-related Infusion Syndrome




two 4mg doses of IV lorazepam • Continues to seize despite adequate load

with fosphenytoin/levetiracetam • Continues to seize despite 2mg/kg/hr IV

midazolam infusion


Definitions




(SRSE)


Seizure activity despite BZD and

one AED

Breakthrough seizures while on CI anesthetics for

24 hours


0 min 5 min Refractory SE Impending SE Established SE Super Refractory SE

30 min >24 hr



LEV: levetiracetam PRO: propofol PBT: pentobarbital



Max 4 mg/dose

MDL 0.2 mg/kg IM Max 10 mg

or

DZP 0.15mg/kg IV

Max 10mg/dose

or

Stage 1

PHT 20mg/kg IV

fPHT 20mg/kg IV PE

or

VPA 20-30 mg/kg IV

LEV 20-60 mg/kg IV

or

or

Stage 2

MDL 0.2 mg/kg load 0.1-2 mg/kg/hr

PRO 1-2 mg/kg load 2-12 mg/kg/hr

or

PBT 5-15 mg/kg load 0.5-5 mg/kg/hr

or

Stage 3 Stage 4


Pharmacoresistance of SE • Increased NMDA receptors • Decreased GABA receptors

• 50% decrease in GABA receptors after 1 hour of SE

• 20-fold decrease in BZD potency within 30 minutes of SE

Naylor DE, et al. J Neurosci 2005;25:7724-33 Kapur J, et al. J Neurosci 1997;17:7532-40

Mazarati AM, et al. Brain Res 1998;814:179-85


Ketamine • NMDA-receptor antagonist • Animal data endorses efficacy • Human data suggests safety and efficacy

• 32% RSE controlled after ketamine • 1.5-4.5 mg/kg load then 2-7.5 mg/kg/hr

• Minimum dose response: 0.9 mg/kg/hr • Earlier it was added, higher chance of control

• No increase in morbidity or mortality

Borris DJ, et al. Epilepsy Res 2000. 42:117-22

Gaspard N, et al. Epilepsia 2013. 54(8):1498-1503


Lacosamide • Enhances slow inactivation of sodium channels • 9 case-series, 10 case-reports

• No data for RSE • 136 patients; 56% success rate

• TRENdS 2013 • LCM 400 mg vs. fPHT 20 mg/kg for NCSE • Terminated in 2014 due to low enrollment

Hofler J, et al. Epilepsia 2013. 54 (3):393-404 Fountain NB, et al. Epilepsia 2013. 54 (1):58-65

Husain AM, et al. Epilepsy Behav 2015. 49:337-39 LCM: Lacosamide fPHT: Fosphenytoin


Super Refractory Status Epilepticus • Isoflurane

• Enhances GABA • Case reports show possibly effective when

combined with hypothermia • Possibly neurotoxic

• Perampanel • AMPA-receptor antagonist • Case reports suggest variable efficacy • Unknown long-term safety profile

Fugate, JE et al. Anesth Analg 2010; 111:1520-4 Husain AM, et al. Epilepsy Behav 2015. 49:337-39


Immunotherapy for SRSE • SRSE may be caused by antibodies against

neural cell receptors • IV immunoglobulins (IVIG)

• 0.4 gm/kg/day x 5 days • Methylprednisolone

• 1 gm/day x 5 days • Plasma exchange

Zeiler FA. Seizure 2015. 32:100-108


• Pyridoxine • Cofactor necessary for GABA

production • 100-300 mg IV

• Magnesium • NMDA-receptor antagonist • 2-6 gm/hr until level of 3.5 mmol/L • 50% controlled in non-eclamptic SE in

recent systemic review • Neurosurgery if lesion identified


Zeiler FA. Seizure 2015. 32:100-108

Glutamate

GABA

GAD, B6


Review • Benzodiazepines to stop initial seizure • Load with an AED to prevent future seizure • Repeat different AED if remain in NCSE with

consciousness; transition to anesthetics more quickly if in GCSE

• Choose anesthetics based on comorbidities and drug properties

• Kitchen sink


Question #2 • Which of the following underlying mechanism(s)

of SRSE makes ketamine an attractive option? A. Increased sensitivity of GABA receptors B. Increased number of GABA receptors C. Increased number of NMDA receptors D. All of the above


Question #3 • When compared to propofol and midazolam,

which of the following is a disadvantage of pentobarbital for RSE?

A. Development of tachyphylaxis B. Increased incidence of hypertriglyceridemia C. Likelihood of developing rhabdomyolysis D. Profound hypotension


Summary • Seizure duration and failure of treatments

differentiate the stages of status epilepticus • Agents used early may no longer be effective

due to development of pharmacoresistance • Increased morbidity and mortality as status

epilepticus becomes more refractory • Treat quickly; time is brain


Questions & Discussion


Is It Time for a Status Update? Transitioning Treatment from Status Epilepticus to Super Refractory Status Epilepticus

David Roy, PharmD PGY1 Pharmacy Resident Pharmacy Grand Rounds May 17th, 2016

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