The document discusses guidelines for the management of status epilepticus, dividing treatment into phases from 0-5 minutes for stabilization, 5-20 minutes for initial benzodiazepine therapy, 20-40 minutes for a second line anti-seizure medication like fosphenytoin, valproic acid, or levetiracetam, and 40-60 minutes for third line therapy if needed. Rapid treatment and identification of any underlying causes is important to prevent complications and mortality from ongoing seizures.

1. MANAGEMENT OF STATUS EPILEPTICUS
Presenter : Dr. Vamsi Krishna Koneru
DM Neurology (CMC Vellore)
PDF Epilepsy (JIPMER)

2. Definition of Status Epilepticus
Modified with permission from Trinka E, et al, Epilepsia.1 © 2015 International League Against Epilepsy

3. Etiology of SE

4. Pathophysiology of SE – in a nutshell
• GABA A receptor internalisation
• NMDA receptor increased expression
• AMPA receptors lose their GLUA 2 subunit
• Potassium-chloride transporter KCC2 phosphorylation and its consequent
internalisation
• Presynaptic adenosine A1 receptor is decreased
• Presynaptic GABA(B) receptor expression is decreased
• Increase in Substance P
• Decrease in Neuro-peptide Y
• Decrease in other inhibitory Neuro-peptides like Galanin, Dynorphin, Somatostatin

5. Classification of SE

6. Introduction
• Management of status epilepticus requires parallel work on different domains
• Standardized information transfer from EMS to the emergency department team
• Acute stabilization and monitoring of vital signs
• Rapid identification of etiologies with independently essential acute treatment
• Start of status epilepticus treatment

7. American Epilepsy Society Convulsive Status Epilepticus management guidelines

8. 0 to 5 minutes : Stabilisation Phase

9. 0 to 5 minutes : Stabilisation Phase
• Maintain patent airway during all stages of management of SE.
• Clear the oral secretions (mouth, followed by nose)
• Keeping in recovery position is advisable to prevent aspiration
• Immobilize cervical spine IF trauma is suspected
• Oral airway : prevent tongue from falling back
• Consider endotracheal intubation if airway is not maintainable with above
measures

10. 0 to 5 minutes : Stabilisation Phase
• All Pt’s with SE should :
• Have their breathing and spo2 monitored continuously.
• Be given supplemental oxygen
• Depending on the degree of altered sensorium and duration of SE maintain
oxygen saturation by:
• Supplemental oxygen,
• AMBU bag,
• Non-invasive continuous positive airway pressure (CPAP) and
• Invasive ventilation by endotracheal intubation.

11. 0 to 5 minutes : Stabilisation Phase
• Hypoxemia may result from :
• Respiratory depression
• Apnea
• Aspiration
• Airway obstruction and
• Neurogenic pulmonary edema
Wijdicks E. Neurologic catastrophies in the emergency department. Boston: Butterworth-Heinemann

12. American Epilepsy Society Convulsive Status Epilepticus
management guidelines

14. • “All children with ongoing seizures should be given supplemental
oxygen to ameliorate cerebral hypoxia, as it has been seen that
the degree of hypoxia is often underestimated”

15. • Other guidelines advocating oxygen supplementation during status epilepticus:
• U.K’s NICE guidelines
• AAN-in it’s Continuum publication
• PALS algorithm

17. 0 to 5 minutes : Stabilisation Phase
• Place continuous cardiorespiratory monitors and pulse oximetry
• Establish IV or IO access at least two lines
• Draw samples for the following laboratory studies :
• Serum electrolytes, including Ca, Mg
• Glucose,
• LFTs,
• CBC,
• Toxicology and
• ASM levels

18. 0 to 5 minutes : Stabilisation Phase
• Check finger stick blood glucose. If glucose < 60 mg/dl then
• Adults: 100 mg Thiamine IV then 50 ml D50W IV
• Children > 2 years: 2 ml/kg D25W IV
• Children < 2 years: 4 ml/kg D12.5W IV

19. 0 to 5 minutes : Stabilisation Phase
Properly managed stabilisation phase will :
• Prevent Respiratory failure
• Major complication
• 80% of patients with generalized SE
• Independent predictor of death
• Identify and treat potential underlying causes
• Hypoglycemia
• Metabolic abnormalites
• Fever/infection

20. 0 to 5 minutes : Stabilisation Phase

21. 5-20 minutes: Initial Therapy Phase

22. 5-20 minutes: Initial Therapy Phase
• Pathophysiology :

23. 5-20 minutes: Initial Therapy Phase
• Nine RCTs addressed the efficacy of initial therapy
• Three class I
• One class II and
• Five class III
• The following are the class I trials :
• 1998 - Veteran’s Affairs status epilepticus study
• 2001 - Comparison of Lorazepam, Diazepam, and Placebo for the Treatment of Out-of-Hospital
Status Epilepticus [NEJM]
• 2012 - RAMPART trial

25. 1998 - Veteran’s Affairs status epilepticus study

26. • Randomized, double-blind trial
• To evaluate IV benzodiazepines administered by paramedics for the
treatment of out-of-hospital status epilepticus
• Intravenous diazepam (5 mg), lorazepam (2 mg), or placebo
• An identical second injection was given if needed

27. • Status epilepticus had been terminated on arrival at E.D in :
• 59.1 percent in Lorazepam group
• 42.6 percent in Diazepam group
• 21.1 percent in Placebo group
• (P=0.001)
• Out-of-hospital complication (hypotension, cardiac dysrhythmia, or respiratory
intervention) occurred in :
• 10.6 percent in Lorazepam group
• 10.3 percent in Diazepam group
• 22.5 percent in Placebo group

28. • RAMPART (Rapid Anti-convulsant Medication Prior To Arrival) trial (NEJM
2012)
• Double-blind, randomized, noninferiority trial
• Comparison of efficacy of IM midazolam with that of IV Lorazepam
• Children and adults in status epilepticus treated by paramedics
• Primary outcome: Absence of seizures at the time of arrival in the
emergency department without the need for rescue therapy

29. • Dosage:
• Adults and children with an estimated body weight of more than 40 kg:
• 10 mg of IM Midazolam followed by IV placebo [or] IM placebo followed
by 4 mg of IV Lorazepam.
• In children with an estimated weight of 13 to 40 kg :
• 5 mg of IM Midazolam or 2 mg of IV Lorazepam.

30. • At the time of arrival in the ED, seizures were absent without rescue
therapy in :
• 329 of 448 subjects (73.4%) in the intramuscular-midazolam group
• 282 of 445 (63.4%) in the intravenous-lorazepam group
• (absolute difference, 10 percentage points; 95% confidence interval, 4.0 to
16.1; P<0.001 for both noninferiority and superiority).

31. 5-20 minutes: Initial Therapy Phase
• Midazolam
• Water-soluble benzodiazepine
• Can be administered by different routes: IV, IM, buccal, and intranasal.
• Ideally suited for early out-of-hospital treatment by caregivers or paramedics
• Non-IV Midazolam by any route VS Diazepam by any route :
• For seizure cessation both groups are equally efficacious
• Time interval btw arrival & seizure cessation was significantly shorter in Midazolam group
• No difference in adverse effects was found between the two groups

32. • Buccal Midazolam was more effective than rectal diazepam in terminating status
epilepticus
• Out-of-hospital status epilepticus : Buccal or intranasal midazolam can be
regarded as the first-choice treatment
• First-line Non-IV treatment will NOT stop status epilepticus in around 20% to 30%
of cases
Brigo F, Nardone R, Tezzon F, Trinka E. Nonintravenous midazolam versus intravenous or rectal diazepam for
the treatment of early status epilepticus: a systematic review with meta- analysis. Epilepsy Behav 2015;49:
5-20 minutes: Initial Therapy Phase

33. Buccal Midazolam administration

34. Nasal Midazolam administration

35. 5-20 minutes: Initial Therapy Phase
• Current guidelines recommended dose for initial buccal or intranasal route :
• 0.3 mg/kg to a maximum of 10 mg
• Dose can be divided and given half in each nostril
• Absorption takes approximately 1–3 minutes
• The efficacy of the alternative routes of midazolam administration was
• 79% for the intranasal route
• 82–100% for intramuscular route

36. • Phenobarbitone :
• Enhances γ-aminobutyric acid (GABA) inhibition.
• One of the oldest drugs used to treat SE
• Efficacy has been demonstrated for both early and established SE.
• However, the unfavourable safety profile of phenobarbital restricts its use
• Respiratory depression,
• Hypotension, and
• Sedation.
• IV loading dose of phenobarbital : 10–20 mg/kg.
• The infusion rate should not exceed :
• 100 mg/min in adults and
• 2 mg/kg/min in children.
5-20 minutes: Initial Therapy Phase

37. Veteran Affairs SE Co-opearive Study Group trial
Veteran Affairs SE Coopearive Study Group trial
Phenobarbital (15 mg/kg) vs Lorazepam (0.1 mg/kg) as a first-line treatment
Lorazepam is no more efficacious than phenobarbital

38. 5-20 minutes: Initial Therapy Phase
• Should begin when the seizure duration reaches 5 minutes
• Should conclude by the 20-minute mark when response (or lack of response)
• A benzodiazepine is recommended as the initial therapy of choice, given their
demonstrated efficacy, safety, and tolerability
• Although IV phenobarbital is established as efficacious and well tolerated as
initial therapy (level A, 1 class I RCT), its slower rate of administration, positions it
as an alternative initial therapy rather than a drug of first choice.

39. 5-20 minutes: Initial Therapy Phase
• Key points to remember :
• Initial therapy should be administered as an adequate single full dose rather than
broken into multiple smaller doses.
• Initial therapies should not be given twice except for IV lorazepam and diazepam
that can be repeated at full doses once (level A, two class I, one class II RCT).
• Doses listed in the initial therapy phase are those used in class I trials.

40. 5-20 minutes: Initial Therapy Phase

42. 20-40 minutes: Second Therapy Phase

43. 20-40 minutes: Second Therapy Phase
• Second therapy phase (20-40 minutes of seizure activity) begins
when response (or lack of response) to the initial therapy becomes
apparent.
• Reasonable options include :
• Fosphenytoin,
• Valproic acid,
• Levetiracetam.

44. ESETT trial
• Established Status Epilepticus Treatment Trial (ESETT) trial
• 384 pediatric and adult patients with convulsive status epilepticus
• Refractory to Benzodiazepines
• Compared Fos-Phenytoin, Valproic acid and Levetiracetam
• Found that all 3 are equally effective and have similar rates of adverse effects
• High-quality evidence
• Choose one among them according to patient baseline characteristics

46. FOSPHENYTOIN
• Fosphenytoin :
• Pro-drug of Phenytoin
• Hydrolyzed to phenytoin by serum phosphatases.
• highly water soluble - unlikely to precipitate during IV administration.
• Risk of local irritation at the site of infusion is significantly less compared to phenytoin
• Infused much more rapidly (up to 150 mg PE/min vs 50 mg/min with phenytoin).
• IM administration possible if IV access cannot be obtained due to it’s water solubility

47. FOSPHENYTOIN
• Fosphenytoin :
• It is the preferred formulation of phenytoin for rapid intravenous dosing.
• The loading dose is 20 mg PE/kg (Max 1500 PE/dose)
• Infused at a rate of 100 to 150 mg PE/minute.
• Cardiac monitoring is required during the infusion of Fosphenytoin or Phenytoin
• Cardiac monitoring should be continued for at least 15 minutes after the end of a
Fosphenytoin infusion,
(while it continues to be dephosphorylated into phenytoin)

48. Fosphenytoin
• For conversion : 15 mg Fosphenytoin = 10mg Phenytoin

49. PHENYTOIN
• Phenytoin is generally started with a loading dose of 20 mg/kg (max 1500mg)
• Infused at a rate of up to 50 mg/minute
• Modify the infusion rate if hypotension or adverse cardiovascular events occur.
• Risk increase with higher infusion rates, due to the propylene glycol
(used to solubilize phenytoin)
• Local pain and injury (including venous thrombosis and the rare purple glove syndrome)
increase with more rapid infusions.
• Risk of cardiac arrhythmias – Hence cardiac monitoring during infusion is mandatory

50. SODIUM VALPROATE
• Loading dose of 40 mg/kg (Maximum dose 3000 mg)
• Infused at a rate of 10 mg/kg per minute in adults
• Full dose can be given in four minutes, with no significant risk of acute adverse effects
• Loading doses in this range yield :
• concentrations in therapeutic ranges without significant sedation

51. SODIUM VALPROATE
• Preferred over phenytoin in patients with primary generalized epilepsies
• Particularly useful in patients with focal or myoclonic status epilepticus (MSE)
• Patients who are on enzyme-inducing ASM’s may need higher maintenance doses or
shorter intervals between doses
• Free phenytoin level often rises markedly with concurrent administration, as both
agents are highly protein-bound

52. Sodium Valproate
• Risk of hepatic toxicity and hyperammonemic encephalopathy
• Particularly in children with Mitochondrial disorders & some Aminoacidopathies
• Risks of hepatic dysfunction and coagulopathy are important considerations

53. LEVETIRACETAM
• Levetiracetam :
• Loading dose of 60 mg/kg IV in adults (maximum 4500 mg)
• Infused over 5 to 15 minutes.
• Doses are typically infused over 15 minutes.
• Retrospective data suggest that rapid intravenous infusion (over 5 minutes) of
levetiracetam in doses up to 4500 mg is safe and well-tolerated

54. LACOSAMIDE
• IV Lacosamide (200 to 400 mg IV bolus) is usually well tolerated
• May have similar efficacy compared with other agents used to treat refractory status
epilepticus
• Rare serious adverse events include second-degree and complete atrioventricular block
• ECG monitoring before and during maintenance period to look for PR prolongation.
• Comorbid heart disease and with concurrent use of other drugs that may prolong the
PR interval – Additional caution required

55. PHENOBARBITONE
• Very effective antiseizure medication,
• Especially in the acute management of seizures,
• High doses of phenobarbital will control almost any seizure
• But at the cost of substantial sedation and potential reduction of blood pressure and
respiration

56. PHENOBARBITONE
• Initial doses of 20 mg/kg infused at a rate of 30 to 50 mg/minute are generally used
• Slower infusion rates should be used in older adult patients
• Careful monitoring of respiratory and cardiac status is mandatory.
• Intubation is often necessary.
• The risk of prolonged sedation with phenobarbital is greater
• Half-life of 87 to 100 hours.

57. Commonly used ASM: Advantages and Disadvantages

58. 20-40 minutes: Second Therapy Phase

59. Treatment failure causes
• Inadequate drug treatment
• Failure to initiate or continue maintenance antiepileptic drug
therapy
• Medical factors can exacerbate seizures
• Failure to treat (or identify) the underlying cause
• Misdiagnosis : pseudo-status epilepticus.

60. • Wilson Disease patients , INH toxicity : Pyridoxine supplementation
• Porphyrias : Use non enzyme inducing ASMs like LEV.
• Coexisting liver disease : Avoid VPA. LEV is best
• Coexisting kidney disease : LEV is best avoided. Or titrate according
to EFR

61. 40-60 minutes: Third Therapy Phase

63. • Randomised controlled prospective study conducted on 150 patients
• To compare the efficacy of phenytoin (n=50), valproate (n=50) and levetiracetam (n=50) along with lorazepam in patients with GCSE.
• All recruited patients received IV lorazepam (0.1mg/kg) followed by one of the 3 AEDs viz. phenytoin (20 mg/kg), valproate (30
mg/kg), Levetiracetam (25 mg/kg).
• Those who remained uncontrolled with 1st AED, received other two AEDs sequentially.
• RESULTS:
• Phenytoin, valproate, and levetiracetam are safe and equally efficacious following lorazepam in GCSE.
• The choice of AEDs could be individualised based on co- morbidities.
• SE could be controlled in 92% of patients with AEDs only and anaesthetics were not required in them

64. 40-60 minutes: Third Therapy Phase

66. Shorvon et al

67. 40-60 minutes: Third Therapy Phase
Lowenstein et al , Lancet

68. Midazolam
• Mechanism of action :
• GABA agonist.
• Dose and administration :
• Bolus: 0.2 mg/kg (0.1 to 0.3mg/kg)
• Continuous infusion: 0.05 – 0.5mg/kg/hr.
• Increase infusion rate by 0.05 mg/kg every 3 hours
• Target :
• To maintain a seizure-free state (or) Burst suppression pattern (5 to 15-second inter-burst interval)
on continuous EEG monitoring
• Maintain midazolam infusion for 24 hr seizure-free period

69. Midazolam
• Side effects : Respiratory depression, hypotension, sedation.
• When used as an infusion:
• Withdrawal syndrome,
• Delirium,
• Tachyphylaxis after 72 hours,
• Respiratory and cough reflex suppression,
• Metabolites accumulation post prolonged infusion.

70. Midazolam
• Very high dose midazolam infusion :
• Non-anion gap hyperchloremic metabolic acidosis
• Resolves once the infusion of midazolam is discontinued.
• Monitoring : Blood gases with continuous infusion

71. Propofol
• NMDA antagonist
• Positively modulates the inhibitory function of the GABA
• Dose and administration :
• 1-2mg/kg bolus administered by IV infusion over approximately five minutes
• Repeated (0.5 to 2 mg/kg) until seizures stop, up to a maximum total dose of 10 mg/kg.
• Start continuous infusion at 1 mg/kg per hour and increase infusion rate (steps of 0.5 mg/kg/hr
every 10 minutes) up to 5mg/kg/hr.
• Target :
• To maintain a seizure-free state or
• Burst suppression pattern on continuous electroencephalogram monitoring

72. Propofol
• Common Side effects of Propofol :
Bradycardia,
Hypotension,
Apnoea,
Arrythmia,
Thrombosis,
Phlebitis,
Deranged liver function tests (particularly transaminases),
Pancreatitis.

73. Propofol
• Propofol Infusion Syndrome (PRIS) : Rare but dangerous adverse effect
• Lactic acidosis,
• Hyperkalaemia,
• Hyperlipidaemia,
• Cardiac dysfunction,
• Rhabdomyolysis,
• Renal failure
• Risk factors for propofol infusion syndrome include :
• Young age (Usually avoided in children)
• Carbohydrate depletion,
• Concomitant use of corticosteroids, and
• Prolonged infusion at high doses
( for longer than 48 h at dosages exceeding 5 mg/kg/h)

74. Propofol
• Monitoring :
• Creatine Kinase (CK) levels should be monitored daily in patients on Propofol.
• Liver function
• Reliable indicator for the development of PRIS :
• Rising CK levels + Acidosis + Increasing lactate levels
• If indicative of PRIS: Consider to stop or reduce the dose of propofol

75. KETAMINE
• NMDA receptor antagonist.
• Dose and administration
• Loading dose of ketamine is 0.5-2 mg/kg, followed by an infusion of 1 to 10
mg/kg per hour
• Titrated to suppression of electrographic seizures or Burst suppression pattern
for 24-48 hrs
• Contraindications
• Patients with severe coronary or myocardial disease or cerebrovascular
accident

76. KETAMINE
• Neuroprotectant against glutamate-induced widespread neuronal necrosis.
• It interacts with opioid, monoaminergic, muscarinic, and nicotinic receptor ion channels and
modulates some cytokines.
• It may reduce the neuroinflammation, which may contribute to the refractoriness of SE
• Fujikawa recommends early initiation of ketamine in Refractory SE
• Fujikawa DG. Starting ketamine for neuroprotection earlier than its current use as an anesthetic/antiepileptic drug late in refractory status epilepticus. Epilepsia.
2019; 60(5):373–380

77. KETAMINE
• Cautions
• Hepatic impairment – metabolised in the liver CYP 450, action may be prolonged in patients
with impaired liver function
• Acute intermittent porphyria
• Psychiatric illness – confusion, agitation, hallucinations – specially during weaning
• Conditions where an elevated ICP or IOP may be detrimental
• Cardiac disease – increases myocardial oxygen consumption
• Deranged liver function tests (when used for >3days)
• Rash

78. KETAMINE
• Midazolam + Ketamine combination :
• Different MOA , hence synergistic effect
• Hypotention + Hypertention
• Neuroprotective effect
• Relative ease of availability and administration

79. Thiopentone sodium
• Thiopental, its first metabolite pentobarbital :
• are the oldest compounds used in the setting of RSE
• In addition to GABAA modulation, barbiturates have an NMDA-antagonist action in vitro
• tendency to accumulate in adipose tissue.
• They have a long half-life (up to 36 h) after continuous administration
• Thiopental Dosage:
• Started with a bolus of 3–5 mg/kg,
• Then further boluses of 1–2 mg/kg every 2–3 min (until seizures are controlled )
• Then continuous infusion at a rate of 3–7 mg/kg/h

80. Thiopentone sodium
• Problematic pharmacokinetics
• Zero order kinetics
• Profound tendency to accumulate
• Auto-induction
• Drug-drug interactions
• Long recovery time
• Hypotension
• Hypothermia
• Cardio-respiratory depression
• Pancreatic and Hepatic toxicity

81. Shorvon et al

82. Points to remember during IV anesthetics treatment in RSE
• Reverse anaesthesia after 24–48h
• If seizures continue, then to re-establish anaesthesia (cycling).
• Such cycles should be repeated several times.
• If the status continues to recur, the duration of individual cycles can be increased,
and anaesthesia continued for up to 5 days at a time.
• The anaesthesia should be weaned slowly on reversal.
• Prolonged anaesthesia carries increasing iatrogenic risks
• Skilled ICU care and monitoring for complications is mandatory
Shorvon et al

83. EEG Target Pattern With IVGA
• Considerable controversy
• Some protocols aim for clinical or electrical suppression of seizure activity,
• Many treatment protocols call for titration to a burst-suppression pattern, and
• Still other protocols suggest that the EEG should be fully suppressed
(Isoelectric).
• Even when burst-suppression is the target there is little agreement as to what
constitutes an optimal burst-suppression pattern.
Burst durations of >10 s, 15–30 s, or 3–9 bursts per min.

84. • “ targeting EEG burst- suppression patterns with an inter-burst interval of about 10s for
24h,followed by progressive tapering over 6–12h under EEG control, seems to be a reasonable
option “

85. • Compared with seizure suppression without full EEG suppression (n = 59),
titration of treatment to EEG background suppression (n = 87) was associated
with :
• Lower frequency of breakthrough seizures (4 % vs 53%; p < 0.001)
• Higher frequency of hypotension (76% vs 29%; p < 0.001).

87. • Current European Guidelines recommend anaesthetic drugs titration to :
• EEG burst-suppression for propofol and thiopental sodium,
• Seizure suppression for midazolam infusion.
• It is suggested that continuous infusions be maintained for at least 24 h at
these endpoints before weaning

88. Duration of Coma Before Reducing IV Anesthetics
• Another facet in the treatment of refractory SE with strong opinions but weak data.
• Recommendations regarding the duration of the initial period of induced coma vary
from 12 to 48 h.
• Holtkamp et al. surveyed 91 'opinion leaders' specializing in critical care neurology or
epileptology in three central European countries
• 22% : reduce drug dose within the first 24 hr
• 72% : reduce dose between 24 and 48 hr and
• 5% : reduce dose between 48 and 72 h.

89. Other Non-Pharmacological Methods
• Ketogenic diet
• Neuro—modulation ( VNS, TMS, DBS, ECT)
• Immunomodulation (IVIG, Steroids, Plasma exchange)
• Magnesium infusion
• Pyridoxine infusion
• Hypothermia
• CSF drainage
• Music therapy

90. Grey areas
• Oxygen administration ?
• Whether or not to give ASM in those patients who achieved seizure control with
benzodiazepines?
• Whether or not to repeat second line therapy at the end of 40 min ?
• EEG target after initiation of IV anesthetic agents ?

91. Thank you