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.
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
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
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
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
16.
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
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
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
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.
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
45.
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)
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.
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
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
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
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).
86.
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.
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 ?
Limitations to the ESETT include a substantial rate (approximately 50 percent) of unblinding of investigators and clinicians to permit choosing a second antiseizure medication for ongoing seizures; inadvertent enrollment of patients without status epilepticus, including patients with psychogenic nonepileptic seizures (approximately 10 percent of the study population, likely unavoidable); capping of weight-based dosing at 75 kg (such that heavier patients received a lower mg/kg dose); and absence of confirmatory EEG.
Published in 2019
The only study that has attempted to compare the relative efficacy of burst-suppression versus full EEG suppression in the treatment of refractory SE is the Claassen et al. review of 193 cases of refractory SE discussed above.
