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Optimizing Seizure and SE Patient Management in the Emergency Department Edward P. Sloan, MD, MPH Edward P. Sloan, MD, MPH Professor Department of Emergency Medicine University of Illinois College of Medicine Chicago, IL Edward P. Sloan, MD, MPH Attending Physician Emergency Medicine University of Illinois Hospital Our Lady of the Resurrection Hospital Chicago, IL Edward P. Sloan, MD, MPH Disclosures • NovoNordisk, King Pharmaceuticals, UCB Pharma Advisory Boards • Eisai Speakers’ Bureau • • • • ACEP Clinical Policies Committee ACEP Scientific Review Committee Executive Board, FERNE FERNE support by Abbott, Eisai, Pfizer, UCB Edward P. Sloan, MD, MPH www.ferne.org Edward P. Sloan, MD, MPH Board Chairman and President FERNE Chicago, IL Edward P. Sloan, MD, MPH Overview Mission Statement • Patients with neurological emergencies deserve quality emergency care. • Quality scientific research. • Case-oriented, evidence-based medical education on optimal acute neurological care. • Use of technology to break down space and time barriers. Edward P. Sloan, MD, MPH • Advocacy. www.ferne.org Edward P. Sloan, MD, MPH Today’s Agenda • Present a clinical case • Review seizure and SE clinical data • Discuss ED management • Provide fosphenytoin data • Consider fosphenytoin use • Examine the patient outcome • Close with a bonus case Edward P. Sloan, MD, MPH A Clinical Case Edward P. Sloan, MD, MPH Patient EMS Data • 50?? yo male John Doe • Generalized tonic-clonic seizure • Chicago Fire Department • Diazepam 5 mg IM, 15 mg IV • Seizure continuous for 15 minutes + • EMS to ED • No change in status Edward P. Sloan, MD, MPH Patient Clinical History • Unknown meds • Unknown medical history • Hx Needs surgery next month ?? • EtOH ?? • Does not appear to be homeless • Accucheck 119 Edward P. Sloan, MD, MPH ED Presentation • Facial and shoulder twitching R • Pt with gurgling BS • Nasopharyngeal airway • No evidence of trauma or toxicity • IV access in neck • Seizure persists x minutes Edward P. Sloan, MD, MPH Seizure/SE Clinical Data Edward P. Sloan, MD, MPH Sz Epidemiology: • Epilepsy seen in 1/150 people • For each epilepsy pt, 1 ED visit every 4 years • 1-2% of all ED visits • Significant costs Edward P. Sloan, MD, MPH Seizure Mechanism: • Sz = abnormal neuronal discharge with recruitment of otherwise normal neurons • Loss of GABA inhibition Edward P. Sloan, MD, MPH Seizures Seizure Classification: • Generalized: both cerebral hemispheres • Partial: one cerebral hemisphere (localized) Edward P. Sloan, MD, MPH Seizures Generalized Seizures: • Convulsive: tonic-clonic • Non-convulsive: absence Edward P. Sloan, MD, MPH Seizures Generalized Seizures: • Primary generalized: starts as tonic-clonic sz • Secondarily generalized: tonic-clonic sz develops from a non-convulsive partial sz, ie aura (common) Edward P. Sloan, MD, MPH Seizures Partial Seizures: • Simple partial: no impaired consciousness • Complex partial: impaired consciousness Edward P. Sloan, MD, MPH Seizures Specific Seizure Types: • Absence: Petit mal • Partial: Jacksonian, focal motor • Complex partial: temporal lobe, psychomotor Edward P. Sloan, MD, MPH Seizures Recurrent Seizure Risk • 51% recurrence risk • 75% of recurrent sz occur within 2 years of first sz • Only a small % of pts will seize within 24 h • Partial sz, CNS abnormality Edward P. Sloan, MD, MPH Status Epilepticus: • Sz > 5- 10 minutes • Two sz without a lucid interval (Assumes ongoing sz during coma) Edward P. Sloan, MD, MPH Status Epilepticus SE Epidemiology: • Risk of SE: greatest at age extremes (pediatric and geriatric populations) • SE: occurs in setting of new onset sz, acute insult, or chronic epilepsy • 150,000 cases per year Edward P. Sloan, MD, MPH Status Epilepticus SE Classification: • GCSE: (Generalized convulsive SE) with tonicclonic motor activity • Non-GCSE Edward P. Sloan, MD, MPH Status Epilepticus Two Non-GCSE Types: • Non-convulsive SE • Absence SE • Complex-partial SE • Subtle SE • Late generalized convulsive SE • Coma, persistent ictal discharge • Very grave prognosis Edward P. Sloan, MD, MPH Seizures/SE Systemic Effects: • Hypertension (early) • Hypotension (later) • 49% will have temp > 100.5 F° • Lactic acidosis • Hypercarbia Edward P. Sloan, MD, MPH Seizures/SE Pathophysiology: • Glutamate toxic mediator • Necrosis occurs even if systemic problems are treated (HTN, fever, rhabdomyolysis, resp acidosis, hypoxia) Edward P. Sloan, MD, MPH Seizures/SE Pathophysiology: • Early compensation for increased CNS metabolic needs • Decompensation at 40-60 minutes, associated with tissue necrosis Edward P. Sloan, MD, MPH Seizures/SE AMS in Seizures: • Mental status should improve by 20-40 minutes • If pt comatose, subtle SE is possible: EEG • Up to 20% of pts in coma are still in SE Edward P. Sloan, MD, MPH Seizures/SE Ongoing SE Effects: • Over 40-60 min, loss of metabolic compensation • With ongoing SE, systemic BP & CBF drop Edward P. Sloan, MD, MPH Status Epilepticus SE Mortality: • SE mortality > 30% when sz longer than 60 minutes • Underlying sz etiology contributes to mortality Edward P. Sloan, MD, MPH Status Epilepticus Subtle SE: • Mortality exceeds 50% • Often after hypoxic insult • Coma • Limited motor activity • Stop the sz, EEG confirm Edward P. Sloan, MD, MPH Status Epilepticus Refractory SE: • No response to first-line drugs (Benzos, phenytoins) • Significant CNS disorders • 6-9% of all SE cases • 20-30% mortality Edward P. Sloan, MD, MPH General ED Management: • ABCs • Glucose, narcan, thiamine • Rapid sequential use of AEDs • Directed evaluation Edward P. Sloan, MD, MPH ED Management Lab Evaluation: • Key lab abnormality: hypoglycemia, in up to 2% • Directed labs, including anti-epileptic drug levels Edward P. Sloan, MD, MPH ED Management Lumbar Puncture: • Fever and CSF pleocytosis can occur in SE without meningitis • Use clinical criteria to determine LP need • AMS, immunocompromise, meningismus Edward P. Sloan, MD, MPH ED Management CT Neuroimaging: • Req’d in new-onset sz • Useful with focal sz, change in sz type or frequency, comorbidity • Non-contrast unless mass lesion suspected Edward P. Sloan, MD, MPH New Onset Sz in Pregnancy • 32 year old Hispanic female • 23 weeks pregnant • G3P2 two live births, no complications • New onset seizure at 530 am in bed • Generalized tonic-clonic seizure • Brief, self-limited, no Rx required • EMS to the ED, no seizure Edward P. Sloan, MD, MPH Edward P. Sloan, MD, MPH Focal hemorrhage Edward P. Sloan, MD, MPH New Onset Sz in Pregnancy – Tertiary center diagnosis: cavernoma – Started on an anti-epileptic drug – No immediate need for operative intervention – Will follow as pregnancy progresses Edward P. Sloan, MD, MPH ED Management MRI Neuroimaging: • Useful with refractory sz • Complements plain CT • Can be done as outpatient Edward P. Sloan, MD, MPH ED Management EEG Monitoring: • Use to rule out subtle SE • Two-lead EEG in ED, within 120 minutes • In RSI, prolonged coma, propofol or pentobarbital induced coma Edward P. Sloan, MD, MPH ED Management AED loading: • Repeated seizures, high-risk population, significant SE risk • No need to determine level in ED after loading • Oral loading in low risk pts Edward P. Sloan, MD, MPH ED Management SE Rx Timeline: • 0-30 min: ABCs, benzos • 30-60 min: Phenytoins • 60-90 min: Levetiracetam, phenobarbital, valproate • 90-120 min: Midazolam, propofol CT, EEG, ICU/OR Edward P. Sloan, MD, MPH Hospital Admission: • Repeated sz, high-risk pt, significant SE risk • Esp if no AED loading • New-onset seizure: admission is preferred (complete w/u, observe) Edward P. Sloan, MD, MPH ED Discharge: • Follow-up & EEG needed, esp if no AED prescribed • Driving documentation is critical. Know state law. Edward P. Sloan, MD, MPH ED Anti-epileptic Drug (AED) Use Edward P. Sloan, MD, MPH Seizure Pharmacotherapy • • • • Benzodiazepines Phenytoins Barbiturates Other agents –levetiracetam –propofol –valproate Edward P. Sloan, MD, MPH Pharmacotherapy Clinical Setting: • Three seizure settings • Self-limited seizure, load req’d • Flurry of seizures, at-risk for SE • Status epilepticus • Provides framework for discussion Edward P. Sloan, MD, MPH Pharmacotherapy General AED Concepts: • Most drugs are at least 80% effective in Rx seizures, SE • Have AEDs available in ED • Use full mg/kg doses • Maximize infusion rates in SE Edward P. Sloan, MD, MPH Pharmacotherapy Benzodiazepines: • GABA inhibition • Diazepam: short acting, limited AMS and protection (intubation more common) • Lorazepam: prolonged AMS and protection • Pediatric sz: IV lorazepam limits respiratory compromise Edward P. Sloan, MD, MPH Pharmacotherapy Rectal Diazepam: • Diazepam rectal gel prepackaged for rapid use • Dose 0.5 mg/kg, less respiratory depression seen than with IV use Edward P. Sloan, MD, MPH Pharmacotherapy Phenytoin: • Stabilize memb Na+ channels, regulate Ca+ + channels • For generalized sz, and SE • Constant infusion over IVP • Use pump to prevent comp • Therapeutic at 10-20 µg/mL Edward P. Sloan, MD, MPH Pharmacotherapy Oral Phenytoin: • 18mg/kg oral load • 64% reach 10mg/mL levels by 8 hrs (therapeutic) • Delayed absorption due to large loading, or drug prep Edward P. Sloan, MD, MPH Pharmacotherapy Fosphenytoin: • Pro-drug, dose same as pht • Infuse at 150 mg/min in SE • Can be given IM up to 20cc • Level 10-20 µg/mL • Delayed level: 2h IV, 4 h IM Edward P. Sloan, MD, MPH Adverse Events Following IV CEREBYX® or IV Phenytoin 100 CEREBYX at 150 mg PE/min (n=90) IV Phenytoin at 50 mg/min (n=22) 59.1 60 40 Pruritis unique to fospht 48.9 44.4 31.1 27.3 27.3 20.0 20 18.2 11.1 ax ia ce en si on H yp ot H ea Pa re st he s ia iti s Pr ur ne ss D iz zi us gm N ys ta da ch e 0.0 0 7.7 4.5 le n 2.2 m no 4.4 So 4.5 At Subjects (%) 80 Refer to full Prescribing Information for the full adverse events incidence. Cerebyx® (fosphenytoin sodium injection) [package insert]. Morris Plains, NJ: WarnerLambert; 2002. 9.1 Pharmacotherapy Fosphenytoin: • Cost-effective in 6 settings –Rapid infusion in “at-risk pts” –Rapid infusion in SE –High-risk IV access –No IV access (IM) –No cardiac monitoring (IM) –Poor patient compliance Edward P. Sloan, MD, MPH Fosphenytoin Rapid Infusion in “At-risk” Pts: • • • • • Infuse at 100-150 mg/min Load in 10-20 minutes Therapeutic after diazepam Limits lorazepam use Lowers monitoring need Edward P. Sloan, MD, MPH Fosphenytoin Rapid Infusion in SE: • • • • • Infuse at 150 mg/min in SE One gram infusion in 7 min Full 20 mg/kg load in 10 min 30 mg/kg load in 15 min Fos resuscitation, next AED Edward P. Sloan, MD, MPH Mean Plasma-Free Phenytoin Concentration (g/mL) CEREBYX® and IV Phenytoin: Comparable Pharmacokinetic Profiles 3 N = 12 2 Similar time to therapeutic free phenytoin level 1 CEREBYX at 150 mg PE/min IV Phenytoin at 50 mg/min 0 0 30 60 90 Time After Start of Infusion (min) Cerebyx® (fosphenytoin sodium injection) [package insert]. Morris Plains, NJ: WarnerLambert; 2002. Always consult full Prescribing Information in package insert. 120 ED Management SE Rx Timeline: 0-30 min: ABCs, benzos • 30-60 min: Phenytoins • 60-90 min: Levetiracetam, phenobarbital, valproate • 90-120 min: Midazolam, propofol CT, EEG, ICU/OR • Edward P. Sloan, MD, MPH Fosphenytoin High-risk IV Access • • • • Murphy’s Law Extravasations will occur Long-term complications go undetected by ED physicians Consider your preferences Edward P. Sloan, MD, MPH Fosphenytoin No IV Access • IVDA in lock-up, prevent SE • Must achieve adequate level • Avoid ED problems • ED nurse time, agitation • Adverse exposure risk • Prolonged ED throughput time Edward P. Sloan, MD, MPH Fosphenytoin No IV Access • Out of hospital setting • Protocol in EMS setting • Long transports in rural EMS • Specialty care providers • Nursing homes • Private MD offices Edward P. Sloan, MD, MPH Pain Scores at Injection Site Following IM Administration of CEREBYX® or Saline None Subjects (%) 100 Mild Moderate Severe 95.8 87.5 83.3 54.2 50 12.5 25.0 16.7 4.2 16.7 4.2 0 Saline CEREBYX Saline (10 mg PE/kg) Immediately Post-Injection CEREBYX (10 mg PE/kg) 1-Hour Follow-up IM fos pain similar to IM saline Adapted with permission from Pryor FM et al. Epilepsia. 2001;42:245-250. Always consult full Prescribing Information in package insert. IM CEREBYX® Administered at a Single and Multiple Sites 60 100 Patients (%) 50 Single Sites Multiple Sites 14 pts, 15+cc IM injection (N = 11) 40 (N = 11) (N = 12) (N = 13) 30 20 (N = 3) (N = 4) 10 (N = 3) (N = 3) 0 ≤10 >10-15 >15-20 Volumes Administered (mL) Ramsay RE et al. Epilepsy Res. 1997;28:181-187. Always consult full Prescribing Information in package insert. >20 Fosphenytoin No Cardiac Monitoring • ED overcrowding • High acuity, stretched resources • Utilize IM loading • No need for monitoring • Less risk of hypotension • No unplanned rapid infusion • More disposition options Edward P. Sloan, MD, MPH Fosphenytoin Poor Patient Compliance • Pt refuses to stay for infusion • About to enter high risk setting • Utilize IM loading • Rapidly therapeutic • Half load IM, half PO • Reduced SE risk • Rapid dispo, not AMA Edward P. Sloan, MD, MPH Fosphenytoin Use in Elderly Patients • • • • Caution with hypotension when rapidly infused CVA neuroprotection study Related to phenytoin moiety Rate related, slow infusion Edward P. Sloan, MD, MPH Fosphenytoin Use in Pediatric Patients • • • • • Used in infants and children Reasonable to use in all ages Safety not an issue IM and IV use both possible Neonate indication and use: in consultation with peds neurology Edward P. Sloan, MD, MPH Pharmacotherapy IV Levetiracetam: • Second generation AED • Oral and IV bioequivalent • Adjunct therapy • No therapeutic level defined • 1500 to 3000 mg infusion • Few adverse effects Edward P. Sloan, MD, MPH Pharmacotherapy IV Phenobarbital: • GABA-inhib, effective SE Rx • Infuse up to 50 mg/min • 20-30 mg/kg, 10 mg/kg doses • Therapeutic > 40 µg/mL • Respiratory depression • Hypotension Edward P. Sloan, MD, MPH Pharmacotherapy IV Valproate: • • • • • • Likely GABA mechanism Useful in peds, possibly SE Rate up to 300 mg/min 25-30 mg/kg, 3-6 mg/kg/min Therapeutic > 100 µg/mL Per mg/kg load, level up 5 µg/mL Edward P. Sloan, MD, MPH Pharmacotherapy IV Lidocaine: • Third-line, stabilizes membrane Na + /K + pump • Decreased neuron excitability, refractory GCSE • 3 mg/kg • Not effective relative to others Edward P. Sloan, MD, MPH Pharmacotherapy IV Midazolam Infusion: • GABA mechanism • Equal to diazepam infusion • Greater breakthru sz rates • Less hypotension –vs. propofol, pentobarb Edward P. Sloan, MD, MPH Pharmacotherapy IV Propofol Infusion: • Likely GABA mechanism • Provides burst suppression • 2 mg/kg loading dose • Hypotension, acidosis, hypoventilation • Rapid onset, easily reversed Edward P. Sloan, MD, MPH Pharmacotherapy IV Pentobarbital: • Likely GABA mechanism • Provides burst suppression • 5 mg/kg loading dose • 25 mg/kg infusion rate • ICU monitoring required Edward P. Sloan, MD, MPH Pharmacotherapy ED Treatment Protocol: • Have AEDs easily available • Rapid sequential AED use • Maximize infusion rate • Maximize mg/kg dosing • Benzos, phenytoins, other bolus AEDs, continuous AEDs Edward P. Sloan, MD, MPH Pharmacotherapy No IV Access: • PR diazepam • IM midazolam • IM fosphenytoin • Buccal, intranasal midazolam • No IM phenytoin/phenobarbital Edward P. Sloan, MD, MPH ACEP Seizure/SE Clinical Policy Edward P. Sloan, MD, MPH Evidence Based Guidelines • Define the clinical question – Focused questions best – Outcome measure must be determined • Grade the strength of evidence • Incorporate practice patterns, available expertise, resources and risk/benefit Edward P. Sloan, MD, MPH ACEP Clinical Policies • Identify questions of clinical importance to ED practitioners • Analyze the quality of data available related to disease state • Differentiate anecdotal experience from practice supported by evidence Edward P. Sloan, MD, MPH Evidence Strength • Strength (Class) of evidence – I: Randomized, double blind interventional studies for therapeutic effectiveness; prospective cohort for diagnostic testing or prognosis – II: Retrospective cohorts, case control studies, cross-sectional studies – III: Observational reports; consensus reports Edward P. Sloan, MD, MPH Recommendation Strength • Strength of recommendations: – A (Standard): High degree of certainty based on Class I studies – B (Guideline): Moderate clinical certainty based on Class II studies – C (Option): Inconclusive certainty based on Class III evidence, consensus Edward P. Sloan, MD, MPH Edward P. Sloan, MD, MPH New Onset Sz: Lab Testing What lab tests are indicated in the otherwise healthy adult patient with a new onset seizure who has returned to a baseline normal neurological status? (Outcome measure: abnormal lab that changes management) Edward P. Sloan, MD, MPH New Onset Sz: Lab Testing • Level B recommendations: – Determine a serum glucose and sodium on patients with a first time seizure with no co-morbidities who have returned to their baseline – Obtain a pregnancy test in women of child bearing age – Perform a LP after a head CT either in the ED or after admission on patients who are immunocompromised Edward P. Sloan, MD, MPH New Onset Sz: Neuroimaging Which new onset seizure patients who have returned to a normal baseline require neuroimaging in the ED? (Outcome measure: abnormal CT) Edward P. Sloan, MD, MPH New Onset Sz: Neuroimaging • Level B recommendations: –When feasible, perform a head CT of the brain in the ED on patients with a first time seizure –Deferred outpatient neuroimaging may be utilized when reliable follow-up is available Edward P. Sloan, MD, MPH New Onset Sz: Dispo/AED Use Which new onset seizure patients who have returned to normal baseline need to be admitted to the hospital and / or started on an AED? (Outcome measure: short term morbidity or mortality) Edward P. Sloan, MD, MPH New Onset Sz: Dispo/AED Use • Level C recommendations: – Patients with a normal neurological examination can be discharged from the ED with outpatient follow-up – Patients with a normal neurological examination and no co-morbidities and no know structural brain disease do not need to be started on an antiepileptic drug in the ED Edward P. Sloan, MD, MPH Sz/SE: Phenytoin Loading What are effective phenytoin dosing strategies for preventing seizure recurrence in patients who present to the ED with a sub-therapeutic serum phenytoin level? (Outcome measure: short term seizure recurrence) Edward P. Sloan, MD, MPH Sz/SE: Phenytoin Loading –Level C recommendation: −Administer an intravenous or oral loading dose of phenytoin or intravenous or intramuscular fosphenytoin, and restart daily oral maintenance dosing. Edward P. Sloan, MD, MPH Sz/SE SE Therapeutics What agent(s) should be administered to a patient in status who continues to seize despite a loading dose of a benzodiazepine and a phenytoin? (Outcome measure: cessation of motor activity) Edward P. Sloan, MD, MPH Sz/SE SE Therapeutics • Level C recommendation: –Administer one of the following agents intravenously: “highdose phenytoin,” phenobarbital, valproic acid, midazolam infusion, pentobarbital infusion, or propofol infusion. Edward P. Sloan, MD, MPH Sz/SE: EEG Monitoring When should an EEG be performed in the ED? Edward P. Sloan, MD, MPH Sz/SE: EEG Monitoring • Level C recommendation: –Consider an emergent EEG for patients suspected of being in nonconvulsive SE or in subtle convulsive SE, for patients who have received a long-acting paralytic, or for patients who are in a drug-induced coma. Edward P. Sloan, MD, MPH ACEP Summary • Evidence based clinical policies are useful tools in clinical decision making • Policy does not create a “standard of care” • Provides a foundation for clinical practice at a national level • The current literature does not support the creation of any “level A” recommendations – 2 of the 6 clinical questions have sufficient evidence to support “level B” recommendations – 4 of the 6 recs are “level C” Edward P. Sloan, MD, MPH ED Patient Outcome Edward P. Sloan, MD, MPH ED Patient Management • • • • • • • • Lorazepam 2 mg IVP x 5 over 10 minutes Persistent facial and R shoulder activity AMS: generalized seizure continues Fosphenytoin 1 gram PE over 10 min Fosphenytoin 1 gram PE over 10 min Seizure ended, pt remained obtunded Intubation immediately followed Lidocaine, sux, rocuronium Edward P. Sloan, MD, MPH ED Diagnostic Evaluation • • • • • Non-contrast CT: Prior strokes, atrophy Metabolic tests normal Toxicology screening negative Phenytoin level cancelled Diagnoses: • AMS • Status Epilepticus • Respiratory Failure Edward P. Sloan, MD, MPH Family Arrives, Pt History • • • • • • • Pt with history refractory seizures Hx carotid artery occlusion R Due for carotid endarterectomy Phenobarbital & dilantin, compliant Prior history of SE treated at UIC No medic alert bracelet No recent illness, trauma, EtOH Edward P. Sloan, MD, MPH Patient Outcome • • • • • EEG in ED, within 150 minutes Neuro consultation, no subtle SE Admit to Neuro ICU Repeated paralytic dosing Final disposition for carotid Rx Edward P. Sloan, MD, MPH Conclusions • Effective ED seizure patient Rx is critical to good long-term outcome • Parenteral ED AED use can be easily implemented for effectiveness • Must understand principles that govern ED AED use and priorities of those that provide long-term epilepsy Rx • Those principles are fortunately simple and straightforward Edward P. Sloan, MD, MPH Recommendations • Be able to identify the seizure type and optimal patient therapies based on etiology, demographics, and risk/benefit • Establish seizure and SE protocol • Understand fully the optimal use of all parenteral and 2nd generation AEDs • Stop the acute seizure & prevent SE • Wisely prescribe so that follow-up epilepsy management can be optimized Edward P. Sloan, MD, MPH Questions? www.FERNE.org [email protected] 312 413 7490 ferne_2007_stcatherine_sloan_seizures_final 5/23/2017 6:15 AM Edward P. Sloan, MD, MPH