Status Epilepticus: Emergency Management

Case

EMS arrives with a 39 year old woman in the midst of a generalized tonic clonic seizure. The seizure has lasted at least 12 minutes now, so this is status epilepticus. No information is available about her past history. The paramedics were unable to start an IV, but did administer one dose of IM midazolam en route…

My approach

Unlike simple seizures, which will resolve without any intervention and require clinical constraint to avoid overtreatment, status epilepticus is a medical emergency that requires immediate management.

Check the sugar

The first words out of your mouth should probably be, “what’s the sugar?” Not only is it embarrassing to miss hypoglycemia, it is an easily identifiable and easily treatable etiology of status epilepticus. If for some reason you are unable to get a level, just go ahead and treat empirically with D50W. (Glauser 2016; Claassen 2017; Zaccara 2017)

Start a benzodiazepine

It really doesn’t matter which benzodiazepine you pick – they all work. (Glauser 2016) Usually this first dose will have already been given before the patient arrives. If an IV has not been started, I will immediately give intramuscular or intranasal midazolam. (Claassen 2017)

Benzo		Pediatric Dose		Usual dose
Lorazepam IV		0.1mg/kg		4-8mg
Midazolam IV		0.1mg/kg		5-10mg
Midazolam IN		0.2mg/kg
Midazolam IM		0.2mg/kg		5-10mg
Diazepam IV		0.2mg/kg		10mg

Note: We frequently underdose benzodiazepines. I think it makes sense to stick to the weight based doses that we use in children, which means using larger doses than usual in adults (8 mg of lorazepam IV or 10 mg of midazolam IV). This is the dose that was used in the classic Vetrans Affairs Cooperative study. (Treiman 1998) Although people worry about respiratory depression, aborting the seizure probably results in less respiratory depression, despite the higher benzodiazepine dose. (Glauser 2016)

Note 2: Since originally publishing this post, I have thought a lot about the use of intranasal midazolam. In a hospital setting, I don’t think it makes any sense to use the intranasal route.

Assess airway and breathing (and place monitors)

Although we normally start with the ABCs, I mention airway after the first dose of benzodiazepine, because terminating seizure activity will often solve airway and breathing issues.

You don’t need to ventilate the patient immediately, but oxygen is important because the patient is burning through it very quickly. I place nasal trumpets bilaterally and apply a non-rebreather facemask in an attempt to provide some apneic oxygenation. (Glauser 2016)

Airway assessment and management is complicated in status. Although most patients can initially be managed without intubation, if there is any concern, or the patient is hypoxic, it is always appropriate to proceed with an RSI. (Brophy 2012)

Get vascular access

The management of status epilepticus requires vascular access. If an IV is not rapidly available, I place an intraosseous (IO) line.

More benzodiazepine

If there is no response 4 minutes after the first benzo, repeat the dose. (Glauser 2016; Claassen 2017)

Give propofol (and phenytoin)

Most published algorithms will have with phenytoin, fosphenytoin, or levetiracetam as the second-line agent. (Claassen 2017) I don’t like these options in the actively seizing patient because they take too long to work. Also, phenytoin is generally contraindicated for toxicologic seizures and I rarely have enough information in the first 15 minutes to exclude overdose. (Sharma 2011) If a patient doesn’t respond to 2 appropriate doses of a benzodiazepine, I use a general anesthetic. (Marik 2004; Glauser 2016; Farkas 2018)

I will also get phenytoin (20 mg/kg over 20 minutes) or levitiracetam (60 mg/kg to a max of 4.5) started as soon as I can after the first dose of benzodiazepine, but it isn’t going to work for 20-30 minutes, so it is really my third line agent. (Glauser 2016) (The ESETT, CONSEPT, and ECLIPSE trials have effectively demonstrated that all of these traditional agents are equally (in)effective. I think phenytoin is still a good choice, but it is contraindicated in toxicologic seizures, and I avoid it in patients with known cardiovascular issues.)

My second line drug is propofol 1.5-2mg/kg IV then 20-200mcg/kg/min. (Marik 2004; Claassen 2017; Farkas 2018) Physiologically speaking, it might also make sense to add ketamine 1 mg/kg.

There is an accompanying post that discusses the logic behind suggesting early aggressive use of anesthetic agents (ie propofol) that can be found here.

Note: There is probably better evidence for using phenobarbital in this early anesthetic approach, especially after a new RCT from South Africa. (Burman 2019) However, I continue to use propofol because it is used far more frequently in the departments where I work, and I think it will be quicker and more reliable to give in the context of a critically ill patient.

Keep the phenytoin (or whatever conventional anticonvulsant you chose) running, even if the seizure is aborted by the propofol.

Advanced airway management

Most patients requiring second line anticonvulsants will require advanced airway management. When using propofol as my second line agent, I assume every patient will need to be intubated.

Because status epilepticus precludes adequate preoxygenation and denitrogenation, these patients are at high risk of rapid desaturation. If the patient already has low sats (<95%) I will proceed immediately to an LMA after pushing propofol (sometimes called “rapid sequence airway”). The patient can be resuscitated with the LMA in place and transitioned to an endotracheal tube when stable.

In patients with adequate sats for an attempt at intubation (>95%), I would suggest a standard RSI for most clinicians. This is a point of significant debate. Paralytics will mask ongoing convulsions, and may increase the rate of nonconvulsive status epilepticus. Thus, this is one of the few scenarios in emergency medicine that a sedative only intubation makes sense. That being said, sedative only intubation is technically difficult, and status patients will be even more difficult because of high rates of trismus and rapid desaturation, so for the average provider (myself included) a standard RSI probably makes the most sense.

If a paralytic is used, EEG monitoring is essential as soon as possible (and that might be a while in most settings) after intubation.

Choice of paralytic

Succinylcholine could cause hyperkalemia if seizures have been extremely prolonged and rhabdomyolysis has already developed or if there is an underlying neurologic disorder. However, the prolonged paralysis of rocuronium increases the risk of developing nonconvulsive status epilepticus. In the ideal situation, nonconvulsive status is quickly and easily diagnosed by EEG, but unfortunately that is just not feasible for many of us. I will will use succinylcholine if I am intubating in the first 15 minutes of a seizure, but after that I worry about contraindications and err on the side of rocuronium.

Search for reversible causes

Finding and treating potential reversible causes of the seizure is essential. Ideally, this search is started simultaneously with the actions above. (History and physical is gathered rapidly in the minutes between benzodiazepine doses). (Marik 2004; Glauser 2016; Farkas 2018)

• Infectious
  • Almost all patients in status are going to be hot, so infectious causes will come to mind. Empiric antibiotics and acyclovir should be given early if infection is a possibility.
• Eclampsia
  • In case it was overlooked in the initial few minutes, all women of childbearing age must be considered for the diagnosis of eclampsia.
• Isoniazid toxicity
  • Depending on your population (urban hospitals or many countries that aren’t Canada), you might want to treat empirically for isoniazid toxicity.
  • The antidote is pyridoxine 1 gram of for every gram of isoniazid (to a max of 5 grams) in a known overdose, or just 5 grams empirically. (Sharma 2011)
• Hyponatremia
  • NaCl 3% 2ml/kg (150 in 70 kg pt); may repeat in 10 minutes if needed. If you don’t have 3% saline, 2 amps of sodium bicarb will have the same effect.
• Sodium channel blocker toxicity
  • Sodium bicarbonate IV (100mEq or 2mEq/kg)
• Alcohol withdrawal
  • You are already treating this, but will need a lot more benzos.
• Raised intracranial pressure
• Hyperthermia (heat stroke, agitated delirium, thyroid storm)
  • Apply external cooling.
• Cyanide
  • Hydroxocobalamin 70mg/kg (5 gram standard dose)
  • Or the cyanide antidote kit (amyl nitrate, sodium nitrite, and sodium thiosulfate)
• Other toxins: tricyclics, cocaine, theophylline, oraganophosphates, local anesthetic toxicity.
• Others: hypoxia, structural, vascular, metabolic.
• NMDA receptor encephalitis is another important cause. We can’t immediately treat it in the ED, but I include it on my list because it is still probably under-diagnosed, so discussing it might help our intensivist colleagues.

Final options

• Barbiturates: Some people might use these in place of propofol higher in this algorithm. That is reasonable. I like propofol because its a drug I use every single shift.
  • Phenobarbital 20 mg/kg loading dose over 15 min; an additional 5-10 mg/kg can be given after 10 minutes. (Claassen 2017; Burman 2019)
• Midazolam infusion
• Levetiracetam: If the first anti-epileptic doesn’t work, you are unlikely to get any benefit from adding a second. However, I don’t know any neurologists who can walk by a seizure patient without starting them on levetiracetam these days, despite much convincing evidence. (Glauser 2016; Lyttle 2019; Dalziel 2019) A loading dose of 1 gram IV is reasonable (20-40 mg/kg).
• Ketamine: Although not backed by great evidence, the use of ketamine (an NMDA receptor antagonist) makes sense in conjunction with the flood of the GABA agonists you have already tried, and there are multiple case reports of success in super refractory status epilepticus.
• Inhalational anesthetics: As a final effort, inhalational anesthetics have been described in cases of status epilepticus. (Holtkamp 2007)

Always consider non-convulsive status

The absence of convulsions does not mean that the patient is safe. Almost half of patients in a persistent coma after termination of overt status epilepticus have ongoing EEG evidence of seizure activity. (Holtkamp 2007) Morality may actually be worse for patients with subtle or non-convulsive status epilepticus. (Millikan 2009) These patients still require aggressive therapy.

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Notes

This post is an update of the original status epilepticus post from 2015. The general algorithm is the same, but a few clarifications were added, and the references were updated.

Although older definitions of status epilepticus focused on seizures lasting more than 30 minutes, a more practical definition is any individual seizure lasting more than 5 minutes or 2 seizures without full recovery of consciousness. From an emergency department standpoint, if a patient is still seizing by the time EMS arrives, it is probably status.

I think the described aggressive approach to status epilepticus makes sense in continuous convulsive seizures. However, in patients whose seizures stop with benzos, but simply recur before the patient returns to their baseline neurologic status, a less aggressive approach is probably warranted. (The key distinction is whether you think there is still generalized seizure activity occurring in the brain, which will result in neuronal death). In intermittent seizures, you probably have time to use a conventional anticonvulsant as the second line therapy.

I don’t recommend fosphenytoin. Although it can be given quicker, it doesn’t work any faster or better than phenytoin. Some studies have demonstrated lower side effects with fosphenytoin, but if you look closely, the only side effect that seems to be decreased is pain at the injection site. (Glauser 2016) That doesn’t make sense for patients in status, as they will be unconscious.

I use the same algorithm in both children and adults, as the underlying pathophysiology is the same, and there is little reason to think that the treatment needs to differ. (Glauser 2016) That being said, outcomes tend to be better in children, so a less aggressive approach may be warranted in some circumstances.

Obviously, this aggressive algorithm is not appropriate for non-epileptic spells, or pseudoseizures. Pseudoseizures are usually relatively obvious clinically. Indicators of a non-epileptic spell include maintained consciousness, poorly coordinated thrashing, purposeful movements, back arching, eyes held shut, head rolling, and pelvic thrusting. (Claassen 2017)

Other FOAMed Resources

There is an accompanying post that goes further into the reasoning for the aggressive, propofol early approach to management.

Rapid Sequence Termination of status epilepticus and Resuscitationist’s guide to status epilepticus on PulmCrit

The SMACC Chicago talk by Tom Bleck – CONTROVERSIES IN THE ACUTE MANAGEMENT OF STATUS EPILEPTICUS – covers a lot of the evidence on which I base my algorithm

EMCrit #155: Status epilepticus with Tom Bleck

Core Cast 9.0 – Pediatric Status Epilepticus on REBEL EM

Emergency Management of Pediatric Seizures on EM Cases

Seizures on EM Basic

Status epilepticus: When the seizure doesn’t stop on Intensive Care Network

Status Epilepticus Critical Care Compendium on Life in the Fastlane

Why we do what we do: Benzodiazepines as first line therapy for status epilepticus on PEMBlog

Seizure answers on EM Lyceum

Special seizures on EMin5:

References

Brophy GM, Bell R, Claassen J, et al. Guidelines for the Evaluation and Management of Status Epilepticus Neurocrit Care. 2012; 17(1):3-23.

Burman RJ, Ackermann S, Shapson-Coe A, Ndondo A, Buys H, Wilmshurst JM. A Comparison of Parenteral Phenobarbital vs. Parenteral Phenytoin as Second-Line Management for Pediatric Convulsive Status Epilepticus in a Resource-Limited Setting Front. Neurol.. 2019; 10.

Claassen J, Goldstein JN. Emergency Neurological Life Support: Status Epilepticus. Neurocritical care. 2017; 27(Suppl 1):152-158. [pubmed]

Claassen J, Goldstein JN. Emergency Neurological Life Support: Status Epilepticus. Neurocritical care. 2017; 27(Suppl 1):152-158. [pubmed]

Dalziel SR, Borland ML, Furyk J, et al. Levetiracetam versus phenytoin for second-line treatment of convulsive status epilepticus in children (ConSEPT): an open-label, multicentre, randomised controlled trial. The Lancet. 2019; http://dx.doi.org/10.1016/S0140-6736(19)30722-6

Farkas J. Status Epilepticus. In: Weingart S and Borshoff D (eds). The Resuscitation Crisis Manual. 2018.

Glauser T, Shinnar S, Gloss D, et al. Evidence-Based Guideline: Treatment of Convulsive Status Epilepticus in Children and Adults: Report of the Guideline Committee of the American Epilepsy Society. Epilepsy currents. 2016; 16(1):48-61. [pubmed]

Holtkamp M. The anaesthetic and intensive care of status epilepticus. Current opinion in neurology. 2007; 20(2):188-93. [pubmed]

Lung DD, Catlett CL, Tintinalli JE. Chapter 165. Seizures and Status Epilepticus in Adults. In: Tintinalli JE et al. eds. Tintinalli’s Emergency Medicine: A Comprehensive Study Guide, 7e. New York, NY: McGraw-Hill; 2011. http://accessmedicine.mhmedical.com/content.aspx?bookid=348&Sectionid=40381644

Lyttle MD, Rainford NEA, Gamble C, et al. Levetiracetam versus phenytoin for second-line treatment of paediatric convulsive status epilepticus (EcLiPSE): a multicentre, open-label, randomised trial. The Lancet. 2019; http://dx.doi.org/10.1016/S0140-6736(19)30724-X

Marik PE, Varon J. The management of status epilepticus. Chest. 2004; 126(2):582-91. [pubmed]

McMullan J, Duvivier E and Pollack C. Chapter 102. Seizure Disorders. In: Marx JA et al. eds. Rosen’s Emergency Medicine, 8e. Philadelphia: Elsevier Saunders; 2014.

Millikan D, Rice B, Silbergleit R. Emergency treatment of status epilepticus: current thinking. Emergency medicine clinics of North America. 2009; 27(1):101-13, ix. [pubmed]

Shearer P, Riviello J. Generalized convulsive status epilepticus in adults and children: treatment guidelines and protocols. Emergency medicine clinics of North America. 29(1):51-64. 2011. PMID: 21109102

Sharma AN, Hoffman RJ. Toxin-related seizures. Emergency medicine clinics of North America. 29(1):125-39. 2011. PMID: 21109109

Treiman DM, Meyers PD, Walton NY, et al. A comparison of four treatments for generalized convulsive status epilepticus. Veterans Affairs Status Epilepticus Cooperative Study Group. N Engl J Med. 1998;339(12):792‐798. doi:10.1056/NEJM199809173391202 PMID: 9738086

Zaccara G, Giannasi G, Oggioni R, et al. Challenges in the treatment of convulsive status epilepticus. Seizure. 2017; 47:17-24. [pubmed]