Aggressive seizure algorithm: why I use propofol early

My approach to status epilepticus is somewhat more aggressive than commonly taught algorithms. It is summarized (overly simply) as “benzo → benzo → propofol”. There have been a number of concerns raised with this strategy recently on twitter. This post outlines the reasoning (and limited evidence) behind my seizure algorithm.

This approach is based on three basic assumptions:

• That longer seizures result in worse outcomes for patients.
• That conventional second line anticonvulsants are not very effective.
• And that general anesthetics are the accepted standard of care for refractory seizures.

I find this logic sound. I think the reasoning, and the available science, is strong enough that I use and teach my suggested algorithm. However, there is a lot of conjecture. There is not strong evidence. There are no large multicenter RCTs. My logic relies heavily on observational trials and animal models, both of which fail frequently in medicine. I think it is the best we have for now, but it is a long way from definitive. With that in mind, this if my thinking.

Current status epilepticus outcomes are bad

In adults, 30 day mortality after an episode of status epilepticus is extremely high, with most estimates over 20%. (Logroscino 1997; Treiman 1998; Legriel 2007; Brophy 2012) Mortality appears to be much lower in pediatric populations, but morbidity secondary to poor neurologic outcomes is quite high. (Maegaki 2005; Brophy 2012; Dalziel 2019; Lyttle 2019)

In one prospective study, only 60% of status patients who responded to second line therapy returned to their baseline neurologic state. Even worse, only 20% of patients with refractory status had a good neurologic outcome. (Novy 2010) A systematic review performed as part of the guidelines for the Neurocritical Care Society found that 11-16% of patients had severe neurologic sequelae after an episode of status, and another 25% had deterioration from their baseline state. By 90 days, 39% had marked functional impairment. (Brophy 2012)

Although a significant proportion of that morbidity and mortality is likely the result of the underlying disease, seizures also directly cause harm.

Longer seizures are worse

There are many reasons to think that earlier termination of status epilepticus is better. At the most basic level, we need to consider the fundamentals of emergency medicine. An actively seizing patient is extremely unstable, with an unprotected airway, and poor, non-existent, or very difficult to assess ventilation. Prolonged seizures also result in hyperthermia, metabolic acidosis, rhabdomyolysis, hypoglycemia, aspiration, and a myriad of other problems.

From a neurological standpoint, seizures longer than 20-30 minutes result in cerebral hypoperfusion, hypoglycemia, and hypoxia, resulting in brain injury. (Chapman 2001; Marik 2004) Furthermore, prolonged seizures directly cause neuronal death through excitotoxicity and a cascade of other cellular changes. (Marik 2004; Millikan 2009; Claassen 2017) Early termination of seizures prevents these harms.

There are numerous trials demonstrating a strong association between length of seizure and poor neurologic outcomes and death. (Towne 1994; Eriksson 2005; Holtkamp 2005; Maegaki 2005) One prehospital RCT comparing benzodiazepines to placebo, although underpowered, suggests benefit from early intervention in seizures. (Alldredge 2001)

The longer a seizure lasts the more likely it is to become refractory or recur. (Morimoto 2004; Eriksson 2005; Millikan 2009) Furthermore, our traditional agents are less less likely to work, because GABA receptors are lost or internalized into cells. (Niquet 2016) Although there is no definitive “time is brain” study, because we are not going to randomize people to a no treatment arm in status epilepticus, all the data we have from observational trials and animal models indicate better outcomes with shorter seizures.

For all these reasons, despite suggesting relatively slow algorithms, all the current guidelines agree that the primary goal in the management of status epilepticus is to stop the seizure as soon as possible. (Glauser 2016; Claassen 2017)

The current algorithm is not very successful

The current algorithm fails for far too many patients, resulting in prolonged seizures, and presumably worse outcomes than if we could stop the seizure earlier. Although a reasonable number of patients will respond to first line anticonvulsants, many fewer respond to second line agents. The literature consistently shows about 20% of patients will remain seizing after both the first and second line agents have been given. (Novy 2010; Millikan 2009; Treiman 1998; Burman 2019) In adult patients, the second line antiepileptic is only successful 5-7% of the time, and the third line agent only 2%. (Millikan 2009; Treiman 1998) The rate of failure seems to be lower in pediatrics, but the second line agent still failed in in approximately 40% of the children in the CONSEPT and ECLIPSE trials. (Dalziel 2019; Lyttle 2019) The current algorithms will leave about 1 in 5 patients seizing after the second line agent, with most of these patients not receiving their third line agent until after the 20-30 minute threshold for significant neuronal death.

Who we are talking about

Before we get too far down the status epilepticus rabbit hole, I think it is important to clarify who we are talking about. We use “status epilepticus” to describe a wide range of patient presentations, with significantly different clinical implications. Although there isn’t a clear cutoff between those who require an aggressive anesthetic early approach, and those who can be treated more conservatively, I think this is a probably distinction emergency physicians can easily make in the moment.

A patient who has not stopped convulsing for 15 minutes despite 2 appropriate doses of benzodiazepine is really sick and requires urgent intervention. I would use propofol.

A patient whose seizure was aborted by a dose of benzodiazepine, but who remains somewhat confused postictally for 30 minutes, with a GCS of 13, and then seizes again is technically also in status epilepticus, but is clearly less sick. Assuming this second seizure stops spontaneously, or again responds to benzodiazepines, I would load phenytoin but not jump immediately to propofol. Similarly, focal status epilepticus probably doesn’t require the same aggressive approach as continuous generalized convulsions.

I am suggesting early aggressive use of anesthetic agents like propofol in the sickest patients in whom we suspect continuous full brain seizures

Both, not either

To be clear: I am not suggesting using propofol instead of an anti-epileptic. I am suggesting both. Once a patient has seized for longer than 5 minutes (is in status epilepticus), they are going to need maintenance antiepileptic therapy. There is no sense in delaying that therapy. My algorithm calls for starting the conventional anticonvulsant immediately after the second dose of benzodiazepine. The primary difference is that I think that it is a bad idea to wait 20 minutes for these agents to (potentially)  work. If the second appropriate dose of benzodiazepine does not abort the seizure, I suggest immediately controlling the seizure by adding an anesthetic agent, and my current choice is propofol.

Propofol

There is not great evidence for propofol. We know propofol should work. It is a strong GABA agonist, putting it in the same class as benzodiazepines, which clearly work. It also acts on sodium channels, calcium channels, and is an NMDA antagonist, all of which should help abort seizures. (Marik 2004; Reznik 2016) Physiologically speaking, general anesthetics are the best treatment we have for seizures, which is why essentially every guideline and review recommends general anesthetics, including propofol, as the definitive treatment of refractory status epilepticus. (Chapman 2001; Marik 2004; Shearer 2011; Glauser 2016; Claassen 2017) There is also evidence from animal models and bench data that propofol is a very effective anticonvulsant. (De Riu 1992; Marik 2004)

There are many case reports of propofol being used in status epilepticus, with very high reported rates of success (but of course, case reports are subject to significant bias). (Mackenzie 1990; Campostrini 1991; Borgeat 1994; Brown 1998; Harrison 1998; Wijdicks 2002; Rossetti 2004)

There is one interesting trial in which propofol was used pre-hospital for the treatment of status epilepticus. (Kuisma 1995) In this trial, 8 adults in status who had failed treatment with diazepam were given 30 mg of propofol every 30 seconds until the seizure stopped. Only 2 of the 8 patients were still seizing on arrival to hospital, and 7 of the 8 patients returned to their baseline neurologic status. Only 1 patient required ICU admission. The dose of propofol required to control seizures was between 100-200 mg (1.5-3 mg/kg).

There is an RCT that demonstrates significant shortening of seizure duration (both clinically and on EEG) with the use of propofol in the setting of electroconvulsive therapy. (Avramov 1995) Another RCT compared propofol to barbiturates as a third line agent for refractory status epilepticus. (Rossetti 2010)  There was no statistical difference, with propofol meeting their EEG based definition of seizure control in 43% of patients and baributuates working in 22% of patients (p=0.4 in this tiny trial). 43% may seem disappointing, but these are patients who had to have at least 30 minutes of seizure and treatment with 2 prior agents. The 43% success rate was after just the first propofol dose and most most stopped with a subsequent infusion. In comparison, in the Veterans Affairs cooperative study, only 7% of patients responded to the second line anticonvulsant (20% relative reduction), so a 43% response rate for a third agent sounds pretty good. (Treiman 1998) Furthermore, propofol primarily acts through GABA receptors, and GABA receptors are lost after about 30 minutes of seizure, so propofol should be more effective if used earlier.

Overall, this is not the most impressive evidence, but I think the numbers look at least as good as our other options. The big difference: I don’t have to wait 20 minutes to know. Like benzos, I can rapidly titrate the dose to effect, which I think is important in these critically ill patients.

Where is the evidence for your algorithm?

As I mentioned at the outset, there are no RCTs supporting this seizure algorithm. Considering my emphasis on evidence based medicine on this blog, that might seem strange. However, although RCTs provide the strongest, least biased form of evidence, there are other sources of information we should consider.

There is reasonable science looking at the current approach, and I think that evidence tells us that the current approach doesn’t work. Our second line agents fail frequently. When they do work, they take too long and cause a large number of adverse events.

I am not suggesting using physiologic reasoning to overrule strong evidence. I am suggesting using physiologic reasoning and observational data to replace a treatment strategy that has been proven to be poor.

I am not suggesting that we know for sure. I think we desperately need an RCT that compares propofol to standard antiepileptics as the second line agent in status epilepticus (preferably looking at long term neurologic outcomes instead of surrogates like seizure length).

In the meantime, I think the evidence is strong enough to tell us that the standard approach doesn’t work well enough, and that it is reasonable to go to an anesthetic agent like propofol as the second line agent in continuously convulsing status epilepticus patients.

Why propofol over other general anesthetics?

Although there isn’t a lot of evidence, propofol seems to have a similar level of efficacy and adverse events to other IV anesthetics. (Reznik 2016) Most status epilepticus patients will present to community emergency departments, so the ideal algorithm will use agents that are easy to administer and well known to emergency department staff. Propofol clearly fits that bill, and so it my first choice.

Note: As I finalized my edits on this post, a new RCT was published comparing phenobarbital to phenytoin as the second line agent in status, and phenobarbital was much better. (Burman 2019) Therefore, it might be reasonable to argue for phenobarbital over propofol. However, I have rarely (if ever) seen phenobarbital used, and ordering it for the first time in an emergency would almost certainly result in delays, and potentially errors. I am sticking with propofol until we see more evidence because familiarity matters in resuscitation. The Burman study has its own blog post here.

Ketamine: An alternative?

Ketamine blocks NMDA receptors and therefore could also theoretically stop seizures. There is reasonable laboratory data that suggests ketamine should stop seizures. (Dorandeu 2013) There are a number of case reports of both ketamine alone and ketamine combined with propofol terminating seizures in patients with super-refractory status epilepticus. (Sabharwal 2015, Ilvento 2015; Zeiler 2015; Hofler 2016)

However, all of the evidence to date looks at ketamine very late, in super-refractory status epilepticus. Although it might be an ideal agent early in status epilepticus, because patients are likely to maintain airway reflexes and continue breathing after ketamine, I don’t think the evidence is strong enough to suggest using it as a solo agent at this time. However, it might make sense to use it early in combination with propofol in an attempt to completely control seizures as soon as possible.

Respiratory depression

Respiratory depression is a concerning side effect from most of the medications we use to treat seizures. However, in status epilepticus the rate of respiratory depression is actually lower in patients treated with benzodiazepines than with placebo. (Glauser 2016) Status directly causes respiratory depression. That is important to keep in mind when considering the effects of our potential treatments.

My seizure algorithm, which suggests adding high dose propofol to multiple doses of benzodiazepine, will increase the rate of respiratory depression, which is why intubation is recommended. These are critically ill patients in whom intubation is entirely appropriate.

A large percentage of patients also end up getting intubated using the standard status algorithm. They just end up intubated later, after longer seizures, potentially resulting in worse neurologic outcomes. In CONSEPT 18-26% of patients ended up intubated. (Dalziel 2019) The number was even higher in ECLIPSE, with 30-35% of patients undergoing RSI to terminate the seizure. (Lyttle 2019) Considering that the CONSEPT and ECLIPSE cohorts included intermittent seizures and focal seizures, the intubation rate in patients with continuous convulsions is likely to be much higher. Furthermore, in the recent RCT comparing phenobarbital to phenytoin as the second line agent, although phenobarbital did result in respiratory depression in 55% of patients, phenytoin (or just the prolonged, unstopped seizure) resulted in respiratory repression in 70% of patients. (Burman 2019)

Ultimately, the question is whether the harm of a brief intubation in the patients who would have stopped seizing with the traditional algorithm is worse than the harm of prolonged seizures and delayed intubation in patients who don’t stop with our current approach. Clearly, I don’t think so.

Is intubation really a bad outcome?

This is a point where opinions really seem to diverge. Intubation is considered a treatment failure in most seizure studies, but I don’t think that makes sense. We intubate critically ill patients all the time and don’t think about it as a failure. Advanced airway control is an essential component of the treatment of many critically ill patients. Patients in status epilepticus are among the sickest that we see, with uncontrolled airways, high aspiration risk, and ineffective ventilation. A watch and wait approach simply doesn’t make sense. Intubation of a critically ill patient, especially one with active airway and ventilation issues, is just good medicine.

Scientifically speaking, we don’t know how the harms of intubation compare to the harms of prolonged seizures. I would love to see an RCT comparing conventional anticonvulsants to anesthetics as second line therapy in status epilepticus. However, we know that modern airway management is quite safe. We know to watch for an mitigate the physiologic risk. We all have backup plans and are ready to rapidly proceed to a surgical airway if necessary. On the other hand, we know that our current approach to status fails frequently and patients have significant morbidity and mortality. For me, the choice is clear.

Are we going to overwhelm the system?

One of the concerns that came up on twitter was the idea that intubating children in status epilepticus would overwhelm PICUs. I think this concern is unfounded. Status epilepticus is a rare condition. In ECLIPSE there were 404 patients recruited from 30 UK emergency departments in just under 3 years. That is 4.5 patients a year per hospital, of whom 60% were already admitted to the PICU. At most, we are talking about 1 or 2 extra admissions a year at each hospital. Hardly overwhelming. (Lyttle 2019) The numbers are similar in CONSEPT, with 7 patients per hospital per year included in the trial (or 11 patients a year if you include the patients they missed). (Dalziel 2019) Furthermore, these numbers are likely over-estimates, as they include patients that are in status by definition, but who are less sick clinically. For example, CONSEPT included patients with focal status epilepticus, who won’t require the same aggressive approach. Finally, because the more aggressive approach is likely to stop more seizures, you might actually see ICU use go down. For example, in the recent RCT comparing phenobarbital to phenytoin as a second line agent, 28% of the phenytoin group required admission to the PICU as compared to only 13% of the phenobarbital group. (Burman 2019)

My seizure algorithm is consistent with the guidelines

Although it sounds extreme because of the way status epilepticus is often taught, my seizure algorithm is actually consistent with what is recommended in the guidelines from the American Epilepsy Society. (Glauser 2016) These guidelines state that “depending on the etiology or severity of the seizure, patients may go through the phases faster or even skip the second phase and move rapidly to the third phase, especially in sick or intensive care unit patients.”

Bottom line

Although the evidence isn’t the highest quality, I think the evidence we have supports a more aggressive approach to status epilepticus. The current seizure algorithm simply fails too often, resulting in prolonged seizures which are known to have bad outcomes. Every expert considers anesthetics like propofol to be the gold standard therapy of status epilepticus. I think we need to get to that therapy much quicker than we are currently. That is why I use the “benzo → benzo → propofol” approach.

Other FOAMed

The main First10EM status epilepticus post

Rapid Sequence Termination (RST) of status epilepticus – PulmCrit

Resuscitationist’s guide to status epilepticus – PulmCrit

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