SCCM Resource Library-Ah, Push It! Is Faster Better?

Video Transcription

Hello, my name is Erin Dudaszewski. I'm a clinical pharmacist in critical care and emergency medicine at Mayo Clinic.  Thank you for joining me as we discuss Ah Push It, Is Faster Better? For Rapid Administration of Anti-Epileptic Drugs.  I have no conflicts of interest related to this presentation to disclose, however I will be discussing the off-label use of levatoraptam and lacostamide.  Status epilepticus is a medical emergency affecting over 200,000 patients per year in  the United States and requiring rapid diagnosis followed immediately by emergent initial control  therapy with benzodiazepines and near simultaneous urgent control therapy with IV antiepileptics.  For patients who are actively seizing, administration of IV antiepileptics should occur as soon as possible after benzodiazepines.  So the goal of this presentation is to evaluate the safety and efficacy of rapid administration techniques of antiepileptics.  There are several factors to take into consideration when determining whether a medication is safe to administer rapidly.  First, and especially if giving an undiluted medication, is the pH and ophthalmolarity. Drugs at extreme high or low pHs increase the risk of tissue necrosis or irritation.  The ideal pH for undiluted administration is somewhere between 5 and 8 for optimal comfort of the patient when giving peripherally.  Ophthalmolarity is another factor when higher ophthalmolarity can increase the risk for phlebitis and irritation, and that usually requires dilution for peripheral administration.  Infusion reactions such as cardiovascular dysrhythmias and neurologic effects, including somnolence, are often rate limiting when it comes to giving antiepileptics, but often  patients can be closely monitored for these effects when they're in the emergency department or the ICU.  And the last two here are more logistical obstacles for bedside compounding, including the number of vials required for a single dose and nursing or administration's comfort  for bedside compounding of these doses. And finally, the National Institute for Occupational Safety and Health, or NIOSH, has standards  for personal protective equipment requirements for compounding hazardous medications which must be followed.  All of these factors must be considered simultaneously before determining if an antiepileptic is suitable for rapid administration.  When thinking about our current first-line therapies for urgent control, we run into a few roadblocks in terms of rapid administration.  For phenytoin, there are several risks associated with rapid administration, including infusion reactions and severe injection site reactions.  Because of this, most institutions preferentially use the prodrug phosphenytoin. However, as an antiepileptic with sodium channel blocking properties, it carries significant  cardiovascular risks and patients should be monitored during and after infusions. Package labeling and guidelines recommend administration no faster than 150 phenytoin  equivalents per minute through a 0.2 micron filter. And further complicating matters are the number of vials required for loading doses, as well  as NIOSH hazardous medication designation requiring PPE during compounding and administration, making this less than an ideal drug for rapid infusions for status epilepticus.  Falproic acid is an attractive agent for rapid administration, as it has been studied at rates up to 10 milligrams per kilogram per minute, but it carries a similar hazardous  drug warning for reproductive risk to phosphenytoin. It requires garbing and double gloving for compounding and makes bedside compounding and administration quite complex.  Phenobarbital is an effective antiepileptic, but it's usually used second or third line due to significant cardiovascular and neurologic effects, such as bradycardia and respiratory  depression, which rapid administration may significantly exacerbate. There are two other antiepileptics we can consider for urgent control therapy, levotiracetam  and lacosamide, which will be the focus for the rest of our presentation. They have relatively few barriers to rapid administration, which we'll discuss in depth.  Levotiracetam requires several vials for loading doses, which can be a barrier when thinking about sterile compounding requirements.  And lacosamide has some sodium channel activity, which can cause PR interval prolongation and bradycardia.  These medications have been studied for rapid administration and we'll assess their safety and efficacy today.  We'll start with levotiracetam, which is a first-line agent for urgent control therapy for its favorable side effect profile compared to other agents we just discussed.  The one downside of levotiracetam is that it is supplied as 500 milligrams per 5mL vials.  Patients presenting with seizures will require anywhere from 20 to 60 milligrams per kilogram as an initial load, up to 4,500 milligrams.  To put that in perspective, a 2-gram load would be just these 4 vials, whereas a 3-gram load would be 6 vials, and then a 4.5-gram load, which would be just for your 75-kilo  patient, would be 9 vials. Some institutions utilize commercially available pre-mixed bags to administer loading doses.  However, these are only available in 500 milligram, 1,000 milligram, and 1,500 milligram doses. So multiple bags are required, which could impede rapid dosing.  Other institutions compound doses at bedside or have them delivered from central pharmacy in small-volume piggybacks, but this takes time as well.  And we intermittently do have shortages of normal saline and other small-volume solutions. So what would be the safest and fastest way to administer levotiracetam to our actively  seizing patient?  Originally, levotiracetam was manufactured as a 200 milligram per milliliter unbuffered solution, which had high rates of irritation with IV administration in early animal studies.  The current IV formulation is supplied as a 100 milligram per milliliter buffered solution with a PHF 5.5, which is right in that sweet spot for comfortability.  The original package labeling recommends all doses to be diluted in 100 milliliters of normal saline, dextrose, or lactated ringers and administered over anywhere from 15 to  60 minutes. There have been two pediatric and adult studies since its initial approval, which use faster administration rates.  Wheelis and colleagues studied patients receiving doses up to three grams and minimally diluted them in a one-to-one dilution administered via an IV pump over six minutes.  They showed no infusion reactions or cardiovascular side effects with this rapid infusion. And then the ECLPS trial in 2019 evaluated efficacy of levotiracetam versus phenytoin  in a pediatric patient, population of convulsive status epilepticus, and they used the recommended  dilution of 100 milliliters, but they infused it over five minutes, and they had no reports of adverse effects.  And finally, the ESET trial compared the efficacy of levotiracetam, valproic acid, and phosphenytoin  for status epilepticus using a one-to-one dilution, and they infused it over 10 minutes with just one report of hypotension and arrhythmia within one hour of the levotiracetam dose.  As levotiracetam has minimal side effects, even at high loading doses up to 60 milligrams  per kilogram used in the ESET trial, these studies have set the stage for rapid administration  of levotiracetam, but the question becomes, can this drug be administered undiluted and as quickly as an IV push?  Here we have three retrospective studies evaluating the safety of IV push levotiracetam. The first study by Morgan and colleagues is a single-arm observational cohort of patients  receiving IV push levotiracetam up to 1,000 milligrams. They included nearly 200 patients with a total of 1,626 doses, and since all the doses were  1,000 milligrams or less, the majority of these patients were on it for seizure prophylaxis or resuming their home maintenance dose in an IV form.  They administered the doses undiluted over two to five minutes as an IV push and reported no injection site reactions, but three patients did have levotiracetam discontinued due to  behavioral adverse effects. Next was the Haller study, which is the largest evaluation of IV push levotiracetam to date, including 953 patients with over 8,500 doses.  This is another observational cohort study, and they included patients receiving doses up to 4,500 milligrams.  However, 92% of the doses were maintenance doses, so a majority were either 2,000 milligrams or less, and only two of them were the highest dose, 4,500 milligrams.  They administered the drug undiluted over five minutes, and to maintain sterility and decrease the number of vial punctures per syringe, nurses were encouraged to administer  all doses sequentially in 10-mL syringes, which are 1,000-milligram doses, until the total dose was given.  For safety outcomes, they noted only two injection site reactions, thought to be related to levotiracetam,  and two other patients did have burning at their injection site, but that was thought to be related to other medications, and that's quite impressive for such a large cohort of  patients and doses. And finally, we have the Alkazemi study, which was published just earlier this year, and  it's a retrospective cohort comparing the safety and efficiency of IV piggyback versus IV push administration of levotiracetam.  They included patients who received doses of at least 1,000 milligrams all the way up  to 4,000 milligrams, and doses in the IV piggyback group were diluted in 100 mL of normal saline  given over 15 minutes, whereas doses in the IV push group, nurses were instructed to dilute the levotiracetam in a one-to-one manner administered over five minutes.  Similar to the Haller study, a majority of the doses were maintenance doses, so over 95% were less than 2,000 milligrams in this study.  The authors did assess injection site reactions, noting zero in the IV push group and only  one in the IV piggyback group, and they also collected data on infusion reactions, including  bradycardia, hypotension, and sedation, which are not common side effects associated with levotiracetam, but they noted low rates of each similar between the two groups.  And finally, they assessed the time from order verification to administration, which was decreased by 20 minutes for the stat orders and decreased by 30 minutes for all first  dose orders between comparing the IV push group to the IV piggyback group. So, overall, it appears that IV push levotiracetam is very safe, with thousands of patients included  in these studies and only three injection site reactions reported. While we gain a great deal of information from these studies of IV push levotiracetam,  there are several limitations that should be addressed, and it leaves us with more questions to be answered.  First, all three studies presented were retrospective in their design, which makes it difficult  to assess for real-time adverse effects, which were not explicitly documented in the chart. Additionally, these studies rely on nurses following medication administration protocols  without deviating from them. One survey by the Institute for Safe Medication Practices showed that over 80% of nurses surveyed  reported diluting medications prior to administration, which could affect the outcomes that are reported in these retrospective studies.  Additionally, efficacy of rapid IV push administration has not been evaluated head-to-head against IV piggyback infusion.  It's hypothesized that an IV push would give a faster time to onset of action, and therefore  a faster termination of seizures, but this has not been evaluated or prospectively studied.  Furthermore, and probably the biggest limitation of the studies I just presented, are the limited evaluation of loading doses above 2,000 milligrams for levotiracetam.  The highest perceived benefit of rapid IV administration of these drugs is in actively seizing patients.  However, these patients need the highest doses, and those have not been well-evaluated as of yet.  Leucosamide is the next drug we'll be discussing for rapid administration. It's an antiepileptic approved for treatment of partial onset seizures, but it's gaining  popularity for off-label treatment of status epilepticus, as an in vitro studies have shown  its ability to stabilize hyperexcitable neuronal membranes and inhibit neuronal firing by slow inactivation of sodium channels.  Due to its activity on the sodium channels, there is a potential for cardiovascular side effects, including PR interval prolongation, hypotension, and bradycardia.  It was initially unknown if giving leucosamide faster than the manufacturer recommended would worsen these side effects.  The original package labeling for leucosamide recommends administration diluted or undiluted over 30 to 60 minutes.  However, two small studies in 2011 by Hoffler and Kellinghaus assessing leucosamide efficacy showed that giving leucosamide as fast as 80 milligrams per minute was well-tolerated  and did not result in increased cardiovascular side effects. Leucosamide is a Schedule V controlled substance, so when it has to be compounded in central  pharmacy, there are significant delays beyond those that a non-controlled substance would have.  Based on these two studies, several institutions have adopted IV-pushed leucosamide as their preferred method of administration in order to expedite drug delivery by placing it in  automated dispensing cabinets for direct undiluted administration.  This is what Davidson and colleagues did in 2018, where they assessed the safety and efficiency of IV piggyback versus IV-pushed leucosamide administration.  They included 166 patients receiving doses ranging from 50 to 400 milligrams. The IV piggyback group received doses from their central pharmacy diluted in 50 mils  of normal saline, administered over 30 minutes. The IV-pushed group received leucosamide from automated dispensing cabinets on the patient  care units and administered it undiluted at a rate of 80 milligrams per minute. Similar to the levotiracetam studies, most of the doses evaluated were maintenance doses  and were 200 milligrams or less. For the safety outcomes, they reported zero injection site reactions in either group.  One patient in the IV piggyback group did have PR prolongation, and then two patients in each group had bradycardia within two hours of receiving leucosamide, but neither of these  required intervention.  For the efficiency outcomes, they noted a 75-minute time to administration improvement, which is likely due to the drug being placed in automated dispensing cabinets.  A recent study of IV piggyback versus IV-pushed administration of leucosamide was published by McLaughlin and colleagues.  The authors noted that in 2018, the small-volume fluid shortage prompted their institution to transition all IV leucosamide doses from piggyback infusions to undiluted IV-push.  They therefore evaluated 175 patients with over 1,000 doses of leucosamide, with dosing ranges from 50 to 400 milligrams.  Although the authors did not report administration rates for each group, it can be inferred that  they utilized a diluted infusion over 30 to 60 minutes in the piggyback group and a rate of 40 to 80 milligrams per minute in the IV-push group.  They report similar safety events in each group, including seven injection site reactions  in the IV-push group and only one instance of phlebitis, which resulted in the line removal.  They also assessed bradycardia and hypotension, as well as sedation on the RAS scale, all of which were low rates in each group, and they were similar between the IV piggyback  and IV-push groups. While these two studies are promising for establishing safety and efficiency of IV-pushed  leucosamide, similar to levotiracetam, we have no comparative data which establishes improved efficacy of IV-pushed leucosamide over an IV infusion.  We again hypothesize that IV-push administration would give us a faster time to therapeutic concentration.  There was, however, one dose-finding study of leucosamide reported in the Australian Package Labeling, which compared IV loading doses to oral doses for bioequivalence.  To orient you to this graph, we have leucosamide concentration over time after administration of a loading dose.  As you can see, a 200 mg IV loading dose over 60 minutes achieves a maximum concentration of about 5, which is the red dotted line.  When a 200 mg loading dose is given over a shorter period, just 15 minutes, the maximum concentration is about 20% higher, and therefore it does not meet bioequivalence criteria to  oral leucosamide, which is shown on the solid black lines. Based on this, I would hypothesize that an IV-push administration of leucosamide would  achieve an even higher maximum concentration initially and potentially terminate seizures faster.  However, that is yet to be proven in clinical scenarios and is definitely an area for further research. To sum up our discussion, I hope you take away a few final pearls.  First, there are several ways to decrease the time to antiepileptic administration,  and based on the data presented today, placement of your antiepileptics in an automated dispensing  cabinet as opposed to being dispensed from central pharmacy is a great first step to shave significant time off.  Next, the data, while retrospective in nature, overwhelmingly shows that rapid IV-push administration  of levotiracetam and leucosamide are safe compared to IV piggyback administration. There are two gaps in the literature still, however, including the safety and efficiency  of rapid administration of very large IV-push doses, especially in our status epilepticus patients. And efficacy data in this patient population is also still lacking.  Future studies should focus on the areas of large doses and efficacy. I want to thank you all very much for your time and the opportunity to speak on this  topic, and I would love to join you in the chat for any questions you might have.

Video Summary

In this video, Erin Dudaszewski, a clinical pharmacist at Mayo Clinic, discusses the safety and efficacy of rapid administration techniques for antiepileptic drugs. Status epilepticus, a medical emergency, requires immediate control therapy with benzodiazepines followed by urgent control therapy with IV antiepileptics. Several factors should be considered when determining if a medication is suitable for rapid administration, including pH, osmolarity, infusion reactions, logistical obstacles, and safety standards. Phenytoin, valproic acid, and phenobarbital have limitations for rapid administration due to risks of infusion reactions or side effects. Levotiracetam and lacosamide are more favorable options. Levotiracetam has been safely administered through rapid IV push with minimal side effects reported. Lacosamide has also shown to be well-tolerated when given as fast as 80 mg per minute. However, more research is needed to evaluate the efficacy of rapid administration for larger doses and to compare IV push to IV infusion.

Asset Subtitle

Neuroscience, GI and Nutrition, 2022

Asset Caption

Status epilepticus is a neurologic emergency associated with significant morbidity and mortality. Aborting status epilepticus as quickly as possible is the mainstay of therapy, accomplished through rapid administration of first- and second-line agents. Unfortunately, up to 30% of patients in status epilepticus fail to respond to initial treatment and 15% continue to have seizures despite the use of three or more agents. These patients' condition is defined as refractory status epilepticus (RSE). Many of these patients progress to super-refractory status epilepticus (SRSE). After treatment failure, practitioners are forced to implement alternative therapies, for which there is little guidance and a lack of clinical trial data. Management through a ketogenic diet has been tried, but there is a lack of clarity as to ideal candidates and successful techniques. This session aims to provide best practices for rapid administration of antiepileptic drugs, identify viable treatment options for RES and SRSE, and help attendees identify candidates for ketogenic diets.

Meta Tag

Content Type Presentation

Knowledge Area Neuroscience

Knowledge Area GI and Nutrition

Knowledge Level Foundational

Knowledge Level Intermediate

Knowledge Level Advanced

Membership Level Select

Tag Seizure

Tag Nutrition

Year 2022

Keywords

rapid administration techniques

antiepileptic drugs

infusion reactions

levotiracetam

lacosamide

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