Post traumatic seizure prophylaxis - Phenytoin

Our current therapeutic interventions that are directed at mitigating the damage of secondary injuries after TBI (ischemia, brain edema, vasospasm and seizures) lack robust data supporting their use. For clinicians in the ED, it’s difficult to make sound therapeutic decisions to help the patient and the team.  Although these are difficult areas to study, we never the less still need to make the best decisions we can.

Posttraumatic seizures (PTS) are seizures that occur after TBI are one of those gray areas of therapeutics. It seems logical to attempt to prevent PTS; it can cloud the neurologic evaluation, aggravate intracranial pathology, and, in some patients, be the precipitating event that leads to herniation—in part because seizures are accompanied by changes in oxygen delivery and CBF, altered blood pressure, and increases in ICP. But since PTS only occurs in approximately 15% of patients with blunt severe, and that antiepileptic drugs (AED) therapy is certainly not benign - risk factors have been identified to provide PTS prophylaxis in appropriate patients.  The BTF guidelines suggest that AEDs are indicated to decrease the incidence of EARLY PTS in patients with one or more PTS risk factors. The BTF guidelines go on to only suggest phenytoin as the preferred first line agent.  A stronger recommendation isn’t possible because, again, there is little robust data to go on.

I wont say phenytoin has been extensively studied in this field, but it is the most studied AED for PTS prophylaxis and its data is the most favorable.

From a meta-analysis conducted by Temkin, phenytoin demonstrated a favorable and significant risk reduction for early seizures, but not for late seizures. And as you can see it and CBZ were the only agents (alone or in combination) that demonstrated a benefit in early seizures.  The use of carbamazepine is limited because it does not have an IV formulation and valproic acid, though a proposed alternative, is not recommended to be used since, when compared to phenytoin has been shown to increase the incidence of late seizures and trend towards worse mortality.

One of, if not the best piece of evidence we’ve got with phenytoin for prevention of phenytoin was conducted back in 1990. The investigators randomized patients to phenytoin or placebo for PTS for one year after serious TBI.  Compared to placebo, patients given phenytoin suffered fewer early seizures compared to placebo.

This risk reduction reached significance for early seizures [RR 0.27 (0.12-0.62)] but no difference for late seizure, or mortality.  ADRs, predomninantly rash cause more patients in the phenytoin arm to discontinue treatment early compared to placebo, but overall, what this study provided was that it added to the data regarding the benefit of phenytoin compared to placebo in preventing early phenytoin and that no benefit exists after 7 days,

Now, yes, this trial was conducted 22 years ago, very little robust data has been published to add or challenge the results of this trial. Small single center studies, case reports are what we’ve got to go on, and the meta-analyses of all these studies again, do little to add or challenge the results of this trial.

In the September issue of Neuro critical care, there was a great series of articles discussing Emergency Neurological Life Support by a number of ED and Neuro physicians (one of those being S Weingart) covered PTS for TBI. This modern, up-to-the-minute review they recommended phenytoin for first line treatment of PTS in appropriate sTBI patients, citing the 1990 Temkin NEJM article reflecting the lack of good, recent data.

Having newer AEDs on the market now compared to 1990, begs the question whether there is a better alternative AED for PTS

In the article, Weingart and his colleagues gave just a one-liner regarding a potential alternative to phenytoin for PTS. That AED is levetiracetam.

Again, since it’s not 1990 anymore, we now know more about the intracranial pathophysiology that occurs after TBI. Looking closer, on a cellular and molecular level, current therapeutic targets under evaluation aim to minimize activation of toxic pathways and to enhance activity of endogenous neuroprotective mechanisms and establishing a balance between these pathways.

It’s been proposed that the reason why the previously studied AEDs have failed to show benefit is that 1) they do not address these mechanisms, being devoid of antiepilepogentic properties (actually preventing seizures rather than just preventing the propagation of localized seizure activity) and 2) are not given at an optimal dose as soon after the primary injury as possible.

Since we know that valproic is probably not the best agent to investigate, levetiracetam is one AED that has been identified to have these properties.

More to come next week.

Reference:

1.     Bratton SL, et al. Guidelines for the Management of Severe Traumatic Brain Injury, 3rd edition: Antiseizure prophylaxis. Journal of Neurotrauma2007;24(S1):S82-S86

2.     Temkin NR. Antiepileptogenesis and seizure prevention trials with antiepileptic drugs: meta-analysis of controlled trials. Epilepsia 2001;42(4): 515-524

3.     Temkin NR, et al. A randomized, double-blind study of phenytoin for the prevention of post-traumatic seizures. NEJM 1990;323(8):497-502

4.     Jensen FE. Posttraumatic epilepsy: Treatable epileptogenesis. Epilepsia, 50(Suppl. 2):1-3, 2009

5.     Benardo LS. Prevention of epilepsy after head trauma: Do we need new drugs or a new approach. Epilepsia 2003;44(Suppl. 10):27-33

Playing the Cards Right with Nicardipine

Since starting my residency, nicardipine has become one of the drugs that I have grown to love…maybe even becoming one of my favorite drugs to use for blood pressure control, especially in neurological emergencies such as acute ischemic stroke and subarachnoid hemorrhage. Time and time again, it has never failed me in these settings. It’s like a best friend who shows up at the right place and at the right time who knows exactly what to do in a difficult situation and does it right.

Nicardipine is a dihydropyridine calcium channel blocker that exerts its physiological effect by relaxing the vascular smooth muscle, leading to vasodilation and reduced systemic blood pressure. The great thing about it in the setting of neurological emergencies is that it has the added benefit of crossing the blood-brain barrier, allowing for relaxation of the smooth muscle within the cerebral vasculature. Its onset of action is anywhere from 5 to 15 minutes, and it has a predictable dose-response relationship. The other property that nicardipine has that makes it an ideal parenteral antihypertensive agent to use is its ease of dose titration, which is illustrated below:

• Starting dose: 5 mg/hr
• Titrate upward by 2.5 mg/hr every 5 to 15 minutes based on observed blood pressure response
• Maximum dose: 15 mg/hr
• Decrease rate by 2.5 mg/hr increments every 15 minutes if blood pressure is overcorrected until target blood pressure is reached

In my own personal experience, however, for some reason, EM attending physicians and EM residents resort to other parenteral antihypertensive medications first. As long as the pulse of the patient can tolerate it, the agent that is chosen first by most of the physicians that I work with is typically labetalol, which in many cases ends up not sufficiently reducing the blood pressure to our target. We usually end up switching to a nicardipine drip anyway. As this study demonstrated for a variety of hypertensive crises, many clinicians ultimately use nicardipine when labetalol fails due to the fact that nicardipine provides more dependable control of blood pressure. Speaking to some of the clinicians at my own institution, they tend to favor nicardipine as well due to the fact that there is a lesser incidence of bradycardia and hypotension compared to labetalol. The one thing that tends to be cumbersome for them with nicardipine is the fact that if a peripheral IV is used to infuse the drug, the line must be changed every 12 hours as long as the infusion is running to minimize irritation of the peripheral veins.

Granted, it may take some time for the nicardipine drip to be made and to program the infusion pump to deliver the medication, but this should not be a limiting factor in not using the medication at all. In fact, it does come in a premixed bag ready for use, so this can certainly reduce some time associated with preparing the product; in addition, the premixed formulation of nicardipine demonstrated greater benefit in controlling blood pressure for patients in the emergency department in comparison to labetalol in the CLUE study.

For neurological emergencies, I recommend the use of nicardipine over labetalol. It is important to remember that in this setting, the blood pressure should not be overcorrected too rapidly; this can be achieved by maintaining the systolic blood pressure between 140 and 160 mmHg. With this kind of control, the cards are indeed played right with nicardipine.

Amide and Ester Local Anesthetics

Ultrasound guided regional nerve block is an evolving trend in ED procedural sedation.  The thought being, local anesthetics could be used instead of benzodiazepines, ketamine or propofol, which could allow for earlier patient discharge from the ED and lower risk of complications (respiratory depression).

Navigating the library of local anesthetics can be complex, particularly if your patient reports some allergy to lidocaine or prilocaine or if the drug is on shortage (an evolving problem in the US).  Let’s just pretend it’s an allergy that you concerned enough about to not use that particular drug, but does that mean local anesthetics are off limits?

Not necessarily.

Local anesthetics are divided into two main groups based on their chemical structure: amides and esters.  Generally, allergy or hypersensitivity to an amide local anesthetic does not “cross react” with ester local anesthetics.

A quick way to remember which agent belongs in which category is that amides generally have two “I”’s and esters have one “I.” The one exception to this is procainamide, which is classified as an ester.

Amides	Esters
Bupivicaine Lidocaine Mepivicaine Prilocaine Ropivacaine Etidocaine	Procaine Chloroprocaine Tetracaine Cocaine Benzocaine Novocaine Procainamide

Including but not limited to…. Thrombolysis Contraindications

An important, but all too often overlooked contraindication to thrombolytics for acute ischemic stroke is known bleeding diathesis including but not limited to current use of oral anticoagulants or an INR > 1.7 or a PT > 15 sec, heparin administration within 48 hours preceding stroke onset and an elevated aPTT at presentation, or platelet count less than 100,000 mm3.

Including but not limited to… Very important, yet easily overlooked.  It also complicates matters, in that, what should or could be included under this contraindication? Platelet dysfunction from HCV, ITP, other oral anticoagulants, hemophilia a or b?

It comes down to risk/benefit. A patient’s risk of ICH secondary to tPA is roughly 8% in the best case (data from NINDS). In real world practice, most likely closer to 13%. Administering tPA to patients with the ‘not limited to’ bleeding diathesis that aren’t explicitly listed could further increase the risk of secondary ICH transformation. All for an improved mRS at 90 days.

The best drug you aren’t using: Fosphenytoin

Fosphenytoin (fosPHT) is not a new drug. It was designed to improve the water solubility of phenytoin (PHT) thereby reducing the risk of cardiac arrhythmias and hypotension during administration (from lack of propylene glycol, although PHT is still a 1b antiarrhythmic). Improved water solubility also eliminates the risk of tissue necrosis if extravasation occurs. This allows for much more rapid infusion of fosPHT (150mg/min) as well as ability to administer IM.  Unfortunately, the drug failed to take-off as a PHT replacement because of its considerably higher acquisition cost.

That was 20 years ago. Today, the two drugs cost virtually the same amount of money. Even when cost is taken out of the equation, hesitance to leave PHT on the shelf still exists.

The main concern that has been expressed to me regarding replacing fosPHT with PHT is the time that it takes to convert fosPHT to active drug will negate its ability to be infused faster.  While this thought is completely logical, pharmacokinetic studies tell us otherwise.

When fosPHT is administered at appropriate infusion rates (150mg/min) and because fosPHT displaces PHT from plasma protein binding sites, the delay in conversion from prodrug to PHT will be compensated.

Let me explain.

In order for fosPHT to be activated, it must be cleaved by phosphatases in the blood and tissues and then spontaneously hydrolyses to PHT. The half-life of this process ranges from 7-15 minutes and conversion occurs faster with higher doses and faster infusions.  This evidence taken alone would certainly lead one to agree with the above concern.

The game-changing characteristic of fosPHT is that it competitively displaces PHT from plasma protein binding sites (albumin).  So after rapid IV administration, the fosPHT that has yet to be activated is increasing the amount of free PHT in the blood due to displacement.  Since only free (unbound) PHT can enter the CNS and exert its antiepileptic activity, free PHT levels are a better measure of pharmacologic activity. As a result, free PHT therapeutic concentrations are reached faster with fosPHT compared to PHT.

What advantage could PHT have now? I say none.

Reading...

Fischer JH, Patel TV, Fischer PA. Fosphenytoin: Clinical Pharmacokinetics and Comparative Advantages in the Acute Treatment of Seizures. Clin Pharmacokinet 2003; 42(1):33-58

Browne TR, Kugler AR, Eldon MA. Pharmacology and pharmacokinetics of fosphenytoin. Neurology. 1996 Jun;46(6 Suppl 1):S3-7

Equiosmolar loads from sodium chloride vs sodium bicarbonate

It's an interesting dilemma when considering how exactly to safely integrate hyperosmolar sodium chloride products into the emergency department.  Stocking vials of 23.4% sodium chloride in the ED, whether in a Pyxis/Omnicell or a locked cabinet, creates an unnecessary risk for significant medication errors. Though no specific threshold exists for what is considered a 'concentrated sodium chloride' product by the joint commission, the decision must be made by the hospital P&T committee. Lower concentrations (3% and 5% saline) will most likely still exceed the threshold.

However, these products can be stocked on the patient unit if 1) they are in their most ready to administer form and 2) if their absence places patients at risk for delays in therapy.

Or, 8.4% sodium bicarbonate could be considered. In most EDs it's already readily accessible from Pyxis/Omnicells.  It's been theorized that administering an equiosmolar load of hyperosmolar treatment to TBI patients should achieve the same ICP reduction. And there is some evidence to suggest this may in fact be the case. (Bourdeaux CP, Brown JM. Randomized controlled trial comparing the effect of 8.4% sodium bicarbonate and 5% sodium chloride on raised intracranial pressure after traumatic brain injury. Neurocrit Care. 2011 Aug;15(1):42-5)

Not to suggest that one should replace the other, but in an emergent situation, if the pharmacy is not able to deliver the hypertonic sodium chloride in a timely fashion, an equiosmolar dose of sodium bicarbonate could be considered.