Use your prophylaxis. When is it necessary? I have nothing to disclose. So let's get started. Despite the title, not only will we be discussing the when, but also the what and the how. Following this talk, hopefully you will be comfortable identifying when prophylaxis is indicated, select an appropriate agent, and then determine the duration. I always like to link to real life, so let me introduce you to ES. He is a 72-year-old gentleman presenting to the trauma bay following a witness fall down six steps with confirmation of a positive head strike. He has a GCS of 13 and is asking repetitive questions. His past medical history was significant for diabetes and hypertension. CT scan confirmed a subdural hematoma with a midline shift. The intern turns to you and asks if seizure prophylaxis is indicated. How would you respond? When we think about head trauma, subdural, intracerebral, and subarachnoid hemorrhages, we also need to think about the associated procedures, such as craniectomy, craniotomy, external ventricular drain placement, MMA embolization, and then additionally, there are other potential indications, such as stroke and tumors. And when we establish the indication, we must also consider the various stages, early versus late, after an immediate seizure, or based on other comorbidities and medications. So where can we go to find the information? There are actually so many places it becomes difficult to sort through it all. Fortunately, there are guidelines. We love guidelines. But guidelines also come with a level of evidence. In 2016, the Brain Trauma Foundation published guidelines for the overall management of severe TBI. In addition, the American Heart and American Stroke Associations provided approaches to seizure prophylaxis in stroke and spontaneous intracerebral hemorrhage. Then we move on to researching the studies that were the basis of the evidence. And then we dig a little further for additional studies. Temkin et al. started us off in the 1990s and then conducted a randomized, double-blind, placebo-controlled trial in the 2000s for both early and late initiation, showing a significant reduction in seizure occurrence early on. His studies were then followed by retrospective cohorts, some other prospective studies, most of them being smaller trials. It can be a bit overwhelming. But then ultimately, we have meta-analyses and Cochrane databases to sum everything up for us. Remember I said that guidelines come with an evidence ranking? Well, the Brain Trauma Foundation issued a level 2A recommendation, which means that it's based on a moderate quality body of evidence, stating that early prophylaxis for a post-traumatic seizure is better than late. But efficacy is pretty noncommittal, as PTS have not been indicative of overall worse outcomes. So back to the literature we go to make our own assessment. In 2018, the Journal of Intensive Care published a review in which the authors proposed a protocol for use in neurointensive care units. This covered a variety of neurologic conditions with seizure potential. For TBI, it confirmed the early stage initiation with a seven-day course. What I really appreciated about this review is that it discussed a two-day course is that it discussed additional risk factors that may increase the chance of PTS, such as the type of injury, alcohol use, GCS on presentation, and age. And this is just a few of them. But what we need to remember is that early prophylaxis does not necessarily reduce the incidence of late onset seizures. So back to the when. You can see highlighted in green, the newer, more robust studies are focused primarily on traumatic brain injury. Older prospective studies using phenytoin for the first week following surgery showed promise. And later, 315 patients were randomized using levotiracetam or phenytoin. Both showed low risk of post-op seizures. With levotiracetam having significantly fewer adverse effects. Another rather small trial alluded to some benefit to an abbreviated course in MMA embolization. But this is confounded by the fact that the fix itself prevented any seizures. The role following stroke has not been supported. And unfortunately, data actually showed worsening in aneurysmal subarachnoid hemorrhage. There is also no conclusive data on any effects for seizures with neoplasm. So which one do we pick? As we become comfortable with the decision to prophylax, we are then faced with selecting an agent. I'll be focusing particularly on two, phenytoin and levotiracetam. However, I will make brief mention of the others. Surprisingly, the two that I will be focusing on are the two that I will be focusing on. And that is the two that I will be focusing on. Of the others, surprisingly, with all of the agents ever studied, this particular indication still remains an off-label use. Phenytoin, by far, is the most studied to date. There are also several others, such as phenobarbital, benzodiazepines. So let's get into the pharmacology. Phenytoin works on the sodium ions across cell membranes. We like when drugs are 100% available, and this one is IV. However, it's very protein bound, 80% to 90%. So what does this impact? Well, if a patient has, let's say, low albumin, that will result in a higher level of free drug. So how do we account for that? We take a look at serum levels to determine if we are in the target range. Now, just because you're in the target range doesn't mean that you don't experience side effects or that you can't have a seizure. It just gives us a starting point. Loading doses are typically given intravenously and are weight-based. It is important to recognize the administration rate of 50 milligrams per minute, as we will see this contributing to some of the adverse effects. Hemodynamic effects can be seen with rapid injection. It is also a vesicant, which, if infiltrated, can cause significant tissue damage and requires what we call a rescue medication, if you can catch it in time. Also, you may have heard the term purple glove. This is aptly named for its appearance. There are some hematologic effects, a granulocytosis, gingival hyperplasia. This was one they always taught us in pharmacy school. Hepatotoxicity and, of course, hypersensitivity. This one is a delayed hypersensitivity, and this could be your Steven Johnson's or DRESS. NIOSH has deemed this and most of the other agents that I'll discuss as hazardous when it comes to handling. Although not studied, NIASH is a drug that has been approved for use by the FDA. I would be remiss if I didn't insert phosphenatoin in here, as this has become the go-to in many institutions. It's thought to have a milder formulation. It's a prodrug of phenytoin and has the benefit of also being able to be given intramuscularly in the event that there's no IV access. There is still a strict infusion rate, and it shares the same side effect profile and therapeutic range. I'm not going to go into a whole lot of detail about the next few agents, as mentioned previously, because they're rarely used for this, but they appear in some of the older literature. So carbamazepine works on the sodium channels, decreases glutamate. Downside is it's an oral formulation only. So if we were to use this in prophylaxis, that's not really conducive to giving something early. It does have a therapeutic range and needs some monitoring. Some adverse effects. The big one here is the nausea and vomiting. It is an oral formulation. And then hematologic disorders, such as aplastic anemia. Valproic acid. This has a whole slew of adverse effects. And in some trials, this actually showed a trend towards higher mortality. This increases availability of GABA, works on the sodium channels. It, too, is highly protein bound. So same issues that we would see with phenytoin and the circulating free drug. There is weight-based loading dose and maintenance dose. This has several different formulations. There's a liquid. There's oral. There's IV. And you can see all of the adverse effects. Thrombocytopenia, decreased platelet aggregation. This is not something that we need in our head please. Hepatotoxicity. And a fun one, hyperammonemia. So whenever we have someone in the unit on valproic acid who has a change in mental status, one of the first things that we do is we check an ammonia level. There's also a delayed hypersensitivity associated. Phenobarbital. Everyone's heard of. It is a barbiturate. This acts on the GABA receptors. GABA A, not GABA B. And it prolongs the amount of time chloride channels stay open. It has significant CNS depression, some adverse effects of hypotension, bradycardia, ataxia, more hypersensitivity. And it is a controlled substance. You'll see later where this can be limiting. And we're all familiar with benzodiazepines. Lorazepam, midazolam, diazepam. They are our go-tos for active seizures. These bind to the benzodiazepine receptors on GABA neuron, opening chloride channels. Some adverse effects, respiratory depression. So this is a good time to look at a benzodiazepine receptor. So this can be very limiting in that it requires some additional monitoring, especially as we get into some higher dosing. Let's get back to that initial study dosing. Some retrospective cohort studies were conducted to show that lower dosing is just as efficacious. Patanwala et al. did a retrospective cohort. This was small, it was 169 patients, and they pulled all patients that had received 500 mg every 12 hours and compared it to existing data to find there was no difference in seizure incidence with higher dosing. Oman et al. also did a retrospective cohort. This one was larger. It had 866 patients, and what they did was pull multiple doses. It was 500 mg, 750 mg, and 1,000 mg every 12 hours. In comparison, there was no difference in seizure incidence. What did this do? This made us much more comfortable using that 500 mg as our maintenance dose. So, I told you the ones that were most studied. I gave you some of the other ones that appeared in some small trials. So let's get back to how do we decide? Let's revisit our Brain Trauma Foundation guidelines with our Level 2A body of evidence. Benatoin is specifically named in the recommendation, and at that time, there was not a lot of evidence around levotriazetam, but remember, this was published in 2016. As we sift through meta-analyses and the database, we find comparative data showing no difference between efficacy. There were some that did benatoin versus carbamazepine. There were some that added in that placebo. There was benatoin versus levotriazetam versus valproic acid. No difference. Benatoin versus levotriazetam. Still no difference. Something else to think about is concomitant medications that can lower the seizure threshold and contribute to early PTS despite prophylaxis. In the world of trauma, oftentimes there are additional injuries for which we may lean towards some multimodal therapy. Tramadol, an opioid, cyclobenzaprine, a muscle relaxant, are noted offenders. Now this does not mean that all opioids lower the seizure threshold or that all muscle relaxants will lower the seizure threshold. Oftentimes it's specific because of the chemical structure. Additionally, some antimicrobials such as fluoroquinolones, and it is the whole class, I listed levofloxacin because it was the first one that come into my head, and carbapenems. And lastly, remember to review home meds when restarting them in the acute phase as some antidepressants and antipsychotics may contribute. These include bupropion, tricyclic antidepressants, and clozapine. So let's get back to ES. So now, based on what you know, did you change your initial answer?

prophylaxis

neurologic conditions

traumatic brain injury

post-traumatic seizures

pharmacological agents

comparative data