Good afternoon. I'm really happy to be here today to talk about weathering the storm, what's new in the treatment of paroxysmal sympathetic hyperactivity, neuropathic pain, spasticity, and dystonia. I have nothing to disclose for today's presentation. In 2014, a consensus guideline or definition was developed to describe paroxysmal sympathetic hyperactivity, or PSH. It is a clinical syndrome of paroxysmal and episodic sympathetic and motor hyperactivity after an acquired brain injury. This can be triggered either by an osteoceptive stimuli or an environmental stimuli, and either way the clinical syndrome remains the same. It consists of sympathetic activity, hyperactivity, including tachycardia, hypertension, and diaphoresis, as well as increased motor activity, like posturing. As we discuss PSH today, it's important to also recognize that this overlaps and clinically looks similar to recognizing pain in these patients. In children with severe neurologic impairment, like Mark just discussed, complexity of pain leads us to sometimes not recognize that a patient is experiencing pain. We also may have a limited understanding of pain behaviors, which I'll talk about in just a second. It's also important to recognize that these patients have many reasons to have both chronic as well as acute sources of pain. And as Mark highlighted as well, it's really important that we incorporate caregiver or parent input as we learn more about these patients and get to know what their specific pain behaviors may be. Some common pain behaviors that we may see in this patient population include things like vocalization, crying or whimpering, restlessness, movements that are above their baseline, atypical features such as laughing or breath holding. And today we'll focus primarily on paroxysmal sympathetic hyperactivity. But some of the other common causes or things that could trigger a PSH episode, such as neuropathic pain, dystonia, and spasticity, we'll cover a little bit more in detail. It's important to recognize these patients have other reasons they may be experiencing pain. Commonly that could be something like a fracture, otitis media, or less commonly something like a dental carry or a UTI. Once we've determined that we've, you know, ruled out pain and we've treated a patient's pain appropriately, we want to start addressing the paroxysmal sympathetic hyperactivity. Unfortunately, there are no consensus guidelines that exist for management and the literature that is present is mostly case studies or case reports and very limited, especially in pediatrics. We want to first start by considering non-pharmacologic management that we can use for these patients. This includes first reducing any stimuli that could be triggering this patient environmentally. Thinking about things like supportive care, managing fluids, dehydration, making sure your patient isn't constipated or having urinary retention, and then checking for wounds. Ultimately, most of these patients will require some type of pharmacologic therapy, and we'll talk about this today as both abortive and then preventative medications. It's important that we use these simultaneously as they're most effective as we can abort an episode and then prevent it going forward. The focus will be symptom management, and this is very patient-specific. So the trigger that your patient is causing the PSH episode is important as we choose these medications. And then ultimately, since there aren't any guidelines, we're going to rely heavily on patient-specific factors and adverse effects of these medications as we choose a medication that's appropriate for this patient. Starting off with abortive therapy, there are four medications which we'll cover today, morphine, propofol, benzodiazepines, and dexmedetomidine. I'll highlight that morphine has really only a role as an abortive medication. Propofol, benzodiazepines, and dexmedetomidine may also have a role in preventative therapy. Starting off with morphine, the data that we have for morphine is extremely limited, as we'll talk about with all of these medications, limited to case reports and case series. But universally, this morphine is most beneficial when the trigger for PSH was pain. Pharmacokinetics that benefit us when using morphine is its onset is very rapid, which is something that we're looking for in an abortive medication. Its half-life is relatively short, so it can be re-dosed. In terms of risks that we think about with morphine, respiratory depression, hypotension, and pruritus, and also tolerance if this becomes a medication that the patient is frequently requiring. All of the literature that's published is mostly using morphine, but you could consider another rapid-acting opioid such as fentanyl. Dexmedetomidine is something that I think is being used a lot more in practice, but really doesn't have very much published literature quite yet. One case report that I'd like to highlight is in an eight-year-old who presented to the ICU post-TBI. On day five of admission to the ICU, this patient was experiencing episodes of PSH that were refractory to increases in sedation of propofol and fentanyl. She was hypertensive, trying to be managed on IV lobatolol, and ultimately required a dexmedetomidine infusion. This was titrated up, and she was able to be transitioned to clonidine and propranolol, and her symptoms improved. Dexmedetomidine is pretty rapid-acting, but not quite as quick-acting as morphine, so you do need to account for the time it takes to reach steady state for this medication. And the biggest benefit for dexmedetomidine in comparison to morphine is that it doesn't suppress the respiratory drive. What we should keep in mind, that if we're going to use dexmedetomidine, it may cause hypotension and bradycardia. Next up is propofol. This medication is a general anesthetic, which induces rapid anesthesia. It has multiple mechanisms, which may help to abort a PSH episode. Its biggest benefits are that it's highly lipophilic, so it has a rapid onset. It also has rapid metabolism, which allows us to quickly sedate, but also shut off and wake the patient up and have a good neuro exam if needed. I would be not a pediatric pharmacist if I didn't highlight that this does come with a risk of propofol infusion syndrome, and we should be mindful, especially if we aren't sure of the duration that we'll need propofol for. The biggest risks with propofol infusion syndrome come with both dose and duration, so its use should be really thoughtful. And the last medication we'll talk about today in terms of abortive medications is benzodiazepines. And I think this medication is used pretty extensively for abortive episodes, but the data that is published is very inconsistent in its results. I think this has a lot to do with the fact that most of these patients, as we'll talk about, use benzodiazepines as part of their preventative regimen, and so most have developed tolerance to the benzodiazepines. In terms of abortive medications and using a benzodiazepine, we would primarily use midazolam or lorazepam due to its more rapid onset. But we do have to be mindful if we choose lorazepam that it does contain large amounts of propylene glycol, and so that will limit how much lorazepam we can use. When we choose benzodiazepines, some of the things that we want to think about is that this can cause respiratory depression and also tolerance, as I mentioned previously. But as a PICU pharmacist, I'm also thinking about this contributing to ICU delirium as well. So once we've chosen an abortive medication, and hopefully it's been successful, we also want to be thinking about what we can be starting as a preventative regimen. I'm going to talk about a lot of these today. Due to the time, we'll really just talk about them briefly. But each of these medications has different benefits and also side effects, and each medication you'll have to choose based on your patient's symptom management that you're targeting, but also side effects that you're concerned with. Starting off with medications that provide sympathetic modulation, these are the most widely used for paroxysmal sympathetic hyperactivity, starting off with a non-selective beta blocker like propranolol. This by far has the most data, both in adult and pediatrics. In a randomized double-blind controlled study in adults, they were all patients presenting to the ICU with TBI. They were randomized to either placebo or propranolol within 24 hours of admission. They all had on the propranolol group less hypertension, tachycardia, and agitation. And this has been seen similarly in pediatric case reports. Propranolol is highly lipophilic and does cross the blood-brain barrier. We should keep in mind, though, that it does cause hypotension and bradycardia, and those might be dose-limiting. Clonidine has a similar mechanism and has similarly shown benefit in vital sign abnormalities in case reports in pediatrics, mostly targeting hypertension and tachycardia. The unique part about clonidine is that we have the ability to give it either enterally and or topically. Topical administration provides a consistent amount of delivery of clonidine. But one of the downsides to clonidine transdermal patches is that many of these patients are going to have issues with hyperthermia and sweating. And so we do sometimes run into issues with having the clonidine patch actually adhere successfully to the patient, something to keep in mind. Side effect profile-wise, very similar to propranolol, but does cause more sedation than propranolol. If your patient has sources of neuropathic pain, it might be useful to add something in that targets neuropathic pain specifically. The medication that has the most data for this is gabapentin, again, limited to mostly case reports, but shown effect for both visceral hyperalgesia, spasticity, and allodynia. Generally, gabapentin is extremely well-tolerated other than sedation, and that can usually be mitigated by titrating the medication slowly. Methadone also is sometimes helpful for neuropathic pain, but unfortunately, in the literature, the efficacy has been quite limited. Methadone also has very challenging pharmacokinetics. It has a very long half-life. And so in choosing this medication, you do have to give it some time to reach steady state. So I think if you would choose methadone as your medication for the patient, you'd have to really be thoughtful about titration and when to assess if this is an effective medication for the patient. If your patient is also experiencing spasticity, you may choose something like baclofen. This is a GABA receptor agonist. And in case reports, it's been shown to improve hypertonia and dystonia. This medication is unique, just like clonidine, in that we can give it enterally, but we can also give it intrathecally. Intrathecally, IT administration has been shown to be more effective. However, it does come with downsides, such as catheter infections and also a much higher risk of baclofen withdrawal. Baclofen withdrawal can ultimately be life-threatening and cause seizures. And IT baclofen has a much higher risk of this. Otherwise, baclofen does cause sedation. And so again, you'd want to titrate this medication up slowly. In terms of treating dystonia specifically, you can choose something like benzodiazepines. And as I mentioned in the abortive literature, it's similar in the preventative literature in that the results are quite mixed. There was a study that looked at patients who used these medications as an as-needed regimen and showed that actually clonazepam was probably more effective than diazepam. But again, in this study, many of these patients had diazepam as part of their spasm or spasticity regimen. And so that's probably why most of these patients didn't respond as well to diazepam. Some of the benefits of using a benzodiazepine in your patient's regimen is that if you use it IV, diazepam IV, it has a rapid onset. But clonazepam has a very long half-life, and that may provide you benefit in a patient that is quite brittle. In terms of risks, they do cause sedation. And then again, I've highlighted it before, but tolerance is a big issue in using benzodiazepines as part of the abortive and preventative regimen. These next couple of medications we're going to talk about have even more limited data. The first one is bromocriptine. This is a direct dopamine agonist. And in case reports, this has been most effective for patients that have hyperpyrexia as part of their underlying conditions. There was a case report in a 10-year-old with a traumatic brain injury who was able to start bromocriptine. She had contraindications to propranolol. She was able to start bromocriptine and wean off of it in five weeks, and it was quite effective for her. But again, I think this is limited to patients who have contraindications to other medications that we've previously discussed or who primarily have hyperpyrexia as their trigger. Bromocriptine does have several side effects to be concerned about, especially in pediatric patients, such as confusion or dyskinesias. Dantrolene is the next medication we'll cover briefly. This is a ryanodine receptor antagonist. This serves as a skeletal muscle relaxant. This is quite effective in case reports, but is primarily limited and used for refractory patients with muscle contractures. The reason for that is that the risk of hepatotoxicity is quite high with dantrolene, and so this is really reserved for refractory cases. Lastly, we'll discuss tetrabenazine. The literature for this is, again, quite limited, but there was a study in pediatric patients looking at using tetrabenazine and hyperkinetic movement disorders. Overall, these patients were shown to have improvement in reduced severity of movements and did have a similar side effect profile to adults. One thing to highlight here is that these patients required much higher doses than what we would typically use in an adult patient to get the same amount of efficacy, and with that does carry a higher risk of side effects. Some of the things we worry about with tetrabenazine, sedation, abnormal movements, or Parkinson-like movements. So as I was putting this together and thinking about what was new in the treatment of PSH, I think the first thing that popped into my literature search was a recently published guideline from a pediatric hospital, and they used locally to direct treatment, especially for providers, as Mark highlighted, who may not be familiar with this condition. This guideline was targeted based on symptom management and provided several medication options for those treatments. It did also include non-pharmacologic interventions, and then as Mark highlighted, the consideration of getting expert consultation either from colleagues in rehab medicine and or neurology. There are several other medications which I did not discuss today that have been shown to be effective in adult patients, but we have to consider things like if this is available in a form that we can give our pediatric patients and how we would dose that. So those are not covered today, but I think there's a lot to be studied in the future. And I think overall, development of either local guidelines or consensus guidelines to help guide providers in treating these patients. In summary, management of PSH in children is complex, and there are no current guidelines that exist to help us guide treatment. Medication and dosing of medication should be individualized and based on patient response. And overall, when we choose a treatment, consider both the source or the trigger of the PSH episode, as well as adverse effects of the medications. Thank you.

Paroxysmal Sympathetic Hyperactivity

Pediatric Treatment

Non-pharmacologic Therapy

Pharmacological Management

Individualized Care