CONTENTS
- Introduction
- Epidemiology
- Clinical findings
- Differential diagnosis
- Approach to the diagnosis
- Treatment
- Podcast
- Questions & discussion
- Pitfalls
basics
- Paroxysmal sympathetic hyperactivity (PSH) is a pattern of recurrent bursts of dysregulated sympathetic activity, resulting from severe brain injury. These episodes of sympathetic activation are short, dramatic, and often triggered by stimulation.
- PSH can be a challenging diagnosis, which may easily be confused with seizure, respiratory failure, withdrawal, or nonspecific agitation.
- PSH has previously been known by dozens of terms, for example:
- Sympathetic storming, autonomic storming.
- Episodic autonomic instability.
- Paroxysmal autonomic instability with dystonia.
- Diencephalic fits.
pathophysiology
- Normally, descending inhibitory pathways from cortical inhibitor areas exert negative, modulatory activity on sympathetic centers in the diencephalon, brain stem, and spinal cord.(32906174) PSH results from a loss of these inhibitory pathways.
- The precise neuroanatomic substrate is unclear. The closest correlate might be with damage to the white matter tracts in the posterior limb of the internal capsule and posterior corpus callosum (e.g., due to diffuse axonal injury following trauma).
- Multiple cortical and subcortical areas are involved in modulation of sympathetic activity, so the development of PSH seems to require relatively diffuse or multifocal cerebral injury.(32906174)
- Without inhibitory modulation from higher brain centers, sympathetic activity spirals out of control. This is analogous to spinal reflexes (e.g., triple flexion) which are normally inhibited by higher brain centers – but may become hyperactive due to inadequate suppression.
- Normally, inhibitory modulation from higher brain centers tempers how the spinal cord processes sensory information. Without this modulation, spinal cord remodeling may occur. This can create a positive feedback loop wherein normal sensations are perceived as painful (allodynia).(29939858) This allodynia can cause relatively minor stimuli to trigger episodes of PSH.
pathologies which commonly cause PSH
- Traumatic brain injury (80% of patients with PSH):
- The rate of PSH among patients with severe traumatic brain injury may be on the order of ~20%.(29939858)
- PSH is associated with younger age, diffuse axonal injury, and a high burden of parenchymal lesions on CT scan.
- Anoxic brain injury (10%).
- Stroke (5%):
- Especially large intracranial or subarachnoid hemorrhage.
- Other (5%):
- Acute hydrocephalus.
- Tumors.
- Hypoglycemic brain injury.
- Infection (e.g., encephalitis).
- Cerebral fat embolism syndrome.
- Autoimmune encephalitis (e.g., anti-NMDA receptor).
risk factors for the development of PSH
- Severity of initial injury.
- Younger age.
- Male sex.
clinical context & pattern
- PSH usually occurs in the context of severe and diffuse brain injury that initially causes prolonged unconsciousness (e.g., traumatic brain injury or anoxia – more on this above).
- PSH most often begins within the first two weeks after initial brain injury. Episodes may become more obvious as opioids and sedatives are weaned off.
- On average, PSH episodes may occur roughly 1-3 times per day.
- PSH usually resolves within a year.(29939858)
episodes of PSH are marked by:
- (1) Sympathetic hyperactivity:
- Tachycardia (~98% of cases), hypertension.
- Tachypnea (which may manifest as ventilator dyssynchrony).
- Diaphoresis.
- Pupillary dilation.
- Hyperthermia or fever can occur.
- (2) Motor activity:
- Tonic posturing (typically symmetric) in <40% of cases.
- Agitation can occur.
chronicity of individual episodes
- Episodes have a rapid onset, often due to an identifiable trigger (e.g., endotracheal tube suctioning, repositioning, pain, or bladder/bowel distension).
- If untreated, episodes may last up to ~30 minutes before abating spontaneously.(32906174)
- If IV opioids or benzodiazepines cause resolution of the episode, this supports the diagnosis of PSH.
- In between episodes, there should be nearly complete resolution.
The differential diagnosis will vary, depending on any individual patient's symptomatology. The first episode of PSH may be the most confusing, before it becomes clear that a recurring pattern is being established. For example, the initial episode of PSH may clinically resemble herniation (with hypertension and symmetric, bilateral posturing).
some other causes of repeated episodes of sympathetic activation
- Seizures may cause hypertension and tachycardia (especially tonic seizures, or temporal lobe seizures).
- Differentiating features: paroxysmal sympathetic hyperactivity may cause excessive diaphoresis, usually lasts longer than a seizure, doesn't cause clonic movements, and only occurs in specific clinical contexts.(31996626)
- Plateau waves due to ICP elevation, although these don't generally cause profuse diaphoresis. 📖 (32906174)
- Episodes of uncontrolled pain or agitation.
- Episodes of dyspnea, due to respiratory failure.
- Withdrawal from opioids or benzodiazepines (this can be confusing, because PSH often arises as sedatives and analgesics are being weaned off).
- Autonomic dysreflexia due to spinal cord injury. This is very similar to PSH, but involves a lesion in the spinal cord (rather than the white matter of the brain). Unlike PSH, episodes may be associated with bradycardia.
- Guillain-Barre syndrome.📖
- Autoimmune encephalitis (limbic encephalitis, including especially anti-NMDA encephalitis).📖
There is no test to prove the presence of PSH. Consequently, evaluation consists predominantly of excluding alternative diagnostic possibilities.
exclusion of alternative diagnoses may involve:
- Exclusion of seizure with video EEG.
- Evaluation for structural brain lesion with neuroimaging and ultrasound (to screen for intracranial pressure elevation).
consider the consensus definition
- Below is a table developed by expert consensus to use as a definition for paroxysmal sympathetic hyperactivity.(24731076)
- This table isn't necessarily intended as a final arbiter of the diagnosis, but it does provide a systematic way of approaching the diagnosis.
avoid triggers of PSH
- Avoid the use of antipsychotics.(32906174) Patients with PSH may be at increased risk of neuroleptic malignant syndrome.(Louis 2021)
- Avoid triggers as able (e.g., bladder distention, endotracheal suctioning).
- If the patient doesn't have a Foley catheter, consider bladder scans every six hours with catheterization as needed to avoid bladder distension.
- An adequate bowel regimen may encourage regular bowel movements, thereby avoiding constipation.
- Consider pre-treatment with opioid or benzodiazepine prior to any unavoidable trigger (e.g., repositioning), if the episodes ensuing are severe.
best supportive care
- Nutritional support: Patients may have increased resting energy expenditure up to two or three times baseline, which can lead to substantial weight loss.(29939858)
- Fluid resuscitation: Profuse diaphoresis can promote volume depletion.
- Fever management: These fevers do not seem to be driven by inflammatory sensors in the hypothalamus, so they may not be responsive to acetaminophen. If the fever poses a risk of secondary brain injury, physical cooling techniques may be required (e.g., a cooling blanket or even an adaptive external cooling device).
concept #1 – multimodal therapy
- There is no single “silver bullet” medical therapy for PSH.
- Most patients will require multimodal therapy:(28816118)
- Multiple medications with complementary mechanisms of action are combined.
- Using moderate doses of multiple medication classes allows for synergistic efficacy, while avoiding the toxicity that would result from using high doses of any single medication.
concept #2 – abortive vs. preventative therapy
- Although there is some overlap, different medications are optimal for aborting an episode of PSH versus preventing future episodes. Patients will often require a combination of scheduled preventative therapies plus abortive therapies as needed.
- Ideal properties of a medication used to abort an episode of PSH:
- The medication may be given intravenously with rapid onset (ideally within minutes).
- PSH episodes will resolve on their own within <30 minutes. Therefore, in order for any abortive medication to be useful, it must be readily available.
- Ideal properties of a medication used to prevent future episodes of PSH:
- These medications may be used on a chronic basis, without provoking excessive amounts of tolerance or withdrawal.
- Often these are oral medications, which can be continued on a long-term basis (e.g., following ICU discharge). One exception is that intravenous dexmedetomidine may be used as a preventative therapy, but this may be transitioned to oral clonidine for longer-term efficacy (both dexmedetomidine and clonidine are central alpha-agonists, with a similar mechanism of action).
rationale for aborting an episode of PSH
- (1) Diagnostic role – Responsiveness to morphine may also help support the diagnosis of PSH, in situations where this is unclear.
- (2) Therapeutic role – Uncontrolled paroxysmal sympathetic hyperactivity can cause hyperthermia and hypertension leading to secondary brain injury, as well as discomfort. The urgency with which an episode requires treatment depends on its severity.
opioids
- The greatest experience is with morphine, typically at doses of ~2-8 mg IV (but occasionally requiring doses up to 15 mg). Morphine is probably the most effective and preferred agent. If morphine is ineffective in stopping an episode, this should suggest the possibility of an alternative diagnosis.
- Fentanyl may offer the advantage of faster onset, at doses of 25-100 mcg IV.(32476028)
propofol
- This is an excellent option for a patient who is intubated.
- To abort an episode, a bolus of 10-20 mg of propofol may be used.(32906174)
benzodiazepines
- These may be helpful (e.g., in patients with marked tolerance to opioids).
- The fastest onset may be obtained with IV diazepam (doses of 5-10 mg) or IV midazolam (doses of 2-5 mg).(32906174)
propranolol
- General comment: Propranolol is a front-line agent to prevent PSH. Propranolol is lipophilic and exerts direct effects on the brain, making it more effective than most other beta-blockers.
- Indications/contraindications: Propranolol is contraindicated in patients with bradycardia, decompensated heart failure, hypotension, or heart block.
- Dose:
- Oral dosing is preferred, often beginning at a dose of ~40 mg PO q6hr. Uptitration as needed, within a range of 20-80 mg q4-8 hours.
- Intravenous dose: Less information on this is available. 1 mg IV q6hr might be reasonable as a starting dose, with uptitration as clinically indicated.(30429730)
gabapentin
- General comment: Gabapentin may be useful here, with a potential to modulate allodynia and neuropathic pain that triggers episodes. An advantage of gabapentin is that it is often well tolerated for longer-term use. Another advantage of gabapentin is that it doesn't cause hypotension, facilitating its combination with propranolol or clonidine.
- Indications/contraindications: This is one of the most useful preventative medications. May be especially helpful for patients who also have neuropathic pain.
- Dose: Start with 300 mg TID. May rapidly uptitrate to a cumulative dose of 3,600 or 4,800 mg/day in patients with normal renal function.(25220846, 28816118)
alpha-2 agonists (clonidine, dexmedetomidine)
- General comment: Centrally acting alpha-2 agonists may down-regulate sympathetic activity, via activity on both the brain and the spinal cord.
- Indications/contraindications:
- (1) Most useful for patients with robust adequate heart rate and blood pressure in between episodes. Otherwise, there may be a risk of precipitating bradycardia or hypotension between episodes.
- (2) These agents also have mild sedative effects, which may be beneficial for some patients.
- (3) Patients who have responded favorably to IV dexmedetomidine may be transitioned to oral clonidine.
- Clonidine dose
- If starting de novo, begin at a dose of 0.1 mg q8hr. May uptitrate to 0.1-0.3 mg q6-8 hours, for a maximal cumulative daily dose of 1.2 mg.(28816118)
- If transitioning from IV dexmedetomidine to PO clonidine: If the patient tolerated dexmedetomidine well, they are less likely to develop hypotension due to clonidine. Consequently, somewhat higher doses of clonidine may be used initially (e.g. 0.2-0.3 mg PO q6hr).📖
- Dexmedetomidine dose: Titrate to effect. Avoid boluses, as these may cause hemodynamic swings.
propofol
- Propofol infusion may be used for intubated patients.
- This isn't a viable long-term strategy, but it may be used while uptitrating other agents.
other options
- Scheduled, long-acting benzodiazepines are an option (with limitations, including increased rates of delirium, tolerance, and reduced efficacy of benzodiazepines to abort episodes of PSH). If absolutely required, options might include clonazepam 0.5-2 mg PO q8hr or possibly diazepam 5-10 mg PO q8hr.
- Baclofen is another option (e.g., 5 mg PO q8hr, uptitrate as needed to a maximum dose of 80 mg/day).(28816118) Similar to benzodiazepines, the long-term use of baclofen may be complicated by delirium, tolerance, and withdrawal. Intrathecal baclofen has been successfully used to treat patients with severe refractory PSH.(30264872)
- Bromocriptine may be used for refractory hyperthermia (more on this here: 📖)
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To keep this page small and fast, questions & discussion about this post can be found on another page here.
- If paroxysmal sympathetic hyperactivity isn't considered, then symptoms may be regarded as a manifestation of untreated pain or agitation. This may lead to inappropriate treatment with high doses of analgesics and sedatives.
- Be wary of trying to make the diagnosis of PSH in patients without an underlying cause.
Acknowledgement: Thanks to Dr. Richard Choi (@rkchoi) for thoughtful comments on this chapter.
References
- 24731076 Baguley IJ, Perkes IE, Fernandez-Ortega JF, Rabinstein AA, Dolce G, Hendricks HT; Consensus Working Group. Paroxysmal sympathetic hyperactivity after acquired brain injury: consensus on conceptual definition, nomenclature, and diagnostic criteria. J Neurotrauma. 2014 Sep 1;31(17):1515-20. doi: 10.1089/neu.2013.3301 [PubMed]
- 25220846 Lump D, Moyer M. Paroxysmal sympathetic hyperactivity after severe brain injury. Curr Neurol Neurosci Rep. 2014 Nov;14(11):494. doi: 10.1007/s11910-014-0494-0 [PubMed]
- 25701906 Takahashi C, Hinson HE, Baguley IJ. Autonomic dysfunction syndromes after acute brain injury. Handb Clin Neurol. 2015;128:539-51. doi: 10.1016/B978-0-444-63521-1.00034-0 [PubMed]
- 26954919 Samuel S, Allison TA, Lee K, Choi HA. Pharmacologic Management of Paroxysmal Sympathetic Hyperactivity After Brain Injury. J Neurosci Nurs. 2016 Apr;48(2):82-9. doi: 10.1097/JNN.0000000000000207 [PubMed]
- 28816118 Meyfroidt G, Baguley IJ, Menon DK. Paroxysmal sympathetic hyperactivity: the storm after acute brain injury. Lancet Neurol. 2017 Sep;16(9):721-729. doi: 10.1016/S1474-4422(17)30259-4 [PubMed]
- 29939858 Thomas A, Greenwald BD. Paroxysmal Sympathetic Hyperactivity and Clinical Considerations for Patients With Acquired Brain Injuries: A Narrative Review. Am J Phys Med Rehabil. 2019 Jan;98(1):65-72. doi: 10.1097/PHM.0000000000000990 [PubMed]
- 31996626 Rabinstein AA. Autonomic Hyperactivity. Continuum (Minneap Minn). 2020 Feb;26(1):138-153. doi: 10.1212/CON.0000000000000811 [PubMed]
- 32476028 Shald EA, Reeder J, Finnick M, Patel I, Evans K, Faber RK, Gilbert BW. Pharmacological Treatment for Paroxysmal Sympathetic Hyperactivity. Crit Care Nurse. 2020 Jun 1;40(3):e9-e16. doi: 10.4037/ccn2020348 [PubMed]
- 32906174 Scott RA, Rabinstein AA. Paroxysmal Sympathetic Hyperactivity. Semin Neurol. 2020 Oct;40(5):485-491. doi: 10.1055/s-0040-1713845 [PubMed]
- Louis ED, Mayer SA, Noble JM. (2021). Merritt’s Neurology (Fourteenth). LWW.