Paroxysmal Sympathetic Hyperactivity: Development of a Pediatric Clinical Practice Guideline Free

Clinical providers in the divisions of pediatric neurology, pediatric critical care, pediatric physical medicine and rehabilitation, and pharmacy identified a need for a CPG for the diagnosis and treatment of paroxysmal sympathetic hyperactivity. Despite its relatively high incidence after a severe brain injury and significant associated morbidity and mortality, PSH has been chronically underrecognized and undertreated, partly because of the absence of clear terminology and definition.³  Even with unifying diagnostic criteria, standardized treatment modalities are limited. Evidence for most therapeutic options is limited, based primarily on case reports or small case series.⁶  The development of PSH is widely considered to be an independent risk factor for graver neurologic outcomes among those with an acquired brain injury. Individuals who develop PSH are more likely to require longer mechanical ventilation^9,23,27  and require tracheostomy,^8,9,18,23  have longer ICU,^8,9,23–25  total hospital,^8,9,24–26  and rehabilitation center length of stay,^24,26  and have worse functional independence measures.²⁴  Hyperthermia and hemodynamic instability frequently prompt infectious testing and empirical antibiotics, and abnormal movements frequently elicit neurology consultation to disprove epileptic etiology. Inconsistent treatment strategies have led to unnecessary polypharmacy. By streamlining the diagnosis and management of PSH, we aim to promote effective, evidence-based treatment while supporting pragmatic resource utilization.

A literature search was performed by using “paroxysmal sympathetic hyperactivity” or other historic synonyms, with eligible studies being randomized control trials, case-control or controlled cohort trials, observational studies, case series, and case reports that identified patients with acute neurologic injury whose clinical course was complicated by paroxysmal sympathetic hyperactivity, and for whom pharmacological intervention was described. Given the lack of availability of purely pediatric studies, we included both adult and pediatric studies for consideration. Thirty-seven studies were evaluated, including 20 case reports, 10 case series, 3 retrospective case-control studies, 2 prospective observational studies, 1 retrospective cohort study, and 1 randomized controlled trial. Treatment agents analyzed included α₂-adrenergic agonists (clonidine, dexmedetomidine), antiseizure medications (phenytoin, carbamazepine, sodium valproate), benzodiazepines (midazolam, clonazepam, lorazepam, diazepam), β-adrenergic antagonists (propranolol, esmolol, metoprolol), barbiturates (phenobarbital), dopamine agonists (bromocriptine), GABA_B receptor agonists (baclofen), gabapentin, labetalol, opiates (morphine, fentanyl, methadone, codeine), and ryanodine receptor antagonists (dantrolene). This study was classified as exempt by our institutional review board.

This CPG was the product of a multidisciplinary collaboration between providers and other clinical personnel at our institution. After administrative approval, our group worked closely with the Evidence Enhanced Medicine Committee to coordinate with other physicians, pharmacists, nursing, and ancillary staff to disseminate information and ensure a CPG implementation of a guideline that would establish a framework for the diagnosis and management of PSH during its acute phase.

To streamline diagnostic criteria in conjunction with the 2014 consensus group, we modified the CFS created by Baguley and colleagues.¹  Using standardized vital sign ranges by age,²⁸  we separated values for heart rate, respiratory rate, systolic blood pressure, and temperature using 3 age groups: 1 to 4 years, 5 to 15 years, and >16 years, and established ranges for 0, 1, 2, and 3 values, as seen in Fig 1. Although diaphoresis and posturing are more subjective measures, we provided instructions for the clinician to quantify these for the scale. Diaphoresis was delineated as mild (“moist or glistening skin”), moderate (“beads of sweat”), or severe (“profuse sweating”). Posturing was delineated as mild (“hypertonicity increases but the tone is easily overcome”), moderate (“hypertonicity which is hard to overcome”), or severe (“inescapable hypertonicity”).¹  The DLT was incorporated as created by Baguley and colleagues, as seen in Fig 2. The Paroxysmal Sympathetic Hyperactivity Assessment Measure (PSH-AM) is calculated as the CFS subtotal plus the DLT subtotal, with a score of <8 unlikely to represent PSH, 8 to 16 possible PSH, and ≥17 probable PSH.

With PSH-AM ≥8, nursing staff record the CFS subtotal once per 12-hour shift, as well as with paroxysms, and document under “Flowsheet” in the electronic medical record to better grade PSH severity over time. Nonpharmacologic measures are to be attempted first, including reducing stimulation levels in the patient’s room, such as dimming lights and turning down the volume or turning off televisions and radios, checking skin for wound breakdown, repositioning the patient, as well as medical devices, and ruling out urinary retention and constipation. Frequently, these measures can be sufficient in abating paroxysms. If these measures are unsuccessful in reducing the CFS, targeted pharmacotherapy is considered.

Because of the heterogeneous nature of PSH and the spectrum of presentation, we categorized treatment modalities by clinical target: increased tone and posturing, vital sign abnormalities, and pain. Often, separate drugs are required to address various components of the syndrome, as well as separate drugs to prevent versus treat paroxysms. Our team contrasted available data collected during our literature review, summarized in Table 1. A widespread educational initiative involving physicians, advanced practice providers, nurses, and ancillary staff counseled on the CFS and DLT, the approach to nonpharmacological interventions, and pharmacological management. Although both the CFS and DLT have subjective components, these have been in widespread use in the treatment of adults with PSH since these scales were released in 2014. The use of validated, reproducible scales with subjective components is common in pediatric critical care. The Withdrawal Assessment Tool-1, Richmond Agitation-Sedation Scale, and Patient Centered Assessment Method are widely accepted tools important in the management of withdrawal, sedation, and delirium, respectively.^29–31  Although patients with PSH will often simultaneously exhibit evidence of increased tone and posturing, vital sign abnormalities, and pain simultaneously, providers were educated on the utilization of a single pharmacological agent to ameliorate the unnecessary polypharmacy to which these patients are frequently exposed. Providers were also educated to use the clinical practice guideline as a framework to guide care but to not let it supersede their own clinical judgment.

Hypertonicity and posturing are to be managed first with baclofen, a GABA_B receptor agonist. Because of its invasive nature and logistical constraints in using intrathecal baclofen, oral baclofen was used by our clinical practice guideline. Because of some evidence of benzodiazepines delaying cognitive recovery in an acquired brain injury when used in the adult population as opposed to baclofen,²¹  benzodiazepines were chosen as second-line treatment. They have been shown to be efficacious for treating posturing and provide an intravenous option when enteral access is unavailable. On the basis of coverage by our state’s public insurance program, diazepam was chosen as our preferred benzodiazepine. Gabapentin was chosen as a third-line treatment on the basis of its relative efficacy in managing pain symptoms, as well as its relatively benign side-effect profile.

Hemodynamic instability warrants close monitoring, often leading to prolonged management in the intensive care setting. Vital sign abnormalities are managed first with propranolol. Propranolol, a β-adrenergic antagonist, was chosen because of its lipophilicity and ability to penetrate the blood-brain barrier, permitting central, cardiac, and peripheral antiadrenergic activity.³²  Propranolol is the only agent with a randomized control trial revealing its efficacy,²²  and overall, has consistent data in treating vital sign abnormalities associated with PSH. Propranolol also has known neuroprotective effects after a neurologic injury via the reduction of cerebral blood flow and decreased cerebral metabolism and, in animal models, has been shown to increase cerebral perfusion, decrease cerebral edema and hypoxia, and improve neurologic outcomes.^33–37  Although not directly related to PSH, the administration of propranolol and phentolamine, an α₁ antagonist, has been shown to reduce mortality and improve long-term neurologic function in patients with subarachnoid hemorrhage.³⁸  Propranolol has also been shown to be efficacious for the treatment of agitation after a TBI.³⁹ 

Clonidine, an α₂-adrenergic agonist, lacks lipophilicity but has consistent data on vital sign abnormalities, as well, and was chosen as a second-line treatment for vital sign abnormalities. Benzodiazepines, in addition to their efficacy in treating hypertonicity, have also been shown to be efficacious with vital sign abnormalities and were chosen as a third-line treatment.

Pain control is necessary given the pervasive allodynia shown in patients with PSH.^5,40  Gabapentin is effective both for controlling allodynia in the setting of PSH and has a benign side-effect profile. Opiates, specifically oxycodone or morphine, were chosen as second-line treatments given widespread data revealing their efficacy in treating acute paroxysms triggered by pain, but potential for less benign side effects.

Despite bromocriptine having compelling data regarding its efficacy in adults,⁴¹  there is a paucity of pediatric data and, thus, was not incorporated into our CPG, but it does represent a future avenue. Although benzodiazepines were considered inconsistently efficacious because of multiple case reports and case series revealing incomplete responses, 2 of the higher-evidence studies conducted by Pozzi¹⁸  and Baguley⁴²  revealed their utility with larger sample sizes.

The first-line medications baclofen and gabapentin require time to reach a steady state, and enteral administration during an acute paroxysm may not always be immediately effective. In both instances, we have provided a second-line medication, diazepam and morphine, respectively, which has parenteral administration and is effective for acute paroxysms in which standing pharmacotherapy is insufficient.

Given the heterogeneity of response to various pharmacologic agents between patients, all medications, especially as-needed medications, that were effective in managing patients’ paroxysms should be documented in the electronic medical record for future reference. Regarding expert consultation, we recommend a consultation for patients for whom PSH symptoms are not improved despite 2 pharmacologic measures or after a 48-hour duration, whichever occurs first. At our institution, Neurology or Physical Medicine and Rehabilitation should be consulted in patients with new-onset PSH, whereas those with a chronic diagnosis of PSH are managed in consultation with the patient’s primary outpatient managing service to provide continuity of care. The involvement of subspecialty providers is necessary in part to ensure appropriate outpatient follow-up because after the acute phase of PSH, many scheduled medications can be titrated or discontinued.

Refractory inpatients who fail 2 medications and continue exhibiting paroxysms should prompt intensive care consultation and the consideration of transfer for closer vital sign monitoring and a possible dexmedetomidine infusion.

We present the evidence-based development of a CPG for the streamlined diagnosis and standardized treatment of PSH (Fig 3). PSH is a frequent consequence of an acquired brain injury, yet our team identified heterogeneous methods of diagnosing and treating PSH.^1,6  The quality of evidence to guide the treatment of PSH is low, primarily case series and case reports, with even fewer pediatric-specific studies. Our framework details a pathway to provide consistent therapy with the best evidence that is currently available. This novel CPG addresses an unmet need in the care of hospitalized children and is reproducible at other institutions beyond our own. Future directions after the implementation of this clinical practice guideline include studying its effect on the total duration of hospital and ICU stay, the effect of management and treatment on short-term and long-term morbidity and mortality, the relative superiority of select treatments, specifically in the pediatric population, and the differences in treatment with select age groups, the underlying mechanism of injury, and differing regions of brain injury.