Curr Neurol Neurosci Rep (2014) 14:494 DOI 10.1007/s11910-014-0494-0

NEUROTRAUMA (J LEVINE, SECTION EDITOR)

Paroxysmal Sympathetic Hyperactivity after Severe Brain Injury Devon Lump & Megan Moyer

# Springer Science+Business Media New York 2014

Abstract Paroxysmal sympathetic hyperactivity (PSH) is characterized by the rapid onset and paroxysmal cycling of agitation and dystonia in association with autonomic symptoms. These symptoms may include the following: tachycardia, hypertension, tachypnea, fever, pupil dilation, decreased level of consciousness, diaphoresis, and ventilator dyssynchrony. In a critically ill patient, these are all nonspecific symptoms that may reflect impending sepsis, seizure, or a number of other complications. This can confound and delay the diagnosis and treatment of PSH. While this phenomenon has been frequently observed in the traumatic brain injured population, management is highly variable, prompting this review of the literature. This article aims to outline the evidence base for the management of PSH, as well as to describe an algorithm for management developed at our institution. Keywords Paroxysmal sympathetic hyperactivity . Traumatic brain injury . Dystonia . Autonomic storming . Autonomic dysregulation

Introduction Severe brain injury induces a dysregulation of the autonomic nervous system that results in marked autonomic instability and paroxysms of fever, hypertension, tachycardia, tachypnea, diaphoresis, and dystonic posturing. Paroxysmal autonomic hyperactivity, thought to be created by the disassociation This article is part of the Topical Collection on Neurotrauma D. Lump (*) : M. Moyer Department of Neurosurgery and Neurocritical Care, Hospital of the University of Pennsylvania, 3rd Floor Silverstein Building, 3400 Spruce St., Philadelphia, PA 19104, USA e-mail: [email protected] M. Moyer e-mail: [email protected]

between the sympathetic and parasympathetic nervous systems, was initially described by Wilder Penfield in 1929 in a patient with a history of traumatic brain injury (TBI) [1]. Since then, this characteristic syndrome has been described in patients with a wide variety of brain injury mechanisms including TBI, ischemic stroke, anoxic injury, intracerebral hemorrhage, and encephalitis. Despite its recognition, standardized clinical criteria are lacking, numerous confusing terms and classification schemes for the same syndrome have been used in the literature, and management is highly variable. Each classification has had its own set of specific diagnostic criteria [2, 3] making the standardization of management and diagnosis challenging. Early reports referred to the syndrome as diencephalic or autonomic seizures [1]. In later studies, it was referred to as a brain stem attack, central dysregulation, acute midbrain syndrome, tonic decerebrate spasms, tonic cerebellar fits, and the sympathoadrenal response. Recent studies have used the terms paroxysmal sympathetic hyperactivity (PSH), autonomic storming (AS), paroxysmal hyperthermic autonomic dysregulation, and simply dysautonomia. PSH captures the salient features of this syndrome, namely the intermittent surges of sympathetic activity, and is the term we advocate and use. This review describes the pathophysiological mechanisms and evidence base for the management of PSH and defines specific clinical criteria that should allow the unambiguous identification of patients with this syndrome. PSH is usually a diagnosis of exclusion; its symptoms and signs overlap with those of sepsis, seizures, hydrocephalus, and many other serious conditions in patients with TBI and other critical illnesses. This overlap may confound and delay the diagnosis and treatment of PSH. Finally, we describe a stepwise algorithm for management developed at our institution.

Incidence PSH is thought to occur in 15 %–33 % of comatose patients with severe TBI. However, the incidence depends on

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definition, duration, and timeframe [4]. PSH can be seen in the hyperacute period (24 hours after injury) to up to weeks following the TBI. Some studies have reported that 62 %– 92 % of patients exhibit at least 1 significantly increased parameter that suggests an increase in sympathetic activation following TBI (eg, heart rate, respiratory rate, or blood pressure,). Only 8 %–12 % of these patients, however, have sustained overactivity that qualifies as dysautonomia [5].

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may include common nursing interventions, such as suctioning, turning, repositioning, and bathing, as well as physiologic triggers such as constipation, urinary retention, and pain. Such stimuli commonly elicit episodes of PSH in brain-injured patients, lending credence to the EIR model. In addition, the EIR model suggests that effective treatment strategies should involve blocking the sensitization process that occurs to incoming sensory information in the spinal cord.

Pathophysiology The pathophysiology of PSH is poorly understood, and autopsy studies have yielded few insights into its anatomic basis [6]. Following trauma, activation of the autonomic nervous system is both a predictable and an expected response. Tachycardia, hypertension, and the redirection of blood flow to muscle and brain occurs to ensure the availability of oxygen and to preserve other vital physiological processes. The parasympathetic nervous system attempts to return the body to a state of homeostasis by reducing the effects of the sympathetic overactivity. However, when this parasympathetic feedback mechanism fails, sympathetic outflow is uninhibited, leading to hyperactivity and ultimately PSH [7]. Initial studies postulated that sympathetic surges were due to epileptic seizures; however, there is little evidence to support an epileptic theory of PSH. While seizures may cause autonomic dysfunction, traditional antiepileptic medications have little efficacy in treating PSH. Current theories propose that autonomic dysfunction results from a disconnection between higher order inhibitory centers that are damaged by injury and brainstem or spinal cord circuits that are left intact and drive sympathetic activity in an uncontrolled fashion. In conventional disconnection theories it is assumed that inhibitory centers in the upper brainstem, diencephalon, and cortex are injured, leading to unopposed sympathetic outflow from downstream brainstem and spinal cord pathways [6]. Despite the intuitive appeal of this theory, pathologic and radiographic evidence suggests that there is often lower brainstem damage in patients with TBI and other forms of severe brain injury that exhibit symptoms of PSH. Thus, it is unlikely that unopposed action of sympathetic pathways in the lower brainstem completely explains the pathophysiology of PSH. The more recent excitatory: inhibitory ratio (EIR) model proposes that there are inhibitory centers in the brainstem and diencephalon that limit the amplification and sensitization of afferent sensory information processed by circuits in the spinal cord. Left unopposed, the plasticity of these spinal cord circuits causes amplification of mild noxious stimuli that leads to allodynia (the inappropriate perception of pain and discomfort with mild sensory stimuli). After brain injury, both noxious and non-noxious stimuli then have the ability to drive a positive feedback loop that produces PSH. These stimuli

Differential Diagnoses, Diagnostic Criteria, and Impact on Outcome Because of its nonspecific symptomatology, PSH is a diagnosis of exclusion. Prior to diagnosing a patient with PSH, other diagnoses that may mimic PSH, such as seizures, intracranial hypertension, hydrocephalus, agitation, pain, central fever, malignant hyperthermia, and withdrawal from sedative or analgesic medications should be investigated and reasonably excluded [8, 9]. While the diagnosis of PSH can be challenging in medically complex ICU patients, early identification is paramount in treating the secondary morbidity caused by PSH in the TBI population. The literature suggests that creation of accurate diagnostic guidelines for PSH is feasible. In 1 literature review, 81 papers were identified, in which cases of PSH were reported or that provided information about the condition. Of these, only 27 papers utilized diagnostic criteria, and 9 sets of diagnostic criteria were newly developed. Most papers agreed that the core clinical features of PSH included increased heart rate, blood pressure, respiratory rate, temperature, sweating, and motor hyperactivity [10]. Hughes and Rabinstein published a study in 2013 that retrospectively reviewed electronic medical records of critically ill patients with acquired brain injury from 2006–2012 who demonstrated PSH. Key search terms included PSH, sympathetic storms, autonomic storms, diencephalic seizures, and paroxysmal autonomic instability with dystonia. Fifty-three patients were identified as having had PSH. Individual patient records, including vital sign data, nursing documentation, and various other clinical notes, were evaluated to ascertain which PSH symptoms were noted to support the diagnosis. Once these, 53 patients were identified and records were reviewed, the authors evaluated how the clinical diagnosis of PSH faired once a strict set of criteria was applied. In their review, 89 % of patients who were clinically diagnosed with PSH, also met the formal diagnostic criteria, suggesting that PSH may be diagnosed accurately in the ICU and that strict diagnostic criteria generally support the clinicians’ impressions. In their review, tachycardia was present in 98 % of identified cases; diaphoresis, fever, hypertension, and tachypnea were present in greater than 71 %; and dystonia and posturing were present in less than 40 % of identified cases [11•].

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Prolonged hypersympathetic tone associated with PSH may lead to additional morbidity, including cardiac damage, weight loss, nutritional deficiencies, and skin breakdown, but its effect on long-term clinical outcome is unclear. It has been suggested that if the diagnosis of PSH is recognized early, morbidity and long term disability might be improved [3, 12]. In a study by Baguley et al. in 2007, the presence of PSH was associated with significantly worse clinical outcomes, longer hospital lengths of stay, and higher health care related cost [13]. In 2012, FernandezOrtega et al. published a prospective study in which they reported a 10.1 % incidence of PSH among all patients admitted to an ICU with severe TBI over an 18-month period. Patients with PSH were compared with those without PSH over the first 6 months of the study period; both groups had similar injury severity-related characteristics on admission. The PSH group had a greater ICU length of stay, higher prevalence of infections, more time spent on mechanical ventilation, higher incidence of tracheostomy placement, and longer course of hospitalization. PSH episodes were noted to last about 30 minutes and occur on average 5.6 times per day. Twenty percent of the PSH group continued to demonstrate episodes at 1 year; PSH did not impact long term clinical outcome [14•]. Furthermore, Laxe et al. (2013) performed a prospective study of patients admitted to neurorehabilitation for TBI over a 3-year period, and analyzed functional outcomes (Glasgow Outcome Scale-extended, the Disability Rating Scale, and the Functional Independence Measure) of those with PSH compared with those without PSH. PSH did not seem to impact recovery during rehab and functional status upon discharge, however, patients with PSH were more likely to require psychoactive medications, and magnitude of improvement (Glasgow Outcome Scale—extended) was significantly greater in the non-PSH group [15•].

Pharmacologic Management Pharmacologic therapy for the treatment of PSH involves 3 general strategies: (1) inhibiting afferent sensory processing to limit the development of allodynia, (2) inhibiting central sympathetic outflow, and (3) blocking end organ responses of the sympathetic nervous system. Medications used target specific cell surface proteins, including voltage gated calcium channels, GABA A and GABA B receptors, alpha and beta-adrenergic receptors, dopamine receptors, and opiate receptors. Voltage gated calcium channel (gabapentin) and GABA B receptor (baclofen) antagonists target afferent spinal cord sensitization. GABA A (propofol, diazepam, lorazepam) antagonists, dopamine agonists (bromocriptine) and opioid receptor agonists (morphine, methadone, fentanyl) target centrally mediated sympathetic outflow. Alpha-adrenergic agonists (clonidine, dexmetatomidine) and beta-blockers (propranolol) likely have both central and peripheral effects.

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In a study from 2004, morphine, benzodiazepines, propranolol, and bromocriptine appeared to be the most efficacious medications for PSH [12]. A more recent study in 2007 found that gabapentin reduced the number of paroxysms and allowed overall reduction in the use of other medications without recurrence of symptoms [16]. Gabapentin acts at the presynaptic alpha2delta subunit of voltage-dependent calcium channel, which is thought to modulate excitatory neurotransmission involved in nociception [17]. It can be helpful in the acute or chronic phase of management for PSH [9]. Bromocriptine, while thought to have variable efficacy for the treatment of PSH, is postulated to work at the dopamine receptor to inhibit sympathoexcitatory structures [6, 18]. It may be particularly useful for managing centrally mediated fever and dystonia. However, bromocriptine may lower the seizure threshold and is contraindicated in the setting of uncontrolled hypertension [9], limiting its use in some patients. In our experience, morphine is extremely effective at aborting PSH episodes in a dose-dependent manner while providing pain control. It is thought to be more effective that other opiate derivatives, likely from modulation of central pathways and suppression of sympathetic outflow [8]. The beta-blocker, propranolol, is lipophilic and penetrates the blood brain barrier, effectively decreasing the catecholamine effects in PSH. It may be used to reduce the frequency of PSH episodes, especially fever, diaphoresis, and tachycardia. Side effects may include bradycardia, bronchospasm, hypotension, and hypoglycemia. In addition, if used in combination with clonidine for the treatment of PSH, close hemodynamic observation is warranted, as the combination may severely depress cardiac function [9]. Clonidine is effective in blocking central adrenergic outflow and can be most effective in treating tachycardia and hypertension. A reduction in circulating plasma levels of catecholamines is seen following clonidine administration [9]. However, it may be less useful for controlling other autonomic symptoms characteristic of PSH [9]. Dexmetatomidine is an intravenous centrally acting alpha-2 adrenergic agonist that can be used as a continuous infusion [19]. Alhtough its efficacy in treating PSH is less well studied, it may be particularly useful in patients requiring treatment in the intensive care unit given its rapid onset and titratability. Select benzodiazepines, including midazolam, lorazepam, and diazepam, bind GABA A receptors and provide effective muscle relaxation and anxiolysis during PSH episodes. They may be less effective than opiates for severe episodes, but may be useful in patients with PSH and severe anxiety [9]. In 2012, a study was published that had followed 43 severe TBI patients with dysautonomia who were treated with intrathecal baclofen (ITB) after noninvasive conventional treatment regimens had failed (mean of 6 months after initial injury). The mean maximal dose of ITB was 232.6 mg per day. Complications related to pharmacologic and device (implanted ITB

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pump/catheter) incidents occurred in 88.4 % of the cohort, and included but not limited to operative site infections, overdoses, withdrawal symptoms, catheter migrations, meningitis, malignant fever, and 1 unexplained death. Almost one-half of the patients required pump replacement during their follow-up (mean pump-life to replacement interval=5.8 years). Long-term assessment consisted of evaluating disorders of consciousness, functional status, and residual long-term impairments including hypertonic attacks, sweating episodes, and voluntary motor responses. Over a mean of 10-year follow-up, it was demonstrated that recovery of long-term consciousness is feasible; poor longterm outcome can be associated with a low level of consciousness recovery and the early development of severe and persistent symptoms of PSH [20]. Early ITB therapy has not been evaluated, and generally only trialed after 6 months from injury.

An Algorithm for PSH Management (Fig. 1) (Table 1)

Because of poor clinical awareness and a lack of published standardized diagnostic criteria, PSH is often under-

Fig. 1 PSH treatment algorithm

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recognized and undertreated. At our institution, unique challenges to treating PSH were identified. The lack of available tools for recognizing and documenting patient-specific stimuli that triggered PSH episodes, individual symptomatology that characterized an episode, and the efficacy of treatment measures led to delays and inconsistencies in treatment. To overcome these challenges and to eliminate unnecessary variability in care, we formed a multidisciplinary group including Neurocritical care (NCC) attending physicians, a neurosurgery attending physician, NCC acute care nurse practitioners, and ICU pharmacists to review relevant literature, and to assess treatment benefit, comparative effectiveness, and side effects of commonly used medications. After the literature review was completed, a bedside tracking tool was developed to identify patients with a high probability of having PSH. Staff education was provided to bedside nurses, NCC fellows, NCC nurse practitioners, and NCC attending physicians. Upon identification of probable PSH by any member of the NCC team, a multidisciplinary team huddle was initiated to discuss the patient’s triggers, clinical manifestations, and devise a plan for PSH-specific management. Practice cards outlining the PSH treatment algorithm, indications for a team

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Paroxysmal sympathetic hyperactivity after severe brain injury.

Paroxysmal sympathetic hyperactivity (PSH) is characterized by the rapid onset and paroxysmal cycling of agitation and dystonia in association with au...
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