Abstract
Paroxysmal sympathetic hyperactivity (PSH) occurs in ∼10% of patients following acute severe brain injury. While PSH is associated with worse outcomes, there are no clinical practice guidelines to inform treatment. We aimed to systematically review the literature on the pharmacological management of PSH. MEDLINE, Embase, and Cochrane library databases were searched from inception to August 2020. Eligible studies met the following criteria: 1) randomized controlled trials, non-randomized controlled trials (case control or controlled cohort), observational studies, case series, and case reports; 2) study population of adult and pediatric patients; 3) exposure to an acute neurological insult complicated by PSH (or historic synonym); 4) description of pharmacological treatment of PSH. Our search retrieved 2729 citations with 83 articles assessed for inclusion. After full text extraction, 56 manuscripts inclusive of 459 patients met eligibility criteria. We identified 31 case reports, 15 case series (152 patients), seven retrospective case control or cohort studies (212 patients), and three prospective observational studies (52 patients). Traumatic brain injury was the most common precipitating insult (407 patients), followed by hypoxic encephalopathy (72 patients) and intracranial hemorrhage (10 patients). There were 48 drugs from 22 classes prescribed for the management of PSH. The most frequently prescribed agents were benzodiazepines, β-blockers, opioids, α-2 agonists, and baclofen. However, route and dose of drug and subsequent outcome were inconsistently reported, such that no summary was possible. While a wide variety of drugs have been reported to treat PSH, there is a lack of even moderate-quality evidence to inform clinical decision making.
Introduction
Paroxysmal sympathetic hyperactivity (PSH) is recognized in approximately 10% of patients with severe acute brain injury. PSH is a syndrome of simultaneous and paroxysmal increases in sympathetic (elevated heart rate, blood pressure, respiratory rate, temperature, sweating) and motor (posturing) activity. 1 –3 Despite striking clinical features, this syndrome has historically been under-recognized, hampered by an absence of a clear definition and terminology. 4 Aside from over 30 eponyms, more descriptive labels have included mesencephalic seizures, autonomic seizures, autonomic storms, hypothalamic storms, and sympathetic storms. 5 It was not until 2010 that “paroxysmal sympathetic hyperactivity” (PSH) was proposed as the unifying term for this condition, and 2014 that an International Consensus Committee established rigorous diagnostic criteria. 3
PSH is a diagnosis of exclusion with paroxysms persisting despite treatment of alternative diagnoses including pain, sepsis, opiate or sedative withdrawal, neuroleptic malignant syndrome, pulmonary embolus, and delirium. 3 Recognition and management of PSH is important, as it is associated with increased health care costs, 2 longer duration of hospital admission, 2,6 –8 and worse neurological outcomes. 2,3,7 While mechanisms driving PSH remain uncertain, reducing paroxysms by physical or pharmacological intervention is important to mitigate secondary brain injury, which may improve subsequent functional outcome. 3,9 We aimed to undertake the first systematic review of the pharmacological management of PSH.
Methods
Study design
We conducted a systematically structured scoping review using the guidelines from the Cochrane Collaboration and Center for Reviews and Dissemination and reported the results according to the PRISMA guideline and its extension for scoping reviews. 10 Methods and inclusion criteria were specified and documented in advance.
Inclusion and exclusion criteria
Eligible studies met the following criteria: 1) randomized controlled trials, non-randomized controlled trials (case control or controlled cohort), observational studies, case series and case reports; 2) study population of adult and pediatric patients; 3) exposure to an acute neurological insult complicated by paroxysmal sympathetic hyperactivity (or historic synonym); and 4) description of pharmacological treatment of paroxysmal sympathetic hyperactivity. We included only studies reported in English. No data or publication status restrictions were imposed.
Data sources and search strategy
A librarian and two reviewers (JT and JR) searched MEDLINE (Ovid), EMBASE (Ovid), and Cochrane Library databases from their inception to August 2020. Searches included synonyms and combinations of the following terms: ‘paroxysmal sympathetic hyperactivity’ OR ‘PSH’ OR ‘diencephalic epilepsy’ OR ‘storm’ OR ‘dysautonomia AND ‘treatment’ OR ‘intervention’ OR ‘management’ OR ‘outcome’ AND ‘traumatic brain injury’ OR ‘head injury’ OR ‘stroke’ OR ‘subarachnoid hemorrhage’ OR ‘intracerebral hemorrhage’ OR ‘cardiac arrest’. Full search strategies are provided in Supplementary File S1. No language restrictions were applied during the searches. Reference lists of retrieved papers were reviewed to identify studies not captured in the primary search.
Study selection and data extraction
Two reviewers (JT and JR) independently screened titles and abstracts of all identified studies. Relevant studies were independently evaluated in full text for eligibility. Disagreements were resolved by consensus or by consultation with a third reviewer (MP). Two reviewers independently extracted data from included studies using a standardized data collection form. Extracted information included study characteristics (author, publication year, design, sample size), participant characteristics, primary pathology, PSH definition, intervention (including dosing regimen), and outcomes. When possible, we categorized the response to the pharmacological agent using an ordinal scale of: “no effect,” “minimal effect,” “partial control,” or “controlled.” We planned a meta-analysis of randomized clinical trials of pharmacological therapy for PSH if the search yielded more than two trials.
Results
Our search retrieved 2729 citations with 83 full-text articles assessed for inclusion. After full-text extraction, 56 manuscripts inclusive of 459 patients met the eligibility criteria (Supplementary Fig. S1). The characteristics of the included studies are summarized in Table 1. There were 31 case reports, 11 –41 15 case series inclusive of 152 patients, 1,9,42 –54 seven retrospective case control or cohort studies inclusive of 212 patients, 55 –61 and three prospective observational studies inclusive of 52 patients. 62 –64 None of the prospective observational studies compared outcomes according to therapeutic intervention. Accordingly, we were unable to undertake an assessment of bias as no studies met the minimal threshold. There were no randomized controlled trials and a meta-analysis could not be performed.
SD, standard deviation; PSH, paroxysmal sympathetic hyperactivity; ICU, intensive care unit; TBI, traumatic brain injury; NR, not recorded; PO, per oral; TDS, three times daily; IV, intravenous; NG, nasogastric; IT, intrathecal; QID, four times daily; SAH, subarachnoid hemorrhage; PAID, paroxysmal autonomic instability with dystonia; BD, twice daily; ICH, intracranial hemorrhage; OD, once daily; PR, per rectal.
Thirty-six articles inclusive of 288 patients reported treatment of PSH in an adult population. 1,12,14 –20,22 –27,31,32,37 –40,42,44,45,47,49 –51,54,55,58,60 –64 Fourteen articles reported treatment of PSH in a pediatric population 11,13,21,28 –30,33 –35,37,41,46,52,57 and four in a mixed population of adult and pediatric patients. 43,48,53,56
Traumatic brain injury (TBI) was the most common acute neurological injury reported in 36 articles inclusive of 407 patients (259 adult: 66 pediatric, 82 not specified). Hypoxic brain injury (72 patients: 62 adult, three pediatric, seven not specified) and intracranial hemorrhage (14 patients: 13 adult, one pediatric) were the next most frequently described. There were 46 articles where treatment for PSH was commenced in the intensive care unit (ICU), 10 in neurorehabilitation, two on the hospital ward, and two articles not specifying the setting.
There were 48 drugs from 22 drug classes prescribed for the management of PSH (Table 2). Two non-pharmacological therapies also were reported, including delivery of the child in a pregnant female with PSH following a TBI, 21 and serial casting in a 3-year-old patient with PSH following a TBI. 29 Drug route, dose, regimens and outcomes for pharmacological agents were inconsistently reported—for example eight articles did not report any outcome data. 1,19,36,43,46,56,61,62 The most frequently prescribed drug classes were benzodiazepines (216 patients: 77 adult, 113 pediatric, 26 not specified), β-blockers (191 patients: 101 adults, 11 pediatric, 79 not specified), opioids (186 patients: 119 adults, 13 pediatric, 54 not specified), α-2 agonists (188 patients: 160 adults, 10 pediatric, 18 not specified), and the GABA-β agonist baclofen (184 patients: 171 adults, four pediatric, nine not specified). The response to the pharmacological agent can be visualized in Supplementary Figure S2. The retrospective cohort study by Pozzi and colleagues 57 was the only article to quantify the efficacy of each agent and these data are presented separately as “efficacy” (Table 2). The supplementary files of all included studies also were examined for the purposes of data extraction.
Drugs Prescribed for the Management of PSH by Class
Pozzi and colleagues (2015).
NR, not reported; IV, intravenous; PO, per oral; QID, four times daily; PR, per rectal; BD, twice daily; TDS, three times daily; OD, once daily; IT: intrathecal.
Discussion
We conducted a systematic review to evaluate interventions for the management of paroxysmal sympathetic hyperactivity. The key finding is that there is a dearth of even modest-quality evidence to guide management of this important condition. Of the 56 included articles, 46 were case reports or case series and only three articles were prospective in design. Moreover, we report dramatic variability in treatment regimens reflected in the use of 48 drugs from 22 classes, and a paucity of quantifiable outcomes for these interventions. From this broad array of evaluated therapeutics, drugs more commonly reported as having a signal of benefit include morphine, propranolol, clonidine, baclofen, diazepam, and gabapentin. This is consistent with expert recommendations and previous evidence-based summaries. 3 –5
Goals for treating patients with PSH include identifying and avoiding triggers that provoke paroxysms and mitigating excessive sympathetic outflow and posturing through pharmacological intervention. Morphine is an opioid that acts centrally on descending inhibitory central nervous system (CNS) pathways. Its primary action is as a mu opioid receptor agonist, but it does convey delta and kappa opioid receptor agonism, albeit to a lesser extent. 65 Peripheral actions on the cardiovascular system via kappa receptors induce depressive effects, 66 making it intuitively appealing for the management of tachycardia and hypertension. In clinical practice, this benefit may be offset by central nervous system depression and sedation, which can confound neurological assessment/recovery. 65
Benzodiazepines are GABA-A receptor agonists that are thought to act at the limbic, thalamic and hypothalamic regions of the CNS resulting in widespread neural depression. 67 In addition to the likely benefits in treating symptoms of posturing and agitation, reports also have suggested benefit in the management of hypertension and tachycardia in patients with PSH. 4 Common side effects include sedation and respiratory depression, which also may confound neurological assessment and recovery. 68 Clonidine is an alpha-2 adrenoreceptor and imidazoline agonist that has antihypertensive, sedative, and analgesic properties. 69 The antihypertensive effect of clonidine arises from a combination of agonistic action on cardiovascular inhibitory neurons in the nucleus tractus solitarii and antagonistic effects in the medulla which result in reduced sympathetic outflow from the CNS. 70 While clonidine does not cause respiratory depression and does not significantly potentiate morphine-induced respiratory depression, it is sedating and can confound neuroprognostication. 71
Propranolol is a lipophilic non-cardioselective beta adrenoreceptor antagonist with negative chronotropic and blood pressure lowering effects. Studies also have suggested efficacy in reducing hyperthermia post brain injury. 72 It has the advantage of attenuating sympathetic drive without causing sedation. Baclofen is a GABA-B receptor agonist that is used in the treatment of muscle spasticity and thought to act primarily at the level of the spinal cord where it reduces excitatory input into the presynaptic neurons while increasing inhibitory signaling to post-synaptic neurons—making it an attractive option for treating posturing associated with PSH. 73,74 Moreover, baclofen has a role in enhancing central vagal tone with inhibition of mesolimbic and nigrostriatal dopaminergic neurons, which may attenuate sympathetic drive. 74 Baclofen is sedating and may confound neuroprognostication.
Finally, while the exact mechanism of gabapentin is unclear, it has been found to have affinity for the alpha-2 delta protein subunit of voltage gated calcium channels responsible for inhibiting the release of central excitatory neurotransmitters, thereby decreasing sympathetic outflow. 75 Accordingly, while there is mechanistic plausibility that each of these drugs that have been studied will attenuate the symptoms of PSH, we have failed to identify moderate-quality evidence to inform clinicians.
Strengths and limitations
To our knowledge this is the first systematic review of the pharmacological management of PSH. To increase the breadth of the review we included case series and case reports, acknowledging that these yield a lower quality of evidence, and these articles formed the bulk of the review. Within the included case reports and case series, treatment regimens were infrequently described in sufficient detail to know if drugs were given in combination and how the doses were titrated. While it is intuitively plausible that multi-modal therapy will be beneficial in controlling PSH symptoms, we are unable to provide even modest-quality evidence supporting this claim.
Implications and future directions
While a broad range of therapeutic targets and regimens have been proposed to prevent or diminish the severity of paroxysms, this review identifies the lack of evidence to guide clinical practice. This can largely be attributed to the relative contemporaneity of PSH as a recognized clinical entity with rigorous established diagnostic criteria. In the 20 years preceding the 2014 publication of the International Consensus definition, there had been nine diagnostic criteria for PSH that differed according to timing and clinical features. 4 Accordingly, early observational studies and case reports served to establish the diagnostic features of PSH rather than assess response to treatment, reflected by the large number of articles not reporting treatment outcomes. The recent development of diagnostic criteria has provided an essential framework for prospective trials of therapeutic interventions for PSH such as the DASH trial, an ongoing double-blind randomized clinical trial comparing combination propranolol and clonidine therapy with placebo in adult patients post-TBI. 76 Given the difficulties in diagnosing the condition and infrequent reporting, such studies would benefit from multi-center study designs in high volume trauma centers.
Conclusion
A large number of drug classes have been reported to control symptoms of PSH; however, there are no high-quality data to guide clinical decision making. Therapeutics that have demonstrated promise in case series/case reports include morphine, propranolol, clonidine, gabapentin, benzodiazepines, and baclofen.
Footnotes
Funding Information
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Author Disclosure Statement
No competing financial interests exist.
Supplementary Material
Supplementary File S1
Supplementary Figure S1
Supplementary Figure S2
References
Supplementary Material
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