Paroxysmal sympathetic hyperactivity (‘neurostorming’) following traumatic brain injury: a narrative review

Introduction

Paroxysmal sympathetic hyperactivity (PSH) is a complex autonomic disorder that arises following severe traumatic brain injury (TBI). In this review, PSH will be used as the preferred term. Historically, the syndrome has been described by various names. Originally designated as diencephalic seizures in 1929, PSH has gone through roughly 31 different names, such as dysautonomia, sympathetic storming, neurostorming, and paroxysmal autonomic instability (1). This variation in nomenclature reflects decades of inconsistent terminology and diagnostic uncertainty. In 2014, an international consensus panel standardized the term “Paroxysmal Sympathetic Hyperactivity” and established unified diagnostic criteria, helping differentiate PSH from mimics such as seizures, sepsis, withdrawal states, inadequate sedation or uncontrolled pain, and elevated intracranial pressure (ICP). PSH is characterized by abrupt, recurrent episodes of sympathetic overactivity featuring hypertension, tachycardia, tachypnea, hyperthermia, diaphoresis, and dystonic posturing from increased muscle tone (2). Episodes are frequently stimulus-induced (3), may resolve spontaneously, and often interfere with ongoing neurocritical care by provoking ventilator asynchrony and acute increases in physiologic parameters such as blood pressure and ICP, which may disrupt strict management targets (2).

Epidemiologic studies estimate PSH to occur in approximately 8–33% of adults and 13–14% of children with acute brain injury (4-6). The wide range reported across studies is likely a result of variation in how providers interpret subjective diagnostic criteria, differing injury severity thresholds, and study constraints. While most associated with TBI, PSH is also reported in survivors of intracerebral hemorrhage and hypoxic-ischemic brain injury (7,8). Importantly, PSH does not correlate reliably with initial TBI severity; it is observed in both moderate and severe injuries, particularly in patients with diffuse axonal injuries (DAIs) and in adults and older pediatric populations (4,9). Despite its frequency, PSH remains diagnostically challenging, largely due to fluctuating clinical expression and substantial overlap with other common intensive care unit (ICU) complications such as infection, inadequate sedation, or uncontrolled pain. Additionally, PSH may be underdiagnosed when it is not routinely considered in the differential diagnosis of autonomic instability in critically ill patients. As a result, treatment remains highly variable between institutions, with uncertain effects on long-term morbidity and mortality (10).

To understand PSH, it must be placed within the broader landscape of contemporary neurocritical care, where prevention of secondary brain injury is the central organizing principle (11). Patients with severe TBI require coordinated management of ICP, cerebral perfusion pressure (CPP), brain tissue oxygenation (PbtO₂), ventilatory targets, and hemodynamic stability (11,12). Core elements include meticulous avoidance of hypotension, hypoxia, hypocapnia, anemia, hyperthermia, and hyperglycemia, physiologic derangements known to worsen cerebral ischemia and other physiologic derangements that increase mortality (11-14). Standard precautions for patients with brain injuries include measures such as head-of-bed elevation, maintenance of neutral cervical alignment, avoidance of venous outflow obstruction, and treatment of agitation or hypertension, which also apply to patients with PSH (12).

Similarly, neurocritical care bundles used to stabilize the TBI patient overlap with, mask, or modulate PSH expression. Sedation, analgesia, and neuromuscular blockade are essential components of neurocritical care management used to control ICP, facilitate ventilation, and reduce metabolic demand. Inadequate sedation, painful stimuli, or routine ICU procedures may precipitate sympathetic surges in susceptible patients, highlighting the importance of careful titration of analgesia and sedation in patients with severe brain injury (15,16). Airway protection and mechanical ventilation prevent hypoxemia and allow controlled carbon dioxide targets (17); however, ventilator desynchrony, suctioning, repositioning, or other routine procedures are potent triggers for PSH episodes (18). Temperature management becomes especially important, as PSH-related fevers are common yet must be differentiated from infectious or hypothalamic causes to avoid under- or over-treatment (13,19).

Beyond cerebral and cardiorespiratory management, systemic ICU care also shapes the identification and impact of PSH. Prophylaxis for venous thromboembolism, stress gastritis prevention, and timely initiation of enteral nutrition are standard components of care for patients with severe TBI. In patients who develop PSH, frequent autonomic surges may complicate overall ICU management and prolong critical care needs (20-23). Endocrine and electrolyte disturbances, including Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH), cerebral salt wasting, diabetes insipidus, and hypopituitarism, are common after severe brain injury and can worsen autonomic instability or confound interpretation of tachycardia, hypertension, and fever (24-27). Maintaining moderate glycemic control is equally essential, as both hyperglycemia and hypoglycemia may amplify sympathetic activation or mimic features of PSH (14,28).

Within this integrated framework, PSH represents not merely a standalone autonomic disorder but rather a dynamic, secondary injury pathway that interacts with nearly every major domain of neurocritical care. Its presence complicates the management of ICP, PbtO₂, sedation, temperature, and hemodynamics; contributes to metabolic stress and weight loss; and can hinder timely rehabilitation (6,11,12,23). Because PSH episodes resemble many other ICU emergencies, timely recognition is crucial to guide appropriate pharmacologic and non-pharmacologic treatment, prevent iatrogenic mismanagement, and maintain stability of systemic and cerebral physiology.

Given the syndrome’s prevalence, clinical impact, and diagnostic complexity, a consolidated review of PSH within the broader context of TBI critical care is essential. This article therefore, synthesizes current evidence surrounding the definition, diagnostic criteria, epidemiology, pathophysiology, and treatment of PSH, while explicitly situating the syndrome within modern ICU strategies for severe TBI. By integrating PSH management with established neurocritical care principles, this review aims to support more unified, physiologically informed, and outcome-oriented approaches to care.

Although several recent reviews have summarized aspects of PSH following brain injury, important questions remain regarding the integration of emerging mechanistic insights with clinical management in the neurocritical care setting. Prior reviews have often focused on isolated aspects of PSH, such as diagnostic criteria or pharmacologic management. The present review aims to provide a consolidated synthesis that integrates current understanding of PSH pathophysiology, risk factors, monitoring strategies, and treatment approaches within the broader context of contemporary neurocritical care for TBI. By situating PSH within this clinical framework, this review seeks to highlight areas of uncertainty and identify priorities for future investigation. We present this article in accordance with the Narrative Review reporting checklist (available at https://jni.amegroups.com/article/view/10.21037/jni-25-70/rc).

Methods

Relevant literature was identified through targeted searches of major biomedical databases to capture foundational and representative studies addressing PSH following brain injury. The selection of literature was intended to support a narrative synthesis of key concepts rather than an exhaustive systematic review. B.M.H. performed the database searches. B.M.H. and L.A.H. independently screened all records for inclusion, with disagreements resolved through discussion and consensus between these authors. Eligible studies included randomized trials, prospective or retrospective observational studies, case series, systematic reviews, narrative reviews, meta-analyses, and relevant animal studies addressing PSH following brain injury. Articles published after 1993 and before October 2025 in PubMed, MEDLINE, Embase, and Google Scholar were screened (Table 1). To our knowledge, there does not exist a Cochrane systematic review or guidelines on PSH. Search strategies were tailored to each database, using a combination of MeSH terms, title/abstract keywords, and Boolean operators. Key words utilized in searches included “Paroxysmal Sympathetic Hyperactivity”, “PSH”, “Traumatic Brain Injury”, “Autonomic Nervous System Diseases”, “Diffuse Axonal Injury”, “neurostorming”, “sympathetic storm”, “sympathetic hyperactivity”, “autonomic dysregulation”, “sympathetic overactivity”, and “brain injury sympathetic crisis”. By narrowing the scope to only PSH following TBI, the authors aimed to synthesize a more homogeneous set of evidence regarding pathophysiology, treatment response, and monitoring. This was done to minimize the confounding effects of varied primary pathologies, such as intracranial hemorrhage seen in strokes or global hypoxia. No language restrictions were applied at the search stage; however, only studies with full text available in English were included in the review. Reference lists were manually screened to identify other relevant studies. Eligible studies included randomized trials, prospective or retrospective observational studies, case reports, case series, systematic reviews, narrative reviews, meta-analyses, and relevant animal studies addressing PSH following TBI. Studies focusing on non-PSH autonomic dysfunction, non-traumatic etiologies, or lacking accessible full text were excluded. The figures within the study were created by the authors in BioRender.

Incidence, prevalence, and risk factors

Reported incidence of PSH varies widely across studies, with estimates ranging from approximately 8–33% among adults with severe TBI and approximately 13–14% in pediatric populations. Variability in reported rates likely reflects differences in diagnostic criteria, injury severity, patient populations, and study methodologies. Several studies have also suggested that PSH may occur more frequently in younger adults, potentially reflecting patterns of injury severity and mechanisms of TBI. Key epidemiologic findings, including reported incidence, prevalence, and major clinical risk factors for PSH following TBI, are summarized in Table 2.

Studies examining the likelihood of developing PSH show that younger adults are more prone to experiencing sympathetic storms (8,9,29). In a prospective case-control study by Lv et al. (9), the mean age of patients with PSH after a TBI (25.9±10 years) differed significantly (P<0.001) compared to those without PSH after a TBI (44.8±18 years). This study looked at 79 individuals who experienced a TBI, with 16 developing PHS. In contrast, a study by Rabinstein (8) reported a non-significant difference between groups (35±15 years for those with PSH compared to 46±19 years for those without PSH after TBI, P=0.07) when examining 17 patients who developed PSH out of 43 who experienced a TBI. Differences in findings across studies may reflect variation in patient populations, injury severity, and the diagnostic criteria used to identify PSH. Additionally, the prospective design and multivariate analysis used by Lv et al. (9) provide stronger evidence by allowing for better control of confounding variables and more standardized data collection. In contrast, the retrospective design of Rabinstein (8) is more susceptible to unmeasured confounding variables.

In the same study by Rabinstein (8), statistical significance (P=0.01) was gained when the age of patients with PSH (35±14 years) was compared to the general population (51±18 years). In a separate study by Lv et al. (29), age was again seen to be a predictor of PSH following a TBI [odds ratio (OR) 1.173; P=0.003]. In a study examining pediatric patients, regression analysis suggested that older age might be associated with a higher likelihood of developing PSH (OR 1.08; 95% confidence interval (CI), 1.00–1.16; P=0.042) (4). These studies suggest that the risk associated with age peaks during late childhood and into early adulthood. Further studies are needed to characterize the exact form of this relationship.

There is conflicting evidence for variation in PSH development when examining sex differences. Lv et al. (9) determined no correlation between sex and PSH likelihood. In contrast, Fernandez-Ortega et al. (30) found a significant (P=0.048) difference in men and women for PSH development (n=179 TBI patients, 18 who experienced PSH), indicating men are more likely to develop PSH. In the Fernandez-Ortega et al. (30) study, all PSH cases occur in men, but this finding is limited by a very small PSH sample and an overrepresentation in males in the TBI population examined (3:1 ratio of males to females), which may introduce sampling bias and reduce statistical reliability. Additionally, the absence of multivariate adjustment in the study by Fernandez-Ortega et al. (30) may limit its ability to account for confounding variables such as injury severity or lesion type. However, additional investigation is necessary to elucidate the role of sex as a potential risk factor.

Regarding the TBI event, injury characteristics have also been correlated with varying effects on PSH occurrence. One study identified a fourfold increase in the likelihood of developing PSH after DAI (5). A suggested mechanism for this relationship is the widespread disruption of inhibitory autonomic neurons, leading to an overfiring of sympathetics.

Lesions in several brain regions have been closely associated with an increase in PSH occurrence. These regions include the periventricular white matter, corpus callosum, deep grey matter nuclei, and brainstem (29). This lines up with previously reported locations associated with the autonomic nervous system being in the brainstem, such as the periaqueductal gray matter of the midbrain and various nuclei in the medulla oblongata and pons (31). Screening for damage to these areas of the brain can serve as a good indicator when considering the risk of PSH in patients post-TBI.

A lower Glasgow Coma Scale (GCS) has been associated with an increased likelihood of PSH. In a retrospective cohort study, Bhardwaj et al. (32) reported an admission GCS of 9±2 for those who later developed PSH and 12±2 for those without PSH. This trend can also be seen in a study by Lv et al. (9), where GCS upon admission for those who would develop PSH was 5.19±1.22 and 6.24±1.49 in those without PSH. While the trend stayed consistent, the discrepancy of severity limits the generalizability of this analysis. A comparison of populations with similar GCS could reduce potential confounding variables, such as differences in disease presentation by severity of injury. Monitoring for signs of heightened sympathetics is especially important for patients who score lower on the GCS due to the trend of a lower GCS corresponding to a higher chance of developing PSH.

Overall, the reviewed literature suggests that PSH occurs more frequently in younger patients, including adolescents in pediatric populations and young adults. Current evidence does not consistently demonstrate sex as a definitive risk factor. Structural injuries involving regions associated with autonomic regulation, including the periventricular white matter, corpus callosum, deep gray matter nuclei, and brainstem, have been associated with increased risk of PSH, as have diffuse injury patterns such as DAI. Additionally, lower admission GCS has been correlated with a higher likelihood of PSH development.

Pathophysiology

Although mechanisms underlying PSH are incompletely understood, several interrelated etiologies have been proposed. Disconnection theory is an early pathophysiologic model, which posits that PSH results from the disruption of descending inhibitory cortical pathways to diencephalic and brainstem autonomic centers (10,33). Under typical conditions, regions such as the prefrontal cortex, cingulate cortex, and insula tonically inhibit brainstem autonomic nuclei, allowing sensory stimuli to be processed appropriately without excessive sympathetic activation, as depicted in Figure 1 (10). When these cortical pathways are damaged, tonic inhibitory control is lost, creating an environment where non-noxious stimuli cause unrestrained excitatory activity, and thus exaggerated sympathetic and motor responses (Figure 2) (10). The key to disconnection theory is the concept of tonic disinhibition; however, PSH is episodic. Thus, a newer model has been proposed to explain its intermittent nature.

Figure 1 Normal sympathetic activity in response to non-noxious stimuli. Note the spinal cord segment represents a generalized spinal level. Sympathetic outflow seen here primarily arises from the lateral horn of levels T1–L2, and motor output manifests from the ventral horn at most spinal levels.

Figure 2 Disconnection theory. Loss of cortical inhibition (dashed red lines) allows for hyperactive descending excitatory activity (large blue arrows) in response to non-noxious stimuli. This model allows for tonic hyperactive sympathetic and motor activity. The spinal cord segment represents a general spinal cord. The increased sympathetic output occurs from the spinal levels T1–L2, arising from the lateral horn. The increased motor output flows from the ventral horn of spinal levels related to motor output.

The excitation-inhibition imbalance model (Figure 3) proposes a two-step process. The first step follows the same anatomic concept of disconnection theory: injury to cortical pathways disrupts descending inhibitory control. Building upon this, in the second step, the loss of inhibition from higher structures creates maladaptive spinal circuit excitation (10). This creates an imbalance where excitatory interneurons gain dominance over inhibitory interneurons. As a result, normal sensory stimuli, which should be perceived as non-noxious, now trigger increased spinal cord motor and sympathetic output via spinal reflex arcs that are hyperactive secondary to these maladaptive changes. Thus, non-noxious stimuli cause increased motor and sympathetic output spinally, which is then perceived as noxious centrally due to spinal hyperactivity. In theory, because inhibitory interneurons persist in the spinal cord, albeit at an imbalance to the excitatory ones, episodes eventually self-resolve, with PSH as a whole resolving when and if cortical inhibitory pathways recover.

Figure 3 Excitation-inhibition theory. Loss of cortical inhibition, as seen in disconnection theory, in addition to maladaptive spinal cord plasticity with hyperactive excitatory interneurons (large green arrows) and hypoactive inhibitory interneurons (small orange arrows). This model allows for episodic sympathetic and motor hyperactivity. The spinal cord segment represents a general spinal cord. The increased sympathetic output occurs from the spinal levels T1–L2, arising from the lateral horn. The increased motor output flows from the ventral horn of spinal levels related to motor output.

Beyond neural network dysfunction, emerging evidence implicates neuroendocrine dysregulation in PSH pathophysiology. Severe illness or TBI can disturb the hypothalamic pituitary adrenal (HPA) axis and other peripheral hormonal pathways, altering the body’s adaptive stress-response systems (34). Under normal conditions, the paraventricular nucleus (PVN) of the hypothalamus integrates autonomic and endocrine stress responses by releasing corticotropin-releasing hormone, which stimulates pituitary adrenocorticotropic hormone (ACTH) and, subsequently, cortisol secretion. Cortisol then exerts negative feedback at the level of the hypothalamus, pituitary and hippocampus to restrain further activation of the stress axis (34).

After TBI, several mechanisms can impair this feedback loop, such as direct injury, axonal injury, or inflammatory cytokines. Direct injury to the hypothalamus, pituitary stalk, or anterior pituitary can blunt ACTH release or disrupt glucocorticoid receptor-mediated signaling (26,27). Axonal injury involving limbic structures, especially the hippocampus, can reduce the brain’s ability to sense circulating cortisol and terminate the stress response (26,27). Inflammatory cytokines released after severe injury can downregulate glucocorticoid receptor sensitivity, contributing to a state of functional cortisol resistance (35). These disturbances result in impaired cortisol feedback, leaving sympathetic pathways more vulnerable to unchecked activation.

Moreover, systemic illness commonly seen in TBI patients, including sepsis, systemic inflammatory response syndrome, acute respiratory failure, and multiorgan dysfunction, can provoke overlapping endocrine and autonomic adaptations, blurring the distinction between primary autonomic dysregulation and secondary stress-response mechanisms (34-36). Such systemic factors blur the boundary between primary central autonomic dysregulation and secondary stress-response phenomena, complicating both the diagnosis and mechanistic interpretation (34-36).

In a rodent model using DAI, Zhu et al. (37) modeled TBI and the subsequent mechanism of sympathetic hyperactivity seen in PSH. The levels of catecholamine metabolites, metanephrine and normetanephrine, were assessed following DAI. The results show these levels begin to increase at the 9-hour mark, peak at 72 hours, then remain elevated. Concurrently, neutrophil extracellular traps (NETs) accumulation in the PVN of the hypothalamus was monitored via western blot of citrullinated histone H3, which serves as a marker for NET activity (37). Notably, a strong correlation between plasma metanephrine (r=0.879; P<0.001; n=36) and NETs was observed. Plasma normetanephrine also displayed a positive, yet weaker, correlation (r=0.683; P=0.002; n=36), with NETs (37).

Diving further into the mechanism in rodents, the authors used systems of isolated neutrophils and microglia to show that a component of NETs, LL37, activates receptors on microglia that initiate the Hippo/MST1 pathway (37). The pathway eventually cascades into increased microglial IL-1β, an inflammatory protein that can induce sympathetic activation (37). Based on this mechanism, IL-1β is a plausible upstream mediator of PSH (37). Inhibition of IL-1β could decrease episodes of PSH post-TBI. However, this remains theoretical, as the animal models do not fully replicate PSH. Thus, additional clinical trials are required to determine if this inhibition of inflammatory processes would reduce the frequency or intensity of the sympathetic episodes seen in PSH.

However, serious limitations in this model must be considered. The controlled nature of the DAI to rodents does not transfer to the real-world, where TBIs present with a spectrum of etiology relating to the exact mechanism of injury. The complex pathologies in human injury may influence autonomic regulation in ways not captured by isolated diffuse injury models. Additionally, the environment after the TBI varies vastly between the model and what is seen in ICUs. Clinically, PSH is characterized by stimulus-triggered surges precipitated by external conditions. Muscarine models are unable to reproduce similar environments.

These models should be interpreted for their potential mechanistic relationships rather than direct clinical comparisons. Further studies that examine comparable pathways in humans could elucidate the mechanism of PSH in humans. Developing a more complete understanding of PSH, there is the potential for targeted therapeutic strategies, particularly based on the inflammatory IL-1β association proposed by the rat model.

Overall, current evidence suggests that PSH arises from the disruption of inhibitory cortical pathways and an imbalance within central autonomic networks following brain injury. Emerging research also implicates neuroendocrine dysregulation and inflammatory signaling pathways as potential contributors. While several mechanistic models have been proposed, including disconnection and excitation-inhibition imbalance theories, further research is required to fully clarify the underlying pathophysiology.

Diagnosis and monitoring

Diagnosis of PSH can be challenging due to overlap with other causes of autonomic instability in critically ill patients. Key diagnostic criteria and common differential diagnoses encountered in neurocritical care settings are summarized in Table 3.

Initial diagnosis of PSH has been partially standardized through the PSH Assessment Measure (PSH-AM). The diagnostic framework is comprised of the Clinical Feature Scale (CFS) and the Diagnosis Likelihood Tool (DLT). The CFS analyzes six domains during episodes: heart rate (HR), respiratory rate, systolic blood pressure, temperature, sweating, and posturing. These values are compared to the expected physiological range (38). Each domain is given a value from zero to three, with zero indicating no deviation from expected values and three indicating the largest disruption from the normal range (38). A composite score is generated from these categories that quantifies the characteristic manifestations of PSH based on severity (38). The DLT scores are based on the presence of distinct features associated with PSH (38). This component of PSH-AM evaluates the probability that the episodic autonomic events represent PSH or are manifestations of other autonomic dysfunctions (38). The sum of CFS and DLT then determines the likelihood of PSH as unlikely, possible, or probable (38). While this method has helped by providing a framework for diagnosis, there remains a major gap in standardized treatment following diagnosis, and emerging reviews (39,40) emphasize the need for PSH-AM-based, protocolized care pathways.

Previous reviews by Panjaitan et al. (39) and Yin et al. (40) provided a meta-analysis of prevalence in adult populations and a review on neuro-inflammatory theory, respectively. A gap in these studies is addressing emerging potentials for early detection of PSH. A recent study by Burzyńska et al. (41) discussed heart rate variability (HRV) and cerebral autoregulation in 66 patients who suffered traumatic brain injuries. Two potential predictors of PSH after TBI were identified to be significant: an increase (253±178 vs. 176±227 ms², P=0.04) in HRV in the low-frequency range (0.04–0.15 Hz) and a decrease (70±7 vs. 78±19 bpm, P=0.03) in mean HR directly post-injury. Both of which were collected during the first 5 days in the ICU, preceding a diagnosis of PSH around day 12, giving a prediction window of around 7 days. The study employs multivariate logistic regression that confirmed the clinical applicability of these metrics, with mean HR (OR 0.91; 95% CI, 0.84–0.98) and DAI (OR 10.82; 95% CI, 1.70–68.98) acting as significant independent predictors (41).

Together, these findings align with the idea that autonomic nervous system dysregulation can occur during PSH episodes but also be detectable prior to their onset. These findings complement newer physiologic modelling approaches. Najda et al. (42) analyzed transient dynamics between autonomic signals and cerebral hemodynamics, including relationships between HR, ICP, and cerebrovascular reactivity, to model the risk of PSH in patients with severe TBI. Together, such work supports the feasibility of incorporating neurophysiologic and neuromonitoring “signatures” into early PSH detection and risk stratification.

Although HRV analysis has been explored as a potential physiologic marker of autonomic instability in PSH, the current evidence remains limited and heterogeneous. Interpretation of HRV in neurocritical care settings is complicated by several confounding factors, including sedation, mechanical ventilation, vasoactive medications, and nonstationary physiologic signals. Methodological variability across studies, including differences in signal acquisition (electrocardiographic RR intervals versus pulse-derived intervals), preprocessing techniques, and analytic approaches, also limits comparability of findings. Recent work by Riganello et al. (43) has further explored HRV dynamics during PSH episodes in disorders of consciousness, suggesting that autonomic signal patterns may provide insight into the physiological evolution of these events, although additional validation in larger neurocritical care cohorts is required.

Overall, diagnosis of PSH relies primarily on clinical recognition supported by structured tools such as the PSH-AM. Emerging monitoring strategies, including analysis of autonomic metrics such as HRV and physiologic time-series data, may improve early identification and risk stratification in patients with severe brain injury.

Treatments

Based on currently available evidence and expert consensus from neurocritical care literature, management of PSH generally follows a multimodal and stepwise approach. First-line therapy often includes centrally acting beta-blockers such as propranolol due to their ability to cross the blood-brain barrier and blunt sympathetic surges. If symptoms persist, adjunctive agents such as alpha-2 agonists (e.g., clonidine or dexmedetomidine) may be added to further reduce sympathetic outflow. Gabapentin is frequently incorporated as an adjunctive therapy, particularly in patients with suspected neuropathic or spinal-mediated components contributing to sympathetic hyperactivity. In patients who remain refractory to single-agent therapy, combination regimens targeting multiple pathways are commonly required. Treatment strategies should therefore be individualized based on symptom severity, response to therapy, and the overall neurologic status of the patient.

Evidence detailing specific pharmacologic regimens for PSH remains unstandardized. This likely reflects the heterogeneity of underlying brain injuries, variability in symptom presentation among patients, and the limited availability of large prospective studies and validated outcome measures to guide standardized treatment approaches, yet identifying timely and effective therapeutic options is critical, as PSH has been associated with prolonged hospitalization, delayed rehabilitation, and increased overall healthcare costs (44). Treatment is generally divided into two components: abortive therapy to control immediate sympathetic surges, and preventive therapy to mitigate recurrence and reduce episode severity (44,45). Contemporary narrative reviews likewise describe a multimodal approach that combines non-pharmacologic strategies, symptomatic abortive agents, and longer-term preventive regimens (39,40).

Among preventive medications, the lipophilic nonselective beta-blocker propranolol is the most commonly reported agent, largely due to its ability to cross the blood–brain barrier and attenuate central sympathetic activity. In contrast, not all beta-blockers demonstrate similar effectiveness in PSH management (46). This drug has been shown to reduce the length of hospital stay and mortality among patients with TBI who develop PSH (46). Scoping and narrative reviews identify propranolol as a core component of many PSH treatment protocols because of its lipophilicity, ability to cross the blood-brain barrier, reduction of tachycardia and hypertension, and potential to limit hyperthermia and agitation (39,40,46). Recent case-based reports further support its role in PSH management: in a DAI case, addition of low-dose propranolol allowed rapid suppression of otherwise refractory PSH attacks and facilitated weaning from sedatives (47).

Gabapentin is an additional medication that acts on voltage-gated calcium channels in the CNS to reduce excitatory neurotransmission and dampen afferent nociceptive input, thereby decreasing PSH episode frequency (10,40). Bromocriptine, a dopamine D2 receptor agonist, has been employed to curtail hyperthermia and rigidity in PSH patients (10,40). Baclofen, a GABA_B agonist, is another major preventive agent used particularly when spasticity and dystonia are prominent; both oral and intrathecal formulations have been described, although data are limited to small series and case reports (10,40). Collectively, these preventive medications are often administered in combination before anticipated sympathetic surges, and their use remains guided largely by expert consensus and institutional practice patterns rather than high-quality comparative trials.

Beyond the PSH-specific literature, a broader body of TBI research links beta-blocker therapy, particularly propranolol, to improved outcomes. A randomized controlled trial of adults with severe TBI by Khalili et al. (48) showed that, in the subgroup with isolated severe TBI, propranolol significantly reduced in-hospital mortality and improved 6-month functional outcome compared with standard care. Multiple observational cohorts and a recent systematic review and meta-analysis similarly associate in-hospital beta-blocker exposure with lower mortality and, in some studies, better functional status at discharge or follow-up (49-54). Although these studies do not explicitly identify PSH, they address hyperadrenergic states after TBI and support the biologic rationale that attenuating catecholamine surges may improve outcomes. Taken together, this broader TBI literature indirectly strengthens the case for more rigorous trials using propranolol as a logical first-line preventive agent when PSH is suspected.

Abortive therapy focuses on rapid-acting agents that can resolve symptoms during PSH episodes. Opioids like morphine and fentanyl attenuate both pain-related triggers and sympathetic discharge (2,36,38). Short-acting benzodiazepines such as diazepam or midazolam provide additional sedation, anxiolysis, and reduction in muscle tone via their GABA_A-agonist effects (2,36,38). In intensive care settings, sedative infusions, particularly propofol, are frequently used to control refractory episodes, though prolonged sedation may delay neurologic recovery and complicate ventilator weaning (39,44). Dantrolene, which inhibits calcium release from the sarcoplasmic reticulum to block muscle contraction, can be deployed to reduce dystonia and severe rigidity (8).

Some agents function as both preventive and abortive therapies. By dampening sympathetic outflow through presynaptic inhibition of norepinephrine release, alpha-2 agonists such as clonidine and dexmedetomidine can be used to control symptoms both before and during episodes (10). Dexmedetomidine, in particular, has been associated with reduced incidence and severity of PSH episodes in small retrospective cohorts and case reports involving postoperative and severe TBI populations. These studies show that dexmedetomidine may be superior to propofol for controlling hyperthermia and tachycardia in some settings (40,55). However, these findings are limited by sample sizes and non-randomized study designs, resulting in a low level of evidence. As such, these results should be interpreted with caution, and randomized controlled trials are needed to better define the role of dexmedetomidine in PSH management.

Another potential candidate for prophylactic treatment shown to regulate sympathetic tone in mouse models is melatonin. This hormone preferentially enhances the activity of GABA_A receptors in the PVN of the hypothalamus, producing inhibitory effects on pre-sympathetic neurons in the PVN. In mouse models of sympathetic vasomotor tone, melatonin has been shown to decrease sympathetic excitatory outflow to the spinal cord (55). However, no dedicated TBI or PSH-specific rodent models have studied this effect. Extrapolating this model to humans raises the possibility that melatonin could reduce the frequency and intensity of sympathetic storms. However, further studies that model TBI or PSH conditions in rodents would greatly support further research into melatonin’s potential role as a therapeutic intervention for humans.

Non-pharmacological approaches such as minimizing environmental stimuli, maintaining hydration and nutrition, and optimizing temperature regulation can be beneficial as adjuncts to medical therapies (40,56). Exposure to cold is known to activate the sympathetic nervous system, triggering vasoconstriction, shivering thermogenesis, and increased catecholamine release as the body attempts to maintain core temperature (57). In patients with impaired autonomic regulation, such physiologic responses may further amplify sympathetic outflow, making cold environments a potentially preventable trigger for PSH episodes. A recent pilot study in 8 pediatric patients found that lower ambient room temperatures ≤69 ℉ were significantly (P=0.002) linked to the occurrence of PSH, suggesting that environmental adjustments may serve as useful adjuncts to pharmacologic management (58).

The strength of evidence supporting current pharmacologic strategies for PSH remains limited. Most treatment recommendations are derived from observational studies, case series, and expert consensus rather than randomized controlled trials. While some agents, such as beta-blockers and alpha-2 agonists, are supported by relatively larger observational datasets and broader neurocritical care experience, many other therapies have primarily been described in small cohorts or individual case reports. This highlights the need for prospective studies and standardized outcome measures to better evaluate treatment effectiveness.

Overall, management of PSH remains largely supportive and multimodal, incorporating both preventive and abortive pharmacologic strategies along with careful environmental and physiologic management. Although agents such as beta-blockers and alpha-2 agonists are commonly used, treatment approaches remain heterogeneous and further research is needed to establish standardized therapeutic protocols.

A summary of commonly used pharmacologic therapies for PSH, including their proposed mechanisms and clinical indications, is provided in Table 4.

Study strengths and limitations

This review has several strengths and limitations. By synthesizing current literature on PSH pathophysiology, diagnosis, monitoring strategies, and treatment approaches within the context of modern neurocritical care, this review provides a consolidated overview of an increasingly recognized complication of TBI. However, several limitations should be acknowledged. As a narrative review, the literature selection was not intended to be exhaustive and may be subject to selection bias. Additionally, much of the available evidence regarding PSH management is derived from case reports, case series, and observational studies, with limited high-quality prospective trials. These limitations highlight the need for future research aimed at developing standardized diagnostic criteria, improving physiologic monitoring approaches, and establishing evidence-based treatment strategies for PSH. In the interim, awareness of PSH, use of structured diagnostic tools such as the PSH-AM, attention to risk factors, and incorporation of multimodal, beta-blocker- and alpha-2 agonist-based regimens into standardized ICU pathways may help reduce the morbidity associated with PSH.

Conclusions

PSH is a clinically important but still incompletely characterized complication of TBI. Despite increased recognition and the establishment of diagnostic tools such as the PSH-AM, gaps remain in understanding its mechanisms and in establishing standardized approaches to prediction and management. Current data support a multifactorial pathophysiology involving disrupted inhibitory pathways, excitatory-inhibitory imbalance within the central autonomic network, and possible neuro-endocrine contributions. However, these mechanisms require further clarification in future studies. Contemporary reviews highlight that PSH is frequently under-recognized in both adult and pediatric practice and emphasize the importance of distinguishing it from other causes of fever, tachycardia, and agitation in the ICU.

Recognition of PSH in patients with severe TBI is essential for optimizing neurocritical care management. Early identification using structured diagnostic tools such as the PSH-AM may help clinicians distinguish PSH from other causes of autonomic instability in the intensive care setting. Integrating awareness of common triggers, physiologic monitoring, and multimodal pharmacologic strategies may improve symptom control and reduce complications related to sympathetic surges. Future research should prioritize development of validated risk prediction models, standardized diagnostic pathways, and prospective studies evaluating targeted treatment strategies to improve outcomes for patients experiencing PSH.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://jni.amegroups.com/article/view/10.21037/jni-25-70/rc

Peer Review File: Available at https://jni.amegroups.com/article/view/10.21037/jni-25-70/prf

Funding: None.

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