Neuropsychiatric outcomes in sepsis: A vital sign worth monitoring

Abstract

Septic shock is a state of physiological disarray that disrupts perfusion, overwhelms inflammatory control, and, as evidence now shows, compromises the structural and functional integrity of the brain. In their recent study, Li et al explored how specific hemodynamic derangements, such as reduced cardiac index, low mean arterial pressure, and elevated lactate, correlate with neuropsychiatric outcomes including delirium, depression, anxiety, and post-traumatic stress disorder. The findings reframe psychiatric symptoms not only as downstream consequences, but as measurable, clinically relevant expressions of unstable physiology. This editorial argues that neuropsychiatric outcomes in sepsis should be regarded as a vital sign worth tracking, and maybe more importantly, worth preventing. Rather than viewing altered cognition and mood as potentially unavoidable sequelae, perhaps we should begin monitoring them with the same intensity as lactate clearance and oxygen saturation. Doing so may not only preserve cognitive health, but also refine our hemodynamic goals themselves. Psychiatry, critical care, and neuroscience each have a role to play in defining this new frontier of care, one where protecting the mind begins in the intensive care unit.

Key Words: Septic shock; Delirium; Post-traumatic stress disorder; Anxiety; Depression; Hemodynamic instability; Sepsis-associated encephalopathy; Critical care; Neuroinflammation

Core Tip: Neuropsychiatric symptoms such as delirium, anxiety, and post-traumatic stress disorder in septic shock are often dismissed as secondary or unavoidable outcomes of critical illness. New data suggest that these symptoms may be real-time indicators of hemodynamic instability and cerebral hypoperfusion. This editorial argues that altered cognition and mood during septic shock should be monitored alongside traditional vital signs like mean arterial pressure and lactate.

INTRODUCTION

Septic shock is a severe manifestation of infection characterized by circulatory, cellular, and metabolic dysfunction that disrupts multiple physiological systems and carries a high risk of mortality[1]. It is clinically characterized by severe infection-induced hypotension that is unresponsive to volume resuscitation, often necessitating vasopressor support, and is frequently accompanied by signs of tissue hypoperfusion such as hyperlactatemia, requiring rapid intervention[2]. The internationally accepted diagnostic criteria, established by the Society of Critical Care Medicine and the European Society of Intensive Care Medicine, identifies septic shock as sepsis accompanied by hypotension requiring vasopressors to maintain a mean arterial pressure (MAP) of at least 65 mmHg, along with a serum lactate concentration greater than 2 mmol/L, despite adequate fluid resuscitation[1].

For decades, management strategies for septic shock have centered around early goal-directed therapy, which emphasizes achieving specific physiologic targets to mitigate organ dysfunction, including MAP, central venous pressure, urine output, and central venous oxygen saturation[3,4]. Early recognition of infection, administration of antibiotics, aggressive fluid resuscitation, and hemodynamic stabilization are the cornerstones of care. Clinicians have relied heavily on metrics like the Sequential Organ Failure Assessment score to monitor dysfunction and guide therapy. Recent protocols are increasingly judged on long-term organ function and patient quality of life in addition to short-term outcomes such as 28-day mortality[3].

Yet within this emphasis on cardiovascular, renal, and pulmonary endpoints, the impact of septic shock on the brain has remained relatively underappreciated. Sepsis-associated encephalopathy, an acute alteration in mental status ranging from delirium to coma, is one of the most frequent neurological complications of sepsis, affecting up to 70% of patients in the intensive care unit (ICU)[5-7]. The consequences of this brain dysfunction extend well beyond the ICU. Survivors often experience lasting cognitive deficits including memory loss and impaired executive function, which may persist for years and are associated with increased risk of developing dementia[8,9]. In addition to cognitive impairment, many patients suffer from mood disturbances such as anxiety, depression, and post-traumatic stress disorder[10,11].

Despite the frequency and severity of these neuropsychiatric complications, they have long been thought of as unavoidable consequences. However, emerging data now challenge this belief. The study by Li et al[12] links these outcomes to hemodynamic instability, suggesting that mental status changes during septic shock may serve as real-time indicators of systemic dysfunction. This shifts the focus toward proactive monitoring, where neuropsychiatric symptoms are viewed as real-time indicators of physiological instability that can inform hemodynamic management, and not as delayed complications.

INTERPRETING THE STUDY: HEMODYNAMICS AND THE MIND

The recent study by Li et al[12] offers a framework for understanding how hemodynamic collapse during septic shock sets off a cascade of disruptions that manifest as neuropsychiatric symptoms. Using retrospective data from ICU patients with septic shock, the study demonstrates that classic markers of circulatory instability, such as low MAP, reduced cardiac index, elevated lactate, and diminished venous oxygen saturation, are strongly correlated with neuropsychiatric manifestations such as delirium, anxiety, depression, and posttraumatic stress disorder (PTSD).

Multivariate analysis revealed that a MAP < 65 mmHg and cardiac index < 2.5 L/minute/m² were independently associated with an increased risk of delirium, while elevated lactate levels (> 4 mmol/L) were associated with greater neuropsychiatric symptom severity. Additionally, systemic vascular resistance, pulmonary artery wedge pressure, and stroke volume were significantly linked to cognitive impairment, poor sleep quality, and PTSD severity. These findings highlight that the brain is not only highly susceptible to perfusion deficits, but that neuropsychiatric symptoms may reflect active physiological disruption rather than delayed effects.

Critically, the study’s use of standardized assessments, including the Confusion Assessment Method, Hospital Anxiety and Depression Scale, and PTSD scales, provides empirical support for this idea. These clinical findings were accompanied by elevations in inflammatory markers [e.g., interleukin (IL)-6, tumor necrosis factor-alpha (TNF-α)] and imbalance in neurotransmitter levels (e.g., serotonin, dopamine, glutamate) which aligns with the growing body of evidence supporting a neuroinflammatory model of sepsis-associated brain dysfunction. Li et al[12] described a framework in which impaired perfusion, inflammatory signaling, and neurotransmitter imbalances interact to affect cognition, mood, and consciousness, framing these neuropsychiatric outcomes as relevant indicators of systemic dysfunction.

While the findings by Li et al[12] strengthen the link between hemodynamic instability and neuropsychiatric symptoms, it is important to acknowledge the potential confounding effect of underlying physical illness. Many of the illnesses that lead to septic shock, including pneumonia, intra-abdominal infections, or urinary tract infections, can themselves trigger cognitive or mood symptoms through systemic inflammation or metabolic disturbance[13,14]. This raises the question of whether the observed neuropsychiatric changes are truly unique to septic shock, or rather reflect the broader impact of physical illness. Future research should aim to clarify these effects by comparing neuropsychiatric outcomes across similarly ill patients with and without septic shock, attempting to control for illness severity.

THE MISSED OPPORTUNITY IN CRITICAL CARE

Despite growing evidence linking hemodynamic instability to neuropsychiatric complications, current protocols under-address the psychiatric component of critical illness. Most ICU guidelines narrowly focus on the detection and management of delirium, with little focus on broader psychiatric assessments. For example, the Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption guidelines from the Society of Critical Care Medicine only recommend routine delirium screening using validated tools such as the Confusion Assessment Method for the ICU or the Intensive Care Delirium Screening Checklist[15]. While comprehensive psychiatric screening may not be feasible during acute septic shock, broadening the focus beyond delirium to include observable neurobehavioral changes may help guide hemodynamic management and clinical decision-making.

Even within the focus on delirium, implementation is inconsistent. Observational studies have shown that a large proportion of ICU patients are never formally assessed for delirium, and almost none are routinely evaluated for other psychiatric conditions[16-18]. Pilot studies exploring early psychiatric consultation during ICU or post-ICU care have shown promise, but these approaches are not widely integrated into clinical practice[19,20]. As a result, patients may suffer from unrecognized neuropsychiatric symptoms that may limit functional recovery.

This oversight is especially concerning given that many survivors of septic shock experience significant neuropsychiatric morbidity, yet psychiatric status rarely informs hemodynamic management decisions. As Evans et al[3] noted, cognitive and psychiatric outcomes are typically addressed only after the acute phase, creating a gap where symptoms are seen as consequences rather than potential indicators of instability. Integrating neuropsychiatric monitoring into standard care could provide early insight into cerebral vulnerability, helping tailor hemodynamic support to individual physiology.

A CALL TO RECALIBRATE CLINICAL PRIORITIES

The findings of Li et al[12] highlighted the need to broaden how we monitor and manage septic shock. If neuropsychiatric complications like delirium, PTSD, and depression are linked to hemodynamic instability, then mental status deserves early and systematic attention. Just as lactate is trended to guide therapy, cognitive changes could serve as dynamic indicators of cerebral vulnerability and treatment response. Expanding septic shock goals to include neurocognitive health does not detract from current priorities, it supplements them.

While delirium tools like Confusion Assessment Method for the ICU and Intensive Care Delirium Screening Checklist remain foundational, future efforts should focus on expanding neuropsychiatric surveillance. Validated scales such as the Hospital Anxiety and Depression Scale, the Impact of Event Scale-Revised, and the Posttraumatic Stress Disorder Checklist for Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition have been used in ICU and post-ICU populations and may help identify patients at risk for persistent psychiatric symptoms[21-24]. Implementation would likely include structured cognitive trending over time, standardized daily mental status scoring, or using digital tools like tablet-based cognitive assessments during recovery phases. Electroencephalography-based monitoring and pupillometry may also offer objective markers of neurologic function in sedated or non-verbal patients. Integrating neuropsychiatric data alongside existing protocols such as MAP, lactate, and oxygenation could make mental status monitoring as automatic and actionable as vital signs.

Beyond behavioral assessments, inflammatory biomarkers may provide valuable insight into neuropsychiatric vulnerability. While cytokines such as IL-6, IL-8, and TNF-α are often elevated in septic shock, they are not routinely measured in most ICU settings; C-reactive protein remains the most commonly tracked marker. Findings from Li et al[12] showed that patients with septic shock had significantly higher levels of IL-6, TNF-α, IL-1β, and C-reactive protein compared to those with sepsis alone, and these elevations were associated with more severe and persistent neuropsychiatric symptoms, including delirium and PTSD. Although routine cytokine monitoring may not yet be justified or feasible, these results suggest that neuroinflammatory markers serve an important role in brain dysfunction in sepsis. Further research is warranted to determine their utility in clinical decision-making and guiding targeted interventions in the future.

While early detection of neuropsychiatric symptoms is essential, the prevention of outcomes like delirium remains challenging. Systematic reviews have highlighted uncertainty regarding the efficacy of both pharmacologic and psychosocial interventions for delirium prevention in critically ill patients[25-27]. Also, while multicomponent protocols show promise, they are often difficult to implement consistently in routine care due to resource constraints in ICU settings[28]. These limitations underscore the need for targeted research into practical strategies on how to integrate mental status monitoring into existing workflows. Future areas of investigation may include minimizing deep sedation, promoting sleep hygiene, enabling early mobility, ensuring access to sensory aids, and involving family members in reorientation when feasible.

CONCLUSION

As survival rates for septic shock continue to improve, so too must our definition of what it means to recover. The link between hemodynamic instability and neuropsychiatric outcomes suggests that cognitive health should be considered a key aspect of critical care. Moving forward, management decisions should account for outcomes such as mental clarity, emotional stability, and cognitive function, which are increasingly recognized as important indicators of long-term recovery.

Addressing this challenge will require collaborative effort across disciplines. Psychiatry may become more involved in acute ICU care, including the initial phases of treatment and extending into post-discharge recovery. Neurology can contribute to a better understanding of the mechanisms underlying sepsis-associated brain dysfunction, while intensivists may begin to incorporate neurocognitive outcomes into hemodynamic monitoring and management. Together, these efforts can help refine the goals of critical care to more fully support both survival and cognitive recovery.