An approach for the emergency diagnosis and treatment of sepsis-associated encephalopathy in elderly individuals: a literature review

Abstract

BACKGROUND:

Sepsis-associated encephalopathy (SAE) is a diffuse dysfunction of the nervous system resulting from sepsis originating outside the central nervous system. Elderly individuals (≥65 years of age) constitute a particularly vulnerable population comprised by a high burden of underlying diseases and complications, which frequently leads to underdiagnosis or misdiagnosis. These patients are at increased risk of long-term or permanent central nervous system impairment, making rapid and accurate diagnosis and treatment especially critical. The review is expected to promote improvements in the diagnosis and treatment of SAE in elderly patients, ultimately achieving more standardized and efficient SAE management.

METHODS:

We performed a literature search in four databases—PubMed, Embase, China National Knowledge Infrastructure (CNKI), and Wanfang—from inception to April 2025 using bilinguals (Chinese and English).

RESULTS:

The diagnostic criteria for SAE in elderly individuals include the following: (1) sepsis; (2) new-onset neurological dysfunction; and (3) exclusion of other causes of neurological dysfunction. Physicians should develop tailored empiric anti-infective plans for elderly SAE patients, considering comorbidities, organ function, infection site, local bacterial spectrum, and resistance. The treatment protocol can be adjusted once the pathogen is identified. Stabilizing hemodynamics and ensuring cerebral perfusion are two fluid resuscitation strategies used in elderly SAE patients. An individualized approach to fluid resuscitation using restrictive fluid volumes should be employed. Supportive treatment for elderly SAE patients focuses on improving tissue perfusion/oxygenation, controlling blood glucose levels, and correcting internal imbalances. Early rehabilitation, nutritional support, cognitive training, and family-based emotional support are important components of comprehensive care.

CONCLUSION:

The diagnosis and management of SAE in elderly patients support early recognition and timely intervention.

INTRODUCTION

Sepsis-associated encephalopathy (SAE) is a form of diffuse neurological dysfunction that arises secondary to sepsis in the absence of overt central nervous system (CNS) infection.^[1] The increasing incidence of sepsis among older adults (aged ≥65 years) has led to a corresponding increase in SAE cases within this population.^[2] Owing to atypical clinical presentations, multiple comorbidities, and age-related complications, elderly patients with SAE frequently experience delays in diagnosis and treatment, which may result in long-term or irreversible CNS injury. Consequently, timely and accurate diagnosis and intervention are essential for optimizing outcomes in this vulnerable population. However, standardized diagnostic and therapeutic protocols for SAE in elderly patients are currently lacking.

METHODS

We performed a literature search in four databases—PubMed, Embase, China National Knowledge Infrastructure (CNKI), and Wanfang—from inception to April 2025 via bilinguals (Chinese and English). Keywords included “sepsis-associated encephalopathy,” “diagnostic criteria for sepsis-associated encephalopathy,” “therapeutic strategies for sepsis-associated encephalopathy,” and “geriatric sepsis.” Eligible sources included meta-analyses, systematic reviews, randomized controlled trials (RCTs), retrospective studies, case reports, clinical guidelines, and expert consensus statements.

RESULTS

Risk factors

Studies have shown that a history of CNS disorders (e.g., stroke and epilepsy), long-term psychotropic drug use,^[3] acute kidney injury, and homeostatic disorders are key risk factors for SAE in elderly individuals.^[4] Acute kidney injury can lead to acidosis and metabolic abnormalities, resulting in the accumulation of neurotoxic substances. Geriatric sepsis is often associated with metabolic imbalances such as hypoglycemia, hyperglycemia, and hypernatremia, which further increase the risk for SAE.^[5,6] Additionally, the CNS in older adults is more susceptible to injury during sepsis as a result of reduced tolerance to hypoxia and impaired vascular autoregulation. In this context, low mean arterial pressure (MAP), a reliable indicator of tissue perfusion, can result in cerebral hypoperfusion and neuronal injury, thereby contributing to the development of SAE.^[7]

Clinical features

Elderly patients—particularly those aged ≥80 years—often cannot provide accurate medical histories as a result of memory loss or dementia. The clinical manifestations of SAE in this population are frequently atypical, with approximately one-quarter of patients presenting with nonspecific symptoms. These patients often lack clear signs of systemic infection (e.g., fever or elevated white blood cell count).^[8] Some patients may exhibit altered mental status (e.g., changes in cognition or arousal, confusion, or impaired attention^[9]), whereas others may present in coma, leading to misdiagnosis as other CNS disorders.

Older adults often have multiple chronic conditions (e.g., diabetes, cancer, congestive heart failure) and a weakened immune system, which increase their susceptibility to infection.^[10] In these cases, SAE typically arises from the combined effects of chronic disease and sepsis rather than an isolated dysregulated immune response. This complex interplay complicates diagnosis, making early identification of SAE particularly important in elderly individuals. Table 1 outlines the differential diagnosis of SAE and other conditions based on clinical features.

Table 1.

Differential diagnosis of sepsis-associated encephalopathy (SAE) and other conditions based on clinical features

Features	SAE	Stroke	Epilepsy	Metabolic encephalopathy
Disease onset and state of consciousness	• Synchronized with sepsis • Progressive impairment of consciousness • Delirium • Decreased concentration or orientation • Coma	• Acute onset (minutes to hours) • Sudden focal neurological deficits • Level of consciousness depends on lesion location (e.g., brainstem lesions may cause coma)	• Episodic (lasting seconds to minutes) • Loss of consciousness during the ictal phase (tonic-clonic seizures) • Normal consciousness between episodes	• Onset synchronized with metabolic disturbances (e.g., hyponatremia, liver failure) • Fluctuating levels of consciousness • Drowsiness progressing to coma
Neurological signs	• No focal neurological deficits • Diffuse hypertonia or hypotonia	• Focal deficits (e.g., hemiplegia, aphasia, visual field loss) • Positive pathological reflexes	• Tonic‒clonic seizures during the ictal phase • Postictal paralysis (Todd’s paralysis)	• Symmetrical tremor • Ataxia (e.g., Wernicke’s encephalopathy) • Asterixis (e.g., hepatic encephalopathy)
Accompanying symptoms	• Nausea and vomiting • Dyspnea	• Headache (suggestive of hemorrhagic stroke) • Vertigo (posterior circulation stroke) • Dysarthria or dysphagia	• Preictal auras (e.g., visual hallucinations, olfactory hallucinations) • Tongue biting • Urinary or fecal incontinence	Symptoms of underlying disease: • Jaundice (e.g., hepatic encephalopathy) • Polyuria/oliguria (e.g., renal failure) • Hunger pangs (e.g., hypoglycemia)
Accompanying signs	Signs of sepsis-associated organ failure: • Skin mottling • Acral cyanosis (hypoperfusion) • Decreased urine output	Vascular indicators: • Carotid bruit • Atrial fibrillation • Acute hypertension (hemorrhagic stroke)	Ictal indicators: • Mydriasis (tonic) • Tachycardia or apnea	Signs of metabolic disturbances: • Kayser-Fleischer rings (Wilson’s disease) • Signs of clinical dehydration (e.g., hyperosmolar coma) • Palmar erythema or spider angiomas (hepatic encephalopathy)

Common diagnostic methods

Diagnostic approaches for SAE include the testing of sepsis biomarkers, neuronal injury markers, and neuroimaging studies (Table 2). In elderly patients presenting with new-onset neurological dysfunction, prompt evaluation with routine blood and urine tests; biochemical panels; measurements of C-reactive protein (CRP), serum lactate (Lac), procalcitonin (PCT), and heparin-binding protein (HBP); and cranial computed tomography (CT) are essential to exclude alternative diagnoses, such as stroke or intracranial masses, and to enable early sepsis screening.^[11,12] Where resources permit, additional assessments—including markers of sepsis-induced neuronal injury, cytokine/chemokine profiling, brain magnetic resonance imaging (MRI), electroencephalography (EEG), and cerebrospinal fluid (CSF) analysis—should be undertaken. MRI is recommended for SAE diagnosis and management, as abnormal findings are observed in more than 70% of affected patients.^[13] Given the limited specificity and the need for expert interpretation, EEG is not suitable for the emergency diagnosis of SAE but may be valuable for monitoring and prognostic evaluation in the intensive care unit.^[14] CSF analysis plays a critical role in excluding CNS infection, hemorrhage, and other specific encephalopathies.

Table 2.

Common diagnostic methods for SAE

Types	Specific methods	Clinical significance
Laboratory and metabolic testing	• Blood and urine routine tests, electrolytes, liver and kidney function tests, blood glucose, blood gas analysis, serum lactate • Infection markers (e.g., PCT, CRP, HBP) • IL-1β and TNF-α • Etiological testing	• Aids in early detection of infection and systemic inflammatory response
Neuronal injury biomarkers	• NSE • S100β • GFAP • NfL	• Indicates neuronal or glial injury
Neuroelectrophysiological monitoring	• EEG	• Detects slow waves, epileptiform discharges, and suppressed brain activity; useful for monitoring and prognostication
Neuroimaging	• CT • MRI of the brain (e.g., DWI and FLAIR sequences)	• Excludes acute intracerebral hemorrhage and infarction; assesses structural abnormalities and white matter or microvascular damage
Other specialized tests	• CSF analysis (cell count, protein, glucose, etc.,) • Serum autoantibodies	• Helps exclude CNS infections, autoimmune encephalitis, and other specific encephalopathies

SAE: sepsis-associated encephalopathy; PCT: procalcitonin; CRP: C-reactive protein; HBP: heparin-binding protein; IL-1β: interleukin-1 beta; TNF-α: tumor necrosis factor-alpha; NSE: neuron-specific enolase; GFAP: glial fibrillary acidic protein; NfL: neurofilament light chain; EEG: electroencephalogram; CT: computed tomography; MRI: magnetic resonance imaging; DWI: diffusion-weighted imaging; FLAIR: fluid-attenuated inversion recovery; CSF: cerebrospinal fluid; CNS: central nervous system.

Diagnosis

Although no unified diagnostic standard currently exists for SAE, diagnosis requires the simultaneous fulfillment of three essential criteria: (1) the presence of sepsis; (2) new-onset neurological dysfunction; and (3) the exclusion of alternative causes of neurological impairment (e.g., stroke, intracranial infection, poisoning, hepatic encephalopathy, pulmonary encephalopathy, or diabetic hyperglycemic hyperosmolar syndrome).^[15] In elderly patients, sepsis often presents atypically,^[16] and neurological symptoms may constitute the initial manifestation.^[17] For the early detection of sepsis in older adults with neurological changes, the quick Sequential Sepsis-related Organ Failure Assessment (qSOFA) and the modified Early Warning System (MEWS) are both recommended tools.^[18] Emergency physicians should maintain a high index of suspicion for neuropsychiatric signs—such as confusion, impaired concentration, dyspraxia, delirium, and agitation—upon admission of geriatric patients with suspected sepsis.^[19] For clinical evaluation, the Richmond Agitation-Sedation Scale (RASS) and the Intensive Care Delirium Screening Checklist (ICDSC) are useful for assessing delirium, whereas the Glasgow Coma Scale (GCS) is appropriate for evaluating comatose state.

Screening for infection foci

Accurate identification and early control of infection foci are central to the management of SAE. In patients aged ≥85 years, lower respiratory tract and urinary tract infections are the most prevalent causes of sepsis.^[20-22] Aspiration pneumonia is particularly common in this age group as a result of impaired swallowing, weakened cough reflexes, muscle loss, and senescence.^[23] Viral pneumonia accounts for more than one-third of community-acquired pneumonia cases in adults and is associated with a high sepsis rate (61%). It affects older individuals and is frequently accompanied by neurological symptoms.^[24] Two studies reported that 35.17% of elderly patients with COVID-19 exhibited cognitive impairment, and 59.24% had persistent deficits six months post-discharge.^[25,26]

Urinary tract infections are also more common in elderly individuals as a result of immunosenescence, age-related physiological changes, and frequent catheter use—factors that increase the risk of progression to sepsis and SAE.^[27] Bloodstream and intra-abdominal infections, while less common, are characterized by rapid deterioration and high mortality. European and North American studies report a 12%-20% mortality rate for bloodstream infections, with over half occurring in patients over 65 years of age. In such cases, early identification of the pathogen and infection source is critical. The diagnosis of intra-abdominal infections is often delayed in elderly patients with nonspecific symptoms, which accelerates progression to sepsis and, ultimately, SAE.

Principles of treatment

Key principles in the treatment of SAE include rapid recognition and early identification of sepsis, comprehensive assessment, identification of the infectious source and causative pathogens, and timely initiation of antimicrobial therapy. In addition to targeted anti-infective measures, supportive care—such as individualized early fluid resuscitation, oxygen therapy, correction of internal environmental disturbances, and appropriate sedation—is essential for promoting functional recovery and improving the prognosis of elderly SAE patients (Figure 1 for the diagnostic and treatment flowchart).

Figure 1. Diagnostic and treatment algorithm for sepsis-associated encephalopathy in elderly individuals. CRP: C-reactive protein; PCT: procalcitonin; HBP: heparin-binding protein; CT: computed tomography; MRI: magnetic resonance imaging; CNS: central nervous system; RASS: Richmond Agitation-Sedation Scale; SAE: sepsis-associated encephalopathy.

Antimicrobial therapy

SAE in the elderly is most commonly of bacterial origin. Empiric antimicrobial therapy should be guided by regional patterns of bacterial epidemiology and resistance, as well as the patient’s systemic condition and organ function. In cases associated with lower respiratory, urinary, or intra-abdominal infections, gram-negative bacilli are the predominant pathogens.^[23] Empiric options may include β-lactam/β-lactamase inhibitor combinations (e.g., cefoperazone/sulbactam or piperacillin/tazobactam). For severe or drug-resistant bacterial infections, imipenem/cilastatin, meropenem, imipenem/cilastatin/relebactam, and ceftolozane-tazobactam are recommended. In elderly patients with bloodstream infections caused by gram-positive cocci—especially methicillin-resistant Staphylococcus aureus (MRSA)—vancomycin may be used. For infections caused by vancomycin-resistant enterococci (VREs), linezolid should be considered. Viral sepsis is also relatively common in this population and may lead to early neurological impairment and long-term cognitive decline.^[24] In patients with confirmed viral sepsis, antiviral treatment should be initiated promptly. Older adults with SAE—particularly those over 80 years of age or with comorbidities—are at increased risk of coinfection with multiple pathogens, and repeated sampling for pathogens may be necessary to improve pathogen detection. In addition to pharmacological therapy, early removal of infection sources—such as sputum drainage, percutaneous abscess drainage, or surgical debridement—is also critical.

Antimicrobial selection must consider factors such as patient age and renal function (e.g., creatinine clearance). Where feasible, therapeutic drug monitoring can assist in optimizing individual dosing. Antimicrobials known to cause neurotoxicity should be avoided in elderly SAE patients with epilepsy, preexisting CNS disorders, or renal insufficiency. Inappropriate or prolonged use of broad-spectrum antibiotics may lead to adverse outcomes,^[28] including disruption of the intestinal microbiota and antimicrobial-associated diarrhea.

Ensuring perfusion and improving oxygenation

Early restoration of hemodynamic stability and timely fluid resuscitation to maintain cerebral perfusion pressure are crucial for SAE management in elderly patients. Given the diminished cardiopulmonary reserve, older adults exhibit reduced responsiveness to volume expansion and limited tolerance for fluid loading; excessive fluid administration can therefore precipitate pulmonary edema.^[29] As such, fluid resuscitation in elderly SAE patients should be individualized and restrictive. (1) For patients with arteriosclerosis and/or hypertension, a higher MAP target of 75-85 mmHg (1 mmHg=0.133 kPa) is recommended to preserve organ and cerebral perfusion.^[30] Evidence suggests that maintaining a slightly elevated MAP is associated with reduced in-hospital mortality in SAE patients.^[31-33] However, the indiscriminate pursuit of MAP targets should be avoided. Vasopressors such as norepinephrine may be used when necessary. (2) Volume status should be reassessed every 2-4 h, with resuscitation adjusted accordingly to prevent fluid overload. (3) In cases of volume overload (e.g., pulmonary edema), diuretics and fluid restriction should be employed; renal replacement therapy may be considered if needed. (4) Colloids may be used to limit capillary leakage.^[34] Resuscitation strategies include: (1) quantification of fluid intake/output and close monitoring of vital signs; (2) the passive leg raising test, which assesses fluid responsiveness without additional volume administration; (3) bedside ultrasound for rapid assessment of volume status in the emergency setting; and (4) serial measurement of blood lactate levels, as persistently elevated lactate is associated with poor prognosis.

Optimizing oxygenation is also critical in elderly SAE patients. Depending on clinical status—including disease severity, level of consciousness, and spontaneous respiratory effort—oxygen may be delivered via nasal cannula, high-flow nasal cannula, or non-invasive/invasive mechanical ventilation to maintain an oxygen saturation at or above 93%.

Management of blood glucose and the internal environment

Blood glucose should be actively controlled in elderly SAE patients.^[35] Insulin therapy should be initiated when blood glucose levels reach ≥10 mmol/L. Although hypoglycemia is an independent risk factor for in-hospital mortality among septic patients, overly aggressive glucose-lowering strategies—with target levels of 5.0-6.1 mmol/L—markedly increase the risk of hypoglycemia.^[36] For elderly SAE patients receiving insulin, glucose should be monitored at intervals of no longer than one hour. Once the blood glucose level and insulin infusion rates stabilize, monitoring may be extended every 2-4 h. However, if hypoglycemia occurs, the monitoring frequency should increase every 15 min until the glucose level stabilizes within the target range. Electrolyte imbalances, particularly disturbances in sodium levels, must also be promptly corrected. The key principles for managing electrolyte abnormalities in elderly SAE patients include: (1) screening for underlying conditions such as hypothyroidism, adrenal insufficiency, or heart failure; and (2) adjusting the correction speed appropriately, as rapid correction may induce osmotic shifts leading to cerebral edema, whereas delayed correction may hinder treatment and increase mortality.

Sedation

For elderly SAE patients requiring sedation, both “shallow sedation” and “intermittent sedation” are recommended, with a target RASS score of −2 to +1.^[37] Dexmedetomidine, a highly selective α2-adrenergic receptor agonist that acts on both central and peripheral receptors, is the preferred agent. Its immunomodulatory and anti-inflammatory properties make it well-suited for use in septic patients.^[38] However, in elderly SAE patients, dexmedetomidine may induce bradycardia and hypotension; therefore, a reduced loading dose (0.5 μg/kg over 10 min) followed by a maintenance infusion of 0.2-0.7 μg/(kg·h) is recommended. It should be diluted in saline or glucose solution, with continuous monitoring of heart rate and blood pressure during administration. If bradycardia or hypotension occurs, the infusion should be reduced or discontinued. Dexmedetomidine is not recommended for patients with severe heart block or ventricular dysfunction. As it undergoes hepatic metabolism and is renally excreted 95% of the time, dose adjustment is required in patients with hepatic insufficiency but is generally not necessary for short-term use in elderly patients with renal impairment.^[39]

Propofol and ciprofol, characterized by a rapid onset (within 1 min) and short duration of action (3-10 min), may serve as adjunctive sedatives for elderly SAE patients requiring brief, reversible sedation for procedures such as bedside bronchoscopy or blood purification in patients with poor cooperation. Research has confirmed that ciprofol is a novel sedative drug with a sedative compliance rate comparable to that of propofol and a lower incidence and shorter duration of adverse reactions such as hypotension.^[40]

Traditional Chinese medicine

In traditional Chinese medicine, SAE is categorized as a manifestation of “unconsciousness” (Shen disturbance), with core pathophysiological mechanisms involving excessive heat toxin, obstruction of the orifices by phlegm and static blood, and a deficiency of vital qi. These factors interact to form a self-perpetuating pathological cycle. The primary therapeutic principles are “clearing heat and removing toxicity” and “clearing phlegm for resuscitation”. In elderly SAE patients, in whom patterns of deficiency and excess often coexist, syndrome differentiation should be carefully refined to guide the selection of appropriate interventions. For heat-blocking syndromes—characterized by high fever, unconsciousness, facial flushing, tachypnea, delirium, agitation, and a red tongue with yellow, dry coating—Angong Niuhuang pill or its derivative Xingnaojing Injection may be used. Angong Niuhuang pill has been reported to regulate blood-brain barrier permeability, protect the vascular endothelium, and suppress inflammation, thereby reducing cerebral edema and preserving brain tissue integrity.^[41] Elderly individuals with severe vital qi deficiency are predisposed to septic shock, leading to SAE manifestations such as unconsciousness, pallor, cyanotic lips, clammy skin, pale tongue, and weak pulse—collectively referred to as yang collapse syndrome in traditional Chinese medicine. In such cases, Shenfu injection is indicated for yang restoration.^[42] Acupuncture at Baihui, Shenmen, Xinyu, Shenting, Neiguan, and Shuigou may also be employed to refresh consciousness, open orifices, calm the heart, and stabilize the spirit.

Prognostic assessment and rehabilitation for elderly SAE patients

Monitoring and prognosis assessment

Systematic assessment of consciousness and continuous monitoring should be performed daily for elderly SAE patients admitted to the intensive care unit. Prolonged delirium or coma indicates severe neurological injury and is associated with an elevated risk of long-term cognitive and motor impairment. Delirium can be assessed via the RASS and ICDSC, whereas the GCS and Full Outline of Unresponsiveness (FOUR) score are appropriate for evaluating coma severity and brainstem reflexes. In SAE patients complicated by epilepsy, refractory status epilepticus (RSE) serves as a critical predictor of poor prognosis. RSE can result in sustained cerebral hypoxia, brain edema, and metabolic disturbances, further exacerbating neurological damage. In elderly patients, RSE is associated with increased mortality due to limited cerebral perfusion and oxygenation reserves. Therefore, if feasible, long-term (24-72 h) continuous EEG monitoring is recommended to facilitate dynamic evaluation of survival and neurological outcomes.^[43]

Rehabilitation

The neuropsychiatric sequelae of SAE in older adults may persist for months or even years, contributing to cognitive decline and psychological disorders (e.g., depression and anxiety). These complications, in combination with underlying comorbidities and malnutrition,^[44] may lead to permanent disability or premature death. Sepsis in elderly patients also reduces physical endurance, often resulting in prolonged bed rest and complications such as recurrent urinary tract infections, hypostatic pneumonia, pressure ulcers, deep vein thrombosis, and sarcopenia. Early initiation of rehabilitation, including nutritional support, psychological evaluation, cognitive training, and emotional support from family members, offers a multi-dimensional approach to recovery. Such interventions can enhance physical function, mental well-being, and overall prognosis in elderly SAE patients.^[45]

CONCLUSION

The diagnosis and management of SAE in elderly patients support early recognition and timely intervention.

Funding: This work was supported by the Beijing Clinical Key Specialty Project (2023).

Ethical approval: Not needed.

Conflicts of interest: The authors declare that there are no conflicts of interest.

Contributors: CZL, GQZ, MRX, YFM, WG (Wei Guo), and WG (Wei Gu) contributed to the study design. WG (Wei Gu) and JZ (Jie Zhong) contributed to the literature review and drafted the manuscript.