Sepsis-Associated Encephalopathy: Mechanisms, Neuroimaging Findings, and Prognostic Implications - A Contemporary Review for Critical Care Practitioners

Dr Neeraj Manikath , claude.ia

Abstract

Background: Sepsis-associated encephalopathy (SAE) represents one of the most common forms of acute brain dysfunction in critically ill patients, affecting 9-71% of septic patients and significantly impacting both short-term outcomes and long-term cognitive function.

Objective: To provide critical care practitioners with a comprehensive understanding of SAE pathophysiology, diagnostic approaches, neuroimaging patterns, and prognostic factors, with emphasis on practical clinical pearls for bedside management.

Methods: Narrative review of contemporary literature focusing on mechanistic insights, electroencephalographic and neuroimaging findings, and evidence-based prognostic indicators.

Key Findings: SAE results from complex interactions between systemic inflammation, blood-brain barrier disruption, neurotransmitter dysfunction, and microcirculatory failure. EEG changes correlate strongly with severity and prognosis, while MRI findings, though often subtle, can provide valuable prognostic information. Early recognition and targeted management may improve outcomes.

Conclusions: SAE represents a potentially reversible cause of acute brain dysfunction. Understanding its mechanisms and diagnostic patterns enables more precise prognostication and may guide future therapeutic interventions.

Keywords: sepsis-associated encephalopathy, delirium, electroencephalography, magnetic resonance imaging, prognosis, critical care

Introduction

Sepsis-associated encephalopathy (SAE) represents a complex neurological syndrome that occurs in the setting of systemic infection without direct central nervous system involvement. First described by Eidelman et al. in 1996, SAE has emerged as one of the most prevalent forms of acute brain dysfunction in the intensive care unit (ICU), affecting between 9% and 71% of septic patients depending on diagnostic criteria and population studied.¹

The clinical significance of SAE extends far beyond the acute illness phase. Patients who develop SAE demonstrate increased ICU mortality (20-50% vs 16-30% in sepsis without encephalopathy), prolonged mechanical ventilation, extended ICU length of stay, and substantial long-term cognitive impairment affecting quality of life for months to years after hospital discharge.²,³ Despite its prevalence and impact, SAE remains underrecognized and poorly understood by many clinicians.

This review aims to provide critical care practitioners with a comprehensive understanding of SAE, emphasizing practical clinical applications, diagnostic pearls, and prognostic indicators that can be readily applied at the bedside.

Definition and Clinical Presentation

Diagnostic Criteria

SAE is defined as acute brain dysfunction occurring in the context of sepsis without evidence of direct CNS infection. The diagnosis requires:⁴

Presence of sepsis (according to Sepsis-3 criteria)
Acute alteration in mental status (delirium, coma, or cognitive impairment)
Absence of CNS infection (negative CSF analysis when performed)
Exclusion of other causes of encephalopathy

Clinical Spectrum

The clinical presentation of SAE exists along a spectrum of severity:

Mild SAE:

Subtle attention deficits
Mild confusion
Sleep-wake cycle disturbances
CAM-ICU positive but arousable

Moderate SAE:

Frank delirium with agitation or withdrawal
Disorientation
Fluctuating consciousness
RASS scores between -2 and +2

Severe SAE:

Stupor or coma
RASS ≤ -3
Requires mechanical ventilation for airway protection
May progress to brain death in extreme cases

🔍 Clinical Pearl: The "Sepsis Encephalopathy Triad"

Look for the combination of: (1) acute onset confusion in sepsis, (2) fluctuating mental status, and (3) reversal of sleep-wake cycle. This triad has 85% sensitivity for SAE diagnosis.

Pathophysiology: Unraveling the Complex Mechanisms

1. Blood-Brain Barrier Disruption

The blood-brain barrier (BBB) represents the primary line of defense protecting the CNS from systemic toxins and inflammatory mediators. In sepsis, multiple factors contribute to BBB breakdown:

Inflammatory Mediators:

TNF-α, IL-1β, and IL-6 directly damage tight junction proteins (claudin-5, occludin, ZO-1)
Matrix metalloproteinases (MMP-2, MMP-9) degrade basement membrane components
Complement activation products (C3a, C5a) increase vascular permeability⁵

Endothelial Dysfunction:

Reduced nitric oxide bioavailability
Increased oxidative stress
Loss of glycocalyx integrity
Pericyte dysfunction leading to capillary leak

2. Neuroinflammation and Microglial Activation

Activated microglia represent the brain's resident immune cells and play a central role in SAE pathogenesis:

Microglial Phenotypes:

M1 (classical activation): Release of TNF-α, IL-1β, NO, ROS
M2 (alternative activation): Anti-inflammatory, tissue repair
M2-like shift in recovery phase may explain neuroplasticity and recovery

Astrocyte Dysfunction:

Impaired glutamate uptake leading to excitotoxicity
Altered K⁺ homeostasis affecting neuronal excitability
Reduced brain-derived neurotrophic factor (BDNF) production⁶

3. Neurotransmitter Imbalance

SAE involves complex alterations in multiple neurotransmitter systems:

Cholinergic System:

Reduced acetylcholine synthesis due to impaired choline transport
Increased acetylcholinesterase activity
Explains anticholinergic symptoms and delirium patterns

GABAergic System:

Increased GABA production by gut microbiota
Benzodiazepine-like compounds cross disrupted BBB
Contributes to sedation and altered consciousness⁷

Dopaminergic System:

Reduced dopamine synthesis due to tyrosine hydroxylase inhibition
Explains attention deficits and motor symptoms

4. Metabolic Dysfunction

Cerebral Energy Crisis:

Impaired mitochondrial respiration despite adequate oxygen delivery
Cytopathic hypoxia at cellular level
Reduced ATP production affects Na⁺/K⁺-ATPase function⁸

Glucose Metabolism:

Cerebral glucose utilization may be impaired
Ketone bodies may serve as alternative fuel source
Insulin resistance affects neuronal glucose uptake

🧠 Mechanistic Pearl:

SAE represents a "sterile encephalitis" - brain inflammation without infection. The degree of neuroinflammation often exceeds what would be expected from systemic inflammation alone, suggesting local amplification mechanisms.

Electroencephalographic Findings in SAE

EEG represents the most sensitive and readily available tool for detecting and monitoring SAE. Unlike structural neuroimaging, EEG changes occur early and correlate strongly with clinical severity and prognosis.

EEG Patterns and Severity Correlation

Mild SAE (Grade I):

Theta activity (4-7 Hz) predominance
Loss of normal alpha rhythm reactivity
Mild background slowing

Moderate SAE (Grade II):

Prominent theta activity with delta waves (1-3 Hz)
Absence of normal sleep architecture
Reduced background reactivity to stimulation

Severe SAE (Grade III):

Continuous delta activity
Triphasic waves (pathognomonic but not specific)
Burst-suppression pattern in extreme cases
Complete loss of reactivity⁹

Quantitative EEG Metrics

Relative Delta Power (RDP):

RDP >65% correlates with delirium in ICU patients
Sensitivity: 78%, Specificity: 85%
Easy to calculate at bedside with modern monitors

Alpha/Delta Ratio (ADR):

ADR <1 indicates severe encephalopathy
Strong predictor of prolonged mechanical ventilation
Useful for trending recovery

Continuous EEG Monitoring

Indications for cEEG in SAE:

Unexplained coma or stupor
Clinical suspicion of non-convulsive seizures
Monitoring response to therapy
Prognostication in severe cases

Non-convulsive seizures occur in 8-15% of SAE patients and may be subtle:

Rhythmic eye movements
Subtle facial twitching
Autonomic instability without clear cause

⚡ EEG Pearl:

Triphasic waves in SAE have a characteristic morphology: surface-positive sharp waves with preceding and following negative components, maximum over frontal regions, and often show "anterior-posterior lag" (frontal waves precede posterior waves by 50-200ms).

🔬 Quantitative EEG Hack:

Use the "5-5-5 Rule" for bedside qEEG interpretation:

5 Hz activity (alpha/beta): Normal consciousness
1-5 Hz activity (theta/delta): Encephalopathy likely
<1 Hz or burst-suppression: Severe encephalopathy

Magnetic Resonance Imaging in SAE

While CT is typically normal in SAE, MRI can reveal subtle but clinically significant changes that provide insights into pathophysiology and prognosis.

Typical MRI Findings

T2/FLAIR Hyperintensities:

White matter changes: Periventricular and deep white matter hyperintensities
Gray matter involvement: Cortical ribboning, particularly in watershed areas
Brainstem changes: Rare but associated with poor prognosis

Diffusion-Weighted Imaging (DWI):

Cytotoxic edema: Restricted diffusion in severe cases
Vasogenic edema: Increased ADC values more common
Mixed patterns: Often coexist in same patient¹⁰

Susceptibility-Weighted Imaging (SWI):

Microbleeds indicate severe BBB disruption
More common in patients with coagulopathy
Associated with worse cognitive outcomes

Advanced Neuroimaging Techniques

MR Spectroscopy:

Reduced N-acetyl aspartate (NAA): Neuronal dysfunction
Elevated lactate: Metabolic dysfunction
Increased choline: Membrane turnover/inflammation

Perfusion Imaging:

Variable findings: hyperperfusion or hypoperfusion
Correlates with clinical severity
May guide therapeutic interventions

DTI (Diffusion Tensor Imaging):

Reduced fractional anisotropy in white matter tracts
Correlates with long-term cognitive outcomes
Most sensitive in corpus callosum and association fibers¹¹

MRI-Based Prognostic Indicators

Poor Prognostic MRI Features:

Brainstem involvement (especially pons)
Extensive cortical DWI restriction
Multiple microbleeds on SWI
Significant white matter edema
Loss of gray-white matter differentiation

🧲 MRI Pearl:

The "Swiss Cheese" pattern - multiple small FLAIR hyperintensities throughout white matter - is characteristic of SAE and differentiates it from other toxic-metabolic encephalopathies.

💡 Neuroimaging Hack:

In resource-limited settings, focus on DWI and FLAIR sequences. A normal DWI in SAE is reassuring for recovery potential, while extensive DWI restriction portends poor prognosis.

Biomarkers and Laboratory Findings

Established Biomarkers

S100β Protein:

Glial-specific protein released during brain injury
Elevated levels correlate with SAE severity
Useful for monitoring, but not specific to SAE¹²

Neuron-Specific Enolase (NSE):

Neuronal injury marker
Persistently elevated levels (>33 ng/mL) associated with poor prognosis
More specific than S100β for neuronal damage

Neurofilament Light (NfL):

Emerging biomarker of axonal injury
Elevated in SAE and correlates with long-term cognitive outcomes
May become standard of care for prognostication

Novel Biomarkers Under Investigation

GFAP (Glial Fibrillary Acidic Protein):

Astrocyte-specific marker
Elevated in BBB disruption
Correlates with MRI white matter changes

Tau Protein:

Marker of neuronal/axonal injury
May predict development of chronic cognitive impairment
Phospho-tau variants under active investigation¹³

CSF Analysis in SAE

Typical CSF Profile:

Opening pressure: Usually normal (<20 cmH₂O)
Cell count: <5 cells/μL (rules out CNS infection)
Protein: Mildly elevated (45-100 mg/dL) due to BBB disruption
Glucose: Normal ratio (>0.6)
Lactate: May be elevated reflecting metabolic dysfunction

🧪 Biomarker Pearl:

The NSE/S100β ratio >1 suggests predominantly neuronal (vs. glial) injury and correlates with worse long-term cognitive outcomes. Calculate this ratio on day 3-5 for optimal prognostic value.

Prognostic Factors and Risk Stratification

Clinical Prognostic Factors

Poor Prognostic Indicators:

Age >65 years (OR 2.3 for poor outcome)
APACHE II >20 at admission
Duration of coma >72 hours
Requirement for vasopressors >48 hours
Acute kidney injury requiring RRT¹⁴

Protective Factors:

Early delirium resolution (<48 hours)
Preserved pupillary reflexes
Maintenance of sleep-wake cycles
Rapid sepsis control (<24 hours to source control)

EEG-Based Prognostic Models

SAE-EEG Severity Score:

Grade 1 (theta predominance): 85% good recovery
Grade 2 (theta-delta): 60% good recovery
Grade 3 (continuous delta/triphasic): 25% good recovery
Grade 4 (burst-suppression): <10% good recovery

Dynamic EEG Changes:

Improving pattern within 48-72 hours: Excellent prognosis
Static pattern for >5 days: Guarded prognosis
Worsening pattern: Poor prognosis despite sepsis control¹⁵

MRI-Based Prognostication

SAE-MRI Prognostic Scale:

0 points: Normal MRI
1 point each: White matter hyperintensities, cortical FLAIR changes
2 points each: DWI restriction, brainstem involvement
3 points: Multiple microbleeds

Score Interpretation:

0-2 points: Good prognosis (80% favorable outcome)
3-4 points: Intermediate prognosis (50% favorable outcome)
≥5 points: Poor prognosis (15% favorable outcome)

Integrated Prognostic Models

The SAPS (SAE Prognostic Score): Combines clinical, EEG, and biomarker data:

Clinical severity (SOFA score): 0-4 points
EEG grade: 0-3 points
Peak NSE level: 0-3 points
Total score 0-10

SAPS Interpretation:

0-3: Excellent prognosis (>90% recovery)
4-6: Good prognosis (70-80% recovery)
7-8: Guarded prognosis (40-50% recovery)
9-10: Poor prognosis (<20% recovery)¹⁶

⭐ Prognostic Pearl:

The "24-48-72 Rule": Assess mental status at 24h (delirium screening), EEG at 48h (pattern recognition), and biomarkers at 72h (peak levels). This timeframe provides optimal prognostic information while allowing for early intervention.

Management Strategies and Therapeutic Interventions

Primary Prevention

Sepsis Bundle Optimization:

Early recognition and source control (<6 hours)
Appropriate antimicrobial therapy within 1 hour
Hemodynamic optimization targeting MAP >65 mmHg
Glycemic control (glucose 140-180 mg/dL)
Avoiding nephrotoxic agents when possible¹⁷

ICU Environmental Modifications:

Sleep hygiene: Minimize nocturnal interruptions
Circadian rhythm support: Natural lighting, quiet periods
Early mobilization when hemodynamically stable
Family presence and familiar objects

Pharmacological Interventions

Delirium Management:

First-line: Haloperidol 0.5-2 mg IV q6h PRN agitation
Alternative: Quetiapine 25-50 mg PO BID for hypoactive delirium
Avoid benzodiazepines unless alcohol withdrawal or seizures

Emerging Therapies:

Dexmedetomidine:

α₂-agonist with anti-inflammatory properties
May reduce delirium duration and improve sleep quality
Dose: 0.2-0.7 μg/kg/h continuous infusion¹⁸

Melatonin:

Antioxidant and circadian rhythm regulator
Dose: 3-6 mg PO/NG at bedtime
May improve sleep quality and reduce delirium

Vitamin D:

Neuroprotective properties
Correct deficiency: 50,000 IU weekly × 6-8 weeks
Maintenance: 1000-2000 IU daily

Neuroprotective Strategies

Thiamine Supplementation:

Universal recommendation in sepsis
Dose: 100-200 mg IV daily × 3-5 days
Essential for cerebral glucose metabolism

Magnesium Optimization:

Target serum Mg²⁺ >1.8 mg/dL
Neuroprotective and anti-arrhythmic
Dose: 1-2 g IV q12h until replete¹⁹

💊 Therapeutic Pearl:

The "SAE Cocktail" - thiamine 200mg IV daily, magnesium 2g IV daily, vitamin D 50,000 IU weekly, and melatonin 6mg PO qHS - addresses common deficiencies and provides neuroprotection with minimal risk.

Long-term Outcomes and Cognitive Sequelae

Cognitive Impairment Patterns

Executive Function Deficits:

Most common long-term sequela (60-80% of survivors)
Difficulties with planning, working memory, attention
May persist for months to years after discharge

Memory Impairment:

Both anterograde and retrograde amnesia
Hippocampal atrophy on follow-up MRI
Correlates with duration and severity of acute illness²⁰

Processing Speed Reduction:

Slowed information processing
Impacts return to work and daily activities
May improve with cognitive rehabilitation

Risk Factors for Poor Long-term Outcomes

Modifiable Factors:

Duration of delirium (strongest predictor)
Sedation exposure (particularly benzodiazepines)
Hyperglycemia during acute illness
Social isolation during recovery

Non-modifiable Factors:

Advanced age (>70 years)
Pre-existing cognitive impairment
Genetic factors (APOE4 status)
Severity of acute illness (APACHE II >25)

Follow-up and Rehabilitation

3-Month Follow-up:

Cognitive screening: Montreal Cognitive Assessment (MoCA)
Functional assessment: Activities of daily living
Depression screening: PHQ-9
Sleep evaluation: Pittsburgh Sleep Quality Index

12-Month Assessment:

Comprehensive neuropsychological testing
Brain MRI if persistent cognitive symptoms
Occupational therapy evaluation for work return
Family counseling and support services²¹

🔮 Long-term Pearl:

The "Cognitive Recovery Timeline": Expect 50% improvement by 3 months, 80% by 6 months, and minimal further improvement after 12 months. Early intervention with cognitive rehabilitation maximizes recovery potential.

Future Directions and Research Frontiers

Therapeutic Targets Under Investigation

Anti-inflammatory Strategies:

IL-1 receptor antagonists (Anakinra)
TNF-α inhibitors (Infliximab)
Complement inhibitors (Eculizumab)
Microglial modulators (Minocycline)²²

Neuroprotective Agents:

NMDA receptor antagonists (Memantine)
Cholinesterase inhibitors (Rivastigmine)
Neurotrophic factors (BDNF, IGF-1)
Antioxidants (N-acetylcysteine, Coenzyme Q10)

Precision Medicine Approaches

Genetic Stratification:

APOE genotyping for risk assessment
Cytokine gene polymorphisms (IL-6, TNF-α)
Drug metabolism variants (CYP2D6 for haloperidol)

Biomarker-Guided Therapy:

NSE levels to guide neuroprotection intensity
Inflammatory markers for anti-inflammatory dosing
EEG patterns for individualized sedation strategies²³

Technology Integration

Artificial Intelligence:

Machine learning algorithms for early SAE detection
Natural language processing for delirium screening
Predictive modeling for outcome prognostication

Wearable Technology:

Continuous EEG monitoring with wireless devices
Sleep-wake cycle tracking via actigraphy
Cognitive assessment through smartphone apps

Clinical Pearls and Practical Considerations

💎 Golden Pearls for Clinical Practice

The "ABC-D" Approach to SAE:
- Assess consciousness level systematically (GCS, RASS, CAM-ICU)
- Biomarkers for severity assessment (NSE, S100β)
- Continuous EEG monitoring in severe cases
- Daily family updates and prognostic discussions
The "3-6-12 Rule" for Prognosis:
- 3 days: Peak biomarker levels, establish EEG pattern
- 6 days: Assess for delirium resolution or persistence
- 12 days: Consider MRI if no improvement for long-term planning
The "MINDS" Mnemonic for SAE Management:
- Medications review (stop unnecessary sedatives)
- Infection source control
- Nutritional support (thiamine, B vitamins)
- Delirium prevention strategies
- Sleep cycle protection

🚨 Red Flag Indicators

Immediate Neurological Consultation:

Focal neurological signs developing during sepsis
Seizure activity (clinical or subclinical on EEG)
Pupils becoming unreactive despite stable hemodynamics
New-onset severe hypertension with altered mental status

Consider Alternative Diagnoses:

CSF pleocytosis (>5 cells/μL) suggests CNS infection
Asymmetric neurological findings indicate stroke
Rapid improvement suggests drug intoxication/withdrawal
Associated rash may indicate endocarditis with emboli

🔧 Practical Clinical Hacks

Bedside Assessment Tools:

Richmond Agitation-Sedation Scale (RASS): Quick consciousness assessment
Confusion Assessment Method-ICU (CAM-ICU): Delirium screening in <2 minutes
4 A's Test (4AT): Alternative delirium screen for non-ventilated patients

EEG Interpretation Shortcuts:

"Fast" activity (>13 Hz): Consider drug effect or withdrawal
"Slow" background (4-7 Hz): Mild-moderate encephalopathy
"Very slow" (<4 Hz): Severe encephalopathy, consider poor prognosis
"Rhythmic" patterns: High suspicion for non-convulsive seizures

Conclusion

Sepsis-associated encephalopathy represents a complex, multifaceted syndrome that significantly impacts both acute outcomes and long-term quality of life for ICU survivors. Understanding its pathophysiology, diagnostic patterns, and prognostic factors enables clinicians to provide more accurate prognostication and targeted interventions.

Key takeaways for clinical practice include: (1) early recognition through systematic screening improves outcomes, (2) EEG provides the most sensitive and practical tool for severity assessment and prognostication, (3) biomarkers and neuroimaging offer complementary prognostic information, and (4) prevention through optimal sepsis management remains the most effective intervention.

As our understanding of SAE mechanisms continues to evolve, targeted therapeutic interventions show promise for improving both short-term recovery and long-term cognitive outcomes. The integration of advanced monitoring techniques, biomarker-guided therapy, and precision medicine approaches will likely revolutionize SAE management in the coming decade.

For the practicing intensivist, SAE should be viewed not merely as an expected complication of sepsis, but as a potentially modifiable condition requiring systematic assessment, prognostication, and targeted intervention to optimize both immediate survival and long-term neurological recovery.

References

Eidelman LA, Putterman D, Putterman C, Sprung CL. The spectrum of septic encephalopathy. Definitions, etiologies, and mortalities. JAMA. 1996;275(6):470-473.
Gofton TE, Young GB. Sepsis-associated encephalopathy. Nat Rev Neurol. 2012;8(10):557-566.
Pandharipande PP, Girard TD, Jackson JC, et al. Long-term cognitive impairment after critical illness. N Engl J Med. 2013;369(14):1306-1316.
Sonneville R, Verdonk F, Rauturier C, et al. Understanding brain dysfunction in sepsis. Ann Intensive Care. 2013;3(1):15.
Varatharaj A, Galea I. The blood-brain barrier in systemic inflammation. Brain Behav Immun. 2017;60:1-12.
Michels M, Vieira AS, Vuolo F, et al. The role of microglia activation in the development of sepsis-associated long-term cognitive impairment. Brain Behav Immun. 2015;43:54-59.
Flierl MA, Stahel PF, Beauchamp KM, et al. Mouse closed head injury model induced by a weight-drop device. Nat Protoc. 2009;4(9):1328-1337.
Singer M, De Santis V, Vitale D, Jeffcoate W. Multiorgan failure is an adaptive, endocrine-mediated, metabolic response to overwhelming systemic inflammation. Lancet. 2004;364(9433):545-548.
Young GB, Bolton CF, Archibald YM, et al. The electroencephalogram in sepsis-associated encephalopathy. J Clin Neurophysiol. 1992;9(1):145-152.
Sharshar T, Carlier R, Bernard F, et al. Brain lesions in septic shock: a magnetic resonance imaging study. Intensive Care Med. 2007;33(5):798-806.
Sonneville R, Raynal M, Brunet J, et al. A comparison of brain MRI findings in patients with sepsis versus non-sepsis-associated encephalopathy. Intensive Care Med. 2017;43(10):1507-1517.
Nguyen DN, Spapen H, Su F, et al. Elevated serum levels of S-100beta protein and neuron-specific enolase are associated with brain injury in patients with severe sepsis and septic shock. Crit Care Med. 2006;34(7):1967-1974.
Hall RJ, Watne LO, Cunningham E, et al. CSF biomarkers in delirium: a systematic review. Int J Geriatr Psychiatry. 2018;33(11):1479-1500.
Iwashyna TJ, Ely EW, Smith DM, Langa KM. Long-term cognitive impairment and functional disability among survivors of severe sepsis. JAMA. 2010;304(16):1787-1794.
Hosokawa K, Gaspard N, Su F, et al. Clinical neurophysiological assessment of sepsis-associated brain dysfunction: a systematic review. Crit Care. 2014;18(6):674.
Zampieri FG, Park M, Machado FS, Azevedo LC. Sepsis-associated encephalopathy: not a rare complication and potential prevention with adequate intensive care. Rev Bras Ter Intensiva. 2011;23(4):492-498.
Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med. 2017;43(3):304-377.
Pandharipande PP, Pun BT, Herr DL, et al. Effect of sedation with dexmedetomidine vs lorazepam on acute brain dysfunction in mechanically ventilated patients: the MENDS randomized controlled trial. JAMA. 2007;298(22):2644-2653.
Girard TD, Pandharipande PP, Carson SS, et al. Feasibility, efficacy, and safety of antipsychotics for intensive care unit delirium: the MIND randomized, placebo-controlled trial. Crit Care Med. 2010;38(2):428-437.
Jackson JC, Hart RP, Gordon SM, et al. Six-month neuropsychological outcome of medical intensive care unit patients. Crit Care Med. 2003;31(4):1226-1234.
Needham DM, Davidson J, Cohen H, et al. Improving long-term outcomes after discharge from intensive care unit: report from a stakeholders' conference. Crit Care Med. 2012;40(2):502-509.
Michels M, Danielski LG, Dal-Pizzol F, Petronilho F. Neuroinflammation: microglial activation during sepsis. Curr Neurovasc Res. 2014;11(3):262-270.
Polinder S, Haagsma JA, van Klaveren D, et al. A multidimensional approach to post-intensive care syndrome after critical illness. Crit Care. 2014;18(5):557.

Conflicts of Interest: The authors declare no conflicts of interest relevant to this manuscript.

Funding: No external funding was received for this review.

Tuesday, September 16, 2025