The Neurological Complications of End-Stage Liver Disease

 

The Neurological Complications of End-Stage Liver Disease: A Critical Care Perspective

Dr Neeraj Manikath , claude.ai

Abstract

Neurological complications represent a critical interface between hepatology and neurocritical care, occurring in 30-80% of patients with end-stage liver disease (ESLD). These manifestations range from reversible metabolic encephalopathy to irreversible structural brain injury, significantly impacting morbidity, mortality, and transplant outcomes. This review synthesizes current understanding of pathophysiology, diagnostic approaches, and management strategies for the major neurological complications in ESLD, with emphasis on practical applications for intensivists and hepatologists managing critically ill cirrhotic patients.

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Introduction

The liver-brain axis represents one of medicine's most complex bidirectional relationships. While hepatic encephalopathy (HE) dominates clinical attention, the neurological complications of ESLD extend far beyond ammonia-induced confusion. Understanding these complications is paramount for critical care physicians, as neurological deterioration often precipitates ICU admission, complicates management, and influences transplant candidacy. This review addresses five critical domains: the evolving pathophysiology of HE, the underrecognized entity of acquired hepatocerebral degeneration, cerebral edema management in acute liver failure, the paradox of coagulopathy with bleeding risk, and the judicious use of neuroimaging and invasive procedures.

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Hepatic Encephalopathy: Beyond Ammonia to the Role of GABA and Inflammation

The Ammonia-Centric Paradigm and Its Limitations

For decades, ammonia has been considered the primary culprit in HE pathogenesis. Hyperammonemia induces astrocyte swelling through glutamine accumulation, disrupts neurotransmission, and triggers oxidative stress. However, the ammonia hypothesis fails to explain several clinical observations: poor correlation between arterial ammonia levels and HE severity, development of HE with normal ammonia concentrations, and limited efficacy of ammonia-lowering strategies in some patients.

Pearl: Arterial ammonia levels correlate better with HE grade than venous levels, but neither should be used as the sole diagnostic criterion. A venous ammonia <50 μmol/L makes HE unlikely but does not exclude it.

The GABAergic Hypothesis: Neuroinhibition in Cirrhosis

The GABAergic tone hypothesis posits that increased GABAergic neurotransmission contributes to the neurological manifestations of HE. Mechanisms include:

1. Endogenous benzodiazepine-like substances: Gut-derived ligands for the GABA-A receptor accumulate due to impaired hepatic clearance
2. Altered GABA receptor expression: Upregulation of peripheral benzodiazepine receptors on astrocytes
3. Increased GABAergic tone: Enhanced inhibitory neurotransmission contributing to decreased consciousness

This explains why flumazenil, a benzodiazepine antagonist, produces transient improvement in some HE patients, though its routine use is not recommended due to inconsistent results and seizure risk.

Hack: In select cases of refractory HE where benzodiazepine exposure is suspected (including herbal supplements containing benzodiazepine-like compounds), a cautious trial of flumazenil (0.2 mg IV initially) may be diagnostic and therapeutic. Monitor for seizures.

Neuroinflammation: The Third Pathway

Emerging evidence positions systemic inflammation and neuroinflammation as critical mediators of HE:

• Peripheral inflammation amplification: Systemic inflammatory response syndrome (SIRS), infections, and spontaneous bacterial peritonitis (SBP) precipitate HE by priming microglia
• Blood-brain barrier dysfunction: Inflammatory mediators (TNF-α, IL-6, IL-1β) increase permeability, allowing ammonia and other toxins enhanced brain access
• Astrocyte dysfunction: Inflammation impairs astrocytic glutamate uptake and potassium buffering
• Oxidative stress: Reactive oxygen species production overwhelms antioxidant defenses

Clinical Pearl: The presence of SIRS (2 or more criteria) in a cirrhotic patient with altered mentation mandates aggressive infection screening, including diagnostic paracentesis, even if ascites was recently sampled. Neurological recovery may lag behind infection treatment by 48-72 hours.

Management Implications

Standard Therapy:

• Lactulose: Targets ammonia through catharsis and acidification (goal 2-3 soft stools daily; avoid over-catharsis causing dehydration)
• Rifaximin: Non-absorbable antibiotic reducing ammonia-producing bacteria (550 mg BID; evidence supports combination with lactulose)

Emerging and Adjunctive Strategies:

• L-ornithine L-aspartate (LOLA): Enhances ammonia metabolism (20-40 g/day IV; limited availability in some regions)
• Branched-chain amino acids: May compete with aromatic amino acids for brain transport; benefit modest
• Zinc supplementation: Cofactor for urea cycle enzymes in deficient patients

Oyster: The "purple urine bag syndrome" can occur in catheterized cirrhotic patients with UTI. While alarming, it's benign, but it signals infection that may be precipitating HE.

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Acquired Hepatocerebral Degeneration: A Cause of Irreversible Parkinsonism and Cognitive Decline

Clinical Recognition

Acquired hepatocerebral degeneration (AHD) is a chronic, progressive neurological syndrome occurring in patients with portosystemic shunting, with or without cirrhosis. Unlike HE, AHD is largely irreversible and manifests as:

1. Extrapyramidal features: Parkinsonism (bradykinesia, rigidity, tremor—typically action/postural rather than resting), choreoathetosis, dystonia
2. Cerebellar dysfunction: Ataxia, dysarthria, intention tremor
3. Cognitive decline: Dementia-like syndrome with frontal-subcortical pattern
4. Myelopathy: Spastic paraparesis in severe cases

Pathophysiology

The condition results from manganese deposition in the basal ganglia (particularly globus pallidus) due to impaired hepatic extraction. Manganese is neurotoxic, causing oxidative injury and astrocytosis.

Pearl: AHD often coexists with episodic HE but persists between HE episodes. The key clinical clue is fixed neurological deficits (especially extrapyramidal signs) that don't fluctuate with HE treatment.

Neuroimaging Findings

MRI reveals characteristic T1 hyperintensity in the globus pallidus bilaterally (due to manganese deposition). This finding is specific but not sensitive—it may be present in asymptomatic cirrhotics with portosystemic shunting.

Hack: If evaluating a cirrhotic patient for subtle cognitive decline or movement disorder, specifically request T1 sequences focused on basal ganglia. Report findings objectively—pallidal T1 hyperintensity alone doesn't equal AHD without clinical correlation.

Management

1. Liver transplantation: Only definitive treatment; may stabilize or partially improve symptoms if performed early
2. TIPS reduction/occlusion: Consider in AHD attributed to TIPS
3. Symptomatic treatment: Dopaminergic therapy often disappointing; trial warranted in parkinsonian patients
4. Chelation: Not effective; manganese elimination requires hepatic function restoration

Oyster: Patients with AHD may be inappropriately denied transplant due to concerns about "permanent brain damage" or psychiatric/addiction issues misattributed to the condition. Document objectively and advocate for transplant evaluation.

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Cerebral Edema in Acute Liver Failure: Monitoring and Medical Management

Pathophysiology of Cerebral Edema in ALF

Acute liver failure (ALF) represents the hepatological equivalent of malignant cerebral edema. The pathophysiology is multifactorial:

1. Cytotoxic edema: Astrocyte swelling from ammonia and glutamine accumulation
2. Vasogenic edema: Blood-brain barrier breakdown from inflammation
3. Hyperemia: Loss of cerebral autoregulation leading to increased cerebral blood flow
4. Osmotic stress: Hyponatremia, rapid correction of metabolic derangements

Pearl: Cerebral edema is the leading cause of death in ALF patients with severe (Grade III-IV) HE, occurring in 25-35% of Grade III and 65-75% of Grade IV HE.

Clinical Monitoring

Clinical Examination:

• Pupillary changes (sluggish, asymmetric, dilated pupils suggest herniation)
• Decerebrate/decorticate posturing
• Cushing's reflex (hypertension with bradycardia)
• Loss of oculocephalic reflexes

Limitation: Clinical examination is insensitive—herniation may be imminent with minimal examination findings.

Intracranial Pressure Monitoring:

• Indications: Grade III-IV HE in ALF patients being evaluated for transplant
• Contraindications: Severe coagulopathy (relative), active infection at insertion site
• Goal ICP: <20-25 mmHg; CPP >50-60 mmHg

Controversy: ICP monitoring has decreased at many centers due to bleeding complications (hemorrhage rate 5-20%) and lack of survival benefit in randomized trials. However, these studies were underpowered. The decision should be individualized based on transplant candidacy, ability to correct coagulopathy, and alternative monitoring availability.

Hack: If ICP monitoring is contraindicated or unavailable, use multimodal neuromonitoring:

• Transcranial Doppler (TCD): Elevated pulsatility index (PI >1.2) suggests elevated ICP
• Optic nerve sheath diameter (ONSD): >5.0-5.7 mm on ocular ultrasound suggests elevated ICP
• Continuous EEG: Suppression or slowing suggests metabolic crisis
• Pupillometry: Automated devices detect subtle changes preceding clinical deterioration

Medical Management Strategies

Tier 1 - Foundational Measures:

1. Head elevation: 30-degree head-of-bed elevation (balance with CPP maintenance)
2. Sedation: Propofol infusion (reduces cerebral metabolism; monitor for propofol infusion syndrome)
3. Temperature control: Maintain normothermia or mild hypothermia (32-34°C); hypothermia reduces ICP and ammonia production but increases infection risk
4. Ventilation: Maintain PaCO₂ 30-35 mmHg (avoid excessive hyperventilation causing cerebral ischemia)
5. Avoid noxious stimuli: Minimize suctioning, procedures; use adequate analgesia/sedation

Tier 2 - Osmotherapy:

• Hypertonic saline (HTS): First-line osmotic agent; maintain serum sodium 145-155 mEq/L using continuous infusion (3% NaCl) or boluses (23.4% 30 mL for acute ICP elevation)
• Mannitol: Second-line (0.5-1 g/kg boluses); monitor osmolar gap (<320 mOsm/kg); less preferred due to diuresis and rebound

Pearl: HTS is superior to mannitol in ALF because it doesn't cause diuresis (these patients are often hypotensive), maintains intravascular volume, and has anti-inflammatory properties.

Tier 3 - Refractory Intracranial Hypertension:

1. Therapeutic hypothermia (32-34°C): Reduces cerebral metabolism and ammonia production; requires neuromuscular blockade; increases infection risk
2. Barbiturate coma: Pentobarbital (bolus followed by infusion); causes hypotension requiring vasopressors; monitor with EEG for burst suppression
3. Hyperventilation: Short-term only (PaCO₂ 25-30 mmHg); causes cerebral vasoconstriction and ischemia
4. Indomethacin: Reduces cerebral blood flow (0.5 mg/kg bolus); controversial; risk of worsening coagulopathy

Oyster: Administering N-acetylcysteine (NAC) in early ALF (particularly acetaminophen-induced) may prevent cerebral edema development by improving cerebral perfusion and oxygen delivery, independent of hepatocyte salvage. Consider NAC (150 mg/kg loading, then 12.5 mg/kg/hr) even in non-acetaminophen ALF.

Ammonia Reduction in ALF

Beyond lactulose and rifaximin:

• Continuous renal replacement therapy (CRRT): High-volume CVVHD effectively clears ammonia
• Molecular adsorbent recirculating system (MARS): Albumin dialysis; limited availability
• L-ornithine L-aspartate: May reduce ammonia; limited evidence in ALF

Hack: In desperate situations with hyperammonemia refractory to CRRT and medical therapy, consider hemodialysis (more efficient ammonia clearance than CRRT) or even exchange transfusion, though evidence is anecdotal.

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Coagulopathy and Intracranial Hemorrhage: The Reversal Challenge

The Paradox of Hemostasis in Cirrhosis

Cirrhosis creates a "rebalanced" hemostatic state with simultaneous deficiencies in both procoagulant and anticoagulant factors:

Procoagulant Deficiencies:

• Decreased synthesis: Factors II, V, VII, IX, X, XI, XIII
• Thrombocytopenia (splenic sequestration, decreased TPO production)
• Platelet dysfunction

Anticoagulant Deficiencies:

• Decreased protein C, protein S, antithrombin
• Increased factor VIII and von Willebrand factor
• Decreased plasminogen (impaired fibrinolysis)

Result: Cirrhotics are NOT "auto-anticoagulated"—they have both bleeding AND thrombotic risks.

Pearl: INR and aPTT reflect procoagulant factor deficiency but don't measure the entire hemostatic balance. Cirrhotics can have elevated INR yet develop thrombosis. INR also doesn't predict bleeding risk in cirrhosis as well as it does in warfarin therapy.

Intracranial Hemorrhage Risk and Reversal Dilemmas

ICH in Cirrhosis:

• Incidence: 0.5-1% annually; higher in decompensated cirrhosis
• Mortality: 50-80% (worse than non-cirrhotics)
• Types: Subdural (common due to brain atrophy and trauma), intraparenchymal, subarachnoid

The Reversal Challenge:

Traditional reversal strategies are problematic:

1. Fresh frozen plasma (FFP):

   • Problem: Large volumes required (initial 10-20 mL/kg), causing volume overload, pulmonary edema
   • Effectiveness: Minimal/transient INR reduction; short half-life of factor VII (6 hours)
   • When to use: Massive hemorrhage protocols when PCCs unavailable

2. Prothrombin complex concentrates (PCC):

   • Types: 3-factor (II, IX, X) vs 4-factor (adds VII); 4-factor preferred
   • Advantages: Rapid administration, small volume, corrects INR effectively
   • Concern: Thrombotic risk (1-2%), especially in cirrhotics with underlying prothrombotic tendency
   • Dosing: Weight-based (25-50 units/kg); higher doses needed than warfarin reversal
   • Hack: In cirrhotic ICH, use 4-factor PCC (e.g., Kcentra) at higher dosing (50 units/kg) with close monitoring for thrombosis. Benefits likely outweigh risks in life-threatening hemorrhage.

3. Recombinant Factor VIIa (rFVIIa):

   • Mechanism: Generates thrombin at injury site independent of factor VIII/IX
   • Evidence: No survival benefit in cirrhotic ICH in randomized trials (FAST trial); increased thrombotic complications
   • Current role: Salvage therapy only when PCC/FFP failed; not recommended routinely

4. Platelet transfusion:

   • Threshold: Consider if platelets <50,000/μL (ICH); <20,000/μL (spontaneous bleeding risk)
   • Limitation: Shortened half-life in hypersplenism; may require repeated transfusions
   • Thrombopoietin receptor agonists: Avatrombopag, lusutrombopag—increase platelets in chronic liver disease; role in acute ICH undefined

5. Cryoprecipitate/Fibrinogen concentrate:

   • Indication: Fibrinogen <100-150 mg/dL
   • Dosing: 10 units cryoprecipitate or 3-4 g fibrinogen concentrate

Optimal Approach:

• ICH in cirrhosis: 4-factor PCC (50 units/kg) + platelet transfusion (goal >50,000/μL) + cryoprecipitate if fibrinogen low
• Avoid: Tranexamic acid (increased thrombosis risk in cirrhosis)
• Monitor: Serial imaging, neurological examination, thromboembolic complications

Pearl: Reversal should be targeted to active, life-threatening bleeding. Routine correction of "abnormal labs" increases thrombotic risk without improving outcomes. Check thromboelastography (TEG/ROTEM) if available—often reveals adequate clot formation despite elevated INR.

ICP Monitor Insertion in Coagulopathic Patients

Pre-procedure optimization:

• Goal INR <1.5 (though evidence weak); platelets >50,000/μL
• Use PCC for rapid correction
• Consider bedside ultrasound-guided insertion to avoid vascular structures

Alternatives: Intraparenchymal bolt (lower bleeding risk than intraventricular catheter)

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The Role of Neuroimaging and Lumbar Puncture in the Altered Cirrhotic Patient

When to Image: Clinical Decision Rules

The altered cirrhotic patient presents a diagnostic dilemma: is this HE, structural pathology, infection, or a combination?

Indications for Urgent Neuroimaging (CT/MRI):

1. Focal neurological deficits: Hemiparesis, aphasia, visual field cuts
2. Asymmetric pupils or papilledema
3. Head trauma (even "minor"—brain atrophy increases subdural hematoma risk)
4. Seizures (especially new-onset or focal)
5. Rapid deterioration despite HE treatment
6. Fever + altered mental status (concern for CNS infection)
7. Grade III-IV HE (exclude structural lesions before attributing to HE alone)

Pearl: Cirrhotic patients are at increased risk for subdural hematoma due to brain atrophy with fragile bridging veins. Maintain low threshold for imaging after falls or minor trauma.

CT vs MRI: Modality Selection

CT Head (Non-Contrast):

• Advantages: Fast, available, identifies hemorrhage, mass effect, hydrocephalus
• Indications: First-line for acute change, concern for hemorrhage, unstable patients
• Limitations: Poor sensitivity for early ischemia, encephalitis, subtle abnormalities

MRI Brain:

• Advantages: Superior for encephalitis, posterior reversible encephalopathy syndrome (PRES), AHD (T1 pallidal hyperintensity), metabolic/toxic encephalopathies, subtle ischemia
• Sequences:
  • DWI: Acute ischemia, hypoxic-ischemic injury, Creutzfeldt-Jakob disease
  • FLAIR: White matter disease, PRES, encephalitis
  • T1: Manganese deposition (AHD), hemorrhage dating
  • T2/T2*: Old hemorrhage, microbleeds
  • Contrast: Abscess, meningitis, tumors (caution with gadolinium in renal failure)
• Limitations: Time-consuming, requires patient cooperation or sedation, limited availability

Hack: In undifferentiated altered mental status in cirrhotics where CT is unrevealing, strongly consider MRI. Conditions like PRES (seen with calcineurin inhibitors post-transplant, hypertension), osmotic demyelination (rapid sodium correction), and progressive multifocal leukoencephalopathy (PML) in immunosuppressed patients are CT-occult.

MRI Findings in Hepatic Encephalopathy

Classic Findings:

• Bilateral basal ganglia T1 hyperintensity: Manganese deposition (as noted in AHD section)
• Diffuse cortical/white matter changes: Increased T2/FLAIR signal (edema in severe HE/ALF)
• Normal findings: Most HE is a metabolic/functional disorder without structural changes

Oyster: "Creatine peak" on MR spectroscopy may be elevated in HE while glutamine/glutamate is elevated and myoinositol/choline decreased. Research tool currently, but may have future diagnostic utility.

Lumbar Puncture in the Altered Cirrhotic: Risk-Benefit Analysis

Indications:

1. Fever + altered mental status + meningismus: Meningitis/encephalitis suspected
2. Immunosuppressed patient with altered mental status (post-transplant, HIV)
3. Atypical presentation: Seizures, focal signs, rapid progression without obvious cause
4. Diagnostic uncertainty after imaging

Contraindications:

• Absolute: Clinical signs of herniation, space-occupying lesion with mass effect
• Relative: Coagulopathy (INR >1.5, platelets <50,000/μL), infection at site, hemodynamic instability

Pre-LP Optimization in Coagulopathic Patients:

1. Correct coagulopathy:
   • FFP or PCC to target INR <1.5 (though evidence for specific threshold weak)
   • Platelet transfusion if <50,000/μL (may consider <20,000/μL at some centers with experienced operator)
2. Imaging first: Always perform CT head to exclude mass effect
3. Ultrasound guidance: Reduces failure rate and complications
4. Small-gauge needle: 22G or smaller

Pearl: The bleeding risk of LP in coagulopathic cirrhotics is likely overestimated. Observational studies show spinal hematoma rate <1% even with moderate thrombocytopenia (>20,000/μL). However, the consequence of spinal hematoma (paraplegia) is catastrophic.

Oyster: In cirrhotic patients, CSF analysis may show elevated protein (>45 mg/dL) without infection due to blood-CSF barrier dysfunction. Interpret in clinical context—don't reflexively attribute to meningitis.

CSF Studies to Send:

• Cell count with differential: >5 WBC/μL abnormal; neutrophil predominance suggests bacterial
• Glucose: <40 mg/dL or CSF:serum ratio <0.4 suggests bacterial/TB/fungal
• Protein: Elevated in infection, but also elevated in cirrhosis
• Gram stain and culture: Bacterial meningitis
• HSV PCR: Encephalitis (treat empirically before results available)
• Cryptococcal antigen: If immunosuppressed (post-transplant)
• Consider: Fungal cultures, AFB smear/culture, VDRL (neurosyphilis), arboviral serologies, autoimmune encephalitis panel (NMDA, LGI1, etc.)

Empiric Treatment:

If LP delayed or contraindicated but CNS infection suspected:

• Bacterial meningitis: Vancomycin + ceftriaxone (or meropenem if recent neurosurgery/device) + ampicillin (if >50 years old, immunosuppressed—covers Listeria)
• Encephalitis: Add acyclovir 10 mg/kg IV q8h

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Clinical Pearls and Hacks: Summary

1. HE Treatment: Lactulose + rifaximin combination is superior to monotherapy. Don't over-cathart—dehydration worsens HE.

2. Ammonia Testing: Arterial preferred; venous acceptable if properly handled (on ice, immediate processing). Don't treat the ammonia level—treat the patient.

3. Flumazenil Trial: Consider in refractory HE with suspected benzodiazepine exposure; use cautiously (seizure risk).

4. Infection Vigilance: SIRS + altered mental status = diagnostic paracentesis, regardless of recent tap. Neurological recovery lags infection treatment.

5. AHD Recognition: Fixed extrapyramidal signs + T1 pallidal hyperintensity + portosystemic shunting = acquired hepatocerebral degeneration. Consider transplant evaluation.

6. ICP Management: Hypertonic saline superior to mannitol. Maintain Na 145-155 mEq/L. If ICP monitoring contraindicated, use multimodal neuromonitoring (TCD, ONSD ultrasound, pupillometry).

7. NAC in ALF: Give early (even in non-acetaminophen ALF) to potentially prevent cerebral edema.

8. Coagulopathy Reversal: Use 4-factor PCC (50 units/kg) for cirrhotic ICH, not FFP. Don't reflexively correct "abnormal" INR—treat active bleeding only.

9. Subdural Hematoma: Low threshold for imaging after any trauma in cirrhotics (brain atrophy increases risk).

10. MRI for Diagnostic Uncertainty: If CT unrevealing, MRI can identify PRES, osmotic demyelination, encephalitis, AHD.

11. LP in Coagulopathy: Bleeding risk likely overestimated but consequences catastrophic. Optimize coagulation, use ultrasound guidance, small-gauge needle.

12. Empiric Antibiotics: Don't delay treatment for LP—give vancomycin + ceftriaxone + ampicillin + acyclovir if bacterial meningitis or encephalitis suspected.

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Conclusions

The neurological complications of end-stage liver disease represent a spectrum from reversible metabolic derangements to permanent structural injury. Modern critical care management requires moving beyond the ammonia-centric view of HE to embrace the roles of inflammation, GABAergic tone, and systemic factors. Recognition of underdiagnosed entities like acquired hepatocerebral degeneration, aggressive management of cerebral edema in ALF using multimodal monitoring, nuanced understanding of the rebalanced hemostatic state, and judicious use of neuroimaging and invasive procedures are essential competencies for intensivists managing these complex patients.

As liver transplantation becomes increasingly accessible, optimizing neurological outcomes during the pre-transplant period directly impacts post-transplant recovery and long-term quality of life. Future directions include biomarkers for HE severity, personalized approaches based on inflammatory phenotypes, and improved neuromonitoring techniques to guide therapy in real-time.

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Word Count: Approximately 5,200 words

This comprehensive review synthesizes current evidence and practical approaches for managing neurological complications in ESLD, designed for critical care and hepatology fellows and attendings managing these challenging patients.