1. Mechanical Ventilation Strategies

In ALF with grade III–IV hepatic encephalopathy (HE), early intubation is critical to protect the airway and enable precise control of PaCO₂ and oxygenation, which helps mitigate cerebral edema and intracranial pressure (ICP) elevation.

Indications for Intubation

• HE grade III–IV with loss of protective airway reflexes, refractory hypercapnia, or severe metabolic acidosis.
• Significant aspiration risk due to agitation, seizures, or persistent vomiting.

Ventilator Settings

• Lung-Protective Strategy: Employ low tidal volumes (6–8 mL/kg of predicted body weight) and maintain a plateau pressure below 30 cm H₂O to prevent ventilator-induced lung injury.
• Normocapnia Target: Strictly target a PaCO₂ between 35–40 mm Hg. Hypercapnia causes cerebral vasodilation, worsening ICP, while aggressive hyperventilation can cause vasoconstriction and cerebral ischemia.
• PEEP Considerations: Start with low to moderate PEEP (5–8 cm H₂O). Higher levels can impede cerebral venous outflow and increase ICP, so careful monitoring is essential.

2. Hemodynamic Support and Vasopressors

The distributive shock characteristic of ALF requires a careful balance of fluid resuscitation and vasopressor therapy to maintain mean arterial pressure (MAP) and organ perfusion without exacerbating fluid overload and cerebral edema.

3. Thrombosis and Bleeding Prophylaxis

ALF creates a state of “rebalanced hemostasis.” Despite a high INR, the pro- and anti-coagulant factors are both depleted, leading to a concurrent risk of both bleeding and thrombosis. Management requires a nuanced approach to prophylaxis.

Venous Thromboembolism (VTE) Prophylaxis

Immobility and systemic inflammation place ALF patients at high risk for VTE. Prophylaxis is recommended unless a contraindication exists.

• Indications: Initiate in all patients unless active, significant bleeding is present or platelet count is <30,000/µL.
• Agents: Unfractionated heparin (UFH) 5,000 units SC q12h or enoxaparin 40 mg SC daily (requires dose adjustment for CrCl <30 mL/min).

Stress Ulcer Prophylaxis (SUP)

Coagulopathy and shock increase the risk of stress-related mucosal bleeding.

• Agents: Proton pump inhibitors (e.g., pantoprazole 40 mg IV daily) or H₂-receptor antagonists (e.g., famotidine).

Coagulopathy Correction

Routine correction of INR is not recommended and can lead to volume overload and mask prognostic trends.

• Indications: Reserve fresh frozen plasma (FFP) and platelets for patients with active bleeding or prior to an invasive, high-risk procedure.
• Guidance: Thromboelastography (TEG) can help guide goal-directed transfusion to minimize unnecessary product administration.

4. Infection Surveillance and Management

Patients with ALF are profoundly immunocompromised and highly susceptible to bacterial and fungal infections, which are a major cause of morbidity and mortality. A proactive strategy of surveillance and early empirical therapy is key.

Surveillance and Diagnosis

• Routine Cultures: Obtain blood, urine, and tracheal aspirate (if intubated) cultures every 48–72 hours, even in the absence of fever.
• Fungal Monitoring: Maintain a high index of suspicion for fungal infections, particularly in patients with prolonged ICU stays, on broad-spectrum antibiotics, or with central venous catheters.

Empirical Antibiotic Therapy

• Triggers for Treatment: Initiate broad-spectrum antibiotics promptly for any new hemodynamic instability, worsening encephalopathy (grade III–IV), development of new organ dysfunction, or signs of systemic inflammatory response syndrome (SIRS).
• Antimicrobial Stewardship: Once culture sensitivities are available, de-escalate to the narrowest effective agent. Limit the duration of therapy to 5–7 days if there is a clear clinical improvement to reduce resistance and toxicity.

5. Iatrogenic Organ Dysfunction

Therapeutic interventions necessary for ALF management can themselves induce organ injury. Proactive monitoring and preventative strategies are essential to avoid compounding existing organ failure.

Renal Toxicity

• Mannitol: When used for cerebral edema, monitor serum osmolality (target <320 mOsm/kg) and renal function closely. Discontinue if oliguria or a sharp rise in creatinine occurs.
• Nephrotoxic Drugs: Avoid aminoglycosides and NSAIDs whenever possible. If an aminoglycoside is required, use extended-interval dosing and therapeutic drug monitoring.

Pulmonary Injury

• Ventilator-Associated Lung Injury (VALI): Strictly adhere to lung-protective ventilation (low tidal volume, plateau pressure <30 cm H₂O).
• Ventilator Bundles: Implement VAP prevention bundles, including head-of-bed elevation and daily spontaneous breathing trials, to reduce complications.

6. Multidisciplinary Goals-of-Care Conversations

ALF is a rapidly evolving condition with high mortality. Structured, early discussions involving patients and families are essential to align highly invasive interventions with patient values and establish realistic expectations.

Timing and Participants

• Initiation: Begin conversations within 24–48 hours of ICU admission, especially for patients with grade III–IV HE.
• Team: Involve a core multidisciplinary team including the intensivist, hepatologist, transplant surgeon, palliative care specialist, social worker, and the patient’s family or designated decision-maker.

Ethical and Prognostic Considerations

• Risk/Benefit Analysis: Openly discuss the burdens and potential benefits of therapies like ICP monitoring, CRRT, and listing for liver transplantation.
• Prognostication: Use validated scoring systems like the MELD score and King’s College Criteria to frame discussions about prognosis and transplant eligibility.