1. Mechanical Ventilation and Respiratory Support

Rationale: Acute rejection and its high-dose immunosuppressive therapies often precipitate respiratory failure from pulmonary edema, infection, or diffuse alveolar damage. Early, decisive airway management and subsequent lung-protective ventilation are critical to minimize secondary lung injury and support the patient through the acute phase.

A. Indications for Invasive Ventilation

• Refractory Hypoxemia: PaO₂/FiO₂ ratio less than 150 mm Hg despite optimized noninvasive support (e.g., high-flow nasal cannula).
• Acute Respiratory Acidosis: Arterial pH less than 7.25 with a progressively rising PaCO₂, indicating ventilatory failure.
• Signs of Impending Respiratory Collapse: Obvious accessory muscle use, diaphoresis, paradoxical breathing, or altered mentation signal that the work of breathing is unsustainable.
• Hemodynamic Instability: Shock or refractory pulmonary edema that requires the controlled environment of mechanical ventilation to manage.

B. Lung-Protective Strategies

• Low Tidal Volume Ventilation: Target 4–8 mL/kg of predicted body weight to prevent volutrauma.
• Plateau Pressure Limitation: Maintain plateau pressure (Pplat) at or below 30 cm H₂O to avoid barotrauma.
• PEEP Titration: Use decremental PEEP trials to identify the optimal level that maximizes alveolar recruitment and oxygenation without causing overdistension and hemodynamic compromise.
• Recruitment Maneuvers: Consider brief, sustained inflation maneuvers (e.g., 30 cm H₂O for 30 seconds) in patients with early ARDS, but only with continuous hemodynamic monitoring.

C. Ventilator Liberation Protocols

• Daily Spontaneous Breathing Trials (SBT): Assess readiness for extubation daily in stable patients, often using a rapid shallow breathing index (RSBI) target of < 105 breaths/min/L.
• Sedation Interruption: Daily “sedation vacations” are crucial to assess underlying neurologic status and intrinsic respiratory drive.
• Post-Extubation Support: Proactively use high-flow nasal cannula or noninvasive ventilation immediately post-extubation to reduce the work of breathing and prevent reintubation.

2. Hemodynamic Support

Rationale: Shock in acute rejection is common and multifactorial, often a mix of vasodilatory shock (from systemic inflammation) and cardiogenic shock (from myocardial stunning or rejection). The goal is to use targeted vasopressors, inotropes, and judicious fluid management to preserve both systemic and allograft perfusion.

A. Vasopressor and Inotrope Selection

• First-Line Vasopressor: Norepinephrine. Its potent α₁-agonist effects increase systemic vascular resistance (SVR) to combat vasodilation, while its modest β₁-agonist effects support cardiac contractility. Start at 0.01–0.05 µg/kg/min and titrate to a mean arterial pressure (MAP) of ≥ 65 mm Hg.
• Adjunctive Vasopressor: Vasopressin. Added as a fixed-dose infusion (0.02–0.04 units/min) to norepinephrine in refractory shock. It acts on V1 receptors, providing catecholamine-sparing vasoconstriction. Particularly useful in patients with severe acidosis or those on high-dose catecholamines.
• Inotrope: Dobutamine. Indicated for patients with evidence of a low cardiac output state (e.g., poor peripheral perfusion, rising lactate despite adequate MAP). Start at 2–10 µg/kg/min and monitor closely for tachyarrhythmias.

B. Fluid Management

Initial resuscitation may require fluids, but a conservative strategy should be adopted quickly to prevent worsening pulmonary edema and facilitate ventilator weaning.

• Guidance: Use dynamic indices of fluid responsiveness (e.g., pulse pressure variation, stroke volume variation) in mechanically ventilated patients to guide fluid boluses.
• Fluid Choice: Prefer balanced crystalloids (e.g., Lactated Ringer’s, Plasma-Lyte) over normal saline to minimize the risk of hyperchloremic metabolic acidosis and acute kidney injury.
• De-resuscitation: Once the patient is hemodynamically stable, focus on achieving a net-negative fluid balance. Continuous renal replacement therapy (CRRT) is an excellent tool for controlled fluid removal in patients who are anuric or hemodynamically fragile.

3. ICU Complication Prophylaxis

Rationale: The combination of critical illness and profound immunosuppression places transplant patients at extremely high risk for preventable complications. Standardized prophylaxis against thrombosis, stress ulcers, and opportunistic infections is a cornerstone of supportive care.

4. Management of Immunosuppression-Related Toxicities

Rationale: The core medications used to treat rejection, particularly calcineurin inhibitors (CNIs) and antiproliferatives, have narrow therapeutic windows and frequent, severe toxicities. Proactive monitoring and dose adjustment are required to mitigate harm.

5. Multidisciplinary Goals-of-Care Conversations

Rationale: Despite aggressive support, some patients may not recover from severe rejection, and the burden of ICU therapies may outweigh the potential for meaningful recovery. Structured, empathetic communication is essential to guide shared decision-making with patients and their families.

• Ethical Framework: Ground decisions in the core principles of beneficence (acting in the patient’s best interest) and non-maleficence (avoiding harm). Engage the hospital ethics committee for complex cases or when there is conflict.
• Team Involvement: Involve the entire multidisciplinary team, including transplant coordinators, social workers, and palliative care specialists, to ensure that medical interventions are aligned with the patient’s stated values and to reduce the provision of non-beneficial care.