1. Indications and Considerations for Intensive Support

Patients with severe drug-induced hematologic toxicities are at high risk for developing acute respiratory distress syndrome (ARDS), shock, and multi-organ failure. The early initiation of protocolized supportive care is critical to improving outcomes.

A. Mechanical Ventilation

Indications:

• Hypoxemic respiratory failure with a PaO₂/FiO₂ ratio ≤150 mm Hg, especially with increased work of breathing or hemodynamic instability.
• ARDS secondary to underlying processes like thrombotic microangiopathy (TMA), sepsis, or transfusion-related acute lung injury (TRALI).

Lung-Protective Strategy:

• Tidal Volume: Target 6 mL/kg of predicted body weight.
• Plateau Pressure: Maintain ≤30 cm H₂O to minimize barotrauma.
• Driving Pressure (ΔP): Keep plateau pressure minus PEEP ≤15 cm H₂O.
• PEEP Titration: Use ARDSNet low/high PEEP tables or bedside compliance measurements to optimize oxygenation and recruitment.
• Adjuncts: Consider recruitment maneuvers (e.g., 30–40 cm H₂O for 30 seconds) and prone positioning for ≥12 hours per day if PaO₂/FiO₂ remains <150 mm Hg on moderate FiO₂.

B. Hemodynamic Support

Indications:

• Mean arterial pressure (MAP) <65 mm Hg despite adequate fluid resuscitation.
• Signs of end-organ hypoperfusion: lactate >2 mmol/L, oliguria (<0.5 mL/kg/hr), or altered mentation.

Fluid Resuscitation:

• Initiate with a 30 mL/kg bolus of balanced crystalloids; perform dynamic reassessments (e.g., passive leg raise, stroke volume variation) after every 500–1,000 mL to guide further administration and avoid fluid overload.
• Consider albumin supplementation if large volumes (>4 L) of crystalloids are required or in the presence of significant hypoalbuminemia.

Vasopressors & Inotropes:

• First-line: Norepinephrine (0.05–3 µg/kg/min) to target a MAP ≥65 mm Hg.
• Second-line: Add Vasopressin (0.01–0.03 units/min) as a catecholamine-sparing agent.
• Inotropes: Add Dobutamine (2–20 µg/kg/min) if there is evidence of low cardiac index (CI) despite an adequate MAP.
• Avoid Dopamine due to its higher risk of tachyarrhythmias and mortality compared to norepinephrine.

2. Prevention of ICU-Related Complications

Prophylaxis against thrombosis, stress ulcers, and nosocomial infections is crucial to reducing morbidity in critically ill, often immunocompromised, patients with hematologic disorders.

A. Venous Thromboembolism (VTE) Prophylaxis

• Preferred Agents: Low-molecular-weight heparin (LMWH), such as Enoxaparin 40 mg SC daily. Dose-adjust to 30 mg SC daily for CrCl <30 mL/min.
• Alternative: Unfractionated heparin (UFH) 5,000 units SC every 8–12 hours is preferred in severe renal failure or when there is a high risk of bleeding, due to its short half-life and reversibility.
• Contraindications: Active bleeding or severe thrombocytopenia (e.g., platelet count <30 × 10⁹/L) without other compelling risk factors.
• Reversal: Protamine sulfate can fully reverse UFH and partially neutralize LMWH.

B. Stress-Related Mucosal Bleeding Prophylaxis

Restrict prophylaxis to patients with major risk factors, such as mechanical ventilation for >48 hours, shock, or coagulopathy. Agents include proton pump inhibitors (PPIs) like Pantoprazole 40 mg IV daily or H₂-receptor antagonists (H₂RAs) like Famotidine 20 mg IV twice daily. Be mindful of the potential association of PPIs with C. difficile infection and nosocomial pneumonia.

C. Infection Prevention

Adherence to evidence-based bundles is paramount. For antimicrobial stewardship, de-escalate broad-spectrum antibiotics based on culture data within 48–72 hours to limit the emergence of multidrug-resistant organisms.

3. Management of Iatrogenic Organ Dysfunction

Vigilant monitoring for renal, hepatic, and other organ toxicities from hematologic therapies is essential to mitigate harm and prevent progression to irreversible organ failure.

A. Nephrotoxicity

Calcineurin Inhibitor-Induced AKI:

• Mechanism: Predominantly caused by afferent arteriolar vasoconstriction, leading to a reduction in glomerular filtration rate.
• Monitoring: Daily serum creatinine and therapeutic drug monitoring (target troughs: Cyclosporine 100–200 ng/mL; Tacrolimus 5–15 ng/mL).
• Management: Reduce the CNI dose by 25–50%, avoid concomitant nephrotoxins (e.g., NSAIDs, aminoglycosides), and consider renal replacement therapy (RRT) for refractory complications like hyperkalemia or severe volume overload per KDIGO criteria.

IVIG-Associated Osmotic Nephrosis:

• Risk Factors: High-sucrose formulations, rapid infusion rates, and pre-existing renal dysfunction.
• Prevention: Ensure adequate hydration, limit infusion rates (<0.08 mL/kg/min), and preferentially use low-sucrose or sucrose-free IVIG products.

4. Pharmacotherapy Considerations

The selection and titration of vasoactive and prophylactic agents require a deep understanding of their pharmacokinetics and pharmacodynamics, with careful adjustments for organ dysfunction.

A. Vasoactive Agents

B. Anticoagulant and Stress Ulcer Prophylaxis

Refer to Section 2 for detailed guidance on agent selection, dosing, and monitoring. In patients with severe hepatic impairment, H₂RAs may be preferred over PPIs for stress ulcer prophylaxis due to differences in metabolism.

5. Multidisciplinary Goals-of-Care Discussions

Early and structured conversations are essential to align intensive medical interventions with the patient’s values and goals, particularly when therapies carry a high burden and uncertain benefit.

• Ethical Framework: Proactively identify advance directives and surrogate decision-makers. Ground discussions in the principles of autonomy, beneficence, non-maleficence, and justice.
• Communication Strategy: Schedule formal family meetings within 48 hours of ICU admission. Use clear, non-technical language to explain prognosis and treatment options. Clearly document agreed-upon goals, code status, and thresholds for escalation or de-escalation of care.
• Team Integration: Involve palliative care, primary hematology/oncology teams, ethicists, and other consultants early and often. Reassess goals of care every 3–5 days or after any major clinical change.