Supportive Care and Monitoring of CRS-Associated Complications

1. Respiratory Support Strategies

CRS-related inflammatory lung injury causes hypoxemia and respiratory distress. A stepwise approach—from supplemental oxygen to mechanical ventilation—is essential to stabilize gas exchange while minimizing ventilator-associated injury.

A. Oxygen Therapy Modalities

Nasal cannula: 2–6 L/min to maintain SpO₂ ≥ 92%.
High-flow nasal cannula (HFNC): Up to 60 L/min; provides low-level positive end-expiratory pressure (PEEP), washes out anatomical dead space, and lowers the work of breathing.
Noninvasive ventilation (NIV; BiPAP/CPAP): Indicated for moderate distress in cooperative, hemodynamically stable patients. Monitor closely for patient–ventilator asynchrony and be mindful of aerosolization risk.

Key Clinical Pearl: Early HFNC

Initiate HFNC early to improve oxygenation and potentially avert intubation. Closely monitor work of breathing and tidal volumes for any signs of fatigue, which would prompt escalation of care.

B. Indications for Mechanical Ventilation

Endotracheal intubation is required when noninvasive measures fail or when there is evidence of respiratory muscle fatigue, hypercapnia, or neurologic decline.

Persistent PaO₂/FiO₂ < 150 mm Hg on HFNC/NIV
Respiratory rate > 30–35 breaths/min with accessory muscle use
Arterial PaCO₂ > 60 mm Hg or pH < 7.25
Altered mental status or significant hemodynamic instability

Clinical Pearl: Timely Intubation

Do not prolong NIV if the patient’s distress is worsening. Timely, controlled intubation is far safer than managing an emergent airway crisis.

C. Ventilator Management: Lung-Protective Strategies

Use low tidal volumes and appropriate PEEP to minimize ventilator-induced lung injury (VILI) while preserving hemodynamics.

Tidal volume: 4–8 mL/kg of predicted body weight
Plateau pressure: Maintain < 30 cm H₂O
Driving pressure (Plateau – PEEP): Target ≤ 15 cm H₂O
PEEP titration: Follow standard FiO₂/PEEP tables or perform incremental PEEP trials, carefully monitoring for hypotension from decreased venous return.

Key Clinical Pearl: Driving Pressure

Targeting driving pressure rather than absolute PEEP increments has been shown to reduce mortality risk in ARDS.

2. Hemodynamic Management

Shock in CRS is complex, often combining vasodilation, capillary leak, and myocardial depression. Management begins with judicious fluid resuscitation, followed by vasopressors guided by continuous perfusion metrics.

A. Fluid Resuscitation

Initial bolus: Use balanced crystalloids (e.g., lactated Ringer’s or PlasmaLyte) at 20 mL/kg.
Assess preload responsiveness: Use dynamic measures like pulse pressure variation, passive leg raise, or stroke volume changes to guide further fluid administration.
Conservative strategy: Transition to a conservative fluid strategy once perfusion is restored to avoid worsening pulmonary edema and organ dysfunction.

Clinical Pearl: Early Vasopressors in ARDS

In patients with concurrent ARDS, initiating vasopressors early may allow for lower cumulative fluid volumes, potentially reducing the severity of lung edema.

B. Vasopressors for Hypotension

Initiate vasopressors when the mean arterial pressure (MAP) remains < 65 mm Hg despite adequate fluid resuscitation or in patients who are not preload responsive. Titrate to perfusion targets and wean as shock resolves.

Common Vasopressors in CRS-Associated Shock
Agent (Line)	Mechanism & Rationale	Typical Dose
Norepinephrine (First-line)	Potent α₁-agonist with modest β₁ activity. Increases SVR with less arrhythmogenicity than other catecholamines.	Start 0.05–0.1 μg/kg/min; titrate to MAP ≥ 65 mm Hg.
Vasopressin (Adjunct)	V₁ receptor–mediated vasoconstriction. Used as a catecholamine-sparing agent.	Fixed dose of 0.03 units/min.
Phenylephrine (Situational)	Pure α₁-agonist. Useful in severe tachyarrhythmias that limit catecholamine use.	0.5–5 μg/kg/min.

Monitoring & Weaning: Guide therapy with invasive arterial pressure monitoring, lactate clearance (>10% per hour), urine output, and capillary refill time. Wean vasopressors once perfusion metrics have normalized.

Pitfalls: Excessive Catecholamines

Overuse of catecholamines can lead to tachyarrhythmias, increased myocardial oxygen consumption, and regional ischemia (e.g., gut, digital). Use the lowest effective dose to achieve perfusion goals.

Controversy: MAP Targets

Higher MAP targets (75–80 mm Hg) may benefit patients with chronic hypertension or coronary artery disease, but specific data for the CRS population are lacking. The standard target remains a MAP ≥ 65 mm Hg.

3. Prevention of ICU-Related Complications

The combination of systemic inflammation and immunosuppression in CRS increases the risk for venous thromboembolism (VTE), stress ulcers, and nosocomial infections. Prophylaxis and strict adherence to protocols are key to mitigating these complications.

A. VTE Prophylaxis

Pharmacologic: Enoxaparin 40 mg SC daily or unfractionated heparin 5,000 units SC every 8 hours.
Contraindications: Hold pharmacologic prophylaxis if platelets are < 50,000/µL or if there is active bleeding; use mechanical compression devices instead.
Special Populations: Monitor anti-Xa levels in patients with obesity or renal dysfunction to ensure adequate prophylaxis.

B. Stress Ulcer Prophylaxis

Indications: Mechanical ventilation > 48 hours, coagulopathy (INR > 1.5), or high-dose vasopressor use.
Agents: Pantoprazole 40 mg IV daily (PPI) is preferred. Famotidine 20 mg IV every 12 hours (H₂RA) is an alternative, especially in renal failure.
De-escalation: Discontinue prophylaxis once risk factors resolve to reduce the risk of C. difficile infection and pneumonia.

C. Infection Prevention

Line Management: Use maximal sterile barriers for central line insertion, perform daily reviews of line necessity, and ensure prompt removal when no longer needed.
Antimicrobial Stewardship: Tailor empiric coverage to local antibiograms, narrow therapy based on culture results, and limit the duration of antibiotics.
Nutrition: Initiate early enteral nutrition to maintain gut integrity and reduce the risk of bacterial translocation.

Key Clinical Pearl: Masked Infection

IL-6 blockade (e.g., tocilizumab) and corticosteroids can mask fever and blunt inflammatory markers like CRP. Maintain a low threshold for a full infection workup in patients who deteriorate unexpectedly.

4. Management of Immunotherapy-Related Organ Toxicities

Early detection and targeted treatment of organ-specific toxicities are crucial to prevent irreversible damage and facilitate patient recovery.

A. Neurotoxicity (ICANS)

Monitoring: Use the ICE score every 8 hours in adults or the CAPD score in pediatrics to screen for Immune Effector Cell-Associated Neurotoxicity Syndrome.
Treatment: Administer dexamethasone 10 mg IV every 6 hours or methylprednisolone 1–2 mg/kg/day. Taper over 1–2 weeks upon improvement.
Note: Tocilizumab is not effective for ICANS due to poor CNS penetration.

Clinical Pearl: Early Steroids for ICANS

Initiate steroids at the first sign of a decline in the ICE score to prevent progression to seizures and cerebral edema.

B. Hepatotoxicity

Monitoring: Check AST, ALT, and bilirubin daily.
Treatment: For Grade ≥ 3 transaminitis, start methylprednisolone 1–2 mg/kg/day and taper over 4–6 weeks. Add mycophenolate mofetil for refractory cases.

C. Cytopenias

Monitoring: Perform a daily complete blood count (CBC).
Support: Consider G-CSF after CRS has resolved (e.g., Day 14–21); avoid during active CRS.
Transfusion Thresholds: Transfuse platelets for counts < 10,000/µL (prophylactic) or < 20,000/µL with active bleeding.

D. Cardiac Complications

Surveillance: Monitor troponin, BNP, and obtain an echocardiogram if the patient is symptomatic or hemodynamically unstable.
Management: For suspected myocarditis, initiate high-dose steroids and provide aggressive hemodynamic support. Involve cardiology early.

Clinical Pearl: Cardiac Monitoring

Noninvasive monitoring with biomarkers and echocardiography is often sufficient for diagnosis. Reserve endomyocardial biopsy for atypical cases or when the diagnosis is uncertain.

5. Multidisciplinary Goals-of-Care Discussions

It is vital to align treatment intensity with patient goals, CRS severity, and overall organ function. Early involvement of palliative care can optimize quality of care and support shared decision-making.

A. Therapy Continuation Criteria

Reevaluate the appropriateness of continuing immunotherapy if there is persistent grade ≥ 3 CRS despite maximal interventions or evidence of irreversible end-organ injury.

B. Palliative Care & Ethical Considerations

Proactively address symptom burden, advance directives, and patient/family preferences. Balance the potential benefits of immunotherapy against the burdens of intensive care.

C. Communication Frameworks

SBAR (Situation, Background, Assessment, Recommendation): Use for structured handoffs between teams and shifts.
Daily Multidisciplinary Rounds: Involve oncology, critical care, pharmacy, neurology, cardiology, and palliative care to ensure a unified care plan.

Key Clinical Pearl: Structured Communication

Using structured communication tools and holding regular multidisciplinary rounds reduces medical errors and ensures that treatment plans remain aligned with the patient’s overarching goals of care.

References

Lee DW, Gardner R, Porter DL, et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood. 2014;124(2):188–195.
Lee DW, Santomasso BD, Locke FL, et al. ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol Blood Marrow Transplant. 2019;25(4):625–638.
Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune effector cell–related adverse events. J Immunother Cancer. 2020;8(2):e001511.
Hill JA, Li D, Hay KA, et al. Infectious complications of CD19-targeted CAR T-cell immunotherapy. Blood. 2018;131(1):121–130.
Gust J, Hay KA, Hanafi LA, et al. Endothelial activation and blood–brain barrier disruption in neurotoxicity after adoptive immunotherapy with CD19 CAR-T cells. Cancer Discov. 2017;7(12):1404–1419.
Frigault MJ, Maziarz RT, Park JH, et al. Itacitinib for the prevention of immune effector cell therapy–associated cytokine release syndrome: results from a phase II placebo-controlled trial. Blood. 2023;142(Suppl 1):356–358.
Le RQ, Li L, Yuan W, et al. FDA approval summary: tocilizumab for treatment of severe or life-threatening CAR T cell–induced cytokine release syndrome. Oncologist. 2018;23(8):943–947.
Agarwal R, Epstein AS. Advance care planning and end-of-life decision making for patients with cancer. Semin Oncol Nurs. 2018;34(3):316–326.
Hui D, Nooruddin Z, Didwaniya N, et al. Management of dyspnea in advanced cancer: ASCO guideline. J Clin Oncol. 2021;39(12):1389–1411.

Lesson Objective