The Crashing Cancer Patient: Oncologic Emergencies Beyond Neutropenia

A Comprehensive Review for Critical Care Practitioners

Dr Neeraj Manikath , claude.ai

Abstract

Oncologic emergencies represent a diverse spectrum of life-threatening conditions that demand immediate recognition and intervention in the intensive care unit. While febrile neutropenia remains well-recognized, numerous other cancer-related emergencies pose significant diagnostic and therapeutic challenges for the intensivist. This review examines five critical oncologic emergencies: malignant airway obstruction, malignant pericardial effusion with tamponade, hyperviscosity syndrome in Waldenström's macroglobulinemia, syndrome of inappropriate antidiuretic hormone secretion (SIADH) associated with small cell lung cancer, and immune checkpoint inhibitor-related toxicities. We provide evidence-based management strategies, practical clinical pearls, and identify common diagnostic pitfalls to optimize outcomes in this vulnerable population.

Keywords: Oncologic emergencies, malignant airway obstruction, cardiac tamponade, hyperviscosity syndrome, SIADH, immune checkpoint inhibitors, critical care oncology

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Introduction

The intersection of oncology and critical care has evolved dramatically over the past two decades. Advances in cancer therapeutics have extended survival, while simultaneously increasing the complexity of acute complications encountered in the intensive care unit (ICU). Contemporary data suggest that up to 15% of cancer patients require ICU admission during their disease course, with non-infectious complications accounting for a substantial proportion of these admissions.[1,2]

The paradigm shift in critical care oncology recognizes that ICU admission is no longer futile for many cancer patients. Recent studies demonstrate that selected solid tumor patients have ICU mortality rates comparable to non-cancer populations, challenging historical nihilism.[3] However, optimal outcomes depend on rapid recognition and aggressive management of specific oncologic emergencies.

While febrile neutropenia dominates educational curricula, intensivists must possess expertise in managing less common but equally lethal oncologic crises. This review focuses on five high-acuity scenarios that demand immediate intervention: malignant airway obstruction, malignant pericardial effusion, hyperviscosity syndrome, paraneoplastic SIADH, and immune checkpoint inhibitor toxicity. Understanding these conditions is essential for the modern intensivist managing increasingly complex cancer patients.

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Malignant Airway Obstruction: From Stents to Emergent Radiotherapy

Clinical Presentation and Pathophysiology

Malignant airway obstruction (MAO) represents a true airway emergency, occurring in 20-30% of patients with lung cancer and as a complication of mediastinal lymphomas, thyroid cancers, and metastatic disease.[4] The obstruction may be intraluminal (endobronchial tumor growth), extraluminal (external compression from lymphadenopathy or mediastinal masses), or mixed. Tracheal obstruction becomes symptomatic when the luminal diameter is reduced by 50-75%, while main bronchial obstruction manifests with similar or greater reductions.[5]

Patients present with progressive dyspnea, stridor (particularly inspiratory stridor in upper airway involvement), hemoptysis, post-obstructive pneumonia, and in severe cases, impending respiratory failure. The critical distinction between MAO and other causes of respiratory distress lies in the characteristic flow-volume loop demonstrating fixed or variable obstruction, though this test is often impractical in the crashing patient.

Diagnostic Approach

Pearl #1: The "four signs of critical airway obstruction" include stridor at rest, suprasternal retractions, decreased air entry bilaterally, and altered mental status. Presence of two or more signs mandates immediate airway management consideration.[6]

Oyster #1: Conventional chest radiography frequently underestimates the severity of central airway obstruction. A "mediastinal mass" on chest X-ray may represent complete tracheal compression. CT imaging with 3D reconstruction is the gold standard for anatomic evaluation, providing precise localization and extent of obstruction.[7]

Initial assessment should include:

• Pulse oximetry and arterial blood gas: To assess gas exchange impairment
• CT chest with IV contrast: Defines anatomic location, extent, and vascular involvement
• Flexible bronchoscopy: Provides direct visualization and therapeutic access (see precautions below)

Hack #1: In suspected critical MAO, position the patient upright or in the position of greatest comfort. Supine positioning can precipitate complete obstruction due to mass effect and loss of anterior-posterior chest diameter.

Airway Management Considerations

The decision to intubate a patient with MAO requires careful consideration. Positive pressure ventilation may be impossible distal to a critical stenosis, and the rigid laryngoscope can convert partial to complete obstruction.

Pearl #2: Before any airway intervention, assemble a multidisciplinary team including anesthesiology, interventional pulmonology, thoracic surgery, and radiation oncology. Have a rigid bronchoscopy setup immediately available.

Oyster #2: Never paralyze a patient with critical MAO without ensuring that ventilation will be possible. Awake fiberoptic intubation or inhalational induction maintaining spontaneous ventilation are preferred strategies.[8] If intubation is necessary:

• Use a smaller endotracheal tube (ETT) that can pass the obstruction
• Have multiple ETT sizes available
• Consider advancing the ETT beyond the obstruction if feasible
• Prepare for emergency surgical airway or cardiopulmonary bypass in worst-case scenarios

Therapeutic Interventions

Management of MAO employs a multimodal approach tailored to obstruction characteristics, patient performance status, and local expertise.

Immediate Mechanical Interventions

1. Rigid Bronchoscopy

Rigid bronchoscopy remains the gold standard for immediate relief of central airway obstruction, allowing large-bore instrumentation, superior ventilation during the procedure, and multiple therapeutic modalities.[9]

Techniques include:

• Core-out debulking: Direct tumor removal using the rigid scope
• Mechanical dilation: Serial bougie dilation
• Laser therapy: Nd:YAG laser for vaporization of endobronchial lesions
• Argon plasma coagulation (APC): Non-contact thermal ablation
• Cryotherapy: Freeze-thaw tumor destruction

Hack #2: For intraluminal lesions, the "debulk-then-stent" approach is preferred. Stenting alone without debulking leads to tumor overgrowth and stent failure.

2. Airway Stenting

Silicone or self-expanding metal stents (SEMS) provide structural support for malignant airway obstruction.[10]

Stent Selection Guide:

• Silicone stents (Dumon): Preferred for benign disease, easy to remove, require rigid bronchoscopy for placement, higher migration rate
• Self-expanding metal stents: Easier to deploy, better conform to irregular airways, difficult to remove, higher granulation tissue formation
• Hybrid stents: Combine benefits of both designs

Pearl #3: Silicone stents are generally preferred in MAO due to lower complication rates and easier removal/repositioning if tumor responds to therapy.

Oyster #3: Stent complications include migration (10-15%), mucus plugging, granulation tissue formation, infection, and stent fracture. Post-stent placement requires aggressive pulmonary toilet and close surveillance bronchoscopy.[11]

Emergent Radiotherapy

External beam radiation therapy (EBRT) provides durable relief for radiosensitive tumors, with symptom improvement in 60-80% of patients within 2-4 weeks.[12]

Indications for emergent radiotherapy:

• Radiosensitive tumors (lymphoma, small cell lung cancer, thyroid cancer)
• Extraluminal compression not amenable to mechanical interventions
• Adjunct to stenting for long-term local control

Hack #3: "Compress and radiate" – For lymphomas causing critical MAO, consider administering dexamethasone 10mg IV immediately, which may reduce edema and buy time for radiation planning. Some centers deliver a single 4-8 Gy emergent fraction within hours of diagnosis.[13]

Radiation dosing:

• Emergent palliative: 17 Gy in 2 fractions or 20 Gy in 5 fractions
• Definitive (concurrent with chemotherapy): 60-70 Gy in standard fractionation for non-small cell lung cancer

Systemic Therapies

For chemo-sensitive tumors, particularly lymphomas and small cell lung cancer, systemic therapy may provide rapid response.

Pearl #4: In diffuse large B-cell lymphoma with critical airway obstruction, consider reduced-intensity chemotherapy (e.g., prednisone alone or reduced-dose R-CHOP) to avoid tumor lysis while achieving tumor reduction.[14]

Outcomes and Prognostic Factors

Technical success rates for bronchoscopic intervention exceed 90%, with immediate clinical improvement in 70-85% of patients.[15] However, median survival post-intervention remains limited (3-7 months), emphasizing the palliative nature of most interventions.

Favorable prognostic factors:

• Performance status (ECOG 0-2)
• Radiosensitive or chemosensitive tumor histology
• Intraluminal rather than extraluminal obstruction
• Absence of distant metastases

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Malignant Pericardial Effusion & Tamponade: Diagnosis and Pericardiocentesis

Epidemiology and Pathophysiology

Malignant pericardial effusion (MPE) occurs in 5-15% of cancer patients, most commonly with lung cancer (35%), breast cancer (25%), lymphomas and leukemias (15%), and melanoma.[16] The effusion develops through direct pericardial invasion, lymphatic obstruction, or as a paraneoplastic phenomenon. Approximately 30-60% of pericardial effusions in cancer patients contain malignant cells on cytology.[17]

Cardiac tamponade physiology results from accumulation of pericardial fluid exceeding the compensatory capacity of the parietal pericardium. Unlike acute traumatic tamponade, malignant effusions typically accumulate subacutely, allowing pericardial stretch and accommodation of large volumes (often >1 liter) before hemodynamic compromise. However, once decompensation occurs, progression to cardiovascular collapse can be rapid.

Clinical Presentation and Diagnosis

Classic Presentation: The patient presents with the Beck's triad (hypotension, muffled heart sounds, jugular venous distension), though this classical triad is present in only 30% of cases.[18] More sensitive findings include:

• Dyspnea (85-90%)
• Chest discomfort (30-40%)
• Peripheral edema (30%)
• Pulsus paradoxus >10 mmHg (75% in tamponade)
• Tachycardia
• Tachypnea

Oyster #4: Malignant pericardial effusion can masquerade as decompensated heart failure, pulmonary embolism, or sepsis. The key distinguishing feature is elevated jugular venous pressure with clear lung fields (in isolated tamponade without concomitant pulmonary pathology).

Pearl #5: Electrical alternans on ECG, while specific (90%), is only 20% sensitive for tamponade. Low voltage QRS complexes are more common but less specific.[19]

Diagnostic Approach

Transthoracic Echocardiography (TTE) is the gold standard diagnostic modality, providing:

• Effusion size and distribution
• Real-time hemodynamic assessment
• Guidance for pericardiocentesis

Echocardiographic signs of tamponade physiology:[20]

1. Right atrial collapse in diastole (>33% of cardiac cycle) – highly sensitive
2. Right ventricular collapse in early diastole – more specific
3. Respiratory variation in mitral inflow >25% and tricuspid inflow >40%
4. Inferior vena cava plethora with <50% inspiratory collapse
5. Swinging heart – pendular cardiac motion within effusion

Hack #4: In the unstable patient, obtain a bedside ultrasound immediately. A subcostal view takes 30 seconds and can confirm the diagnosis. Don't wait for formal echocardiography if tamponade is suspected clinically.

CT Imaging: While not required for diagnosis, CT may reveal:

• Pericardial thickening or enhancement suggesting malignancy
• Associated mediastinal lymphadenopathy
• Primary tumor identification

Management of Malignant Pericardial Effusion

Initial Stabilization

Pearl #6: The hemodynamic management of tamponade differs from other shock states:

• Volume resuscitation: Aggressive IV fluids increase venous return and temporarily improve cardiac output
• Avoid positive pressure ventilation: Intubation and positive pressure can precipitate cardiovascular collapse by decreasing venous return
• Inotropes/vasopressors: May provide temporary support but definitive drainage is required
• Position upright: Sitting position may improve hemodynamics

Oyster #5: Do NOT administer diuretics to a patient with cardiac tamponade, even if they appear volume overloaded. This can precipitate cardiovascular collapse.

Pericardiocentesis: Technique and Considerations

Pericardiocentesis remains the primary intervention for symptomatic malignant pericardial effusion, with success rates exceeding 95% when performed under echocardiographic guidance.[21]

Approaches:

1. Subxiphoid (most common): 30-45° angle toward left shoulder, 1-2 cm inferior to xiphoid process
2. Apical: Left 5th-6th intercostal space, mid-clavicular line
3. Parasternal: Adjacent to sternum, rarely used due to internal mammary artery

Step-by-Step Technique:[22]

Pre-procedure checklist:

• Informed consent (if time permits)
• Echocardiographic confirmation of effusion >10mm in diastole
• Coagulation parameters (correct INR >1.5, platelets <50,000/μL if possible)
• Continuous cardiac monitoring and pulse oximetry
• Resuscitation equipment immediately available

Procedure:

1. Position patient supine with head of bed 30-45°
2. Sterile preparation and local anesthesia with 1% lidocaine
3. Echo-guided identification of optimal entry site and trajectory
4. Insert 18-gauge introducer needle with continuous aspiration and echo visualization
5. Advance until pericardial fluid aspirated (often hemorrhagic in malignancy)
6. Pass guidewire through needle using Seldinger technique
7. Dilate tract and place pigtail drainage catheter (6-8 Fr)
8. Secure catheter and connect to drainage bag
9. Obtain fluid for:
   • Cell count and differential
   • Cytology (sensitivity 60-90% for malignant diagnosis)[23]
   • Gram stain, culture (to exclude bacterial pericarditis)
   • Chemistry (protein, LDH, glucose)
   • Consider flow cytometry if lymphoma suspected

Hack #5: Send pericardial fluid for tumor marker studies (CEA, CA 125, CA 15-3) if cytology is initially negative but clinical suspicion for malignancy remains high. Elevated tumor markers support malignant etiology.[24]

Pearl #7: Drain slowly to avoid re-expansion pulmonary edema and hypotension from acute increase in ventricular volumes. Remove 1-1.5 liters over the first hour, then as tolerated.

Complications of Pericardiocentesis

• Cardiac perforation/laceration (1-1.5%)
• Coronary artery injury (<1%)
• Pneumothorax (2-5%)
• Arrhythmias (10-15%, usually self-limited)
• Hemothorax
• Peritoneal entry (subxiphoid approach)

Oyster #6: ST segment elevation during pericardiocentesis suggests myocardial contact. Withdraw the needle immediately, as continued advancement risks myocardial perforation.

Definitive Management Strategies

After initial drainage, prevention of reaccumulation is essential, as recurrence rates approach 40-70% with catheter drainage alone.[25]

Options for definitive management:

1. Pericardial Sclerotherapy

• Instillation of sclerosing agents through pericardial catheter after drainage
• Agents: Doxycycline (500mg), bleomycin (60 units), or tetracycline
• Success rates: 70-90% in preventing recurrence[26]
• Technique: Drain effusion to <25-50 mL, instill sclerosant, clamp catheter for 2-4 hours with patient position changes, then open to drainage for 24-48 hours

2. Pericardial Window (Surgical or Percutaneous)

• Creation of communication between pericardium and pleural space
• Indications: Loculated effusions, failed sclerotherapy, need for tissue diagnosis
• Success rates: >90% for recurrence prevention[27]
• Can be performed via:
  • Subxiphoid surgical window: Preferred in most cases
  • Video-assisted thoracoscopic surgery (VATS): Allows extensive pericardial resection
  • Percutaneous balloon pericardiotomy: Less invasive, comparable outcomes

3. Systemic Therapy

• For chemosensitive tumors (lymphoma, breast cancer)
• Effective systemic therapy may control effusion long-term
• Consider in patients with good performance status and treatment-responsive tumors

Hack #6: For patients with limited life expectancy (<3 months) and recurrent symptomatic effusions, consider leaving an indwelling pericardial catheter for intermittent home drainage, similar to pleural catheters.

Prognosis

Median survival after malignant pericardial effusion diagnosis is poor, ranging from 3-6 months, though highly variable by primary tumor type.[28] Factors associated with better outcomes include:

• Lymphoma or leukemia (vs. solid tumors)
• Absence of metastases at other sites
• Good performance status
• Tumor responsiveness to systemic therapy

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Hyperviscosity Syndrome in Waldenström's Macroglobulinemia: The Role of Plasmapheresis

Pathophysiology and Clinical Context

Hyperviscosity syndrome (HVS) represents a true hematologic emergency occurring when serum viscosity increases to a level that impairs blood flow and oxygen delivery. While HVS can occur in any paraproteinemia, it is most commonly associated with Waldenström's macroglobulinemia (WM), a lymphoplasmacytic lymphoma characterized by IgM monoclonal protein production.[29]

The pathophysiology stems from the unique properties of IgM:

• Large pentameric structure (molecular weight ~970 kDa vs. 150 kDa for IgG)
• Predominantly intravascular distribution (80% vs. 50% for IgG)
• Lower concentration threshold for viscosity symptoms (~3-4 g/dL IgM vs. >5-6 g/dL IgG)

Normal serum viscosity is 1.4-1.8 centipoise (cP). Symptoms typically develop when viscosity exceeds 4-5 cP, though the correlation is imperfect, and symptoms should guide management rather than absolute viscosity values.[30]

Oyster #7: Serum viscosity measurements are not universally available and require specialized equipment. Do not delay treatment awaiting viscosity results if clinical syndrome is evident.

Clinical Presentation

The classic HVS triad consists of:

1. Neurologic manifestations (60-80%)
2. Visual disturbances (50-60%)
3. Bleeding diathesis (30-50%)

Detailed Clinical Manifestations

Neurological:

• Headache, confusion, altered mental status
• Dizziness, vertigo, ataxia
• Seizures
• Stroke or transient ischemic attacks
• Peripheral neuropathy (chronic)
• Coma (severe cases)

Ocular:

• Blurred vision, diplopia
• Fundoscopic findings (pathognomonic):
  • "Sausage-link" or "boxcar" retinal veins – segmented blood columns due to increased viscosity
  • Retinal hemorrhages
  • Papilledema
  • Flame-shaped hemorrhages

Bleeding:

• Epistaxis, gum bleeding
• Gastrointestinal hemorrhage
• Acquired von Willebrand syndrome (coating of platelets by IgM impairs function)
• Prolonged bleeding time despite normal platelet count

Cardiovascular:

• High-output heart failure
• Cardiomyopathy
• Conduction abnormalities

Pearl #8: Always perform fundoscopy in suspected HVS. The presence of "hyperviscosity retinopathy" with sausage-link veins is virtually diagnostic and indicates need for urgent intervention.[31]

Diagnostic Evaluation

Laboratory Assessment:

• Serum protein electrophoresis (SPEP): Tall, narrow spike in gamma region
• Immunofixation: Identifies IgM monoclonal protein
• Quantitative immunoglobulins: IgM typically >3-4 g/dL (often >5 g/dL)
• Serum viscosity: >4 cP supportive (if available)
• Complete blood count: May show anemia, thrombocytopenia
• Peripheral smear: Rouleaux formation (RBC stacking)
• Coagulation studies: Often normal PT/PTT despite bleeding risk
• Blood typing: Can be challenging due to RBC agglutination; warm blood at 37°C

Bone marrow examination: Confirms WM diagnosis (lymphoplasmacytic infiltration, must include MYD88 L265P mutation testing)

Oyster #8: Laboratory tests can be spuriously affected by hyperviscosity:

• Pseudohyponatremia: Protein displaces water in serum, artifactually lowering sodium
• Pseudohypoxemia: Oxygen consumption by WBCs after blood draw
• Spurious anemia: Plasma volume expansion from high protein content

Hack #7: When blood bank struggles with typing/crossmatch due to rouleaux, ask them to wash the red cells with warm saline at 37°C before testing. This dissolves IgM coating on RBCs and allows accurate typing.

Management: The Role of Plasmapheresis

Acute Management: Therapeutic Plasma Exchange

Therapeutic plasma exchange (TPE), commonly called plasmapheresis, is the definitive urgent treatment for symptomatic HVS, providing rapid reduction in IgM levels and viscosity.[32]

Indications for urgent plasmapheresis:

• Symptomatic hyperviscosity syndrome
• Severe neurologic symptoms
• Visual changes with fundoscopic findings
• Bleeding complications
• IgM >5 g/dL with symptoms (even if mild)

Pearl #9: Plasmapheresis can improve symptoms within hours and normalize viscosity within 1-3 sessions. The clinical response often precedes laboratory normalization, so treat based on clinical improvement.[33]

Plasmapheresis Technical Considerations:

Procedure parameters:

• Replacement fluid: 5% albumin preferred (FFP if concurrent bleeding); 1-1.5 plasma volumes exchanged per session
• Frequency: Daily or every other day until symptom resolution
• Access: Large-bore central venous catheter (temporary dialysis catheter or equivalent)
• Target: IgM reduction of 30-50% per session
• Duration: Typically 3-5 sessions required for sustained benefit

Expected response:

• Immediate (within hours): Symptomatic improvement
• 24-48 hours: Viscosity reduction, improved perfusion
• 3-7 days: IgM nadir (but rebound begins without definitive therapy)

Hack #8: For patients with severe cardiovascular compromise, coordinate closely with the apheresis team to avoid hemodynamic instability. Consider prophylactic vasopressor support during the procedure if blood pressure is borderline.

Complications of plasmapheresis:

• Hypotension (most common)
• Hypocalcemia (citrate anticoagulation)
• Allergic reactions to replacement fluid
• Catheter-related complications
• Coagulopathy (if excessive plasma removed without replacement)
• Thrombocytopenia

Oyster #9: IgM has a half-life of 5 days and rebounds rapidly after plasmapheresis. Bridge to definitive chemotherapy immediately; plasmapheresis alone is temporizing, not curative.

Definitive Therapy: Chemotherapy Initiation

While plasmapheresis provides acute relief, definitive treatment requires reducing IgM production through WM-directed therapy.[34]

First-line therapy options for WM:

1. Rituximab-based regimens:

• R-bendamustine: Rituximab + bendamustine (preferred if rapid reduction needed)
• R-CHOP: Rituximab + cyclophosphamide, doxorubicin, vincristine, prednisone
• DRC: Dexamethasone, rituximab, cyclophosphamide

Warning – IgM flare: Rituximab monotherapy can cause transient IgM elevation (IgM flare) in 40-60% of WM patients, potentially worsening hyperviscosity. Strategies to mitigate:

• Combine rituximab with chemotherapy from cycle 1
• Delay rituximab for 1-2 cycles if severe HVS
• Use plasmapheresis prophylactically if rituximab given early[35]

2. BTK inhibitors (Bruton tyrosine kinase):

• Ibrutinib or zanubrutinib (preferred due to better tolerability)
• Advantages: Oral therapy, rapid IgM reduction (50% reduction in 4-8 weeks)
• Disadvantages: Slower than chemotherapy, bleeding risk
• Increasingly used as first-line therapy, especially in older/frail patients[36]

3. Proteasome inhibitors:

• Bortezomib-based regimens
• Caution: Higher peripheral neuropathy risk in WM

Pearl #10: For critically ill patients with HVS, consider combination approach: plasmapheresis for immediate relief + rapid-acting chemotherapy (bendamustine-rituximab) + bridge with additional plasmapheresis sessions until chemotherapy takes effect.

Supportive Care Considerations

Avoid precipitating factors:

• Hyperviscosity exacerbation: Dehydration, erythropoietin (increases RBC mass)
• Bleeding risk: NSAIDs, antiplatelet agents, anticoagulation (unless absolutely required)

Transfusion strategy:

• RBC transfusions: Use cautiously; increasing hematocrit worsens viscosity. Transfuse only for symptomatic anemia or Hgb <7 g/dL. Consider plasmapheresis before or concurrent with transfusion.
• Platelet transfusions: For bleeding with thrombocytopenia or platelet dysfunction

Fluid management:

• Maintain euvolemia; avoid dehydration (worsens viscosity) and overload (worsens heart failure)

Hack #9: In HVS patients requiring RBC transfusion, coordinate with apheresis to perform plasmapheresis immediately before transfusion. This allows you to improve oxygen-carrying capacity while mitigating the viscosity increase from higher hematocrit.

Outcomes and Prognosis

With prompt recognition and treatment, HVS is reversible, and patients can achieve excellent long-term outcomes. Median overall survival for WM is 8-10 years, with many patients living significantly longer with modern therapies.[37] However, untreated HVS can lead to irreversible neurologic damage or death.

Prognostic factors in WM:

• Age >65 years
• Hemoglobin <11.5 g/dL
• Platelet count <100,000/μL
• Beta-2 microglobulin >3 mg/L
• Serum monoclonal protein >7 g/dL

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SIADH of Malignancy (Small Cell Lung Cancer): Challenging Fluid Management

Pathophysiology and Epidemiology

The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is the most common cause of hyponatremia in cancer patients, occurring in 15-30% of hospitalized oncology patients.[38] Small cell lung cancer (SCLC) is the quintessential malignancy associated with SIADH, with 10-15% of SCLC patients developing this paraneoplastic syndrome.[39]

Mechanisms of SIADH in SCLC:

1. Ectopic ADH production: SCLC tumor cells synthesize and secrete arginine vasopressin (AVP)
2. Autonomous secretion: Independent of normal osmotic and volume regulatory mechanisms
3. Atrial natriuretic peptide (ANP) secretion: Some SCLCs also produce ANP, exacerbating hyponatremia

The resulting pathophysiology includes:

• Excessive free water retention
• Euvolemic or slightly hypervolemic state
• Dilutional hyponatremia
• Inappropriate urinary sodium wasting (paradoxically concentrated urine despite hyponatremia)

Oyster #10: SIADH causes euvolemic hyponatremia, but clinical assessment of volume status is notoriously unreliable. Do not assume hyponatremia is due to SIADH without confirming diagnostic criteria.

Clinical Presentation

Symptoms correlate with both the severity of hyponatremia and the rapidity of development. Chronic, slowly developing hyponatremia may be asymptomatic even at very low sodium levels (100-110 mEq/L), while acute drops precipitate severe symptoms at higher sodium concentrations.

Symptom severity stratification:[40]

Mild (Na+ 125-135 mEq/L):

• Often asymptomatic
• Mild confusion, difficulty concentrating
• Nausea, malaise

Moderate (Na+ 115-125 mEq/L):

• Headache, nausea, vomiting
• Confusion, disorientation
• Gait disturbances

Severe (Na+ <115 mEq/L or acute severe symptoms):

• Altered mental status, obtundation
• Seizures
• Respiratory depression
• Coma
• Risk of cerebral edema, herniation, death

Pearl #11: The rate of sodium decline matters more than the absolute value. A patient with chronic sodium of 118 mEq/L may be asymptomatic and walking around, while an acute drop from 135 to 125 mEq/L over 24 hours can cause severe symptoms requiring urgent intervention.

Diagnosis of SIADH

SIADH remains a diagnosis of exclusion requiring fulfillment of specific criteria:

Diagnostic criteria (Bartter-Schwartz criteria):[41]

1. Hyponatremia: Serum sodium <135 mEq/L
2. Low serum osmolality: <275 mOsm/kg
3. Inappropriately elevated urine osmolality: >100 mOsm/kg (often >300 mOsm/kg)
4. Elevated urine sodium: >40 mEq/L (with normal salt intake)
5. Clinical euvolemia: No edema, no orthostasis, normal skin turgor
6. Normal renal, adrenal, and thyroid function
7. No recent diuretic use

Oyster #11: Urine sodium >40 mEq/L is not specific for SIADH—it simply indicates the kidney is wasting sodium, which can occur in multiple conditions. The diagnosis requires the entire clinical context and exclusion of other causes.

Differential diagnosis of euvolemic hyponatremia:

• Hypothyroidism
• Adrenal insufficiency
• Medications (SSRIs, carbamazepine, cyclophosphamide, vincristine, cisplatin)
• Cerebral salt wasting (post-neurosurgery, traumatic brain injury)
• Psychogenic polydipsia
• Beer potomania (chronic beer intake with poor protein intake)
• Reset osmostat

Hack #10: Fractional excretion of uric acid (FEUA) can help distinguish SIADH from other causes of hyponatremia. FEUA >12% suggests SIADH (normal is 4-11%). This is particularly useful when volume status is ambiguous.[42]

Formula: FEUA = (Urine uric acid × Serum creatinine) / (Serum uric acid × Urine creatinine) × 100

Management: The Fluid Restriction Challenge

Management of SIADH-related hyponatremia in SCLC requires careful consideration of symptom severity, chronicity, and underlying malignancy treatment plans. The fundamental challenge lies in balancing the need for sodium correction with the risks of both under-correction (persistent symptoms, cerebral edema) and over-correction (osmotic demyelination syndrome).

Acute Symptomatic Hyponatremia

Severe symptoms (seizures, coma, respiratory distress) – MEDICAL EMERGENCY:

Pearl #12: This is one of the few scenarios in medicine where hypertonic saline is genuinely life-saving. Do not hesitate to administer 3% saline for severe symptomatic hyponatremia.[43]

Immediate management:

1. 3% hypertonic saline: 100 mL bolus IV over 10 minutes
2. Reassess: Check sodium 20 minutes after bolus
3. Repeat: If symptoms persist, give another 100 mL bolus (up to 2-3 boluses)
4. Target: Increase sodium by 4-6 mEq/L in first 1-2 hours (sufficient to abort symptoms)
5. Then transition: To slower correction rate (see below)

Oyster #12: The goal in acute symptomatic hyponatremia is NOT to normalize sodium rapidly, but to increase it just enough (4-6 mEq/L) to reverse life-threatening symptoms. Over-rapid correction risks osmotic demyelination syndrome (ODS).

Correction rate limits (to prevent ODS):[44]

• Maximum correction: 8-10 mEq/L in first 24 hours
• Maximum correction: 18 mEq/L in first 48 hours
• High-risk patients (chronic alcoholism, malnutrition, cirrhosis, hypokalemia): Aim for even lower rates (6-8 mEq/L in 24h)

Hack #11: Calculate the expected sodium rise from 3% saline using the Adrogue-Madias formula:

Change in serum Na+ = (Infusate Na+ - Serum Na+) / (Total body water + 1)

Where:

• 3% saline Na+ = 513 mEq/L
• Total body water (TBW) = 0.6 × body weight (kg) for men, 0.5 × body weight for women

Example: 70 kg man, serum Na+ 112 mEq/L

• TBW = 0.6 × 70 = 42 L
• Change per liter of 3% saline = (513 - 112) / (42 + 1) = 9.3 mEq/L rise
• To achieve 6 mEq/L rise: 6/9.3 = 0.64 L = 640 mL of 3% saline over 24 hours = 27 mL/hour

Monitoring during hypertonic saline:

• Serum sodium every 2 hours initially, then every 4-6 hours
• Strict intake/output monitoring
• Neurological assessments
• If correction exceeds target: Stop hypertonic saline and consider D5W to re-lower sodium

Chronic or Moderately Symptomatic Hyponatremia

Most SCLC patients with SIADH present with chronic, mild-to-moderate hyponatremia that has developed over weeks.

Management options:

1. Fluid Restriction

The cornerstone of chronic SIADH management, though often the most difficult to implement.

Principles:

• Target: 800-1000 mL/day total fluid intake (sometimes requires 500-800 mL/day for severe cases)
• Expected response: Sodium increase of 1-2 mEq/L per day
• Time to effect: 2-4 days
• Success rate: 50-70% (highly dependent on patient adherence)

Pearl #13: Fluid restriction fails more often from poor compliance than true resistance. True resistance suggests ongoing excessive ADH effect or concomitant renal sodium wasting.[45]

Oyster #13: "Fluid restriction" means ALL fluids—oral intake, IV fluids, medications mixed in fluids, even ice chips. Patients and nursing staff often don't appreciate this, leading to inadvertent fluid administration.

Challenges in the ICU setting:

• IV medication administration (antibiotics, infusions)
• Enteral feeding (significant free water content)
• Chemotherapy administration (pre-hydration protocols)

Hack #12: Calculate the free water content of tube feeds and subtract from daily fluid allowance. Most standard tube feeds are 70-85% water. For example, 1000 mL of standard formula contains ~800 mL free water.

2. Sodium Supplementation

Oral salt tablets:

• 1-2 grams sodium chloride TID
• Increases serum sodium by promoting osmotic diuresis
• Often poorly tolerated (GI side effects)
• Most effective when combined with fluid restriction

Hypertonic saline (non-emergent use):

• 3% saline at controlled rates (20-30 mL/hour) with close monitoring
• Reserve for moderate-to-severe symptomatic hyponatremia or ICU setting with ability to monitor frequently
• Requires central venous access (peripheral administration risks phlebitis)

3. Loop Diuretics

Rationale: Interfere with urinary concentration mechanism, promoting free water excretion

Protocol:

• Furosemide 20-40 mg IV/PO daily or BID
• Replace urinary sodium losses (but not free water)
• Monitor electrolytes closely

Pearl #14: The loop diuretic approach works best when combined with oral salt supplementation. The diuretic promotes free water loss, while salt tablets maintain sodium intake.[46]

Pitfall: Overaggressive diuresis can cause volume depletion, triggering non-osmotic ADH release and paradoxically worsening hyponatremia.

4. Vasopressin Receptor Antagonists (Vaptans)

Vaptans are selective V2 receptor antagonists that promote aquaresis (free water excretion without electrolyte loss).

Available agents:

• Tolvaptan (oral): 15-60 mg daily
• Conivaptan (IV): 20 mg loading dose, then 20-40 mg continuous infusion over 24h (max 4 days)

Indications in SIADH:

• Moderate-to-severe hyponatremia unresponsive to fluid restriction
• Inability to restrict fluids adequately (ongoing chemotherapy, medication requirements)
• Need for more rapid correction than fluid restriction provides

Efficacy: Increase sodium by 4-8 mEq/L within 24-48 hours in 60-70% of patients[47]

Pearl #15: Vaptans are highly effective but expensive (~$300-500/day). Reserve for patients who truly cannot tolerate fluid restriction or require ongoing IV therapy that precludes adequate fluid restriction.

Oyster #14: The most dangerous aspect of vaptan therapy is overcorrection. Patients can have dramatic sodium rises (>12 mEq/L in 24 hours), risking ODS. Mandatory precautions include:

• Check sodium at 4-6 hour intervals for first 24 hours
• Have D5W ready to administer if sodium rises too rapidly
• Discontinue vaptan if target correction achieved
• Consider holding initial dose in severe hyponatremia (Na+ <120 mEq/L) until corrected to safer range

Contraindications:

• Hypovolemic hyponatremia
• Anuric renal failure
• Inability to monitor sodium frequently
• Hepatic impairment (tolvaptan carries black box warning for hepatotoxicity)

5. Demeclocycline

An older tetracycline antibiotic that induces nephrogenic diabetes insipidus.

Dosing: 300-600 mg PO BID Onset: 3-5 days (too slow for acute management) Efficacy: 60-70% response rate Use: Largely supplanted by vaptans; consider for chronic outpatient management if cost-prohibitive for vaptans

Side effects: Nephrotoxicity, photosensitivity, GI upset

Special Considerations in SCLC

Chemotherapy as definitive SIADH treatment:

The single most effective intervention for SIADH in SCLC is treating the underlying malignancy. Chemotherapy-sensitive SCLC often demonstrates normalization of sodium within 2-3 weeks of initiating treatment.[48]

Pearl #16: If a patient with newly diagnosed SCLC presents with SIADH, prioritize rapid initiation of chemotherapy (cisplatin/etoposide or carboplatin/etoposide). Many oncologists will treat through mild-to-moderate hyponatremia (Na+ 125-130 mEq/L) rather than delay cancer treatment.

Chemotherapy-induced SIADH: Paradoxically, certain chemotherapy agents (cisplatin, cyclophosphamide, vincristine) can worsen or induce SIADH. Close sodium monitoring during chemotherapy cycles is essential.

Hack #13: For patients receiving cyclophosphamide (known to cause SIADH), prophylactic aggressive fluid restriction or vaptan therapy during the infusion can prevent severe hyponatremia.

Glucocorticoid considerations:

Many oncologists empirically add dexamethasone to SCLC regimens, partly for anti-tumor effect but also because steroids can help improve hyponatremia through multiple mechanisms (treating possible adrenal insufficiency, promoting free water excretion). Consider dexamethasone 4mg daily in SIADH refractory to other measures.

Osmotic Demyelination Syndrome (ODS)

The most feared complication of hyponatremia correction is osmotic demyelination syndrome (formerly called central pontine myelinolysis).

Risk factors:[49]

• Over-rapid correction (>10 mEq/L in 24h, >18 mEq/L in 48h)
• Severe chronic hyponatremia (Na+ <105 mEq/L)
• Chronic alcoholism, malnutrition
• Liver disease
• Hypokalemia, hypophosphatemia

Clinical features:

• Onset: Typically 2-6 days after over-rapid correction
• Symptoms: Dysarthria, dysphagia, altered mental status, quadriparesis, pseudobulbar palsy, "locked-in" syndrome
• Diagnosis: MRI brain shows T2 hyperintensity in pons (classic) or extrapontine regions
• Prognosis: Variable—some patients recover, others have permanent neurologic deficits

Oyster #15: There is no proven treatment for established ODS. Prevention through adherence to correction rate limits is essential. If over-correction occurs, some experts recommend re-lowering sodium with D5W (or even desmopressin + D5W), though evidence supporting this is limited.[50]

Cerebral Salt Wasting vs. SIADH

A critical diagnostic dilemma in cancer patients, particularly those with brain metastases.

Cerebral salt wasting (CSW):

• Renal sodium wasting due to brain injury
• Results in hypovolemia (vs. euvolemia in SIADH)
• Occurs post-neurosurgery, traumatic brain injury, subarachnoid hemorrhage, brain tumors

Distinguishing features:

Feature	SIADH	CSW
Volume status	Euvolemic	Hypovolemic
BUN/Creatinine	Normal	Often elevated
Uric acid	Low (<4 mg/dL)	Low to normal
Response to fluids	Worsens hyponatremia	Improves hyponatremia
Hematocrit	Normal/low	Elevated

Hack #14: When uncertain between SIADH and CSW in a brain metastases patient, give a 1-2 L bolus of normal saline. If sodium improves → CSW. If sodium worsens or doesn't change → SIADH. This "therapeutic trial" can be diagnostic.[51]

Management differences:

• SIADH: Fluid restriction
• CSW: Fluid and sodium replacement (aggressive normal saline ± 3% saline)

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Managing Immune Checkpoint Inhibitor Toxicity (Myocarditis, Colitis)

Background and Epidemiology

Immune checkpoint inhibitors (ICIs) have revolutionized oncology, providing durable responses in previously untreatable malignancies. These agents—targeting CTLA-4 (ipilimumab), PD-1 (nivolumab, pembrolizumab, cemiplimab), and PD-L1 (atezolizumab, durvalumab, avelumab)—unleash anti-tumor immunity by removing inhibitory signals on T cells.[52]

However, by removing immune checkpoints, ICIs simultaneously predispose to immune-related adverse events (irAEs), affecting virtually any organ system. While most irAEs are mild-to-moderate (rash, fatigue, diarrhea), severe toxicities require ICU-level care and can be fatal if not recognized and treated promptly.[53]

Epidemiology of severe irAEs:

• Any grade irAE: 60-85% of patients on combination therapy (anti-CTLA-4 + anti-PD-1)
• Grade 3-4 irAEs: 10-30% (combination), 5-15% (monotherapy)
• ICU admission for irAE: 1-5% of ICI-treated patients
• Mortality from irAE: 0.5-1.5% overall, higher for specific toxicities

Pearl #17: ICI toxicities can occur at any time—within days of first infusion, months into treatment, or even after treatment discontinuation (median onset varies by organ). Maintain high clinical suspicion in any patient with current or prior ICI exposure.[54]

This section focuses on two life-threatening irAEs commonly encountered in critical care: ICI-related myocarditis and colitis.

ICI-Related Myocarditis

Epidemiology and Pathophysiology

ICI-myocarditis is rare (0.3-1.5% incidence) but carries mortality rates of 25-50%, making it the most lethal immune-related adverse event.[55,56]

Risk factors:

• Combination ICI therapy (anti-CTLA-4 + anti-PD-1): 5-10× higher risk vs. monotherapy
• Pre-existing cardiovascular disease
• Concomitant immune-related myositis (30-50% overlap)
• Concomitant immune-related myasthenia gravis

Pathophysiology: Cytotoxic T-cell infiltration of myocardium, often with concomitant skeletal muscle involvement. Endomyocardial biopsy shows lymphocytic infiltration, myocyte necrosis, and variable fibrosis.

Timing: Median onset 17-34 days after ICI initiation (earlier than most other irAEs), though can occur at any point.[57]

Clinical Presentation

Oyster #16: ICI-myocarditis presents insidiously and atypically. Many patients have minimal or non-specific symptoms (fatigue, mild dyspnea) until sudden cardiovascular collapse. This makes early recognition challenging but critical.

Symptoms:

• Dyspnea (85%)
• Chest pain (45%) – often atypical, not classic anginal
• Fatigue, weakness (40%)
• Peripheral edema (30%)
• Palpitations, syncope
• Asymptomatic (15% – diagnosed incidentally based on troponin/ECG abnormalities)

Signs:

• Tachycardia (most common)
• Hypotension, cardiogenic shock
• New arrhythmias (ventricular tachycardia, complete heart block, atrial fibrillation)
• Signs of heart failure (elevated JVP, pulmonary edema)

Associated findings:

• Myositis overlap (30-50%): Proximal muscle weakness, myalgias, elevated CK
• Myasthenia gravis overlap (10-15%): Ptosis, diplopia, dysphagia, respiratory failure

Pearl #18: The triad of elevated troponin + conduction abnormalities + left ventricular dysfunction in an ICI-treated patient = ICI-myocarditis until proven otherwise. Do not delay treatment awaiting definitive diagnosis.[58]

Diagnostic Approach

Laboratory evaluation:

• Troponin: Elevated in >90% (often markedly elevated, >10× ULN)
• BNP/NT-proBNP: Typically elevated
• CK: Often elevated (especially if concomitant myositis; CK >10,000 U/L suggests skeletal muscle involvement)
• CRP, ESR: Often elevated (non-specific)

Electrocardiogram:

• Conduction abnormalities (40-60%): AV block (1st, 2nd, or 3rd degree), bundle branch blocks
• ST-segment changes mimicking MI or pericarditis
• Arrhythmias: ventricular tachycardia, atrial fibrillation, premature ventricular contractions
• Low voltage, non-specific T-wave abnormalities

Oyster #17: Unlike typical myocarditis or MI, ST-elevation is uncommon in ICI-myocarditis. Conduction disturbances and arrhythmias are the hallmark ECG findings.

Echocardiography:

• Left ventricular dysfunction (40-70%): Regional or global
• Right ventricular involvement (30%)
• Pericardial effusion (15-25%)
• Normal wall motion in 25-30% (absence doesn't exclude diagnosis)

Cardiac MRI:

• Gold standard non-invasive test (if patient stable enough for imaging)
• Findings: Myocardial edema (T2 hyperintensity), late gadolinium enhancement (LGE), pericardial involvement
• Sensitivity 75-85%, specificity ~90%[59]

Endomyocardial biopsy:

• Definitive diagnosis but rarely performed (risk of complications, sampling error)
• Reserved for unclear cases or when alternative diagnosis considered
• Findings: Lymphocytic infiltration (CD3+, CD8+ T cells), myocyte necrosis

Hack #15: In stable patients with suspected ICI-myocarditis, obtain cardiac MRI if available. The combination of elevated troponin + conduction abnormalities + MRI findings (edema, LGE) essentially confirms the diagnosis without need for biopsy.[60]

Management

Immediate actions upon suspicion:

1. Discontinue ICI permanently (do NOT re-challenge)
2. Continuous cardiac monitoring (telemetry at minimum, ICU if unstable)
3. Hold potentially cardiotoxic medications (non-essential beta-blockers, ACE inhibitors if hypotensive)
4. Initiate high-dose corticosteroids immediately

Pearl #19: Time is myocardium. Unlike other irAEs where you might observe mild symptoms, suspected ICI-myocarditis warrants immediate high-dose immunosuppression. Delayed treatment is associated with significantly higher mortality.[61]

Corticosteroid therapy:

Initial treatment:

• Methylprednisolone 1-2 mg/kg/day IV (some experts use even higher doses: 500-1000 mg/day for 3-5 days for severe cases)
• Continue high-dose for minimum 3-5 days, assess response
• If improving: Gradual taper over 4-6 weeks (slower than other irAEs)
• If not improving or worsening: Escalate to additional immunosuppression

Steroid-refractory myocarditis (30-40% of cases):

Add second-line agent, do not delay:

Options:[62]

1. Infliximab (anti-TNF-α): 5 mg/kg IV (preferred by many experts)
   • Rapid onset (24-48 hours)
   • Avoid in heart failure (controversial, but relative contraindication)
2. Mycophenolate mofetil: 1000 mg PO BID
   • Slower onset, consider if infliximab contraindicated
3. IVIG: 2 g/kg divided over 2-5 days
   • Data limited but case reports suggest benefit
4. Anti-thymocyte globulin (ATG): For refractory cases
   • Reserve for dire circumstances; significant immunosuppression
5. Abatacept (CTLA-4 Ig): Emerging data for anti-CTLA-4-induced myocarditis

Hack #16: For fulminant ICI-myocarditis with cardiogenic shock, consider starting methylprednisolone 1000mg IV + infliximab 5mg/kg simultaneously on day 1 rather than sequential therapy. Emerging data suggest better outcomes with early aggressive dual immunosuppression.[63]

Supportive cardiovascular management:

Arrhythmia management:

• Conduction blocks: Temporary pacemaker for high-degree AV block; consider permanent pacemaker if block persists >2 weeks
• Ventricular arrhythmias: Amiodarone preferred over other antiarrhythmics
• Wearable defibrillator: Consider for high-risk patients after hospital discharge

Heart failure management:

• Standard guideline-directed medical therapy: diuretics, ACE-inhibitors/ARBs (if tolerated), beta-blockers (when stable)
• Avoid beta-blockers if conduction abnormalities present
• Mechanical circulatory support (IABP, Impella, VA-ECMO) for cardiogenic shock[64]

Oyster #18: Unlike typical myocarditis where beta-blockers are cornerstone therapy, conduction abnormalities in ICI-myocarditis make beta-blockers potentially dangerous (can worsen bradycardia, heart block). Use cautiously and only when arrhythmia/tachycardia is primary problem.

Anticoagulation considerations:

• No routine anticoagulation unless specific indication (atrial fibrillation, LV thrombus, concurrent PE)
• If LV dysfunction severe (EF <35%), consider apixaban 5mg BID for stroke prevention

Prognosis and Follow-up

Outcomes:

• Mortality: 25-50% despite treatment
• Cardiac recovery: Variable—some patients fully recover, others have persistent LV dysfunction
• Median time to improvement: 4-8 weeks with aggressive immunosuppression

Pearl #20: All patients recovering from ICI-myocarditis require long-term cardiac follow-up (serial ECGs, echocardiograms, troponins every 3-6 months indefinitely). Late relapses can occur, especially if steroids tapered too quickly.

ICI resumption: Absolutely contraindicated. Rechallenge carries high risk of fatal recurrence.[65]

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ICI-Related Colitis

Epidemiology and Pathophysiology

ICI-colitis is one of the most common severe irAEs, occurring in 8-27% of patients receiving combination therapy (anti-CTLA-4 + anti-PD-1) and 1-8% on monotherapy.[66] Unlike myocarditis, colitis is rarely fatal (<1% mortality) but causes significant morbidity and can lead to ICU admission if complicated by perforation, toxic megacolon, or severe hemorrhage.

Risk factors:

• Anti-CTLA-4 therapy (ipilimumab): Highest risk
• Combination ICI therapy
• NSAIDs, antibiotics (may trigger or worsen)
• Pre-existing inflammatory bowel disease (IBD) – relative contraindication to ICIs

Pathophysiology: T-cell-mediated colonic inflammation, histologically resembling acute inflammatory bowel disease (mixed acute and chronic inflammation, crypt abscesses, ulceration).

Timing: Median onset 6-8 weeks after ICI initiation (later than myocarditis), though can occur throughout treatment course.

Clinical Presentation and Severity Grading

Symptoms:

• Diarrhea (defining symptom): Watery or bloody
• Abdominal pain, cramping
• Hematochezia (20-40% of cases)
• Fever (in severe cases)
• Nausea, vomiting
• Weight loss (chronic cases)

Common Terminology Criteria for Adverse Events (CTCAE) Grading:[67]

Grade
Diarrhea frequency
Management
Grade 1
<4 stools/day over baseline
Outpatient, symptomatic treatment
Grade 2
4-6 stools/day over baseline
Outpatient corticosteroids
Grade 3
≥7 stools/day over baseline, incontinence, hospitalization indicated
Inpatient corticosteroids
Grade 4
Life-threatening (perforation, toxic megacolon, hemorrhage)
ICU, high-dose steroids + additional immunosuppression

Pearl #21: The absolute stool frequency matters less than the change from baseline. A patient going from 1 to 7 stools/day has grade 3 colitis even though "7 stools" might not sound dramatic.

Diagnostic Evaluation

Laboratory assessment:

• Inflammatory markers: CRP, ESR typically elevated
• Complete blood count: Anemia (blood loss), leukocytosis (severe inflammation)
• Comprehensive metabolic panel: Electrolyte abnormalities, dehydration
• Infectious workup: Critical to exclude infectious colitis

Oyster #19: The most critical step in diagnosing ICI-colitis is excluding infectious causes, particularly Clostridioides difficile, cytomegalovirus (CMV), and bacterial/parasitic pathogens. Never assume it's immune-mediated without testing.[68]

Stool studies:

• C. difficile PCR
• Bacterial culture (Salmonella, Shigella, Campylobacter, E. coli)
• Ova and parasites
• Fecal calprotectin (elevated, confirms colonic inflammation but non-specific)
• Consider CMV PCR if history of immunosuppression

Imaging:

• CT abdomen/pelvis with IV contrast:
  • Findings: Colonic wall thickening (>3mm), mucosal enhancement, pericolonic fat stranding
  • Distribution: Often pancolitis, can be segmental
  • Rules out complications: Perforation, abscess, toxic megacolon
• Abdominal X-ray: If concerned for toxic megacolon or perforation

Colonoscopy:

• Indications: Grade 2+ colitis requiring corticosteroids, any case needing confirmation
• Contraindications: Toxic megacolon, free perforation, severe coagulopathy
• Findings: Erythema, ulceration, friability, pseudomembranes (can mimic C. diff)
• Biopsy: Active inflammation, crypt abscesses, lamina propria lymphocytosis

Hack #17: Request the pathologist specifically assess for CMV inclusion bodies on colonic biopsies. CMV colitis can coexist with ICI-colitis, especially after corticosteroid initiation, and requires antiviral therapy.

Management

Management is stratified by severity grade, with escalation based on response.

Grade 1 (Mild):

• Continue ICI (hold only if progresses)
• Symptomatic treatment: Loperamide, dietary modifications
• Close monitoring (daily stool counts, weekly labs)

Grade 2 (Moderate) – Outpatient Corticosteroids:

• Hold ICI until resolution to grade ≤1
• Prednisone 0.5-1 mg/kg/day PO (typically 40-60 mg daily)
• Monitor response over 3-5 days
• If improving: Taper over 4-6 weeks
• If worsening or not improving: Hospitalize, escalate to IV steroids

Grade 3-4 (Severe/Life-threatening) – Hospitalization Required:

Initial management:

1. NPO or clear liquids
2. IV fluids: Aggressive resuscitation if dehydrated
3. Methylprednisolone 1-2 mg/kg/day IV (40-60 mg Q8h typical)
4. Infectious workup: Stool studies, blood cultures
5. CT abdomen/pelvis: Rule out complications
6. Flexible sigmoidoscopy/colonoscopy: Confirm diagnosis, obtain biopsies (if safe)
7. Discontinue ICI permanently (grade 4 or recurrent grade 3)

Pearl #22: Assess response to IV corticosteroids at 3-5 days. If no improvement (persistent ≥6 stools/day, ongoing bleeding, worsening inflammatory markers), escalate immediately to second-line therapy. Delayed escalation is associated with worse outcomes and higher colectomy rates.[69]

Steroid-refractory colitis (20-30% of severe cases):

Second-line options:[70]

1. Infliximab (preferred):

• Dosing: 5 mg/kg IV at weeks 0, 2, 6, then every 8 weeks if needed
• Efficacy: 60-80% response rate
• Onset: Improvement within 24-72 hours in responders
• Contraindications: Active infection, perforated viscus

Oyster #20: Screen for latent tuberculosis (QuantiFERON, PPD) before infliximab if time allows. If not feasible in acute setting, consider empiric TB prophylaxis in high-risk patients (history of TB exposure, endemic regions).

2. Vedolizumab:

• Dosing: 300 mg IV at weeks 0, 2, 6
• Mechanism: Gut-selective integrin antagonist (less systemic immunosuppression than infliximab)
• Efficacy: 50-70% response rate
• Onset: Slower than infliximab (may take 2-4 weeks)
• Use: Consider if infection concern makes infliximab risky, or if infliximab fails

3. Mycophenolate mofetil:

• Dosing: 500-1000 mg PO BID
• Use: Third-line or in combination with steroids

4. Tacrolimus:

• Dosing: Target trough 10-15 ng/mL
• Use: Limited data, reserve for refractory cases

Hack #18: For steroid-refractory colitis, many experts now advocate "early infliximab" at day 3-5 rather than waiting longer. Early escalation appears to reduce colectomy rates and shorten hospitalizations.[71]

Surgical Considerations

Indications for surgical consultation:

• Toxic megacolon (colonic diameter >6 cm with systemic toxicity)
• Free perforation
• Massive hemorrhage requiring >4 units pRBC in 24 hours
• Persistent grade 3-4 colitis despite maximum medical therapy (steroids + infliximab)

Surgery options:

• Subtotal colectomy with end ileostomy: Standard approach
• Total proctocolectomy: If rectal involvement severe

Colectomy rates: 1-5% of all ICI-colitis cases, 10-15% of grade 3-4 cases requiring hospitalization.[72]

Pearl #23: Early surgical consultation (within 48 hours of admission) for severe ICI-colitis improves outcomes. Surgeons can provide serial abdominal exams and advise on timing of intervention if medical therapy fails.

Complications

Intestinal perforation (2-5%):

• Often subtle presentation (may lack peritoneal signs due to corticosteroids)
• High index of suspicion if sudden worsening, new fever, or leukocytosis
• Diagnosis: CT abdomen showing free air
• Management: Emergent surgery

Toxic megacolon (<1%):

• Criteria: Colonic diameter >6 cm + systemic toxicity (fever, tachycardia, altered mental status)
• Associated with high mortality if not recognized
• Management: NPO, NG tube decompression, broad-spectrum antibiotics, surgical consultation, consider infliximab if no perforation, surgery if worsening

CMV reactivation:

• Risk increased by corticosteroid therapy
• Suspect if: Steroid-refractory colitis, persistent fevers, worsening despite immunosuppression
• Diagnosis: CMV PCR in blood/stool, immunohistochemistry on colonic biopsies
• Treatment: Ganciclovir 5 mg/kg IV Q12h or valganciclovir 900 mg PO BID

Hack #19: If a patient with ICI-colitis on high-dose steroids develops new fever or worsening despite therapy, always check CMV PCR. CMV reactivation is common and requires antiviral treatment, not more immunosuppression.

Long-term Management and ICI Resumption

Steroid taper:

• Duration: 4-8 weeks for grade 2, 6-12 weeks for grade 3-4
• Taper cautiously (reduce by 10 mg prednisone equivalent every 7-14 days)
• Relapse rate with too-rapid taper: 20-30%

ICI resumption considerations:[73]

• Grade 1: Can resume after resolution
• Grade 2: Can consider resumption after complete resolution and successful steroid taper (recurrence risk ~20-30%)
• Grade 3-4: Generally permanent discontinuation (recurrence risk 40-50% if resumed)
• After surgical intervention: Absolute contraindication to resumption

Monitoring after resolution:

• Serial stool counts, inflammatory markers
• Consider fecal calprotectin for objective monitoring
• Maintain low threshold for repeat colonoscopy if symptoms recur

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General Principles in Managing Oncologic Emergencies

Multidisciplinary Approach

Pearl #24: Every oncologic emergency discussed in this review benefits from immediate multidisciplinary consultation:

• Oncology: Treatment plans, prognosis, goals of care discussions
• Interventional specialties: (pulmonology, cardiology, radiology) for procedures
• Palliative care: Symptom management, prognostic discussions, transition planning
• Surgery: When complications arise or definitive procedures needed

Early involvement of all relevant teams optimizes decision-making and avoids delays in definitive management.

Goals of Care Discussions

Oncologic emergencies often occur in patients with advanced disease and limited prognosis. The intensivist must balance aggressive intervention with realistic prognostic counseling.

Key questions to address:[74]

1. What is the underlying malignancy and its treatment responsiveness?
2. What are the patient's performance status and baseline quality of life?
3. Are there other treatment options available if the patient survives this acute event?
4. What are the patient's values and preferences regarding aggressive intervention?
5. What is the likelihood of meaningful recovery?

Oyster #21: Not all oncologic emergencies warrant ICU admission. A patient with refractory, multi-metastatic cancer experiencing their fourth malignant pericardial effusion may benefit more from comfort-focused care than repeat pericardiocentesis. Have honest conversations early.

Hack #20: Use the "surprise question"—"Would I be surprised if this patient died in the next 6 months?"—as a screening tool for palliative care involvement. If the answer is no, palliative care consultation should occur within 24-48 hours of ICU admission.[75]

Prognostic Factors in Critical Care Oncology

Recent data have refined our understanding of which cancer patients benefit from ICU care:[76]

Favorable prognostic factors:

• Solid tumor malignancy (vs. hematologic)
• Disease in remission or responding to treatment
• Good performance status (ECOG 0-2)
• First ICU admission
• Non-invasive ventilation rather than intubation
• Single organ failure

Poor prognostic factors:

• Hematologic malignancy with active disease, especially post-HSCT
• Refractory/progressive disease despite multiple lines of therapy
• Poor baseline performance status (ECOG 3-4)
• Multi-organ failure
• Need for mechanical ventilation + vasopressors + renal replacement therapy

Pearl #25: ICU mortality for cancer patients has improved significantly over the past decade. With appropriate patient selection, many cancer patients have outcomes comparable to non-cancer ICU populations. Avoid therapeutic nihilism.[77]

Infection Prophylaxis in Immunosuppressed Patients

Many oncologic emergencies require high-dose immunosuppression (ICI toxicities, tumor lysis syndrome treatment). Consider prophylaxis:

Pneumocystis jirovecii pneumonia (PCP) prophylaxis:

• Indicated for: Corticosteroids ≥20 mg prednisone daily for ≥4 weeks
• Agent: Trimethoprim-sulfamethoxazole DS 1 tab daily or 3× weekly
• Alternative: Dapsone 100 mg daily, atovaquone 1500 mg daily

Fungal prophylaxis:

• Consider in high-risk patients (prolonged neutropenia, high-dose steroids + chemotherapy)
• Agents: Fluconazole 400 mg daily (yeast coverage), voriconazole or posaconazole (mold coverage)

Viral prophylaxis:

• HSV/VZV: Acyclovir 400 mg PO BID for patients on high-dose steroids or anti-thymocyte globulin
• CMV: Monitor weekly CMV PCR in high-risk patients on immunosuppression; pre-emptive therapy if positive

Common Pitfalls and How to Avoid Them

Pitfall #1: Attributing symptoms to cancer when it's a treatable emergency

• Dyspnea in a lung cancer patient may be pulmonary embolism, not disease progression
• Always maintain broad differential and investigate acute changes

Pitfall #2: Delaying intervention while awaiting definitive diagnosis

• Suspected ICI-myocarditis: Start steroids immediately, don't wait for MRI or biopsy
• Suspected cardiac tamponade: Drain first, obtain cytology later

Pitfall #3: Under-treating severe irAEs

• Use adequate steroid doses (1-2 mg/kg, not 20-40 mg total daily)
• Escalate early to second-line agents if no improvement in 3-5 days

Pitfall #4: Over-correcting hyponatremia in SIADH

• Frequent sodium monitoring (every 2-4 hours initially)
• Have D5W ready to slow correction if overshoot occurs
• Remember the 8-10 mEq/L per 24-hour limit

Pitfall #5: Forgetting that oncologic emergencies can recur

• Malignant pericardial effusions reaccumulate without definitive therapy
• Plasmapheresis for hyperviscosity is temporizing only
• Plan for definitive treatment (chemotherapy, sclerotherapy, etc.) while managing acute crisis

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Conclusion

Oncologic emergencies beyond neutropenia encompass a diverse array of life-threatening conditions requiring immediate recognition and intervention. The modern intensivist must possess expertise in managing malignant airway obstruction, cardiac tamponade, hyperviscosity syndrome, paraneoplastic SIADH, and immune checkpoint inhibitor toxicities.

Key principles unify the management of these diverse emergencies:

1. Early recognition through high clinical suspicion
2. Immediate stabilization while establishing definitive diagnosis
3. Multidisciplinary collaboration engaging oncology, interventional specialists, and supportive care teams
4. Aggressive intervention in appropriately selected patients
5. Transition to definitive therapy targeting the underlying malignancy when feasible
6. Realistic prognostic counseling balancing intervention with patient values and goals

As cancer therapies continue to advance and patient survival extends, critical care physicians will increasingly encounter these complex emergencies. Familiarity with the diagnostic approaches, therapeutic interventions, and potential complications outlined in this review will optimize outcomes for this vulnerable patient population.

The intersection of oncology and critical care continues to evolve. Intensivists should remain current with emerging therapies, particularly novel immunotherapies and their associated toxicities. With appropriate expertise and aggressive management, many patients experiencing oncologic emergencies can achieve meaningful survival and quality of life.

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Key Takeaway Pearls and Oysters - Quick Reference

Malignant Airway Obstruction

• ✓ Pearl: Four signs of critical obstruction: stridor at rest, suprasternal retractions, decreased bilateral air entry, altered mental status
• ✗ Oyster: Chest X-ray underestimates severity; CT is gold standard
• Hack: Keep patient upright; supine position can precipitate complete obstruction

Malignant Pericardial Effusion

• ✓ Pearl: Beck's triad only 30% sensitive; look for elevated JVP with clear lungs
• ✗ Oyster: Never give diuretics for tamponade—causes cardiovascular collapse
• Hack: Bedside ultrasound subcostal view takes 30 seconds—don't wait for formal echo

Hyperviscosity Syndrome

• ✓ Pearl: "Sausage-link" retinal veins are virtually diagnostic—always do fundoscopy
• ✗ Oyster: Rituximab causes IgM flare in 40-60% of WM patients—combine with chemo or delay
• Hack: Warm blood at 37°C to dissolve IgM coating for accurate typing/crossmatch

SIADH in SCLC

• ✓ Pearl: Rate of sodium decline matters more than absolute value
• ✗ Oyster: Maximum correction 8-10 mEq/L per 24h; overcorrection causes osmotic demyelination
• Hack: NS bolus can distinguish SIADH from cerebral salt wasting—therapeutic trial as diagnostic

ICI-Related Myocarditis

• ✓ Pearl: Troponin + conduction abnormalities + LV dysfunction = myocarditis until proven otherwise
• ✗ Oyster: ICI-myocarditis presents insidiously; sudden collapse can occur with minimal prior symptoms
• Hack: Consider dual immunosuppression (methylprednisolone + infliximab) immediately for fulminant cases

ICI-Related Colitis

• ✓ Pearl: Absolute stool frequency less important than change from baseline
• ✗ Oyster: Always exclude C. diff and CMV before assuming immune-mediated
• Hack: Early infliximab (day 3-5) for steroid-refractory colitis reduces colectomy rates

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References

1. Azoulay E, Mokart D, Pène F, et al. Outcomes of critically ill patients with hematologic malignancies: prospective multicenter data from France and Belgium. J Clin Oncol. 2013;31(22):2810-2818.
2. Taccone FS, Artigas AA, Sprung CL, et al. Characteristics and outcomes of cancer patients in European ICUs. Crit Care. 2009;13(1):R15.
3. Soares M, Caruso P, Silva E, et al. Characteristics and outcomes of patients with cancer requiring admission to intensive care units: a prospective multicenter study. Crit Care Med. 2010;38(1):9-15.
4. Ernst A, Feller-Kopman D, Becker HD, Mehta AC. Central airway obstruction. Am J Respir Crit Care Med. 2004;169(12):1278-1297.
5. Murgu SD, Egressy K, Laxmanan B, et al. Central airway obstruction: benign strictures, tracheobronchomalacia, and malignancy-related obstruction. Chest. 2016;150(2):426-441.
6. Wood DE. Management of malignant tracheobronchial obstruction. Surg Clin North Am. 2002;82(3):621-642.
7. Ferretti GR, Jankowski A, Perrin MA, et al. Multi-detector CT evaluation in patients suspected of tracheobronchomalacia: comparison of end-expiratory with dynamic expiratory volumetric acquisitions. Eur J Radiol. 2008;68(2):340-346.
8. Conacher ID. Anaesthesia and tracheobronchial stenting for central airway obstruction in adults. Br J Anaesth. 2003;90(3):367-374.
9. Mathisen DJ, Grillo HC. Endoscopic relief of malignant airway obstruction. Ann Thorac Surg. 1989;48(4):469-473.
10. Ost DE, Ernst A, Grosu HB, et al. Therapeutic bronchoscopy for malignant central airway obstruction: success rates and impact on dyspnea and quality of life. Chest. 2015;147(5):1282-1298.
11. Saad CP, Murthy S, Krizmanich G, Mehta AC. Self-expandable metallic airway stents and flexible bronchoscopy: long-term outcomes analysis. Chest. 2003;124(5):1993-1999.
12. Rodrigues G, Videtic GM, Sur R, et al. Palliative thoracic radiotherapy in lung cancer: An American Society for Radiation Oncology evidence-based clinical practice guideline. Pract Radiat Oncol. 2011;1(2):60-71.
13. Haas RL, Poortmans P, de Jong D, et al. High response rates and lasting remissions after low-dose involved field radiotherapy in indolent lymphomas. J Clin Oncol. 2003;21(13):2474-2480.
14. Dunleavy K, Pittaluga S, Maeda LS, et al. Dose-adjusted EPOCH-rituximab therapy in primary mediastinal B-cell lymphoma. N Engl J Med. 2013;368(15):1408-1416.
15. Folch E, Keyes C. Airway stents. Ann Cardiothorac Surg. 2018;7(2):273-283.
16. Cardiac tamponade. In: Yeh E, Bickford C, eds. Cardiovascular Problems in Cancer Care. Springer; 2019:209-227.
17. Burazor I, Imazio M, Markel G, Adler Y. Malignant pericardial effusion. Cardiology. 2013;124(4):224-232.
18. Spodick DH. Acute cardiac tamponade. N Engl J Med. 2003;349(7):684-690.
19. Eisenberg MJ, de Romeral LM, Heidenreich PA, et al. The diagnosis of pericardial effusion and cardiac tamponade by 12-lead ECG: a technology assessment. Chest. 1996;110(2):318-324.
20. Adler Y, Charron P, Imazio M, et al. 2015 ESC Guidelines for the diagnosis and management of pericardial diseases. Eur Heart J. 2015;36(42):2921-2964.
21. Tsang TS, Enriquez-Sarano M, Freeman WK, et al. Consecutive 1127 therapeutic echocardiographically guided pericardiocenteses: clinical profile, practice patterns, and outcomes spanning 21 years. Mayo Clin Proc. 2002;77(5):429-436.
22. Maisch B, Seferović PM, Ristić AD, et al. Guidelines on the diagnosis and management of pericardial diseases executive summary. Eur Heart J. 2004;25(7):587-610.
23. Meyers DG, Meyers RE, Prendergast TW. The usefulness of diagnostic tests on pericardial fluid. Chest. 1997;111(5):1213-1221.
24. Duygu H, Ozerkan F, Zoghi M, et al. Cytology and tumor markers in the diagnosis of malignant pericardial effusions. Cardiovasc Pathol. 2006;15(1):17-21.
25. Vaitkus PT, Herrmann HC, LeWinter MM. Treatment of malignant pericardial effusion. JAMA. 1994;272(1):59-64.
26. Tomkowski WZ, Wiśniewska J, Szturmowicz M, et al. Evaluation of intrapericardial cisplatin administration in cases with recurrent malignant pericardial effusion and cardiac tamponade. Support Care Cancer. 2004;12(1):53-57.
27. Cullinane CA, Paz IB, Schaff H, et al. Subxiphoid pericardial window for pericardial effusion: contemporary surgical treatment. ANZ J Surg. 2011;81(7-8):506-511.
28. Gornik HL, Gerhard-Herman M, Beckman JA. Abnormal cytology predicts poor prognosis in cancer patients with pericardial effusion. J Clin Oncol. 2005;23(22):5211-5216.
29. Gertz MA. Waldenström macroglobulinemia: 2019 update on diagnosis, risk stratification, and management. Am J Hematol. 2019;94(2):266-276.
30. Mehta J, Singhal S. Hyperviscosity syndrome in plasma cell dyscrasias. Semin Thromb Hemost. 2003;29(5):467-471.
31. Menke MN, Feke GT, McMeel JW, Treon SP. Hyperviscosity-related retinopathy in Waldenstrom macroglobulinemia. Arch Ophthalmol. 2006;124(11):1601-1606.
32. Schwab PJ, Fahey JL. Treatment of Waldenstrom's macroglobulinemia by plasmapheresis. N Engl J Med. 1960;263:574-579.
33. Gertz MA, Kyle RA. Hyperviscosity syndrome. J Intensive Care Med. 1995;10(3):128-141.
34. Castillo JJ, Advani RH, Branagan AR, et al. Consensus treatment recommendations from the tenth International Workshop for Waldenström Macroglobulinaemia. Lancet Haematol. 2020;7(11):e827-e837.
35. Treon SP, Hanzis C, Tripsas C, et al. Terms of clarification: variant and "delayed" IgM flare following rituximab in Waldenström macroglobulinaemia. Clin Lymphoma Myeloma Leuk. 2010;10(1):E3-E5.
36. Dimopoulos M, Sanz RG, Lee HP, et al. Zanubrutinib for the treatment of MYD88 wild-type Waldenström macroglobulinemia: a substudy of the phase 3 ASPEN trial. Blood Adv. 2020;4(23):6009-6018.
37. Kastritis E, Leblond V, Dimopoulos MA, et al. Waldenstrom's macroglobulinaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018;29(Suppl 4):iv41-iv50.
38. Berghmans T, Paesmans M, Body JJ. A prospective study on hyponatraemia in medical cancer patients: epidemiology, aetiology and differential diagnosis. Support Care Cancer. 2000;8(3):192-197.
39. Hansen O, Sørensen P, Hansen KH. The occurrence of hyponatremia in SCLC and the influence on prognosis: a retrospective study of 453 patients treated in a single institution in a 10-year period. Lung Cancer. 2010;68(1):111-114.
40. Verbalis JG, Goldsmith SR, Greenberg A, et al. Diagnosis, evaluation, and treatment of hyponatremia: expert panel recommendations. Am J Med. 2013;126(10 Suppl 1):S1-S42.
41. Ellison DH, Berl T. Clinical practice. The syndrome of inappropriate antidiuresis. N Engl J Med. 2007;356(20):2064-2072.
42. Maesaka JK, Imbriano LJ, Ali NM, Ilamathi E. Is it cerebral or renal salt wasting? Kidney Int. 2009;76(9):934-938.
43. Sterns RH, Nigwekar SU, Hix JK. The treatment of hyponatremia. Semin Nephrol. 2009;29(3):282-299.
44. Sterns RH, Riggs JE, Schochet SS Jr. Osmotic demyelination syndrome following correction of hyponatremia. N Engl J Med. 1986;314(24):1535-1542.
45. Ellison DH, Berl T. Clinical practice. The syndrome of inappropriate antidiuresis. N Engl J Med. 2007;356(20):2064-2072.
46. Decaux G, Brimioulle S, Genette F, Mockel J. Treatment of the syndrome of inappropriate secretion of antidiuretic hormone by urea. Am J Med. 1980;69(1):99-106.
47. Schrier RW, Gross P, Gheorghiade M, et al. Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia. N Engl J Med. 2006;355(20):2099-2112.
48. List AF, Hainsworth JD, Davis BW, et al. The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) in small-cell lung cancer. J Clin Oncol. 1986;4(8):1191-1198.
49. Laureno R, Karp BI. Myelinolysis after correction of hyponatremia. Ann Intern Med. 1997;126(1):57-62.
50. Gankam Kengne F, Nicaise C, Soupart A, et al. Astrocytes are an early target in osmotic demyelination syndrome. J Am Soc Nephrol. 2011;22(10):1834-1845.
51. Palmer BF. Hyponatremia in patients with central nervous system disease: SIADH versus CSW. Trends Endocrinol Metab. 2003;14(4):182-187.
52. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252-264.
53. Postow MA, Sidlow R, Hellmann MD. Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med. 2018;378(2):158-168.
54. Weber JS, Kähler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol. 2012;30(21):2691-2697.
55. Mahmood SS, Fradley MG, Cohen JV, et al. Myocarditis in patients treated with immune checkpoint inhibitors. J Am Coll Cardiol. 2018;71(16):1755-1764.
56. Johnson DB, Balko JM, Compton ML, et al. Fulminant myocarditis with combination immune checkpoint blockade. N Engl J Med. 2016;375(18):1749-1755.
57. Salem JE, Manouchehri A, Moey M, et al. Cardiovascular toxicities associated with immune checkpoint inhibitors: an observational, retrospective, pharmacovigilance study. Lancet Oncol. 2018;19(12):1579-1589.
58. Escudier M, Cautela J, Malissen N, et al. Clinical features, management, and outcomes of immune checkpoint inhibitor-related cardiotoxicity. Circulation. 2017;136(21):2085-2087.
59. Zhang L, Awadalla M, Mahmood SS, et al. Cardiovascular magnetic resonance in immune checkpoint inhibitor-associated myocarditis. Eur Heart J. 2020;41(18):1733-1743.
60. Thavendiranathan P, Zhang L, Zafar A, et al. Myocardial T1 and T2 mapping by magnetic resonance in patients with immune checkpoint inhibitor-associated myocarditis. J Am Coll Cardiol. 2021;77(12):1503-1516.
61. Moslehi JJ, Salem JE, Sosman JA, et al. Increased reporting of fatal immune checkpoint inhibitor-associated myocarditis. Lancet. 2018;391(10124):933.
62. Brahmer JR, Lacchetti C, Schneider BJ, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2018;36(17):1714-1768.
63. Salem JE, Allenbach Y, Vozy A, et al. Abatacept for severe immune checkpoint inhibitor-associated myocarditis. N Engl J Med. 2019;380(24):2377-2379.
64. Heinzerling L, Ott PA, Hodi FS, et al. Cardiotoxicity associated with CTLA4 and PD1 blocking immunotherapy. J Immunother Cancer. 2016;4:50.
65. Dolladille C, Ederhy S, Sassier M, et al. Immune checkpoint inhibitor rechallenge after immune-related adverse events in patients with cancer. JAMA Oncol. 2020;6(6):865-871.
66. Wang DY, Salem JE, Cohen JV, et al. Fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis. JAMA Oncol. 2018;4(12):1721-1728.
67. U.S. Department of Health and Human Services. Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. National Institutes of Health, National Cancer Institute. 2017.
68. Abu-Sbeih H, Ali FS, Alsaadi D, et al. Outcomes of vedolizumab therapy in patients with immune checkpoint inhibitor-induced colitis: a multi-center study. J Immunother Cancer. 2018;6(1):142.
69. Wang Y, Abu-Sbeih H, Mao E, et al. Endoscopic and histologic features of immune checkpoint inhibitor-related colitis. Inflamm Bowel Dis. 2018;24(8):1695-1705.
70. Bergqvist V, Hertervig E, Gedeon P, et al. Vedolizumab treatment for immune checkpoint inhibitor-induced enterocolitis. Cancer Immunol Immunother. 2017;66(5):581-592.
71. Abu-Sbeih H, Tang T, Ali FS, et al. The impact of immune checkpoint inhibitor-related adverse events and their immunosuppressive treatment on patients' outcomes. J Immunother Precis Oncol. 2018;1(1):7-18.
72. Geukes Foppen MH, Rozeman EA, van Wilpe S, et al. Immune checkpoint inhibition-related colitis: symptoms, endoscopic features, histology and response to management. ESMO Open. 2018;3(1):e000278.
73. Santini FC, Rizvi H, Plodkowski AJ, et al. Safety and efficacy of re-treating with immunotherapy after immune-related adverse events in patients with NSCLC. Cancer Immunol Res. 2018;6(9):1093-1099.
74. Azoulay E, Schellongowski P, Darmon M, et al. The Intensive Care Medicine research agenda on critically ill oncology and hematology patients. Intensive Care Med. 2017;43(9):1366-1382.
75. Prigerson HG, Bao Y, Shah MA, et al. Chemotherapy use, performance status, and quality of life at the end of life. JAMA Oncol. 2015;1(6):778-784.
76. Schellongowski P, Sperr WR, Wohlfarth P, et al. Critically ill patients with cancer: chances and limitations of intensive care medicine—a narrative review. ESMO Open. 2016;1(5):e000018.
77. Taccone FS, Artigas AA, Sprung CL, et al. Characteristics and outcomes of cancer patients in European ICUs. Crit Care. 2009;13(1):R15.# The Crashing Cancer Patient: Oncologic Emergencies Beyond Neutropenia