Evaluation of Sudden Onset Generalized Flushing
The evaluation of sudden onset generalized flushing must immediately prioritize ruling out anaphylaxis, which is a life-threatening emergency requiring urgent epinephrine administration, followed by systematic exclusion of serious endocrine and neoplastic causes including carcinoid syndrome, pheochromocytoma, and mastocytosis. 1
Immediate Assessment: Rule Out Anaphylaxis
First, determine if the patient meets clinical criteria for anaphylaxis, as this requires immediate intervention and can be fatal if epinephrine is delayed. 1
Anaphylaxis is highly likely if ANY ONE of these criteria is present:
Acute onset (minutes to hours) with skin/mucosal involvement (generalized urticaria, flushing, angioedema) PLUS either:
Two or more organ systems involved rapidly after allergen exposure:
Reduced blood pressure after known allergen exposure (systolic BP <90 mmHg or >30% decrease from baseline in adults) 1
Critical distinction: Anaphylaxis is characterized by urticaria, angioedema, pruritus, and tachycardia in addition to flushing, whereas isolated flushing without these features suggests alternative diagnoses. 2
If Anaphylaxis is Suspected:
- Administer epinephrine 0.3 mg intramuscularly immediately into the mid-outer thigh 1
- Delayed epinephrine is associated with increased mortality and poor outcomes including hypoxic-ischemic encephalopathy 1
- Obtain serum tryptase levels 15 minutes to 3 hours after symptom onset (serial measurements more useful than single values) 1
- Plasma histamine rises within 5 minutes and remains elevated for 15-60 minutes 1
- Normal tryptase or histamine levels do NOT rule out anaphylaxis 1
Systematic Evaluation for Non-Anaphylactic Flushing
History and Clinical Context
Obtain detailed medication history, as drug-induced flushing is extremely common and includes:
- SSRIs (escitalopram and other selective serotonin reuptake inhibitors) 3
- Niacin, nicotine, catecholamines 2
- ACE inhibitors 2
- Vancomycin (red man syndrome) 2
- Calcium channel blockers and nitrates 3
- Prostacyclins (epoprostenol, treprostinil, iloprost) 3
- Chemotherapy agents (particularly monoclonal antibodies causing infusion reactions) 1
Assess alcohol consumption history:
- Alcohol-induced facial flushing suggests ALDH2 deficiency (affects approximately 540 million people worldwide with the ALDH2*2 genetic variant) 2
- Associated with tachycardia, palpitations, and reduced alcohol tolerance 2
- Screen for alcohol use disorder using AUDIT-C ≥4 or AUDIT >8 2
Determine timing and pattern:
- Flushing within first couple hours of drug infusion suggests infusion-related reaction or cytokine release syndrome 1
- Episodic attacks suggest neuroendocrine causes 4, 5
- Relationship to meals may indicate dumping syndrome or scombroid fish poisoning 2, 6
Critical Life-Threatening Diagnoses to Exclude
The following serious conditions must be systematically ruled out through laboratory and imaging studies: 2, 5, 7
Carcinoid Syndrome
- Measure serum serotonin and 24-hour urinary 5-hydroxyindoleacetic acid (5-HIAA) 2
- Characterized by episodic dry flushing (without sweating) with gastrointestinal symptoms 6
Pheochromocytoma
- Measure plasma-free metanephrines and urinary vanillylmandelic acid 2
- Flushing accompanied by hypertensive episodes, headache, palpitations 5, 7
Mastocytosis and Mast Cell Activation Disorders
- Consider in patients with recurrent flushing, urticaria, and gastrointestinal symptoms 5, 6
- Obtain serum tryptase (baseline, not during acute episode for mastocytosis screening) 7
Medullary Thyroid Carcinoma
VIPoma (Vasoactive Intestinal Peptide-secreting tumor)
- Consider in patients with watery diarrhea and flushing 6
Additional Screening Based on Clinical Context
Screen for liver disease in patients with alcohol-induced flushing who continue drinking:
- AST/ALT with AST/ALT ratio >1.5 2
- Elevated GGT (sensitive but not specific marker) 2
- Elevated bilirubin, macrocytic anemia 2
Consider postmenopausal vasomotor symptoms in appropriate demographic 2, 4
Evaluate thyroid function if hyperthyroidism suspected 2, 6
Grading Severity for Infusion-Related Reactions
If flushing occurs during drug infusion, use standardized grading to guide management: 1
- Grade 1 (Mild): Transient flushing or rash, drug fever <38°C; intervention not indicated 1
- Grade 2 (Moderate): Infusion interruption indicated; responds promptly to symptomatic treatment 1
- Grade 3 (Severe): Prolonged symptoms not rapidly responsive; hospitalization indicated 1
- Grade 4 (Life-threatening): Urgent intervention required; may include hypotension requiring pressors 1
Management of Infusion Reactions
- Stop infusion immediately if symptoms develop 1
- Monitor vital signs (BP, pulse, respiratory rate, O2 saturation, temperature) 1
- For hypotension: recline patient, administer NS bolus 1000-2000 mL 1
- Consider hydrocortisone 100-500 mg IV and famotidine 20 mg IV for moderate reactions 1
- Administer epinephrine 0.3 mg IM for severe reactions with hypotension, angioedema, or multi-organ involvement 1
Common Pitfalls to Avoid
- Do not assume isolated flushing is benign without systematic evaluation 4, 5
- Do not delay epinephrine if anaphylaxis criteria are met while waiting for laboratory confirmation 1
- Do not rely solely on tryptase or histamine levels to rule out anaphylaxis 1
- Do not overlook medication-induced flushing, which is far more common than neoplastic causes 2, 3
- Do not miss scombroid fish poisoning (histamine from spoiled fish), which can mimic anaphylaxis 2
- In patients with ALDH2 deficiency who continue drinking, do not prescribe disulfiram, as it causes acetaldehyde accumulation and worsens flushing 2