28.2 Adverse Drug Reactions: Anaphylaxis, Severe Cutaneous Reactions & Hyperthermic Syndromes
Key Takeaways
Intramuscular epinephrine 0.3 to 0.5 mg in the anterolateral thigh is first-line for anaphylaxis, repeated every 5 to 15 minutes, with an infusion for refractory shock.
Patients on beta-blockers with refractory anaphylaxis may respond to glucagon 1 to 5 mg intravenously because it bypasses beta-receptor blockade.
Serotonin syndrome features clonus, hyperreflexia, and mydriasis with rapid onset after a serotonergic drug, whereas neuroleptic malignant syndrome has lead-pipe rigidity and bradyreflexia developing over days.
Malignant hyperthermia follows volatile anesthetics or succinylcholine with masseter spasm, rising end-tidal CO2, and rigidity, and is treated with dantrolene 2.5 mg/kg repeated as needed.
DRESS presents 2 to 8 weeks after drug exposure with fever, rash, eosinophilia, and organ involvement, and often requires systemic corticosteroids with a slow taper.
Anaphylaxis
Diagnosis is clinical: acute onset with skin or mucosal involvement plus respiratory compromise or hypotension, or two or more organ systems after a likely allergen, or hypotension after a known allergen. Up to 20% of cases have no skin findings, which is why hypotension with bronchospasm after a drug must be treated as anaphylaxis.
Common ICU triggers: beta-lactams and other antibiotics, neuromuscular blockers, iodinated contrast, chlorhexidine, latex, protamine, blood products, and NSAIDs.
Treatment:
- Epinephrine 0.3 to 0.5 mg intramuscularly in the anterolateral thigh, repeated every 5 to 15 minutes. Intramuscular dosing gives faster, more reliable absorption than subcutaneous.
- Position supine with the legs elevated (sitting a hypotensive patient up has caused "empty ventricle" arrest), give high-flow oxygen, and secure intravenous access.
- Fluid resuscitation: 1 to 2 liters of crystalloid rapidly, because massive capillary leak can shift a large share of intravascular volume.
- Refractory shock: an epinephrine infusion (0.05 to 0.5 micrograms/kg/min), then norepinephrine or vasopressin. Consider methylene blue for refractory vasoplegia.
- Patients on beta-blockers: glucagon 1 to 5 mg IV bypasses the beta-receptor and raises cyclic AMP directly.
- Adjuncts (never substitutes for epinephrine): H1 and H2 antihistamines for itch and urticaria, inhaled beta-agonists for bronchospasm, and corticosteroids (which do not treat the acute event and have unproven benefit for biphasic reactions).
- Airway: anticipate rapid laryngeal edema; intubate early with a smaller tube, prepared for a surgical airway.
- Observe for a biphasic reaction, which recurs in a minority within 1 to 12 hours; severe or epinephrine-refractory cases warrant longer monitoring.
- Document the trigger, prescribe an epinephrine autoinjector, and refer for allergy evaluation. A tryptase level drawn within a few hours (with a baseline later) supports the diagnosis.
Hereditary angioedema and ACE inhibitor angioedema do not respond to epinephrine (see the airway section).
Severe Cutaneous Adverse Reactions
| Reaction | Timing after drug start | Features | Management |
|---|---|---|---|
| Stevens-Johnson syndrome and toxic epidermal necrolysis | 4 days to 4 weeks | Painful skin with dusky macules and target lesions, mucosal involvement at two or more sites, positive Nikolsky sign; SJS below 10% body surface area detachment, overlap 10% to 30%, TEN above 30%. Causes include sulfonamides, allopurinol, lamotrigine, carbamazepine, phenytoin, nevirapine, NSAIDs | Stop the drug, burn-unit-level care (fluid and electrolyte management, temperature control, wound care, analgesia, ophthalmology and urology involvement), avoid prophylactic antibiotics; cyclosporine, etanercept, or IVIG are used, with steroids debated. SCORTEN estimates mortality |
| DRESS (drug reaction with eosinophilia and systemic symptoms) | 2 to 8 weeks (later than most reactions) | Fever, facial edema, morbilliform rash, eosinophilia, lymphadenopathy, hepatitis, kidney injury, myocarditis; HHV-6 reactivation. Causes include allopurinol, anticonvulsants, sulfonamides, vancomycin, minocycline | Stop the drug; systemic corticosteroids with a slow taper over weeks, because relapse is common; monitor for late thyroiditis and myocarditis |
| Acute generalized exanthematous pustulosis | Days | Sterile pustules on erythema with fever and neutrophilia; usually from beta-lactams | Stop the drug; supportive care, topical steroids |
| Drug-induced vasculitis and serum sickness | 1 to 3 weeks | Palpable purpura, arthralgia, fever | Stop the drug, steroids if severe |
| Vancomycin infusion reaction | Minutes, during infusion | Flushing of the face and torso from direct mast cell activation, not IgE-mediated | Slow the infusion, antihistamine; the drug can usually be continued |
Drug-induced thrombotic thrombocytopenic purpura and immune thrombocytopenia (quinine, ticlopidine, heparin, vancomycin) and drug-induced liver injury complete the systemic picture; severe liver injury with jaundice and coagulopathy requires transplant center discussion.
Hyperthermic Syndromes: Telling Them Apart
| Syndrome | Trigger and onset | Motor and pupillary signs | Specific treatment |
|---|---|---|---|
| Malignant hyperthermia | Volatile anesthetics or succinylcholine; minutes to hours (occasionally later) | Masseter spasm, generalized rigidity, rising end-tidal CO2, mixed acidosis, hyperkalemia, rhabdomyolysis | Stop the trigger, 100% oxygen with high flows, dantrolene 2.5 mg/kg IV repeated every 5 to 10 minutes to 10 mg/kg or more, active cooling, treat hyperkalemia and arrhythmias (avoid calcium-channel blockers with dantrolene), monitor for recrudescence and compartment syndrome |
| Serotonin syndrome | Serotonergic drug addition or overdose: SSRIs, SNRIs, MAO inhibitors, tramadol, fentanyl, linezolid, methylene blue, triptans; within 24 hours | Clonus (inducible, spontaneous, ocular), hyperreflexia, tremor, mydriasis, agitation, diarrhea; lower limbs affected more than upper | Stop the agents, benzodiazepines, aggressive cooling, cyproheptadine 12 mg then 2 mg every 2 hours; paralysis with a nondepolarizing agent and intubation for severe hyperthermia; avoid antipyretics and physical restraints (isometric contraction raises temperature) |
| Neuroleptic malignant syndrome | Dopamine antagonists (haloperidol, atypical antipsychotics, metoclopramide, promethazine) or withdrawal of dopaminergic therapy; days to weeks | "Lead-pipe" rigidity, bradyreflexia, akinesia, altered consciousness, autonomic instability, very high creatine kinase | Stop the antagonist or restart the dopaminergic drug, supportive cooling and fluids, benzodiazepines; bromocriptine or amantadine, and dantrolene for severe rigidity and hyperthermia |
| Anticholinergic toxicity | Antihistamines, tricyclics, scopolamine, jimsonweed | Dry flushed skin, mydriasis, urinary retention, absent bowel sounds, delirium with mumbling speech; no clonus or rigidity | Supportive care and benzodiazepines; physostigmine for pure antimuscarinic delirium (avoid with a wide QRS or tricyclic overdose) |
| Sympathomimetic toxicity | Cocaine, amphetamines, MDMA, cathinones | Diaphoresis (unlike anticholinergic), mydriasis, agitation, hypertension, tachycardia | Benzodiazepines, cooling, fluids; avoid beta-blocker monotherapy |
| Heat stroke | Environmental or exertional | No specific motor signature; hot skin | Rapid cooling (see the environmental section); dantrolene and antipyretics ineffective |
| Thyroid storm | Thyrotoxicosis plus a stressor | Hyperreflexia, tremor, atrial fibrillation, goiter, eye signs | Beta-blockade, thionamide, iodine after thionamide, steroids |
| Baclofen or sedative withdrawal | Abrupt discontinuation, pump failure | Rigidity, fever, autonomic instability | Restore the drug urgently; benzodiazepines |
The practical discriminators: clonus and hyperreflexia point to serotonin syndrome, lead-pipe rigidity with bradyreflexia to neuroleptic malignant syndrome, a rising end-tidal CO2 during anesthesia to malignant hyperthermia, and dry skin to anticholinergic toxicity (where sympathomimetic toxicity gives wet skin).
Supportive Priorities Common to All
- Stop the offending agent and avoid re-exposure (document it prominently).
- Cool actively when the core temperature exceeds about 39 to 40 °C: evaporative cooling, ice packs, cold fluids, and intravascular or surface devices. Sedate and paralyze for refractory hyperthermia from muscle activity, because continued contraction generates heat.
- Protect the kidneys: fluids for rhabdomyolysis, follow creatine kinase and potassium, and anticipate compartment syndrome.
- Treat hyperkalemia and arrhythmias aggressively.
- Screen for disseminated intravascular coagulation and hepatic injury, which complicate severe hyperthermia.
- Counsel the family in malignant hyperthermia about genetic testing, and report to a registry.
A 34-year-old woman develops hypotension of 70/40 mmHg with severe bronchospasm 5 minutes after the first dose of intravenous cefazolin. She has no rash. She takes metoprolol for migraine prophylaxis. After intramuscular epinephrine, fluids, and an epinephrine infusion, she remains hypotensive. Which additional therapy is most appropriate?
Intravenous glucagon 1 to 5 mg
Intravenous diphenhydramine 50 mg and methylprednisolone 125 mg as definitive therapy
Sitting her upright to reduce pulmonary edema
Intravenous esmolol to control the reflex tachycardia
A 47-year-old man taking sertraline is started on linezolid for a resistant infection. Twelve hours later he is agitated and diaphoretic with a temperature of 39.8 °C, heart rate of 128 bpm, mydriasis, hyperreflexia, and sustained inducible ankle clonus that is worse in the legs than the arms. Which diagnosis and treatment are correct?
Neuroleptic malignant syndrome, treated by stopping the dopamine antagonist and giving bromocriptine with supportive cooling
Serotonin syndrome, treated by stopping the serotonergic drugs, giving benzodiazepines and cyproheptadine, and active cooling
Malignant hyperthermia, treated with dantrolene 2.5 mg/kg intravenously, repeated until the rigidity and hypercapnia resolve
Anticholinergic toxicity, treated with physostigmine after an electrocardiogram confirms a normal QRS duration
A 29-year-old woman started allopurinol 5 weeks ago and presents with fever of 39 °C, facial edema, a diffuse morbilliform rash covering 60% of her body, cervical lymphadenopathy, eosinophils of 2,400/µL, ALT of 480 U/L, and creatinine of 2.1 mg/dL. There is no mucosal detachment. Which management is most appropriate?
Continue allopurinol and give antihistamines for a benign drug exanthem
Stop allopurinol and give systemic corticosteroids with a slow taper, monitoring for myocarditis and late thyroiditis
Stop allopurinol and transfer to a burn unit for epidermal detachment care
Stop allopurinol and start cyclosporine as first-line therapy for toxic epidermal necrolysis
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