1. Immediate Management

Prompt withdrawal of the offending agent and early identification of immunosuppression triggers are critical to limit organ damage.

A. Drug Cessation and Cross-Reactivity

• Identify and discontinue the suspected culprit (e.g., aromatic anticonvulsants, allopurinol, sulfonamides).
• Review structural cross-reactivity (e.g., carbamazepine ↔ oxcarbazepine) and HLA risk alleles (e.g., HLA-B*58:01 for allopurinol).
• Document the allergy profile in the electronic medical record (EMR) and update order-sets to prevent re-exposure.

B. Immunosuppression Triggers

Initiate systemic immunosuppression if ANY of the following criteria are met:

• Extensive Rash: >50% body surface area involvement, particularly with facial or truncal distribution.
• Hepatic Injury: Transaminases >5 times the upper limit of normal (ULN) or total bilirubin >2 mg/dL.
• Renal Injury: Acute kidney injury (AKI) Stage 2–3, defined as serum creatinine ≥2 times baseline or urine output <0.5 mL/kg/h.
• Pulmonary Involvement: New-onset dyspnea, hypoxemia, or radiographic evidence of pneumonitis.

Aim to start therapy within 48 hours of recognition to improve outcomes.

2. First-Line Therapy: Systemic Corticosteroids

High-dose corticosteroids form the foundation of DRESS management, leveraging both genomic and non-genomic effects to suppress the widespread T-cell–mediated inflammation.

A. Mechanism of Action

• Genomic: The glucocorticoid receptor binds to DNA, leading to transrepression of pro-inflammatory genes (e.g., interleukins, TNF-α) and upregulation of anti-inflammatory genes.
• Non-genomic: Provides rapid modulation of cell membranes and intracellular signaling pathways, contributing to immediate anti-inflammatory effects.

B. Agent Selection

• IV Methylprednisolone: Preferred for patients with hemodynamic instability, NPO status, or concerns for poor gut absorption.
• Oral Prednisone: Transition to oral therapy once the patient is hemodynamically stable and able to tolerate oral intake. The equimolar conversion is approximately 4 mg of methylprednisolone to 5 mg of prednisone.

C. Dosing Strategies

• Moderate Disease: 1 mg/kg/day of prednisone-equivalent, typically administered as IV methylprednisolone divided q6–8 hours.
• Severe Multiorgan Involvement: 2 mg/kg/day of prednisone-equivalent for more aggressive initial control.
• Typical Duration: A prolonged course of 6–8 weeks is often necessary, followed by a very gradual taper.

D. Taper Protocols and Relapse Monitoring

• Reduce the total daily dose by approximately 10% every 1–2 weeks, guided by clinical improvement (rash resolution) and laboratory markers (eosinophil count, LFTs).
• If relapse occurs (recurrent rash, rising LFTs, eosinophilia), revert to the last effective dose and slow the subsequent taper schedule.

E. Safety Monitoring

• Glucose: Check every 6–12 hours initially; manage hyperglycemia aggressively with an insulin protocol.
• Infection: Perform daily clinical assessments. Initiate prophylaxis for Pneumocystis jirovecii pneumonia (PJP) if the prednisone-equivalent dose is >20 mg/day for >4 weeks.
• Adrenal Suppression: During the taper, be vigilant for signs of adrenal insufficiency. Consider checking morning cortisol levels if symptoms arise.

3. Second-Line and Adjunctive Agents

In cases that are steroid-refractory, steroid-contraindicated, or life-threatening, additional agents like cyclosporine, intravenous immunoglobulin (IVIG), or mycophenolate mofetil can be added to achieve disease control.

A. Cyclosporine

Initiate at 3 mg/kg/day (PO or IV), divided twice daily. Adjust dose to target a 12-hour trough level of 100–200 ng/mL. In patients with hepatic impairment, start with a lower dose and monitor levels closely every 48–72 hours. Monitor serum creatinine and blood pressure daily due to the high risk of nephrotoxicity.

B. Intravenous Immunoglobulin (IVIG)

Administer 0.4 g/kg/day (based on ideal body weight) over 4–6 hours for a total of 5 days. Ensure adequate pre-hydration to mitigate renal injury. In patients with pre-existing renal insufficiency, use low-osmolality, sucrose-free formulations and consider a slower infusion rate.

C. Mycophenolate Mofetil

Standard dosing is 1 g PO twice daily. No routine renal dose adjustment is needed, but it is removed by dialysis. In significant hepatic impairment, consider reducing the initial dose by 25% and titrate as tolerated. Monitor CBC weekly for the first month, then monthly. Separate administration from antacids and phosphate binders by at least 2 hours.

4. PK/PD Considerations in Critical Illness

The physiologic derangements of critical illness significantly alter drug distribution and clearance, requiring vigilant dosing adjustments and therapeutic monitoring.

• Volume of Distribution (Vd): Systemic inflammation and fluid resuscitation increase the Vd for hydrophilic drugs. This may necessitate higher initial loading doses.
• Protein Binding: Hypoalbuminemia is common and increases the free (active) fraction of highly protein-bound agents like cyclosporine, potentially increasing toxicity even with “therapeutic” total drug levels.
• Renal Replacement Therapy: Continuous renal replacement therapy (CRRT) effectively removes smaller, water-soluble drugs like mycophenolate. Supplemental dosing post-session or adjusted continuous infusions may be required.

5. Pharmacoeconomics and Clinical Decision Points

Beyond clinical efficacy, economic factors, institutional protocols, and logistical considerations often drive agent selection in DRESS.

A. Cost–Benefit Analysis

• Corticosteroids: Low acquisition cost, widely available, and have well-defined monitoring parameters, making them the universal first-line choice.
• IVIG: High acquisition cost (often >US$10,000 per course) and potential for supply shortages. Its use is typically reserved for refractory cases or severe presentations with extensive mucocutaneous involvement.
• Cyclosporine & Mycophenolate: Offer a moderate- and low-cost oral alternative, respectively, but require specialized therapeutic drug monitoring.

B. Guideline Controversies

There is no universal consensus on the optimal second-line agent. Some expert panels favor cyclosporine for its rapid and potent inhibition of T-cells. Others cite IVIG’s broader immunomodulatory effects despite its cost. Mycophenolate is an emerging, cost-effective option but currently lacks robust support from randomized controlled trials.