What is the role and dosage of dexamethasone in treating typhoid (Salmonella Typhi) encephalopathy?

Dexamethasone in Typhoid Encephalopathy

Dexamethasone should be administered to all patients with typhoid encephalopathy at a dose of 3 mg/kg IV as an initial bolus, followed by 1 mg/kg IV every 6 hours for a total of 48 hours (8 doses), given alongside appropriate antibiotic therapy. 1, 2

Evidence for Use

The role of dexamethasone in typhoid encephalopathy is well-established based on landmark evidence demonstrating dramatic mortality reduction:

• A randomized, double-blind, placebo-controlled trial demonstrated that high-dose dexamethasone reduced mortality from 55.6% to 10% (p=0.003) in patients with severe typhoid fever presenting with delirium, obtundation, stupor, coma, or shock. 2

• More recent retrospective data confirms these findings, showing 100% of survivors with enteric fever encephalopathy received high-dose dexamethasone versus 0% of non-survivors (p<0.001). 3

• The mechanism involves attenuating the subarachnoid space inflammatory response, decreasing cerebral edema, reducing increased intracranial pressure, improving altered cerebral blood flow, mitigating cerebral vasculitis, and reducing neuronal injury mediated by pro-inflammatory cytokines. 1

• Recent mechanistic studies demonstrate that typhoid toxin disrupts the blood-brain barrier, and corticosteroids are effective at mitigating this BBB disruption in vivo. 4

Specific Dosing Protocol

Adults

• Initial dose: 3 mg/kg IV bolus 2
• Maintenance: 1 mg/kg IV every 6 hours for 48 hours (total of 8 doses) 2
• Alternative guideline-based dosing: 10 mg IV every 6 hours for 4 days 1

Children

• 0.15 mg/kg IV every 6 hours for 2-4 days 1
• The steroid should ideally be administered 10-20 minutes before or concomitant with the first antimicrobial dose 1

Clinical Indications

Dexamethasone is specifically indicated for patients with typhoid fever who present with:

• Delirium 2
• Obtundation 2
• Stupor 2
• Coma 2
• Shock 2
• Encephalopathy with altered mental status 3, 5

These neurological signs are grave prognostic indicators that predict high risk of death, making dexamethasone essential rather than optional. 2

Critical Pitfalls to Avoid

• Do not withhold dexamethasone while awaiting blood culture results - patients with presumptive typhoid encephalopathy based on clinical presentation (jaundice, encephalopathy, thrombocytopenia, elevated alkaline phosphatase) should receive empiric treatment with both antibiotics and dexamethasone. 5

• Do not use dexamethasone for uncomplicated typhoid fever - it is unnecessary for most patients with typhoid and should be reserved specifically for those with neurological complications. 2

• Monitor for hypoglycemia - survivors were significantly less likely to have hypoglycemia compared to non-survivors (6% vs 67%, p=0.045), suggesting this complication requires vigilant monitoring during treatment. 3

Antibiotic Considerations

All patients should receive appropriate antimicrobial therapy alongside dexamethasone:

• The original landmark trial used chloramphenicol 2
• More recent data supports ciprofloxacin for patients presenting with jaundice and encephalopathy 5
• Be aware that multi-drug resistant Salmonella Typhi and Paratyphi strains are increasingly common 3

Distinguishing Features

When evaluating patients with jaundice and encephalopathy, features suggesting typhoid fever (rather than fulminant hepatic failure) include:

• Liver span >9 cm on physical examination 5
• Thrombocytopenia 5
• Elevated alkaline phosphatase 5
• AST > ALT 5
• Only mild prolongation of prothrombin time 5

The excellent response to ciprofloxacin and dexamethasone in confirmed typhoid cases (0% mortality, normalization of liver tests in 2 weeks) contrasts sharply with the 83% mortality in nontyphoid fulminant hepatic failure, underscoring the importance of early recognition and treatment. 5