How do I treat delirium in a patient with a complex medical history, including encephalitis, and potential neurological and psychiatric comorbidities, when all medical tests are negative?

Treatment of Delirium When All Medical Tests Are Negative

When all medical tests are negative in a delirious patient, prioritize non-pharmacological interventions first, and reserve pharmacological treatment only for patients with distressing symptoms (such as hallucinations or perceptual disturbances) or safety concerns where the patient poses a risk to themselves or others. 1

Step 1: Implement Non-Pharmacological Interventions as First-Line Treatment

Before considering any medications, implement comprehensive environmental and supportive measures: 1

• Optimize the care environment by providing appropriate lighting, clear signage, and ensuring a clock (consider a 24-hour clock in ICU settings) and calendar are easily visible 1
• Maintain continuity of care by ensuring the patient is cared for by a familiar team and avoiding unnecessary room or ward transfers 1
• Provide reorientation through calm communication, explaining where the patient is, who you are, and your role; introduce cognitively stimulating activities like reminiscence 1
• Facilitate regular family visits as family members can assist with reorientation and provide comfort 1
• Ensure adequate hydration by encouraging oral intake or considering subcutaneous/intravenous fluids if necessary (while being cautious in patients with heart failure or chronic kidney disease) 1
• Implement fall prevention measures and maintain a calm, quiet environment that promotes orientation 1

Step 2: Consider EEG to Rule Out Non-Convulsive Status Epilepticus

Even when standard medical tests are negative, obtain an EEG, particularly in patients with hypoactive delirium or persistent consciousness disorder, to exclude a potentially treatable non-convulsive status epilepticus. 1 This is a critical step that is often overlooked and represents a reversible cause even when other tests are unrevealing.

Step 3: Reassess for Subtle Reversible Causes

When initial testing is negative, reconsider: 1

• Opioid-induced delirium: If the patient is on opioids, consider opioid rotation with a 30-50% dose reduction in equianalgesic dosing 1
• Medication review: Systematically review all medications for anticholinergic burden and potentially deliriogenic agents, even if not initially obvious 2
• Dehydration: Even with normal laboratory values, clinical dehydration may contribute; consider a trial of hydration on a case-by-case basis if aligned with patient goals 1

Step 4: Pharmacological Treatment (Only When Indicated)

Medications should be used in the lowest effective dose and for the shortest period of time, and only when the patient has distressing symptoms or poses safety risks. 1

For Hyperactive Delirium with Distressing Symptoms:

• Haloperidol can be an option for hyperactive delirium, though recent evidence shows it may not benefit mild-to-moderate delirium and could worsen symptoms 1
• Olanzapine may offer benefit in symptomatic management of delirium (available in parenteral or orally dispersible formulations) 1
• Quetiapine may offer benefit (oral formulations only; sedation may be advantageous in hyperactive delirium) 1
• Aripiprazole may offer benefit (available in parenteral or orally dispersible formulations in some countries) 1

Important caveat: Administration of haloperidol or risperidone has no demonstrable benefit in mild-to-moderate delirium and is not recommended in this context, as these medications may actually worsen symptoms. 1

For Hypoactive Delirium:

• There is currently no pharmaceutical therapeutic option for hypoactive delirium 1
• Methylphenidate may improve cognition in hypoactive delirium in which neither delusions nor perceptual disturbances are present and for which no cause has been identified 1

For Severe Agitation or Safety Concerns:

• Benzodiazepines (midazolam or lorazepam) are effective at providing sedation and potentially anxiolysis in acute management of severe symptomatic distress, but should only be used after careful assessment of patient distress level, safety risks, and patient mobility 1
• Benzodiazepines are not part of initial delirium management strategy as they are sedating, deliriogenic, and increase fall risk 1

Step 5: Address Goals of Care and Prognosis

When delirium persists despite negative workup and interventions, consider: 1

• Discuss prognosis and goals of care with the patient (when able) and family, particularly if the patient has underlying conditions like encephalitis or advanced illness 1
• Focus on symptom relief and quality of life rather than aggressive reversal attempts if the delirium appears irreversible 1
• Provide education and support to family members through written materials and psychological support, as delirium causes significant distress for families who may feel helpless 1

Critical Pitfalls to Avoid:

• Do not treat asymptomatic bacteriuria with antibiotics in delirious patients without evidence of infection, as this leads to worse functional recovery and increased Clostridium difficile infections 1
• Do not use antipsychotics routinely for mild-to-moderate delirium without distressing symptoms, as they provide no benefit and may cause harm 1
• Do not overlook non-convulsive status epilepticus as a treatable cause, even when other tests are negative 1
• Avoid prolonged use of antipsychotics, which carries significant risks including extrapyramidal symptoms, metabolic syndrome, and increased mortality, especially in elderly patients with dementia 2