1. Introduction: Role of Pharmacotherapy in Delirium

Nonpharmacologic strategies, such as the ABCDE bundle, are the foundation of delirium management. Pharmacotherapy is reserved for specific, high-risk situations where the benefits of sedation outweigh the risks.

Indications for Pharmacotherapy

• Severe agitation posing a danger to the patient or staff.
• Failure to wean from mechanical ventilation due to agitation.
• Distressing symptoms like hallucinations or paranoia from a pre-existing psychiatric comorbidity.

Goals of Therapy

• Achieve targeted symptom control (e.g., a calm, cooperative state; RASS -1 to 0).
• Avoid oversedation, which can prolong ventilation and ICU stay.
• Minimize drug-related toxicity and adverse effects.

2. First-Line Therapy: Haloperidol

Haloperidol remains the go-to agent for acute hyperactive or mixed delirium in the ICU. Its high-potency D2 receptor antagonism effectively controls agitation with minimal anticholinergic or antihistaminic effects. It is indicated for emergent agitation and risk of self-injury, not for routine prophylaxis or to shorten delirium duration.

3. Adjunctive and Second-Line Agents

When haloperidol is insufficient or contraindicated, atypical antipsychotics or dexmedetomidine are valuable alternatives, selected based on patient-specific factors like enteral access and sedation goals.

3.1 Atypical Antipsychotics (Quetiapine, Olanzapine)

These agents block both D2 and 5-HT2A receptors. Quetiapine’s H1 blockade provides sedation, while olanzapine has more anticholinergic activity. They are indicated when enteral access is available and sedation for insomnia is desired. They carry a lower risk of EPS than haloperidol but can cause oversedation.

3.2 Dexmedetomidine

As a central α2-adrenergic agonist, dexmedetomidine provides cooperative sedation with minimal respiratory depression. It is ideal for ventilator-dependent patients whose agitation is precluding weaning, with a target RASS of –1 to 0.

• Dosing & Titration: 0.2–0.7 µg/kg/h IV infusion. Increase by 0.1 µg/kg/h every 30–60 minutes as needed.
• Monitoring: Continuous heart rate and blood pressure telemetry is essential due to the risk of bradycardia and hypotension.
• Pearls: May reduce delirium incidence compared to benzodiazepines. Though costly, it is often reserved for facilitating extubation.

4. Pharmacokinetic and Pharmacodynamic Considerations

Critical illness profoundly alters drug PK/PD. An expanded volume of distribution, hypoalbuminemia, capillary leak, and organ dysfunction all impact drug behavior.

• Volume of Distribution (Vd): Lipophilic drugs like haloperidol have an increased Vd, leading to a prolonged elimination half-life.
• Protein Binding: Hypoalbuminemia raises the free (active) fraction of highly protein-bound drugs, intensifying their effects and toxicity.
• Metabolism: Hepatic injury can impair CYP2D6/3A4 metabolism, prolonging the half-life of antipsychotics.
• Receptor Sensitivity: Altered blood-brain barrier permeability and receptor sensitivity in critical illness may necessitate dose reductions.

5. Organ Dysfunction Dosing Adjustments

Dosing must be tailored in the setting of hepatic or renal failure and during continuous renal replacement therapy (CRRT).

• Hepatic Impairment: Reduce initial doses of haloperidol and dexmedetomidine by 25–50% and extend dosing intervals. Monitor closely for signs of accumulation.
• Renal Impairment: Active metabolites of haloperidol may accumulate. Use lower initial bolus doses and monitor carefully for prolonged effects.
• CRRT: Most antipsychotics are highly protein-bound and lipophilic, resulting in limited removal by CRRT. Dose adjustments are typically driven by hemodynamic tolerance rather than clearance.

6. Routes of Administration and Delivery Devices

The route of administration is chosen based on desired onset of action and patient factors like enteral access and coagulation status.

• Haloperidol: IV for rapid onset; IM is an option but should be avoided in patients with coagulopathy.
• Quetiapine/Olanzapine: Enteral (PO/NG) only. Ensure feeding tube patency and flush thoroughly before and after administration to prevent clogging.
• Dexmedetomidine: IV infusion exclusively, typically via a central line.

7. Monitoring Plan and Toxicity Surveillance

A structured monitoring plan is essential to mitigate the risks of QT prolongation, extrapyramidal symptoms (EPS), and sedation overshoot.

QTc and Electrolyte Protocol

1. Obtain a baseline ECG before starting antipsychotics and repeat after any significant dose increase.
2. Initiate continuous telemetry if the baseline QTc is > 450 ms or if the patient has multiple risk factors (e.g., other QTc-prolonging drugs, female sex, heart failure).
3. Proactively maintain serum potassium > 4.0 mEq/L and magnesium > 2.0 mg/dL.

Neurologic Monitoring

• Assess sedation depth using the Richmond Agitation-Sedation Scale (RASS) every 2–4 hours, with a target of –1 (drowsy) to 0 (alert and calm).
• Perform a daily clinical assessment for EPS (tremor, rigidity, akathisia).

8. Pharmacoeconomic Analysis

A comprehensive cost analysis must balance drug acquisition costs against the costs of monitoring and potential impact on patient outcomes.

• Haloperidol: Low acquisition cost, but requires significant resources for ECG and electrolyte surveillance.
• Atypical Antipsychotics: Moderate drug cost with similar monitoring requirements to haloperidol.
• Dexmedetomidine: High acquisition cost. However, this may be offset by a reduction in ventilator days and overall ICU length of stay in select patients.

9. Integration into Clinical Algorithms

A stepwise approach ensures that pharmacotherapy is used judiciously. Escalation begins with foundational nonpharmacologic care, followed by haloperidol for severe agitation, and then consideration of second-line agents based on clinical context. De-escalation should occur as soon as agitation resolves.