1. Overview of Pharmacologic Approach

Critically ill patients with delirium and agitation require prompt control of dangerous behaviors while minimizing long-term cognitive harm and adverse events. The approach is a careful balance of immediate safety and long-term recovery.

Goals of Therapy

• Rapid control of agitation to prevent self-harm or removal of life-sustaining devices.
• Preservation of cognition and facilitation of weaning from mechanical ventilation.
• Minimization of adverse effects, including cardiac, neurologic, and hemodynamic complications.

Escalation Framework

1. Always begin with nonpharmacologic measures (e.g., reorientation, sleep hygiene, early mobility).
2. Initiate a first-line agent, typically an antipsychotic, for severe hyperactive delirium.
3. Add adjunctive agents (e.g., alpha-2 agonists, or benzodiazepines for specific withdrawal syndromes) if agitation persists or the etiology indicates a specific need.
4. Transition to enteral therapy as soon as feasible and actively de-escalate daily.

2. Antipsychotics

Typical and atypical antipsychotics remain first-line for managing the symptoms of hyperactive delirium. The choice between agents is guided by the required route of administration, safety profile, and patient-specific comorbidities.

A. Haloperidol (Typical)

• Mechanism of Action: Potent dopamine D₂ receptor antagonism effectively reduces psychomotor agitation.
• Indications: Hyperactive delirium with risk of harm to self or others; agitation jeopardizing essential medical care.
• Rationale: High provider familiarity, availability of an IV formulation for rapid onset, and minimal hemodynamic effects.
• Dosing: Start with a low dose of 0.5–1 mg IV bolus over 2–5 minutes, which can be repeated every 4 hours as needed. For persistent agitation, a continuous infusion of 0.5–3 mg/hr can be titrated to a Richmond Agitation-Sedation Scale (RASS) target of –1 to +1.
• Monitoring: Obtain a baseline and daily ECG to monitor the QTc interval (hold or stop if >500 ms). Assess for extrapyramidal symptoms (EPS) using the Abnormal Involuntary Movement Scale (AIMS) every shift. Be vigilant for signs of neuroleptic malignant syndrome (fever, rigidity, autonomic dysfunction).

B. Atypical Antipsychotics (Quetiapine, Olanzapine)

• Mechanism of Action: Broader receptor profile, including serotonin 5-HT₂A and dopamine D₂ receptor modulation.
• Indications: Mixed or refractory delirium, patients with EPS intolerance, or as a transition to enteral therapy.
• Dosing & Titration: Quetiapine is typically started at 12.5–50 mg PO every 4–6 hours. Olanzapine is dosed at 2.5–5 mg PO every 12–24 hours. Doses should be adjusted for hepatic impairment.
• Monitoring: Monitor for oversedation and orthostatic hypotension. Periodically check metabolic panels for hyperglycemia and dyslipidemia with longer-term use.

3. Alpha-2 Agonists

Dexmedetomidine provides cooperative sedation with modest analgesic effects and minimal respiratory depression, making it a valuable agent in the ICU. Evidence suggests it may reduce delirium duration compared to benzodiazepine-based sedation.

Dexmedetomidine

• Mechanism of Action: Central α₂-adrenergic agonism produces sedation and sympatholysis, leading to a calm but arousable state.
• Indications: Continuous sedation for agitated or delirious patients, particularly those who must maintain their own respiratory drive or are being weaned from mechanical ventilation.
• Dosing: An optional loading dose of 0.5–1 µg/kg over 10–20 minutes can be given, followed by a maintenance infusion of 0.2–1.4 µg/kg/hr, titrated to a RASS target of –1 to +1.
• Monitoring: Requires continuous heart rate and blood pressure monitoring due to the risk of bradycardia and hypotension. Perform daily sedation interruptions when clinically feasible to assess neurologic status and prevent tolerance.
• Contraindications: Use with caution or avoid in patients with second- or third-degree heart block (without a pacemaker), severe baseline bradycardia, or unresuscitated hypovolemia.

4. Benzodiazepines

Benzodiazepines are now considered second- or third-line agents for general ICU sedation due to their strong association with causing and prolonging delirium. Their use should be reserved for specific indications.

Lorazepam, Midazolam

• Mechanism of Action: Potentiate the effect of the inhibitory neurotransmitter GABA at the GABAₐ receptor, causing generalized CNS depression.
• Primary Indications: Management of alcohol or benzodiazepine withdrawal syndromes (where they are first-line), or as rescue therapy for severe agitation refractory to other agents.
• Dosing: For intermittent use, lorazepam 0.5–2 mg IV every 4–6 hours PRN. For continuous sedation, a midazolam infusion of 0.02–0.1 mg/kg/hr can be titrated to the sedation goal.
• Monitoring: Closely monitor for oversedation and respiratory depression. Perform daily delirium assessments (e.g., CAM-ICU), as these agents can exacerbate the condition.
• Disadvantages: Independently associated with increased risk of delirium, prolonged sedation, and accumulation of active metabolites in patients with renal or hepatic dysfunction.

5. Adjunctive Agents

Several non-antipsychotic adjuncts have been studied for delirium, but most have limited or negative evidence. Their use should be highly selective.

• Melatonin Analogs: Evidence for reducing delirium incidence or duration is inconsistent. Their role is primarily limited to regulating the sleep-wake cycle rather than treating active delirium.
• Cholinesterase Inhibitors (e.g., Rivastigmine): Studies have shown these agents may increase mortality and prolong delirium duration in the ICU. They are not recommended and should be avoided.
• Thiamine: A meta-analysis suggests a potential benefit, showing a significant reduction in the odds of developing ICU delirium. It is reasonable to consider 100–200 mg IV daily in patients at risk for deficiency (e.g., alcohol use disorder, malnutrition).

6. PK/PD Considerations in Critical Illness

The physiologic derangements of critical illness significantly alter drug pharmacokinetics (PK) and pharmacodynamics (PD), requiring individualized dosing and vigilant monitoring.

• Volume of Distribution: Systemic inflammation and aggressive fluid resuscitation lead to an increased volume of distribution, potentially requiring higher loading doses for hydrophilic drugs.
• Hypoalbuminemia: Low albumin levels increase the free fraction of highly protein-bound drugs (e.g., benzodiazepines), increasing the risk of toxicity. Consider reducing initial doses by 25–50%.
• Hepatic Metabolism: Shock states can impair hepatic blood flow, prolonging the half-life of lipophilic drugs like midazolam and fentanyl.
• Renal Clearance: Acute kidney injury can lead to the accumulation of active metabolites. Conversely, continuous renal replacement therapy (CRRT) can clear certain drugs and metabolites, sometimes requiring dose adjustments.
• Drug Interactions: Polypharmacy is common. Always review for significant interactions, such as CYP3A4 inhibitors (e.g., azole antifungals) increasing levels of quetiapine and midazolam.

7. Monitoring and Safety

A structured monitoring plan is essential to guide therapy, ensure efficacy, and prevent adverse events.

8. Pharmacoeconomics and Resource Utilization

The choice of agent should balance direct acquisition cost with the indirect costs associated with monitoring burden and downstream complications.

• Cost of Delirium: Each episode of ICU delirium is estimated to increase ICU and hospital costs by over $10,000 due to longer stays and increased care needs.
• Agent-Specific Costs:
  • Haloperidol/Atypicals: Low drug acquisition cost but require resources for ECG and neurologic monitoring.
  • Dexmedetomidine: High per-hour drug cost, which may be offset by potential reductions in ventilation days and overall ICU length of stay.
  • Benzodiazepines: Low acquisition cost but contribute significantly to prolonged sedation and delirium-related expenses.
• Bundled Protocols: Implementing bundled sedation protocols, such as analgesia-first sedation and daily sedation interruptions, has been shown to reduce overall drug use, ventilation time, and resource utilization.

9. Clinical Algorithms and Decision Support

Structured pathways and integrated decision support tools can facilitate timely and appropriate agent selection, escalation, and de-escalation, standardizing care and improving outcomes.