Monotherapy Versus Combination Therapy in Agitation Management in the Intensive Care Unit: A Narrative Review

Agitation, defined as excessive restlessness or psychomotor activity leading to potential harm or disruption, is a common and challenging complication in the intensive care unit (ICU), often associated with delirium, withdrawal syndromes, or environmental stressors. Monotherapy refers to the use of a single pharmacologic agent (commonly benzodiazepines or antipsychotics), whereas combination therapy involves the concurrent use of both classes. Agitation contributes to adverse outcomes, including prolonged mechanical ventilation, unintentional removal of intravenous lines, feeding tubes, or endotracheal tubes. This can increase morbidity in rare cases, such as patients with difficult airways who can self-extubate, which may increase mortality. This narrative review evaluates evidence from 2000 to 2025, comparing monotherapy and combination therapy in ICU agitation. Although benzodiazepines remain essential for alcohol or sedative withdrawal, their broader use is associated with higher delirium incidence and longer ICU stay. Antipsychotics are widely used but have not consistently demonstrated improvement in delirium outcomes in randomized trials. Combination therapy may provide rapid behavioral control in refractory or mixed etiology agitation, but it appears to increase the risk of oversedation, hypotension, and prolonged mechanical ventilation. Current critical care guidelines, including the 2018 Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption (PADIS) recommendations, do not recommend routine combination therapy; instead, they emphasize individualized patient selection, structured sedation protocols, and cautious titration. Clinical decision-making should balance immediate control of agitation with long-term neurologic and functional outcomes.