Maximizing trEatment of Neurological Dysfunction Using INtravenous Guanfacine Study

Delirium during critical illness is, to date, the primary potentially modifiable risk factor for acquired dementia after critical illness (ADRD). There are, however, no Food and Drug Administration (FDA) approved medications to mitigate delirium. Benzodiazepines are ineffective at reducing the incidence or duration of delirium, and on the contrary, increase the risk. Furthermore, large randomized controlled studies have shown that antipsychotic agents have no effect (vs. placebo) on delirium duration, mechanical ventilation, hospital length of stay, or death. Therefore, current clinical practice guidelines no longer recommend routine use of benzodiazepines or antipsychotics for treatment of delirium. Despite these recommendations, benzodiazepine, antipsychotics, and other drugs are routinely prescribed to critically ill patients due to the urgent clinical need to control delirium symptoms. The alpha-2 agonist dexmedetomidine is the most successful agent for delirium identified to date. However, it is typically administered as a continuous infusion and requires ICU-level monitoring due to hypotension and bradycardia risks. The delirium sparing benefits of dexmedetomidine have been postulated to result from alpha-2 agonist mediated modulation of CNS inflammation, microcirculatory blood flow, and biomimetic sleep. The alpha-2 agonist guanfacine, an FDA-approved medication for use in hypertension and attention deficit hyperactivity disorder, has a higher selectivity for the alpha-2A receptor in the central nervous system. Thus, delirium sparing benefits may be improved with guanfacine while reducing systemic effects. Further, instead of a continuous infusion, the pharmacokinetic and pharmacodynamic properties of guanfacine favor a twice a day bolus dosing schedule. This Maximizing trEatment of Neurological Dysfunction using INtravenous Guanfacine (MENDING) study will investigate the benefits of intravenous (IV) guanfacine. In this phase II proof-of-concept trial of IV guanfacine vs. placebo for the treatment of critical illness delirium, the following specific aims will be tested in critically ill patients with delirium: Aim 1: To determine whether IV guanfacine will increase the number of days alive without delirium and coma (DCFDs) over 14 days relative to placebo. Aim 2: To evaluate whether IV guanfacine twice a day will increase days alive and free of mechanical ventilation (VFDs) and days alive and free of the ICU (IFDs) over 28 days relative to placebo. Aim 3: To assess whether IV guanfacine can reduce the development of ADRD after critical illness. Identifying a safe and effective treatment for delirium would have exponential benefits to patients, families, healthcare, and society. This first study of IV guanfacine builds upon extensive research regarding the benefits of alpha-2 agonists for brain dysfunction.