Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT04578886 |
| Other study ID # |
Guanfacine for Delirium |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 3
|
| First received |
|
| Last updated |
|
| Start date |
November 23, 2020 |
| Est. completion date |
April 1, 2023 |
Study information
| Verified date |
April 2024 |
| Source |
University of Alabama at Birmingham |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Delirium in patients in the intensive care unit (ICU) is a common problem associated with
increased mortality and morbidity, including increased hospital and ICU length of stay,
greater hospital cost, increased ventilator days, and long-term cognitive disability. Various
pharmacologic agents including dopamine antagonists, acetylcholinesterase inhibitors,
melatonin, antipsychotics, alpha-2 agonists, and glutamate antagonists are used for treatment
of delirium in the ICU despite the lack of clear evidence of efficacy.Since there is no
evidence-based pharmacologic treatment of ICU delirium, current therapy is focused on
non-pharmacologic prevention techniques and pharmacologic agents are used once delirium is
established. Guanfacine, an alpha-2 agonist, has been identified as a potential medication
that may be of benefit in the treatment of delirium. The purpose of this study to investigate
the effects of guanfacine versus placebo on delirium in critically ill patients admitted to
the ICU and to determine whether guanfacine along with standard of care reduces the duration
of delirium, compared to standard of care alone.
Description:
Delirium is a common problem in critically ill patients with a reported prevalence in the ICU
ranging from 11% to 83%. Delirium has been associated with worse clinical outcomes including
increased days on mechanical ventilation, length of hospital stay, cost of care, self-removal
of important devices (endotracheal tubes, central venous catheters), use of physical
restraint, long-term cognitive impairment, readmission, and mortality. The etiology of
delirium is multifactorial, and risk factors include advanced age, substance abuse, metabolic
derangements, and sleep disturbances.
Unfortunately, evidence-based strategies for treatment of ICU delirium do not exist. Even
with the lack of strong evidence, both non-pharmacologic and pharmacologic therapies are used
as standard care in clinical practice. Non-pharmacologic strategies considered as standard
care include removal of causative factors, sleep maintenance, reorientation during the day,
early mobilization activities, timely removal of catheters and physical restraints, and use
of a scheduled pain management protocol. In combination with these non-pharmacologic
strategies, ICU patients are treated with pharmacologic agents to render the patient safe and
manageable and to promote sleep and normal circadian cycle. Despite lack of an FDA approved
drug for treating delirium and clear-cut efficacy of any drug, various pharmacologic agents
standardly used to treat delirium in the ICU include dopamine antagonists,
acetylcholinesterase inhibitors, melatonin, antipsychotics, alpha-2 agonists, and glutamate
antagonists. Antipsychotics, such as haloperidol, have been most commonly used. However, the
effectiveness of routinely using antipsychotics in managing delirium has been questioned
given the potential for adverse effects, medication interactions, and unproven benefit.
Haloperidol can cause serious side effects including Q-T prolongation, sedation, and
extrapyramidal symptoms. For this reason the use of haloperidol is less than ideal in the
elderly patient population. Recent studies have looked at the perioperative use of
dexmedetomidine in mechanically ventilated patients experiencing hyperactive delirium.
Dexmedetomidine is a centrally-acting alpha 2 adrenergic receptor (α2-AR) agonist that
generally quiets noradrenergic activity, producing sedative, analgesic and antihypertensive
effects. When compared to haloperidol, patients receiving dexmedetomidine have fewer
ventilation days, shorter ICU length of stay, less need for tracheostomy, and quicker
resolution of delirium symptoms. Unfortunately, dexmedetomidine is expensive and delivered as
an intravenous infusion.
Guanfacine, an alpha-2A antihypertensive agent with a safe pharmacodynamic profile, has also
been reported as treatment of ICU delirium. It has found use as an adjunct therapy in the
management of Attention Deficit Hyperactivity Disorder (ADHD). Compared to dexmedetomidine,
guanfacine is a pure alpha-2A agonist with higher selectivity for the dorsolateral PFC
structures leading to improved neuronal function by enhancing short-term memory. Noting a
similarity between the inattention and hyperactivity of emergence and ADHD itself, clinicians
have started using guanfacine to manage young, healthy males who were commonly at risk for
emergence delirium after anesthesia. In this context, the drug has gained popularity for its
off label use perioperatively in a wide variety of patients with anxiety issues, known or
predicted to have potential for combative or difficult emergence.
Compared to dexmedetomidine, guanfacine may have a more unique and specific mechanism of
behavior modification that could be beneficial as a treatment in delirium. Furthermore, oral
guanfacine is cheaper and easier to use, with the ability to continue it outside the ICU.
From a pharmacokinetic standpoint, guanfacine is absorbed with peak onset over 1-4 hour and
has a half-life of 16 hours. The long half-life allows once-daily dosing before sleep.
Maximal drug levels at night promote sleep, with some drug remaining during the day to
provide a lesser degree of sedation. Outpatient studies have detected a ceiling effect on the
antihypertensive effect of guanfacine, wherein doses of 1 mg, 2 mg, or 3 mg all have the same
effect on blood pressure. This implies that up-titrating the guanfacine dose beyond 1 mg
daily might increase sedative/hypnotic effects, without increasing hemodynamic instability.
Maldonado et al at Stanford has utilized guanfacine for delirious/withdrawing patients (0.5-3
mg total daily dose). A recent case report by Dr. Habib Srour and colleagues described
successful use of guanfacine (1 mg q12hr) to control refractory agitation in an ICU patient
with a history of opioid misuse.
The investigators propose to perform a pilot trial to evaluate protocol adherence, estimate
recruitment rates, and evaluate the safety and efficacy of guanfacine with standard care,
compared to standard care alone, on delirium in ICU patients. Before testing other drugs
compared with guanfacine, evidence needs to be collected to investigate if guanfacine is more
effective than placebo in treating delirium in ICU patients. The control intervention is
therefore chosen to be placebo along with standard or usual care. Given the literature and
our own experience with the drug for ICU delirium, the investigators plan to use a dose of 2
mg nightly for efficacy and minimization of side effects. The investigators will withhold
guanfacine or placebo if a patient does not have delirium for four consecutive assessments or
for safety reasons. The investigators will permanently discontinue guanfacine or placebo for
any life-threatening, serious adverse event that was related to the intervention. The trial
drug or placebo will be discontinued after the 14-day intervention period or at ICU
discharge, whichever occurs first.
