The Effect of Guanfacine on Delirium in Critically Ill Patients

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.

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.

Placebo, lactulose monohydrate, encapsulated, once nightly at 2100, for up to 14 day study duration or otherwise indicated by study protocol.

Guanfacine immediate-release, 2mg dose, over-encapsulated tablet, once nightly at 2100, for up to 14 day study duration or otherwise indicated by study protocol.

The primary outcome will be the proportion of delirium-free assessments as measured by the Confusion Assessment Method- Intensive Care Unit (CAM-ICU). CAM-ICU measures a patient's fluctuations in mental status, inattention, disorganized thinking, and consciousness. The CAM-ICU will be used twice daily with all patients for up to 14 days. Patients will be diagnosed with delirium when they have at least one positive CAM-ICU. The CAM-ICU is based on the assessment of errors made during the assessment. A score greater than 3 errors indicates delirium. The CAM-ICU score is only reported as a positive or negative value.

The Richmond Agitation and Sedation Score (RASS) is a method to assess a patient's level of sedation in hospitalized patients. The score range is incremental and from -5 to +4. The minimum value is -5:unarousable, middle range value is 0:alert and calm, and maximum value is +4:combative. Based on the clinician's judgment and RASS, the participants will be categorized as having either hyperactive delirium defined (a RASS score of +1 to +4 at the time of positive Confusion Assessment Method- Intensive Care Unit (CAM-ICU)), or hypoactive delirium (a RASS score -3 to 0 with a positive CAM-ICU score).

Confusion Assessment Method- Intensive Care Unit (CAM-ICU) score only indicates a positive or negative result but does not quantify severity of delirium. If the CAM-ICU score is positive, the secondary outcome of delirium severity will be assessed using the Confusion Assessment Method for the Intensive Care Unit-7 (CAM-ICU-7). CAM-ICU-7 scores range from 0 to 7 errors, with 0-2 errors indicating no delirium, 3-5 errors mild to moderate delirium, and 6-7 errors as severe delirium. Indirect markers of delirium severity will also be recorded daily until ICU discharge or day 14 after enrollment. These markers are: 1) need for anti- psychotics or sedation (total daily doses will be calculated); 2) need for physical restraints; 3) patient removal of intravenous lines, drains or catheters.

Inclusion criteria Patients admitted to the UAB hospital Surgical Intensive Care Unit (SICU) 18 years of age or older Expected total ICU length of stay of 72 hours or more per treating physician Diagnosed with delirium based on CAM-ICU assessment (see attached CAM-ICU assessment form) Exclusion Criteria Patients younger than 18 years old Expected discharge from ICU within 72 hours of admission Expected or inevitable death with 48 hours of enrollment Pregnancy or breast feeding Non-English speaking Patients unable to be assessed by CAM-ICU due to neurologic illness Altered consciousness unable to participate in CAM-ICU assessment Patients with previous diagnosis of chronic, acute, subacute neurologic disease, or neurodegenerative disease Mental illness and/or psychosis Acute alcohol withdrawal No enteral route available for administration Severe hypotension (defined as requiring a vasopressor for longer than 24 hours) or bradycardia (Hr<50 bpm) at the time of screening Hepatic encephalopathy Blind or Hearing impaired Taking Guanfacine, for any reason Receiving Clonidine at time of screening On CYP3A inhibitor such as azole antifungals or clarithromycin On CYP3A inducers such as phenytoin or rifampin Severe xerostomia Enrolled in another interventional research trial