Flumazenil for Hypoactive Delirium Secondary to Benzodiazepine Exposure

Study Overview
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Brief Summary
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Delirium within the intensive care unit (ICU) is associated with poor outcomes such as increased mortality, ICU and hospital length of stay (LOS), and time on mechanical ventilation. Benzodiazepine (BZD) exposure is an independent risk factor for development of delirium. Reversal of hypoactive delirium represents a potential opportunity for reducing duration of delirium and subsequent complications. This is a single-center randomized, double-blind, placebo-controlled study of critically ill adult patients with benzodiazepine-associated hypoactive delirium. The hypothesis is that flumazenil continuous infusion may reverse hypoactive delirium associated with BZD exposure and thereby reduce duration of delirium and ICU LOS.

Detailed Description
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Benzodiazepines are commonly used for discomfort, anxiety, agitation, and alcohol withdrawal syndrome (AWS) in the ICU. End organ dysfunction and extended exposure can increase the risk of complications associated with BZDs, which include increased ICU LOS, time on mechanical ventilation, and mortality. Flumazenil as a 1, 4-imidazobenzodiazepine is a competitive antagonist for the benzodiazepine binding site with weak intrinsic or partial agonistic activity on the GABA receptor. Multiple studies have confirmed the safety and effectiveness of flumazenil for the reversal of sedation. Pilot studies have demonstrated safe reversal of over-sedation and statistically significant improvements in patient cooperation and time to extubation. The current standard for suspected BZD-associated hypoactive delirium is cessation of benzodiazepine administration and supportive care. The role of continuous infusion flumazenil for rapid and sustained reversal of hypoactive delirium in the ICU has not been evaluated prospectively and therefore remains poorly defined.

Official Title
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Effect of Flumazenil on Hypoactive Delirium in the ICU: A Double-Blind, Placebo-Controlled Pilot Study

Conditions
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Hypoactive Delirium

Intervention / Treatment
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* Drug: Flumazenil
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: critically ill adults RASS score of -3 to 0 after receiving benzodiazepine therapy CAM-ICU positive no benzodiazepine therapy within the previous 12 hours Exclusion Criteria: contraindications to flumazenil including hypersensitivity receipt of benzodiazepines for control of potentially life-threatening conditions (e.g., control of intracranial pressure or status epilepticus) active seizure disorder or on current anti-convulsant therapy for history of seizure disorder. Seizures secondary to alcohol withdrawal will NOT be excluded. history of traumatic brain injury complicated by seizures acute episode (within prior 30 days) of severe traumatic brain injury history of structural lesion (e.g. subarachnoid hemorrhage, cerebrovascular accident, intra-parenchymal hemorrhage) complicated by seizures acute episode (within prior 14 days) of structural lesion (e.g. subarachnoid hemorrhage, cerebrovascular accident, intra-parenchymal hemorrhage) brain tumor complicated by seizure history of anoxic brain injury third-degree burn with total body surface area (TBSA) burn greater than 20% chronic benzodiazepine (clonazepam:lorazepam:diazepam approximately 4:8:40 mg per day) for 7 consecutive days with no taper chronic delirium that is attributable to other causes anticipated to transfer to lower level of care within 24 hours admitted for polysubstance overdose as determined by initial drug toxicity screening recent exposure (prior 7 days) to pro-convulsant medications (identified via medication list, medication reconciliation performed by PI/pharmacy medication reconciliation team, or urine drug screening) children, incarcerated individuals, and pregnant women unable to provide consent and the legally authorized representative is unable to provide consent

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Flumazenil Infusion<br>The flumazenil continuous infusion is started at an initial dose of 0.1 mg/hr., and can be titrated up to a maximum of 0.3 mg/hr. Dose titrations may occur every 60 minutes to maintain RASS scores of 0 to +1. The maximum rate is 0.3 mg/hr. | Drug: Flumazenil<br> <br> * Other names: Romazicon;|
| Placebo Comparator: Placebo Infusion<br>The placebo continuous infusion is started at an initial dose of 0.1 mg/hr (2 ml/hr)., and can be titrated up to a maximum of 0.3 mg/hr. Dose titrations may occur every 60 minutes to maintain RASS scores of 0 to +1. The maximum rate is 0.3 mg/hr. | Drug: Placebo<br>* 0.9% normal saline<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Delirium-free Days | Defined by the number of days in the 14-day period after randomization that the patient was alive and not delirious (i.e. CAM-ICU negative). Zero delirium-free days will be observed for patients that die within the 14-day period. | up to 14 days after randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Delirium Resolution | defined by the proportion of patients who were delirium free at 14 days after randomization | up to 14 days after randomization | 
| Intensive Care Unit Length of Stay | length of time that the patient was admitted to an intensive care unit service during the hospital stay | duration of admission to the intensive care unit | 
| Number of Mechanical Ventilator Free Days | number of days within the first 28 days after enrollment that the patient was free from needing mechanical ventilation | up to 28 days after randomization | 
| Occurrence of Agitation Requiring Use of Rescue Sedatives While on Study Infusion | number of times that a RASS score of + 2 to +4 occurred that did not resolve with decreasing study infusion | up to 72 hours after the start of the infusion | 
| Average Duration of Study Infusion | average duration of time patient was randomized to each infusion up to 72 hours | up to 72 hours after the start of the infusion | 
| Average Maximum Rate of Study Infusion | average maximum rate (ml/hr) during the 72 hours after study infusion | up to 72 hours after the start of the infusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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delirium, flumazenil, hypoactive delirium, benzodiazepine, benzodiazepine antagonist, critical care