Hypoactive Delirium
Conditions
Keywords
delirium, flumazenil, hypoactive delirium, benzodiazepine, benzodiazepine antagonist, critical care
Brief summary
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
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.
Interventions
DRUGFlumazenil
DRUGPlacebo
0.9% normal saline
Sponsors
University of California, Davis
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
1. contraindications to flumazenil including hypersensitivity 2. receipt of benzodiazepines for control of potentially life-threatening conditions (e.g., control of intracranial pressure or status epilepticus) 3. active seizure disorder or on current anti-convulsant therapy for history of seizure disorder. Seizures secondary to alcohol withdrawal will NOT be excluded. 4. history of traumatic brain injury complicated by seizures 5. acute episode (within prior 30 days) of severe traumatic brain injury 6. history of structural lesion (e.g. subarachnoid hemorrhage, cerebrovascular accident, intra-parenchymal hemorrhage) complicated by seizures 7. acute episode (within prior 14 days) of structural lesion (e.g. subarachnoid hemorrhage, cerebrovascular accident, intra-parenchymal hemorrhage) 8. brain tumor complicated by seizure 9. history of anoxic brain injury 10. third-degree burn with total body surface area (TBSA) burn greater than 20% 11. chronic benzodiazepine (clonazepam:lorazepam:diazepam approximately 4:8:40 mg per day) for 7 consecutive days with no taper 12. chronic delirium that is attributable to other causes 13. anticipated to transfer to lower level of care within 24 hours 14. admitted for polysubstance overdose as determined by initial drug toxicity screening 15. 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) 16. children, incarcerated individuals, and pregnant women 17. unable to provide consent and the legally authorized representative is unable to provide consent
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Delirium-free Days | up to 14 days after randomization | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Intensive Care Unit Length of Stay | duration of admission to the intensive care unit | length of time that the patient was admitted to an intensive care unit service during the hospital stay |
| Number of Mechanical Ventilator Free Days | up to 28 days after randomization | number of days within the first 28 days after enrollment that the patient was free from needing mechanical ventilation |
| Number of Participants With Delirium Resolution | up to 14 days after randomization | defined by the proportion of patients who were delirium free at 14 days after randomization |
| Average Duration of Study Infusion | up to 72 hours after the start of the infusion | average duration of time patient was randomized to each infusion up to 72 hours |
| Average Maximum Rate of Study Infusion | up to 72 hours after the start of the infusion | average maximum rate (ml/hr) during the 72 hours after study infusion |
| Occurrence of Agitation Requiring Use of Rescue Sedatives While on Study Infusion | up to 72 hours after the start of the infusion | number of times that a RASS score of + 2 to +4 occurred that did not resolve with decreasing study infusion |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Flumazenil Infusion 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.
Flumazenil | 11 |
| Placebo Infusion 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.
Placebo: 0.9% normal saline | 11 |
| Total | 22 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 1 | 0 |
| Overall Study | Physician Decision | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo Infusion | Total | Flumazenil Infusion |
|---|---|---|---|
| Age, Continuous | 59.4 years STANDARD_DEVIATION 7.6 | 58.9 years STANDARD_DEVIATION 7.2 | 58 years STANDARD_DEVIATION 7 |
| Days in Hospital Prior to Enrollment | 10.6 days STANDARD_DEVIATION 7.5 | 9.5 days STANDARD_DEVIATION 5.8 | 8.5 days STANDARD_DEVIATION 2.8 |
| Lorazepam Equivalents | 110.3 milligrams | 113.6 milligrams | 117 milligrams |
| Race and Ethnicity Not Collected | — | 0 Participants | — |
| Region of Enrollment United States | 11 Participants | 22 Participants | 11 Participants |
| Sex: Female, Male Female | 3 Participants | 7 Participants | 4 Participants |
| Sex: Female, Male Male | 8 Participants | 15 Participants | 7 Participants |
| Time Since Last Benzodiazepine | 55 hours STANDARD_DEVIATION 37.1 | 49 hours STANDARD_DEVIATION 31.5 | 43 hours STANDARD_DEVIATION 23 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 11 | 0 / 11 |
| other Total, other adverse events | 0 / 11 | 0 / 11 |
| serious Total, serious adverse events | 0 / 11 | 0 / 11 |
Outcome results
Primary
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.
Time frame: up to 14 days after randomization
Population: One patient randomized to the flumazenil and one randomized to the placebo never received the study infusion. The patient in the flumazenil group died from a massive hemorrhage within 1 hour of infusion initiation, and it was deemed nonattributable to study infusion. Twenty patients were included in the final analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Flumazenil Group | Number of Delirium-free Days | 12.7 days |
| Placebo Group | Number of Delirium-free Days | 9.2 days |
Secondary
Average Duration of Study Infusion
average duration of time patient was randomized to each infusion up to 72 hours
Time frame: up to 72 hours after the start of the infusion
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Flumazenil Group | Average Duration of Study Infusion | 54.8 hours | Standard Deviation 16.8 |
| Placebo Group | Average Duration of Study Infusion | 58.2 hours | Standard Deviation 23.5 |
Secondary
Average Maximum Rate of Study Infusion
average maximum rate (ml/hr) during the 72 hours after study infusion
Time frame: up to 72 hours after the start of the infusion
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Flumazenil Group | Average Maximum Rate of Study Infusion | 5 milliliters per hour | Standard Deviation 2 |
| Placebo Group | Average Maximum Rate of Study Infusion | 5.2 milliliters per hour | Standard Deviation 2 |
Secondary
Intensive Care Unit Length of Stay
length of time that the patient was admitted to an intensive care unit service during the hospital stay
Time frame: duration of admission to the intensive care unit
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Flumazenil Group | Intensive Care Unit Length of Stay | 7.8 days | Standard Deviation 4.8 |
| Placebo Group | Intensive Care Unit Length of Stay | 7 days | Standard Deviation 6 |
Secondary
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
Time frame: up to 28 days after randomization
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Flumazenil Group | Number of Mechanical Ventilator Free Days | 23.6 days | Standard Deviation 4.4 |
| Placebo Group | Number of Mechanical Ventilator Free Days | 24.9 days | Standard Deviation 5 |
Secondary
Number of Participants With Delirium Resolution
defined by the proportion of patients who were delirium free at 14 days after randomization
Time frame: up to 14 days after randomization
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Flumazenil Group | Number of Participants With Delirium Resolution | 9 Participants |
| Placebo Group | Number of Participants With Delirium Resolution | 7 Participants |
Secondary
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
Time frame: up to 72 hours after the start of the infusion
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Flumazenil Group | Occurrence of Agitation Requiring Use of Rescue Sedatives While on Study Infusion | 0 Participants |
| Placebo Group | Occurrence of Agitation Requiring Use of Rescue Sedatives While on Study Infusion | 0 Participants |