- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02899156
Flumazenil for Hypoactive Delirium Secondary to Benzodiazepine Exposure (FLYP)
Effect of Flumazenil on Hypoactive Delirium in the ICU: A Double-Blind, Placebo-Controlled Pilot Study
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.
Study Overview
Status
Conditions
Intervention / Treatment
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.
Study Type
Enrollment (Actual)
Phase
- Phase 4
Contacts and Locations
Study Locations
-
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California
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Sacramento, California, United States, 95817
- UC Davis Medical Center
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-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Quadruple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Active Comparator: 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.
|
Other Names:
|
Placebo Comparator: 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.
|
0.9% normal saline
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Number of Delirium-free Days
Time Frame: 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.
|
up to 14 days after randomization
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Number of Participants With Delirium Resolution
Time Frame: up to 14 days after randomization
|
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
Time Frame: 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
|
duration of admission to the intensive care unit
|
Number of Mechanical Ventilator Free Days
Time Frame: 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
|
up to 28 days after randomization
|
Occurrence of Agitation Requiring Use of Rescue Sedatives While on Study Infusion
Time Frame: 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
|
up to 72 hours after the start of the infusion
|
Average Duration of Study Infusion
Time Frame: up to 72 hours after the start of the 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
Time Frame: up to 72 hours after the start of the infusion
|
average maximum rate (ml/hr) during the 72 hours after study infusion
|
up to 72 hours after the start of the infusion
|
Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Kendra J Schomer, PharmD, University of California, Davis
- Principal Investigator: Jeremiah J Duby, PharmD, BCPS, University of California, Davis
Publications and helpful links
General Publications
- Ely EW, Shintani A, Truman B, Speroff T, Gordon SM, Harrell FE Jr, Inouye SK, Bernard GR, Dittus RS. Delirium as a predictor of mortality in mechanically ventilated patients in the intensive care unit. JAMA. 2004 Apr 14;291(14):1753-62. doi: 10.1001/jama.291.14.1753.
- Devlin JW, Roberts RJ, Fong JJ, Skrobik Y, Riker RR, Hill NS, Robbins T, Garpestad E. Efficacy and safety of quetiapine in critically ill patients with delirium: a prospective, multicenter, randomized, double-blind, placebo-controlled pilot study. Crit Care Med. 2010 Feb;38(2):419-27. doi: 10.1097/CCM.0b013e3181b9e302.
- Ely EW, Truman B, Shintani A, Thomason JW, Wheeler AP, Gordon S, Francis J, Speroff T, Gautam S, Margolin R, Sessler CN, Dittus RS, Bernard GR. Monitoring sedation status over time in ICU patients: reliability and validity of the Richmond Agitation-Sedation Scale (RASS). JAMA. 2003 Jun 11;289(22):2983-91. doi: 10.1001/jama.289.22.2983.
- Ely EW, Inouye SK, Bernard GR, Gordon S, Francis J, May L, Truman B, Speroff T, Gautam S, Margolin R, Hart RP, Dittus R. Delirium in mechanically ventilated patients: validity and reliability of the confusion assessment method for the intensive care unit (CAM-ICU). JAMA. 2001 Dec 5;286(21):2703-10. doi: 10.1001/jama.286.21.2703.
- Ely EW, Gautam S, Margolin R, Francis J, May L, Speroff T, Truman B, Dittus R, Bernard R, Inouye SK. The impact of delirium in the intensive care unit on hospital length of stay. Intensive Care Med. 2001 Dec;27(12):1892-900. doi: 10.1007/s00134-001-1132-2. Epub 2001 Nov 8.
- Zaal IJ, Devlin JW, Hazelbag M, Klein Klouwenberg PM, van der Kooi AW, Ong DS, Cremer OL, Groenwold RH, Slooter AJ. Benzodiazepine-associated delirium in critically ill adults. Intensive Care Med. 2015 Dec;41(12):2130-7. doi: 10.1007/s00134-015-4063-z. Epub 2015 Sep 24.
- Salluh JI, Wang H, Schneider EB, Nagaraja N, Yenokyan G, Damluji A, Serafim RB, Stevens RD. Outcome of delirium in critically ill patients: systematic review and meta-analysis. BMJ. 2015 Jun 3;350:h2538. doi: 10.1136/bmj.h2538.
- Sessler CN, Gosnell MS, Grap MJ, Brophy GM, O'Neal PV, Keane KA, Tesoro EP, Elswick RK. The Richmond Agitation-Sedation Scale: validity and reliability in adult intensive care unit patients. Am J Respir Crit Care Med. 2002 Nov 15;166(10):1338-44. doi: 10.1164/rccm.2107138.
- Pandharipande P, Shintani A, Peterson J, Pun BT, Wilkinson GR, Dittus RS, Bernard GR, Ely EW. Lorazepam is an independent risk factor for transitioning to delirium in intensive care unit patients. Anesthesiology. 2006 Jan;104(1):21-6. doi: 10.1097/00000542-200601000-00005.
- Girard TD, Exline MC, Carson SS, Hough CL, Rock P, Gong MN, Douglas IS, Malhotra A, Owens RL, Feinstein DJ, Khan B, Pisani MA, Hyzy RC, Schmidt GA, Schweickert WD, Hite RD, Bowton DL, Masica AL, Thompson JL, Chandrasekhar R, Pun BT, Strength C, Boehm LM, Jackson JC, Pandharipande PP, Brummel NE, Hughes CG, Patel MB, Stollings JL, Bernard GR, Dittus RS, Ely EW; MIND-USA Investigators. Haloperidol and Ziprasidone for Treatment of Delirium in Critical Illness. N Engl J Med. 2018 Dec 27;379(26):2506-2516. doi: 10.1056/NEJMoa1808217. Epub 2018 Oct 22.
- Shehabi Y, Bellomo R, Reade MC, Bailey M, Bass F, Howe B, McArthur C, Seppelt IM, Webb S, Weisbrodt L; Sedation Practice in Intensive Care Evaluation (SPICE) Study Investigators; ANZICS Clinical Trials Group. Early intensive care sedation predicts long-term mortality in ventilated critically ill patients. Am J Respir Crit Care Med. 2012 Oct 15;186(8):724-31. doi: 10.1164/rccm.201203-0522OC. Epub 2012 Aug 2.
- Patel SB, Poston JT, Pohlman A, Hall JB, Kress JP. Rapidly reversible, sedation-related delirium versus persistent delirium in the intensive care unit. Am J Respir Crit Care Med. 2014 Mar 15;189(6):658-65. doi: 10.1164/rccm.201310-1815OC.
- Brogden RN, Goa KL. Flumazenil. A reappraisal of its pharmacological properties and therapeutic efficacy as a benzodiazepine antagonist. Drugs. 1991 Dec;42(6):1061-89. doi: 10.2165/00003495-199142060-00010. Erratum In: Drugs 1992 Apr;43(4):442.
- Breheny FX. Reversal of midazolam sedation with flumazenil. Crit Care Med. 1992 Jun;20(6):736-9. doi: 10.1097/00003246-199206000-00006.
- Pepperman ML. Double-blind study of the reversal of midazolam-induced sedation in the intensive care unit with flumazenil (Ro 15-1788): effect on weaning from ventilation. Anaesth Intensive Care. 1990 Feb;18(1):38-44. doi: 10.1177/0310057X9001800107.
- Penninga EI, Graudal N, Ladekarl MB, Jurgens G. Adverse Events Associated with Flumazenil Treatment for the Management of Suspected Benzodiazepine Intoxication--A Systematic Review with Meta-Analyses of Randomised Trials. Basic Clin Pharmacol Toxicol. 2016 Jan;118(1):37-44. doi: 10.1111/bcpt.12434. Epub 2015 Jul 28.
- Kreshak AA, Cantrell FL, Clark RF, Tomaszewski CA. A poison center's ten-year experience with flumazenil administration to acutely poisoned adults. J Emerg Med. 2012 Oct;43(4):677-82. doi: 10.1016/j.jemermed.2012.01.059. Epub 2012 Jul 4.
- Moore PW, Donovan JW, Burkhart KK, Waskin JA, Hieger MA, Adkins AR, Wert Y, Haggerty DA, Rasimas JJ. Safety and efficacy of flumazenil for reversal of iatrogenic benzodiazepine-associated delirium toxicity during treatment of alcohol withdrawal, a retrospective review at one center. J Med Toxicol. 2014 Jun;10(2):126-32. doi: 10.1007/s13181-014-0391-6.
- Bodenham A, Park GR. Reversal of prolonged sedation using flumazenil in critically ill patients. Anaesthesia. 1989 Jul;44(7):603-5. doi: 10.1111/j.1365-2044.1989.tb11455.x.
- Spivey WH, Roberts JR, Derlet RW. A clinical trial of escalating doses of flumazenil for reversal of suspected benzodiazepine overdose in the emergency department. Ann Emerg Med. 1993 Dec;22(12):1813-21. doi: 10.1016/s0196-0644(05)80407-x.
- Krewulak KD, Stelfox HT, Leigh JP, Ely EW, Fiest KM. Incidence and Prevalence of Delirium Subtypes in an Adult ICU: A Systematic Review and Meta-Analysis. Crit Care Med. 2018 Dec;46(12):2029-2035. doi: 10.1097/CCM.0000000000003402.
- Avelino-Silva TJ, Campora F, Curiati JAE, Jacob-Filho W. Prognostic effects of delirium motor subtypes in hospitalized older adults: A prospective cohort study. PLoS One. 2018 Jan 30;13(1):e0191092. doi: 10.1371/journal.pone.0191092. eCollection 2018.
- Ely EW. The ABCDEF Bundle: Science and Philosophy of How ICU Liberation Serves Patients and Families. Crit Care Med. 2017 Feb;45(2):321-330. doi: 10.1097/CCM.0000000000002175.
- Bassett R, Adams KM, Danesh V, Groat PM, Haugen A, Kiewel A, Small C, Van-Leuven M, Venus S, Ely EW. Rethinking critical care: decreasing sedation, increasing delirium monitoring, and increasing patient mobility. Jt Comm J Qual Patient Saf. 2015 Feb;41(2):62-74. doi: 10.1016/s1553-7250(15)41010-4.
- Balas MC, Vasilevskis EE, Olsen KM, Schmid KK, Shostrom V, Cohen MZ, Peitz G, Gannon DE, Sisson J, Sullivan J, Stothert JC, Lazure J, Nuss SL, Jawa RS, Freihaut F, Ely EW, Burke WJ. Effectiveness and safety of the awakening and breathing coordination, delirium monitoring/management, and early exercise/mobility bundle. Crit Care Med. 2014 May;42(5):1024-36. doi: 10.1097/CCM.0000000000000129.
- Barnes-Daly MA, Phillips G, Ely EW. Improving Hospital Survival and Reducing Brain Dysfunction at Seven California Community Hospitals: Implementing PAD Guidelines Via the ABCDEF Bundle in 6,064 Patients. Crit Care Med. 2017 Feb;45(2):171-178. doi: 10.1097/CCM.0000000000002149.
- Trogrlic Z, van der Jagt M, Lingsma H, Gommers D, Ponssen HH, Schoonderbeek JFJ, Schreiner F, Verbrugge SJ, Duran S, Bakker J, Ista E. Improved Guideline Adherence and Reduced Brain Dysfunction After a Multicenter Multifaceted Implementation of ICU Delirium Guidelines in 3,930 Patients. Crit Care Med. 2019 Mar;47(3):419-427. doi: 10.1097/CCM.0000000000003596.
- Hojer J, Baehrendtz S, Magnusson A, Gustafsson LL. A placebo-controlled trial of flumazenil given by continuous infusion in severe benzodiazepine overdosage. Acta Anaesthesiol Scand. 1991 Oct;35(7):584-90. doi: 10.1111/j.1399-6576.1991.tb03353.x.
- Weinbroum A, Rudick V, Sorkine P, Nevo Y, Halpern P, Geller E, Niv D. Use of flumazenil in the treatment of drug overdose: a double-blind and open clinical study in 110 patients. Crit Care Med. 1996 Feb;24(2):199-206. doi: 10.1097/00003246-199602000-00004.
- Chern CH, Chern TL, Wang LM, Hu SC, Deng JF, Lee CH. Continuous flumazenil infusion in preventing complications arising from severe benzodiazepine intoxication. Am J Emerg Med. 1998 May;16(3):238-41. doi: 10.1016/s0735-6757(98)90091-2.
- Flumazenil [package insert]. San Francisco, CA, Genentech Inc, 2010
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Mental Disorders
- Nervous System Diseases
- Neurologic Manifestations
- Confusion
- Neurobehavioral Manifestations
- Neurocognitive Disorders
- Dyskinesias
- Delirium
- Hypokinesia
- Physiological Effects of Drugs
- Neurotransmitter Agents
- Molecular Mechanisms of Pharmacological Action
- Protective Agents
- GABA Modulators
- GABA Agents
- Antidotes
- Flumazenil
Other Study ID Numbers
- 837421
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
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