Rapid Reversal of CNS-Depressant Drug Effect Prior to Brain Death Determination

NCT ID: NCT03743805

Last Updated: 2024-10-31

Basic Information

• Recruitment Status: WITHDRAWN
• Clinical Phase: EARLY_PHASE1
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-01-01
• Study Completion Date: 2021-07-21

Brief Summary

Current standard of care prior to determination of brain death in subjects with suspected anoxic brain injury is to exclude complicating medical conditions that may confound clinical assessment (such as severe electrolyte, acid base, endocrine or circulatory disturbance), achieve normothermia and normal systolic blood pressure over 100 mmHg (with or without vasopressor use), exclude the presence of neuromuscular blocking agents (with the presence of a train of 4 twitches with maximal ulnar nerve stimulation) as well as to exclude the presence of CNS depressant drug effects. At the present time the latter is done by history, drug screen and allowing enough time for paralytic and sedative drugs to be metabolized and cleared from the body. Clearance is calculated by using 5 times the drug's half-life assuming normal hepatic and renal functions. Half-life can also be prolonged in subjects who have been treated with induced hypothermia. Literature search revealed articles with general guidelines and approaches to brain death, but none addressed pharmacological reversal of sedative drugs

Detailed Description

Question of proposed study is whether a subject's comatose state is secondary to delayed clearance of a previously administered CNS depressant. By using pharmacologic reversal agents of commonly used benzodiazepines and opioids, the investigators aim to identify participants that may likely improve after complete clearance of the drugs from their system.

Prospective trial with enrollment of 30 subjects in 2 intensive care units at Palmetto Health Richland from January 1st 2019 to June 30th 2020. Research procedures will be performed in the intensive care setting. If participants had undergone targeted temperature management (33-36 degrees Celsius for 24 hours via intravascular or surface control methods, with or without sedation or neuromuscular blockade, followed by rewarming actively or passively at 0.25-0.5 degrees per hour over 8-12 hours to 37 degrees) investigators will wait 24 hours after rewarming prior to testing. End point is to evaluate if pharmacological reversal agents would result in improved GCS scores or return of cerebral or brainstem functions in some comatose subjects, which will be considered a positive test result.

Conditions

Brain Death; Anoxic Brain Injury; Cardiac Arrest; Sedative Intoxication; Narcotic Intoxication

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: DIAGNOSTIC
• Blinding Strategy: NONE

Study Groups

Reversal drugs

Flumazenil and naloxone

Group Type: EXPERIMENTAL

Flumazenil

Intervention Type: DRUG

0.2 mg IV push, which may be repeated every 20 minutes for up to a total of 1 mg

Naloxone

Intervention Type: DRUG

0.4 mg IV push, which may be repeated every 2 minutes for up to a total of 2 mg

Interventions

Flumazenil

0.2 mg IV push, which may be repeated every 20 minutes for up to a total of 1 mg

Intervention Type: DRUG

Naloxone

0.4 mg IV push, which may be repeated every 2 minutes for up to a total of 2 mg

Intervention Type: DRUG

Other Intervention Names

Romazicon; Narcan; Evzio

Eligibility Criteria

Inclusion Criteria

• Adults with cardiac arrest who may have completed targeted temperature management (hypothermia protocol) and have had no neurological recovery after 24 hours of rewarming will be enrolled. Subjects will have a suspected diagnosis of anoxic brain injury secondary to cardiac arrest, and seizures ruled out with an EEG. All subjects are expected to be unable to consent and consent will be obtained from their legal authorized representative.

Exclusion Criteria

• Spontaneous recovery of neurological functions, presence of seizures on EEG, individuals who are not yet adults, pregnant women and prisoners.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Prisma Health-Midlands

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Sameh R Hanna, MD

Role: PRINCIPAL_INVESTIGATOR

Palmetto Health-University of South Carolina Medical Group

Locations

PRISMA Health Midlands

Columbia, South Carolina, United States

Countries

United States

References

Varelas PN, Lewis A. Modern Approach to Brain Death. Semin Neurol. 2016 Dec;36(6):625-630. doi: 10.1055/s-0036-1592317. Epub 2016 Dec 1.

Reference Type: BACKGROUND

PMID: 27907967 (View on PubMed)

Wijdicks EF. Brain death guidelines explained. Semin Neurol. 2015 Apr;35(2):105-15. doi: 10.1055/s-0035-1547532. Epub 2015 Apr 3.

Reference Type: BACKGROUND

PMID: 25839719 (View on PubMed)

Gardiner D, Shemie S, Manara A, Opdam H. International perspective on the diagnosis of death. Br J Anaesth. 2012 Jan;108 Suppl 1:i14-28. doi: 10.1093/bja/aer397.

Reference Type: BACKGROUND

PMID: 22194427 (View on PubMed)

Wijdicks EF. Brain death worldwide: accepted fact but no global consensus in diagnostic criteria. Neurology. 2002 Jan 8;58(1):20-5. doi: 10.1212/wnl.58.1.20.

Reference Type: BACKGROUND

PMID: 11781400 (View on PubMed)

Wijdicks EF. The diagnosis of brain death. N Engl J Med. 2001 Apr 19;344(16):1215-21. doi: 10.1056/NEJM200104193441606. No abstract available.

Reference Type: BACKGROUND

PMID: 11309637 (View on PubMed)

Wijdicks EF. Determining brain death in adults [RETIRED]. Neurology. 1995 May;45(5):1003-11. doi: 10.1212/wnl.45.5.1003. No abstract available.

Reference Type: BACKGROUND

PMID: 7746373 (View on PubMed)

Wahlster S, Wijdicks EF, Patel PV, Greer DM, Hemphill JC 3rd, Carone M, Mateen FJ. Brain death declaration: Practices and perceptions worldwide. Neurology. 2015 May 5;84(18):1870-9. doi: 10.1212/WNL.0000000000001540. Epub 2015 Apr 8.

Reference Type: BACKGROUND

PMID: 25854866 (View on PubMed)

Wijdicks EF, Varelas PN, Gronseth GS, Greer DM; American Academy of Neurology. Evidence-based guideline update: determining brain death in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2010 Jun 8;74(23):1911-8. doi: 10.1212/WNL.0b013e3181e242a8.

Reference Type: BACKGROUND

PMID: 20530327 (View on PubMed)

Greer DM, Varelas PN, Haque S, Wijdicks EF. Variability of brain death determination guidelines in leading US neurologic institutions. Neurology. 2008 Jan 22;70(4):284-9. doi: 10.1212/01.wnl.0000296278.59487.c2. Epub 2007 Dec 12.

Reference Type: BACKGROUND

PMID: 18077794 (View on PubMed)

Shappell CN, Frank JI, Husari K, Sanchez M, Goldenberg F, Ardelt A. Practice variability in brain death determination: a call to action. Neurology. 2013 Dec 3;81(23):2009-14. doi: 10.1212/01.wnl.0000436938.70528.4a. Epub 2013 Nov 6.

Reference Type: BACKGROUND

PMID: 24198290 (View on PubMed)

Other Identifiers

Pro00077995

Identifier Type: -

Identifier Source: org_study_id