Arousal Pathways and Emergence From Sedation

NCT02253758 | Unknown

• 1 other identifier: TASMC-14-IM-0383-CTIL
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 2

Brief Summary

Emergence from sedation involves an increase in both the level of consciousness and arousal. Some insight to the neural core of consciousness was gained in the recent past. Our research objective is to characterize for the first time the spatiotemporal mobilization of the ascending reticular activating system during emergence from sedation; stated otherwise - to capture the neural core of arousal. To achieve this objective we plan to utilize the advanced imaging modality of EEG-fMRI. In short, volunteers will be placed in the MRI. Following baseline recordings they will be sedated with a continuous drip of propofol, titrated to deep sedation. Once in that sedation level, propofol administration will cease until emerging to an awake-calm/light sedation. Continuous EEG recordings and fMRI scans will be taken, both task specific (auditory oddball) and resting-fMRI. Analyses will focus (but will not be restricted to) on constituents of the ascending reticular activating system. The expected advances of this proposal are:

1. 1.Emergence from sedation (and anesthesia) is one of the critical stages and least elucidated area in the practice of anesthesia. Delayed awakening of varying degree is not uncommon after anesthesia and may have a number of different causes, individual or combined, which may be both drug or non-drug related, thus causing a diagnostic dilemma. Eventually - better insight into this subject will lead to better clinical practice and better understanding why patients emerge in such a diverse and sometimes unexpected manner.
2. 2.Knowledge of the internal structure underlying arousal from anesthesia will help develop / upgrade brain monitors that could tell the anesthesiologist the patient's level of consciousness and prediction of arousal.
3. 3.A detailed reproducible mapping of the arousal process may serve as the core of a drug screening platform for drugs that may expedite patient arousal.
4. 4.Elucidation of the arousal paradigm from sedation will enhance our knowledge of physiological sleep.

Conditions

Anesthesia

Keywords

Magnetic Resonance Imaging; Electroencephalography; Conscious Sedation; Deep Sedation; Arousal; Consciousness

Outcome Measures

Primary Outcomes (1)

• Characterization of brain network connectivity underlying arousal from anesthesia.

  Network connectivity of brain loci involved in arousal pathways will be evaluated for each patient at these time points: baseline, deep sedation and return to conscious state. The identification of these time points will be decided according to the Ramsay clinical scale for sedation depth. A score of 2 for baseline, 5 for deep sedation, and 2-3 for regaining consciousness. An external validation for these time points will derive from the oddball auditory test, in which the brain reaction to a sound in a different pitch is recorded. In the sedated state this reaction is perturbed.

  Data collection time frame will not exceed one hour post propofol infusion cessation.

Secondary Outcomes (1)

• Characterization of the internal structure and temporal hierarchy underlying arousal from anesthesia.

  Data collection time frame will not exceed one hour post propofol infusion cessation.

Study Arms (1)

Sedation

EXPERIMENTAL

Volunteers will be sedated to Ramsay score 4-5 with propofol, and data will be recorded during arousal

Drug: Propofol

Interventions

Propofol DRUG

Propofol will be injected as a continuous infusion by TCI intravenously

Also known as: Propofol Liporum 1%

Sedation

Eligibility Criteria

• Age: 20 Years - 40 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Healthy males (ASA scale 1-2), volunteers only

You may not qualify if:

• Use of chronic medications or illicit drugs
• Metallic implants
• Previous brain injury
• General anaesthesia up to a week earlier to research examination
• Known drug sensitivity to Propofol, soybean oil or peanuts

Sponsors & Collaborators

• Tel-Aviv Sourasky Medical Center: lead

Study Sites (2)

Division of Anesthesia, Pain and Critical Care, Tel-Aviv Sourasky Medical Center

Tel Aviv, Israel

Location

Whol Institute for Advanced Imaging, Tel Aviv Sourasky Medical Center

Tel Aviv, Israel

Location

Related Publications (26)

• Brown EN, Lydic R, Schiff ND. General anesthesia, sleep, and coma. N Engl J Med. 2010 Dec 30;363(27):2638-50. doi: 10.1056/NEJMra0808281. No abstract available.

  PMID: 21190458 BACKGROUND

• Lee U, Mashour GA, Kim S, Noh GJ, Choi BM. Propofol induction reduces the capacity for neural information integration: implications for the mechanism of consciousness and general anesthesia. Conscious Cogn. 2009 Mar;18(1):56-64. doi: 10.1016/j.concog.2008.10.005. Epub 2008 Dec 2.

  PMID: 19054696 BACKGROUND

• Breshears JD, Roland JL, Sharma M, Gaona CM, Freudenburg ZV, Tempelhoff R, Avidan MS, Leuthardt EC. Stable and dynamic cortical electrophysiology of induction and emergence with propofol anesthesia. Proc Natl Acad Sci U S A. 2010 Dec 7;107(49):21170-5. doi: 10.1073/pnas.1011949107. Epub 2010 Nov 15.

  PMID: 21078987 BACKGROUND

• Hwang E, Kim S, Han K, Choi JH. Characterization of phase transition in the thalamocortical system during anesthesia-induced loss of consciousness. PLoS One. 2012;7(12):e50580. doi: 10.1371/journal.pone.0050580. Epub 2012 Dec 7.

  PMID: 23236379 BACKGROUND

• Alkire MT, Hudetz AG, Tononi G. Consciousness and anesthesia. Science. 2008 Nov 7;322(5903):876-80. doi: 10.1126/science.1149213.

  PMID: 18988836 BACKGROUND

• Tononi G. An information integration theory of consciousness. BMC Neurosci. 2004 Nov 2;5:42. doi: 10.1186/1471-2202-5-42.

  PMID: 15522121 BACKGROUND

• Tononi G, Koch C. The neural correlates of consciousness: an update. Ann N Y Acad Sci. 2008 Mar;1124:239-61. doi: 10.1196/annals.1440.004.

  PMID: 18400934 BACKGROUND

• Franks NP. General anaesthesia: from molecular targets to neuronal pathways of sleep and arousal. Nat Rev Neurosci. 2008 May;9(5):370-86. doi: 10.1038/nrn2372.

  PMID: 18425091 BACKGROUND

• Brown EN, Purdon PL, Van Dort CJ. General anesthesia and altered states of arousal: a systems neuroscience analysis. Annu Rev Neurosci. 2011;34:601-28. doi: 10.1146/annurev-neuro-060909-153200.

  PMID: 21513454 BACKGROUND

• Saper CB, Chou TC, Scammell TE. The sleep switch: hypothalamic control of sleep and wakefulness. Trends Neurosci. 2001 Dec;24(12):726-31. doi: 10.1016/s0166-2236(00)02002-6.

  PMID: 11718878 BACKGROUND

• Solt K. General anesthesia: activating a sleep switch? Curr Biol. 2012 Nov 6;22(21):R918-9. doi: 10.1016/j.cub.2012.09.033.

  PMID: 23137688 BACKGROUND

• Baumann CR, Bassetti CL. Hypocretins (orexins) and sleep-wake disorders. Lancet Neurol. 2005 Oct;4(10):673-82. doi: 10.1016/S1474-4422(05)70196-4.

  PMID: 16168936 BACKGROUND

• Kelz MB, Sun Y, Chen J, Cheng Meng Q, Moore JT, Veasey SC, Dixon S, Thornton M, Funato H, Yanagisawa M. An essential role for orexins in emergence from general anesthesia. Proc Natl Acad Sci U S A. 2008 Jan 29;105(4):1309-14. doi: 10.1073/pnas.0707146105. Epub 2008 Jan 14.

  PMID: 18195361 BACKGROUND

• Langsjo JW, Alkire MT, Kaskinoro K, Hayama H, Maksimow A, Kaisti KK, Aalto S, Aantaa R, Jaaskelainen SK, Revonsuo A, Scheinin H. Returning from oblivion: imaging the neural core of consciousness. J Neurosci. 2012 Apr 4;32(14):4935-43. doi: 10.1523/JNEUROSCI.4962-11.2012.

  PMID: 22492049 BACKGROUND

• Mukamel EA, Pirondini E, Babadi B, Wong KF, Pierce ET, Harrell PG, Walsh JL, Salazar-Gomez AF, Cash SS, Eskandar EN, Weiner VS, Brown EN, Purdon PL. A transition in brain state during propofol-induced unconsciousness. J Neurosci. 2014 Jan 15;34(3):839-45. doi: 10.1523/JNEUROSCI.5813-12.2014.

  PMID: 24431442 BACKGROUND

• Purdon PL, Pierce ET, Mukamel EA, Prerau MJ, Walsh JL, Wong KF, Salazar-Gomez AF, Harrell PG, Sampson AL, Cimenser A, Ching S, Kopell NJ, Tavares-Stoeckel C, Habeeb K, Merhar R, Brown EN. Electroencephalogram signatures of loss and recovery of consciousness from propofol. Proc Natl Acad Sci U S A. 2013 Mar 19;110(12):E1142-51. doi: 10.1073/pnas.1221180110. Epub 2013 Mar 4.

  PMID: 23487781 BACKGROUND

• Moruzzi G, Magoun HW. Brain stem reticular formation and activation of the EEG. Electroencephalogr Clin Neurophysiol. 1949 Nov;1(4):455-73.

  PMID: 18421835 BACKGROUND

• Schmidt C, Collette F, Leclercq Y, Sterpenich V, Vandewalle G, Berthomier P, Berthomier C, Phillips C, Tinguely G, Darsaud A, Gais S, Schabus M, Desseilles M, Dang-Vu TT, Salmon E, Balteau E, Degueldre C, Luxen A, Maquet P, Cajochen C, Peigneux P. Homeostatic sleep pressure and responses to sustained attention in the suprachiasmatic area. Science. 2009 Apr 24;324(5926):516-9. doi: 10.1126/science.1167337.

  PMID: 19390047 BACKGROUND

• Garcia-Rill E, Kezunovic N, Hyde J, Simon C, Beck P, Urbano FJ. Coherence and frequency in the reticular activating system (RAS). Sleep Med Rev. 2013 Jun;17(3):227-38. doi: 10.1016/j.smrv.2012.06.002. Epub 2012 Oct 6.

  PMID: 23044219 BACKGROUND

• Schroter MS, Spoormaker VI, Schorer A, Wohlschlager A, Czisch M, Kochs EF, Zimmer C, Hemmer B, Schneider G, Jordan D, Ilg R. Spatiotemporal reconfiguration of large-scale brain functional networks during propofol-induced loss of consciousness. J Neurosci. 2012 Sep 12;32(37):12832-40. doi: 10.1523/JNEUROSCI.6046-11.2012.

  PMID: 22973006 BACKGROUND

• Marsh B, White M, Morton N, Kenny GN. Pharmacokinetic model driven infusion of propofol in children. Br J Anaesth. 1991 Jul;67(1):41-8. doi: 10.1093/bja/67.1.41.

  PMID: 1859758 BACKGROUND

• Ramsay MA, Savege TM, Simpson BR, Goodwin R. Controlled sedation with alphaxalone-alphadolone. Br Med J. 1974 Jun 22;2(5920):656-9. doi: 10.1136/bmj.2.5920.656.

  PMID: 4835444 BACKGROUND

• Meir-Hasson Y, Kinreich S, Podlipsky I, Hendler T, Intrator N. An EEG Finger-Print of fMRI deep regional activation. Neuroimage. 2014 Nov 15;102 Pt 1:128-41. doi: 10.1016/j.neuroimage.2013.11.004. Epub 2013 Nov 15.

  PMID: 24246494 BACKGROUND

• Abraham E, Hendler T, Shapira-Lichter I, Kanat-Maymon Y, Zagoory-Sharon O, Feldman R. Father's brain is sensitive to childcare experiences. Proc Natl Acad Sci U S A. 2014 Jul 8;111(27):9792-7. doi: 10.1073/pnas.1402569111. Epub 2014 May 27.

  PMID: 24912146 BACKGROUND

• Weinstein M, Ben-Sira L, Levy Y, Zachor DA, Ben Itzhak E, Artzi M, Tarrasch R, Eksteine PM, Hendler T, Ben Bashat D. Abnormal white matter integrity in young children with autism. Hum Brain Mapp. 2011 Apr;32(4):534-43. doi: 10.1002/hbm.21042.

  PMID: 21391246 BACKGROUND

• Ben Bashat D, Kronfeld-Duenias V, Zachor DA, Ekstein PM, Hendler T, Tarrasch R, Even A, Levy Y, Ben Sira L. Accelerated maturation of white matter in young children with autism: a high b value DWI study. Neuroimage. 2007 Aug 1;37(1):40-7. doi: 10.1016/j.neuroimage.2007.04.060. Epub 2007 May 18.

  PMID: 17566764 BACKGROUND

MeSH Terms

Interventions

Propofol

Intervention Hierarchy (Ancestors)

Phenols; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals

Study Officials

• Idit Matot, Prof. M.D.

  Tel-Aviv Sourasky Medical Center

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Idit Matot, Prof. M.D.

CONTACT

97236974758; iditm@tlvmc.gov.il

Miri Davidovich

CONTACT

97236974758; mirid@tlvmc.gov.il

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER GOV
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Dr. Michal Roll

Study Record Dates

• First Submitted: August 10, 2014
• First Posted: October 1, 2014
• Study Start: October 1, 2014
• Primary Completion: December 1, 2015
• Study Completion: December 1, 2016
• Last Updated: October 1, 2014

Record last verified: 2014-09

Locations

IL (2)