<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03290495</url>
  </required_header>
  <id_info>
    <org_study_id>isoflurane ketamine gamma</org_study_id>
    <nct_id>NCT03290495</nct_id>
  </id_info>
  <brief_title>Ketamine Effect on Isoflurane Anesthesia</brief_title>
  <official_title>Electroencephalographic Effects of Ketamine During Isoflurane Maintenance and Recovery</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Minia University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Minia University</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Ketamine effect on isoflurane anesthesia This study is designed to study the effect of&#xD;
      ketamine on isoflurane anesthesia. As both drugs are hypnotic and are used to cause sleep&#xD;
      during surgery and other painful procedures, it was long believed that the actions of two&#xD;
      drugs add to each other. For example if a man received both drugs, this man will become awake&#xD;
      from anesthesia much later than if this man was given either of them alone.&#xD;
&#xD;
      However recent studies showed that this is not the case and ketamine can cause fast recovery&#xD;
      from hypnotic effects of isoflurane. This was confirmed in animals.&#xD;
&#xD;
      The aim of current study is to investigate if this effect applies for humans, using a state&#xD;
      of art brain monitoring device in wide use nowadays called BIS or bispectral index. This&#xD;
      device can also shed some light on how ketamine can cause, if any, fast recovery from&#xD;
      isoflurane anesthesia. Simply, by studying electrical wave coming from brain to head skin.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      In an animal study, the authors found that intraperitoneal injection of a sub-anesthetic dose&#xD;
      of ketamine amidst isoflurane anesthesia in rats induced early recovery. A finding the&#xD;
      authors explained, to be due to increased NMDA mediated increase of acetyl choline secretion&#xD;
      in the prefrontal area of rats' brains. This rise, in the authors opinion, antagonized the&#xD;
      GABA mediated isoflurane anesthesia resulting in hastened recovery. Meanwhile, the authors&#xD;
      found association between hastened recovery and increased Electroencephalographic gamma (EEG&#xD;
      γ) wave fronto-parietal projection. This is compatible with cognitive unbinding explanation&#xD;
      of unconsciousness during anesthesia.&#xD;
&#xD;
      In current proposed study, the investigator will examine tow hypothesis:&#xD;
&#xD;
      Recovery time:&#xD;
&#xD;
      If the recovery hastening effect of sub anesthetic ketamine on recovery from isoflurane&#xD;
      anesthesia is also present in human patients. The assumption will be that ketamine either&#xD;
      prolong or has no effect on recovery time from isoflurane anesthesia. The claim well be that&#xD;
      ketamine will decrease the recovery time.&#xD;
&#xD;
      Put in statistical terms:&#xD;
&#xD;
      H0: recovery with ketamine ≥ recovery without ketamine. H1: recovery with ketamine ˂ recovery&#xD;
      without ketamine. 2. EEG (γ) wave activity: As the investigator will record EEG activity&#xD;
      during the procedure via Bispectral monitor, the investigator will analyze the records for&#xD;
      presence of enhanced (γ) activity during recovery. the investigator aim is also to detect any&#xD;
      significant difference in (γ) wave amplitude or other characteristics between isoflurane only&#xD;
      and ketamine group.&#xD;
&#xD;
      The assumption will be that (γ) activity will either show no difference between the two&#xD;
      groups or be lower than in ketamine group than isoflurane group during recovery. The claim&#xD;
      will be increased (γ) activity with ketamine group during recovery.&#xD;
&#xD;
      Put in statistical terms:&#xD;
&#xD;
      H0: (γ) activity with ketamine ≤ isoflurane only. H1: (γ) activity with ketamine &gt; isoflurane&#xD;
      only. N.P: as the sampling frequency of EEG data exported from BIS Vista is 128Hz, the upper&#xD;
      limit of the current study of (γ) activity will necessarily be 64Hz.&#xD;
&#xD;
      Sample size calculation:&#xD;
&#xD;
      the mean measured variable of the current study will be the recovery time. Recovery time will&#xD;
      be defined as the time between stop of isoflurane inhalation until recovery of verbal&#xD;
      response to name called every 30 seconds. A 30% reduction in recovery time in ketamine group&#xD;
      as compared with isoflurane is considered to be statically significant enough to reject the&#xD;
      null hypothesis of recovery time. According to one study , recovery time from isoflurane only&#xD;
      anesthesia is around 12 minutes so the sample size calculation will be as following:&#xD;
&#xD;
      Equation:&#xD;
&#xD;
      n&gt;((ᶻ &quot;1- α ̸2&quot; +ᶻ&quot;1-β&quot; )&quot;2&quot; σ&quot;2&quot; )/δ&quot;2&quot; Where n = sample size required for each group, ᶻ&#xD;
      &quot;1-α&quot; = the value for the standard normal distribution for (1-α̸2) percentile, ᶻ &quot;1-β&quot; =the&#xD;
      standard normal distribution for 100(1-β) percentile, δ&quot;2&quot; = the difference to detect, σ&quot;2&quot; =&#xD;
      the variance in the underling 2 population.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">September 30, 2017</start_date>
  <completion_date type="Actual">November 25, 2017</completion_date>
  <primary_completion_date type="Actual">November 15, 2017</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>An intravenous catheter was placed and normal saline (0.9%) will be infused. Spinal anesthesia will be given. The stability of spinal anesthesia will be assured before propofol injection and at the end of procedure.&#xD;
Propofol will be given to facilitate isoflurane inhalation which will be varied between 0.8-1.2percent to keep (BIS) in the range 40-60. Anesthesia will be kept as so for 30 minutes. Then the test drug (either ketamine or saline) will be given slowly, to pressor response in case of ketamine. Anesthesia will be maintained for another 30 minutes then isoflurane is discontinued. Recovery from anesthesia will then be tested.. No other drugs will be routinely given. Development of complications or signs of inadequate anesthesia will cause drop of the case from study and any measures will be taken to insure patient safety and comfort.The patient will be let to recover from anesthesia then transferred to postoperative care unit.</intervention_model_description>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>Triple (Participant, Investigator, Outcomes Assessor)</masking>
    <masking_description>The patients well be randomized to one of the two groups by closed envelope technique. After opening the envelope, the study drug (ketamine 100µg/kg total body weight (Isoket group)) or normal saline ((Isonly) or control group) will be prepared, made up to 10 ml and administered by an assistant in the proper timing. The patient identification will be written on a slip and put back into an envelope and sealed. The person doing the procedure and monitoring along with the patient will be blinded to the dose and nature of solution. The equal volume test solution will be given intravenously by an assistant who was not involved in the administration of anesthesia and monitoring</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>recovery time</measure>
    <time_frame>Time Frame: 1 hour</time_frame>
    <description>recovery time in this study is defined as time between stop of isoflurane inhalation and recovery of consciousness . this will be assessed by calling the patient first name loudly until the patient verbally respond.time will be recorded in seconds.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>gamma wave activity</measure>
    <time_frame>Time Frame: 2 hour</time_frame>
    <description>EEG will recorded after test drug administration and during recovery. recorded data will be offline analysed for EEG wave activity. the results will be compared between the two study groups.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>processed EEG parameters</measure>
    <time_frame>Time Frame: 2 hour</time_frame>
    <description>this include but not limited to BIS value, spectral edge frequency 95. these value will be online received from BIS monitor.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">30</enrollment>
  <condition>Post-anesthesia Recovery</condition>
  <arm_group>
    <arm_group_label>isonly</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>This arm will receive spinal anesthesia. then this arm will receive saline during isoflurane anesthesia. this arm will serve as a control group.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>isoket</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>this arm will receive spinal anesthesia. then will receive isoflurane inhalation. during isoflurane inhalation, this arm will receive single injection of ketamine. at end of anesthesia, effect of ketamine on recovery will be monitored.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>ketamine</intervention_name>
    <description>ketamine hydrochloride 250microgram/ ml for iv injection after 30 minutes of stable isoflurane anesthesia</description>
    <arm_group_label>isoket</arm_group_label>
    <other_name>Calypsol</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>saline</intervention_name>
    <description>a similar volume of normal saline 0.9% for intravenous injection instead of ketamine will be given to the control group. this because the attending anesthesiologist will be blinded to the study drugs and aim according to the study proposal.</description>
    <arm_group_label>isonly</arm_group_label>
    <other_name>normal saline, Atsuka</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Consent: patient must be legally fit to consent. Informed consent will be get from&#xD;
             each patient.&#xD;
&#xD;
          -  ASA status: I or II.&#xD;
&#xD;
          -  Fully conscious at time of induction of anesthesia.&#xD;
&#xD;
          -  No history of side effects related to any drugs used in the study.&#xD;
&#xD;
          -  Planned surgery can be performed under spinal anesthesia&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Incompetence: failure to give informed consent or refusal.&#xD;
&#xD;
          -  Neurological or psychiatric disorders&#xD;
&#xD;
          -  Addiction&#xD;
&#xD;
          -  Recent intake of drugs affecting central nervous system&#xD;
&#xD;
          -  ASA state more than II&#xD;
&#xD;
          -  Morbid obesity&#xD;
&#xD;
          -  Surgery cannot solely performed under spinal anesthesia&#xD;
&#xD;
          -  Contraindication to spinal anesthesia as coagulopathy&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Mamdouh H Hassan, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Minia faculty of Medicine. Minia university. Egypt</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Minia University Hospital (main hospital)-kornish elnil st.</name>
      <address>
        <city>Al Minyā</city>
        <state>Minya</state>
        <zip>61511</zip>
        <country>Egypt</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Egypt</country>
  </location_countries>
  <reference>
    <citation>Li D, Hambrecht-Wiedbusch VS, Mashour GA. Accelerated Recovery of Consciousness after General Anesthesia Is Associated with Increased Functional Brain Connectivity in the High-Gamma Bandwidth. Front Syst Neurosci. 2017 Mar 24;11:16. doi: 10.3389/fnsys.2017.00016. eCollection 2017.</citation>
    <PMID>28392760</PMID>
  </reference>
  <reference>
    <citation>Mashour GA. Cognitive unbinding: a neuroscientific paradigm of general anesthesia and related states of unconsciousness. Neurosci Biobehav Rev. 2013 Dec;37(10 Pt 2):2751-9. doi: 10.1016/j.neubiorev.2013.09.009. Epub 2013 Sep 26.</citation>
    <PMID>24076246</PMID>
  </reference>
  <reference>
    <citation>Philip BK, Kallar SK, Bogetz MS, Scheller MS, Wetchler BV. A multicenter comparison of maintenance and recovery with sevoflurane or isoflurane for adult ambulatory anesthesia. The Sevoflurane Multicenter Ambulatory Group. Anesth Analg. 1996 Aug;83(2):314-9. doi: 10.1097/00000539-199608000-00019.</citation>
    <PMID>8694311</PMID>
  </reference>
  <reference>
    <citation>Campbell MJ, Julious SA, Altman DG. Estimating sample sizes for binary, ordered categorical, and continuous outcomes in two group comparisons. BMJ. 1995 Oct 28;311(7013):1145-8. doi: 10.1136/bmj.311.7013.1145. Erratum In: BMJ 1996 Jan 13;312(7023):96.</citation>
    <PMID>7580713</PMID>
  </reference>
  <reference>
    <citation>Florey CD. Sample size for beginners. BMJ. 1993 May 1;306(6886):1181-4. doi: 10.1136/bmj.306.6886.1181.</citation>
    <PMID>8499826</PMID>
  </reference>
  <verification_date>November 2017</verification_date>
  <study_first_submitted>September 8, 2017</study_first_submitted>
  <study_first_submitted_qc>September 19, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 25, 2017</study_first_posted>
  <last_update_submitted>November 25, 2017</last_update_submitted>
  <last_update_submitted_qc>November 25, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">November 28, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Minia University</investigator_affiliation>
    <investigator_full_name>Hassan, Mamdouh Hassan Mohamed</investigator_full_name>
    <investigator_title>lecturer of anesthesia and intensive care</investigator_title>
  </responsible_party>
  <keyword>ketamine</keyword>
  <keyword>isoflurane</keyword>
  <keyword>electroencephalography</keyword>
  <keyword>maintenance</keyword>
  <keyword>recovery</keyword>
  <keyword>anesthesia</keyword>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Ketamine</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03290495
org study id: isoflurane ketamine gamma
nct id: NCT03290495
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Ketamine effect on isoflurane anesthesia This study is designed to study the effect of
      ketamine on isoflurane anesthesia. As both drugs are hypnotic and are used to cause sleep
      during surgery and other painful procedures, it was long believed that the actions of two
      drugs add to each other. For example if a man received both drugs, this man will become awake
      from anesthesia much later than if this man was given either of them alone.

      However recent studies showed that this is not the case and ketamine can cause fast recovery
      from hypnotic effects of isoflurane. This was confirmed in animals.

      The aim of current study is to investigate if this effect applies for humans, using a state
      of art brain monitoring device in wide use nowadays called BIS or bispectral index. This
      device can also shed some light on how ketamine can cause, if any, fast recovery from
      isoflurane anesthesia. Simply, by studying electrical wave coming from brain to head skin.
In an animal study, the authors found that intraperitoneal injection of a sub-anesthetic dose
      of ketamine amidst isoflurane anesthesia in rats induced early recovery. A finding the
      authors explained, to be due to increased NMDA mediated increase of acetyl choline secretion
      in the prefrontal area of rats' brains. This rise, in the authors opinion, antagonized the
      GABA mediated isoflurane anesthesia resulting in hastened recovery. Meanwhile, the authors
      found association between hastened recovery and increased Electroencephalographic gamma (EEG
      γ) wave fronto-parietal projection. This is compatible with cognitive unbinding explanation
      of unconsciousness during anesthesia.

      In current proposed study, the investigator will examine tow hypothesis:

      Recovery time:

      If the recovery hastening effect of sub anesthetic ketamine on recovery from isoflurane
      anesthesia is also present in human patients. The assumption will be that ketamine either
      prolong or has no effect on recovery time from isoflurane anesthesia. The claim well be that
      ketamine will decrease the recovery time.

      Put in statistical terms:

      H0: recovery with ketamine ≥ recovery without ketamine. H1: recovery with ketamine ˂ recovery
      without ketamine. 2. EEG (γ) wave activity: As the investigator will record EEG activity
      during the procedure via Bispectral monitor, the investigator will analyze the records for
      presence of enhanced (γ) activity during recovery. the investigator aim is also to detect any
      significant difference in (γ) wave amplitude or other characteristics between isoflurane only
      and ketamine group.

      The assumption will be that (γ) activity will either show no difference between the two
      groups or be lower than in ketamine group than isoflurane group during recovery. The claim
      will be increased (γ) activity with ketamine group during recovery.

      Put in statistical terms:

      H0: (γ) activity with ketamine ≤ isoflurane only. H1: (γ) activity with ketamine > isoflurane
      only. N.P: as the sampling frequency of EEG data exported from BIS Vista is 128Hz, the upper
      limit of the current study of (γ) activity will necessarily be 64Hz.

      Sample size calculation:

      the mean measured variable of the current study will be the recovery time. Recovery time will
      be defined as the time between stop of isoflurane inhalation until recovery of verbal
      response to name called every 30 seconds. A 30% reduction in recovery time in ketamine group
      as compared with isoflurane is considered to be statically significant enough to reject the
      null hypothesis of recovery time. According to one study , recovery time from isoflurane only
      anesthesia is around 12 minutes so the sample size calculation will be as following:

      Equation:

      n>((ᶻ "1- α ̸2" +ᶻ"1-β" )"2" σ"2" )/δ"2" Where n = sample size required for each group, ᶻ
      "1-α" = the value for the standard normal distribution for (1-α̸2) percentile, ᶻ "1-β" =the
      standard normal distribution for 100(1-β) percentile, δ"2" = the difference to detect, σ"2" =
      the variance in the underling 2 population.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: An intravenous catheter was placed and normal saline (0.9%) will be infused. Spinal anesthesia will be given. The stability of spinal anesthesia will be assured before propofol injection and at the end of procedure.
Propofol will be given to facilitate isoflurane inhalation which will be varied between 0.8-1.2percent to keep (BIS) in the range 40-60. Anesthesia will be kept as so for 30 minutes. Then the test drug (either ketamine or saline) will be given slowly, to pressor response in case of ketamine. Anesthesia will be maintained for another 30 minutes then isoflurane is discontinued. Recovery from anesthesia will then be tested.. No other drugs will be routinely given. Development of complications or signs of inadequate anesthesia will cause drop of the case from study and any measures will be taken to insure patient safety and comfort.The patient will be let to recover from anesthesia then transferred to postoperative care unit.
primary purpose: Basic Science
masking: Triple (Participant, Investigator, Outcomes Assessor)
masking description: The patients well be randomized to one of the two groups by closed envelope technique. After opening the envelope, the study drug (ketamine 100µg/kg total body weight (Isoket group)) or normal saline ((Isonly) or control group) will be prepared, made up to 10 ml and administered by an assistant in the proper timing. The patient identification will be written on a slip and put back into an envelope and sealed. The person doing the procedure and monitoring along with the patient will be blinded to the dose and nature of solution. The equal volume test solution will be given intravenously by an assistant who was not involved in the administration of anesthesia and monitoring
measure: recovery time
time frame: Time Frame: 1 hour
description: recovery time in this study is defined as time between stop of isoflurane inhalation and recovery of consciousness . this will be assessed by calling the patient first name loudly until the patient verbally respond.time will be recorded in seconds.
measure: gamma wave activity
time frame: Time Frame: 2 hour
description: EEG will recorded after test drug administration and during recovery. recorded data will be offline analysed for EEG wave activity. the results will be compared between the two study groups.
measure: processed EEG parameters
time frame: Time Frame: 2 hour
description: this include but not limited to BIS value, spectral edge frequency 95. these value will be online received from BIS monitor.
arm group label: isonly
arm group type: Active Comparator
description: This arm will receive spinal anesthesia. then this arm will receive saline during isoflurane anesthesia. this arm will serve as a control group.
arm group label: isoket
arm group type: Active Comparator
description: this arm will receive spinal anesthesia. then will receive isoflurane inhalation. during isoflurane inhalation, this arm will receive single injection of ketamine. at end of anesthesia, effect of ketamine on recovery will be monitored.
intervention type: Drug
intervention name: ketamine
description: ketamine hydrochloride 250microgram/ ml for iv injection after 30 minutes of stable isoflurane anesthesia
arm group label: isoket
other name: Calypsol
intervention type: Drug
intervention name: saline
description: a similar volume of normal saline 0.9% for intravenous injection instead of ketamine will be given to the control group. this because the attending anesthesiologist will be blinded to the study drugs and aim according to the study proposal.
arm group label: isonly
other name: normal saline, Atsuka
criteria: 
gender: All
minimum age: 18 Years
maximum age: 70 Years
healthy volunteers: No
last name: Mamdouh H Hassan, MD
role: Principal Investigator
affiliation: Minia faculty of Medicine. Minia university. Egypt
facility: 
country: Egypt
citation: Li D, Hambrecht-Wiedbusch VS, Mashour GA. Accelerated Recovery of Consciousness after General Anesthesia Is Associated with Increased Functional Brain Connectivity in the High-Gamma Bandwidth. Front Syst Neurosci. 2017 Mar 24;11:16. doi: 10.3389/fnsys.2017.00016. eCollection 2017.
PMID: 28392760
citation: Mashour GA. Cognitive unbinding: a neuroscientific paradigm of general anesthesia and related states of unconsciousness. Neurosci Biobehav Rev. 2013 Dec;37(10 Pt 2):2751-9. doi: 10.1016/j.neubiorev.2013.09.009. Epub 2013 Sep 26.
PMID: 24076246
citation: Philip BK, Kallar SK, Bogetz MS, Scheller MS, Wetchler BV. A multicenter comparison of maintenance and recovery with sevoflurane or isoflurane for adult ambulatory anesthesia. The Sevoflurane Multicenter Ambulatory Group. Anesth Analg. 1996 Aug;83(2):314-9. doi: 10.1097/00000539-199608000-00019.
PMID: 8694311
citation: Campbell MJ, Julious SA, Altman DG. Estimating sample sizes for binary, ordered categorical, and continuous outcomes in two group comparisons. BMJ. 1995 Oct 28;311(7013):1145-8. doi: 10.1136/bmj.311.7013.1145. Erratum In: BMJ 1996 Jan 13;312(7023):96.
PMID: 7580713
citation: Florey CD. Sample size for beginners. BMJ. 1993 May 1;306(6886):1181-4. doi: 10.1136/bmj.306.6886.1181.
PMID: 8499826
responsible party type: Principal Investigator
investigator affiliation: Minia University
investigator full name: Hassan, Mamdouh Hassan Mohamed
investigator title: lecturer of anesthesia and intensive care
mesh term: Ketamine
sharing ipd: Undecided