Ketamine Effect on Isoflurane Anesthesia
Condition: Post-anesthesia Recovery
Study type: Interventional
Phase: Phase 4

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): ketamine; saline
Intervention type(s): Drug; Drug
Intervention description(s): ketamine hydrochloride 250microgram/ ml for iv injection after 30 minutes of stable isoflurane anesthesia; 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.
Other intervention name(s): Calypsol; normal saline, Atsuka
Intervention MeSH terms: Ketamine
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.
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Basic Science
Keywords: ketamine; isoflurane; electroencephalography; maintenance; recovery; anesthesia