Racemic Ketamine Versus S-ketamine With Arterial Spin Labeling (ASL)-MRI in Healthy Volunteers
Condition: Healthy; Abnormal Vascular Flow
Study type: Interventional

Summary: 
      Racemic ketamine and S-ketamine are used in clinical practice today. Little is known of their
      difference in effect on cerebral blood flow, volume and metabolism. cerebral blood flow (CBF)
      measuring techniques are limited in time so constant measurement to mirror a dynamic process
      is impossible or very difficult. A novel MRI application, arterial spin labeling, offers the
      possibility that without radiation or contrast, to measure semi-continuous CBF with
      measurements every 60-120 seconds. The investigators will give 14 healthy volunteers both
      study drugs in a randomised sequence with one week apart and measure regional CBF during the
      study period of 45 minutes after a sub-anaesthetic bolus dose of 0,6 mg/kg racemic ketamine
      and 0,3 mg/kg S-ketamine The investigators hypothesize that there is no difference between
      racemic ketamine and S(+)-ketamine with regards to Arterial Spin Labeling (ASL) measured
      cerebral blood flow.
    

Detailed description: 
      In this investigator-initiated randomised, double-blinded, crossover study, adult healthy
      volunteers will be randomised to receive, as 60-second iv bolus injections on two different
      occasions with at least seven days interval, 0.3 mg kg of S-ketamine (Ketanest® 5.0 mg/ ml,
      Pfizer, USA) or 0.6 mg/kg of racemic ketamine (Ketalar® 10 mg/ml, Pfizer, USA) supplied by
      the hospital pharmacy.

      The volunteers will consecutively be given specific inclusion numbers and randomized
      according to a schedule with corresponding randomization codes prepared in advance by the
      Research & Development Centre of the Skåne Region, Skåne University Hospital, Lund, Sweden.
      Before each investigation, a sealed envelope marked with the corresponding inclusion number,
      will be opened in a separate room by a nurse not taking further part in the study. The nurse
      prepared the study drug according to the randomization code in a 20 ml syringe based on a
      bodyweight-based dosing schedule, and diluted the study drug with saline to a total volume of
      20 ml. The prepared syringe, marked with the inclusion number, date and signature, will be
      handed over to the investigator.

      After an initial 10-minute period of dynamic baseline measurements, the study drug will be
      injected manually by the investigator. ASL measurements will be made over a 45-minute study
      period starting from the injection of study drug, and the volunteer will be brought to the
      preparation room for at least 60 minutes of further supervision until clinical routine
      criteria for postoperative discharge will be met.

      Fourteen healthy (American Society of Anaesthesiologists physical status 1) adult volunteers
      will be included after physical examinations and individual written informed consents. Female
      subjects will be required to use effective anti-conception methods during the study period.
      The volunteers will have to refrain from caffeine, nicotine, alcohol and medications for 72
      hours, and fast for six hours, but will be allowed to drink water until two hours before each
      ASL-MRI investigation.

      Each volunteer will be offered ear plugs, asked to rest with eyes closed during the scanning
      procedure, and left undisturbed throughout the study period. Oxygen 2 l/min will be delivered
      by nasal cannula.

      A hand vein will be cannulated with a 20 G (1.1 mm) 45 mm teflon catheter for injection of
      study drug, and a balanced glucose solution will be infused at a rate of 1.0 ml/kg/h iv. The
      radial artery will be cannulated at wrist level with a 20 G 45 mm teflon catheter after local
      infiltration with 2-3 ml of lidocaine. Each volunteer will be connected to an N-MRI2-01
      monitoring device recording the ECG, invasive blood pressure, SpO2, ETCO2 and respiratory
      rate.

      Monitored data will be sampled minutely throughout the study period, saved onto a PC card and
      analyzed with the Datex-Ohmeda S/5Collect version 4.0™ software package.

      Arterial blood for blood gas analysis was obtained at baseline and at 1, 5, 10 and 15 min
      after injection of the study drug. Analyses were made on a Radiometer ABL800 FLEX device The
      ASL data will be acquired using a 3 Tesla MRI unit. A three-dimensional (3D) GRASE pulse
      sequence will be employed (2), using a labeling and saturation schedule based on FAIR (3) and
      Q2TIPS (4).

      Drug-induced changes in regional perfusion will be monitored over time using a single
      inversion time (TI) of 2000 ms and repeated 115 times, and a repetition time (TR) of 3000 ms.
      For multiple TI, ten time points were acquired with a starting point at TI = 300 ms and an
      increment of 300 ms between time points, the total inflow time was 1400 ms and the TR was set
      to 3700 ms.

      Data sets will be preprocessed using realign tools of the Statistical Parameters Mapping
      version 8.0 (SPM8) software package (Wellcome Department of Imaging Neuroscience, London, UK;
      http://www.fil.ion.ucl.ac.uk/spm) and executed in the Matlab 7.11 software package. The
      labeled and control images will be pair-wise subtracted to produce CBF-weighted ASL images
      from re-aligned control/tag images, and these difference maps were denoised using an
      established wavelet-domain filtering method (5), and an in-house software program written in
      IDL 7.1 (ITT Visual Information Solutions, Boulder, CO, USA). Values of CBF (in ml/100g/min)
      will be calculated using a general kinetic model (6) according to the Buxton equation CBF
      values will be determined by drawing different numbers of symmetrical cerebral regions of
      interest (ROI) bilaterally to outline the grey matter of the frontal lobes, parietal lobes,
      temporal lobes, occipital lobes, insular cortex, anterior cingulate, posterior cingulate,
      thalamus, caudate nucleus and putamen. Global CBF values will determined by drawing a large
      ROI to outline the whole brain tissue within the skull.
    

Intervention name(s): Racemic ketamine; S-ketamine
Intervention type(s): Drug; Drug
Intervention description(s): 0.6 mg/kg; 0.3 mg/kg
Other intervention name(s): Ketamine; Ketanest
Intervention MeSH terms: Ketamine; Esketamine
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Basic Science
Keywords: racemic ketamine; S-ketamine; Cerebral blood flow; Magnetic resonance imaging; arterial spin labeling; healthy volunteers