Study design and participants
This study was a randomised single-blinded phase 2 clinical drug trial (part of the Xe-HYPOTHECA trial) at two multipurpose intensive care units in Finland (ClinicalTrials.gov,
number NCT00879892).
The study was approved by the ethics committee of the Hospital District of Southwest Finland and the institutional review boards of the Helsinki University Hospital and the Finnish Medicines Agency.
All patients’ next of kin or legal representative gave written informed assent within 4 hours after hospital arrival.
Consent was sought from patients if they regained consciousness.
An independent data and safety monitoring committee reviewed data after enrollment of every 4 patients and after each 6-month interval.
The study was conducted according to good clinical practice and the latest revision of the Declaration of Helsinki.
Consecutive comatose survivors of out-of-hospital cardiac arrest admitted to the Turku and Helsinki University hospitals between August 2009 and September 2014 were screened for eligibility.
110 comatose OHCA patients were randomised to receive either therapeutic hypothermia treatment alone or inhaled xenon in combination with hypothermia for 24 hours.
Diffusion Tensor Imaging
Both DTI and MRS were acquired using a 3T MRI (Siemens Magnetom Verio) with 12-element Head Matrix coil in both MRI centers.
DTI data was acquired using diffusion weighted spin-echo echo planar imaging (SE-EPI) sequence with 20 diffusion encoding directions and b-value of 1000 s/mm2.
Quality control of the DTI data was performed using the DTIprep software [2] and the diffusion tensor image model was fitted using the dtifit tool (FSL 5.0,
Analysis Group,
FMRIB,
Oxford,
United Kingdom).
FA images were aligned to a typical FA image in the dataset using the nonlinear registration tool FNIRT [3] and then aligned dataset was affine-transformed into 1x1x1 mm3 standard space (MNI152).
Following the default tract-based spatial statistics (TBSS) pipeline,
all individual patients’ spatially normalised fractional anisotropy images were projected onto a skeletonised mean fractional anisotropy map for statistical voxel-wise regression analysis between the two patient groups [4,5].
Global FA value of white matter was calculated as a mean value of all the voxels in the skeleton.
As described previously,
the tract-wise distribution of percentages of voxels with significantly lower fractional anisotropy was also analysed.[6]
In addition,
segmentation of the basal ganglia for quantitative mean diffusivity analysis was performed by co-registering diffusion images with isotropic T1-weighted images using the standard FSL tools.
Proton Magnetic Resonance Spectroscopy
1H-MRS data were acquired from the region of basal ganglia by utilising Chemical Shift Imaging (CSI) technique.
Point-Resolve Spectroscopy (PRESS) sequence was used to acquire multivoxel spectra where the volume of interest (VOI) was 8 by 8 voxels and the size of an individual voxel 10x10x15 mm3.
Acquired data were analysed using the LCModel software (version 6.3-0C) which provided information about relative concentrations of several metabolites.[7] However,
data with poor quality were omitted from further analysis by using spectral and fitting quality parameters as exclusion criteria.
The quality of the data was sufficient to reliably resolve only N-acetylaspartate and N-acetylaspartylglutamate (total N-acetylaspartate; tNAA),
glycerophosphocholine and phosphocholine (total Choline; tCho),
and creatine and phosphocreatine (total creatine; tCr) metabolites from the spectra.
An average of all analysed voxels,
except the ones containing cerebrospinal fluid (CSF) were selected for the final analysis (see Fig. 1).
The metabolite concentration values were corrected for relaxation effects using literature based relaxation times [8] but absolute concentration values were not feasible to use.
Therefore,
the amount of tNAA and total choline were expressed as ratios over total creatine,
i.e.
tNAA/tCr and tCho/tCr,
as it is expected to remain stable.
In addition,
tNAA/tCho ratio was presented as both the amount of tNAA and tCho is considered to be related to neuronal density,
activity and integrity.[9]
Receiver operating characteristic analysis
The predictive accuracy of DTI and 1H MRS for mortality at six months were assessed by area under the receiver operating characteristic (ROC) curve .