Introduction

Therapeutic hypothermia (TH) is modestly effective in reducing death and severe disability for neonatal HIE [1], but its neuroprotective properties rely on timely lowering of brain temperature [2,3]. Depending on the method of cooling and presence/absence of brain injury, a temperature gradient can form between deep and peripheral brain, with deep structures being warmer [4,5]. The resistance of local brain structures to TH may not be clinically obvious, because of the lack of clinically feasible brain temperature monitoring and the reliance of core body temperature as a surrogate measure of brain temperature. Advances in MR science allows for non-invasive measurement of regional brain temperature to an accuracy of approximately 0.2°C [6,7] (Fig. 1).

Methods

Fifty-three newborns with birth complications and HIE (22 males and 31 females, mean gestational age 38.3±2 weeks, birthweight 3247±630g) were enrolled prospectively. MR spectra of basal ganglia (BG), thalamus (Thal), cortical gray matter (GM), and white matter (WM) were acquired during TH. Depth of regions of interest was measured as the shortest distance from the center of the voxel to the outer edge of the cranium. The targeted rectal temperature (33.5±0.5°C) was monitored and maintained during the MR examination. All MR measurements were performed on a 3T clinical scanner using single voxel PRESS (TE=35ms, TR=2s, 128 averages). Regional brain tissue temperatures were calculated from the chemical shift difference between water signal and metabolites in the MR spectra after performing calibration measurements. Overall difference in regional temperature was analyzed by mixed effects model and temperature among different patterns and severity of injury on MRI were also analyzed. Correlation between temperature and depth of brain structure was analyzed using repeated measures correlation. MR spectra were acquired at mean age of 2.2±0.6 days. A total of 201 MR spectra were included in the analysis.

Results

Overall, Thal, the deepest structure (36.4±2.3 mm from skull surface), was lowest in temperature (33.2±0.8°C, compared to BG: 33.5±0.9°C; GM: 33.6±0.7°C; WM: 33.8±0.9°C, all p<0.001, Fig. 2). Temperatures in more superficial GM and WM regions (21.9±2.4 and 21.5±2.2mm) were significantly higher than the rectal temperatures (33.4±0.4°C, p<0.03). There was a significant negative correlation between temperature and depth of brain structure (rrm=0.36, p<0.001).When severity of injury was included in the analysis, infants with more severe brain injury on MRI had a significantly higher brain temperature than those without evidence of brain injury (Mann Whitney test: mean rank 82.5 vs. 65.8, p =0.02, Fig. 3). In those with “normal” pattern of injury (n=30), there was a significant difference in regional brain temperature, [F(3.01, 77.46)=3.99, fixed effect p=0.01] with post-hoc multiple comparisons revealing significant temperature difference between Thal and GM (33.05 ± 0.89°C vs. 33.58 ± 0.70°C, p<0.01) and Thal and WM (33.05 ± 0.89°C vs. 33.78 ± 0.98°C, p<0.01). However, there was no significant regional temperature difference among those with central BG-T injury [F(1.82, 14.10), p=0.10] or WS pattern of brain injury [F(2.60, 28.60)=3.03, p=0.05]. There was also no significant difference in regional temperature among those with severe injury on MRI [F(2.16,23.75, p=0.11)].

Discussion

Using MR thermometry, we measured temperatures of various brain structures that were at risk of hypoxic-ischemic injury and correlated the measurements to physical depth of tissue, and characteristic of brain injury. The results of this investigation revealed that whole-body TH effectively lowered deep grey matter structures, while temperatures of more superficial structures such as GM and WM were slightly, but significantly higher than rectal temperatures. Effective cooling of deep structures by whole body TH may be related to the distribution of blood supply in the core grey matter. The dissipation of heat in deep cerebral tissues is largely dependent on the thermal gradient between brain tissue and surrounding arterial blood temperature. In normal physiological conditions, cerebral arterial blood flow acts as the heat sink absorbing heat from surrounding tissue. During whole body TH, cooled systemic arterial blood circulates through the circle of Willis before reaching watershed regions that are more peripheral in location.

Conclusions

Deep brain structures were effectively cooled by whole body hypothermia. Infants with more severe brain injury exhibited higher brain temperatures without regional temperature differences

Acknowledgements

Rudi Schulte Research Institute

References

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