Neuroprotective Effect of Mild Hypothermia Versus Normothermia During Cardiopulmonary Bypass of Coronary Artery Surgery

In high-income countries, 36.7 coronary artery bypass grafting (CABG) procedures are performed per 100,000 population each year, translating to approximately 136,000 procedures in the European Union, and thereby underscoring the significant healthcare burden and importance of optimizing surgical outcomes. During cardiac surgery, cardiopulmonary bypass (CPB), a cornerstone of cardiac surgery, ensures extracorporeal perfusion to critical organs.

Historically, hypothermic CPB has been employed in the majority of cardiac operations and remains one of the most common methods for organ protection in routine cardiac surgery. The biological rationale for hypothermia is grounded in its multiple mechanisms of neuroprotection. Despite these findings, the superiority of hypothermic CPB over normothermic CPB in terms of neuroprotection remains uncertain.

In its 2024 guidelines, the European Association for Cardio-Thoracic Surgery recommends considering normothermia (defined as temperatures ≥ 35°C) to reduce the risk of postoperative neurocognitive dysfunction (Class II, Level A recommendation). Hypothermia, in this context, is defined as a core temperature below 35°C. The recommendation is based on two recent meta-analyses: Abbasciano et al. 2022 and Linassi et al. 2022. However, the 2024 recommendation is underpinned by evidence that remains limited in quality and relevance. The key studies included in these meta-analyses exhibit methodological inconsistencies and rely on outdated definitions and clinical practices, thereby limiting the generalizability and applicability of the findings to current cardiac surgical and anesthetic practice. Notably, the recommendation itself acknowledges the need for large randomized controlled trials to determine the optimal target temperature management (TTM) during cardiopulmonary bypass (CPB).

Previous studies using diffusion-weighted imaging (DWI) in magnetic resonance imaging (MRI) have revealed silent ischemic brain lesions, predominantly deep white matter lesions, in approximately 30% of patients following CABG. Furthermore, postoperative neurocognitive decline occurs in an average of 30.2% of CABG patients. However, earlier DWI and neurocognitive studies have not demonstrated statistically significant differences between normothermic and hypothermic CPB.

Diffusion tensor imaging (DTI) extends the capabilities of DWI and offers several advantages. Unlike DWI, which measures diffusion magnitude, DTI provides detailed quantitative insights into white matter architecture and allows for visualization and quantification of white matter tracts through tractography. Fractional anisotropy (FA), a key DTI parameter, quantifies the magnitude and directionality of water diffusion within white matter tracts. FA has shown independent prognostic value for neurological outcomes in patients with traumatic brain injury, subarachnoid hemorrhage, or cardiac arrest. Despite its potential, DTI has not yet been applied to CABG patients. This technique could significantly enhance our understanding of white matter microintegrity evolution and overall injury burden following CABG, insights necessary for optimizing TTM during CPB.

In addition to brain imaging with DTI, blood-based biomarkers such as glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), neuron-specific enolase (NSE), and total tau (T-tau) provide complementary tools for monitoring brain injury progression and improving prognostication of long-term neurological outcomes. Each biomarker are expressed in different cellular origins and exhibit distinct characteristics and temporal dynamics, potentially offering unique insights into the extent of brain injury post-CABG. However, their ability to independently or synergistically measure white and gray matter injury in combination with DTI parameters remains unexplored in CABG patients.

To optimize TTM during CPB, this study will investigate the neuroprotective effects of hypothermic (33-34 °C) and normothermic (36.5 °C) CPB by evaluating their impact on white matter injury, cerebral perfusion, and whole-brain neural networks using advanced MRI techniques.

The primary aim of this study is to evaluate whether mild hypothermic CPB offers superior neuroprotection compared to normothermic CPB. This will be assessed using brain DTI and blood-based biomarkers following CABG. Secondary objectives include evaluating the evolution of white matter architecture, the extent of global ischemic injury to white matter microintegrity, and the association between these factors, postoperative blood-based biomarker levels, and neurocognitive decline. In addition, an objective is to develop innovative and highly precise prognostic models by integrating advanced brain imaging technologies with comprehensive biomarker analysis. Ultimately, the overarching goal is to identify factors that can improve the treatment outcomes for patients undergoing CABG.

• Change in hippocampal volume in milliliters (ml) from preoperative day 4 (+/- 3 days) to postoperative day 6 (+/-1 day) between the control and the intervention group [Time frame: Change of hippocampal volume between preoperative day 4 +/- 3 days and postoperative day 6 +/- 1day]
• Number of participants with treatment related adverse events as assessed by CTCAE v 4.0 [Time frame: From enrollment to the end of follow-up at 1 year]
• Change in hippocampal ischemic injury from preoperative day 4 +/- 3 days to postoperative day 6 +/- 1 day between the control group and the intervention group. [Time frame: The change of hippocampal ischemic injury from the preoperative day 4 +/-3 days to postoperative day 6 +/- 1 day]
• Change in ischemic injury of basal ganglia from preoperative day 4 +/- 3 days to postoperative day 6+/- 1 day between the control group and the intervention group [Time frame: The change of ischemic injury in basal ganglia from the ppreoperative day 4 +/- 3 days to postoperative day 6 +/- 1 day]
• Change of global white matter injury as assessed with diffusion tensor imaging between the control group and the intervention group from preoperative day 4 +/- 3 days to postoperative day 6 +/- 1 day and to 3 months +/- 7 days [Time frame: Change of global ischemic white matter injury from preoperative day 4 +/- 3 to postoperative day 6 +/-1 day and to 3 months +/- 7 days]
• Change of global gray matter injury between the control group and the intervention group from preoperative day 4 +/- 3 days to postoperative day 6 +/- 1 day and to 3 months +/- 7 days [Time frame: Change of global gray matter injury from preoperative day 4 +/- 3 days to postoperative day 6 +/- 1 day and to 3 months +/- 7 days after operation]
• Difference of blood-based neuron specific enolase (NSE) between the control group and the intervention group [Time frame: NSE is analysed immediately prior to anesthesia induction and at postoperative 24, 48 and at 72 hours]
• Difference of blood-based neurofilament light chain (NfL) between the control group and the intervention group [Time frame: NfL is analyzed immediately prior to anesthesia induction and at postoperative 24, 48 and at 72 hours]
• Difference of blood-based glial fibrillary acidic protein (GFAP) between the control group and the intervention group [Time frame: GFAP is analyzed immediately prior to anesthesia induction and at postoperative 24, 48 and at 72 hours]
• Difference of blood-based total tau between the control group and the intervention group [Time frame: total tau is analyzed immediately prior to anesthesia induction and at postoperative 24, 48 and at 72 hours]
• Difference of neurocognitive outcomes between the control group and the intervention group as assessed with the Cambridge Neuropsychological Test Automated Battery (CANTAB) [Time frame: CANTAB will be assessed at preoperative day 2 +/- 1 day and postoperatively at 3 and at 12 months]
• Difference of intraoperative Near-Infrared Spectroscopy NIRS values between the control and the intervention group during . [Time frame: NIRS will be measured intraoperatively]