When it comes to mitigating against postoperative cognitive decline and preserving functional brain connectivity after circulatory arrest for aortic arch surgery, deep hypothermia is superior to high-moderate hypothermia, a pilot study has concluded. A larger prospective trial is underway to confirm these results.
“Deep hypothermia—which constitutes cooling the body to a temperature of less than or equal to 20° C—has ushered in the modern era of safe and effective aortic arch surgery,” said Rebecca Y. Klinger, MD, assistant professor of anesthesiology at Duke University Medical Center, in Durham, N.C. “This process allows for safe circulatory arrest, because a progressive reduction in brain temperature leads to a reduction in the cerebral metabolic rate of oxygen.”
Despite these potential benefits, deep hypothermia is associated with longer cardiopulmonary bypass times, leading some centers to turn to either low-moderate (20.1°-24.0° C) or high-moderate hypothermia (24.1°-28.0° C), coupled with selective ante grade cerebral perfusion.
“Ultimately, the optimal temperature for neuroprotection remains unclear,” she added, “as most of the current studies are limited by either their retrospective nature and/or lack of objective testing.”
As such, the researchers sought to combine comprehensive neurocognitive testing with functional neuroimaging techniques to evaluate cognitive outcomes related to the three different temperature strategies for surgical hypothermic arrest.
Three Temperature Groups
Dr. Klinger and her colleagues enrolled 34 informed and consenting patients (mean age, 61.7±11.1 years; 32% women) into the trial; each was undergoing hypothermic circulatory arrest for elective proximal aortic reconstructive surgery (ascending aorta plus aortic valve or root), with concomitant proximal hemiarch replacement. All patients completed a battery of neurocognitive tests at baseline and then four weeks after surgery. A subgroup of 15 patients also underwent resting functional MRI.
Patients were categorized into three temperature groups at the initiation of circulatory arrest. Cognitive function was compared between the three groups; contrast analyses were used to identify group differences in resting-state functional connectivity patterns associated with perioperative cognitive changes, after adjusting for baseline cognitive abilities.
“Resting-state functional connectivity represents synchronous neural activity in anatomically disparate brain regions,” Dr. Klinger explained. “It is assessed by examining spontaneous low-frequency MRI signal fluctuations among functionally related but anatomically separate brain regions.”
As reported at the 2016 annual meeting of the American Society of Anesthesiologists (abstract BOC05), the neurocognitive change score from baseline to four weeks fell in the 10 patients undergoing high-moderate hypothermia (global mean z score, –0.04±0.40). By contrast, the 10 patients in each of the low-moderate (0.17±10) and deep hypothermia (0.26±0.21) groups experienced positive cognitive changes (P=0.17). This, the researchers said, represents an effect size difference of 0.99 between the deep and high-moderate hypothermia groups.
The most pronounced differences were seen in short-term memory (high moderate, –0.15±0.37; low moderate, 0.17±11; deep, 0.32±0.37; P=0.04) and executive function (high moderate, 0.02±13; low moderate, 16±1.48; deep, 16±0.67; P=0.03).
Analyses of resting-state functional capacity revealed significant gray matter regional differences in the right parahippocampal, mesial frontal, and posterior cingulate cortices between the deep and high-moderate hypothermia groups, associated with perioperative short-term memory changes. Indeed, short-term memory decline in the high-moderate group was associated with perioperative decreases in intrinsic resting-state functional capacity in the posterior cingulate and mesial frontal cortices, but increases in parahippocampal resting-state functional capacity.
“These preliminary data show that patients who underwent surgical circulatory arrest with high-moderate hypothermia had worse cognitive scores at follow-up than those who underwent deep or low-moderate hypothermia,” Dr. Klinger concluded. “The resting-state MRI data suggest that patients with reduced cognitive function—specifically short-term memory decline—have a pattern of decreased default mode network connectivity, with a possible increase in connectivity in the parahippocampus.
“Taken together, the data suggest that deep hypothermia may be superior to high-moderate hypothermia with respect to protecting against early cognitive decline and preserving functional brain connectivity, particularly in brain regions important to the default mode network,” she said. “A larger prospective, randomized trial is ongoing to evaluate these outcomes.”
Jeffrey Planchard, MD, a resident at the Cleveland Clinic, asked about the numbers of patients included in the current and future trials. “I noticed that you had a sample size of 34 and that some of your confidence intervals overlap,” Dr. Planchard noted. “How much larger is your prospective trial? And do you think you’ll encounter any ethical issues if you start to see more profound results in the deep hypothermia group than the other groups?”
“The larger trial is going to be close to 100 patients, based on the preliminary data that we show here,” Dr. Klinger replied. “With respect to your second question, that trial will obviously be monitored. Nevertheless, you bring up a good point that, should there be significant differences between the various temperature groups, it’s something that would ethically need to be addressed, including possible termination of the study.”