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Calafiore et al. Vessel Plus 2023;7:18 https://dx.doi.org/10.20517/2574-1209.2023.42 Page 13 of 21

Even with these drawbacks, clinical results are in general good [93-96] . Results of DHCA associated with RCP
in hemiarch replacement (n = 500) have been recently reported by Brown et al. in chronic and acute aortic
[94]
pathologies . Stroke rate was 2.6% vs. 6.8% in chronic and acute settings, respectively. CA time was
15(12.0-20.0) vs. 24.5(20.0-30.0) min (P < 0.001). Tanaka et al. reported 1,443 patients (non-AAD 67.5% and
AAD 32.5%) operated on DHCA and RCP. Overall stroke rate was 7.8% (4.5% vs. 14.6%), with a median CA
[95]
time of 23(17-35) . The Authors concluded that the safe time for RCP was 30 min. The same team,
however, reported in a previous paper that the stroke rate in patients with > 40 min of RCP was very low,
[93]
1.7% .
Neurocognitive decline was investigated in a randomized controlled trial by Harrington et al., who found
that adding RCP to DHCA is associated with a high incidence of neuropsychometric deficits despite the
[97]
absence of clinical deficits . Differences between DHCA with ACP or RCP (60 patients, 30 in each group)
were explored by Okita et al., who found similar PNDs, but higher TNDs in patients where RCP was added.
[98]
There was no difference in neurocognitive tests .

AFTER CIRCULATORY ARREST: DELAYED REWARMING
The rationale behind the use of delayed rewarming (DR) after straight DHCA is strictly related to brain
energetics.

As previously stated, a good part of the glucose enters the brain through astrocytes [15,16] [Figure 1], from
where it moves to neurons as lactate that, after being converted into pyruvate, enters the TCA cycle.
Oligodendrocytes can transport lactates produced by themselves or by astrocytes, or glucose, if necessary,
[18]
to neurons through the myelin [Figure 1]. Astrocytes store glucose as glycogen as well, an energetic reserve
for the brain metabolism when glucose uptake is reduced or in stress condition.

Glutamate, released into the synaptic cleft in a process called exocytosis, is the main neurotransmitter in the
adult central nervous system. Glutamate, after being released, is taken up by surrounding astrocytes, is
converted to glutamine, and then is recycled to neuronal terminals, where it is converted again into
glutamate to restore the glutamate pool [24-26] .

In the absence of ischemia or hypoxia, subjecting astrocyte cultures to deep hypothermia and rewarming
leads to a significant elevation of extracellular glutamate concentration . This in vitro observation may
[99]
offer an explanation to the speculations [100,101] made in previous clinical observations that extracellular
excitatory amino acid concentration could be related to the increased neuronal damage observed after large
temperature changes. During deep hypothermia and after rewarming, the level of extracellular glutamate
continues to increase dramatically, even in the presence of normoxia, with a progressive decrease in
glycogen in astrocytes . It is then possible that, in normoxic conditions, astrocytes subjected to deep
[99]
hypothermia and subsequent rewarming have a reduced capacity to produce energy via their oxidative
phosphorylation and must then rely more on glycolysis . The reduction in glycogen content decreases
[99]
glycolysis activity, which inhibits glutamate uptake via the Na -dependent glutamate transporter in cultured
+
astrocytes .
[102]
The excessive amount of glutamate in the extracellular space has been suggested to be one of the
determining factors involved in postoperative neuronal dysfunction in patients after CA. Mechanisms of
cold and rewarming injury involve intracellular Ca++ accumulation mediated by receptors activated by
[103]
glutamate excess (glutamate excitotoxicity).