Discussion
In this study, we aimed to identify risk factors such as inflammatory
markers or gene expression that may contribute the neurocognitive
dysfunction following cardiac surgery in patients with diabetes. We
found a large portion of patients are affected by decreased
neurocognitive function in the early postoperative period (73%). While
this is higher than often reported in other studies, our RBANS test was
designed to pick up even minor neurocognitive deficits and reflect any
decrease from baseline. Surprisingly, we found no effect of blood
glucose or HbA1c on the rate of NCD after surgery.
Acute kidney injury is known to cause inflammatory mediators to reach
the brain and have downstream effects including diminished neurologic
function.6 Furthermore, it has been recently shown
that patients who experience AKI during hospitalization are
significantly more likely to develop dementia even after controlling for
other various comorbidities.7 It is therefore not
surprising that we observed a correlation between patients who had an
AKI during their hospitalization and suffered NCD (as defined as
Cr≥1.2mg/dL). CKD is not associated with dementia given the influx of
neurotoxic uremic substances and the permeability of the blood-brain
barrier8, therefore we did omit patients from this
study who had an elevated baseline creatinine. However, even mild
inflammation from acute kidney injury appears to be correlated to
neurocognitive decline at POD4, suggesting that fluid status and renal
perfusion are of utmost importance in both short- and long-term outcomes
of cardiac surgery.
Regarding inflammatory markers, postoperative leukocytosis (WBC ≥
10.5x103mm) was correlated with a decreased scoring in
neurocognitive testing at POD4. One marker for systemic inflammatory
response syndrome (SIRS) is leukocytosis and it has been shown that SIRS
is known to negatively affect cognitive function, particularly in the
elderly, and can last for years following the event.9
The increased expression of cytokines, chemokines, and growth factors
such as IL-6 six-hours postoperatively have been previously shown; and
we demonstrated this again, along with other cytokines including IL-10,
SCF, HGF, MCP1, VEGF-A and VEGF-D.10 These cytokines,
chemokines, and growth factors largely work to modulate the innate
immune response, which is likely why there is an upregulation at six
hours after a major procedure. Increased IL-6 levels have been shown to
result in neurocognitive decline in animal models as it disrupts the
blood-brain barrier and activates microglia, however, our findings do
not support this effect in our study population.11Surprisingly, we saw a decrease in other inflammatory cytokines
including TNF-α, IL-1β and IL-23.
IL-8 is a chemokine which is involved in chemotaxis of neutrophils as
well as angiogenesis. Release of IL-8 from astrocytes and microglia
results in activation of neutrophils and their subsequent adhesion to
endothelial cells causing, leakiness in the blood-brain
barrier.12 Therefore, increased IL-8 levels in
patients at six-hours postoperatively, may contribute to the penetration
of inflammatory cytokines across the blood-brain barrier, leading to
neurocognitive decline in the post-operative period. Furthermore,
inhibition of IL-8 could serve as a valuable therapeutic target for
prevention of neurocognitive decline in cardiac surgery.
Patients with diabetes, particularly those with poorly controlled
diabetes and elevated HbA1c levels, have been shown to have higher rates
of baseline cognitive dysfunction.13,14 Additionally,
patients with diabetes have been shown to have higher rates of
complications following CPB.15,16 Thus, it was
hypothesized that patients with diabetes, and especially those with
poorly control diabetes, would have greater neurocognitive decline
following cardiac surgery. It was further hypothesized that this may be
related to microvascular changes and altered regulation of perfusion
that occurs in the brain and other organs during and after cardiac
surgery.17–20 Marked alterations in vasomotor
regulation have been documented after cardiac surgery utilizing
cardiopulmonary bypass both in vivo21 and in
vitro.17–20,22,23 These changes in vasomotor
regulation and other cellular signaling are exacerbated or different in
patients with poorly controlled diabetes compared to patients without
diabetes or well controlled diabetes.22–25
While hyperglycemia is often seen as an inflammatory state and therefore
theorized to be associated with inflammatory markers penetrating the
blood-brain barrier and causing decreased neurocognitive function, we
did not observe that in this study. Neither did pre-existing diabetes,
as determined by an elevated pre-operative HbA1c level, nor elevations
of glucose levels the morning of or intra-operatively have any effect on
early neurocognitive function. It is possible that the tight
intra-operative glucose control regularly achieved may have minimized
this risk to an undetectable finding in our small sized study but would
perhaps be more evident in a much larger cohort; or perhaps, the
insidious nature of the complications of diabetes are such that an
operation is not a sufficiently large enough event to trigger earlier
development and detection of such complications like neurocognitive
dysfunction. Interestingly, a subset of the ACCORD trial showed that
while total brain volume was smaller in patients with less-tightly
controlled diabetes, more subtle neurocognitive outcomes were not
different between groups at 20 and 40 months, suggesting that these more
subtle differences may be well-compensated in the early years of
progression of poorly controlled diabetes.26
Anemia and heart failure are potential risk factors for NCD. Low output
heart failure, in particular, after cardiac surgery may be contributory
to postoperative neurological decline. Unfortunately, while anemia has
been shown to be a greater risk, patients who receive intraoperative RBC
transfusions are at higher risk of low output heart
failure.27 In our study, we found that lower ejection
fractions (<55%) were associated with neurocognitive decline
on POD4. This is not a surprising finding given the presumed etiology of
lower blood flow to the brain having negative consequences. However,
increasing hematocrit intraoperatively does not appear to alleviate the
low output heart failure, and therefore is unlikely to alleviate
neurocognitive decline. Furthermore, our center has shown that while
pre-operative anemia is associated with neurocognitive decline,
transfusion does not improve this outcome.5
Genetic regulation has been previously shown to be associated with
neurocognitive decline via pathways of inflammation, cell-death, and
neurological dysfunction in blood samples of patients before and after
cardiopulmonary bypass.2,28 Our study similarly
demonstrates differences in genetic expression amongst groups, but
further subdivides between those with and without diabetes.
Neurocognitive decline appears to be associated with upregulation of a
variety of genes (over 400) at POD4, which may relate to a higher
inflammatory state than those who do not experience neurocognitive
decline postoperatively. The presence of pre-existing diabetes did not
seem to have a large difference in genetic upregulation or
downregulation when compared to patients without diabetes. This once
again may reflect the tight glucose control in both the intra- and
postoperative period; therefore, minimizing any potential difference due
to the lack of significant time spent with hyperglycemia. However, the
variability in genetic upregulation and downregulation among patients
with and without pre-existing diabetes who experienced NCD, suggests a
closer look at the role diabetes plays in neurocognitive outcomes in
cardiac surgery is warranted. Compared to patients with diabetes who
experienced NCD following cardiac surgery, patients with diabetes
without NCD were found to upregulate a number of genes involved in
immune system functioning. Although it is difficult to evaluate the role
that single genes play in the greater context of an inflammatory
response; patients with diabetes and no NCD were found to upregulate
several genes with anti-inflammatory effects. Among these genes was
Annexin A1 which is the main downstream effector of the
anti-inflammatory effects of glucocorticoids.29 Among
its anti-inflammatory functions, annexin A1 has been found to inhibit
phospholipase A2 and therefore the production of eicosanoids, thus
reducing neutrophil extravasation, promoting apoptosis, and inducing the
conversion of macrophages to anti-inflammatory phenotypes that promote
the resolution of the inflammatory response.29,30Additionally, TGF-β was upregulated in patients with diabetes but
without NCD following cardiac surgery. TGF-β has well known
anti-inflammatory properties which include the inhibition of NF-κB
activity via NF-κB/REI inhibitor protein, increased expression of IL-10,
and promoting the differentiation of anti-inflammatory M2
macrophages.31,32 Neurocognitive decline after cardiac
surgery has been partly attributed to the inflammatory milieu that may
lead to increased vascular permeability in the
brain.33 Therefore, it is plausible that in patients
with diabetes that did not experience NCD, the actions of TGF-β and
annexin A1 collectively help limit the inflammatory response; although
more research is needed to elucidate the complex regulatory mechanisms
that modulate the inflammatory response and its role in NCD.