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.