Emerging evidences suggest that POD is strongly correlated with multiple pre-surgical factors including age, alcohol addiction, electrolyte or glucose dysregulation, reduced functional and cognitive capacity, and type of surgery [15]. However, there are limited studies on the relationships between hormones/inflammatory cytokines and POD. In this study, we adjusted the pre- and intra-operative predictor factors, namely, sex, BMI, drinking history, serum total bilirubin, platelet, hemoglobin, creatinine, intraoperative packed RBC transfusion, deep hypothermic circulatory arrest time, cardiopulmonary bypass time, aortic cross clamp time, and identified the stand-alone POD risk factors for patients with ATAAD. Based on our analysis, reduced preoperative free FT3, and elevated cortisol, IL-2, and PCT levels are strongly associated with POD occurrence.

Patients diagnosed with clinical hypothyroidism and cerebral dysfunction exhibit reduced T3 levels and enhanced POD incidences [16]. The severity of thyroid functional impairment is directly associated with disease status, reduced TH content, and poor prognosis in POD patients [17]. POD occurs in about 37.86% of ATAAD patients after MTBSG implantation [2]. Moreover, POD patients exhibit reduced pre-surgical free FT3 levels, which corroborates our findings [18]. Non-thyroidal illness syndrome (NTIS) is characterized by TH dysregulation in individuals who do not have a thyroid-related illness, such as infectious infections, burns, cancer, or trauma [19]. NTIS brought on by critical illness is manifested by a marked reduction in serum thyroid-stimulating hormone (TSH), triiodothyronine (T3), and thyroxine (T4) [20]. This is also prevalent in other serious conditions, including acute myocardial infarction [21], heart failure [22], and post-cardiac surgery [23]. Under these circumstances, alterations in the thyroid activity negatively modulate patient prognosis, thus, resulting in POD [5]. In this study, we demonstrated marked associations between reduced FT3 concentration and POD in ATAAD patients. Acute inactivation of THs through inner-ring deiodination has been reported to be a compensatory mechanism that restores the body to baseline, lowers systemic energy consumption and metabolic rate, and improves survival [24]. However, dysregulated TH levels can potentially alter neurotransmitter synthesis and cytokine release, which eventually contributes to POD occurrence [25]. TH level aberrations can be partially diminished using cytokines or other inflammatory factors, which act upon the thyroid gland, hypothalamus, hepatic deiodinase system, pituitary gland, as well as the interaction between thyroxine and thyroid-associated globulin.

This study also assessed the association between pre-surgical cortisol levels and POD in ATAAD patients, who underwent MTBSG surgery. Cortisol content is known to regulate cognitive dysfunction during POD after coronary bypass [9]. There are further evidences suggesting that the hypothalamic–pituitary–adrenal (HPA) axis disturbance, in combination with the enhanced release of inflammatory factors and cortisol, modulates cognitive decline and impairment [26]. Moreover, POD patients exhibit markedly elevated pre-surgical cerebrospinal fluid cortisol levels [27]. Likewise, high cortisol concentration is also prevalent in Alzheimer’s, dementia, and mild cognitive dysregulation patients [28]. These evidences suggest that the dysregulated HPA axis produces high levels of cortisol, which promote cognitive impairment, which results in POD [28]. The mechanism may involve that glucocorticoids inhibit endothelial cell proliferation and turnover in the hippocampus and prefrontal cortex [29], whilst HPA axis dysregulation results in decreased hippocampus volume [30]. In this investigation, we demonstrated a strong association between plasma cortisol concentration and POD. Acute damage to blood vessels and severe pain markedly enhance HPA axis activity, which, in turn, activates the immune system, thus elevating plasma cortisol and inflammatory cytokine levels, which ultimately contribute to the brain neuroendocrine and neurotransmitter dysbalance, which results in POD [31]. Thus, we measured cortisol prior to surgery to examine the validity of the connection between higher pre-surgical cortisol concentration and POD.

IL-2 is commonly used as a therapy for metastatic malignancy patients. More than half of patients who had CABG surgery were found to suffer from significant behavioral and/or cognitive impairment (disorientation and cognitive decline). Acute treatment was necessary for 34% of patients because of the behavioral changes [32]. IL-2 levels in the peripheral immune system and the brain were shown to be crucial for promoting either neurodegeneration or neuroregeneration [33] in animal experiments. We next examined the relationship between augmented IL-2 levels and POD among MTBSG implantation patients. AAD induces severe pain, which, in turn, activates complex neuroendocrine and tissue responses that protect the body from injury, and aid in the recovery of body integrity. Unfortunately, this also initiates a “hormonal storm” involving the sympathetic nervous system, sympatho-adrenomedullary, HPA activation, and periphery, as inflammatory factors like IL-2 are released at the injury site [34]. IL-2 is a T cell-released pro-inflammatory cytokine. Multiple sources suggest an active role of inflammatory molecules in POD pathogenesis [35]. Moreover, for both delirium and dementia, cognitive impairment is regulated by cytokines. For example, IL-2 promoted the survival and extension of cultured neurons, while encouraging oligodendrocyte maturation and proliferation, as well as a behavioral shift within the CNS [36].

Another major finding of our investigation was that enhanced pre-surgical PCT is a stand-alone regulator of POD occurrence after MTBSG surgery, based on our multivariate logistic regression model. PCT is a precursor of the calcitonin peptide and is used as an inflammation biomarker. It is widely used in identifying bacterial infections and in monitoring antibiotic therapy in septic patients. Interestingly, increasing literature suggests that pre-surgical PCT can serve as a biomarker for adverse patient prognosis in non-infectious diseases. A prior investigation reported the significance of pre-surgical PCT in predicting POD following cardiac surgery [7]. Based on their observation, about 50% of cardiac surgery patients experienced POD, and only 27% of the non-POD patients exhibited pre-surgical PCT above the normal range. Furthermore, they revealed, based on multivariate logistic regression data, that the preoperative PCT markedly enhanced POD risk, with an odds ratio of 3.05. Receiving a cardiopulmonary bypass (CPB) activates the systemic inflammatory response, which, in turn, enhances the synthesis of a myriad of inflammatory factors both during and after surgery [37].

POD etiology is multifactorial. In this study, our multivariable model of POD prediction after MTBSG surgery included preoperative PCT levels, with an OR of 1.06, even after adjustments for confounding factors like age and CPB duration. Our results also correlated with prior published research [7]. In AAD patients, blood vessel injury activates the systemic inflammatory response. Subsequently, multiple inflammatory factors, including PCT, are secreted, which leads to systemic effects like vasodilatation and microcirculatory dysregulation [38]. Additional inflammatory factors are synthesized by microglial cells after they have been activated by components released during the systemic inflammation response via the blood–brain barrier (BBB), which is comparable to the POD neuroinflammatory hypothesis. As a result, the brain tissue, neuronal activity, the neurotransmitter system, and synaptic conduction become impaired, resulting in significant leakage from the intercellular connections of the BBB cells [39].

In this study, we evaluated PCT since it is easy to obtain routine PCT readings, and prior studies confirmed that PCT is predictive in identifying problems after cardiac surgery [40]. McGrane et al. previously showed that increased PCT levels upon ICU admission indicate long-term acute brain dysregulation in non-cardiac ICU patients. This shows that inflammation and POD 43 are closely linked [41]. We demonstrated markedly upregulated median PCT levels following surgery, with a peak on post-surgical day 2. Moreover, the PCT levels were markedly elevated in POD versus non-POD patients. Since PCT evaluations are easily available (point of care testing or hospital laboratory), and they are quick and cost-effective, they may be used as an additional early predictor of POD in ATAAD patients post MTBSG surgery.

Firstly, our cross-sectional study limits the establishment of a causal or temporal association between pre-surgical THs, cortisol levels, and POD in ATAAD patients. Secondly, since all patients received CTA, we were unable to exclude thyroid hormonal changes caused by iodinated contrast media, even though the prevalence of this is relatively low. In addition, here, we did not analyze the dynamic information involving the influence of THs and cortisol on POD. Lastly, we are aware that the peripheral recordings of these hormones and cytokines are indirect indexes of central neurotransmitter function, and that extrapolation to brain function is somewhat speculative.