POCD following cardiac surgery is one of the frequently reported complications affecting postoperative outcome, characterized by the impairment of memory or concentration, detected by neuropsychological testing and clinically presenting with deficits in cognition and memory. According to the study that assessed neurological complications after CABG the incidence was 3%. The results of the studies are contradictory and POCD after cardiac surgery operations is still the topic of research. Patients who have undergone the off-pump CABG procedure had lower incidence of early POCD in 46% of the cases, while the results where similar to on-pump CABG patients after one year [3, 4]. Patients who have undergone valvular replacement had more POCD compared to patients who have undergone CABG. The patients with valvular disease were excluded from the research, considering the differences in the pathology and operative procedure. Although the risk of air and tissue debris embolism is obviously greater in valvular surgery and the higher incidence of POCD after valvular surgery than after CABG has been reported, currently available evidence with regard to cerebral desaturation and POCD are mostly confined to CABG [19].
The aetiology of POCD is considered multifactorial with the most commonly cited aetiologies being embolism and hypoperfusion related to CPB, affecting the cerebral oxygen supply–demand balance [19, 20] and pathophysiologic influences of the partial aortic clamp, inflammatory mediators, anaesthetics, atrial fibrillation, intra-aortic balloon pump (IABP) use, prolonged and repeated use of the extracorporeal circulation machine for cardiopulmonary bypass (CPB), inotrope use, ascendant aortic and carotid artery disease, previous cerebrovascular accident (CVA), age above 70, systolic hypertension, pulmonary disease, diabetes, and alcohol abuse [2,3,4].
In our research, we only included the male patients to get clearer results considering the gender-related neurotoxic effects. The male brain is more vulnerable to many toxic exposures than the female brain, with evidence suggesting this difference includes: greater neuroinflammatory response in males; reduced vulnerability to oxidative stress in females; and neuroprotective effects of oestrogen and progesterone, especially in the reduction of inflammation and oxidative stress [21].
POCD in cardiac surgery has been investigated in the last decades, giving contradictory results. Some studies showed that perioperative neurocognitive decline predicts long-term cognitive dysfunction [20, 22]. The use of the CPB machine is frequently suspected as contributing to the risk of POCD, because the CPB machine can cause embolization, as well as activate systemic inflammatory pathways. A study done on the Chinese population shows that although CPB increased the number of cerebral micro-emboli, it did not increase the incidence of POCD compared with the off-pump group, suggesting another aetiology for cognitive decline, perhaps by the activation of inflammatory pathways. Pro-inflammatory cytokines that are released in response to surgery include the tumour necrosis factor α (TNF-α) and interleukin (IL) IL-1β and IL-6, which can then induce the production and release of other pro-inflammatory cytokines, resulting in neuroinflammation leading to Aβ plaque formation, which is known to be associated with AD pathology [16]. Although not well understood, several potential activities have been discovered for Aβ, including the activation of kinase enzymes, protection against oxidative stress, regulation of cholesterol transport, functioning as a transcription factor, and anti-microbial activity (potentially associated with Aβ's pro-inflammatory activity) [5,6,7,8,9,10,11,12,13,14,15,16]. The damage of overexpressed Aβ to memory, learning, and hippocampal volume has been related to acetylcholine synthesis and release in the central nervous system (CNS). Nicotine acetylcholine receptors have the key role in the neurotransmission and regulation of memory, consciousness, and learning. The brain-blood barrier (BBB) damage caused by inflammatory mediators as a response to iatrogenic factors such as intraoperative cerebral hypoxia, hypocapnia, hypoperfusion with loss of autoregulation, cerebral emboli, or high glucose concentrations has been proposed as a possible cause of POCD [5,6,7,8,9,10,11,12,13,14,15,16]. The most recent publication showed that older adults with early cognitive dysfunction develop brain capillary damage associated with mural cell pericyte injury and BBB breakdown in the hippocampus irrespective of Aβ changes, suggesting that BBB breakdown is an independent, early biomarker of cognitive impairment unrelated to Aβ [17]. On the other hand, one of the physiological functions of Aβ is to control cholesterol transport and homeostasis, so the overproduction of Aβ blocks cholesterol trafficking, leading to neurodegeneration [18].
Most of the studies have found no significant difference comparing on-pump CABG to off-pump CABG regarding POCD. This could be further confirmation of the suggestions that many other factors such as inflammatory processes including sternotomy, heparin administration, and hemodynamic variations may be responsible for cognitive dysfunction [20].
We compared the on-pump and the off-pump procedure regarding both the POCD and the Aβ1-42 plasma concentrations and found that in the on-pump CABG group, the absolute difference in the Aβ1-42 preoperative and postoperative values was significantly larger and associated to cognitive decline. The ROC analysis showed that the absolute difference in plasmatic Aβ1-42 values before and after the operation and the plasmatic Aβ1-42 postoperative values are significant factors predicting worse postoperative neurocognitive status. We suggest that the use of CPB and the associated inflammatory processes contribute great deal to the POCD aetiology. Another argument for the benefit of off-pump surgery regarding POCD is the fact that the patients in the off-pump group were significantly older and yet had better results and less cognitive decline.
Since the off-pump group, although older, had better cognitive outcomes, we suggest that there is a relation to surgical factors. We can assume that these factors include the ECC affecting the patient’s inflammatory response leading to different cognitive outcomes and amyloid concentrations. Other possible factors could include the number of proximal anastomoses because of the partial clamping of the aorta although the partial clamping was used in all of the patients, cross clamping in CABG patients, mild hypothermia, etc.
Our results also showed the association of the anaesthesia duration to the POCD but only in the off-pump group, which is quite interesting and different from the results in the available literature. In the off-pump group, the duration of the anaesthesia was correlated to worse results in the DRS attention tests.
There are many studies in the available literature comparing the different types of anaesthesia to different cognitive outcomes with various and contradictive results. In our study, the anaesthetic protocol was standard for all the patients, there was combined intravenous and inhalational anaesthetics so there was no bias resulting from different types of anaesthesia.
Since various factors associated to anaesthesia such as mechanical ventilation time and ICU time could affect cerebral oxygen metabolism according to multiple studies with contradictory results, we also compared the groups considering mechanical ventilation and ICU time and there were no significant differences. Intraoperative blood transfusion was significantly more common in the CABG group but we still did not find significant difference between the group considering the POCD.
The possible confounding bias caused by BMI, diabetes, heart failure and left ventricular ejection fraction was excluded dividing the patients in subgroups and comparing them considering the POCD where there were no significant differences. The correlations of age, BMI, ejection fraction, prothrombin time, urea and creatinine to Aβ1-42 concentrations and absolute changes of the concentration were tested with Spearman’s correlation factor and while there were no significant results, the only significant result was the correlation of BMI to smaller absolute change in Aβ1-42 plasmatic concentrations after the surgery (Table 3). This result is interesting because it is not expected—it can be interpreted in a way that the patients with larger BMI (obese patients) had ‘better’ results in the plasmatic amyloid shift. While there was no correlation of BMI to POCD, this smaller shift in the plasmatic amyloid concentrations could mean that there are complex processes in the amyloid pathophysiology connected to metabolic reactions.
In the CABG group the median systolic function of left ventricle is 59% (49%-61% interquartile range) which is significantly higher than the median ejection fraction of patients in the off-pump group (Mann Whitney U test, P = 0.04). 70.4% of the patients have ejection fraction higher than 50% and it was not significantly correlated to POCD (Table 3). In our study there were no patients with an acute heart failure, it was part of the exclusion criteria.
The association of POCD with postoperative amyloid values implicates Aβ proteins in the pathogenesis of early POCD, at least at this particular time interval. The relationship of Aβ1-42 to POCD in the early postoperative period may have important clinical implications, such as using amyloid levels as a mechanism for screening the patients with higher risk after they have undergone the surgery procedure. This screening could additionally guide the surgeon in the postoperative recovery using amyloids as a biomarker for cognitive impairment after surgery. If the POCD does result from mechanisms related to AD, then these patients may provide a suitable group for testing prophylactic therapies against AD, because effects would be seen in a short period. Our results could also be used in the development and application of non-pharmacological and pharmacological neuroprotective strategies and might lead to the study of amyloid-specific interventions to prevent these long term post-surgical effects. Since this is the first study comparing the on-pump CABG and off-pump procedures regarding both the POCD and potential biomarkers, we believe our results show the advantage of the off-pump surgery in patients with higher neurological risks and contributes to further research. Efforts should also be made in developing techniques which would lessen the duration of both on-pump and off-pump procedures, since the duration of the anaesthesia seems to be correlated to worse neurocognitive decline in the off-pump group. Further studies are needed to continue the investigation of the factors influencing the cognitive decline and amyloid shifting, such as ECC variables, partial clamping and others that could be modified and in that way improve the surgical technique.
Study limitations
We did not evaluate the binary outcomes of the data regarding the cognitive decline because the tests refer to different variables and cannot be compared in general, thus we believe we achieved more precise conclusions evaluating each test separately. This separate interpretation of the data limits the study in generalising the data. Another limitation is still not knowing the long term outcomes of the patients. Therefore, we are planning another study which would complete these early POCD data with the long term outcomes. The surgical procedures were performed by different surgeons so that might also be one of the limits, although there were no significant differences in operating time.