CPB during cardiac surgery has been demonstrated to cause alterations of the cerebral blood flow [14]. The main objective of this study was to evaluate if such changes in brain perfusion, as assessed by TCD, are related to the development of postoperative delirium, being one of the most frequent neuropsychologic complications in cardiac surgery. Our analyses revealed that patients with a reduced baseline MCAV, measured before CPB, are prone to experience relative cerebral hyperperfusion during CPB, when pump flow of the HLM is adjusted according to body weight and height. These patients demonstrated a significantly higher prevalence of delirium during the early postoperative period.
In the healthy adult brain, under physiological and normal intracranial pressure conditions, CBF is maintained constant over a definite range of perfusion pressure, i.e. systemic blood pressure. This phenomenon, termed cerebral autoregulation (CAR), ensures a CBF of about 50 ml per 100 g of brain tissue per minute, given that perfusion pressure is within a range of 60 to 160 mmHg [15]. During mild hypothermia for cardiac surgery, it is accepted that autoregulation is preserved [16]. In our study, overall static AI was 0.18 for the whole cohort, with no significant differences between the two groups, suggesting intact CAR in our patients. Hypothermia was very mild, as the mean body temperature was around 34 °C in both subgroups. Furthermore, PaCO2 values did not differ among no-POD and POD patients.
Delirium is one cardinal complication in cardiac surgery, significantly influencing the patients’ outcome [1]. Often occurring during the early postoperative period, it accounts for prolonged lengths of ICU and hospital stay. A number of risk factors have been identified, however, the detailed underlying pathogenetic mechanisms are still elusive [2, 17]. Although it is generally assumed that neurologic or neuropsychologic complications arise from insufficient cerebral perfusion (i.e. too low CBF), there is evidence for a critical role of cerebral hyperperfusion [15]. Patel et al. demonstrated a significant decline in late postoperative cognitive function in patients whose CBF during CPB was almost doubled compared to those that were clinically unremarkable [16]. Venn et al. could confirm these findings [18]. Cerebral hyperperfusion syndrome has originally been described as a result of therapeutic interventions on arterial vessels providing blood supply to the brain, e.g., following carotid endarterectomy (CEA) [19]. Usual symptoms include a triad of headache, seizure, and transient neurologic deficits. CT or MR imaging reveals, among others, a brain edema as pathophysiologic correlate [20]. Although rare, case reports give anecdotal reference to hyperperfusion syndrome following cardiac surgery, presenting with postoperative delirium [21]. In an animal model of selective cerebral perfusion, used during aortic surgery, Haldenwang et al. could demonstrate that high CBF, compared to a low-flow regimen, resulted in cerebral edema and increasing intracranial pressure [22]. Studies on septic, non-cardiac surgery patients revealed sepsis-induced disturbed CAR, likewise being associated with delirium and suggesting a role for hyperperfusion during episodes of critical surges of arterial blood pressure that overstress the autoregulative capacity of cerebral vessels [23,24,25,26].
We performed serial studies on cardiac surgery patients that revealed a significant association of the risk for postoperative delirium with increased mean CBF velocities, as assessed by TCD during CPB, relative to the pre-bypass baseline. These increases were not limited to any specific phase of CPB. Prevalence of POD in our cohort was 27%, being in accordance with recent review literature [12]. Our findings are in line with what is described by Hori et al., who used near-infrared spectroscopy (NIRS) to determine the upper limit of CAR [4]. Their analyses revealed that excursions of the MAP above this limit were significantly associated with an increased risk for postoperative delirium. According to calculation of AI, pressure CAR was intact in our patients, and MAP values during CPB did not differ between the two groups. However, we see intergroup differences in relative cerebral blood flow. This highlights the impact of HLM pump flow rate, which may affect cerebral perfusion completely independent of other CBF-regulating parameters such as systemic blood pressure [27].
In our patients, in contrast to the relative CBF, absolute MCAV during CPB did not differ between POD and no-POD group. Therefore, basal MCAV, which was used as reference when calculating the relative hyperperfusion during CPB, was significantly lower in patients that developed POD. The patients’ age has consistently been identified as one well-documented independent risk factor for the development of POD in cardiac surgery [2, 28]. Although cerebrovascular alterations or an increased incidence of neuropsychiatric disorders in the elderly patient likely play a pathogenetic role, specific underlying mechanisms for this relation have not yet been identified. Our analyses revealed a significant association between the patients’ age and a reduced baseline MCAV, which is known from previous studies [29, 30]. We defined cerebral hyperperfusion as relative MCAV > 100%, normalized to the baseline, suggesting that age-related reduced basal MCAV is a source of hyperperfusion during CPB. However, if a low pre-bypass baseline MCAV actually increases the individual vulnerability to intraoperative hyperperfusion leading to subsequent delirium, or if it may be just a reflection of a reduced cerebral metabolism in the elderly patient that per se increases the risk for POD cannot be answered clearly by our results. We observed that the risk for POD was markedly increased particularly in those patients with reduced baseline MCAV that were actually hyperperfused during CPB, compared to those without hyperperfusion periods. Furthermore, the cumulative duration of such hyperperfusion periods was associated with the development of delirium. This all gives rise to the assumption that CPB-induced hyperperfusion may reflect one possible mechanistic link between age and POD, when HLM pump flow is adjusted only according to the patient’s body weight and height. But additional studies are urgently required, including prospective design and randomized interventional perfusion strategies (e.g., conservative CPB management vs. adjustment to continuously monitored CBF), to determine the mechanistic role of age-related reduced MCAV for the development of POD following cardiac surgery and to clarify if prevention of relative cerebral hyperperfusion during CPB may reduce the risk for POD.
The relationship between CBF and TCD-derived MCAV remains one potential methodical limitation of our findings. Since Aaaslid et al. first described the use of TCD to assess CBF in 1982, numerous authors aimed to validate this method for various clinical situations, including CPB (see also Caldas et al. [31]). During mild hypothermic CPB, results may be ambiguous, but it can be assumed that at least changes of flow velocity in the MCA reflect changes in CBF as long as arterial CO2 partial pressure and thus the diameter of the basal cerebral arteries remain constant [32, 33]. Therefore, assessing cerebral perfusion as well as pressure CAR during CPB using TCD appears to be valid. In addition, although the impact of usual dosages of volatile anesthetics on this relationship seems to be small, we intentionally determined baseline MCAV in anesthetized and not in awake patients prior to CPB to exclude an effect of anesthesia induction on TCD measurements [34].
Preoperative hematocrit values were significantly higher than those obtained postoperatively. Although its influence is rather small, compared to pump flow or systemic blood pressure, changing hematocrit may alter CBF [35, 36]. If hemodilution affects the validity of TCD to evaluate CBF during CPB is still uncertain. While some authors showed that during deep hypothermic CPB, CBFV increases with decreasing hematocrit [37], others have demonstrated that under conditions of laminar flow, the linear association between flow and velocity is not altered by changes in hematocrit in clinically relevant ranges [38]. Moreover, non-pulsatile flow during CPB itself may reduce the impact of hemodilution on CBFV [39]. Thus, the findings of Paut and Bissonnette “[...] support the use of transcranial Doppler sonography to estimate cerebral blood flow [...] during bypass.” [38]. Furthermore, it has been shown that cerebral autoregulation is preserved even with decreasing hematocrit as long as PaCO2 is held within normal ranges [40]. In our patients, pre- as well as postoperative hematocrit values in the POD group equaled those in the no-POD group. Furthermore, neither in the whole cohort nor in any of the subcohorts, relative changes of hematocrit correlated with the relatively changing MCAV. Together with the observed association of subsequent POD not only with increased relative CBFV but also its duration, this makes a relevant effect of intraoperative hemodiluation on our findings highly unlikely.
In addition, other important possible confounders such as preexisting micronutrient deficiencies or clinically inconspicuous cognitive impairment cannot be ruled out with absolute certainty, as comprehensive preoperative tests (e.g., Nutritional Risk Screening (NRS), see also Ringaitienė et al. [41]) have not been performed. Furthermore, due to the short follow-up period of 48 h following extubation, we have no data on the possible development of postoperative cognitive dysfunction (POCD), which is said to occur weeks, months or even years after surgery, in contrast to POD, which is seen during the immediate postoperative period [10]. Further studies with extended follow-up are needed.