The relationship between intraoperative cerebral oximetry and postoperative delirium in patients undergoing off-pump coronary artery bypass graft surgery: a retrospective study

Cerebral oximetry has been widely used to measure regional oxygen saturation in brain tissue continuously and non-invasively, especially during general anesthesia [1]. Using near-infrared spectroscopy (NIRS), cerebral oximetry measures regional cerebral oxygen saturation (rSO₂) by analyzing the different intensities of light at specific wavelengths transmitted and received [2, 3] and monitor rSO₂ underlying frontal lobes, which are vulnerable to hypoxic and hypotensive injury [4].

Because the neurological outcome is still a matter of concern in cardiac surgery, cerebral oximetry-based resuscitation during cardiac surgery has been increasingly adopted by anesthesiologists [5]. Among post-cardiac surgery neurologic complications, the reported prevalence of delirium is from 3.1% up to 52% by population and diagnostic methods, with higher prevalence in older population and aortic surgery patients, and more detection with precise cognitive function test by highly trained personnel [6‐9]. Moreover, delirium is known to prolong intensive care unit and hospital stays, increase morbidity and mortality, and reduce cognitive and functional recovery [10‐12]. Thus, among neurologic complications, delirium is a serious and relatively common neurologic complication.

Despite the widespread use of cerebral oximetry, there have been inconsistent results regarding the relationship between the intraoperative use of cerebral oximetry and improved postoperative neurologic outcomes in cardiac surgery patients [13‐17]. There have been few trials designed to identify the optimal cut-off values for cerebral oximetry, resulting in various criteria being used by different studies. Moreover, few studies on cerebral oximetry in patients undergoing off-pump coronary artery bypass graft surgery (OPCAB) have been carried out.

To evaluate the relationship between the intraoperative cerebral oximetry and postoperative delirium and identify the optimal cut-off values for intraoperative cerebral oximetry during OPCAB, we retrospectively analyzed data of intraoperative cerebral oximetry values and postoperative delirium from patients who underwent OPCAB.

During the study period, 2333 patients underwent CABG. 1945 patients were undergone isolated CABG with general anesthesia. We also excluded 506 patients because of the perioperative support of IABP or ECMO, or intraoperative use of CPB. Finally, 1439 patients were included in the study. After data pre-processing, 815 patients in total were included. The flow chart for patient selection is shown in Fig. 1.

The baseline and perioperative characteristics of the patients are shown in Table 1 (no delirium group vs. delirium group, 710 [87.1%] vs. 105 [12.9%] patients). The delirium group had a higher average age and C-reactive protein level, and lower hematocrit, eGFR, and albumin readings, and more underlying hypertension. The group also had longer ICU and hospital stays and more frequent postoperative acute kidney injury and new onset atrial fibrillation and reintubation. In-hospital deaths numbered 3 (2.9%) in the delirium group and 0 in the no delirium group, but this did not reach the level of statistical significance.

The duration and number of intraoperative rSO₂ measurements below each cut-off are shown in Table 2. The duration of rSO₂ reduction was significantly longer in patients with delirium for the cut-offs of < 50 and 45% (for each group, mean duration (SD) of 138.7(202.7) and 64.6(141.5) vs. 100.9(159.6) and 39.3(100.6), p = 0.031 and 0.027, respectively). There was a significantly higher proportion of patients with an rSO₂ reduction < 45% among those with delirium (for each group, number of patients (%) of 228(32.1) vs. 44(41.9), p = 0.048). We also calculated number needed to treat (NNT) for the cut-off of 45%. According to the Table 2, the control event rate (CER) for delirium is 44/(44 + 228) = 0.16 and the experimental event rate (EER) for delirium is 61/(61 + 482) = 0.11. The absolute risk reduction (ARR) = CER-EER = 0.16–0.11 = 0.05, therefore the NNT is 1/(ARR) = 1/0.05 = 20. That is, 20 patients need to be treated to reduce 1 episode of delirium.

Intraoperative hemodynamic variables are shown in Supplementary Table 1 in Additional file 1. Based on the results of an ROC analysis for the mean values of each variable, the cut-off was determined as 68 mmHg, 2.2 L/min/m², and 64% for MAP, C.I., and SvO₂, respectively. The total durations of reduction below the cut-off and minimum values were calculated. For all three variables, the total duration of reduction below each cut-off was significantly longer in the delirium group than the no delirium group (p = 0.001), and these cut-off values were selected for a multivariable analysis as categorical variables.

The odds ratio (OR), 95% confidence interval (CI), and p-values of rSO₂ for each cut-off are shown in Table 3. The OR and 95% CI were calculated for every 5 min of rSO₂ reduction below each cut-off value. Age, sex, hypertension, preoperative hematocrit, eGFR, serum albumin and C-reactive protein level, intraoperative MAP, C.I. and SvO₂ reduction below each cut-off of ROC analysis were considered as covariables. There was no multicollinearity between the variables included in the analysis, especially between the intraoperative hemodynamic variables and rSO₂ for the occurrence of postoperative delirium. Multivariable logistic regression analysis revealed that the duration of rSO₂ below the 50 and 45% cut-offs was significantly associated with postoperative delirium (for every 5 min, adjusted OR 1.007 [95% CI 1.001–1.014] and 1.012 [1.003–1.021]; p = 0.024 and 0.011, respectively). Each model showed good fitness (Hosmer-Lemeshow’s goodness-of-fit: p = 0.729 and 0.962, respectively). The rSO₂ values below 45% for at least one measurement were significantly associated with postoperative delirium, and the model fitness was good (adjusted OR 1.737, p = 0.027; Hosmer-Lemeshow’s goodness-of-fit: p = 0.923; Table 4). According to the analysis of variance between the two group for the duration of rSO₂ reduction < 45% or 50%, and delirium, the p-values of linearity were < 0.05 and the p-values of deviation from linearity were > 0.05, indicating that there is a linear relationship between the duration of rSO₂ reduction below 45% or 50% and the probability of postoperative delirium. The duration of rSO₂ below 50 and 45% was also associated with postoperative acute kidney injury, a longer ICU stay, and longer hospital stay (Supplementary Table 2 in Additional file 1).

A post hoc power analysis was performed for the occurrence of rSO2 reduction < 45% with chi-squared test based on the result described in Table 2. The analysis revealed a power of this study above 0.95 for the occurrence of rSO2 reduction < 45%.

Based on the ROC analysis, the cut-off age for postoperative delirium occurrence was 68. We conducted a subgroup analysis based on this cut-off. Among 815 patients, 398 (48.8%) were under age 68, and delirium occurred in 19 patients (4.8%). Baseline and perioperative characteristics, including intraoperative hemodynamic variables, are shown in Supplementary Table 3 in Additional file 1. Based on a univariable analysis, preoperative EF, and albumin and C-reactive protein levels were selected for a multivariable analysis. Supplementary Table 4 Additional file 1 shows the duration and number of intraoperative rSO₂ values below each cut-off in patients under 68 years of age. The mean and minimum rSO₂ values were significantly lower in the delirium group. The duration of rSO₂ reduction was significantly longer in patients with delirium for the cut-offs of < 55, 50, and 45%, and the proportion of patients with an rSO₂ reduction below 50 and 45% was significantly higher among those with delirium. These cut-offs were higher than those of the overall group in Table 2. In the multivariable logistic regression analysis, the duration of rSO₂ lower than 55, 50, and 45% was significantly associated with postoperative delirium (for every 5 min, adjusted OR 1.012, 1.015, and 1.015, p = 0.035, 0.006, and 0.024, respectively), as shown in Table 5. However, the model fitness for the cut-off of 55% was not good (Hosmer-Lemeshow’s goodness-of-fit: p = 0.022), whereas those for the other cut-offs were good. The area under receiver operating characteristic (AUROC) for prediction models for patients under 68 years of age are shown in Additional file 2. The AUROC for the model without rSO₂ was 0.688 (95% CI 0.565–0.816, p = 0.007), and improved with rSO₂ measurement, up to 0.752 (95% CI 0.640–0.865, p < 0.001) with the duration of rSO₂ < 50%.

Among 417 patients over 68 years of age, the incidence of delirium was 20.6% (86/417). In the univariable analysis, older age, hypertension, and low preoperative eGFR were significantly associated with postoperative delirium in the old age group. However, there was no significant association between intraoperative reduction in rSO₂ and postoperative delirium for all cut-offs in either the univariable or the multivariable logistic regression analysis.

The results of this study suggest that decreases in intraoperative rSO₂ below 50% are associated with postoperative delirium after OPCAB. This was also associated with postoperative acute kidney injury and longer ICU and hospital stays. Among patients less than 68 years of age, rSO₂ lower than 55% was associated with postoperative delirium. However, in patients more than 68 years old, intraoperative rSO₂ was not associated with postoperative delirium.

The incidence of delirium in this study was 12.9%, slightly lower than reported by previous studies using similar diagnostic methods (23 to 52%) [9]. One of the reasons for this difference may be the age of the included patients, half of whom were under 68 years of age. Conversely, previous studies have included mostly patients over 60 years of age [9]. Age is one of the most powerful risk factors for delirium after cardiac surgery [29]. Furthermore, we selected only patients who had underwent OPCAB, while in previous studies both on-pump and off-pump cardiac surgery were included, with on-pump surgery being more common [9, 18, 19, 29]. Although the topic remains controversial, some studies have suggested that beating heart surgery can lower the risk of delirium caused by solid microemboli or the alteration of cerebral autoregulation during the cardiopulmonary bypass (CPB) period [18, 23, 30].

Considering the cut-off values for intraoperative rSO₂ during cardiac surgery, Yao and colleagues [17] set multiple thresholds indicating different degrees of hypoxic brain injury. They used 50, 45, 40, 35, and 30% as absolute values, corresponding to the baseline value minus 1, 1.5, 2, 2.5, and 3 SDs. A rSO₂ reduction below 40% was significantly associated with postoperative neurologic dysfunction after cardiac surgery with CPB based on a multivariable analysis. In several studies, including randomized controlled trials, prolonged cerebral desaturation below 50% as an absolute value or more than 20% of baseline was associated with postoperative cognitive decline [31‐34]. However, these studies were mostly conducted on cardiac surgery with CPB and evaluated only one or two thresholds rather than various cut-off ranges.

We aimed to determine whether there is a certain cut-off value for intraoperative rSO₂ during OPCAB associated with increased postoperative delirium. Previously, it has been shown that rSO₂ values measured by cerebral oximetry reflect a balance between oxygen consumption and supply in the frontal lobe, especially in the “water-shed” area in the junction between the anterior and middle cerebral arteries [3, 16]. Intraoperative cerebral hypoperfusion is also known to be related to postoperative neurological dysfunction after cardiac surgery [17, 30‐32]. However, several randomized controlled trials showed inconsistent results regarding the relationship between intraoperative rSO₂ reductions during cardiac surgery and postoperative neurologic outcomes. Two meta-analyses focusing on the use of cerebral oximetry and postoperative outcomes after cardiac surgery concluded that there was a low level of evidence linking intraoperative reductions in rSO₂ with postoperative neurologic outcomes [13, 35].

There may be several reasons for the inconsistent results regarding the usefulness of cerebral oximetry during cardiac surgery. First, heterogeneous patients were enrolled in previous studies. These studies involved various types of cardiovascular surgeries, including valvar surgery, coronary artery bypass surgery, cardiac tumor surgery, and aortic surgery, which involve different applications of intraoperative CPB and hypothermia. Transient but significant dysfunction in cerebral autoregulation and cerebral desaturation due to hemodilution or microemboli may occur with CPB. Cerebral oxygen consumption is also altered during CPB and hypothermia [14, 15, 17, 18, 36, 37]. Thus, with or without CPB, these heterogeneous populations may have led to inconsistent results. In the current study, to increase the homogeneity of patients, we included only patients who had undergone OPCAB without CPB.

In addition, previous studies including several randomized controlled trials, used various protocols and rSO₂ cut-off values to trigger intervention to restore rSO₂. This may also have contributed to the inconsistent results. Conversely, we evaluated the relationship between rSO₂ reductions and postoperative delirium at various cut-off values. By analyzing not only the occurrence but also the total duration of rSO₂ reduction, we aimed to identify the threshold of hypoxia exceeding the compensating capacity of the brain relating to the duration of cerebral desaturation.

We also included intraoperative MAP, C.I., and SvO₂ as risk factors for postoperative delirium occurrence. Although these hemodynamic variables can affect intraoperative cerebral perfusion and consequently postoperative delirium, they have not been included in many previous studies. In our study, by conducting a regression analysis, we attempted to rule out the possibility of multicollinearity between these hemodynamic variables and rSO₂.

In the subgroup analysis of patients under age 68, only preoperative EF, level of albumin, and C-reactive protein were associated with postoperative delirium by univariable analysis. The cut-off value of rSO₂ associated with postoperative delirium was 55%, which was slightly higher than the 50% cut-off for the entire study group. Moreover, in patients over age 68, rSO₂ was not associated with postoperative delirium. The pathophysiology of postoperative delirium is complex, and age is one of the most powerful risk factors, along with history of hypertension [6, 9, 19, 21]. Thus, in old patients, other factors associated with old age may more strongly influence the occurrence of postoperative delirium than intraoperative brain oxygenation.

This study has several limitations. First, because this study was retrospective in nature, risk factors that could affect postoperative delirium could not be perfectly controlled. Similarly, the anesthetic management to maintain or restore rSO₂ was not controlled. Second, this study involved cardiac surgery cases from 2004 to 2016, and surgical and anesthetic methods and techniques evolved over this period. These changes may have influenced the occurrence of postoperative delirium. Third, preoperative neurologic function was not assessed, and postoperative delirium was estimated using medical records and prescription history. The incidence of postoperative delirium may therefore have been underestimated. Finally, we could not assess the baseline rSO₂ values. Previous studies consistently found that preoperative baseline rSO₂ was associated with postoperative delirium in cardiac surgery [13, 15, 35]. However, since this was a retrospective study we could not access or identify the baseline rSO₂ before anesthesia induction or at the beginning of the surgery, and also the impact of baseline rSO₂ on postoperative delirium could not be evaluated. Consequently, the decrease in rSO₂ relative to the baseline was not estimated. The differences between the patients who were with low baseline and lesser reduction of rSO₂ and with high baseline and more reduction of rSO₂, could not be evaluated. We suggested that the baseline value itself may not be in normal physiologic values for cardiac surgery patients and the reserves from the baseline values may be different by the individuals. We based our hypothesis on our clinical experience, and thus we considered absolute cut-offs to be of more clinical significance. Considering the limitations of this study, prospective, randomized controlled studies may be needed to evaluate the effect of intervention to maintain rSO₂ over 50% (or 55% for patients under 68 years of age) during OPCAB.

In patients undergoing OPCAB, intraoperative rSO₂ below 50% was associated with postoperative delirium. Among patients younger than 68 years old, rSO₂ below 55% was associated with postoperative delirium. Therefore, rSO₂ should be maintained at over 50%, or over 55% among patients less than 68 years old, during OPCAB.