Cerebral Small Vessel, But Not Large Vessel Disease, Is Associated With Impaired Cerebral Autoregulation During Cardiopulmonary Bypass: A Retrospective Cohort Study

Abstract

BACKGROUND:

Impaired cerebral blood flow (CBF) autoregulation during cardiopulmonary bypass (CPB) is associated with stroke and other adverse outcomes. Large and small arterial stenosis is prevalent in patients undergoing cardiac surgery. We hypothesize that large and/or small vessel cerebral arterial disease is associated with impaired cerebral autoregulation during CPB.

METHODS:

A retrospective cohort analysis of data from 346 patients undergoing cardiac surgery with CPB enrolled in an ongoing prospectively randomized clinical trial of autoregulation monitoring were evaluated. The study protocol included preoperative transcranial Doppler (TCD) evaluation of major cerebral artery flow velocity by a trained vascular technician and brain magnetic resonance imaging (MRI) between postoperative days 3 and 5. Brain MRI images were evaluated for chronic white matter hyperintensities (WMHI) by a vascular neurologist blinded to autoregulation data. “Large vessel” cerebral vascular disease was defined by the presence of characteristic TCD changes associated with stenosis of the major cerebral arteries. “Small vessel” cerebral vascular disease was defined based on accepted scoring methods of WMHI. All patients had continuous TCD-based autoregulation monitoring during surgery.

RESULTS:

Impaired autoregulation occurred in 32.4% (112/346) of patients. Preoperative TCD demonstrated moderate-severe large vessel stenosis in 67 (25.2%) of 266 patients with complete data. In adjusted analysis, female sex (odds ratio [OR], 0.46; 95% confidence interval [CI], 0.25–0.86; P = .014) and higher average temperature during CPB (OR, 1.23; 95% CI, 1.02–1.475; P = .029), but not moderate-severe large cerebral arterial stenosis (P = .406), were associated with impaired autoregulation during CPB. Of the 119 patients with available brain MRI data, 42 (35.3%) demonstrated WMHI. The presence of small vessel cerebral vascular disease was associated with impaired CBF autoregulation (OR, 3.25; 95% CI, 1.21–8.71; P = .019) after adjustment for age, history of peripheral vascular disease, preoperative hemoglobin level, and preoperative treatment with calcium channel blocking drugs.

CONCLUSIONS:

These data confirm that impaired CBF autoregulation is prevalent during CPB predisposing affected patients to brain hypoperfusion or hyperperfusion with low or high blood pressure, respectively. Small vessel, but not large vessel, cerebral vascular disease, male sex, and higher average body temperature during CPB appear to be associated with impaired auto-regulation. (Anesth Analg 2018;127:1314–22)

Clinically asymptomatic strokes detected with brain imaging are prevalent in the elderly affecting over 25% of individuals ≥80 years of age.^1,2 Many of these strokes result from cerebral vascular disease manifest as stenosis of major cerebral arteries and/or as narrowing of small, penetrating arteries. The former is termed “large vessel disease” detected with various arterial imaging methods including catheter cerebral angiography, magnetic resonance angiography, or computed tomography angiography. In contrast, “small vessel disease” is indicated as white matter hyperintensities (WMHI) detected with conventional brain magnetic resonance imaging (MRI).^3,4 Several investigations have shown that WMHI are prevalent in patients undergoing cardiac surgery and that they are associated with postoperative stroke, delirium, and cognitive dysfunction.^5–9

The mechanism for the relationship between cerebral vascular disease and neurological complications after cardiac surgery is not entirely clear, but, in many cases, injury may result from cerebral hypoperfusion during cardio-pulmonary bypass (CPB).^10,11 Our group has found that approximately 20% of patients undergoing cardiac surgery have impaired cerebral blood flow (CBF) blood pressure autoregulation during CPB.^12,13 In this situation, CBF is pressure-passive predisposing to cerebral hypoperfusion or hyperperfusion with low and high blood pressure, respectively. We have found a relationship between excursions of mean arterial pressure (MAP) outside the CBF autoregulation range during CPB to be associated with stroke, postoperative delirium, and organ injury.^13–17 Given that WMHI are believed to result from atherosclerotic narrowing of penetrating arteries supplying subcortical and periventricular brain areas, it is plausible that perioperative neurological events in affected patients might be explained by impaired CBF.^1,3,4 Impaired autoregulation may further result from large vessel cerebral arterial stenosis.^13,18

Cerebral vascular disease is an important cause of stroke and cognitive decline in the general population, thus, identifying affected individuals is of high public health priority to institute secondary stroke preventative strategies.^1,3,4 Because brain imaging is not routinely performed before cardiac surgery, identifying surrogates of cerebral large and/or small arterial disease might provide perioperative physicians the opportunity for postoperative secondary prevention measures. The purpose of this study was to evaluate whether there is a relationship between cerebral large or small vessel disease and impaired CBF autoregulation during CPB. We hypothesize that patients with large cerebral artery and/or WMHI would have a higher prevalence of impaired CBF autoregulation during CPB.

METHODS

From October 2009 to December 2015, 349 patients undergoing cardiac surgery at The Johns Hopkins Hospital, Baltimore, MD, were enrolled in an ongoing prospective randomized clinical trial evaluating the value of real-time cerebral autoregulation monitoring for determining MAP targets during CPB for improving neurological outcomes. This retrospective cohort analysis involves data collected from that study. Thirteen patients were enrolled in 2009, 83 in 2010; 85 in 2011; 75 in 2012; 55 in 2013; 49 in 2014; and 25 in 2015. This retrospective cohort analysis involves data collected from that study. We have previously reported on outcomes from this patient group but have not previously evaluated cerebral vascular disease data in relation to autoregulation metrics.^{15–17,19,20} The study received the approval of the institutional review board of The Johns Hopkins Medical Institutions and all patients provided written informed consent. The clinical trial was registered at clinicaltrials.gov before patient enrollment (NCT00981474; Principal Investigator, Charles W. Hogue, MD; Registered September 22, 2009).

Preoperative Transcranial Doppler Evaluation

The patients underwent preoperative transcranial Doppler (TCD) examination by a trained vascular technologist 1–2 days before surgery. This occurred during their preoperative evaluation visit or on the hospital ward when the patients were admitted to the hospital before surgery. The primary aim of this examination was to confirm the presence of at least 1 transtemporal window for TCD monitoring of the middle cerebral artery during subsequent surgery. In compliance with institutional regulations, complete evaluation of cerebral hemodynamics of all major cerebral arteries is performed to assess for significant stenosis of the major cerebral arteries regardless if TCD is performed for research or clinical indications. For the present study, “large vessel” cerebral vascular disease was defined by the presence of characteristic TCD changes associated with stenosis of the major cerebral arteries. A short focal arterial stenosis produces an increase in maximal flow velocity (MFV); a reduced velocity can be observed in the presence of a long arterial narrowing or multiple distal stenoses.^18,21 Maximum flow velocities was obtained from the major arteries of the circle of Willis with a 4-second spectral Doppler data acquisition sweep. For the middle cerebral and the vertebral/basilar arteries, MFV was classified as normal when 46–70 cm/s. For the middle cerebral arteries, MFV was classified as consistent, with a moderate (>50%) or severe stenosis (>70%) when >100 or >120 cm/s, respectively. For the vertebral/basilar arteries, MFV was classified as consistent, with a moderate or severe stenosis when >80 or >110 cm/s, respectively.²²

The pulsatility index was determined to obtain information about impedance to blood flow.²³ A decrease in the pulsatility index of the middle cerebral artery can result from stenosis or occlusion of the internal carotid artery. An increase in pulsatility index can result from increased resistance distal to the site of insonation as caused by distal arterial stenosis.^22,24 Pulsatility index was calculated as: peak systolic velocity − end diastolic velocity/MFV. Normal pulsatility index ranges from 0.6 to 1.1, while values ≥1.2 indicate increased distal resistance.²² The accuracy of TCD for detecting intracranial arterial stenosis compared with computed tomography angiography is reported to be 89.5% (95% confidence interval [CI], 84.5%–94.4%).²²

Hemodynamic Management and Anesthesia

General anesthesia was with midazolam, fentanyl, and isoflurane, and vecuronium or rocuronium was given for skeletal muscle relaxation. Heparin was administered to achieve an activated clotting time >480 seconds. Nonpulsatile CPB flow was maintained with a target of 2.0–2.4 L/min/m². MAP was monitored from a radial artery catheter. The patients were managed with α-stat pH management. Continuous inline arterial blood gas monitoring was performed and calibrated hourly against arterial blood gas results. The patients were separated from CPB using institutional standard of care which includes administration of protamine when the patient was deemed stable.

Transcranial Doppler-Based Autoregulation Monitoring

Intraoperative TCD monitoring (DWL, Compumedics DWL, El Paso, TX) of the right and left middle cerebral arteries was initiated after the patients were anesthetized and their trachea intubated. This was performed by positioning two 2.5-MHz transducers fitted on a headband over the temporal bone. Depth of insonation was varied between 35 and 52 mm until representative spectral CBF flow was identified. Analog arterial pressure and TCD signals from the operating room hemodynamic monitor were processed with a data acquisition module (DT9800, Data Translation Inc, Marlboro, MA) and then analyzed by ICM+ software (University of Cambridge, Cambridge, United Kingdom) as described previously.^12,13,25 These signals were filtered as nonoverlapping 10-second mean values that were time-integrated, which is equivalent to having a moving average filter with a 10-second time window and resampling at 0.1 Hz, eliminating high-frequency components caused by respiration and pulse waveforms. Further high-pass filtering was applied with a DC cutoff set at 0.003 Hz. A continuous, moving Pearson correlation coefficient between changes in MAP and mean middle cerebral artery blood flow velocity was calculated to render the variable mean velocity index (Mx). Consecutive, average Mx values within a 10-second window were collected as 30 data points to monitor each Mx in a 300-second window. Mx approaches 1 when MAP is outside the limits of autoregulation, indicating pressure-passive CBF. In contrast, Mx approaches 0 or is negative when MAP is within the CBF autoregulation range. Average Mx values obtained during CPB were placed in 5 mm Hg MAP bins. Impaired CBF autoregulation was defined as an Mx ≥0.4 at all recorded MAPs.¹³

Magnetic Resonance Imaging

Brain MRI was performed between postoperative days 3 and 5. Brain imaging was not performed in patients who refused, who had retained temporary cardiac pace-making leads, when the research MRI scanner was not available, or when the patient was not deemed stable by the clinical team for transport to the MRI facility. The postoperative MRI scans were obtained as part of the parent study protocol to evaluate for diffusion-weighted injury patterns. The imaging sequences included oblique axial diffusion coefficient maps, T2, fluid-attenuated inversion recovery (FLAIR), and 3-dimensional spoiled gradient-echo (which allows 3-dimensional reconstruction) scans. These data were acquired on a Philips 3T MRI instrument (Philips Healthcare, Andover, MA).²⁶ Each MRI image was registered (first registering the corresponding spoiled gradient-echo scans) to a spatial standard, a digital form of the Montreal Neurological Institute atlas, using local registration methods or image warping, in which each voxel is individually displaced.²⁷ This technique results in better registration to an atlas than do global methods.²⁸ Registered images were read by a neurologist blinded to the patients’ preoperative TCD and intraoperative autoregulation data. WMHI were graded on a 0–9 scale by comparison to reference images as previously developed and validated for the Cardiovascular Health Study.^29,30 This scale accounts for a successive increase in the severity of WMHI from virtually absent (grade 0) to confluent periventricular WMHI (grade 9). All WMHI scores were assigned by a board-certified vascular neurologist (R.F.) who was blinded to the patients’ clinical and physiological data. “Small vessel” cerebral vascular disease was defined as a score ≥3.0.³¹

Data Analysis

This preoperative TCD portion of the protocol was stopped on November 14, 2014 due to logistic issues in obtaining timely examinations by the trained vascular technologist during the outpatient preoperative evaluation session when other testing was performed. The sample size of this study represents enrolled patients in whom TCD evaluation of the major cerebral arteries was performed. The present study was not an originally planned analysis of the prospectively performed study and, thus, is exploratory. Thus, a formal sample size calculation was not a performed for this aspect of the clinical trial.

Continuous variables were compared between groups using t test or Wilcoxon rank-sum test. Categorical variables were analyzed by χ² or Fisher exact test. All tests were run at a 0.05 level of significance. Logistic regression model was used to estimate the relationship between the probability of impaired autoregulation and large vessel cerebral vascular disease and separately for WMHI after adjustment for potential confounders. Variables chosen for the model are those that differed between patient with and without impaired cerebral autoregulation. Other variables included in each separate model were those variables that differed between each form of cerebral vascular disease (P < .05). All analyses were performed with Stata (Version 14.1, Stata Corp, College Station, TX).

RESULTS

Cerebral autoregulation data were not available from 3 of 349 patients. Characteristics and operative data for the remaining 346 patients comprising the study cohort are shown in Table 1. A study flow diagram is shown in Figure 1. Patient data in Table 1 are further divided for patients with versus those without large vessel cerebral vascular disease and for those with and without WMHI.

Table 1.

Demographic Information and Medical Characteristics for the Study Cohort and for Patients Based on the Presence or Absence of Large Vessel Cerebral Vascular Disease Based on Formal Transcranial Doppler Examination or MRI Determined WMHI

	Entire Study Cohort n = 346	No Large Vessel Disease n = 199	Large Vessel Disease Present n = 67	P Valuea	No WMHI n = 77	WMHI Present n = 42	P Valueb
Age (y), mean ± SD	70.8 ± 8.0	70.5 ± 8.0	70.1 ± 7.9	.737	69.1 ±8.0	73.7 ± 8.3	.004
Male sex, n (%)	244 (70.5)	141 (70.9)	47 (70.1)	.913c	57 (74.0)	12 (28.6)	.830c
Atrial fibrillation, n (%)	66 (19.1)	37 (18.6)	9 (13.4)	.455c	10 (13.0)	10 (23.8)	.198c
Chronic obstructive pulmonary disease, n (%)	38 (11)	25 (12.6)	8 (11.9)	1.0c	7 (9.1)	6 (14.3)	.540c
Asthma, n (%)	24 (6.9)	13 (6.5)	2 (3.0)	.369c	6 (7.8)	2 (4.8)	.711c
Current tobacco smoker, n (%)	33 (9.5)	23 (11.6)	4(6)	.245d	7 (9.1)	6 (14.3)	.540c
Diabetes mellitus, n (%)	162 (46.8)	94 (47.2)	33 (49.3)	.775d	39 (50.6)	21 (50.0)	.946d
Hypertension, n (%)	303 (87.6)	173 (86.9)	59 (88.1)	1.0c	63 (81.8)	36 (85.7)	.798c
Congestive heart failure, n (%)	64 (18.5)	31 (15.6)	12 (17.9)	.702c	15 (19.5)	5 (11.9)	.442c
Prior myocardial infarction, n (%)	82 (23.7)	53 (26.6)	15 (22.4)	.491d	18 (23.4)	14 (33.3)	.282c
Prior stroke, n (%)	34 (9.8)	17 (8.5)	11 (16.4)	.104c	3 (3.9)	5 (11.9)	.129c
Prior carotid endarterectomy, n (%)	16 (4.6)	6(3.0)	8 (11.9)	.009c	1 (1.3)	1 (2.4)	1.0c
Peripheral vascular disease, n (%)	62 (17.9)	28 (14.1)	18 (26.9)	.017d	10 (13.0)	11 (26.2)	.083c
Prior cardiac surgery, n (%)	38 (11)	18 (9.0)	10 (14.9)	.175d	4(5.2)	7 (16.7)	.051c
Medications
Aspirin, n (%)	271 (78.8)	152 (76.8)	56 (83.6)	.303c	61 (80.3)	33 (78.6)	.816c
“Statin” drugs, n (%)	107 (78.1)	47 (71.2)	20 (74.1)	1.0c	21 (77.8)	12 (85.7)	.214c
Angiotensin-converting enzyme inhibitors, n (%)	136 (39.5)	75 (037.9)	35 (52.2)	.039d	12 (30.3)	16 (38.1)	.418c
Angiotensin receptor blockers, n (%)	17 (12.5)	7 (10.8)	2 (7.4)	1.0c	3 (11.5)	4 (28.6)	.214c
β blockers, n (%)	226 (65.7)	121 (61.1)	51 (76.1)	.026d	45 (59.2)	24 (57.1)	.827d
Calcium channel blockers, n (%)	83 (24.1)	45 (22.7)	17 (24.4)	.658d	12 (15.8)	13 (31.0)	.063c
Diuretics, n (%)	139 (40.4)	84 (42.4)	29 (43.3)	.902d	24 (31.6)	13 (31.0)	1.0c
Nitrates, n (%)	70 (20.3)	40 (20.2)	17 (25.4)	.373d	17 (22.4)	14 (33.3)	.274c
Preoperative creatinine (mg/dL), mean ± SD	1.1 ±0.3	1.0 ± 0.3	1.1 ±0.3	.042	1.0 ± 0.3	1.0 ± 0.3	.417
Preoperative hemoglobin (g/dL), mean ± SD	12.6 ± 2.0	12.5 ± 2.0	12.7 ± 2.0	.542	12.7 ± 1.9	12.1 ± 1.5	.077
Preoperative systolic blood pressure (mm Hg), mean ± SD	137.1 ±21.2	136.3 ± 21.8	139.0 ± 20.5	.367	137.5 ± 22.9	139.3 ± 22.4	.680
Preoperative mean blood pressure (mm Hg), mean ± SD	94.0 ± 13.1	93.6 ± 13.5	94.8 ± 13.2	.520	93.7 ± 13.9	94.8 ± 13.6	.694
Duration of CPB (min)e	105(83–137)	104 (84–138)	101 (76–132)	.280	99 (79–130)	108 (69–143)	.865
Duration of aortic cross-clamping (min)e	67 (51–88)	65 (52–90)	65.5 (49–76)	.174	65 (53–90)	60 (44–92)	.294
Lowest hemoglobin during surgery (g/dL), mean ± SD	8.9 ± 2.3	9.0 ± 2.6	8.4 ± 1.5	.163	9.2 ± 2.8	8.5 ± 1.1	.179
Average rSco2 (%) during CPBe	55.7 (49.3–60.9)	55.5 (50.0–60.4)	54.7 (47.4–61.0)	.868	56.1 (50.5–60.2)	53.9 (45.5–60.7)	.282
Paco2 during CPB (mm Hg), mean ± SD	41.3 ± 3.0	41.1 ± 3.1	41.7 ± 2.4	.441	41.6 ± 2.8	40.3 ± 3.0	.021
Pao2 during CPB (mm Hg), mean ± SD	266.1 ± 44.7	264.5 ± 44.5	270.4 ± 48.2	.362	272.3 ± 58.4	272.1 ± 37.5	.948
pH during CPB, mean ± SD	7.39 ± 0.03	7.39 ± 0.03	7.39 ± 0.03	.760	7.39 ± 0.03	7.40 ± 0.04	.112
Average temperature during CPB (°C), mean ± SD	33.9 ± 1.6	33.8 ±1.5	34.0 ± 1.5	.450	33.9 ± 1.3	34.0 ± 1.6	.651
Minimum temperature during CPB (°C), mean ± SD	31.4 ± 3.0	31.4 ± 2.9	31.6 ± 3.3	.539	31.4 ± 2.6	31.5 ±2.7	.486
Mean arterial pressure during CPB (mm Hg)e	74.2 (69.6–78.9)	73.8 (69.4–79.3)	73.8 (69.2–79.2)	.864	74.7 (70.0–80.2)	74.3 (70.5–79.0)	.543
Lower limit of autoregulation during CPB (mm Hg), mean ± SD	66.3 ± 11.9	65.8 ± 11.8	66.8 ± 13.5	.626	65.6 ± 12.1	65.2 ± 12.0)	.877

Transcranial Doppler examination was obtained in 266 patients; brain MRI in 119 patients.

Abbreviations: CPB, cardiopulmonary bypass; MRI, magnetic resonance imaging; rSco2, regional cerebral oximetry determined with near-infrared spectroscopy monitoring; SD, standard deviation; WMHI, white matter hyperintensities.

^aP value refers to the comparison between patients with and without large vessel cerebral vascular disease.

^bP value refers to comparison between patients with and without WMHI.

^cFisher exact test.

^dχ² test.

^eData are listed as median, 25th–75th percentile.

Figure 1.

Study flow diagram. MRI indicates magnetic resonance imaging; TCD, transcranial Doppler.

Preoperative TCD examination of major cerebral arteries was performed in 282 of 346 patients. Usable TCD data were available, however, in only 266 patients. Thus, the evaluation of large vessel cerebral vascular disease is limited to the latter cohort. Of those patients, moderate-severe arterial stenosis of any major cerebral artery was detected in 67 (25.2%) of 266 patients. The majority of this disease was observed in the middle cerebral arteries (52 [19.5%] patients), with moderate-severe stenosis occurring less frequently in the basilar artery (23 [8.7%] patients) and vertebral artery (5 [1.8%] patients). Variables associated with large cerebral arterial disease included prior carotid endarterectomy (P = .009), peripheral vascular disease (P = .017), preoperative treatment with an angiotensin-converting enzyme inhibitor (P = .039) or β blocker (P = .026), and pre-operative serum creatinine level (P = .042),

Brain MRI data were available from 119 of 346 patients. Small vessel disease was detected in 42 (35.3%) of these patients. The frequency of the MRI flair score used for determining the presence of WMHI is shown in Figure 2. Reasons for not performing MRI were patient refusal (57 [25.1%] patients), research scanner not available (43 [18.8%] patients), discharge from hospital before scan (33 [14.4%] patients), retention of epicardial pacing wires (30 [13.3%] patients), retained facial metal detected with pre-MRI x-ray (20 [8.7%] patients), unable to tolerate MRI scan (21 [9.5%] patients), withdrawal from the study (12 [5.2%] patients), or mortality before MRI (11 [4.3%] patients).

Figure 2.

Brain magnetic resonance imaging results showing the percent of patients on the y-axis and the flair score on the x-axis. White matter hyperintensities were graded by a neuroradiologist blinded to other patient data based on the flair score using a scale from 0 to 9 (see Methods section). White matter hyperintensities were defined as flair score ≥3.^29,30

Of 86 patients with available TCD data and brain MRI scans, 13 (15.1%) had moderate-severe arterial stenosis of a cerebral artery, 26 (30.2%) had WMHI, and 4 (4.6%) had both moderate-severe arterial stenosis of a cerebral artery and WMHI. In this group of 86 patients, 21 (24.4%) had impaired CBF autoregulation. This was observed in 30 (34.9%) with WMHI and 17 (19.8%) with large vessel disease. Variable associated with WMHI included patient age (P = .004) and average Paco₂ during CPB (P = .021).

Impaired CBF autoregulation was observed during CPB in 112 of 346 (32.4%) patients. Patient demographic and medical information for these patients are shown in Table 2. Compared with patients with functional autoregulation, those with impaired autoregulation were more likely to be male (P = .012), have a shorter duration of CPB (P = .014), have lower average pH (P = .012), and have a higher average and minimum body temperature (P = .005). The patients with impaired autoregulation had a higher lower limit of autoregulation than patients with functional autoregulation (P < .001).

Table 2.

Demographic Information and Medical Characteristics for the Final Study Cohort and for Patients Based on the Presence or Absence of Impaired Cerebral Blood Flow Autoregulation During Cardiopulmonary Bypass Based on TCD

	Patients With Functional Autoregulation n = 234	Patients With Impaired Autoregulation n = 112	P Value
Age (y), mean ± SD	71.2 ± 7.8	69.9 ± 8.3	.140
Male sex, n (%)	155 (66.2)	89 (79.5)	.012a
Atrial fibrillation, n (%)	49 (20.9)	17 (15.2)	.202a
Chronic obstructive pulmonary disease, n (%)	28 (12)	10 (8.9)	.465b
Asthma, n (%)	17 (7.3)	7 (6.2)	.824b
Current tobacco smoker, n (%)	25 (10.7)	8 (7.1)	.334b
Diabetes mellitus, n (%)	115 (49.1)	47 (42)	.210a
Hypertension, n (%)	203 (86.8)	100 (89.3)	.602b
Congestive heart failure, n (%)	48 (20.5)	16 (14.3)	.185b
Prior myocardial infarction, n (%)	59 (25.2)	23 (20.5)	.338a
Prior stroke, n (%)	23 (9.8)	11 (9.8)	1.000b
Prior carotid endarterectomy, n (%)	9 (3.8)	7 (6.2)	.412b
Peripheral vascular disease, n (%)	42 (17.9)	20 (17.9)	.983a
Prior cardiac surgery, n (%)	27 (11.5)	11 (9.8)	.716b
Medications
Aspirin, n (%)	182 (78.1)	89 (80.2)	.661a
“Statin” drugs, n (%)	68 (75.6)	39 (83)	.388b
Angiotensin-converting enzyme inhibitors, n (%)	91 (39.1)	45 (40.5)	.792a
Angiotensin receptor blockers, n (%)	11 (12.1)	6 (13.3)	1.000b
β blockers, n (%)	157 (67.4)	69 (62.2)	.340a
Calcium channel blockers, n (%)	58 (24.9)	25 (22.5)	.631a
Diuretics, n (%)	94 (40.3)	45 (40.5)	.972a
Nitrates, n (%)	44 (18.9)	26 (23.4)	.328a
Preoperative creatinine (mg/dL), mean ± SD	1.07 ± 0.34	1.04 ± 0.27	.359
Preoperative hemoglobin (g/dL), mean ± SD	12.5 ± 2.0	12.7 ± 1.8	.289
Preoperative systolic blood pressure (mm Hg), mean ± SD	137.0 ± 21.5	137.4 ± 20.6	.859
Preoperative mean blood pressure (mm Hg), mean ± SD	93.7 ± 13.0	94.7 ± 13.3	.507
Duration of CPB (min)c	111 (84–142)	97 (80–121)	.014
Duration of aortic cross-clamping (min)c	69 (51.5–89.5)	63 (51–84)	.159
Lowest hemoglobin during surgery (g/dL), mean ± SD	9.0 ± 2.5	8.7 ± 1.5	.448
Average rSco2 (%) during CPBc	55.4 (49.3–60.4)	56.4 (49.9–62.3)	.246
Paco2 during CPB (mm Hg), mean ± SD	41.2 ± 3.1	41.6 ± 2.6	.162
Pao2 during CPB (mm Hg), mean ± SD	268.9 ± 46.4	260.1 ± 40.3	.084
pH during CPB, mean ± SD	7.39 ± 0.04	7.38 ± 0.03	.012
Average temperature during CPB (°C), mean ± SD	33.7 ± 1.6	34.2 ± 1.5	.005
Minimum temperature during CPB (°C), mean ± SD	31 ± 3.04	32.3 ± 2.7	<.001
Mean arterial pressure during CPB (mm Hg)c	74.6 (70.3–79.2)	73.7 (68.9–78.6)	.172
Lower limit of autoregulation during CPB (mm Hg), mean ± SD	64.8 ± 11.4	72.1 ± 11.9	<.001

Abbreviations: CPB, cardiopulmonary bypass; rSco₂, regional cerebral oximetry determined with near-infrared spectroscopy monitoring; SD, standard deviation; TCD, transcranial Doppler.

^aχ² test.

^bFisher exact test.

^cData are listed as median, 25th to 75th percentile.

Of the 67 patients with moderate-severe large vessel disease, 26 (38.8%) had impaired autoregulation during CPB. Variables associated with impaired autoregulation for patients with preoperative TCD assessment of the major cerebral arteries are shown in Table 3. In the adjusted model, female sex was associated with a lower odds for impaired autoregulation during CPB (odds ratio, 0.46; 95% CI, 0.25–0.86; P = .014), while higher average temperature during CPB was associated with a higher risk for impaired autoregulation (odds ratio, 1.23; 95% CI, 1.02–1.47; P = .029). Moderate-severe large cerebral arterial stenosis was not associated with impaired autoregulation during CPB in the adjusted model (P = .406).

Table 3.

Results of Multivariable Logistic Regression Model to Assess the Relationship Between Impaired Cerebral Blood Flow Autoregulation During Cardiopulmonary Bypass and Presence of Moderate to Severe Arterial Large Vessel, Among Patients With Usable Preoperative Transcranial Doppler Assessment of the Major Cerebral Arteries (n = 266 of 346 Patients in the Study Cohort)

	Adjusted Odds Ratio (95% Confidence Interval)	P Value
Moderate-severe arterial large vessel cerebral vascular disease	1.28 (0.71–2.29)	.406
Female versus male sex	0.46 (0.25–0.86)	.014
Age (per 1 y)	0.98 (0.95–1.01)	.279
Average temperature during CPB (per 1°C)	1.23 (1.02–1.47)	.029

The presence of large vessel cerebral vascular disease involving major cerebral arteries was based on characteristic transcranial Doppler findings as described in the Methods section. Area under ROC curve: (n = 266) 0.64 (95% confidence interval, 00.57–0.71).

Abbreviations: CPB, cardiopulmonary bypass; ROC, receiver operator curve.

Impaired autoregulation occurred in 15 (35.7%) of 42 patients with small vessel cerebral vascular disease. Variables that were associated with impaired CBF autoregulation during CPB for patients with MRI based on adjusted analysis are listed in Table 4. The presence of small vessel cerebral vascular disease was associated with a 3.2-fold higher odds (95% CI, 1.21–8.71; P = .019) of impaired CBF autoregulation during CPB after adjustment for age, history of peripheral vascular disease, preoperative hemoglobin level, and preoperative treatment with calcium channel blocking drugs. A higher proportion of patients in the impaired CBF autoregulation group had missing MRI data than in the functional CBF autoregulation group (74% vs 62%). Patient and procedural variables listed in Table 2 were evaluated between patients with and without brain MRIs. Factors associated with missing MRI data were history of hypertension (P = .067), preoperative treatment with angiotensin-converting enzyme treatment (P = .073), nitrates (P = .044), β-adrenergic receptor blockers (P = .045), and/or diuretics (P = .013).

Table 4.

Results of Multivariable Logistic Regression Model to Assess the Relationship Between Impaired Cerebral Blood Flow Autoregulation During Cardiopulmonary Bypass Among Patients and Postoperative Brain MRI Results to Determine the Presence of Small Vessel Cerebral Vascular Disease (N = 118)

Variable	Adjusted Odds Ratio (95% Confidence Interval)	P Value
Small vessel cerebral vascular disease	3.25 (1.21–8.71)	.019
Age (per 1 y)	1.01 (0.95–1.07)	.779
Peripheral vascular disease	0.58 (0.18–1.94)	.380
Calcium channel blocking drug use	0.86 (0.27–2.70)	.799
Preoperative hemoglobin level (per 1 g/dL)	1.20 (0.91–1.60)	.202

Small vessel cerebral vascular disease was diagnosed base on the scoring of the brain MRIs for white matter hyperintensities as described in the Methods section. Area under ROC curve: (N = 118) 0.65 (95% confidence interval, 0.53–0.78).

Abbreviations: MRI, magnetic resonance imaging; ROC, receiver operator curve.

DISCUSSION

In this study, we observed moderate-severe arterial stenosis of any major cerebral artery in 25.2% of patients. Cerebral small artery stenosis was observed in 35.3% of patients in whom brain MRI data were available. There was no significant relationship between large vessel disease of the major cerebral arteries and impaired autoregulation during CPB. Our results demonstrate that patients with small vessel cerebral vascular disease are more likely than those without this condition to have impaired CBF autoregulation during CPB. In adjusted analysis, the presence of small vessel cerebral vascular disease was associated with a 3.2-fold higher odds of impaired CBF autoregulation.

Approximately 8%–10% of the 900,000 strokes or transient ischemic attacks in the United States each year are due to intracranial arterial stenosis.^1,32 The risk of recurrent strokes in this population is estimated to be 23% at 1 year.^1,32 Identifying stroke subtype is advocated as a means to allow for a disease-specific treatment strategy.^1,33 The latter should include adherence to the American Heart Association/American Stroke Association guidelines for the prevention of stroke (eg, blood pressure control, statin therapy, use of aspirin when indicated, anticoagulation for atrial fibrillation, revascularization of carotid artery stenosis, etc).¹ The relationship between stenosis of major cerebral arteries and neurological complications after cardiac surgery is not well defined. Lee et al⁹ performed magnetic resonance angiography on 1367 Korean patients before CABG surgery. Nearly one-half of the 33 (45%) strokes early after surgery were judged as due to narrowing of large cerebral arteries. The nonsignificant relationship between moderate-severe large cerebral artery stenosis and impaired CBF autoregulation that we observed in this study might reflect collateral blood supply overcoming upstream obstruction to perfusion.

Cerebral small vessel disease manifest as WMHI is more common than large vessel disease particularly in elderly patients.¹ The latter lesions result from demyelination, axonal loss, and microinfarction due mostly to chronic ischemia.^3,4 WMHI are detected in 11%–21% of individuals >60 years of age but in up to 94% of individuals >80 years of age.^1,3,4 Several investigations have linked WMHI with risk for stroke, postoperative cognitive decline, and delirium after cardiac surgery.^5–8,34 Survival rate and stroke-free survival after a mean follow-up of 6 ± 4.3 years was lower in the patients with preexisting cerebral disease (P < .0001).⁸ Perfusion to cerebral white matter is via penetrating arteries that have poor collateral blood supply and thus are susceptible to hypotension.^3,4 Our finding that cerebral small vessel disease is associated with impaired CBF autoregulation is, thus, not surprising. Thus, monitoring of CBF auto-regulation during surgery might provide an approach for individualizing MAP targets to ensure perfusion to avoid ischemic brain injury.

We observed that male sex was associated with impaired CBF autoregulation. These results are somewhat surprising insofar as most women were elderly and postmenopausal and thus lacked the vascular protective effects of estrogens.³⁵ We are unable to explain this observation other a failure to consider an unknown residual confounding variable in our analysis. Patients with impaired autoregulation were also observed to have lower average pH during CPB and higher average temperature. Lower pH would conceivably lead to cerebral arterial dilation, but this is unlikely to explain impaired autoregulation insofar as pH remained within normal limits during CPB. Furthermore, continuous monitoring of arterial pH and Paco₂ was performed during surgery and adjustments to CPB flow and membrane oxygenator air/oxygen flow were made accordingly. We have previously noted that the rewarming phase of CPB is associated with a higher frequency of impaired autoregulation.¹² Our findings of higher average temperature during CPB in patients with impaired autoregulation compared with those with functional autoregulation, thus, is consistent with our previous findings. One might speculate that more aggressive patient rewarming could lead to higher cerebral temperature and cerebral vessel vasodilation contributing to our observations. Our findings, thus, further underscore the importance of temperature management for optimizing brain protection during surgery.³⁶

Our study has several limitations, particularly the likely lack of power to accurately ascertain any relationship between large cerebral artery stenosis and impaired CBF autoregulation. The sample size of this study was limited by the availability of a complete TCD examination by a vascular technologist. Despite this weakness, there are limited data from previous investigations that have provided an extensive TCD evaluation for major cerebral artery stenosis. The rate of moderate-severe intracranial stenosis in this cohort compared to that observed in primarily Asian populations (35.8% vs 13%–17%) might be explained in part by our enrollment of patients with higher risk for neurological complications and perhaps the different methodology.³⁷ Brain MRI data were available in only 119 patients, and the imaging was performed after surgery. As stated, WMHI primarily result from the effects of chronic brain ischemia leading to demyelination and microinfarction.^3,4 Acute brain ischemic injury during surgery is unlikely to contribute significantly to new WMHI in the short time frame that our postoperative brain imaging was performed. Thus, we assume that WMHI primarily represent preexisting brain ischemic injury from small cerebral vascular disease. Brain imaging is a challenging study end point in the immediate period after cardiac surgery, and reasons for not obtaining an MRI are listed in the Results section. Nonetheless, it is possible that failure to obtain MRI data may have led to unintended bias that may have reduced or increased the strength of the relationship between WMHI and impaired CBF autoregulation.

There is great interest in developing strategies for reducing the frequency of neurological complications of cardiac surgery given their relationship with other morbidity, mortality, and health care costs.³⁶ For the most part, these strategies have focused on the perioperative period. Many individuals, however, are vulnerable to stroke, cognitive decline, and stroke-related disability and mortality after hospital discharge from an index cardiac surgical procedure.^38,39 Thus, a comprehensive strategy for improving neurological outcomes for patients undergoing cardiac surgery should include the perioperative period and care after hospital discharge. Our results suggest that monitoring of CBF autoregulation during surgery holds promise in achieving both aims by allowing for individualization of MAP targets during and after surgery but also potentially by identifying individuals at high risk for small vessel vascular disease whom may benefit for secondary stroke prevention therapies. Nonetheless, this potential remains speculative and will require future investigations to fully address.

KEY POINTS.

• Question: Is cerebral small or large vessel vascular disease, a prevalent condition in elderly patients, associated with impaired cerebral blood flow autoregulation during cardiopulmonary bypass?

• Finding: We found stenosis of large cerebral arteries in 25% of patients, and brain magnetic resonance imaging detected white matter hyperintensities, an indicator of stenosis of small cerebral arterioles, in 35% of patients having brain magnetic resonance imaging. White matter hyperintensities, but not large cerebral arterial disease, were associated with impaired cerebral autoregulation.

• Meaning: Cerebral autoregulation monitoring may offer a potential biomarker of white matter hyperintensities in patients who may require careful perioperative blood pressure management and initiation of secondary stroke prevention strategies.