Cerebral Autoregulation Status in Relation to Brain Injury on Electroencephalogram and Magnetic Resonance Imaging in Children Following Cardiac Surgery

Abstract

Background

Disturbed cerebral autoregulation has been reported in children with congenital heart disease before and during cardiopulmonary bypass surgery, but not after. We sought to characterize the cerebral autoregulation status in the early postoperative period in relation to perioperative variables and brain injuries.

Methods and Results

A prospective and observational study was conducted in 80 patients in the first 48 hours following cardiac surgery. Cerebral oximetry/pressure index (COPI) was retrospectively calculated as a moving linear correlation coefficient between mean arterial blood pressure and cerebral oxygen saturation. Disturbed autoregulation was defined as COPI >0.3. Correlations of COPI with demographic and perioperative variables as well as brain injuries on electroencephalogram and magnetic resonance imaging and early outcomes were analyzed. Thirty‐six (45%) patients had periods of abnormal COPI for 7.81 hours (3.38 hours) either at hypotension (median <45 mm Hg) or hypertension (median >90 mm Hg) or both. Overall, COPI became significantly lower over time, suggesting improved autoregulatory status during the 48 postoperative hours. All of the demographic and perioperative variables were significantly associated with COPI, which in turn was associated with the degree of brain injuries and early outcomes.

Conclusions

Children with congenital heart disease following cardiac surgery often have disturbed autoregulation. Cerebral autoregulation is at least partly the underlying mechanism of brain injury in those children. Careful clinical management to manipulate the related and modifiable factors, particularly arterial blood pressure, may help to maintain adequate cerebral perfusion and reduce brain injury early after cardiopulmonary bypass surgery. Further studies are warranted to determine the significance of impaired cerebral autoregulation in relation to long‐term neurodevelopment outcomes.

Nonstandard Abbreviations and Acronyms

CICU

cardiac intensive care unit

COPI

cerebral oximetry/pressure index

CPB

cardiopulmonary bypass

ScO₂

cerebral oxygen saturation

STS‐EACTS

Society of Thoracic Surgeons‐European Association for Cardio‐Thoracic Surgery

Clinical Perspective.

What Is New?

• Disturbed cerebral autoregulation is reported in children with congenital heart disease before and during cardiopulmonary bypass surgery, but not after.

• Cerebral oximetry/pressure index was retrospectively calculated as a moving linear correlation coefficient between mean arterial blood pressure and cerebral oxygen saturation.

• We characterized the cerebral autoregulation status in 80 children in the early postoperative period in relation to perioperative variables and brain injuries.

What Are the Clinical Implications?

• Children following cardiac surgery often lose autoregulation at either hypotension or hypertension or both.

• Careful clinical management to maintain arterial blood pressure within a certain range may help to maintain adequate cerebral perfusion and reduce brain injury early after cardiac surgery.

Neurological sequelae in children with congenital heart disease (CHD) following cardiac surgery are well established. ¹ , ² , ³ , ⁴ , ⁵ Early postoperative brain injury occurs in 20% to 70% of patients, which is associated with poor neurodevelopmental outcomes. ⁶ , ⁷ , ⁸ Magnetic resonance imaging (MRI) and electroencephalography are often required to delineate these otherwise clinically silent lesions. ⁶ , ⁷ , ⁸ , ⁹ , ¹⁰ The cause of brain injury in these patients is multifactorial, involving in utero fetoplacental circulation as well as perioperative insults resulting from unstable hemodynamics (systemic and cerebral) and clinical interventions. ⁹ , ¹¹ , ¹² , ¹³

A potential cause is disturbed cerebral pressure autoregulation. Cerebral autoregulation is an intrinsic tendency of the brain to maintain a relatively constant cerebral blood flow across a range of arterial blood pressure. Disturbed autoregulation may present as the lack of good autoregulation of cerebral blood flow over the entire range of arterial pressure or as good autoregulation over an abnormally narrow range of arterial pressure, resulting in more time spent beyond the limits of autoregulation. Autoregulation is easily disturbed by different kinds of disturbing factors such as brain trauma, ¹⁴ ischemia, ¹⁵ or hypercapnia. ¹⁶ , ¹⁷ Optimal management of blood pressure in these patients is critical but difficult to achieve because of limited monitoring capabilities.

Near‐infrared spectroscopy is routinely used to monitor perioperative cerebral oxygen saturation (ScO₂) in children with CHD in many centers including ours. ScO₂ provides a noninvasive surrogate of cerebral blood flow when oxidative metabolism is relatively constant. ¹⁸ , ¹⁹ A moving, linear correlation coefficient between the change in ScO₂ and spontaneous fluctuation of blood pressure can be calculated as cerebral oximetry/pressure index (COPI). ¹⁸ COPI ranges from −1 to +1. When autoregulation is intact, the indices are near 0 or negative because blood pressure and cerebral blood flow are either weakly or negatively correlated. It should be noted the ScO₂ signal measured by near‐infrared spectroscopy contains both arterial and venous blood in the tissue. If an increase in arterial pressure causes cerebral arterial/arteriolar constriction, the amount of arterialized blood with high oxygen saturation will decrease relative to the venous compartment with low oxygen saturation. This will decrease ScO₂ and yield a negative correlation with blood pressure, although the cerebral venous oxygen saturation may not decrease. When blood pressure is outside the limits of autoregulation, COPI becomes increasingly more positive and approaches +1. This method has been validated in animal experiments ¹⁸ and applied in clinical settings. ²⁰ , ²¹ , ²² , ²³

Previous studies on autoregulation in children with CHD have focused primarily on pre‐ ²³ and intraoperative autoregulation. ²² , ²⁴ , ²⁵ Little is known about the postoperative status of autoregulation. ²⁶ The early postoperative period is vulnerable and characterized by systemic and cerebral hemodynamic instability and high incidence of new brain injury. ⁵ , ⁶ , ⁷ , ⁸ , ¹¹ Equally, previous studies have mostly focused on the lower limits of autoregulation and the risks of hypoperfusion with hypotension, ²⁰ , ²¹ , ²² , ²³ However, hypertension is not uncommon in children after cardiac surgery. In cardiac intensive care unit (CICU) management, catecholamines remain the mainstay to maintain blood pressure, but the treatment protocols may be inadequate due to the lack of scientific data. ¹¹ The upper limit of pressure autoregulation and its implications have not been examined.

Disturbed autoregulation has been linked with development of intracranial hemorrhage in newborns with hypoxic–ischemic encephalopathy ²⁰ and poor neurodevelopmental outcomes at 6 months or death after traumatic brain injury. ²¹ , ²⁷ In children during cardiopulmonary bypass (CPB) surgery, disturbed autoregulation has been related to elevation of brain injury biomarker serum glial fibrillary acidic protein. ²⁴ Other than these, the potential clinical implications of disturbed autoregulation remain largely to be explored in this special group of patients.

We hypothesized that disturbed or lost cerebral autoregulation would be frequently present in children with CHD early after cardiac surgery. It would occur at both hypo‐ and hypertensive states. It might be influenced by the demographic and perioperative factors and implicated with postoperative brain injuries on electroencephalogram and MRI and early outcomes (durations of CICU and hospital stay).

METHODS

The data supporting the analyses are presented in the Open Science Framework at https://osf.io/an5h4/

Ethical Statement

This prospective and observational study was approved by the institutional ethics committee at the Guangzhou Women and Children's Medical Center, Guangzhou, China (number 46201), and written informed consent was obtained.

Patients

Eighty patients undergoing cardiac surgery were enrolled between August 2020 and August 2021. Patients with more complex CHD were selected daily from the surgery list when 1 of the 3 electroencephalography machines was available. Patients with recognizable syndrome of congenital anomalies, previous CPB surgery, and scalp vein puncture were excluded.

Intraoperative Procedures and Postoperative Management

All patients received standard surgical procedures. ⁹ , ¹¹ CPB surgery was performed on all patients except those with coarctation of the aorta (n=7). Deep hypothermic circulatory arrest (range, 14–39 minutes; median, 18 minutes) was used in patients with interrupted aortic arch (n=2) or with coarctation of the aorta with ventricular septal defect (n=8). All patients received standard postoperative management as described in previous research. ⁹ , ¹¹

Methods of Measurements

Mean Arterial Blood Pressure

The MostCare device (Vytech, Padova, Italy) powered by the pressure recording analytical method was routinely used to monitor patients' postoperative systemic hemodynamics in the CICU. Detailed technique and setup are described elsewhere. ¹¹ A MostCare transducer was connected to 1 output of an indwelling arterial catheter. The raw data of mean arterial blood pressure were derived from the continuously recorded measures of systemic hemodynamics with sampling frequency of 1000 Hz. Obvious data artifacts were manually deleted.

Cerebral Oxygen Saturation

ScO₂ as a surrogate of cerebral blood flow was continuously monitored by INVOS 5100C near‐infrared spectroscopy (Medtronic and Covidien, Troy, MI) at a sampling rate of −0.17 Hz. Bilateral ScO₂ was averaged. Obvious data artifacts were manually deleted.

Cerebral Autoregulation

Consecutive raw data of mean arterial blood pressure and ScO₂ from MostCare and INVOS, respectively, were recorded simultaneously with a 6‐second interval and transferred to the bedside computer using Serial Port Analysis software (www.daxia.com). A continuous, moving Pearson correlation coefficient between mean arterial blood pressure and ScO₂ was calculated to generate the COPI, ²⁴ using the following formula:

where n indicates the number of samples in each data set, x indicates blood pressure, and y indicates cerebral oxygen saturation.

Consecutive, paired values from 300‐seconds duration (50 data sets) were used for each calculation. COPI was calculated every 6 seconds from overlapping time periods. Disturbed or lost cerebral autoregulation was defined as COPI >0.3. ²⁴ A histogram was graphed for each subject with COPI values placed into each paired 5‐mm Hg mean arterial blood pressure bins. The individual lower and upper limits of pressure autoregulation were defined as the 1 of 4 contiguous bin averages >0.3. ²⁴ Each patient's autoregulation curve was analyzed to identify the lower and higher limits of autoregulation and optimal range of arterial blood pressure that was spontaneously fluctuated.

Electroencephalogram

The Nicolet Monitor (CareFusion, Middleton, WI) with international 10 to 20 system was used for continuous video electroencephalogram recording. ²⁸ The electroencephalogram background was categorized as normal, mild, moderate, and severe based on previous methods. ²⁹ Spike/sharp waves were defined as high amplitude (≥2.5 times of background voltage) and short duration (<200 ms). Electrographic seizures were defined as epileptiform discharges ≥10 s. ³⁰ The number of spikes/sharp waves and the duration of seizures were summarized every 1 hour. The delta brushes consisted of slow waves (0.3–1.5 Hz) and superimposed fast activity (8–22 Hz). ³¹ Abnormal sleep–wake cycling was defined as sleep–wake cycling absence in neonate or stage 2 sleep transients' absence in children. ²⁹ All electroencephalograms were analyzed by the qualified technicians (R.L. and S.N.) independently.

The above monitoring was started after arrival in the CICU and continued for 48 hours.

Cerebral MRI

Cerebral MRI scans were performed on a 3.0T magnetic resonance system (Magentom Prisma scanner; Siemens, Germany) after surgery before discharge. The MRI sequences consisted of standard T1‐, T2‐, and diffusion‐weighted imaging and diffusion‐tensor imaging. Brain injury was graded as normal, mild, moderate, and severe according to the presence of white matter injury, infarction stroke, and hemorrhage (intraparenchymal, intraventricular, and subdural). ³² All MRI results were evaluated by a pediatric neuroradiologist (M. Zhang).

Clinical and Demographic Data

Demographic and Society of Thoracic Surgeons‐European Association for Cardio‐Thoracic Surgery (STS‐EACTS) Morbidity and Mortality Category, ³³ , ³⁴ durations of CPB surgery, and aortic cross‐clamping, deep hypothermic circulatory arrest, and postoperative mechanical ventilation were collected.

Administration of Inotropic and Vasoactive Drugs

Dose of inotropes (dopamine, epinephrine, and milrinone) along with blood gases and lactate were collected every 3 hours. The doses of inotropic and vasoactive drugs were adjusted to maintain arterial blood pressure (systolic pressure 60–90 and 90–105 mm Hg and diastolic pressure of 40–60 and 55–66 mm Hg in neonates and children, respectively). The inotropic and vasoactive drugs were adjusted by the clinicians who were unaware of the autoregulation status.

Statistical Analysis

Data were described as mean (SD), median (range), or frequency (percent) when appropriate. The independent‐samples t test, Mann‐Whitney U test, or χ² test were used to compare demographic and clinical data between groups. Mixed linear regression for repeated measures was used to analyze the temporal trends of the variables and correlations of COPI with other variables. The parameter estimate used indicated the degree or slope and direction of the correlations. The PROC HPMIXED procedure was used to fit the large‐scale data (SAS 9.4; SAS Institute, Cary, NC).

Results

Table 1 presents demographic and clinical data of the 80 patients. There were no major adverse events (cardiac arrest, use of extracorporeal membrane oxygenation, or death) during hospitalization.

Table 1.

Demographics and Clinical Data in 80 Patients Undergoing Cardiac Surgery

Variable	Patients with abnormal COPI, n=36	Patients without abnormal COPI, n=44	P value
Sex			0.489
Boy	24	24
Girl	12	19
Weight, kg	5.6 (2.7)	5.9 (1.8)	0.610
Height, cm	60.6 (10.0)	62.4 (7.9)	0.385
Age, d	118.5 (3–1541)	134.0 (4–635)	0.456
STS‐EACTS Morbidity Category			0.754
1	16 (44%)	21 (48%)
DCRV repair, n=1		n=1
TOF repair, no ventriculotomy or transannular patch, n=19	n=7	n=12
VSD closure, n=17	n=9	n=8
2	9 (25%)	14 (32%)
Bidirectional Glenn, n=1	n=1
Coarctation of aorta repair, n=7	n=3	n=4
Complete AVSD repair, n=3	n=1	n=2
RV to PA conduit placement, n=1		n=1
RVOT procedure, n=4	n=2	n=2
TOF repair, ventriculotomy, transannular patch, n=5	n=2	n=3
Tricuspid valvuloplasty, n=2		n=2
3	7 (19%)	6 (14%)
Anomalous origin of coronary artery repair, n=1	n=1
Aortic arch repair, n=1	n=1
Coarctation of aorta and VSD repair, n=8	n=3	n=5
DORV, intraventricular tunnel repair, n=1	n=1
Pulmonary artery sling repair, n=2	n=1	n=1
4	4 (11%)	3 (7%)
ASO and VSD repair, n=1		n=1
Interrupted aortic arch repair, n=2	n=1	n=1
Modified Blalock‐Taussig shunt, n=1	n=1
TAPVC repair, n=3	n=2	n=1
STS‐EACTS Mortality Category			0.524
1	16 (44%)	21 (48%)
2	9 (25%)	11 (25%)
3	5 (14%)	9 (20%)
4	6 (17%)	3 (7%)
Cardiopulmonary bypass time, min	113.4 (60.1)	114.7 (55.3)	0.918
Aortic cross‐clamping time, min	62 (0–203)	62 (0–174)	0.835
Deep hypothermic circulatory arrest time, min	0 (0–39)	0 (0–27)	0.643
Postoperative mechanical ventilation time, h	48.5 (0–211)	28.5 (0–1218)	0.097
Temperature, °C	37.0 (34.8–39.0)	37.1 (36.0–38.8)	0.001
PaCO2, mm Hg	36.0 (18.0–61.5)	36.8 (21.0–84.0)	0.019
PaO2, mm Hg	115.5 (27.75–374.25)	113.25 (47.25–385.25)	0.526
SaO2, %	99 (66–100)	99 (69–100)	0.066
Lactate, mmol/L	1.2 (0.3–15.0)	0.9 (0.2–12.8)	<0.001
Dopamine, mcg/kg per min	6.0 (0–10.0)	6.0 (0–9.9)	0.012
Milrinone, mcg/kg per min	0.54 (0–0.84)	0.56 (0–0.83)	0.144
Epinephrine, mcg/kg per min	0.05 (0–0.5)	0.05 (0–0.17)	<0.001
CICU stay, d	4 (0–13)	4 (0–99)	0.287
Hospital stay, d	12 (4–31)	9.5 (4–99)	0.167

ASO indicates arterial switch operation; AVSD, atrioventricular septal defect; CICU, cardiac intensive care unit; COPI, cerebral oximetry/pressure index; DCRV, double‐chambered right ventricle; DORV, double outlet right ventricle; PA, pulmonary artery; PaCO₂, partial pressure (arterial) of carbon dioxide; PaO₂, partial pressure (arterial) of oxygen; RV, right ventricle; RVOT, right ventricular outflow tract; SaO₂, saturation of oxygen; STS‐EACTS, Society of Thoracic Surgeons‐European Association for Cardio‐Thoracic Surgery; TAPVC, total anomalous pulmonary venous connection; TOF, tetralogy of Fallot; and VSD, ventricular septal defect.

Changes of COPI, Electroencephalogram, and Clinical Variables in the First Postoperative 48 Hours

COPI significantly decreased during the 48 hours from 0.01 (0.38) to −0.05 (0.34) (parameter estimate, −2.7E‐6; P<0.0001). The time spent with COPI >0.3 was significantly less in the second 24 hours compared with the first 24‐hour period (4.70 versus 5.14 hours, P<0.0001). COPI >0.3 suggesting disturbed cerebral autoregulation was found in 36 (45%) patients with cumulative periods of 7.81 (3.38) hours (range, 0.28–14.76 hours). The lower and upper limits of autoregulation of COPI were <40 to 55 mm Hg (median, 45; n=16) and >75 to 115 mm Hg (median, 90; n=11), respectively (Figure [A] and [B]). The remaining 9 patients showed disturbed autoregulation at both hypotension and hypertension (Figure [C]). Compared between the first and second 24‐hour periods, the lower and upper limits of autoregulation of COPI were identified in 36 patients as being <40 to 60 mm Hg (median, 45 mm Hg) and >77 to 100 mm Hg (median, 92 mm Hg) in the first 24 hours; the lower and upper limits of autoregulation of COPI were identified in 24 patients as being <35 to 55 mm Hg (median, 50 mm Hg) and >60 to 104 mm Hg (median, 95 mm Hg) in the second 24 hours.

Figure Figure. . Continuous autoregulatory measurements.

For each subject, cerebral oximetry/pressure index (COPI) is plotted over mean arterial blood pressure (MABP), and a COPI value of 0.3 (horizontal dashed line) is the threshold of lost autoregulation used in this study. Examples demonstrate abnormal COPI below the lower limit of autoregulation in a 10‐day‐old boy with coarctation of the aorta and ventricular septal defect (A), above the upper limit of autoregulation in a 98‐day‐old boy with tetralogy of Fallot (B), and beyond both the lower and upper limits of autoregulation in a 44‐day‐old boy with ventricular septal defect (C).

There was a significant increase in central body temperature and partial arterial pressure of carbon dioxide, and decrease in mean arterial blood pressure, partial arterial pressure of oxygen and saturation of oxygen, lactate, and doses of dopamine, epinephrine, and milrinone over the 48 hours (P≤0.0008) (Table 2).

Table 2.

Mean (SD) of the Clinical Data During the First 48 Hours After Cardiac Intensive Care Unit Admission in 80 Patients

Variable	Time, h
	0	3	6	9	12	15	18	21	24	27	30	33	36	39	42	45	48	Parameter estimates	P time value
Cerebral oximetry/pressure index	0.01 (0.38)	0.01 (0.36)	0.00 (0.36)	0.01 (0.36)	0.03 (0.37)	−0.01 (0.37)	−0.01 (0.40)	−0.01 (0.39)	−0.01 (0.36)	−0.01 (0.36)	−0.01 (0.38)	0.01 (0.36)	0.01 (0.35)	−0.03 (0.37)	0.00 (0.35)	−0.01 (0.34)	−0.05 (0.34)	−0.00066	<0.0001
Temperature, °C	36.9 (0.6)	37.3 (0.7)	37.2 (0.5)	37.2 (0.5)	37.1 (0.5)	37.1 (0.6)	37.0 (0.5)	37.1 (0.5)	37.1 (0.5)	37.1 (0.6)	37.1 (0.5)	37.1 (0.6)	37.1 (0.6)	37.1 (0.5)	37.0 (0.6)	37.1 (0.5)	37.0 (0.4)	0.002505	<0.0001
Mean arterial blood pressure, mm Hg	64.8 (10.6)	65.2 (11.7)	66.3 (10.6)	65.0 (10.3)	62.2 (10.2)	62.6 (9.4)	61.6 (9.8)	63.4 (9.6)	64.1 (11.3)	63.3 (10.5)	64.2 (10.1)	62.8 (9.9)	61.8 (9.8)	62.2 (10.0)	63.7 (9.8)	65.4 (10.6)	68.8 (10.2)	−0.01766	<0.0001
PaCO2, mm Hg	38.3 (7.6)	37.1 (8.5)	34.6 (7.3)	35.1 (6.2)	33.1 (5.3)	36.2 (6.9)	36.2 (6.5)	34.8 (4.8)	35.8 (6.7)	37.1 (7.2)	37.1 (6.7)	38.7 (6.2)	38.6 (5.6)	38.7 (6.9)	38.3 (6.9)	37.9 (6.4)	38.5 (7.4)	0.08244	<0.0001
PaO2, mm Hg	152.4 (66.0)	128.8 (46.2)	120.2 (41.5)	115.3 (49.3)	121.1 (46.2)	119.9 (52.2)	114.5 (47.5)	129.3 (54.3)	124.6 (50.2)	127.8 (65.1)	115.9 (50.0)	107.9 (32.7)	117.5 (48.6)	122.7 (41.0)	119.7 (40.4)	116.0 (44.2)	127.7 (52.5)	−0.5192	<0.0001
SaO2, %	98.1 (3.5)	97.2 (5.7)	97.4 (4.5)	97.5 (2.5)	97.1 (5.4)	97.4 (3.5)	97.4 (3.4)	97.9 (3.8)	97.9 (2.8)	97.8 (2.5)	97.4 (3.8)	97.8 (2.1)	97.3 (3.8)	98.4 (1.4)	97.6 (3.6)	97.7 (2.4)	98.0 (2.7)	−0.00149	0.0008
Lactate, mmol/L	2.1 (1.7)	2.5 (2.2)	2.4 (2.5)	2.4 (2.6)	1.7 (1.9)	1.8 (1.6)	1.5 (1.3)	1.3 (1.0)	1.4 (1.5)	1.3 (0.9)	1.2 (1.1)	1.3 (0.8)	1.2 (1.2)	1.2 (0.7)	1.4 (1.7)	1.3 (1.7)	1.3 (1.6)	−0.01915	<0.0001
Dopamine, mcg/kg per min	6.1 (1.5) (n=79)	6.1 (1.4) (n=79)	6.1 (1.4) (n=79)	6.2 (1.4) (n=79)	6.1 (1.4) (n=79)	6.1 (1.5) (n=79)	6.0 (1.7) (n=76)	5.9 (1.9) (n=77)	6.0 (1.8) (n=76)	6.0 (1.6) (n=75)	5.9 (1.7) (n=75)	5.9 (1.8) (n=75)	5.8 (1.8) (n=74)	5.7 (2.1) (n=71)	5.2 (2.4) (n=65)	5.2 (2.4) (n=65)	5.2 (2.4) (n=63)	−0.01292	<0.0001
Milrinone, mcg/kg per min	0.6 (0.1) (n=74)	0.6 (0.1) (n=74)	0.6 (0.1) (n=74)	0.6 (0.1) (n=74)	0.6 (0.1) (n=74)	0.6 (0.1) (n=74)	0.6 (0.1) (n=72)	0.6 (0.1) (n=69)	0.6 (0.1) (n=68)	0.6 (0.1) (n=67)	0.6 (0.1) (n=67)	0.6 (0.1) (n=66)	0.5 (0.1) (n=65)	0.5 (0.2) (n=64)	0.5 (0.2) (n=59)	0.5 (0.2) (n=58)	0.5 (0.2) (n=56)	−0.00075	<0.0001
Epinephrine, mcg/kg per min	0.08 (0.05) (n=49)	0.09 (0.07) (n=49)	0.08 (0.07) (n=49)	0.09 (0.07) (n=49)	0.08 (0.06) (n=49)	0.08 (0.06) (n=49)	0.07 (0.04) (n=45)	0.07 (0.05) (n=45)	0.07 (0.05) (n=41)	0.07 (0.05) (n=38)	0.07 (0.05) (n=38)	0.07 (0.05) (n=37)	0.07 (0.05) (n=37)	0.06 (0.05) (n=35)	0.06 (0.05) (n=33)	0.05 (0.05) (n=30)	0.05 (0.05) (n=29)	−0.00075	<0.0001

PaCO₂ indicates partial pressure (arterial) of carbon dioxide; PaO₂, partial pressure (arterial) of oxygen; and SaO2, saturation of oxygen.

Electroencephalogram background abnormality was found in 37 (46.3%) patients, a mild degree in 29 patients, moderate in 3 patients, and severe in 5 patients. Electroencephalogram seizures were found in 10 (12.5%) patients (seizure time range, 96–38 808 s; median, 2830 s), spikes/sharp wave in 77 patients (96.3%), abnormal sleep–wake cycling in 8 patients (10%), delta brushes in 3 patients (3.8%). Overall, the degree of background abnormalities reduced gradually over 48 hours. Spikes/sharp waves and abnormal sleep–wake cycling reduced significantly (P<0.0001). The onset of seizures was not related to time (P=0.23).

Brain Injury on MRI

Postoperative MRI was performed in 65 (81.3%) patients on postoperative day 7 (2.5). Among them, a normal MRI was found in 31 (47.7%) patients, a mild degree of brain injury in 32 (49.2%) patients, and a severe degree in 2 (3.1%) patients. Among these patients, 2 (3.1%) patients had white matter injury and stroke, and 34 (52.3%) patients had hemorrhage.

Correlations of COPI With Demographic and Perioperative Variables

In both univariable and multivariable regression analyses, the magnitude and duration of COPI were significantly correlated with all of the demographic and perioperative variables (P≤0.0001) except central body temperature (range, 34.8–38.8 °C; median, 37.0 °C), partial arterial pressure of oxygen (range, 28–485 mm Hg; median, 114 mm Hg), and saturation of oxygen (range, 66–100 mm Hg; median, 99 mm Hg) in univariable regression analysis (Table 3).

Table 3.

Regression Analysis Results of the Cerebral Oximetry/Pressure Index Correlations With Demographic and Perioperative Variables

	Univariable regression analysis		Multivariable regression analysis
	Parameter estimate	P value	Parameter estimate	P value
Age	−0.0000	<0.0001	0.000036	<0.0001
BSA	−0.2691	<0.0001	−0.3051	<0.0001
STS‐EACTS Morbidity Category	0.0218	<0.0001	0.008244	<0.0001
STS‐EACTS Mortality Category	0.0192	<0.0001	0.007959	<0.0001
Cardiopulmonary bypass time	−0.0000	<0.0001	0.000524	<0.0001
Aortic cross‐clamping time	−0.0002	<0.0001	−0.00083	<0.0001
Deep hypothermic circulatory arrest use	0.0529	<0.0001	0.007127	0.0026
Postoperative mechanical ventilation time	0.0002	<0.0001	0.000108	<0.0001
Temperature	0.0013	0.1860	…	…
PaCO2	0.0007	<0.0001	−0.00035	0.0030
PaO2	0.0000	0.1401	…	…
SaO2	−0.00	0.9819	…	…
Lactate	−0.0066	<0.0001	…	…
Dopamine	−0.0138	<0.0001	0.01623	<0.0001
Milrinone	−0.1098	<0.0001	−0.3351	<0.0001
Epinephrine	0.2257	<0.0001	0.2498	<0.0001

BSA indicates body surface area; PaCO₂, partial pressure (arterial) of carbon dioxide; PaO₂: partial pressure (arterial) of oxygen; SaO₂, saturation of oxygen; and STS‐EACTS, Society of Thoracic Surgeons‐European Association for Cardio‐Thoracic Surgery.

Correlations of COPI With Brain Injuries on Electroencephalogram and MRI and Early Outcomes

The magnitude or duration or both of COPI significantly correlated with electroencephalogram abnormalities after being adjusted for time (P<0.0001). COPI also significantly correlated with the degree of brain injuries on MRI (P<0.0001) (Table 4). There was no significant difference in white matter injury, stroke on MRI between patients with abnormal cerebral autoregulation at hypotension or hypertension and patients without abnormal COPI. In patients with abnormal cerebral autoregulation at both hypo‐ and hypertension, the incidence of hemorrhage was significantly higher compared with the normal group without disturbed autoregulation (P=0.023). In the 45% of patients with periods of COPI >0.3, both the electroencephalogram and MRI brain injury were significantly greater compared with those without COPI >0.3 (P<0.0001).

Table 4.

Correlations of Cerebral Oximetry/Pressure Index With Electroencephalogram and MRI Abnormalities

Dependent variable	Magnitude of cerebral autoregulation index		Duration of abnormal cerebral autoregulation index
	Parameter estimate	P value	Parameter estimate	P value
Electroencephalogram abnormalities
Background abnormalities	0.01527	<0.0001	0.02426	0.2908
Seizures duration	250.57	<0.0001	681.97	<0.0001
No. of spikes/sharp waves	0.09827	<0.0001	1.5655	0.3939
No. of delta brushes	0.01424	0.4817	−0.2016	<0.0001
Abnormal sleep–wake cycling	0.02718	0.3700	0.006866	<0.0001
Intraoperative isoelectric state	4.7007	<0.0001	2.7555	<0.0001
Abnormal background by 48 h	0.02307	<0.0001	−0.00271	<0.0001
Degree of MRI brain injury	0.2070	<0.0001	0.02743	<0.0001

MRI indicates magnetic resonance imaging.

Discussion

The major findings of this study are as follows: (1) 45% of patients had periods of abnormal COPI at either hypotension (median, <45 mm Hg) or hypertension (median, >90 mm Hg) or both during the 48 hours following cardiac surgery. (2) Overall, COPI became significantly lower over time. (3) Most of the demographic and perioperative variables significantly correlated with COPI, which in turn significantly correlated with the degree of brain injuries on electroencephalogram and MRI and durations of CICU and hospital stay, indicating cerebral autoregulation is, at least partly, the underlying mechanism of brain injury in these children.

Traditionally, this concept of autoregulation is presented in the medical literature as an all‐or‐nothing phenomenon, where pressure reactivity is fully operational within a range of arterial blood pressure, and complete pressure passivity is observed outside that range. Values of COPI in our study allow identification and quantification of the magnitude of autoregulation status. We found that COPI was gradually decreased over the first postoperative 48 hours, and that the time spent with COPI >0.3 was significantly less in the second 24 hours compared with the first 24 hours, which may indicate improved autoregulation (4.70 versus 5.14 hours). In other words, the lower and upper limits of autoregulation of COPI were <40 to 60 mm Hg (median, 45 mm Hg) and >77 to 100 mm Hg (median, 92 mm Hg) in the first 24 hours, and were <35 to 55 mm Hg (median, 50 mm Hg) and >60 to 104 mm Hg (median, 95 mm Hg) in the second 24 hours. These results suggest that the range of blood pressure with good autoregulation widened over time or the control of blood pressure within the autoregulatory range improved over time.

In this cohort, 45% of patients had periods of abnormal COPI, lower than the pre‐ (100%) and intraoperative incidence (82%) in previous reports. ²³ , ²⁴ There has been only 1 study, to the best of our knowledge, on postoperative autoregulation after CPB surgery. Bassan and colleagues evaluated COPI at the postoperative sixth and 20th hour, and found increased COPI at hypotension in about 13% of patients. ²⁶ The low incidence in their study may be due at least partly to the discrete and brief times studied rather than continuous monitoring as in our study.

Furthermore, previous studies on autoregulation in patients with CHD or another critical illness have largely focused on the lower limits of autoregulation (ie, hypotension was associated with an increased COPI). One study in neonates with hypoxic–ischemic encephalopathy reported that those with brain injury had a late failure of cerebral autoregulation, manifested as a hyperperfusion burden on day 3 of hypothermia. ¹⁵ In our study, abnormal COPI was found at either hypo‐ or hypertension or both. There was no significant difference in the white matter injury and stroke on MRI between patients with abnormal COPI and those without abnormal COPI. The incidence of hemorrhage was significantly higher in the abnormal COPI group. This is likely due to the small number of patients with white matter injury and stroke (n=2), and a majority had hemorrhage. This is different from previous reports on MRI, which showed mostly white matter injury, ⁵ , ⁶ , ⁷ , ⁸ likely due to difference in age and CHD types. Previous studies enrolled neonates with complex CHD (STS‐EACTS Morbidity and Mortality Category 5), ⁷ , ⁸ , ¹⁰ , ³⁵ whereas our present cohort was older (range, 3–1541 days; median, 130 days) with less complex CHD (STS‐EACTS Morbidity and Mortality Category 1 to 4).

Although the cause of neurologic deficits is unclear, brain injury in patients undergoing cardiac surgery results primarily from stroke, hemorrhage, hypoxia, and ischemia. Because white matter injury in infants following CPB surgery is the most common acute change seen in neonates with complex CHD, efforts to improve and ensure oxygen delivery are pursued in some centers, but these practices are not known to modify the occurrence of periventricular white matter injury. ⁸ The significant correlations of the magnitude and duration of COPI with the demographic and perioperative variables delineated the risk factors in the clinical management of these patients, namely preoperative (younger age, lower body surface area, higher STS‐EACTS Morbidity and Mortality Category scores), intraoperative (longer durations of CPB surgery, aortic cross‐clamping, the use of deep hypothermic circulatory arrest), and postoperative (higher levels of lactate, lower dose of milrinone, and higher dose of epinephrine). Most of these factors are modifiable except for STS‐EACTS Morbidity and Mortality Category. Careful perioperative management, particularly arterial blood pressure, may help to reduce the time spent with the loss of autoregulation and reduce brain injury. Ideally, clinical management of a patient should maintain the blood pressure where autoregulation is intact and robust. For instance, favorable neurological outcomes for patients with traumatic brain injury have been associated with arterial blood pressure management that optimizes autoregulation. ²¹

Limitations

The observational and post hoc nature of this study is subject to several limitations. (1) COPI was retrospectively calculated from the prospectively collected data. Ideally, autoregulation‐oriented treatment will be evaluated by prospective randomized clinical trials. (2) We studied a heterogeneous group of less‐complex CHD compared with patient populations from the advanced centers. ⁵ , ⁶ , ⁷ , ⁸ A larger multicenter study, including neonatal surgeries and complex cases, is warranted to quantitatively define autoregulation status across varied types of CHD and cardiac surgeries. (3) We examined only early outcomes in the acute phase. The potential effect of abnormal COPI on long‐term neurodevelopmental outcomes is being conducted in our center.

Conclusions

Children with CHD following cardiac surgery often have disturbed autoregulation at either hypotension or hypertension or both. Careful clinical management to manipulate the related and modifiable factors, particularly arterial blood pressure, may help to reduce the time spent with the loss of autoregulation and reduce brain injury early after cardiac surgery. Further studies are warranted to determine the significance of disturbed cerebral autoregulation in relation to long‐term neurodevelopmental impairment.

Sources of Funding

None.

Disclosures

None.