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J Thorac Cardiovasc Surg 1994;108:126-133
© 1994 Mosby, Inc.

CARDIOPULMONARY BYPASS,
MYOCARDIAL MANAGEMENT, AND SUPPORT TECHNIQUES

Mechanisms of brain injury with deep hypothermic circulatory arrest and protective effects of coenzyme Q10

Ren Zhen, MD, Ding Wenxiang, MD, Su Zhaokang, MD, Gu Xinling, MD, Huang Huiming, MD, Liu Jingfeng, MD, Yan Qing, MB, Zhang Weizhong, MB, Yu Xiaoqing, EB


Shanghai, People's Republic of China

From the Department of Pediatric Cardiothoracic Surgery, Xinhua Hospital, Shanghai Second Medical University, Shanghai, People's Republic of China.

Received for publication Aug. 4, 1993. Accepted for publication Dec. 14, 1993. Address for reprints: Ren Zhen, MD, Department of Cardiothoracic Surgery, Nanjing Children's Hospital, Nanjing 210008, People's Republic of China.

Abstract

Sixteen dogs, divided randomly into a control group and coenzyme Q10 group (10mg/kg, intraperitoneally before the operation), underwent deep hypothermic circulatory arrest with cardiopulmonary bypass, as is done clinically. At four time points cerebral cortex and cerebrospinal fluid specimens were collected to study free radical formation, energy metabolism, and ultrastructure. During cardiopulmonary bypass cerebral electron spin resonance spectra and malondialdehyde contents were progressively higher than before bypass, especially at the 60 minutes of circulatory arrest and 30 minutes of reperfusion (p1 < 0.01, p2 < 0.05). In the coenzyme Q10 group at the latter two time points, they had increased less than in the control group at same time points (p1 < 0.02, p2 < 0.005). Adenosine triphosphate content in the cortex during bypass decreased gradually from the prebypass level (p1 < 0.02, p2 = p3 < 0.001), while lactate in cerebrospinal fluid increased (p1 < 0.05, p2 = p3 < 0.001). In the coenzyme Q10 group, adenosine triphosphate at the latter two time points was greater than that in the control group (p1 = p2 < 0.05), while the lactate changes were not significantly different from control at each time point (all p > 0.05). Ultrastructure of the cortex was normal before bypass and almost normal during bypass, but it was obviously abnormal at 60 minutes of circulatory arrest and more seriously abnormal at 30 minutes of reperfusion. In the coenzyme Q10 group the abnormality was obviously reduced. The results suggest that oxygen-derived free radicals and abnormal energy metabolism might play critical roles in brain ischemia/reperfusion injury. Coenzyme Q10 could protect the brain by improving cerebral metabolism. (J THORACCARDIOVASCSURG1994;108:126-33)

Deep hypothermic circulatory arrest is commonly used for cardiac operations. In recent years it has been of particular value in the development of intracardiac procedures for complex congenital heart diseases in infants. However, brain injury of different degrees (including subclinical brain injury) after operation is still an important complication. Go Go 1,2 The mechanism has not been clarified. Recently the roles of oxygen-derived free radicals in ischemia/reperfusion injury and antioxidant coenzyme Q10 (CoQ10) in myocardial protection have been reported. Go Go 3-6 This experimental study was carried out to explore the mechanism of brain injury and protective effects of CoQ10 on the brain with regard to free radical, energy metabolism, and cell ultrastructure. We attempt to provide a theoretic basis and to find a new effective method for brain protection.

MATERIALS AND METHODS

Sixteen healthy mongrel dogs of either sex weighing 11 to 20 kg (14.8 ± 2.9 kg) were randomly divided into two groups: control group (n = 8) and CoQ10 group (n = 8, CoQ10 10 mg/kg, preoperative intraperitoneal injection).

The dogs were anesthetized with sodium pentobarbital 30 mg/kg by intravenous injection, were intubated with a cuffed endotracheal tube, and were supported with a pressure-cycled ventilator. The electrocardiogram and arterial blood pressure were monitored. Right frontoparietal craniotomies were performed. Temperature probes (Yellow Springs Instrument Co., Yellow Springs, Ohio), accurate to ± 0.2° C, were inserted into the extradural area beneath bone edges and the rectum to a level 5 cm up from the anal verge. The dura was removed carefully and the brain surface was covered with saline gauze. Cisternal puncture was done to collect cerebrospinal fluid (CSF).

The pericardium was opened through a median sternotomy, and heparin (2 mg/kg) was given. Aortic and right atrial cannulas were placed. Cardiopulmonary bypass (CPB) was instituted with a membrane oxygenator (AL-2, Instrument Plant of Fudan University, Shanghai) and sodium lactate Ringer's solution prime. The hematocrit value was 13% to 26% (18.3% ± 3.2%). The perfusion rate was 100 to 120 ml/kg per minute and gradually decreased as the body cooled. The gas/ blood ratio for the oxygenator was 1:1. Cooling rate was about 1° C/min. Temperature gradient between water, blood, and body was less than 10° C. During cooling with CPB to a brain temperature of 18° to 20° C and a rectal temperature of 20° C, the aorta was clamped, cardioplegic solution was injected from the root of the aorta, and circulatory arrest was achieved. After 60 minutes the aortic clamp was removed, and reperfusion with CPB and rewarming were begun. Thirty minutes later CPB was stopped while the brain temperature was about 35° C (rectum 32° C). During CPB mean arterial pressure was maintained at 7.98 to 13.3 kPa (60 to 100 mm Hg). Blood pH, oxygen tension, and carbon dioxide tension were regulated to normal according to arterial blood gas analysis.

All dogs received humane care in compliance with the "Principles of Laboratory Animal Care" formulated by the National Society for Medical Research and the "Guide for the Care and Use of Laboratory Animals" prepared by the National Academy of Sciences and published by the National Institutes of Health (NIH Publication No. 80-23, revised 1978).

Sample collection
Before CPB, during CPB, at 60 minutes of circulatory arrest, and at 30 minutes of reperfusion, brain biopsy specimens separated by enough distance (1 cm) in the right frontoparietal cortex and specimens of CSF were obtained. For each of the biopsy specimens about 40 mg of tissue was rapidly frozen in liquid nitrogen (-196° C) within 2 seconds for electron spin resonance (ESR) spectroscopy and for measurement of malondialdehyde (MDA) and adenosine triphosphate (ATP). One milliliter of CSF was collected to determine lactate. Tissue obtained at the same four time points was fixed in lanthanum for electron microscopy.

Data collection
(1) ESR spectroscopy is the only physical method that directly demonstrates the production of free radicals. Go 7 ESR spectrum of this experiment was recorded on a Brüker ER200D spectrometer (Brüker Medizintechnik GmbH, Karlsruhe, Germany), power 10 dB, 20 mW, 100 kHz modulation, magnetic field 5G, 196K in a variable temperature unit. (2) MDA is a final product of liquid hyperoxidation and may indirectly indicate the production of oxygen-derived free radicals. The thiobituric acid method Go 8 was used in this study. (3) ATP contents were measured by direct fluorometric enzymatic procedures. Go 9 (4) Lactate in CSF was determined by a lactate analyzer (Yellow Springs Instrument Co.). (5) Ultrastructure of the brain cortex was observed by a transmission electron microscope (Hitachi Ltd., Tokyo, Japan).

Statistical analysis
Values were expressed as mean ± standard deviation. Paired Student's t test was used in a group. Statistical comparison was performed between two groups by grouping Student's t tests. The correlations between MDA, ATP, and lactate were analyzed.

RESULTS

The level of free radical in the cerebral cortex
ESR spectra changes show that during CPB, at 60 minutes of circulatory arrest, and at 30 minutes of reperfusion, ESR spectra peak values (millimeters per milligram of tissue, mean ± standard deviation) were progressively higher than before CPB, especially at 30 minutes of reperfusion (p < 0.01). ESR spectra peak values of the CoQ10 group showed less evidence of free radicals than the control group at the latter two time points (p1 = p2 < 0.01) (Fig. 1). MDA content was more significantly increased during the operation than before CPB, especially at 60 minutes of circulatory arrest and 30 minutes of reperfusion (p1 < 0.01, p2 < 0.05). MDA content of the CoQ10 group at the latter two time points was more remarkably decreased than that of the control group at same time points (p1 < 0.02, p2 < 0.005) (Fig. 2).



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  		Fig. 1. ESR spectra changes in brain cortex (millimeters per milligram tissue). Spectrometer conditions of two groups were equal.

 


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  		Fig. 2. MDA changes in brain cortex (mean ± standard deviation). CA, Circulatory arrest.

 
Energy metabolism in brain tissue
ATP content in the cerebral cortex during the operation was significantly less than the level before CPB (p1 < 0.02, p2 = p3 < 0.001). In the CoQ10 group, ATP at 30 minutes of reperfusion was higher than at 60 minutes of circulatory arrest (p1 < 0.05); ATP content before CPB and at 30 minutes of reperfusion was higher in the CoQ10 group than in the control group at same time points (p1 = p2 < 0.05) (GoTable I). Lactate in CSF during the operation progressively increased relative to the pre-CPB value (p1 < 0.05, p2 = p3 < 0.001), but the differences between the CoQ10 group and control group were not significant at each time point (all p > 0.05) (Fig. 3).


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  		Table I. ATP changes in brain cortex (micromoles pergram wet tissue,mean ± standard deviation)
 


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  		Fig. 3. Lactate changes in CSF (mean ± standard deviation). CA, Circulatory arrest.

 
Correlation analysis
Statistical analysis shows that the CSF lactate content had a negative linear correlation with ATP content in the cerebral cortex (r = -0.649, p < 0.001, y = 4.361 - 0.371x) (Fig. 4). ATP content had negative linear correlation with MDA content (r = -0.488, p < 0.05, y = 2.225 - 0.0790x) (Fig. 5).



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  		Fig. 4. Correlation between lactate and ATP.

 


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  		Fig. 5. Correlation between ATP and MDA.

 
Ultrastructure of cerebral cortex
Structure was normal before CPB and almost normal during CPB, but it was abnormal at 60 minutes of circulatory arrest and more seriously so at 30 minutes of reperfusion. Abnormal ultrastructure of neurons included swollen mitochondria with disorted cristae, vacuolization of the mitochondria with disorted cristae, or vacuolization of the mitochondria with broken cristae and membrane rupture with lanthanum granules entering the cytoplasm and mitochondra. In the CoQ10 group the abnormalities of neuron ultrastructure appeared to be reduced (Fig. 6).



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  		Fig. 6. Cell ultrastructure changes of the cerebral cortex during operation.A, At 60 minutes of circulatory arrest, the majority of mitochondria were swollen and showed vacuolization (magnification x 15,000). B, At 30 minutes of reperfusion, all mitochondria were swollen and showed vacuolization, and some lanthanum granules were entering the cytoplasm and mitochondria (magnification x 20,000). C, In the CoQ10 group and at 60 minutes of circulatory arrest, a part of the mitochondria were slightly swollen (magnification x 8000). D, In theCoQ10 group and at 30 minutes of reperfusion, mitochondria were slightly swollen without remarkable vacuolization. Lanthanum granules were rarely seen entering the cytoplasm (magnification x 17,000).

 
DISCUSSION

It has generally been considered that deep hypothermia (15° to 20° C) with hemodilution does not result in brain injury Go 10; injury appears to be related to CPB and circulatory arrest, such as microembolism from the operative field and CPB circuit, inappropriate cerebral perfusion, inadequate cooling and rewarming, and excessive duration of circulatory arrest. All these factors may lead to microcirculatory obstruction, cerebral ischemia, anoxia, and edema, Go Go Go 1,2,11 but details of these mechanisms are unknown. Recent research suggests that reaction of oxygen-derived free radicals during ischemia and anoxia results in lipid peroxidation and injury of cellular membrane structure. This theory has been confirmed in studies of coronary heart disease and myocardial protection in surgery. Go Go 3,4 Whether free radicals form in the brain during deep hypothermic circulatory arrest has not been reported. This study addresses this issue.

The role of oxygen-derived free radicals in brain ischemia/reperfusion injury
After brain ischemia (circulatory arrest) ATP in cerebral cells is degraded rapidly to hypoxanthine. Because energy is depleted, calcium pump failure leads to massive influx of calcium ions. Intracellular Ca++ activates proteases, which convert hypoxanthine to uric acid. Meanwhile the superoxide radical, 0-, is produced and initiates a chain reaction of oxygen-derived free radicals. During ischemia and anoxia, the enzyme system that eliminates oxygen-derived free radicals is destroyed and thus elimination is reduced. Hyperoxia at reperfusion may result in a burst of oxygen-derived free radical production. Go Go 12,13 In addition, the complement activated during CPB and bacterial endotoxin contamination may stimulate neutrophils to produce a greater load of oxygen-derived free radicals. Go 14 Oxygen-derived free radicals from these sources result in peroxidation of polyunsaturated fatty acids at cerebral cell membranes, disorders of membrane permeability, and dissolution and necrosis of cells. Go Go 12-14 Lipid peroxidation also inhibits the synthesis of prostaglandin I2 and leads to vessel contraction and blood coagulation. Go 15 As a result, brain ischemia becomes more serious and a vicious circle occurs.

The technique of ESR spectroscopy provides a direct demonstration of free radical production, and the intensities of the ESR peaks observed are directly proportional to the free radical content of the samples. Go 7 MDA indirectly indicates the production of oxygen-derived free radical. Go 8 This experiment demonstrates that during CPB, at 60 minutes of circulatory arrest and 30 minutes of reperfusion, ESR peak values and MDA contents both were higher than before CPB, especially at the latter two time points; ESR peaks and MDA contents of the CoQ10 group were significantly less than for the control group. This suggests that CPB alone might enhance cerebral oxygen-derived free radical production, that a number of oxygen-derived free radicals were produced and initiated lipid hyperoxidation of membrane in the early reperfusion period, and that CoQ10 used preoperatively might reduce the production of oxygen-derived free radicals.

Energy metabolism disorder and lactic acidosis in the brain
Among the available biochemical indicators of cerebral metabolic activity, the absolute concentration of high-energy phosphate compounds, specifically ATP, most consistently reflects the functional capacity of the intact brain under a variety of adverse conditions, such as ischemia, anoxia, hyperoxia, and profound hypothermia. Go 16 Hypothermia preserves stores of high-energy phosphates and intermediary metabolites by decreasing the metabolic rate and preserving high intracellular pH. Go 17 However, during ischemia the mitochondria are damaged to a point at which they are incapable of synthesizing ATP at a rate commensurate with cellular needs. The rate of glycolytic conversion of glucose to lactate accelerates in a futile and inefficient attempt to produce the necessary level of ATP. This may exacerbate the problem by creating a pathologically acidic intracellular environment because of the accumulation of lactate. Go 18 Lactic acidosis may lead to a disorder of homeostasis that is necessary for intracellular normal metabolism. Go 19 "No-reflow lesion" at reperfusion also enhances the obstruction of microcirculation. Go 20 Therefore, the depletion and inadequate generation of ATP, as well as lactic acidosis, decrease the cortical energy state and increase structural damage during reperfusion. Go 17 This experiment demonstrates that during CPB and deep hypothermic circulatory arrest, ATP content gradually decreased while lactate progressively increased in the brain, and lactate had a negative correlation with ATP (r = -0.649, p < 0.01). This has confirmed that during CPB and deep hypothermic circulatory arrest, ATP is depleted while lactate from anoxic glycolysis accumulates.

This study demonstrates that cerebral ATP had a negative corelation with malondialdehyde content (r = - 0.418, p < 0.05), which indicated an association between energy metabolism disorder and oxygen-derived free radical production as above. Recently, some authors have suggested, regarding production of free radical, that the effect of lactic acidosis is more important than acidosis resulting from increased carbon dioxide tension because lactic acidosis might accelerate the separation of iron ion from iron-conjugated protein and thus enhance the abnormal reaction of oxygen-derived free radicals. Go 21Avoiding preischemic hyperglycemia Go 19 and using Ca++ channel blockers, such as nimodipine, may reduce the postischemic lactate level in the brain. Nimodipine also may increase postischemic cerebral blood flow by dilating vessels. Go 22

Mechanism of protection of CoQ10 for ischemia/ reperfusion damage in the brain
CoQ10 is a lipid-soluble benzoquinone with a long isoprenoid side chain (10 units). It is an essential cofactor in the mitochondrial respiratory chain and is the sole mobile carrier for reducing equivalents responsible for aerobic ATP generation. Because CoQ10 is also a reducing agent, it may function as an oxygen-derived free radical scavenger and has the added action of stabilizing cell membranes by inhibiting phospholipase activity. CoQ10-pretreated animal hearts were able to enhance oxidative phosphorylation and cellular resynthesis of ATP and to prevent cellular and mitochondrial calcium overload. Go 5 Clinically, the CoQ10-treated group had a significantly lower postoperative incidence of low cardiac output states after cardiac surgery. Go 6 CoQ10 also is used in the treatment of patients with angina pectoris, congestive heart failure, hypertension, arrhythmia, and myocardial protection. Go 23 However, reports of CoQ10 for brain protection have not yet been made. CoQ10 is fat soluble and can pass through the blood-brain barrier and have direct effects on brain tissue. This study indicates that after CoQ10 was used preoperatively, (1) ESR peaks and malondialdehyde contents of the brain were remarkably decreased, demonstrating its effectiveness as a free radical scavenger; (2) ATP contents were significantly increased (nearly a fourfold increase in the CoQ10 group before CPB), which showed that CoQ10 could enhance ATP generation; and (3) ultrastructure of neurons was improved, which showed that CoQ10 was effective in stabilizing cellular membranes and maintaining mitochondrial function. These results are similar to those reported for myocardial protection.

We conclude that brain damage during CPB and deep hypothermic circulatory arrest is a complex pathophysiologic process. The excessive production of oxygen-derived free radicals and the process of lipid peroxidation, as well as the disorder of energy metabolism, might play critical roles in ischemia/reperfusion injury, which may be related to subclinical brain injury. CoQ10 was demonstrated to protect the brain by improving cerebral metabolism and ultrastructure.

Acknowledgments

We express our gratitude to Dr. Richard A. Jonas, MD, at the Departments of Cardiac Surgery, Cardiology, and Anesthesiology, Children's Hospital, and Harvard Medical School, Boston, Massachusetts, for his helpful criticism and advice regarding the graphics and the manuscript.

Footnotes

Read partly at the International Conference of Asian Association of Pediatric Surgeons, Beijing, People's Republic of China, May 13-16, 1991. Back

References

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