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Ann Thorac Surg 2004;77:2138-2143
© 2004 The Society of Thoracic Surgeons

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Original article: cardiovascular

Comparison of low-flow cardiopulmonary bypass and circulatory arrest on brain oxygen and metabolism

^a Department of Anesthesiology and Critical Care, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
^c Department of Anesthesiology, Mayo Clinic, Rochester, Minnesota, USA
^b Department of Biochemistry and Biophysics, The University of Pennsylvania, School of Medicine, Philadelphia, Pennsylvania, USA

Accepted for publication December 10, 2003.

^* Address reprint requests to Dr Pastuszko, Department of Biochemistry and Biophysics, 901 Stellar-Chance Bldg, University of Pennsylvania, Philadelphia, PA 19104, USA
e-mail: pastuszk{at}mail.med.upenn.edu

	Abstract

Top Abstract Introduction Material and methods Results Comment Conclusion Acknowledgments References

 
BACKGROUND: In the neonatal brain we measured oxygen (BO₂), extracellular striatal dopamine (DA), and striatal tissue levels of ortho-tyrosine (o-tyr) during low-flow cardiopulmonary bypass (LFCPB) or deep hypothermic circulatory arrest (DHCA) and the post-bypass recovery period.

METHODS: Newborn piglets were assigned to sham (n = 6), LFCPB (n = 8), or DHCA (n = 6) groups. Animals were cooled to 18°C and underwent DHCA or LFCPB (20 mL · kg^–1 · min^–1) for 90 minutes. The BO₂ was measured by quenching the phosphorescence, DA by microdialysis, and hydroxyl radicals by o-tyr levels. The results are presented as the mean ± SD (p < 0.05 was significant).

RESULTS: Baseline BO₂ was between 45 to 60 mm Hg. At the end of LFCPB, BO₂ was 10.5 ± 1.2 mm Hg. By 5 and 30 minutes of arrest during DHCA, BO₂ fell to 4.2 ± 2.5 mm Hg and 1.4 ± 0.7 mm Hg, respectively. Compared with control, extracellular DA did not change during LFCPB. During DHCA extracellular levels of DA increased, by 750-fold from baseline at 45 minutes and to a maximum of 53,000-fold at 75 minutes. After 2 hours of recovery from DHCA, the o-tyr within the striatum increased about sixfold as compared with control. There was no change in o-tyr measured after LFCPB.

CONCLUSIONS: In DHCA, but not LFCPB, levels of DA and o-tyr increased considerably in the striatum of piglets, a finding that may indicate the exhaustion of cellular energy levels and contribute substantially to cellular injury.

	Introduction

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The factors affecting cerebral oxygen delivery during cardiopulmonary bypass (CPB), and the mechanisms by which they disturb cerebral metabolism and lead to cerebral pathology or injury, remain incompletely understood. An important limitation in the published studies is the lack of direct measurements of oxygen pressure during CPB and post-bypass recovery.

In the present study, we used an optical method, oxygen-dependent quenching of phosphorescence, to continuously measure the oxygen levels in the microvasculature throughout low-flow cardiopulmonary bypass (LFCPB), deep hypothermic circulatory arrest (DHCA), and post-bypass recovery. The changes in brain oxygenation were correlated with two markers of disturbance in brain metabolism: extracellular striatal dopamine and striatal tissue levels of ortho-tyrosine. The first was chosen because the dopaminergic system of the striatum of a newborn piglet's brain has been shown to be very sensitive to the local oxygen pressure. Our earlier studies showed that even small decreases in oxygen pressure cause significant increases in the levels of extracellular dopamine and in dopamine metabolism [1–3]. Dopamine can also be a mediator of neuronal injury, particularly within the striatum. The second marker, ortho-tyrosine, was chosen because the level of this compound in the tissue can be used as a reliable measurement of in vivo hydroxyl radical production. This compound is not formed by metabolism and results only from -OH radical attack on the ortho position of free and bound phenylalanine.

We report that in newborn piglets during DHCA, the tissue oxygen pressures fell to zero, whereas LFCPB resulted in the tissue oxygen pressures remaining at several millimeters of mercury. The DHCA procedure, in contrast to LFCPB, caused a massive release of dopamine into the extracellular space and an increased generation of hydroxyl radicals.

	Material and methods

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Animal model
Twenty newborn piglets, 2 to 4 days of age (1.4 to 2.5 kg) were randomly assigned to sham-operated, LFCPB, or DHCA groups. Protocol and techniques were described in detail previously [4]. Briefly, after induction with halothane, a tracheotomy was performed and the piglets were then placed on a ventilator and anesthesia maintained with fentanyl. Femoral venous and arterial cannulas were placed for the collection of samples and for monitoring blood pressure. The head of the animal was placed in a stereotactic holder, the scalp was removed, and a hole approximately 8 mm in diameter was made over the right parietal hemisphere for measuring oxygen pressure. A small hole was drilled over the left parietal hemisphere for implantation of a microdialysis probe into the left striatum. After a 2-hour stabilization period, CPB was performed. All animal procedures were in strict accordance with the "Guide for the Care and the Use of Laboratory Animals" prepared by the Institute of Laboratory Animal Resources and published by the National Institute of Health (National Institutes of Health publication 5377-3, 1996) and have been approved by the local Animal Care Committee.

Cardiopulmonary bypass technique and experimental protocol
Full CPB flow was set at 125 mL · kg^–1 · min^–1. Anesthesia was maintained during CPB using isoflurane at 0.5 to 1.0 volume %, pancuronium boluses of 0.1 mg/kg intravenously (IV), and a fentanyl infusion of 10 µg · kg^–1 · h^–1 IV.

Low-flow hypothermic cardiopulmonary bypass
Once CPB was begun, the animals were cooled to a nasopharyngeal temperature of 18°C for more than 20 to 25 minutes. Ventilation was stopped shortly after initiation of CPB. When the temperature reached 18°C, the CPB circuit flow was reduced to 20 mL · kg^–1 · min^–1. After 90 minutes of LFCPB, the flow was gradually increased again to 125 mL · kg^–1 · min^–1 and the piglets were rewarmed to a temperature of 36°C over a 30-minute period.

Deep hypothermic cardiac arrest
After cooling to a nasopharyngeal temperature of 18°C, the CPB pump was turned off. After circulatory arrest for 90 minutes, CPB was gradually resumed at 125 mL · kg^–1 · min^–1 and the piglet was rewarmed as described above. Recovery was continued for 2 hours, after which the animals were euthanized with 4 mol/L KCl. The brain tissue was then frozen for analysis of ortho-tyrosine levels.

Measurements of oxygen pressure and oxygen distribution by the oxygen-dependent quenching of phosphorescence
The cortical oxygen pressure was measured using oxygen-dependent quenching of phosphorescence [1–4]. The technical basis for determining the distribution of oxygen in the microcirculation of tissue by measuring the distribution of lifetimes of a phosphor dissolved in the serum of blood has been described in detail elsewhere [5, 6]. Briefly, a near-infrared oxygen-sensitive phosphor (Oxyphor G2) was injected IV at approximately 1.5 mg/kg. The measurements were made using a multifrequency phosphorescence lifetime instrument. The excitation light (635 nm), modulated by the sum of 84 sinusoidal waves with frequencies spanned between 100 Hz and 40 kHz, was carried to the tissue through a 4-mm light guide. The phosphorescence (_max = 790 nm) emitted from the tissue was collected through a second light guide placed against the tissue at approximately 8 mm from the excitation light guide. This positioning of the light guides allowed effective sampling of brain tissue oxygenation down to about 6 mm under the neocortical surface. The phosphorescence was optically filtered and the signal from the detector amplified, digitized, and analyzed to give oxygen distribution in the volume of tissue sampled by the light. Because phosphorescence is quenched by oxygen, the signal from regions with higher oxygen concentrations are weaker than those with low oxygen concentrations, about 11-fold weaker for 140 mm Hg than for 0 mm Hg for Oxyphor G2. The lower signal to noise in the high oxygen region of the histogram, and correspondingly lower accuracy, can result in spurious high oxygen "tails" to the histograms.

Measurement of extracellular dopamine by in vivo microdialysis
The extracellular level of dopamine in striatum was measured as described in earlier publications [1–3]. The microdialysis probe was implanted and eight dialysis samples were collected at 15-minute intervals before administration of anticoagulants and initiation of the bypass procedure. This strategy allowed sufficient time for resealing of the vessels damaged by insertion of the probe. During the pre-bypass period the extracellular level of dopamine in the perfusate declined from the high values immediately after insertion to a steady state of approximately 1 pmol/mL. The mean from the last three of the pre-bypass samples in each experiment was used as a control value (100%). Identification and quantitation of dopamine was done by comparison with chromatograms of standard solutions. The efficiency of the microdialysis probe was determined in vitro at 36°C and 18°C and the relative recoveries were 16% ± 2% and 5% ± 1.6%, respectively (means ± SD for five experiments). The values for the level of dopamine in the dialysate are presented after correction for relative recovery by the microdialysis probe.

Determination of striatal ortho-tyrosine
Striatal tissue (1 mg protein/mL) was hydrolyzed with 6 N HCl. The hydrolysates were then dried, resuspended in mobile phase, and analyzed for o-tyrosine by HPLC.

Statistical analysis
All values are expressed as means for "n" experiments ± SD. Statistical significance was determined using one-way analysis of variance with repeated measures by Wilcoxon signed-rank test. p less than 0.05 was considered statistically significant.

	Results

Top Abstract Introduction Material and methods Results Comment Conclusion Acknowledgments References

 
Oxygen distribution in brain tissue during low-flow cardiopulmonary bypass and deep hypothermic circulatory arrest and post-bypass reperfusion
Before CPB, the histograms showed maximum values of 45 to 60 mm Hg. During LFCPB, the peak of the histogram, corrected to 18°C, decreased to 9.2 ± 3.7 mm Hg within 5 minutes and remained at that level until the end of bypass, so measurements were presented only at 5 minutes and the end of the bypass. The mean for the peak of the histograms at the end of LFCPB was 10.5 ± 1.2 mm Hg (Table 1). During DHCA, oxygen pressures decreased during the first 5 minutes to 4.23 ± 2.47 mm Hg and continued to fall until reaching 1.37 ± 0.7 mm Hg by 30 minutes of arrest (Table 1). The representative histogram for DHCA is shown in Figure 1. During recovery, the peak values of the histogram increased; however, the distribution was bimodal with substantial fractions of the values remaining near zero (Fig 1). At the end of the 2-hour recovery, the brain tissue histograms still showed significant fractions with very low oxygen levels.

View larger version (27K): [in this window] [in a new window]   Fig 1. Oxygenation of piglet brain during DHCA and post-bypass recovery. Oxygen histograms were determined by deconvolution of the distribution of phosphorescence lifetimes for Oxyphor G2 in the microcirculation. Presented histograms are for a representative DHCA experiment. (DHCA = deep hypothermic circulatory arrest.)

View larger version (24K): [in this window] [in a new window]   Fig 2. The effect of LFCPB and DHCA on the extracellular concentrations of dopamine in striatum of newborn piglets. The microdialysis probe was implanted in the striatum of newborn piglet and perfused with Ringer solution at 1 mL/min. Collection of the microdialysis samples was initiated 2 hours after the probe was inserted and the samples were collected every 15 minutes throughout the remainder of the experiment. The level of dopamine was analyzed by high-performance liquid chromatography with electrochemical detection. The three measurements of the dopamine during the pre-bypass period were averaged and the value considered as the baseline (100%). The results are means for six LFCPB and six DHCA experiments ± SD. *p < 0.001 for significant difference from control values as determined by one-way analysis of variance, followed by the Wilcoxon signed-rank test. (DHCA = deep hypothermic circulatory arrest; LFCPB = low-flow cardiopulmonary bypass.)

	Comment

Top Abstract Introduction Material and methods Results Comment Conclusion Acknowledgments References

A commonly used technique for monitoring the regional cerebral oxygen saturation is near-infrared spectroscopy, but its usefulness has been questioned [10]. This technique relies on the low absorption of near infrared light (700 to 900 nm) by biological tissues, where there are differences in the absorption spectra of oxygenated and deoxygenated hemoglobin. By measuring light attenuation at wavelengths where the absorption of oxygenated and deoxygenated hemoglobin differ, it is possible to monitor the average degree of saturation of hemoglobin with oxygen. Near-infrared spectroscopy measurement of hemoglobin-oxygen saturation represents a mixed vascular saturation weighted toward capillary and venous saturation by the relative blood volumes. The oxygen pressure at which hemoglobin is 50% saturated with oxygen (P₅₀) is strongly dependent on the pH of the blood, 2,3-disphospho-glycerate concentration in the red cell, temperature, and hematocrit. During CPB, the systemic blood flow, temperature, perfusion pressure, arterial blood gases, and hematocrit, even though they are artificially controlled, are never completely normal. In general, local pH and 2,3-disphospho-glycerate concentration can be estimated. The temperature is readily measured, but the temperature dependence is large (the P₅₀ increases by about 10% for each 1°C increase in temperature), which makes accurate temperature correction difficult. Lowering the temperature by even 10°C is sufficient to give nearly complete saturation of hemoglobin at normal venous effluent oxygen pressures. By 18°C, the P₅₀ is less than 8 mm Hg. At normal physiologic oxygen pressures (more than 30 mm Hg) essentially all of the oxygen-carrying capacity of the blood is due to oxygen dissolved in the serum, with hemoglobin providing significant oxygen-carrying capacity only below about 15 mm Hg.

Analysis of the distribution of oxygen in cortical tissue shows that during the first 5 minutes of DHCA, oxygen pressure, measured by the lower oxygen peak of the bimodal distribution, decreased to less than 5 mm Hg and by 15 minutes oxygen pressure was less than 3 mm Hg. During LFCPB, the oxygen pressure, measured the same as for DHCA by the lower oxygen peak of the bimodal distribution, decreased to about 10 mm Hg by 5 minutes and stayed at the same level during the entire bypass period. Histograms that were obtained became bimodal when the flow was stopped, presumably because of the presence of large surface vessels that were not surrounded by oxygen-consuming tissue. In these vessels, the blood deoxygenates only very slowly and may even increase because of diffusion from the surface air. The tissue oxygen pressures were reported as the peak of the lower oxygen part of the bimodal distribution and these were lower than the mean oxygen pressures reported earlier [4]. Our data are in agreement with Hoffman and coworkers [11], who reported that hypothermic cardiac arrest caused severe brain ischemia with delayed reoxygenation during recovery, and with Watanabe and colleagues [12], who showed that, in nonpulsative low-flow perfusion, the oxygen tension in brain tissue was significantly higher than in circulatory arrest and that low-flow bypass results in less brain damage than circulatory arrest.

The question that arises is why, during the first 30 minutes of DHCA and the entire period of LFCPB, did striatal extracellular dopamine not increase. In the present study, it was not possible to measure the oxygen distribution in the striatum (our measurements were in the cortex) and the oxygen requirements of the striatum at 18°C can only be estimated. However, the increase in extracellular dopamine during DHCA suggests that oxygen within the striatum decreased to anoxia or at least to a level of acute oxygen deficiency. This hypothesis is consistent with the observation that, during DHCA, the oxygen histograms for the cortex show essentially zero oxygen levels. The decrease in temperature should slow the metabolic rate, as well as oxygen consumption (ATP use), by at least fourfold. Thus, the at least 10-fold increase in time before dopamine release in DHCA can be explained by the longer time before depletion of the cellular energy supply combined with the greater fraction of hemoglobin with bound oxygen when flow stops. In LFCPB, the measured oxygen is about 10 mm Hg. The P₅₀ for oxygen binding by hemoglobin increases by about 10% per degree increase in temperature, falling to less than 10 mm Hg at 18°C. The oxygen pressure required to maintain mitochondrial oxidative phosphorylation in neuroblastoma is a few millimeters of mercury [13] and there should be sufficient oxygen for ATP synthesis under conditions of LFCPB. Thus, although the peaks of the oxygen pressure histograms in LFCPB are only about 10 mm Hg, at this oxygen pressure the hemoglobin is nearly saturated with oxygen. Increases in striatal dopamine have also been reported to occur in other models of cerebral ischemia/hypoxia. Consistent with this, increases in the concentrations of catecholamines and serotonin have been demonstrated in cerebrospinal fluid of patients with acute ischemic stroke [14] and in cerebral venous blood of baboons with brain ischemia [15].

Two important mechanisms can contribute to the DHCA-induced increase in extracellular dopamine. The first is increase in exocytotic release due to neuronal depolarization. This release depends, in large part, on the influx of extracellular calcium by omega-conotoxin–voltage-sensitive calcium channels. The second mechanism is inhibition of the reuptake transport system, a process that depends on transmembrane ionic gradients. Our earlier studies [16], as well as those of others, demonstrated that reuptake of dopamine is more readily inhibited than that of the other neurotransmitters.

This increase in extracellular dopamine during DHCA may play a major role in mediating neuronal injury, particularly within the striatum. It has been reported that lesions of the substantia nigra have a neuroprotective effect on the striatum related to the inhibition of dopamine release in the latter [17]. Similarly, lesions in the nigrostriatal pathway decreased the excitotoxic effect of striatal injections of N-methyl-D-aspartate and kainate.

Marie and associates [18] evaluated rat brain 72 hours after ischemia and reported that treatment of animals with inhibitor of dopamine synthesis (AMT, -methyl-para-tyrosine) significantly decreased neuronal necrosis in the striatum. They suggested that the striatal cytoprotective effect of AMT is linked to cerebral dopamine depletion and that excessive dopamine release during ischemia plays a detrimental role in the development of ischemic cell damage in the striatum.

Several mechanisms have been proposed for the deleterious effect of dopamine on the ischemic striatum. Dopamine could potentiate neuronal damage through its effects on the glutaminergic system. For example, it has been demonstrated that a unilateral 6-hydroxydopamine lesion of the substantia nigra reduced the volume of striatal necrosis and suppressed the increase in extracellular glutamate concentration in striatum, induced by middle cerebral artery occlusion in rats [19].

Another of the possible mechanisms for the neurotoxic effect of dopamine is through an increase in the production of free radicals. High levels of dopamine, iron, and oxygen are mostly responsible for the generation of free radicals, particularly in regions of the brain such as the putamen and the caudate nucleus. Oxidation of the excess dopamine released during ischemia by molecular oxygen and by monoamine oxidase, which may occur during reperfusion, results in the formation of free radicals. It has been proposed that pargyline, a monoamine oxidase inhibitor, protects against CNS oxygen toxicity in the rat by decreasing intracellular H₂O₂ generation from the oxidation of catecholamines [20].

Our studies show that DHCA increases the level of o-tyrosine within the striatum of newborn piglets, indicating increased generation of hydroxyl radicals within the tissue. It is reasonable to assume that this increase of hydroxyl radicals in the striatum is directly related to the increase in extracellular dopamine. Our earlier study [7] showed that inhibition of dopamine synthesis could completely abolish the ischemia-dependent increase of striatal hydroxyl radicals in newborn piglets. The increase in hydroxyl radicals after DHCA is consistent with data of other investigators. O'Hara and coworkers [21] observed increased numbers of superoxide anions on the cortical surface during reperfusion after DHCA in piglets. It has been proposed that one mechanism of neuronal cell death after CPB and DHCA is formation of free radicals [see for examples 22–27].

	Conclusion

Top Abstract Introduction Material and methods Results Comment Conclusion Acknowledgments References

 
During DHCA, but not LFCPB, extracellular dopamine levels in the striatum increase massively after about 30 minutes. This extracellular dopamine increase may both indicate the exhaustion of cellular energy levels and contribute substantially to cellular injury through increased oxygen radical production and cytotoxic oxidation products.

	Acknowledgments

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Supported by National Institutes of Health Grants, HL-58669, NS 31465, and AHA 0256396U.

	References

Top Abstract Introduction Material and methods Results Comment Conclusion Acknowledgments References

 

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