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Ann Thorac Surg 2003;76:1215-1226
© 2003 The Society of Thoracic Surgeons
a Department of Surgery, , Oulu, Finland
b Department of Anesthesiology, Oulu, Finland
c Department of Forensic Medicine, University of Oulu, Oulu University Hospital, Oulu, Finland
* Address reprint requests to Prof Juvonen, Division of Cardiothoracic and Vascular Surgery, Department of Surgery, Oulu University Hospital, PO Box 21, 90029 Oulu OYS, Finland.
e-mail: tatu.juvonen{at}oulu.fi
Presented at the Poster Session of the Thirty-ninth Annual Meeting of The Society of Thoracic Surgeons, San Diego, CA, Jan 31–Feb 2, 2003.
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Abstract |
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-stat acid-base strategy during cardiopulmonary bypass as a neuroprotective method during hypothermic circulatory arrest is still controversial. In the present study, brain metabolism and outcome have been evaluated in a surviving model of experimental hypothermic circulatory arrest.
METHODS: Twenty pigs undergoing 75-minutes of hypothermic circulatory arrest at a brain temperature of 18°C were randomly assigned to the -stat (n = 10) or pH-stat (n = 10) strategy during cardiopulmonary bypass.
RESULTS: The 7-day survival rate was 90% (9 of 10) in the pH-stat group and 10% (1 of 10) in the -stat group. At the end of cooling, pH-stat strategy was associated with significantly lower brain lactate and pyruvate concentrations and brain lactate-glucose ratio. After reperfusion, brain concentrations of glycerol, lactate, pyruvate, and lactate-glucose ratio were significantly lower in the pH-stat group. This strategy was associated with a faster rise of brain tissue temperature and reoxygenation on reperfusion, which is likely secondary to improved cerebral perfusion.
CONCLUSIONS: During cardiopulmonary bypass before and after a period of hypothermic circulatory arrest, acid-base management according to the pH-stat principles seemed to be associated with less derangements in cerebral metabolism, lower intracranial pressures, and excellent behavioral recovery and survival outcome. Because there is strong evidence of the beneficial metabolic effects related to this method, further studies using an experimental model of combined HCA and embolic brain injury are required to exclude a possible increased risk of cerebral embolism associated with the pH-stat strategy.
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Introduction |
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TopAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
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-stat and pH-stat strategy) used during cardiopulmonary bypass (CPB) before and after a period of HCA has been a topic of intensive investigation. During cooling, carbon dioxide solubility increases, resulting in a decrease of carbon dioxide partial pressure and an alkaline shift of pH. The pH-stat perfusion strategy corrects this alkaline shift by adding carbon dioxide to keep the arterial carbon dioxide partial pressure at 5.3 kPa and the pH at 7.4, as measured at the actual patient's core temperature. This results in a relative hypercarbia and acidemia. On the other hand, the -stat strategy allows such an alkaline shift of pH by keeping the pH at 7.4 corrected to a temperature of 37°C, and not to the actual temperature.
Alpha-stat and pH-stat strategies both have distinct advantages and disadvantages. Alpha-stat strategy has been shown to preserve cerebral autoregulation [1, 2], whereas the pH-stat strategy enhances cerebral blood flow, cerebral oxygenation, maintenance of normal intracellular pH during cooling, and is associated with improved brain cooling and faster recovery of intracellular pH, cerebral high energy metabolites, and oxygenation after HCA [3–6]. Less metabolic suppression in hypothermia [7], intracellular alkalosis during cooling [3], need of higher hematocrit [8], and disturbed cerebral oxygenation during fast rewarming [9] are the disadvantages associated with the use of the -stat strategy. On the other hand, pH-stat has its major drawback in the suggested increased risk of microembolism [10, 11].
The present study was planned to evaluate the metabolic derangements occurring during HCA using these two strategies in particular to assess the changes in brain metabolism as detected by brain microdialysis monitoring.
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Material and methods |
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TopAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
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-stat perfusion strategy (-stat group; n = 10) or with the pH-stat perfusion strategy (pH-stat group; n = 10). Figure 1
summarizes the present porcine model of HCA with probes for monitoring cerebral and hemodynamic measurements.
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Anesthesia and hemodynamic monitoring
Anesthesia was induced with ketamine hydrochloride (350 mg intramuscularly) and midazolam (45 mg intramuscularly). A peripheral catheter was inserted into a vein of the right ear for administration of drugs and to maintain fluid balance with Ringer acetate. Anesthesia was deepened with an intravenous bolus injection of fentanyl (25 µg/kg) and propofol (60 to 120 mg). Anesthesia was maintained by a continuous infusion of fentanyl (25 µg/kg/h), midazolam (0.25 mg/kg/h), pancuronium (0.2 mg/kg/h), and propofol (4 mg/kg/h) throughout the whole experiment, but not during HCA. Propofol was reduced if the mean arterial pressure was lower than 50 mm Hg. Cefuroxime (1.5 g intravenously) was administered twice at anesthesia induction and before extubation.
After endotracheal intubation, the animals were maintained on positive pressure ventilation with 50% oxygen. Electrocardiographic monitoring was started. An arterial catheter was positioned into the left femoral artery for arterial pressure monitoring and blood sampling. A thermodilution catheter (CritiCath, 7 French [Ohmeda GmbH & Co, Erlangen, Germany]) was placed through the left femoral vein to allow blood sampling, pressure monitoring in the pulmonary artery, and for recording the blood temperature and cardiac output. A 10 French catheter was placed in the urinary bladder for urine output monitoring. Temperatures were monitored from blood, the rectum, and the esophagus, and from the epidural and intracerebral spaces.
Brain microdialysis and intracerebral monitoring
A temperature probe was placed into the epidural space through a cranial hole made on the left side of the coronal suture. A catheter for measurement of intracerebral tissue oxygen partial pressure (Revodoxe Brain Oxygen Catheter-Micro-Probe, Ref CC1.SB [GMS, Mielkendorf, Germany]) together with a probe for monitoring intracerebral temperature (Thermocouple Temperature Catheter-Micro-Probe, Ref C8.B [GMS]) were inserted through a hole located at the right side 1 cm anteriorly to the coronal suture. The intracerebral temperature was used as the primary measure of brain temperature. An intracerebral microdialysis catheter was inserted through a hole located at the right side 0.5 cm posteriorly to the coronal suture. A pressure-monitoring catheter (Codman Micro-Sensor ICP Transducer, Codman ICP Express Monitor [Codman & Shurtleff, Inc, Raynham, MA]) was placed through a hole located at the left side posteriorly to the coronal suture.
The microdialysis catheter (CMA 70 [CMA/Microdialysis, Stockholm, Sweden]) was placed into the right brain cortex 0.5 cm posteriorly to the coronal suture to a depth of 15 mm below the dura mater. The catheter was connected to a 2.5 mL syringe placed into a microinfusion pump (CMA 106 [CMA/Microdialysis]) and perfused with Ringer solution at a rate of 0.3 µl/min (Perfusion Fluid CNS [CMA/Microdialysis]). Samples were collected at different time intervals. The concentrations of cerebral tissue glucose, lactate, pyruvate, glutamate, and glycerol were measured immediately after collection with a microdialysis analyzer (CMA 600 [CMA/Microdialysis]) by using ordinary enzymatic methods.
Electroencephalography monitoring
Cortical electrical activity was registered by four stainless-steel screw electrodes of 5 mm in diameter implanted in the skull over the parietal and frontal areas of the cortex using a digital electroencephalography (EEG) recorder (Nervus, Reykjavik, Iceland) and an amplifier (Magnus EEG 32/8, Reykjavik, Iceland). Sampling frequency was 256 Hz and bandwidth was 0.03 to 100 Hz. All EEG recordings were referenced to a frontal screw electrode, which, together with a ground screw electrode, was implanted over the frontal sinuses.
Electroencephalography was recorded for 10 minutes to get a baseline recording before the cooling period. After HCA, EEG recording was restarted and continued until extubation. Artifact periods were excluded from each 5-minute sample. Recovery of different wave bands (alpha, beta, and theta) was calculated from all four electrodes by means of nonlinear analysis. The energy recovery of EEG was evaluated by an algorithm based on the nonlinear energy operator.
Cardiopulmonary bypass
Through a right thoracotomy done in the fourth intercostal space, the right thoracic vessels were ligated, the pericardium was opened, and the heart and great vessels were exposed. A membrane oxygenator (Midiflow D 705 [Dideco, Mirandola, Italy]) was primed with 1 L of Ringer acetate and heparin (5000 IU). After systemic heparinization (500 IU/kg), the ascending aorta was cannulated with a 16 French arterial cannula, and the right atrial appendage was cannulated with a single 24 French atrial cannula. Nonpulsatile CPB was initiated at a flow rate of 90 to 110 mL/kg/min, and the flow was adjusted to maintain a perfusion pressure of 50 to 70 mm Hg. A 12 French intracardiac sump cannula was positioned into the left ventricle through the apex of the heart for decompression of the left side of the heart during CPB. A heat exchanger was used for core cooling.
Experimental protocol of -Stat Versus pH-Stat perfusion strategy
In the -stat group the pH was maintained at 7.40 ± 0.05, with an arterial carbon dioxide tension of 5.2 to 5.4 kPa uncorrected for temperature. In the pH-stat group the temperature corrected arterial carbon dioxide tension was kept between 5.2 and 5.4 kPa and the pH was kept at 7.40 ± 0.05. In both groups the arterial blood was sampled at least every 15 minutes of perfusion, but if arterial carbon dioxide tension was not optimal, samples were obtained every 5 minutes. In both groups, carbon dioxide up to 5% was added to oxygen to maintain arterial carbon dioxide tension. In the -stat group, this was required only during the phase of rewarming perfusion.
A cooling period of 60 minutes was carried out to attain a brain temperature of 18°C. Then a 75-minute period of HCA was started. The ascending aorta was cross-clamped just distal to the aortic cannula, and cardiac arrest was induced by injecting potassium chloride (40 mmol) through the aortic cannula. Cardiac cooling with topical ice slush was begun and maintained throughout the HCA period. During HCA, the intracerebral temperatures were maintained at a level of 18°C with ice packs placed over the head. After 75-minute HCA, rewarming was started. During the cooling and rewarming phases, the heat exchanger-blood temperature gradient was set at approximately 10°C and, during rewarming the heat exchanger temperature only rarely was set to approximately 38°C. Five minutes after the start of rewarming, furosemide (40 mg), mannitol (15 g), methylprednisolone (80 mg), lidocaine (40 to 150 mg), and calcium bioglyconate (2.25 mmol Ca2+) were administered. The left ventricular sump cannula was removed after 45 minutes of rewarming, and weaning from CPB occurred about 60 minutes after HCA. After weaning from CPB, cardiac support was provided with dopamine.
After rewarming on CPB, heat-exchanger mattress, heating lamps, and ice packs regulated the temperatures. The animals of both groups were extubated 8 hours after the start of rewarming when the rectal temperature approximated 37°C, and were then moved to a recovery room.
During the experiment, the hemodynamic and metabolic measurements of heart rate, systemic and pulmonary arterial pressures, central venous pressure, pulmonary capillary wedge pressure, cardiac output, intracranial pressure, intracerebral tissue oxygen partial pressure, temperatures, arterial and venous pH, oxygen and carbon dioxide partial pressure, oxygen saturation, oxygen concentration, hematocrit, hemoglobin, sodium, potassium, glucose (Ciba-Corning 288 Blood Gas System [Ciba-Corning Diagnostic Corp, Medfield, MA]), lactate (YSI 1500 analyzer [Yellow Springs Instrument Co, Yellow Springs, OH]), leukocyte differential count (Cell-Dyn analyzer [Abbot, Santa Clara, CA]), and creatine kinase and its isoenzymes (creatine kinase-MM, creatine kinase-MB, creatine kinase-BB [Hydrasys LC-electrophoresis, Hyrys-densitometry, Sebia, France]) were recorded continuously or at baseline at the end of cooling (immediately before institution of HCA); 30 minutes, 2 hours, 4 hours, and 8 hours after the start of rewarming.
Postoperative evaluation
Postoperatively, all the animals were evaluated daily by an experienced observer who was blinded to the study group using a species-specific quantitative behavioral score. The quantified assessments of mental status (0 = comatose, 1 = stuporous, 2 = depressed, and 3 = normal), appetite (0 = refuses liquids, 1 = refuses solids, 2 = decreased, and 3 = normal), and motor function (0 = unable to stand, 1 = unable to walk, 2 = unsteady gait, and 3 = normal) were summed to obtain a final score, with a maximum score of 9 reflecting apparently normal neurologic function and with lower values indicating substantial brain damage.
Perfusion fixation
Each surviving animal was electively killed on postoperative day 7. Immediately after intravenous injection of pentobarbital (60 mg/kg) and heparin (500 IU/kg), the thoracic cavity was opened, and the descending thoracic aorta was clamped. Ringer solution (1 L) was perfused through the ascending thoracic aorta through the upper body, and blood was suctioned from the superior vena cava until the perfusate was clear of blood. Then 10% formalin solution (1 L/15 minutes) was infused through the brain in the same manner to accomplish a perfusion fixation. Immediately thereafter, the entire brain was harvested, weighed, and immersed in 10% neutral formalin. The same method of fixation procedure was carried out in those animals that died before postoperative day 7.
Histopathologic analysis
The brain was allowed to fix for 1 week en bloc. Thereafter, 3-mm thick coronal samples were sliced from the left frontal lobe, thalamus (including the adjacent cortex) and hippocampus (including the adjacent brainstem and temporal cortex), and sagittal samples from the posterior brainstem (medulla oblongata and pons) and cerebellum were obtained. The specimens were fixed in fresh formalin for another week. After fixation, the samples were processed as follows: rinsing in water for 20 minutes and immersion in 70% ethanol for 2 hours, 94% ethanol for 4 hours, and absolute ethanol for 9 hours. Then the specimens were kept for 1 hour in absolute ethanol-xylene mixture and 4 hours in xylene and embedded in warm paraffin for 6 hours. The specimens were sectioned at 6 µm and stained with hematoxylin and eosin. The sections of the brain specimens of each animal were screened by an experienced senior pathologist (JH) unaware of the experimental design and identity and fate of the individual animals. Each section was carefully examined for the presence or absence of any ischemic or other kinds of tissue damage.
The signs of injury were scored as follows: 1 (slight edema, dark or eosinophilic neurons, or cerebellar Purkinje cells), 2 (moderate edema, at least 2 hemorrhagic foci in the section), and 3 (severe edema, several hemorrhagic foci, infarct foci [local necrosis]). The total regional score was the sum of the scores in each specific brain area (cortex, thalamus, hippocampus, posterior brainstem, and cerebellum). In case of presence of more than one of the previously mentioned findings, the score from each region was calculated in a cumulative way. A total histopathologic score was calculated by summing all the regional scores to allow semiquantitative comparison between the animals.
Statistical analysis
Statistical analysis was performed using an SPSS statistical program (SPSS, version 10.0.7, SPSS Inc, Chicago, IL). Continuous and ordinal variables are expressed as the median with interquartile range (IQR) (25th and 75th percentiles). Analysis of variance for repeated measurements was performed. Comparison between relevant time-points and baseline (reference category) was performed by the paired sample Student's t test or Wilcoxon matched pairs signed-rank test. Differences between groups were determined by the Student's t test or by the Mann–Whitney U test. Fischer's exact two-tailed test was used to determine the significance of mortality rates between groups. Significance levels are reported for comparisons with the two-tailed test (p 
0.05).
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Results |
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TopAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
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-stat group (p = 0.48). The median CPB cooling time was 61.0 minutes (IQR, 60.0 to 62.0 minutes) in the pH-stat group and 61.5 minutes (IQR, 60.0 to 61 minutes) in the -stat group (p = 0.63). The median CPB rewarming time was 61.5 minutes (IQR, 60.0 to 62.0 minutes) in the pH-stat group and 62.0 minutes (IQR, 60.0 to 62.0 minutes) in the -stat group (p = 0.95). The median total CPB time was 122.5 minutes in both groups (IQR, 122.0 to 124.0 minutes, pH-stat group; IQR, 121.0 to 125.0 minutes, -stat group) (p = 0.97). During the HCA, the temperatures did not differ between the study groups (Fig 2).
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-stat group, respectively (p = 1, p = 0.087, and p = 0.001, respectively).
Perfusion data
Physiologic data are reported in Tables 1
–3. Both groups were in the narrow limit according to the -stat and pH-stat strategies (Table 2).
Arterial pH and CO2 were significantly different throughout
the experiment when noncorrected values were used, but there were no differences at baseline and after the end of rewarming. The mixed venous blood temperatures were also similar in both groups during the experiment (Table 2). However, brain temperature was significantly higher in the pH-stat group 15 minutes after the start of rewarming, and such a difference also tended to be significant 30 minutes and 45 minutes after the start of rewarming (Fig 1).
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-stat group (Fig 3) (p = 0.09). Serum ionized calcium levels were higher in the pH-stat group at the end of cooling and at the 30-minute rewarming interval, because of lower pH. Serum ionized calcium was also higher in the pH-stat group 8 hours after HCA, but at this interval, pH was similar in both groups (Tables 2, 3).
Intracranial measurements
Intracranial measurement data are presented in
Figures 4 and 5. Brain glucose tended
to be higher in the pH-stat group during the first hours after the start of rewarming. Brain lactate was lower at the end of cooling perfusion in the pH-stat group (Fig 4). At the end of HCA, brain lactate concentration was higher in the pH-stat group, but after that it was significantly lower at the 2-hour and 3-hour intervals after HCA and also tended to be lower during all subsequent periods (Fig 4).
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-stat group.
Brain lactate-glucose ratio decreased significantly during cooling in the pH-stat group, whereas this ratio increased in the -stat group. Such a difference was statistically significant at the end of cooling and at 30 minutes of HCA (Fig 5). The brain lactate-glucose ratio was also lower in the pH-stat group from the 1-hour to the 4-hour intervals, but such a decrease was statistically significant from the 2-hour to the 3-hour intervals after the start of rewarming (Fig 5). The brain lactate-pyruvate ratio was significantly lower in the pH-stat group at the end of rewarming (50.9 vs 92.1; p = 0.04) (Fig 5).
The median deoxygenation time (time of oxygen to reach zero) was significantly longer in the pH-stat group (961 vs 661 seconds; p = 0.03). Furthermore, the median reoxygenation time (time of oxygen to increase greater than zero after the start of rewarming) was shorter, but not significantly in the pH-stat group (209 vs 269 seconds; p = 0.27). After the end of rewarming perfusion brain tissue oxygen pressure was higher in the -stat group during all the recording points.
The median intracranial pressure was lower from the 2-hour interval after the start of rewarming in the pH-stat group, but such a difference did not reach statistical significance (Fig 4).
Histopathologic findings and postoperative behavioral outcome
No statistically significant differences were observed in the total histopathologic scores between these two groups (9.6 in the pH-stat group vs 12.9 in the -stat group), probably because of too few surviving animals in the -stat group (Table 4).
Remarkable edema with concomitant neurodestruction were the most conspicuous findings in the nonsurvivors of the -stat group and histologic points were rather low in 7 of 10 animals in the pH-stat group. A comparison of behavioral scores between the study groups is not possible, because of the high postoperative mortality affecting the -stat group. Nevertheless, animals in the pH-stat group had an excellent postoperative behavioral recovery (Fig 6).
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-stat group during the latest recording hours, but such a difference not reach statistical significance. |
Comment |
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TopAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
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-stat perfusion strategy before and after HCA has been a topic of continuous debate. The major concerns with use of the pH-stat are the derangement in the acid-base status and possible increased risk of air-debris embolism to the brain because of the excessive, luxuriant cerebral blood perfusion associated with this perfusion strategy. However, the perceived beneficial effects in preventing the brain ischemic injury have led to research of the mechanisms underlying the neuroprotective efficacy of the pH-stat strategy. The encouraging results of experimental studies led to its use also in the clinical field with some distinct positive results [12–14]. However, changes in cerebral metabolism during HCA with the pH-stat blood gas management and its impact on the immediate postoperative outcome are still not extensively investigated. In particular, the outcome has not been well studied as most of studies have used an acute animal model of HCA, and the relative small number of clinical studies published thus far prevents definitive conclusions on the impact of pH-stat strategy on the postoperative outcome.
Herein, we report the results of a study in a surviving animal model of HCA using the pH-stat versus -stat strategy, in which changes in cerebral metabolism were detected by microdialysis analysis and evaluation of postoperative outcome was made possible by allowing the animals to survive up to postoperative day 7.
Despite the severity of brain ischemic insult of such a long period of circulatory arrest at a relatively high cerebral temperature, the pH-stat strategy showed a striking superiority over the -stat strategy both in terms of brain and systemic metabolic changes and in postoperative outcome. However, the survival outcome of animals who have undergone HCA with the -stat strategy was rather low and prevented a thorough evaluation of the long-term end-points, such as the behavioral recovery and histopathologic signs of brain ischemic injury, which, in any case were both excellent in the pH-stat group. Because this could be viewed as a weak point of this study, the changes of the anesthesiology protocol in the present study by introducing propofol could be recognized as a possible cause for such poor outcome results among animals of the -stat group.
Propofol is known to decrease the cerebral blood flow [15], cerebral metabolic rate of oxygen [15], and EEG activity [16]. The perceived neuroprotective effects of propofol against brain ischemic injury seem to also be due to the propofol related inhibition of N-methyl-D-aspartate glutamate receptors and closure of voltage-dependent calcium channels [17]. Despite such good premises, propofol in this setting was associated with such a poor postoperative outcome when associated with -stat strategy. A comparison of these findings with those of our previous studies, in which other anesthesiology protocols were used [18], showed that the use of propofol was associated with unfavorable changes in microdialysis measurements. Propofol may have also had impact on the hemodynamic measurements, resulting in a decrease of cardiac index as compared with our previous experiments. Although propofol has been previously shown to decrease only the mean arterial pressure without affecting cardiac index, our finding of an impact on the cardiac index may explain such a poor outcome among the animals undergoing HCA with -stat strategy. Indeed, we have shown that oxyhemodynamic measurements have a great impact on postoperative survival after experimental HCA [19].
Despite such a possible negative impact of the present anesthesiology protocol on the hemodynamic measurements, the pH-stat strategy was associated with a significantly better outcome. It is possible that the relative hypercapnia turned out to be beneficial, not only in terms of neuroprotection, but also by providing some benefits to the systemic metabolism. The reduced mean arterial pressures and vascular resistances during the cooling period with pH-stat strategy were coupled by a better oxygen delivery and, likely related, lower venous lactate concentration at the end of cooling. It has been shown that hypercapnia improves subcutaneous tissue oxygen tension [20]. Aoki and colleagues [3] did not observe significant differences in regional blood flow in organs other than the brain, with the exception of increased blood flow to the adrenal glands and a decreased blood flow to the kidneys with the pH-stat strategy. However, in their study, systemic lactate levels were lower after HCA with the pH-stat strategy [3]. Such a systemic beneficial effect on mixed blood venous lactate levels was observed in this study at the end of cooling and at 30-minute intervals after the start of rewarming. In a clinical study, Pearl and colleagues [13] demonstrated that the pH-stat strategy is associated with significantly less acid production than the -stat strategy, and such a difference persisted both in normoxia and hyperoxia management strategies. These observations suggest that the relative hypercarbic state associated with the pH-stat strategy increases vasodilatation of the systemic vasculature, resulting in an improved peripheral tissue perfusion. Furthermore, the metabolic inhibition induced by hypercarbia [21] and the reduced oxygen affinity for hemoglobin associated with relative acidosis may further improve peripheral tissue protection during HCA.
Because there is evidence that enhanced oxygenation before a period of HCA is associated with less acid production [13] and improved survival outcome [19], the improved cerebral oxygen delivery induced by the pH-stat strategy [3, 22] is a logical advantage of the latter method over the -stat strategy. The adequate brain tissue loading with oxygen [13], herein proved by an increased pre-HCA brain tissue oxygenation, and better cerebral cooling associated with increased cerebral blood flow induced by the pH-stat strategy are likely to have resulted in lower concentrations of lactate and pyruvate in the brain during the cooling period. This was followed during the early hours after the end of HCA by favorable temporary increases of both brain glucose and lactate concentrations. In particular, as shown in a previous study of ours [18], a transient increase of brain lactate concentration coupled by increased brain glucose concentration after 75-minutes of HCA is associated with a decreased risk of postoperative death and brain infarction. There is evidence that glucose is consumed anaerobically by astrocytes producing lactate that, in turn, is consumed aerobically by neurons after a period of ischemia. This utilization of lactate, not of glucose, is preferred by neurons and fuels the recovery of synaptic function during reoxygenation [23]. In case of severe ischemia and glucose depletion, the astrocytic-neuronal unit metabolic activity turns to uncompensated glycolysis. In this study, the HCA period was preceded and followed-up to the 4-hour postoperative interval by a lower brain lactate-glucose ratio in the pH-stat group, which confirms a better maintenance of brain glucose and lactate metabolism during these two critical periods. However, it is not completely clear why in the pH-stat group, after the 2.5-hour interval from the start of rewarming, brain glucose levels decreased toward baseline values. The decreased brain oxygenation in this study group during the first postoperative hours could offer an explanation for this metabolic change, especially because brain lactate concentration started to decrease as brain oxygenation improved from the 4-hour postoperative interval.
The significantly lower brain glycerol concentrations throughout the postoperative period, as well the faster decrease of brain glutamate concentration upon rewarming, provide further evidence of attenuated brain ischemic injury associated with the use of the pH-stat as being better than the -stat strategy. It is particularly noteworthy that the low intracranial pressure values were observed during the early postoperative hours after HCA using the pH-stat strategy. These were not only lower than in the -stat group, but they were far below the levels observed in a collective, reviewed group of animals that survived 7 days after the experiment and did not have postoperative brain infarction develop [24].
Finally, the pH-stat strategy was associated with a faster rise of intracerebral temperature on reperfusion rewarming, which was likely secondary to the improved cerebral blood flow. During the last studies that used this experimental model, we have shown the detrimental effects of transient and long-term delayed rewarming after HCA [25, 26], and the results of the present study indirectly confirm that prompt rewarming should be favored after a period of HCA.
In conclusion, during CPB perfusion before and after a period of HCA, acid-base management according to the pH-stat principles seem to be associated with less derangements in cerebral metabolism, lower intracranial pressures, excellent behavioral recovery, and survival outcome. Because there is strong evidence of the beneficial metabolic effects related to this method, further studies using an experimental model of combined HCA-embolic brain injury are required to exclude a possible increased risk of cerebral embolism associated with the pH-stat strategy.
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