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Ann Thorac Surg 2007;84:847-855
© 2007 The Society of Thoracic Surgeons

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Original Articles: Cardiovascular

Effects of pH Management During Selective Antegrade Cerebral Perfusion on Cerebral Microcirculation and Metabolism: Alpha-Stat Versus pH-Stat

^a Department of Surgery, Clinical Research Center, Oulu University Hospital and University of Oulu, Oulu, Finland
^b Department of Anesthesiology, Clinical Research Center, Oulu University Hospital and University of Oulu, Oulu, Finland

Accepted for publication March 19, 2007.

^_* Address correspondence to Dr Dahlbacka, Clinical Research Center, Oulu University Hospital, PO Box 5000, Oulu, 90014 OYS, Finland (Email: sdahlbac{at}paju.oulu.fi).

	Abstract

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Background: Selective cerebral perfusion (SCP) is used for extending the period during which surgical procedures can be safely performed. We sought to determine the direct effects of pH management on cerebral microcirculation and metabolism during SCP.

Methods: An experimental SCP porcine model was created by selectively allowing cold perfusate only into the bicarotid brachiocephalic trunk during the SCP period. Twenty-four piglets (6 to 8 weeks; mean weight, 26.1 ± 4.1 kg) underwent 15-minute normothermic cardiopulmonary bypass, 45-minute cooling cardiopulmonary bypass, 60-minute SCP at 25°C, and 45-minute rewarming cardiopulmonary bypass with either -stat or pH-stat perfusion strategy randomly assigned. A cranial window was created over the parietal cortex for visualization of the cerebral vessels with intravital microscopy. Rhodamine-stained leukocytes were observed in cerebral postcapillary venules for adhesion and rolling. Microdialysis analysis was used for determination of brain metabolism.

Results: Brain concentration of lactate was significantly higher in the -stat group at 45 minutes of SCP, and at 15- and 45-minute rewarming intervals (p = 0.03; p = 0.003; and p = 0.05; respectively), reaching borderline statistical significance when assessed throughout the experiment (p = 0.06 for differences between groups). Further, at the end of cooling, the oxygen delivery tended to be higher in the pH-stat group (p = 0.07), whereas at the 30-minute rewarming interval, the oxygen extraction tended to be higher in the -stat group (p = 0.06). There were no statistically significant differences between the groups in leukocyte–endothelial interaction, arterial diameter, or tissue oxygenation.

Conclusions: The higher concentration of brain lactate and the tendency to higher oxygen extraction levels during rewarming with -stat strategy suggests anaerobic metabolism occurred during SCP. No major differences between pH management strategies in cerebral microcirculation could be shown during SCP.

	Introduction

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Selective cerebral perfusion (SCP) has evoked renewed interest in recent years, and has become the primary brain protection method in many centers [1]. Selective cerebral perfusion can be provided by direct cannulation or through a graft anastomosed end-to-side on the right subclavian artery.

Although the -stat strategy has been widely selected for pH management during hypothermic cardiopulmonary bypass (CPB) since the 1980s, the pH-stat regimen has demonstrated positive effects in both experimental [2] and clinical studies [3] in recent years. When comparing the effects of pH management in association with deep hypothermic circulatory arrest (HCA) on cerebral microcirculation, Duebener and colleagues [4] reported that cerebral oxygenation was significantly higher in the pH-stat group at the end of cooling and during early reperfusion. The cerebral microcirculation has not yet been evaluated with intravital microscopy during SCP, although cerebral microcirculatory behavior during retrograde cerebral perfusion has been reported [5], and the optimal pH strategy for SCP has been assessed in two experimental studies previously [6, 7].

Previously, we have studied the effects of pH management on the conduct of HCA [8, 9]. Because of the renewed interest in using SCP as a primary brain protection method, the aim of this study was to establish a new SCP porcine model and to observe cerebral metabolism and microvascular effects during SCP with different pH management, -stat and pH-stat, using microdialysis analysis for metabolic measurements and intravital microscopy for cerebral microcirculation assessment.

	Material and Methods

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Twenty-four female pigs of a native stock were randomly assigned to undergo 60 minutes of selective antegrade cerebral perfusion (SCP) with either -stat (12 pigs) or pH-stat (12 pigs) strategy during cooling CPB, SCP, and rewarming CPB. All animals received humane care in accordance 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 Institute of Laboratory Animal Resources, National Research Council (published by the National Academy Press, revised in 1996). The study was approved by the Research Animal Care and Use Committee of the University of Oulu.

Preoperative Management
The animals were sedated with ketamine hydrochloride (350 mg intramuscularly) and midazolam (45 mg intramuscularly). A peripheral intravenous catheter was inserted into the right ear for administration of drugs and to maintain fluid balance with Ringer’s acetate solution. Anesthesia was deepened with an intravenous bolus injection of thiopental as required. After endotracheal intubation with a 6-mm cuffed endotracheal tube, the balanced anesthesia was maintained by inhaled isoflurane (0.5%) and a continuous infusion of fentanyl (25 µg · kg^–1 · h^–1), midazolam (0.25 mg · kg^–1 · h^–1), and pancuronium (0.2 mg · kg^–1 · h^–1) in both study groups throughout the whole experiment. The animals were maintained on positive-pressure ventilation with 50% oxygen. Electrocardiographic monitoring was performed throughout the experiment. An arterial catheter was positioned into the left femoral artery for arterial pressure monitoring and blood sampling. A thermodilution catheter (CritiCath, 7F; Ohmeda GmbH & Co, Erlangen, Germany) was placed through the left femoral vein to allow blood sampling and monitoring of central venous pressure, pulmonary artery pressure, and pulmonary capillary wedge pressure, and for recording the blood temperature and cardiac output. A 10F catheter was placed in the urinary bladder for monitoring urine output. Temperatures were monitored from pulmonary artery blood, the rectum, and the brain.

Operative Technique
Referring to a precise description of the pig aortic arch anatomy [10], the brachiocephalic artery is the source of both carotid arteries, and isolated perfusion of the bicarotid trunk can be performed through a left thoracotomy. Therefore, through a left thoracotomy in the third intercostal space the pericardium was opened, and the heart and great vessels were exposed. The brachiocephalic trunk, the left subclavian artery, the pulmonary artery, and the ascending and descending aorta were each dissected free and coiled loosely with a vessel loop. After this, the baseline variables were recorded.

A membrane oxygenator (D905 Eos; Dideco, Mirandola, Italy) was primed with 1 L of Ringer’s acetate solution and heparin (5,000 IU). After systemic heparinization (500 IU/kg), the ascending aorta was cannulated with a 16F arterial cannula, and the right atrial appendage was cannulated with a single 24F atrial cannula. Nonpulsatile CPB was initiated at a flow rate of 90 to 110 mL · kg^–1 · min^–1, and the flow was adjusted to maintain a perfusion pressure of 50 to 70 mm Hg. A 12F intracardiac sump cannula was positioned through the left atrial appendage for decompression of the left side of the heart during CPB. A cooling period of 45 minutes was carried out to attain a brain temperature of 25°C. A heat exchanger was used for core cooling.

When the target temperature was reached, 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. The clamp was shifted proximally to the aortic cannula, and the descending aorta and the left subclavian artery were cross-clamped. The SCP flow rate was adjusted to maintain an aortic arch pressure of 50 mm Hg, the flow rate being 10 mL · kg^–1 · min^–1. The intracerebral temperatures were maintained at a level of 25°C with hypothermic SCP. Cardiac cooling with topical ice slush was begun and maintained throughout the 60-minute SCP period. After this, the clamps were removed, and systemic CPB and rewarming was started. Five minutes after the start of rewarming, furosemide (40 mg), mannitol (150 g), methylprednisolone (80 mg), lidocaine (40 mg), and calcium glubionate (137.5 mg) were administered. The sump cannula was removed after 35 minutes of rewarming, and weaning from CPB occurred about 45 minutes after HCA when the rectal temperature approximated 37°C. Dopamine was postoperatively used as required. During rewarming and after weaning from CPB, heat-exchanger mattress and heating lamps regulated the temperatures. The animals of both groups were monitored for 2 hours after the start of rewarming, and were then electively sacrificed by intravenous injection of pentobarbital (60 mg/kg) and disconnection from the ventilator.

Intracerebral Monitoring
A cranial window (15 x 15 mm) for intravital microscopy was created over the right parietal cerebral cortex with an electric drill. After incision of the dura, the surface cortical vessels were visualized. A probe for monitoring intracerebral temperature (Thermocouple Temperature Catheter-Micro-Probe, Ref C8.B [Gesellschaft für medizinische Sondentechnik mbH, Mielkendorf, Germany]) was inserted through a hole drilled left of the sagittal suture and posteriorly to the coronal suture. The intracerebral temperature was used as the primary measure of temperature. Microdialysis samples were collected at different intervals, using the technique described previously [9].

After other baseline variables were recorded, the pig was placed in a prone position and secured. An intravital microscope (Leica Model MZFL III, Leica, Heerbrugg, Switzerland) mounted on a surgical stand was placed over the cranial window. The microscope included three sets of filters: a violet filter (450- to 490-nm excitation, >515-nm emission wavelength) to visualize microvascular perfusion, a green filter (536- to 556-nm excitation, >590-nm emission wavelength) for visualization of rhodamine-labeled leukocytes, and an ultraviolet filter for reduced nicotinamide adenine dinucleotide analysis. The image was captured by the charge-coupled device video camera (Dage-MTI CCD 300-ETRCX) and transferred to a monitor (Samsung LCD SyncMaster 710mp) and videotaped. A frame grabber (Kudo Interactive Frame Grabber) and a computer-assisted image-analysis system (Scion Corporation, Frederick, MD) were later used for off-line analysis. The final magnification on the monitor was 400 times.

The diameter of 20- to 50-µm arterial and venous cerebrocortical microvessels was measured from video still images by using the image-analysis program. In each animal, three arterioles and three venules were selected from the observation area. Each measurement was referred to baseline so that the baseline diameter of the vessel was 100%.

For observation of leukocyte–endothelial cell interactions, the piglet received an intravenous 2-mL (4 mg/mL) loading dose of rhodamine 6G chloride (molecular weight, 479; Sigma Chemical Company, St. Louis, MO) 5 minutes before the initial recording, and thereafter 1 mL (4 mg/mL) of rhodamine before each imaging to stain the activated leukocytes in the circulation. From each animal, one postcapillary venule was selected to represent the amount of adherent and rolling leukocytes. The exact number of adherent leukocytes was calculated from an easily determined 100-µm portion of the vessel, and the number of cells was then related to the surface area rendered. All intravital microscopy measurements were performed in a blinded manner using both still pictures and videotapes. For rolling leukocytes, one specific point of the vessel was selected, and the number of leukocytes rolling past that point was observed during approximately 10 to 15 seconds in each recording.

Recordings were made at 12 times: at baseline, at 10 minutes of normothermic CPB, at 15, 30, and 45 minutes of cooling, at 15, 30, and 45 minutes of SCP, and at 5, 15, 30, and 45 minutes of rewarming. The epi-illumination was limited to less than 1 minute to avoid thermal injury, and the epi-illumination was always stopped between video recordings.

Biochemical Data
Blood gases; pH; electrolytes; serum ionized calcium, glucose, and hemoglobin levels (i-STAT Analyzer; i-STAT Corporation, East Windsor, NJ); leukocyte differential count (Cell-Dyn analyzer; Abbot, Santa Clara, CA); and creatinine (Advia2400 Chemistry System; Siemens Medical Solutions Diagnostics, Los Angeles, CA) were measured at baseline and at the end of cooling (immediately before institution of HCA), as well as 30 minutes and 2 hours after the start of rewarming. To control arterial carbon dioxide gas tension precisely, arterial blood sampling was performed at least every 15 minutes during CPB.

Statistical Analysis
Statistical analysis was performed using SPSS (version 12.0; SPSS Inc, Chicago, IL) and SAS (version 9.1.3; SAS Institute Inc, Cary, NC) statistical software. Continuous and ordinal variables are expressed as medians with 25th and 75th percentiles (IQRs). The mixed model approach was used to analyze repeated measurements using combined covariance pattern and random coefficient model [11]. Reported p values are as follows: p between groups (p_g), indicates a level of difference between the groups, p time*group (p_t*g), indicates group–time interaction, and p_t indicates change over measurement points. Either Student’s t test or Mann-Whitney U test was used to assess the distribution of variables between the study groups. Two-tailed significance levels are reported.

	Results

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Comparison of Study Groups
The preoperative mean weight ± standard deviation of the pigs was 26.6 ± 5.1 kg in the -stat group and 25.6 ± 3.1 in the pH-stat group (p = 0.5). There were no statistically significant differences between the groups regarding preoperative mean arterial pressures, cardiac index, brain and rectal temperatures, hematocrit, venous glucose (Table 1), creatinine, or leukocyte differential count.

When observing the perfusion time separately, the carbon dioxide tension was significantly higher in the pH-stat group compared with the -stat group both when warmed up to 37°C in the blood gas analyzer (p_g < 0.001; p_t*g < 0.001) and when corrected for actual temperature (p_g = 0.003; p_t*g = 0.003). pH was also significantly different between the groups when observed at 37°C (p_g < 0.001; p_t*g < 0.001), but when measured at actual temperature, only a difference in behavior between the groups was observed (p_g = 0.13; p_t*g < 0.001).

Microvascular Diameter
Intravital microscopy data is presented in Figure 1. The median baseline diameters of selected arteries were 29.0 µm (IQR, 17.3 to 36.2 µm) in the -stat group and 34.3 µm (IQR, 23.7 to 40.3 µm) in the pH-stat group (p = 0.52). During normothermic bypass, the arterial diameter increased relative to baseline in the pH-stat group, but decreased in the -stat group (median, 106%; IQR, 95% to 124%; versus median, 92%; IQR, 78% to 138%). At the 30-minute cooling interval the microvascular diameter had further increased in the pH-stat group, but decreased in the -stat group (median, 108%; IQR, 78% to 133%; versus median, 89%; IQR, 72% to 141%). At the end of cooling the arteries of the pH-stat group constricted, being suddenly more constricted than the arteries of the -stat group (median, 76%; IQR, 54% to 114%; versus median, 89%; IQR, 76% to 123%). At the 30-minute SCP interval the arteries in the pH-stat group markedly dilated compared with those of the -stat group (median, 129%; IQR, 97% to 136%; versus median, 103%; IQR, 86% to 135%). At the start of rewarming the arteries continued to constrict in the pH-stat group, but dilated in the -stat group (median, 80%; IQR, 54% to 108%; versus median, 118%; IQR, 68% to 150%). During rewarming the arteries in the pH-stat group remained constricted until the end of rewarming, when the diameter differences between the groups had vanished (median, 109%; IQR, 87% to 127%; versus median, 107%; IQR, 72% to 138%). The differences between the groups were not statistically significant (p_g = 0.97; p_t*g = 0.94).

View larger version (21K): [in this window] [in a new window]   Fig 1. Brain arterial diameters (left), adherent leukocytes (center), and tissue oxygenation (right) in pigs undergoing selective cerebral perfusion (SCP) and being monitored using either -stat (solid squares; n = 10) or pH-stat (open circles; n = 10) strategy. (m = minutes; NADH = reduced nicotinamide adenine dinucleotide.)

The reduced nicotinamide adenine dinucleotide autofluorescence increased in relation to baseline values in both groups during cooling perfusion, but decreased at the middle stage of the SCP period. Higher values indicate worse tissue oxygenation. The pH-stat group had lower reduced nicotinamide adenine dinucleotide fluorescence at the 45-minute interval of SCP (p = 0.14), and returned faster to baseline values, than the -stat group. There were no statistically significant differences between the groups (p_g = 0.66; p_t*g = 0.59).

White Blood Cell Counts
The number of circulating leukocytes decreased markedly because of hemodilution in both groups from the start of perfusion, but increased again from the 30-minute rewarming interval to the 2-hour interval. This return toward baseline values was more obvious in the -stat group, although no statistically significant difference was observed. Less circulating neutrophils were observed in the pH-stat group (p_g = 0.18); statistically significantly, the number of circulating neutrophils decreased more as a function of time in the pH-stat group (p_t*g = 0.04), and less circulating neutrophils were observed at the 2-hour postoperative interval (p = 0.05). No statistically significant difference between the groups was observed in the number of circulating lymphocytes.

Microdialysis Analysis
Microdialysis data are presented in Table 2 and Figure 2. No statistically significant differences between the groups were observed regarding the concentration of brain glucose (p_g = 0.44; p_t*g = 0.06). The brain lactate concentrations tended to be significantly higher in the -stat group (p_g = 0.06; p_t*g = 0.02). There were no statistically significant differences in the brain concentrations of pyruvate (p_g = 0.56; p_t*g = 0.58), glutamate (p_g = 0.28; p_t*g = 0.07), or glycerol (p_g = 0.63; p_t*g = 0.79) between the study groups. Brain glucose concentrations were slightly higher in the -stat group before and after SCP, but during SCP the concentrations of brain glucose were almost identical between the groups. At the 15-minute cooling interval the -stat group had significantly higher concentrations (p = 0.05). The brain glucose concentration increased during the end of cooling in the pH-stat group, whereas in the -stat group it decreased. The concentration of brain lactate increased markedly above baseline level in the -stat group after the 15-minute SCP interval, and was significantly higher at the 45-minute SCP, and 15- and 45-minute rewarming intervals (p = 0.03; p = 0.003; and p = 0.045; respectively). At no time was there a statistically significant difference between the groups regarding the lactate to pyruvate ratio. The concentrations of brain glutamate remained at baseline levels in both groups throughout the experiment, whereas the concentrations of brain glycerol continued to slightly increase from the 15-minute SCP interval until 2 hours postoperatively in both groups.

View larger version (16K): [in this window] [in a new window]   Fig 2. Key brain microdialysis findings for brain lactate concentration (left), brain lactate to pyruvate ratio (center), and brain glycerol concentration (right) in pigs undergoing selective cerebral perfusion (SCP) and being monitored with either -stat (solid squares; n = 12) or pH-stat (open circles; n = 12) strategy. (postop = postoperative.)

	Comment

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

The hypercarbic state related to the pH-stat strategy causes systemic vasodilation and loss of cerebral autoregulation [12]. This results in improved cooling [8] and, consequently, better cerebral tissue oxygenation [4] and metabolic suppression [13], which are favorable before the critical ischemic period with HCA. However, the loss of autoregulation increases cerebral blood flow and may predispose the brain for embolic injury [12, 14–16]. In our previous study using HCA, massive embolization of the epiaortic vessels did not adversely affect the outcome of the animals managed with pH-stat compared with the outcome of the animals managed according to the -stat principles [9].

Halstead and coworkers [6] found no differences in neurobehavioral outcome after SCP between the -stat and pH-stat groups. However, they supported the -stat strategy in clinical aortic surgery involving SCP because it preserves better cerebral autoregulation and the risk of cerebral embolization is less than that with pH-stat management. A recent clinical study did not, however, report any increased risk of embolization with SCP using direct cannulation of the innominate and left carotid arteries [17]. The study of Ohkura and associates [7], undertaken in dogs, showed that pH-stat reduces serum concentrations of brain ischemia markers if an old cerebral infarct is present; in normal animals that have undergone SCP, there were no differences between -stat and pH-stat strategies.

In the present study, we created a new modification of an SCP porcine model, and in this initial series we compared different pH management strategies. Intravital microscopy and brain microdialysis analysis provided the main outcome measures. Both methods allow direct, reliable microcirculatory and biochemical neuromonitoring, which can be used to predict brain injury.

In the pathogenesis of brain injury ischemia–reperfusion injury plays a major role. Although less ischemia–reperfusion injury is associated with SCP than with HCA, the release of the aortic cross-clamp inducing cardiopulmonary reperfusion predisposes the brain for accumulated metabolic products from the lower body. In addition, blood components are activated by the contact of blood with foreign surfaces of the extracorporeal circulation, and inflammatory signals from the damaged area and mechanical shear forces are triggering the harmful leukocyte activation process. The activated leukocytes are considered to undergo three phases; the activated leukocytes form temporary bonds with the vessel wall endothelium mediated by selectin (rolling leukocytes) [18], and eventually stronger bonds (adherent leukocytes) through interaction between leukocyte ß-integrins (CD11 and CD18) and intercellular adhesion molecules (ICAM-1, ICAM-2) [19]. Finally, the leukocytes migrate (migrating leukocytes) into surrounding tissues assisted by interleukin-8 and platelet-endothelial cell adhesion molecule-1 [20, 21].

In the present study, we were not able to observe any statistically significant differences in the leukocyte–endothelial interaction between the groups. Although more adherent leukocytes were seen in the pH-stat group during the SCP period, during the rewarming period, when the harmful activation of leukocytes takes place, the trend was opposite. No statistically significant differences were observed in the microvascular diameters between the groups either. This finding can be explained by the choice of using moderate hypothermia instead of deep hypothermia, although the true effects of carbon dioxide on cerebral autoregulation are to be expected with progressing hypothermia. The behavior of the arteries during cooling was, however, concordant with previous studies [4, 22], dilating in the pH-stat group and constricting in the -stat group. Although pH-stat management has been shown to have significantly higher cerebral oxygenation at the end of cooling and during early rewarming in association with HCA at 15°C [4], we failed to show any statistically significant differences between pH management strategies in cerebral tissue oxygenation and microcirculation during hypothermic CPB and SCP at 25°C. These findings suggest that the advantage of pH-stat strategy compared with -stat strategy is seen only when deep hypothermic CPB and HCA is used.

The higher concentration of brain lactate and the tendency for higher oxygen extraction levels during early reperfusion suggests anaerobic cerebral metabolism during SCP with -stat strategy. This finding is in contrast to a previous study, in which the cerebral blood flow to cerebral metabolic rate of oxygen utilization ratio was shown to increase during cooling to 20°C with -stat management and remain high throughout the 90-minute SCP period [23]. Although we observed a difference between the groups regarding the brain concentration of extracellular lactate, no statistically significant differences were observed in brain concentrations of glutamate or glycerol, which usually indicate ultimate brain damage. Nor did the lactate to pyruvate ratio differ significantly between the groups, suggesting that the accumulated lactate had to be conversed back to pyruvate and taken into the Krebs cycle.

In conclusion, these findings indicate that the differences between pH-stat and -stat strategies in cerebral microcirculation are minimal during moderately hypothermic SCP, although we observed a tendency for anaerobic cerebral metabolism with -stat strategy. In the present study, we created a new modification of an acute SCP porcine model, and further studies at comparing the effects of SCP and different pH management on cerebral embolization are required.

	Acknowledgments

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
This study was supported by grants from the Oulu University Hospital, the Finnish Foundation for Cardiovascular Research, and the Sigrid Juselius Foundation. Doctor Dahlbacka was also supported by grants from the Finnish-Swedish Medical Society, the Science Foundation of Farmos, the Foundation of Aarne Koskelo, and the Finnish Medical Society Duodecim. We express our gratitude to Seija Seljänperä, RN, and Veikko Lähteenmäki, for technical assistance.

	References

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 

1. Di Eusanio M, Schepens MA, Morshuis WJ, et al. Brain protection using antegrade selective cerebral perfusion: a multicenter study Ann Thorac Surg 2003;76:1181-1188.[Abstract/Free Full Text]
2. Sakamoto T, Zurakowski D, Duebener LF, et al. Combination of alpha-stat strategy and hemodilution exacerbates neurologic injury in a survival piglet model with deep hypothermic circulatory arrest Ann Thorac Surg 2002;73:180-189.[Abstract/Free Full Text]
3. du Plessis AJ, Jonas RA, Wypij D, et al. Perioperative effects of alpha-stat versus pH-stat strategies for deep hypothermic cardiopulmonary bypass in infants J Thorac Cardiovasc Surg 1997;114:991-1000.[Abstract/Free Full Text]
4. Duebener LF, Hagino I, Sakamoto T, et al. Effects of pH management during deep hypothermic bypass on cerebral microcirculation: alpha-stat versus pH-stat Circulation 2002;106(Suppl 1):I-103-I-108.[Medline]
5. Duebener LF, Hagino I, Schmitt K, et al. Direct visualization of minimal cerebral capillary flow during retrograde cerebral perfusion: an intravital fluorescence microscopy study in pigs Ann Thorac Surg 2003;75:1288-1293.[Abstract/Free Full Text]
6. Halstead JC, Spielvogel D, Meier DM, et al. Optimal pH strategy for selective cerebral perfusion Eur J Cardiothorac Surg 2005;28:266-273.[Abstract/Free Full Text]
7. Ohkura K, Kazui T, Yamamoto S, et al. Comparison of pH management during antegrade selective cerebral perfusion in canine models with old cerebral infarction J Thorac Cardiovasc Surg 2004;128:378-385.[Abstract/Free Full Text]
8. Pokela M, Dahlbacka S, Biancari F, et al. pH-stat versus alpha-stat perfusion strategy during experimental hypothermic circulatory arrest: A microdialysis study Ann Thorac Surg 2003;76:1215-1226.[Abstract/Free Full Text]
9. Dahlbacka S, Heikkinen J, Kaakinen T, et al. pH-stat versus alpha-stat acid-base management strategy during hypothermic circulatory arrest combined with embolic brain injury Ann Thorac Surg 2005;79:1316-1325.[Abstract/Free Full Text]
10. Hagl C, Khaladj N, Peterss S, et al. Hypothermic circulatory arrest with and without cold selective antegrade cerebral perfusion: impact on neurological recovery and tissue metabolism in an acute porcine model Eur J Cardiothorac Surg 2004;26:73-79.[Abstract/Free Full Text]
11. Brown H, Prescott R. Applied mixed models in medicine2 ed.. Edinburgh: Wiley, Scotland; 2006.
12. Aoki M, Nomura F, Stromski ME, et al. Effects of pH on brain energetics after hypothermic circulatory arrest Ann Thorac Surg 1993;55:1093-1103.[Abstract]
13. Hindman BJ, Dexter F, Cutkomp J, et al. pH-stat management reduces the cerebral metabolic-rate for oxygen during profound hypothermia (17°C): a study during cardiopulmonary bypass in rabbits Anesthesiology 1995;82:983-995.[Medline]
14. Henriksen L. Brain luxury perfusion during cardiopulmonary bypass in humans: a study of the cerebral blood-flow response to changes in CO₂, O₂, and blood pressure J Cereb Blood Flow Metab 1986;6:366-378.[Medline]
15. Plochl W, Cook DJ. Quantification and distribution of cerebral emboli during cardiopulmonary bypass in the swine—the impact of Pa-CO₂ Anesthesiology 1999;90:183-190.[Medline]
16. Cook DJ, Boston US, Orszulak TA, et al. Carbon dioxide management and the cerebral response to hemodilution during hypothermic cardiopulmonary bypass in dogs Ann Thorac Surg 2001;72:1331-1335.[Abstract/Free Full Text]
17. Kamiya H, Klima U, Hagl C, et al. Cerebral microembolization during antegrade selective cerebral perfusion Ann Thorac Surg 2006;81:519-521.[Abstract/Free Full Text]
18. Zimmerman GA, Prescott SM, Mcintyre TM. Endothelial-cell interactions with granulocytes—tethering and signaling molecules Immunol Today 1992;13:93-100.[Medline]
19. Bevilacqua MP. Endothelial-leukocyte adhesion molecules Annu Rev Immunol 1993;11:767-804.[Medline]
20. Huber AR, Kunkel SL, Todd RF, et al. Regulation of transendothelial neutrophil migration by endogenous interleukin-8 Science 1991;254:99-102.[Abstract/Free Full Text]
21. Muller WA, Weigl SA, Deng XH, et al. PECAM-1 is required for transendothelial migration of leukocytes J Exp Med 1993;178:449-460.[Abstract/Free Full Text]
22. Alaoja H, Niemela E, Anttila V, et al. Leukocyte filtration to decrease the number of adherent leukocytes in the cerebral microcirculation after a period of deep hypothermic circulatory arrest J Thorac Cardiovasc Surg 2006;132:1339-1347.[Abstract/Free Full Text]
23. Strauch JT, Spielvogel D, Haldenwang PL, et al. Impact of hypothermic selective cerebral perfusion compared with hypothermic cardiopulmonary bypass on cerebral hemodynamics and metabolism Eur J Cardiothorac Surg 2003;24:807-816.[Abstract/Free Full Text]

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				M. L. Jacobs Invited commentary Ann. Thorac. Surg., September 1, 2007; 84(3): 855 - 856. [Full Text] [PDF]

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