Asian Cardiovasc Thorac Ann 2006;14:495-500
© 2006 Asia Publishing EXchange Ltd
Effect of pH Management on Brain Perfusion During Retrograde Cerebral Perfusion
Yanmin Yang, MD,
Zhijun Li, MD,
Luojia Yang, MD,
Michael Jackson, PhD,
Allan Turner, BSc,
Jian Ye, MD
Institute for Biodiagnostics, National Research Council of Canada, University of British Columbia, Vancouver, Canada
For reprint information contact: Jian Ye, MD Tel: 1 604 806 9349 Fax: 1 604 806 8375 Email: jian.ye{at}nrc-cnrc.gc.ca, Division of Cardiovascular Surgery, University of British Columbia, Rm. 489, Burrard Bldg., 1081 Burrard Street, Vancouver, BC V6Z 1Y6, Canada.
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ABSTRACT
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This study was undertaken to determine the effects of different pH management strategies during retrograde cerebral perfusion on the relationship between retrograde perfusion pressure and brain tissue perfusion. Six pigs were subjected to an alpha-stat strategy and another 6 to a pH-stat strategy during hypothermic (15°C) retrograde cerebral perfusion at perfusion pressures of 10 to 70 mm Hg, in increments of 10 mm Hg every 20 min. Regional cerebral blood flow was significantly higher in the pH-stat group than in the alpha-stat group. The cerebral blood flow peaked at perfusion pressures of 40–50 mm Hg (18.6% ± 10.8% in the pH-stat group vs. 3.6% ± 1.2% in the alpha-stat group). In both groups, the intracranial pressure remained below the critical level of 25 mm Hg, even at a retrograde perfusion pressure of 70 mm Hg. Cerebral lactate production was higher in the alpha-stat group than the pH-stat group during retrograde cerebral perfusion at pressures of 10–30 mm Hg. Compared to the alpha-stat strategy, the pH-stat strategy significantly improved brain tissue perfusion. With an open inferior vena cava, the optimal perfusion pressure seems to be 40–50 mm Hg.
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INTRODUCTION
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Retrograde cerebral perfusion (RCP) was introduced as an adjunct to hypothermic circulatory arrest (HCA) by Ueda and colleagues1 and has been used by many surgeons for more than ten years. Clinical and experimental studies have indicated that RCP during cardiopulmonary bypass (CPB) provides better brain protection than HCA alone. Our studies demonstrated that RCP provides nutrient and blood flow to brain tissue.2 However, the tissue blood supply is not sufficient to meet metabolic requirements, even at 15°C.3–5 The optimal protocol for RCP remains to be determined. Although 25 mm Hg has been presumed to be the maximum safe perfusion pressure, scientific data to support this concept are lacking. Our most recent study on the relationship between RCP pressure and brain perfusion indicates that using an alpha-stat strategy, the optimal RCP pressure is 20–25 mm Hg when the inferior vena cava (IVC) is clamped, and 40–50 mm Hg when the IVC is open.6 The advantages of pH-stat management during hypothermic CPB include increased cerebral blood flow resulting from cerebral vasodilatation secondary to high PCO2, and counteracting the left shift of the oxyhemoglobin dissociation curve induced by hypothermia.7–9 Use of a pH-stat strategy during hypothermia would increase oxygen supply and availability to brain tissue. However, alpha-stat strategy has only been used for pH management during hypothermic RCP as an adjunct to HCA. Our most recent study demonstrated that relative to the alpha-stat strategy, the use of pH-stat strategy during RCP significantly improves brain tissue blood flow and oxygenation, suggesting that pH-stat strategy might be preferred during RCP.10 A few groups have investigated the relationship between perfusion pressure and flow/metabolism/tissue edema in a canine model where alpha-stat was used during RCP.11,12 However, there has been no report on these relationships when a pH-stat strategy is used during RCP. It is not known whether a pH-stat strategy alters the relationship between RCP pressure, brain perfusion, and intracranial pressure (ICP) that is observed with alpha-stat strategy.6 It is also not clear whether different types of pH management during RCP affect the maximum safe perfusion pressure. In this study, laser Doppler flowmetry and near-infrared (NIR) spectroscopy were used to determine the relationship between RCP pressure and brain perfusion, and the optimal perfusion pressures during RCP when using a pH-stat strategy in a pig model.
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MATERIAL AND METHODS
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Twelve pigs less than 5 months of age were used after at least 12 days acclimatization in the animal facility at the Institute for Biodiagnostics. All pigs were fasted with access to water for 12 hrs prior to surgery. All animals received humane care in compliance with the guidelines of the Canadian Council on Animal Care.
Preanesthesia was induced with intramuscular midazolam (0.3 mg·kg–1), ketamine (20 mg·kg–1), and atropine (0.02 mg·kg–1). Muscle relaxation was obtained with pancuronium (0.1 mg·kg–1). After endotracheal intubation, the pig was ventilated mechanically with 60% oxygen and 40% air. Anesthesia was maintained with 1.5%–2.0% isoflurane. A temperature probe was placed in the esophagus to monitor core body temperature. Urine was collected through a bladder catheter. The temporal muscles on both sides of the head were exposed, retracted, and partially excised. Two small holes (0.4 and 0.2 cm in diameter) were made on the right side of the skull bone using a burr drill. The dura was exposed and maintained intact. These holes were prepared for placement of NIR spectroscopy and laser flowmeter probes. A small hole (0.4 cm in diameter) was also made on the left side of the skull bone for placement of a small catheter transducer (1.5 mm in diameter; Millar Instruments, Inc., Houston, TX, USA) beneath the dura, for the measurement of intracranial pressure. A median sternotomy was used to expose the heart. A small catheter was placed in the brachiocephalic artery through the right internal mammary artery, to measure blood pressure and collect venous blood samples during RCP. Another small catheter was placed via the left internal mammary vein into the right internal jugular vein beyond a venous valve, to measure perfusion pressure during RCP and for blood sampling. After heparinization (500 IU·kg–1), the CPB circuit was set up with cannulation of the ascending aorta (22F cannula) and the right atrium (28F single-stage venous cannula). The superior vena cava was cannulated with a small double-lumen cannula. The large lumen was used for RCP through the superior vena cava, and the small lumen was used to monitor central venous pressure. The lungs were not inflated during CPB or HCA. The CPB circuit consisted of Cobe roller pumps (model c22.2; Cobe, Arvada, CO, USA), a cardiotomy reservoir (Cobe HVRF 3700), an arterial filter (40µ, D733; Dideco, Mirandola, Italy), a water bath (Lauda MGW type RMSG, Germany), and a membrane oxygenator (Cobe) with integrated heat exchanger. The system was primed with 1,000 mL Ringer’s lactate solution, 500 mL Pentaspan, 25 mL of 1 mol·L–1 sodium bicarbonate, and 5,000 IU heparin. The CPB circuit was designed to allow switching between RCP and CPB.
Twelve pigs were randomly assigned to one of 2 groups: the pH-stat group (n = 6) in which pH-stat strategy was used during RCP; and the alpha-stat group (n = 6) in which alpha-stat strategy was used during RCP. All pigs received deep HCA at 15°C plus RCP at perfusion pressures of 10 to 70 mm Hg in increments of 10 mm Hg. During RCP, the IVC was open, which was shown to prevent high intracranial pressures and brain edema during RCP performed with the alpha-stat strategy in our previous study.6 The experimental protocol is shown in Table 1
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After preparing equipment for NIR spectroscopy, the laser flowmeter, and ICP measurements, normothermic CPB (37°C) was initiated and continued for 20 min to stabilize body temperature and blood gases. During CPB, mean blood pressure was maintained around 60 mm Hg with pump flows of 95 to 104 mL·kg–1·min–1. After obtaining baseline values for all variables, the pig was gradually cooled from 37°C to 15°C with a temperature gradient of less than 10°C between the water bath and blood, which took approximately 40 min. Circulatory arrest was achieved when the esophageal temperature reached 15°C. Retrograde cerebral perfusion was performed through the superior vena caval catheter at perfusion pressures of 10 to 70 mm Hg in increments of 10 mm Hg. Twenty minutes of RCP were allowed at each pressure increment. This experimental protocol was designed to examine the relationship between retrograde perfusion pressures and brain tissue perfusion/oxygenation, not to be a new protocol used for brain protection during circulatory arrest. During RCP, deoxygenated blood returned to the cardiotomy reservoir through the aortic cannula. The IVC and azygos vein were not snared and were open to gravity drainage during RCP, which was confirmed to be better in preventing high intracranial pressure and brain edema, and improved brain perfusion in our pig model.2,6,10 Our studies further confirmed that clamping the IVC and azygos vein during RCP resulted in critically high ICP and brain edema, even at perfusion pressures of 25–30 mm Hg.6 The RCP pressure in the internal jugular vein was continuously monitored and carefully controlled at the level specified by the protocol. No inotropic drugs were used during the experiments.
Laser flowmetry and NIR were used to continuously monitor brain tissue blood flow and tissue oxygenation (oxyhemoglobin and deoxyhemoglobin), respectively. Cerebral lactic acid production was also determined. The theory and use of the laser flowmeter have been described in detail elsewhere, and used successfully in our pig model.10,13 Regional cerebral blood flow (rCBF) was continuously monitored using a BLF 21D (Advance Company Ltd., Tokyo, Japan) laser Doppler flowmeter fitted with a needle-type probe (type Nspi: 9051U) mounted on a homemade holder. The probe was carefully advanced to touch the dura without visibly indenting it. Areas with visible large blood vessels were avoided. The data were recorded in absolute blood flow units (mL·100g–1·min–1) once the reading was stable. Cerebral oxygenation was monitored using NIR spectroscopy. Near-infrared spectra were acquired using a Foss Analytical NIR Systems 6500 NIR spectrometer (FOSS NIR Systems, Silver Spring, MD, USA) equipped with a randomized bifurcated fiberoptic bundle. The end of the fiberoptic probe was positioned on the cerebral temporal cortex of the right side of the brain through a small hole (0.4 cm diameter) in the skull and held in place with sutures and a homemade holder. An area without any major visible vessels was used for acquisition of NIR spectra. For each measurement, 32 scans were acquired and summed to produce spectra. Three baseline spectra were acquired during normothermic CPB, with spectra acquired every 5 min during the remainder of the experiment.2 The ICP was continuously monitored and recorded using a catheter transducer (Millar Instruments, Inc., Houston, TX, USA) placed in the intracranial space beneath the dura. The hole in the skull was sealed with bone wax. The ICP was recorded as an absolute value (mm Hg). Arterial and venous blood samples were obtained simultaneously at the end of each increment of pressure for measurements of blood lactate. Venous or deoxygenated blood samples were collected from the right internal jugular vein or common carotid artery, respectively, during CPB and RCP. They were analyzed immediately after sample collection using a blood gas analyzer (Stat 9; Nova Biomedical, Waltham, MA, USA). Cerebral lactate production was calculated by the formula: cerebral lactic acid production (mmol·L–1) = perfused lactic acid concentration (mmol·L–1) - returned lactic acid concentration (mmol·L–1).
Mean rCBF, oxyhemoglobin, and deoxyhemoglobin measurements obtained during initial normothermic CPB were used as baseline levels and set at 100%. Statistical analysis was performed using Statistical Analysis System software (SAS Institute, Cary, NC, USA). All data are presented as mean ± standard error of the mean. A repeated-measures analysis of variance and Duncan’s multiple range test were used for comparisons between different time points within a group, and Student’s t test was used for comparison between the groups. A p value less than 0.05 was considered significant.
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RESULTS
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As shown in Figure 1, pump flow during normothermic CPB was 99 to 105 mL·kg–1·min–1 in both groups. Pump flow gradually decreased during the cooling period in both groups. During RCP, pump/retrograde flow increased from 3.3 to 28.4 mL·kg–1·min–1 in the alpha-stat group and from 7.4 to 25.7 mL·kg–1·min–1 in the pH-stat group as retrograde perfusion pressures rose from 10 to 70 mm Hg. There was no statistically significant difference in the pump or retrograde flow between the two groups during RCP at any pressure level.
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Figure 1. Pump flows during experiments in the alpha-stat (triangles) and pH-stat (squares) groups. CPB = cardiopulmonary bypass, RCP = retrograde cerebral perfusion.
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Regional cerebral blood flow was measured continuously throughout the experimental protocol. Laser Doppler flowmetry has limited accuracy in measuring absolute tissue blood flow, but it can monitor changes in tissue blood flow accurately under various physiological conditions. Thus, the mean value of rCBF obtained during the initial normothermic CPB was used as the baseline (100%), and changes in rCBF were followed throughout the protocol. As shown in Figure 2, in the pH-stat group, rCBF increased gradually from 11.2% ± 6.4% to 18.6% ± 10.8% of the baseline as RCP pressures increased from 10 to 50 mm Hg.
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Figure 2. Changes in brain tissue blood flow determined by laser flowmetry during retrograde cerebral perfusion with the pH-stat strategy (squares) and the alpha-stat strategy (triangles). Baseline levels (100%) were obtained during initial normothermic cardiopulmonary bypass. CPB = cardiopulmonary bypass, RCP = retrograde cerebral perfusion.*p < 0.05 vs the alpha-stat group.
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Tissue blood flow reached a plateau when RCP pressure was 40–50 mm Hg, and decreased slightly when RCP pressure was above 50 mm Hg. It was persistently higher in the pH-stat group than in the alpha-stat group at every level of retrograde perfusion pressure, reaching statistical significance at pressures of 20–30 mm Hg.
The changes in ICP during normothermic CPB, hypothermic CPB, and RCP were similar in both groups (Figure 3). During RCP, ICP went up gradually with the increase in perfusion pressure from 10 to 70 mm Hg (from 8.2 ± 1.4 to 18.0 ± 2.2 mm Hg in the alpha-stat group, and 9.9 ± 0.6 to 17.8 ± 3.0 mm Hg in the pH-stat group). Intracranial pressures at retrograde perfusion pressures of 40–50 mm Hg were below the baseline levels observed during normal CPB in both groups. There were no statistical differences in ICP between the two groups at any given RCP pressure.
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Figure 3. Changes in intracranial pressure determined by direct measurement during retrograde cerebral perfusion with the pH-stat strategy (squares) and the alpha-stat strategy (triangles). CPB = cardiopulmonary bypass, RCP = retrograde cerebral perfusion.
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The typical in vivo NIR spectrum from pig brain was detailed in our previous report.2 Briefly, there is a relatively strong absorption feature at 500–600 nm that arises from hemoglobin (oxyhemoglobin and deoxyhemoglobin), which becomes a single peak as the deoxyhemoglobin level increases. A weak absorption feature at 760 nm arises from deoxyhemoglobin, and a broad absorption feature at 900 nm is attributed to oxyhemoglobin. After collecting a spectrum, a computer program written in-house was used to measure the peak areas of deoxyhemoglobin and oxyhemoglobin, which were expressed as the ratios of oxyhemoglobin/total hemoglobin and deoxyhemoglobin/total hemoglobin. The level obtained during initial normothermic CPB was used as the baseline (100%). The changes in tissue oxyhemoglobin and deoxyhemoglobin levels during RCP were very similar in both groups (Figure 4). The oxyhemoglobin level gradually decreased during RCP with increases in perfusion pressures from 10 to 70 mm Hg in both groups. In contrast, the deoxyhemoglobin level increased gradually during RCP in both groups.
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Figure 4. Changes in brain tissue oxyhemoglobin (upper panel) and deoxyhemoglobin (lower panel) determined by near-infrared spectroscopy during experiments in the alpha-stat (triangles) and pH-stat (squares) groups. The levels obtained during initial normothermic cardiopulmonary bypass were used as baselines (CPB-b, 100%). CPB = cardiopulmonary bypass, RCP = retrograde cerebral perfusion.
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During the early period of RCP at perfusion pressures of 10–30 mm Hg, cerebral lactate production was relatively higher in the alpha-stat group than in the pH-stat group. Starting from the perfusion pressure of 40 mm Hg, or after 60 min of RCP, cerebral lactate production increased progressively and significantly in both groups, and there was no statistical difference between the groups (Figure 5).
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Figure 5. Changes in cerebral lactic acid production during experiments in the alpha-stat (triangles) and pH-stat (squares) groups. CPB = cardiopulmonary bypass, RCP = retrograde cerebral perfusion. *p < 0.05 vs the alpha-stat group.
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DISCUSSION
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Our study clearly demonstrates that relative to the alpha-stat strategy, use of the pH-stat strategy during RCP significantly improves brain tissue blood flow at every level of retrograde perfusion pressure from 10 to 70 mm Hg. The difference in brain tissue blood flow was 3–4-fold between the groups. Although the mechanism by which the pH-stat strategy improves cerebral blood flow during hypothermic CPB is known to be hypercapnic vasodilatation, it was not known whether the same mechanism would apply during RCP through the venous system. In this study, we found pump/retrograde flow, retrograde perfusion pressure, and ICP to be similar with either pH-stat or alpha-stat strategy during RCP, but brain tissue blood flow was significantly higher with the pH-stat strategy. Therefore, it is suggested that hypercapnic vasodilatation plays a major role in improving brain tissue blood flow during RCP when using the pH-stat strategy. Hypercapnic dilation of arterioles and arteries would decrease forward flow resistance during RCP. This may be particularly important in increasing retrograde blood flow through brain tissue at the low driving/perfusion pressure during RCP. The exact mechanism by which the pH-stat strategy improves brain tissue perfusion during RCP remains to be determined. The alpha-stat strategy does not require the addition of CO2 and thus cannot reduce vascular tone or resistance, particularly in the arterial system.14
Significantly high intracranial pressures result in brain edema, compress the cerebral vessels, and decrease cerebral blood flow.15 We have demonstrated that when using the alpha-stat strategy, the relationship between intracranial pressure and RCP pressure (internal jugular venous pressure) depends on whether or not the IVC is clamped during RCP. When using the alpha-stat strategy during RCP, the optimal retrograde perfusion pressures appear to be 20–25 mm Hg when the IVC is clamped, and 40–50 mm Hg when the IVC is open.6 In this study, we have shown that the type of pH management used during RCP does not affect the relationship between retrograde perfusion pressure and ICP. With the IVC open during RCP, ICP increases gradually with increasing RCP pressure, regardless of whether pH-stat or alpha-stat strategy is used. At a retrograde perfusion pressure of 70 mm Hg, ICP remains at the baseline level. The optimal retrograde perfusion pressure for RCP should reflect the lowest pressure that provides effective cerebral blood flow and the highest pressure that avoids brain edema.15 The optimal retrograde perfusion pressure for pH-stat management is similar to that for alpha-stat strategy and seems to be 40–50 mm Hg. At this pressure, brain tissue blood flow is maximal and ICP remains far below the critical level of 25 mm Hg that may cause brain edema or injury.11,15 Our previous study demonstrated that with an open IVC during 120 min of RCP, increased retrograde perfusion pressures (35–40 mm Hg) significantly increased brain tissue blood flow and did not cause brain tissue edema.1 According to our studies, temporary closure of the IVC, rather than perfusion pressure during RCP, is the major risk factor for high ICP and brain edema.2,6 In this study, the IVC was kept open and ICP was below the normal baseline level, even at a retrograde perfusion pressure of 70 mm Hg, and thus brain tissue perfusion due to high intracranial pressures and/or brain edema would not be an issue in this study.
In this research, cerebral oxygenation as determined by NIR has not consistently suggested that the amount of oxygen supplied by RCP meets oxygen demand, since a gradual decrease in tissue oxyhemoglobin and a corresponding increase in tissue deoxyhemoglobin are observed during RCP, even with the use of pH-stat strategy. However, the limitation of NIR spectroscopy is that it measures oxyhemoglobin or deoxyhemoglobin from the complete vasculature (venous, arterial, and capillary system), not just from capillaries. During RCP a large portion of blood volume from which NIR is measured is venous blood (oxygenated blood during RCP). Therefore, NIR may not be sufficiently sensitive to detect small changes in either oxyhemoglobin or deoxyhemoglobin in the capillaries. However, NIR data provide an overall pattern of changes in brain tissue oxygenation during the experimental protocol. Interestingly, the pattern of change in deoxyhemoglobin is similar to that of cerebral lactate production; both levels increase progressively during RCP. Lower cerebral lactate production during the early period of RCP at pressures of 10–30 mm Hg (60 min of RCP) in the pH-stat group relative to the alpha-stat group may indicate more oxygen reserve prior to RCP with the use of pH-stat (higher cerebral perfusion during hypothermic CPB with pH-stat), better tissue perfusion during RCP with pH-stat, and/or improved O2 release from hemoglobin with the pH-stat strategy. The significant increase in cerebral lactate production after 60 min of RCP in both groups may be an indication that prolonged RCP is not safe.
As a result of possible anatomical differences between humans and animals, our data may not be completely translated into clinical situations. However, animal models provide controlled experimental conditions and allow measurements that often are not feasible in humans. To our knowledge, this study provides the first detailed report on the relationship between retrograde perfusion pressure and regional cerebral blood flow, brain tissue oxygenation, as well as intracranial pressure during RCP with the use of a pH-stat strategy.
It was concluded that relative to the use of an alpha-stat strategy in our pig model, a pH-stat strategy during RCP significantly improves brain tissue perfusion without causing higher ICP at any level of RCP pressure. The type of acid-base management does not change the optimal retrograde perfusion pressure. Based on the findings from this and previous studies, we also conclude that when the IVC is open, regardless of the use of an alpha-stat or a pH-stat strategy during RCP, the optimal retrograde perfusion pressure appears to be 40–50 mm Hg.2,6 Further studies are necessary to develop an optimal protocol that is suitable for RCP in humans.
Presented at the 56th Annual Meeting of the Canadian Cardiovascular Society, Toronto, Canada, October 24–29, 2003.
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ACKNOWLEDGMENTS
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This work was supported in part by the Canadian Institutes of Health Research (Grant nos. 15352 and 42671), the Heart and Stroke Foundation, and the Manitoba Health Research Council. We thank Jennifer Cherkas, Lori Gregorash, Rachelle Mariash, Amber Stoyko, and Shelly Germscheid for technical assistance.
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REFERENCES
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ABSTRACT
INTRODUCTION
