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Ann Thorac Surg 2005;79:1316-1325
© 2005 The Society of Thoracic Surgeons
-Stat Acid–Base Management Strategy During Hypothermic Circulatory Arrest Combined With Embolic Brain Injury
a Department of Surgery, Oulu University Hospital, University of Oulu, Oulu, Finland
b Department of Anesthesiology, Oulu University Hospital, University of Oulu, Oulu, Finland
c Department of Pathology, Oulu University Hospital, University of Oulu, Oulu, Finland
d Department of Clinical Neurophysiology, Oulu University Hospital, University of Oulu, Oulu, Finland
Accepted for publication September 7, 2004.
* 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).
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Abstract |
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-stat perfusion strategy, but this is tempered by a likely increased risk of embolism to the brain, especially in adult patients. We investigated this possible adverse effect in an experimental model that combined hypothermic circulatory arrest (HCA) and embolic brain injury.
METHODS: Twenty-four female juvenile pigs undergoing 25 minutes of HCA at a brain temperature of 18°C were assigned to either -stat (n = 12) or pH-stat (n = 12) strategy during cardiopulmonary bypass. Before the initiation of HCA, the descending aorta was clamped and 200 mg of albumin-coated polystyrene microspheres (250 to 750 µm in diameter) were injected into the isolated aortic arch in both groups.
RESULTS: The 7-day survival rate was 75% in the pH-stat group and 50% in the -stat group (p = 0.40). The pH-stat group had significantly better behavioral scores on postoperative days 5 (p = 0.03) and 6 (p = 0.04). The pH-stat strategy was associated with better postoperative intracranial pressures and histopathologic scores, but such differences did not reach statistical significance. The -stat group had lower brain glucose concentrations postoperatively as well as higher brain lactate/glucose and lactate/pyruvate ratios
CONCLUSIONS: These results suggest that pH-stat strategy does not cause any worse brain injury than the -stat strategy. Indeed, the pH-stat strategy is associated with a slightly better outcome compared with the -stat strategy, even in the setting of cerebral embolization. This observation suggests that the pH-stat strategy could also be used in adults during deep hypothermic cardiopulmonary bypass despite the increased risk of intraoperative cerebral embolization.
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Introduction |
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-stat and pH-stat strategies affect metabolism are, however, becoming clear. Cooling results in an alkaline shift of the blood pH, as is observed with the -stat strategy. This perfusion strategy is associated with better preservation of cerebral autoregulation. In the pH-stat method, the natural alkaline shift in response to the decreasing temperature is corrected by adding carbon dioxide. The hypercarbia related to the pH-stat strategy causes systemic vasodilatation and loss of cerebral autoregulation [1]. This results in improved cooling [2] and cerebral tissue oxygenation before the critical ischemic period [3] as well as during retrograde cerebral perfusion [4]. There is uncertainty whether the abolished flow/metabolism coupling associated with the pH-stat strategy poses an unnecessarily increased embolic risk or whether this "luxury perfusion" is beneficial by enhancing cerebral cooling and protecting brain areas against ischemic brain injury.
Several experimental studies have evaluated pH-stat acid—base management along with other perfusion-related methods, including low-flow bypass, in the repair of congenital cardiac anomalies. Some clinical studies support its use as a superior strategy over -stat during pediatric cardiac surgery [5–7]. However, no study at present has evaluated the impact of the -stat strategy versus pH-stat strategy in a setting combining both HCA and cerebral embolization. This is of most relevance, especially in adults, as they are at increased risk of cerebral embolization during several phases of aortic arch reconstruction. We sought to determine in a surviving porcine model whether the pH-stat strategy would be more effective than the -stat strategy in attenuating brain ischemic injury during combined HCA and embolization conditions, and thereby to mimic the situation that often exists in adults of an increased risk of cerebral embolization.
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Material and Methods |
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Anesthesia and Monitoring
Twenty-four female juvenile pigs (8 to 10 weeks old) from a native stock, with a median weight of 27.8 kg (interquartile range [IQR], 26.3 to 29.4), were sedated with ketamine hydrochloride (350 mg intramuscularly) and midazolam (45 mg intramuscularly). A peripheral catheter was inserted into a vein of the right ear for the administration of drugs and to maintain fluid balance with Ringer acetate. Anesthesia was deepened with an intravenous bolus injection of fentanyl (25 µg/kg). After endotracheal intubation, the anesthesia was maintained by 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), throughout the whole experiment but not during HCA. The animals were maintained on positive pressure ventilation with 50% oxygen. Cefuroxime (1.5 g intravenously) was administered at anesthesia induction and before extubation.
Electrocardiographic, hemodynamic, intracerebral, electroencephalographic, and systemic metabolic monitoring, as well as an evaluation of behavioral outcome and histopathologic analysis, were accomplished as described in details in a previous study [2].
Changes in brain metabolism during the experiment were evaluated by intracerebral microdialysis. In vivo microdialysis measures the chemical composition of the extracellular fluid. Microdialysis functions on the principle of diffusion of water-soluble substances through the semipermeable dialysis membrane until equilibrium is attained. A microdialysis catheter was inserted through a hole located at the right side, 0.5 cm posteriorly to the coronal suture. A CMA 79 microdialysis catheter (CMA/Microdialysis, Stockholm, Sweden) was placed into the brain cortex for a depth of 15 mm below the dura mater. The catheter was connected to a 2.5-mL syringe placed into a CMA 106 microinfusion pump (CMA/Microdialysis) and perfused with Ringer solution (Perfusion Fluid CNS) at a rate of 0.3 µL/min (CMA/Microdialysis). Samples were collected at different intervals. The concentrations of cerebral tissue glucose, lactate, pyruvate, glutamate, and glycerol were measured immediately after collection with a CMA 600 microdialysis analyzer (CMA/Microdialysis) by using ordinary enzymatic methods.
Study Design
The study groups were randomly assigned to undergo 25 minutes of HCA by using either pH-stat (12 pigs) or -stat (12 pigs) acid–base perfusion strategy during both cooling and rewarming cardiopulmonary bypass (CPB).
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.
The embolization protocol we used was similar to the one described by Juvonen and colleagues [8]. A Midiflow D 705 membrane oxygenator (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 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 into the left ventricle through the apex of the heart for decompression of the left side of the heart during CPB.
A cooling period of 60 minutes was instituted to attain a brain temperature of 18°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. Immediately before initiation of HCA, the descending and the ascending aorta (clamp shifted proximally to the aortic cannula) were cross-clamped and the CPB flow rate, designated as preinjection flow, was adjusted to maintain an aortic arch pressure of 50 mm Hg. This pressure level was stabilized for 1 minute before 200 mg of polystyrene microspheres (250 to 750 µm in diameter) were injected into the isolated aortic arch.
After embolization, the postinjection flow rate was again adjusted to maintain a perfusion pressure of 50 mm Hg and was stabilized for 5 minutes before HCA was initiated. Cardiac cooling with topical ice slush was begun and maintained throughout the 25 minute HCA period. Similarly, the intracerebral temperatures were controlled and maintained at 18°C with ice packs placed over the head. During the CPB phases, the heat exchanger–blood temperature gradient was set at approximately 10°C; during rewarming, the heat exchanger temperature only rarely was set to 38°C.
Five minutes after the start of rewarming, furosemide (40 mg), mannitol (15 g), methylprednisolone (80 mg), lidocaine (40 mg), and calcium glubionate (137.5 mg) were administered. The left ventricular sump cannula was removed after 45 minutes of rewarming, and weaning from CPB occurred about 60 minutes after HCA. No animal needed inotropic drugs postoperatively. During rewarming and after weaning from CPB, a 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 moved to a recovery room.
Each surviving animal was electively sacrificed on postoperative day 7 and underwent perfusion fixation as previously described [2].
Statistical Analysis
Statistical analysis was performed using Statistical Package for Social Sciences (SPSS) Version 11.5 (SPSS Inc, Chicago, IL) and Statistical Analysis System (SAS) Version 8.02 (SAS Institute Inc, Cary, NC) statistical programs. Continuous and ordinal variables are expressed as the median with IQR (25th and 75th percentiles). SAS procedure MIXED was used for repeated measurements. Since the measurement intervals were uneven, spatial exponential covariance structure was defined in repeated statements. Complete independence was assumed across animals (by random statement). Reported p values are as follows: ptime indicates change over time, pbetween groups indicates a level of difference between groups, and ptime*group indicates behavior between groups over time. The Mann-Whitney U test was used to assess the distribution of variables between study groups. The Fisher exact test was used to determine the significance of mortality rates between the groups. Significance levels are reported for comparisons with the two-tailed test (p 
0.05).
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Results |
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-stat group had a higher median fluid balance at baseline (175 mL vs 75 mL; p = 0.07). The median weight of the pigs was 28.8 kg (IQR, 26.6 to 29.4) in the pH-stat group and 27.2 kg (IQR, 26.0 to 28.7) in the -stat group (p = 0.18).
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-stat group (p = 0.40). The surviving animals in each groups failed to reach complete recovery (Fig 1). During the postoperative period, the pH-stat group had significantly higher behavioral scores at postoperative days 5 (p = 0.03) and 6 (p = 0.04), but this difference was not significant at postoperative day 7 (p = 0.13). The survivors in the pH-stat group tended to have a slightly faster recovery (Fig 1).
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-stat strategy (Table 3). The median cooling and rewarming times lasted 60 minutes and did not differ between the study groups. The significantly lower median arterial vascular resistances seen in the pH-stat group during cooling CPB led to significantly lower perfusion pressures (Fig 2) than in the -stat group and were accompanied by significantly higher CPB flow rates, respectively (Table 3). During rewarming perfusion the situation was reversed because the -stat group had lower vascular resistances and pressures; the observed difference did not reach statistical significance. At the time of particulate embolization, the CPB flow rate (designated as the median preinjection flow) was higher (0.61 vs 0.49 L/min; p = 0.02) in the pH-stat group, but the postinjection flow declined to similar levels as animals in the -stat group.
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-stat group, but here the difference was not statistically significant. During reperfusion, the brain glucose concentrations were significantly higher in the pH-stat group at the 1-hour (p = 0.04) and 1.5-hour postoperative intervals (p = 0.04). Although no significant difference was observed later on, the brain concentration of glucose decreased to levels approaching the baseline values in the pH-stat group, whereas in the -stat group it decreased toward nil (pvalue between groups = 0.049, ptime*group = 0.07, Fig 3).
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-stat group at the HCA time points.
Brain lactate concentrations tended to decrease in the pH-stat group from the start of cooling to the initiation of HCA (p = 0.06); however, the brain lactate concentrations during the early postoperative hours were higher than in the -stat group.
Importantly, both the lactate/glucose ratio and the lactate/pyruvate ratio were higher in the -stat group throughout the experiment. The lactate/glucose ratio was significantly lower in the pH-stat group at the 1-hour postoperative interval, and the lactate/pyruvate ratio at the 1-hour, 2-hour, and 2.5-hour intervals (Fig 3).
There were no remarkable differences in the brain concentrations of glutamate (pbetween groups = 0.6) or glycerol (p between groups = 0.4) between the study groups, although the brain concentrations of glycerol tended to be lower postoperatively in the -stat group.
Brain oxygen tension increased during cooling CPB in the pH-stat group over the values observed in the -stat group and tended to be higher until the 2-hour postoperative interval; thereafter, no difference was observed. Overall, the difference between the study groups did not reach statistical significance (p = 0.12).
The median intracranial pressure was higher in the -stat group throughout the postoperative period and reached statistical significance at the 7-hour postoperative interval, although no statistical difference was observed on the whole between the study groups (pbetween groups = 0.20; ptime*group = 0.019). The intracerebral temperature did not differ between the study groups at any interval.
Electroencephalogram Findings
Electroencephalogram (EEG) burst energy recovered faster towards baseline values in the pH-stat group than it did in the -stat group; at the 2-hour postoperative interval, the median rates were 98% versus 88% of baseline rates, respectively (p = 0.10). Full recovery (100%) was reached at the 3-hour postoperative interval in the pH-stat group and at the 5-hour interval in the -stat group. At no time point were the differences between the study groups statistically significant.
Systemic Physiologic and Metabolic Data
Experimental and metabolic data are presented in Tables 1 and 2. The median cardiac index tended to be lower in the pH-stat group postoperatively. A difference in rectal temperatures was observed between the study groups during CPB, but no accompanying difference in brain temperatures was observed during the same period.
The pH-stat strategy was associated with significantly lower arterial oxygen tension throughout the experiment and higher mixed venous oxygen saturations immediately after the HCA. Oxygen extraction was significantly lower in the pH-stat group at the end of cooling (p = 0.008), but it was significantly higher at the 4-hour postoperative interval (p = 0.04). Furthermore, the systemic oxygen consumption was lower during CPB in the pH-stat group than in the -stat group but increased over the -stat group's values after HCA until the 4-hour postoperative interval, although no statistically significant differences were observed.
Serum ionized calcium levels were higher in the pH-stat group at the end of cooling (p = 0.003), likely because of lower pH. Statistically, the venous lactate levels did not differ between the study groups, although venous lactate tended to be higher 30 minutes after the start of rewarming in the -stat group (p = 0.14). The white blood cell count was lower in the pH-stat group during CPB.
Histopathologic Findings
The most conspicuous histopathologic finding was the considerable number of infarcts observed, mostly in the cerebellum. The incidence of brain infarcts was somewhat higher in the -stat group (p = 0.4), as well as the median number per animal (p = 0.6). The thalamus was the region most affected by infarction in the -stat group (p = 0.5). Slight edema and neuron degeneration appeared globally in the brains. Yet, edema appeared more evident in the pH-stat group in the thalamus (p = 0.4) and cerebellum (p = 0.5). A significant statistical difference between the study groups was not noted in the total histopathologic score and the sum score of the main brain regions. The median overall histopathologic score among survivors of the -stat group was 9.5 (IQR, 7.5 to 11.5) versus 9.0 (IQR, 7.0 to 10.0) in the pH-stat group (p = 0.39).
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Comment |
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Even though it likely had an increased burden of embolization, the pH-stat group in the present study tended to be associated with better survival and behavioral recovery than did the -stat group. The higher concentration of brain pyruvate throughout the experiment in the pH-stat group suggests that this method is associated with better aerobic metabolism because pyruvate is accumulated for the Krebs cycle and is not transformed to lactate. This finding is quite different from the previous study in which the pH-stat strategy had lower concentrations of brain pyruvate. However, a comparison with our previous data is not possible because of the shorter duration of HCA in this study and the combination of embolic injury.
The present findings could be interpreted as a consequence of better brain tissue oxygenation during the cooling period as well as after HCA in the pH-stat group. Indeed, we have previously observed that baseline oxygen delivery is an important predictor of death after experimental HCA [12].
The pH-stat group had higher concentrations of brain glucose throughout the experiment, whereas the -stat group showed a tendency of brain glucose concentrations to nil during the late postoperative hours. These observations confirm that the -stat strategy is associated with insufficient metabolic support before the initiation of HCA. In addition, the findings in one of our previous studies [13] suggested that a transient increase of brain lactate concentration, coupled with an increased brain glucose concentration after HCA, is associated with improved survival and decreased risk of brain infarction. This is further confirmed by the results of the present study. In fact, the brain lactate levels were slightly higher in the pH-stat group after the end of rewarming to the 4-hour interval, indicating a better utilization of glucose by astrocytes producing lactate, which is preferred by neurons after a period of ischemia [14–16].
The lower median vascular resistance and mean arterial pressure during cooling CPB in the pH-stat group was similar to our previous study [2], confirming that the associated hypercarbic state increases systemic vasodilatation. By clamping the descending aorta before embolization, we were able to stabilize and evaluate the changes in flow and vascular resistance that occurred afterwards in the upper body in both study groups. In the study by Juvonen and colleagues [8], who used the -stat strategy, the vascular resistance increased and the mean flow rate decreased significantly after microsphere injection but only slightly after saline-solution injection. This increase in vascular resistance was clearly affected by embolization, but the distribution of the emboli to the brain was not evident.
Plochl and colleagues [10] observed in their study a strong correlation between the number of emboli delivered to the brain and the PaCO2 level during normothermic CPB, although the cerebral blood flow was not determined at a PaCO2 level that fulfilled the pH-stat requirements. Herein, we assume that the animals of the pH-stat group were exposed to a similar or possibly higher burden of cerebral embolism than were the animals of the -stat group because of diminished autoregulation secondary to the increased PaCO2 level, as testified by a significant difference in the preinjection blood flow between the groups and a steeper decrease of blood flow in the pH-stat group after embolization. Nevertheless, the present data demonstrate that such an embolic load was not more harmful to the brains of animals undergoing CPB with pH-stat acid–base management strategy compared with the -stat strategy.
These findings suggest that even in a setting of a likely increased risk of cerebral embolization before HCA, the pH-stat strategy does not cause any worse brain injury than the -stat strategy. Indeed, the pH-stat strategy was associated with a slightly better outcome and more favorable cerebral metabolic changes as evaluated by cerebral microdialysis. Despite the pH-stat strategy-related cerebral vasodilatation, this method provided better neuroprotection compared with the -stat strategy. This observation has major clinical implications, as the pH-stat strategy is not currently used in adults because of a perceived increased risk of atherosclerotic particle embolization. Indeed, the massive embolization of the epiaortic vessels used in this chronic porcine model did not adversely affect the outcome of animals undergoing CPB with pH-stat strategy compared with -stat strategy. Thus, we can assume that also in adults undergoing aortic surgery, despite the increased burden of arteriosclerosis and its related embolic risk, the pH-stat perfusion strategy may provide better neuroprotection than the -stat strategy.
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Acknowledgments |
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