Kiziltan, H. Tarik MD*; Baltal, Mehmet MD†ı; Bilen, Ahmet MD‡; Seydaoglu, Gülşah MD§; Incesoz, Muzaffer BS∥; Tasdelen, Atlay MD*ı; Aslamaci, and Sait MD*
Studies suggest that jugular venous oxygen saturation (SJVo2) is a global index reflecting the balance between cerebral metabolic rate for oxygen (CMRo2) and cerebral blood flow (CBF) (1,2). A mismatch between these measures may result in a change in SJVo2. Both jugular venous desaturation and increased SJVo2 during cardiopulmonary bypass (CPB) may be associated with poor performance as measured by postoperative cognitive tests (3,4), although there is some controversy (5). Physiologic variables that may influence SJVo2 include temperature, perfusion pressure, CBF, and partial pressure of CO2 (Paco2) (6–11). Accordingly, jugular venous desaturation was observed during rewarming from alpha-stat hypothermic CPB (6). Patients undergoing normothermic instead of hypothermic CPB were found to be under increased risk of jugular venous desaturation (7). Hypercarbia increased SJVo2 and CBF during alpha-stat hypothermic CPB (uncorrected for body temperature) (10). In a clinical study, mild hypercapnia (alpha-stat management) prevented jugular bulb desaturation during rewarming from hypothermic CPB (11). In an experimental hypothermic circulatory arrest model in piglets, the pH-stat strategy was associated with an increase in cerebral mixed vascular saturation measured by near-infrared spectroscopy (12).
No clinical study has analyzed the effects of different acid-base strategies (corrected versus uncorrected arterial CO2 tension for body temperature) on the incidence of jugular venous oxygen desaturation and cerebral oxygen-glucose use. The purpose of this study was to compare the incidence of jugular venous oxygen desaturation, cerebral arteriovenous oxygen content, and glucose differences between patients who were prospectively randomized to either pH-stat or alpha-stat acid-base management groups during hypothermic CPB.
IRB approval and informed consent were obtained for the study. Fifty-two patients undergoing primary coronary artery bypass surgery were randomized into either alpha-stat or pH-stat groups. Patients with insulin-dependent diabetes mellitus, presence or history of cerebrovascular disease, carotid bruit, or drug allergy or those who needed concomitant valvular replacement or repair were excluded from the study. Octogenarians were also excluded because our CBP protocol includes major differences of temperature and blood pressure in this particular group.
A standardized anesthetic consisting of 10 mg of diazepam was administered the night before surgery, and 15 mg of oral midazolam 60 min before the induction of anesthesia was administered. In the operating room, a radial artery catheter was inserted. Anesthesia was induced with 5 μg/kg of IV fentanyl citrate and 0.1 mg/kg of midazolam. Vecuronium (0.1 mg/kg) was given to achieve and maintain muscular paralysis. The trachea was intubated, and the lungs were ventilated with a Siemens ventilator (Siemens-Elema AB, Solna, Sweden) by using 33% oxygen and 66% air. Anesthesia was maintained with the IV administration of midazolam 0.1 mg · kg−1 · h−1, fentanyl 5 μg · kg−1 · h−1, and vecuronium 0.1 mg · kg−1 · h−1. Immediately before CPB, ventilation was set to achieve a Paco2 level of 40 mm Hg. A triple-lumen catheter (Abbott Laboratories, Chicago, IL) was inserted into either the left or right subclavian vein for venous access. A single-lumen sampling catheter (1.7 mm; Laboratorie Plastimed, Paris, France) was inserted into the jugular bulb retrogradely from the right or left internal jugular vein. Fluoroscopy (Siemens, Erlangen, Germany) was used to confirm the correct catheter positioning in the jugular bulb before the case was included in the study. Heart rate, arterial and right atrial pressures, rectal and nasopharyngeal temperatures, urinary output, and end-tidal CO2 were measured continuously in all cases.
The patients were operated on by one surgeon using a standard surgical technique. The technique included median sternotomy, aortic (3M Health Care, Ann Arbor, MI) and right atrial (36/51F; CalMed Laboratories, Irvine, CA) cannulations, hypothermic CPB at 27°C, single aortic cross-clamping, and the administration of intermittent antegrade tepid blood cardioplegia. A left ventricular venting catheter (DLP; Medtronic Inc., Grand Rapids, MI) was inserted through the right superior pulmonary vein in all patients. After the distal anastomoses were completed, the aortic cross-clamp was released, and proximal anastomoses were performed with the aid of an aortic side-biting clamp during CPB. Full flow was used, and the heart was not allowed to eject blood. In four patients with aortic wall calcification or thickened aorta, proximal anastomoses were performed while the aorta remained cross-clamped. The patients were successfully separated from CPB.
The CPB circuit was primed, and a hematocrit level of 0.25 during CPB was achieved with a balanced electrolyte solution. Nonpulsatile pump (Gambro AB, Lund, Stockholm, Sweden) flow with a rate of 2.0 to 2.5 L · min−1 · m−2 and a nasopharyngeal temperature of 27°C were maintained by a single perfusionist. A membrane oxygenator (Cobe Cardiovascular Inc., Arvada, CO) was used in all cases. During cooling and rewarming, arterial blood inflow-nasopharyngeal temperature gradient was maintained at 10°C. Mean arterial blood pressure (MAP) was maintained between 45 and 65 mm Hg during CPB. If the MAP was below this range, an initial dose of 25 μg of norepinephrine (Arterenol; Hoechst AG, Frankfurt, Germany) was given. If the MAP was above this range, an infusion of 0.5–5 μg · kg−1 · min−1 of nitroprusside was administered.
In the alpha-stat group, Paco2 was maintained at 40 mm Hg with the measurement made at 37°C without temperature correction (13). In the pH-stat group, CO2 was added to the oxygenator inspired gas flow to maintain temperature-corrected pH at approximately 7.40 and Paco2 at approximately 40 mm Hg during CPB at 27°C (14). Achieving this end-point typically required temperature-uncorrected Paco2 values of approximately 70 mm Hg and temperature-uncorrected pH values of approximately 7.24 (15). Rewarming was typically initiated before the start of the last distal anastomosis and continued at a maximum rate of 1°C per minute.
Blood gas tensions, pH, hemoglobin (Hb), and Hb oxygen saturation (Gem Premier; Mallinckrodt Sensor Systems Inc., Milan, Italy) and glucose concentrations (GlucoTrend, Mannheim, Germany) from arterial and jugular venous blood were obtained every 15 min during hypothermic CPB and every 5 min during rewarming. At 15 min after bypass, arterial blood gas data and glucose concentration were obtained. After measurements, arterial to jugular venous blood oxygen content differences (AVDo2) and arterial to jugular venous glucose differences (AVDglu) were calculated. The following equations (7) were used to determine:MATH MATH MATH where Hb is in grams per deciliter, Sato2 is oxygen saturation, and Pao2 and Pvo2 (mm Hg) are arterial and venous partial pressures of oxygen, respectively.
Demographic data, variables during CPB (including MAP), temperature, Hb concentration, arterial and jugular blood gas data (including pH), Pao2, Paco2, bicarbonate, Hb saturation, CBP and cross-clamp times, number of grafts, and arterial and jugular venous glucose concentrations were compared between the groups. An SJVo2 <50% was defined as jugular venous oxygen desaturation and was recorded for each group. Measures in the postoperative period—including the duration of mechanical ventilation, intensive care stay, and hospital stay–were also recorded.
Data are displayed as mean ± sd. Differences from baseline were assessed by Wilcoxon’s signed rank test. Comparison of the mean values between the pH-stat and alpha-stat groups was performed with the Mann-Whitney U-test or Student’s t-test when appropriate.
There were no differences in demographic data presented in Table 1. In the alpha-stat group, target blood pH was not reached in two patients, and they were eliminated from the study. In the pH-stat group, CO2 administration caused a significant increase in temperature-uncorrected Paco2 (62 ± 8 mm Hg versus 42.8 ± 3.3 mm Hg;P < 0.001) and a decrease in arterial temperature-uncorrected pH (7.26 ± 0.04 versus 7.40 ± 0.02;P < 0.001) at 15 min (Table 2). Compared with preoperative values, a statistically significant difference (P < 0.001) in Paco2 and arterial pH values was observed between the groups throughout the study.
With initiation of CPB, AVDo2 decreased significantly in the pH-stat group starting at 15 min of cooling (2.2 ± 0.7 mL/dL versus 3.8 ± 1.4 mL/dL;P < 0.001) (Fig. 1). This was associated with an intergroup difference in AVDo2 that disappeared at 10 min of rewarming. The widest intergroup difference in AVDo2 occurred at 30 min of CPB (1.9 ± 0.8 mL/dL versus 3.9 ± 1.1 mL/dL;P < 0.001). Preoperative SJVo2 levels did not differ between the groups (58.4% ± 10.4% and 60.3% ± 12%;P > 0.05) (Table 2). Cooling caused a significant increase in SJVo2 in both groups (Fig. 2). However, the increase in the pH-stat group was significantly more pronounced, creating an intergroup difference at 15 min (84.1% ± 7.1% and 74.5% ± 8.5%;P < 0.001). This difference continued up to 10 min of rewarming (Fig. 2). With respect to the AVDglu, a significant decrease in the pH-stat group started at 15 min and disappeared at the beginning of rewarming (Fig. 3). The largest intergroup difference in AVDglu occurred at 30 min of cooling (3.6 ± 2.8 mg/dL versus 10.1 ± 5.2 mg/dL;P < 0.001). Parallel to the findings in AVDo2 and AVDglu, the widest difference in mean SJVo2 occurred at 30 min of CPB (86.2% ± 6.1 versus 70.6% ± 9.3%;P < 0.001) (Table 3). There were no significant differences between groups in the incidence of jugular venous desaturation.
Three patients in the pH-stat group experienced four episodes of jugular venous desaturation (versus two in the alpha-stat group; odds ratio [OR], 2.00; 95% confidence interval [CI], 0.49–8.62). Two patients, one in each group, experienced jugular venous desaturation at 10 min of rewarming. These two patients continued to be desaturated, and two other patients from the pH-stat group experienced jugular desaturation at 15 min of rewarming. Overall, 4 patients (6 incidences of desaturation) experienced jugular venous desaturation during CPB ranging from 46% to 49%. Measures of clinical outcome, duration of mechanical ventilation, intensive care stay, and hospital stay did not differ between the groups (Table 4).
As a global index of CBF and metabolic rate, SJVo2 has become a major focus in clinical studies designed to investigate cerebral supply and demand (2,3,6–11). This study shows that in adult patients undergoing CPB at 27°C, the pH-stat group was associated with a substantial increase in SJVo2 compared with the alpha-stat group. This increase was notable at 15 minutes and maximized at 30 minutes, and then it tapered down and became nonsignificant at the end of rewarming. Furthermore, the pH-stat strategy promoted a concurrent decrease in arteriovenous oxygen-glucose differences associated with an increase in SJVo2, maximized at 30 minutes.
We believe, in our study, that increased SJVo2 was a reflection of the differences between the alpha-stat and the pH-stat groups. Those differences are most probably due to vascular dynamics and cascades related to oxygen transfer-utilization in cerebral tissue. Because variables that determine cerebral oxygen consumption, such as temperature and blood pressure, were maintained constant in both groups, mechanisms possibly involved in increased SJVo2 were increased CBF, decreased cerebral oxygen extraction, or both.
Experiments show that with cooling, the pH-stat strategy may suppress CMRo2 more than the alpha-stat strategy (16,17). The pH-stat strategy increases CBF (18,19) and the cooling rate (20) compared with the alpha-stat strategy. Our findings are in agreement with these previous findings. In addition, pH-stat decreases Hb affinity for oxygen, which may enhance the tissue availability of dissolved oxygen. This could provide more oxygen for the cerebral tissue under pH-stat conditions.
During pH-stat CPB, decreased CMRo2 may be related to improved cerebral cooling because of increased CBF (18–20) or to an effect of increased CO2 on cellular function. Intuitively, both of these mechanisms could be responsible for our results. Concurrently, Dexter and Hindman (21) hypothesized that during hypothermic CPB at 27°C, a slight increase in Hb P50 from pH-stat management was unlikely to improve oxygen off-loading or increase CMRo2. Consistent with this hypothesis, rabbit (22) and human (23) studies have found CMRo2 to be equivalent under alpha-stat and pH-stat strategies at 27°C. Therefore, available information highlights the consensus that at moderately hypothermic CPB, brain oxygen extraction is fairly stable under either of these strategies.
Accordingly, under pH-stat conditions, when variables determining cerebral oxygen supply and demand–such as CPB flow, MAP, and temperature—are kept constant, increased SJVo2 would logically and evidently (23) reflect an increased CBF. A purported mechanism is increased CO2, which causes cerebral vasodilation and augments CBF because of pressure-passive cerebral vascular changes. Therefore, we believe that the increase in SJVo2 in our study can be attributed to increased CBF induced by the pH-stat strategy.
We observed a profound decrease in AVDglu with the pH-stat group during cooling, as shown in Figure 3. In contrast, a relatively stable AVDglu was observed with the alpha-stat group (Fig. 3). Similarly, during most of the CPB period, AVDo2 in the pH-stat group was significantly lower. These findings may imply continuance and appropriateness of oxygen-glucose metabolism relative to the CBF in the alpha-stat versus pH-stat groups.
In contrast to general findings, jugular venous desaturation occurred more frequently in the pH-stat group (4 versus 2), although this difference was not statistically significant (P > 0.05; OR, 2.00; 95% CI, 0.49–8.62). All incidences of desaturation occurred during rewarming. In accordance with a previous finding (6), rewarming is a vulnerable period for jugular desaturation. Hanel et al. (11) observed that during alpha-stat CPB management, jugular venous desaturation (<50%) did not occur in patients with mildly induced hypercarbia (Paco2 ≅50 mm Hg). They inferred that hypercapnic cerebrovascular dilation is effective in reversing the imbalance of oxygen demand and supply during the rewarming period. We observed that hypercapnia does not eliminate jugular venous desaturation in patients undergoing pH-stat management, and more episodes (4 versus 2; OR, 2.00; 95% CI, 0.49–8.62) of desaturation occurred in the pH-stat group.
Why does jugular desaturation occur during pH-stat and not during alpha-stat with mildly induced hypercarbia (11) ? The answer is possibly related to cerebral vascular changes. In one study supporting the finding of Hanel et al. (11), increased arterial CO2 tension under the alpha-stat condition was not associated with potentially harmful redistribution of CBF in patients with cerebrovascular disease (24). Regional cerebral hypoxia induced by pressure-passive changes in the presence of globally increased CBF during pH-stat CPB may explain why jugular venous desaturation was not completely eliminated in this study. Additionally, a pressure-passive increase in CBF during pH-stat CPB was linked in one study to more embolic load to brain and to an increased incidence of cognitive dysfunction (2 months after surgery) in patients who had more than 90 minutes of CPB (25). Therefore, current knowledge shows a benefit to the alpha-stat strategy in terms of postoperative cognitive function in adults (25). After alpha-stat management, cognitive decline associated with high SJVo2 was speculatively linked to increased embolic load (4). However, in another study, no significant correlation between intraoperative SJVo2 and cognitive function was found three months after surgery (5). Our study was limited because it was not designed to compare postoperative cognitive performance between the two groups. Further research is needed to investigate the relation between SJVo2 and cerebral microembolic load under different acid-base strategies during CPB in reference to cerebral cellular oxygenation and relevant cognitive outcome.
In conclusion, our results indicate that, compared with alpha-stat, the pH-stat acid-base strategy (corrected for body temperature) is associated with an increased SJVo2, a decrease in arteriovenous oxygen content, and glucose differences in adult patients undergoing CPB at 27°C. There were no differences in the incidence of jugular venous desaturation between the two groups. These findings suggest an increased cerebral blood supply with the pH-stat strategy, although this strategy does not eliminate jugular venous oxygen desaturation during CPB.
We thank Neslihan Yıldız for her excellent secretarial assistance in preparation of the manuscript.
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