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*Pamukkale University Medical School, Denizli, Turkey; and Departments of
Anesthesiology and
Surgery, Mayo Medical School, Rochester, Minnesota
Address correspondence and reprint requests to David J. Cook, MD, 200 First St., SW, Rochester, MN 55905. Address e-mail to cook.david{at}mayo.edu
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Abstract |
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Implications: This study suggests that cerebral oxygen balance during cardiopulmonary bypass is well maintained at more pronounced levels of hemodilution than are typically practiced, because changes in cerebral blood flow compensate for changes in hemoglobin concentration.
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Introduction |
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Patients are hemodiluted during cardiac surgery, but the limits of hemodilution, particularly as determined by patient temperature, are not well characterized. At its most extreme, in congenital heart surgery, the Hct during profound hypothermia may vary from 5% to 30% between institutions (1,2). both practically and physiologically, these values represent a very broad range.
Under both bypass and nonbypass conditions, hemodilution is associated with increases in CBF (3–5). It is unclear if these flow increases are the passive result of changes in blood viscosity (4), or if CDO2 is also actively regulated outside the hypoxic range (6). Ultimately, these increases in CBF offset decreases in arterial O2 content (CaO2), and CDO2 is supported (5,7). However, there is a limit to this compensatory response and for a tissue, or the body as a whole, a critical Hct will be reached where increases in flow cannot compensate for the decreasing CaO2 so that O2 delivery is compromised. If CaO2 is reduced further, ischemia will result in a decrease in O2 consumption (8–11). The critical Hct should therefore be a function of tissue metabolic rate and indirectly of temperature.
A previous report in animals suggested that, at 27°C, CDO2 is sufficient to maintain CMRO2 with a Hgb of 5 g/dL (10). The purpose of this study was, first to demonstrate the adequacy of CDO2 in patients undergoing CPB, with a Hgb of approximately 6 g/dL. Second, we proposed to demonstrate that CDO2 was independent of a Hgb concentration between 6 and 8.5 g/dL during hypothermic CPB.
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Methods |
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Anesthesia consisted of fentanyl (25–50 µg/kg), midazolam (75–100 µg/kg), and isoflurane maintained at 0.5%–1% throughout the study. Inspired O2 fraction and ventilation were regulated to maintain a PaO2 > 150 mm Hg and PaCO2 of 35–40 mm Hg. Heart rate, blood pressure (including arterial, pulmonary arterial, and right atrial), end-tidal CO2 and nasopharyngeal (NP) temperature were continuously assessed. After anesthetic induction, a 16G single lumen catheter was placed into the right jugular bulb to allow sampling of cerebral venous blood for determination of CBF and CMRO2 by the Kety-Schmidt technique (12) a modified for use during CPB (5). Catheter position was confirmed by fluoroscopy.
During CPB, a nonpulsatile flow of 2.2–2.4 L · m-1 · m-2 was established and PaCO2 was adjusted to 35–40 mm Hg using 
-stat management. Flow adjustments and sodium nitroprusside (SNP) infusion were used during CPB to maintain a mean arterial blood pressure (MAP) of 60–80 mm Hg. With the onset of CPB, patients were immediately cooled to 27°–28°C and maintained at this temperature, during which CBF measurements were obtained.
CBF and cerebral arteriovenous O2 content difference (AVDO2) were measured during three periods: 1) prebypass between sternotomy and aortic cannulation, 2) hypothermic CPB (27°C) with a Hgb of approximately 6 g/dL, and 3) hypothermic CPB with a Hgb concentration of approximately 8.5 g/dL. MAP, pump flow rate during CPB, and NP temperature were stable at least 15 min before measurements were made. A minimum of 30 min elapsed between the end of the previous and the beginning of the subsequent measurement. During CPB, the systemic venous Hgb and O2 saturation were continuously monitored (CDI 100, 3M, Minneapolis, MN). The cerebral venous O2 saturation (SjvO2) was determined from a jugular bulb blood sample by blood-gas tension analysis. Measurement of CBF and cerebral AVDO2 allowed subsequent calculation of CMRO2 and CDO2.
To achieve the target Hgb concentrations during CPB, a variety of interventions were used. First, an attempt was made to select moderately anemic patients with a clinical history or physical exam consistent with an elevated blood volume. Second, a subset of patients underwent normovolemic hemodilution removing up to 750 mL of whole blood prior to incision and replacing at 1:1 with 5% albumin. Third, when necessary, patients underwent further hemodilution during CPB cooling to achieve the target Hgb concentration of 6–6.5 g/dL for the first measurement at 27°C. After measurements at the lower Hgb were completed, the Hgb concentration was increased by one or more of the following techniques: hemofiltration (HPH 1000TS Minntech, Minneapolis, MN), diuresis, and retransfusion of autologous blood. Homologous blood was never administered for the purpose of the investigation, although we targeted a Hgb value of at least 7.5 g/dL during rewarming in all patients.
CBF was measured using the nitrous oxide (N2O) washing of technique of Kety and Schmidt (12) according to previously established methods (5). Briefly, 10% N2O was introduced into the ventilator or oxygenator fresh gas flow with an air-O2 mixture. Timed collections of arterial and jugular bulb venous blood were drawn on the following schedule (arterial) at 1.25, 2.25, 3.25, 5.25, 7.25, 9.25, 11.25, and 14.25 min of N2O exposure; and (venous) at 0, 1.5, 2.5, 3.5, 5.5, 7.5, 9.5, 11.5, and 14.5 min of N2O exposure. Each 2-mL sample was drawn anaerobically over 30 s into heparinized syringes. The samples were placed immediately on ice, and the N2O concentration (ppm) in each sample was measured with an infrared N2O analyzer (Trace N2O Monitor, Dynatech Electro-optics, Saline, MI) (resolution 1 ppm, calibrated with 87 ppm span gas). The CBF was calculated from arterial and jugular venous uptake curves fit to the measured N2O concentrations and integrated to 14 min (5). 
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The reported value for 
of 1.06 was used in the prebypass period, and during hypothermia a solubility coefficient of 0.94 was used (13,14).
Cerebral Metabolism Measurement
The CMRO2 was determined from the product of the AVDO2 and the CBF, using the equation:
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Arterial and jugular bulb blood-gas tensions and saturations were determined (IL-BGE Analyzer, IL 4-286 CO-Oximeter, Instrumentation Laboratories, Inc., Boston, MA) during each CBF measurement period. The arterial and venous O2 content (CxO2), CDO2, and CMRO2 at 27°C were calculated as follows:
arterial or internal jugular venous content (CxO2):
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Cerebral arteriovenous O2 content difference (AVDO2):
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Repeated-measures analysis of variance followed by the Bonferroni correction was used to compared CBF, CDO2, CMRO2, and other physiologic values between the three study periods. P < 0.05 was considered significant. A regression curve of the form y = a + b (lnx) was generated for the 36 CBF–Hgb pairs at 27°C. The Spearman-rank order correlation was used to determine the significance of the Hgb–CBF relationship at 27°C. All data are reported as mean ± SD.
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Results |
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In the prebypass period, the MAP at the time of the first cerebral physiologic measurement was 74 ± 16 mm Hg. The Hgb concentration, PaCO2, and patient temperature were 10.1 ± 1.6 g/dL, 35 ± 3 mm Hg, and 35.5 ± 0.5°C, respectively (Table 1). At this time, 5 of 18 patients required (SNP) at a mean dose of 0.42 ± 0.84 µg · kg-1 · min-1 to control MAP. In the prebypass period, the mean CBF was 43 ± 19 mL · 100 g-1 · min-1; CDO2 and CMRO2 were 5.93 ± 2.37 and 2.74 ± 1.12 mL O2 · 100 g-1 · min-1, respectively. The mean SjvO2 was 55 ± 8% (Table 2).
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During CPB at 27°C with a mean Hgb of 6.2 ± 1.2 g/dL, the CBF was 42 ± 20 mL · 100 g-1 · min-1, whereas the CDO2 and CMRO2 were 3.38 ± 1.17 and 0.95 ± 0.32 mL O2 · 100 g-1 · min-1, respectively. The SjvO2 was increased (72 ± 6%) relative to the pre-CPB period. CBF was unchanged from pre-CPB whereas CDO2 and CMRO2 were both reduced (Table 2). Figure 1 plots the CDO2 against CMRO2 during this study period. Points above the dashed line in Fig. 1 have an ordinal value more than twice the corresponding abscissal value; thus, in every patient under this condition, CDO2 was more than twice cerebral O2 demand.
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Before the second set of CPB measurements, the Hgb was increased from a mean of 6.2–8.5 ± 1.2 g/dL. Temperature, PaO2, and CPB flow rate remained unchanged from the first CPB period. The PaCO2 at this time was 39 ± 4 mm Hg and higher (4 mm Hg) than the two previous measurement periods. The MAP during the second CPB measurement period was 69 ± 10 mm Hg and was achieved by a mean SNP infusion of 1.21 ± 1.13 µg · kg-1 · min-1 in 14 of 18 patients (Table 1). Neither the MAP nor SNP dose differed from the first CPB measurement period, although the SNP dose was higher in the second CPB period than in the prebypass period.
With the increase in Hgb concentration, CBF decreased in the second CPB period, although the CMRO2 was unchanged and the PaCO2 was higher. The SjvO2 at the higher Hgb concentration (70 ± 11%) did not differ from that at the lower Hgb concentration (Table 2). In the second CPB period, the decrease in CBF associated with the increased Hgb concentration resulted in a CDO2 (3.40 ± 1.33 mL O2 · 100 g-1 · min-1) that was nearly identical to the CDO2 in the first CPB period (3.38 ± 1.17 mL O2 · 100 g-1 · min-1) (Table 2, see also Fig. 3). In Fig. 2, the mean CDO2 is plotted for each of the three study periods. Figure 3 demonstrates the relationship between Hgb concentration and CBF during CPB at 27°C.
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Discussion |
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This investigation makes two primary observations. First, during hypothermic (27°C) CPB, global brain oxygenation is maintained at a Hgb concentration 6.2 g/dL. Second and related, with stable MAP, cerebral oxygenation is unchanged during hypothermic CPB, with a Hgb concentration between approximately 6 and 8.5 g/dL. This captures most of the range of hemodilution typically experienced during adult cardiac surgery and includes the range in which most decisions about transfusions must be made. These findings complement previous clinical measurements of cerebral O2 balance during normothermia where we found that cerebral oxygenation was independent of Hct between Hgb concentrations of 8.1 and 11 g/dL (6).
Certain caveats must be applied to the interpretation of our findings. First, we are not advocating a Hgb of 6.2 g/dL during hypothermic CPB. Clinical investigations of this type are rigorously controlled. Patients are carefully selected, physiologic control is strict, and there is a protocol for the management of CPB. Although this level of control is possible outside a clinical investigation, it is more difficult to achieve. Second, whereas a Hgb of 6.2 g/dL is tolerated in this group of patients at 27°C, there is physiologic evidence in animal models that the Hgb concentration should be 
7 g/dL as the patient is rewarmed (10,15). We have characterized the brain and body’s requirement for Hgb at different CPB temperatures in an animal model and found that healthy animals require a greater Hgb concentration greater than 6.2 g/dL at normothermia (10,15).
Our data must also be viewed with the critical lens provided by Dexter and Hindman (16), who emphasized the important effect of hypothermia on the P50 of Hgb. They have observed that the SjvO2 value indicative of adequate cerebral oxygenation should increase as temperature is reduced. Their mathematical model indicates that, with -stat management at 27°C, a SjvO2 of 70% is required to be confident that the CMRO2 is at least 90% predicted. With these observations in mind, our data still indicate an adequacy of global cerebral oxygenation with a mean Hgb of 6.2 g/dL. Under this CPB condition, the mean SjvO2 was 72%, even in patients with the lowest Hct values. More important, SjvO2, CDO2, and CMRO2 were unchanged as the Hgb concentration was increased by more than 2 g/dL. If O2 delivery at a Hgb of 6.2 g/dL was inadequate, we would have expected that SjvO2, CDO2, and CMRO2 would have increased as the Hgb was increased, but this did not occur.
A better design for this study would have been to initially study half the patients at the higher Hgb during CPB. Because we felt it was clinically important to have a higher Hgb during rewarming, this was not practical. A potential criticism of our design is that the decrease in CBF seen with an increase in Hgb concentration could be interpreted to be a function of CPB time or continued brain cooling rather than the change in Hgb. Whereas two clinical reports have indicated that CBF decreases during the course of CPB (17,18), there is evidence to suggest that other factors were responsible for their observation (19–21).
Hindman et al. (21) were unable to document an effect of CPB duration on CBF in a rabbit model and speculated that the clinical findings of decreasing CBF over time during CPB were a function of brain cooling not reflected in NP temperature. Similar results were obtained in baboons (19) and dogs (20). The study by Johnston et al. (20) is particularly notable in that blood flow to cerebral cortex and cerebellum were measured in 30, 90, and 150 min of hypothermic CPB, and no decline in CBF was demonstrated under either - or pH-stat conditions. Subsequent clinical studies have also failed to show a decrease in CBF with CPB time (5,22).
Although we did not document cerebral temperature, our study was designed to minimize the potential effect of brain cooling on CBF. We incorporated a 15-min delay after achievement of target temperature before initiating our first CBF measurement. Furthermore, data do not suggest a decrease in brain temperature with time. A decrease in brain temperature not reflected in the NP temperature should be associated with a decrease in CMRO2, and this was not observed. There is good evidence that the decrease in CBF seen in the second CPB period is attributable to the increase in Hgb concentration. The decrease in CBF that we document with hemoconcentration is similar to what has been reported with Hct change under nonbypass conditions in both animal (3,23) and human studies (24,25). Finally, and most importantly, our study documented CDO2 stability in the context of an unchanged cerebral O2 demand. For this combination of reasons, we believe our study has generated reliable results, even given this weakness in design.
In summary, we found that adult cardiac surgical patients without known cerebral vascular disease can tolerate a Hgb concentration of 6.2 g/dL during CPB at 27°C. Specifically, at this level of hemodilution, with a MAP of 65 mm Hg, CDO2 is more than twice cerebral O2 demand. Furthermore, the brain is equally well oxygenated whether the Hgb is 6.2 or 8.5 g/dL. This would suggest we can be more conservative in our transfusion decisions under hypothermic conditions. Although we do no advocate hemodilution to a Hgb of 6.2 g/dL during hypothermic CPB, it can be tolerated under well-defined conditions. A variety of clinical situations would dictate a higher bypass Hgb, and Hgb concentration should probably be increased as patients are rewarmed. Nonetheless, data presented increase our understanding of cerebral physiology during CPB.
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