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Ann Thorac Surg 2001;72:1331-1335
© 2001 The Society of Thoracic Surgeons

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Original article: cardiovascular

Carbon dioxide management and the cerebral response to hemodilution during hypothermic cardiopulmonary bypass in dogs

^a Department of Anesthesiology, Department of Surgery, Mayo Clinic and Foundation, Rochester, Minnesota, USA
^b Division of Cardiothoracic Surgery, Department of Surgery, Mayo Clinic and Foundation, Rochester, Minnesota, USA

Accepted for publication May 29, 2001.

Address reprint requests to Dr Cook, Mayo Clinic-SMH/MB 2-752, 200 First St SW, Rochester, MN 55905
e-mail: cook.david{at}mayo.edu

	Abstract

Top Abstract Introduction Material and methods Results Comment References

 
Background. Increases in blood flow support oxygen (O₂) delivery with hemodilution. However, with -stat management, the cerebral response to hemodilution is blunted. We tested the hypothesis that carbon dioxide (CO₂) management is a primary determinant of the cerebral blood flow (CBF) response to hemodilution during hypothermic bypass.

Methods. Following Animal Care Committee approval, 15 dogs underwent bypass at 18°C (pH-stat, n = 7 or -stat, n = 8). Measurements were obtained after progressive hemodilution, and cerebral blood flow was determined by sagittal sinus outflow. Arterial pressure was maintained at 60 to 70 mm Hg. The CBF response to hemodilution and cerebral metabolic rate were compared in the two groups of animals.

Results. In both groups, hemodilution increased CBF. At every hematocrit, CBF and O₂ delivery in the pH-stat group exceeded that of -stat group, although O₂ demand did not differ between groups. While absolute CBF in the pH-stat group was greater at every hematocrit, the relative change in CBF from control and the slope of the CBF-Hct relationship did not differ between groups.

Conclusions. pH-stat management is associated with a greater absolute CBF and a greater ratio of cerebral O₂ supply to demand for any degree of hemodilution. However, over the range of hematocrits common in practice, CO₂ management per se does not determine the cerebral response to hemodilution.

	Introduction

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Current cardiac surgical practice includes cardiopulmonary bypass (CPB) conducted over a broad range of temperatures and hematocrits. Most CPB is conducted at 27° to 37°C with a hemoglobin (Hgb) concentration of 7 to 8.5 g/dL; however, during bypass, body temperature may be reduced to 15°C, and under special conditions, Hgb concentrations as low as 2 to 3.5 g/dL may be experienced [1, 2].

Cerebral oxygen delivery is maintained during moderate hemodilution because hemodilution reduces vascular resistance, resulting in an increase in tissue blood flow if perfusion pressure is maintained [3, 4]. This increase in cerebral blood flow (CBF) helps compensate for the reduction in arterial oxygen content such that cerebral oxygen (O₂) delivery is supported [5]. We previously documented the CBF-hematocrit and O₂ delivery relationships during CPB in both clinical and animal studies and conducted a series of studies describing the limits of hemodilution during CPB in dogs [6].

Because hypothermia has a profound effect on cerebral metabolic rate (CMRO₂), we predicted that the minimum Hct supporting cerebral O₂ consumption would be shifted well leftward as brain temperature was reduced to 28° or 18°C. However, with progressive hypothermia, the critical Hct only showed a small leftward shift. This is in part a function of blunting of the cerebral blood flow response to hemodilution with progressive hypothermia [6].

Relative to the pH-stat technique, with -stat carbon dioxide (CO₂) management, a relative hypocarbia and cerebral vasoconstriction occur [7–9]. Because this effect is quantitatively greater as temperature is reduced, we speculated that the blunting of the CBF response to hemodilution with progressive hypothermia might be a function of -stat CO₂ management. The purpose of this investigation is to test the hypothesis that CO₂ management is a primary determinant of CBF response to hemodilution during hypothermic CPB in dogs by comparing the response to hemodilution in animals managed with either - or pH-stat strategies at 18°C.

	Material and methods

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After review and approval by the Institutional Animal Care and Use Committee, we studied 15 unmedicated, fasting, adult, female, mongrel dogs, weighing 17 to 22 kg. All dogs received humane care in compliance with the "Guide for the Care and Use of Laboratory Animals." The dogs were placed in a Plexiglas box and anesthesia was induced with 3% to 4% inspired halothane. Intravenous access was secured, muscle relaxation obtained with pancuronium, and the trachea was intubated. Anesthesia was maintained with halothane 0.5% to 1% in O₂ inspired, and fentanyl and midazolam (bolus: 250 µg/kg fentanyl and 350 µg/kg midazolam, followed by infusion: fentanyl 3.0 µg/kg/min and midazolam 9.6 µg/kg/min). A 10-cm no. 18 catheter was surgically inserted into the right femoral artery for mean arterial blood pressure (MAP) measurements and blood sampling. After anticoagulation with heparin (300 U/kg IV), the sagittal sinus was exposed, isolated, and cannulated as described previously [10]. Flow was recorded continuously with a flow-through electromagnetic flow probe (EP300 API; Carolina Medical Electronics, Inc, Kin, NC) calibrated against a graduated cylinder. Brain temperature was measured with a parietal epidural thermocouple. Intracranial pressure (ICP) was determined using an LADD fiberoptic epidural sensor (LADD Industries, Burlington, VT). The cranium was then closed with surgicel and adhesive.

CPB was undertaken through a left thoracotomy. A 36-Fr two-stage cannula was placed in the right atrium. The blood was circulated by centrifugal pump through a combined heat exchanger-oxygenator (Sarns Turbo, Ann Arbor, MI) and returned through a cannula (4.5-mm ID) into the root of the aorta. The CPB circuit was primed with blood (approximately 500 mL) from a donor dog and crystalloid solution (500 mL). MAP was maintained between 60 and 70 mm Hg throughout by altering bypass pump flow. To avoid their potential confounding effects on the cerebral circulation, no vasoconstrictors or vasodilators were used. In-line detectors (CDI 100 and CDI 400; Cardiovascular Devices, Inc, Tustin, CA) continuously monitored arterial hemoglobin concentration and blood gas data.

During cardiopulmonary bypass, CBF was measured and cerebral metabolic rate (CMRO₂) and cerebral oxygen delivery (CDO₂) were determined from the CBF and arteriovenous oxygen content difference (AVDO₂) and arterial oxygen content (CaO₂), respectively:

Arteriovenous oxygen content difference:

Arterial or venous oxygen content:

where Hb = hemoglobin concentration; SxO₂ = oxygen saturation; and PxO₂ = partial pressure of oxygen; x = arterial or venous.

Cerebral oxygen delivery (CDO₂):

Cerebral oxygen extraction ratio (OER):

Dogs were randomly assigned to either pH-stat (n = 7) or -stat (n = 8) management with CPB performed with animals at 18°C. In the -stat group, the CO₂ values were non-temperature corrected (normocarbic when measured at 37°C), while in the pH-stat group, they were temperature corrected (normocarbic when measured at 18°C). After control measurements were obtained under respective CO₂ management strategies at 18°C with a target Hgb of 10.5g/dL, animals were progressively hemodiluted in five experimental steps with target Hgb values of 7.7, 6.5, 5.5, 4.5, and 3.3 g/dL. Dilution was achieved by removing blood from the CPB circuit and replacing it with 6% Dextran 70 to achieve the desired Hgb concentration [6]. Blood gases and Hgb concentration were measured directly by blood gas analyzer (IL-BGE Analyzer; Instrumentation Laboratory, Lexington, MA) and co-oximeter (IL282 co-oximeter; Instrumentation Laboratory, Lexington, MA), and continuously by in-line monitoring as the transitions between each hemodilution step were made. In all animals, HCO₃^- was used to keep arterial pH greater than or equal to 7.20. For the co-oximeter, the coefficient for dog hemoglobin, integrated into the software of the analyser, was used. Each level of hemodilution was maintained for 15 minutes or until the CBF measurement was stable, whichever was longer.

Statistical analysis
A repeated-measures analysis of variance (ANOVA) was used for comparison of systemic and cerebral physiologic variables within each group. When repeated-measures ANOVA showed a significant difference across the five experiment steps when compared with the control, we compared the control values with those obtained at each dilution step using a paired t test. Mean differences in physiologic variables between groups for each experimental step were assessed by two-sample t tests. For each animal, the slope of the CBF (y)-Hct (x) curve was determined by regression using an exponential model. The mean slopes of the CBF-Hct relationship for the two groups were then compared using a two-sample t test. Values were summarized as mean ± SE. Two-tailed p values were considered as evidence of differences not attributable to chance (p 0.05).

	Results

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Systemic physiologic data for the two groups during each of the experimental CPB periods are shown in Table 1. In the CPB control period at 18°C, the two groups did not differ significantly with regard to Hgb, MAP, flow (Q), temperature, PaCO₂, or pH. Furthermore, during the subsequent five dilutional steps, Hgb concentration, MAP (60 to 65 mm Hg), temperature, and CO₂ did not differ between - and pH-stat groups. The only systemic physiologic variables that differed between groups during the six study periods were a higher pump flow in the pH-stat group at the lowest Hgb concentration and a lower pH in the pH-stat group during two of six experimental periods (Table 1).

View this table: [in this window] [in a new window]   Table 1. Systemic Physiological Data in pH-Stat (n = 7) Versus -Stat (n = 8) Managed Dogs

In the initial CPB period at 18°C before hemodilution, the CMRO₂ did not differ between - and pH-stat groups; however, the CBF of the pH-stat group was significantly higher than that of the -stat group (38 ± 4 vs 20 ± 4 mL/100 g/min, p 0.001). Cerebral O₂ delivery was higher in pH-stat animals (5.7 ± 0.6 vs 3.1 ± 0.7 mL O₂/100 g/min, p 0.001), and the OER was lower (0.15 ± 0.03 vs 0.22 ± 0.02, p 0.05) (Table 2).

View this table: [in this window] [in a new window]   Table 2. Cerebral Physiological Data in pH-Stat (n = 7) Versus -Stat (n = 8) Managed Dogs

In both groups, there was an approximately linear relationship between Hgb concentration and CDO₂. Cerebral O₂ delivery in the pH-stat group exceeded the CDO₂ in the -stat group during each study period. With pH-stat management, cerebral oxygen delivery, even at the most extreme level of hemodilution (3.2 g/dL), exceeded the control CDO₂ in the -stat group (Table 2, Fig 1).

View larger version (12K): [in this window] [in a new window]   Fig 1. CDO2 and CMRO2 for O2 in pH-stat (n = 7) (left) and -stat (n = 8) (right) groups. Values are mean ± SD. *p < 0.05 by repeated-measures ANOVA followed by Student-Newman-Keuls test. (CDO2 = cerebral oxygen delivery; CMRO2 = cerebral metabolic rate.)

Although the absolute CBF was greater during every period in pH-stat animals, the mean change in CBF from control through progressive hemodilution was not significant between groups. In the pH-stat group, the mean CBF at 3.2 g/dL was 176% of the mean CBF at a Hgb of 10.6 g/dL. In the -stat group, a decrease in Hgb from 10.8 to 3.4 g/dL was associated with a mean increase in CBF to 170% of the control value. The percentage change in the CBF and the slopes of the Hgb-CBF curves did not differ between groups over this range of Hgb concentrations. The mean slope of the change in CBF versus Hgb relationship in - and pH-stat groups were -11.8 ± 4 and -12.2 ± 6, respectively (p = 0.89) (Fig 2).

View larger version (12K): [in this window] [in a new window]   Fig 2. The change in CBF versus Hgb concentration relationship in -stat (n = 7) (dashed line) and pH-stat (n = 8) (solid line) groups. Curves were generated using an exponential model; R2 and line equations with slopes are shown. p = 0.89 by one-way ANOVA. (CBF = cerebral blood flow; Hgb = hemoglobin.)

	Comment

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In addition to showing that the flow response to hemodilution is not determined by CO₂ management, the data also indicate that outside the ischemic range, the flow response to hemodilution is not a function of brain O₂ demand. This is most clearly evidenced in the pH-stat group, but is also demonstrated in -stat animals. While cerebral O₂ delivery was well in excess of O₂ demand, CBF increased as the Hgb concentration was reduced. This observation is not sufficient to conclude that the CBF response to hemodilution is simply a function of changing blood rheology, but it suggests that the biophysical character of blood is of primary importance in blood flow determination outside the ischemic range. The data also provide a number of secondary observations.

This study provides further illustration of the dominant effect of CO₂ management on cerebral blood flow. Usually, CBF is closely coupled to cerebral O₂ demand. However, as previously described [8, 11] and illustrated by these data, the effect of CO₂ overwhelms flow-metabolism coupling. While CMRO₂ was equivalent between groups, the cerebral blood flow in the pH-stat group was approximately twice that of the -stat group under every experimental condition, including the control period.

Because cerebral O₂ delivery was sufficient to meet CMRO₂ even with Hgb as low as 3.2 g/dL, the data do not provide a clear physiologic indication for either CO₂ management strategy. However, because cerebral O₂ delivery is consistently much greater with pH-stat management, an argument could be made to use this technique under conditions of reduced Hgb, pressure or pump flow where cerebral O₂ delivery might otherwise be compromised. Additionally, a body of work from the Boston Children’s group and others have illustrated advantages to the pH-stat technique independent of its effect on total cerebral O₂ delivery [9, 12–14]. Nevertheless, it should be noted that there is experimental evidence to suggest that increased levels of CO₂ may be associated with increased cerebral embolization [15]. Concern over the potential effects of CO₂ on cerebral embolization would be of primarily relevance in the adult population and is probably of lesser practical relevance during moderate to profound hypothermia.

The data provided also add to the discussion of the effect of CO₂ management on cerebral O₂ consumption. It has been reported that pH-stat management is associated with a reduction in CMRO₂ [16]. However, like other investigators [8, 11], we were unable to identify any effect of CO₂ management on CMRO₂ over the range of temperatures most relevant during CPB. It is not clear why an effect of CO₂ on brain metabolism has been reported, but it does not appear to be a function of the difference in cerebral blood flow with the two CO₂ management techniques [17]. It also seems unlikely that such a fundamental physiologic process is species specific.

The primary criticism of this study may be that we used pump flow to support MAP in the pH-stat group to compensate for the systemic vasodilation associated with this management strategy. While the pump flows in the pH-stat group were greater than those of the -stat group, the MAP was equivalent between groups at each Hct and above the autoregulatory threshold. In both animal models [18–20] and human investigations [21], it has been shown that pump flow does not determine CBF if the MAP is kept within the autoregulatory range. Only if a reduction in pump flow reduces MAP below the critical perfusion pressure will CBF decrease in proportion to the decrease in pump flow. As such, the difference in pump flow between groups is not a confounding variable.

In this investigation, we determined that the blunting of the CBF response to hemodilution with hypothermia is not a function of CO₂ management strategy. While the absolute CBF is greater with pH-stat management for any degree of hemodilution, the slope of the Hct-CBF curve does not differ between - and pH-stat groups. Clinically, the data suggest there may be advantages to the pH-stat strategy under conditions where cerebral O₂ delivery might otherwise be compromised.

	References

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Thomas A. Orszulak Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Cook, D. J. Articles by Slater, J. M. Search for Related Content PubMed PubMed Citation Articles by Cook, D. J. Articles by Slater, J. M. Related Collections Extracorporeal circulation