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J Thorac Cardiovasc Surg 1998;115:1203-1208
© 1998 Mosby, Inc.

CARDIOPULMONARY SUPPORT AND PHYSIOLOGY

Hemodilution and whole body oxygen balance during normothermiccardiopulmonary bypass in dogs

Supported in part by the American Heart Association–MinnesotaAffiliate and the Mayo Foundation.

Received for publication August 15, 1997. Revisions requested Nov. 17, 1997. Revisions received Dec. 17, 1997. Accepted for publication Dec. 22, 1997. Address for reprints: David J. Cook, MD, Department of Anesthesiology,Mayo Clinic, 200 First St. SW, Rochester, MN 55905.

	Abstract

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Objective: The purpose of this study wasto determine the minimum hematocrit value that can support whole body oxygenconsumption during normothermic cardiopulmonary bypass. The effect ofhemodilution on peripheral resistance, whole body oxygen delivery, and oxygenconsumption was determined over a range of hematocrit values.
Methods: Measurements were obtained during 38° Ccardiopulmonary bypass with progressive normovolemic hemodilution (hematocritvalue 40% to 9%) in nine dogs. Dextran 70 (6%) was used asa diluent. Anesthesia consisted of high-dose fentanyl and midazolam. A meanarterial pressure of 60 mm Hg was maintained throughout cardiopulmonary bypassvia increases in pump flow.
Results:Progressive hemodilution was associated with a decreasing total peripheralresistance. During normothermic cardiopulmonary bypass with a whole blood prime,the whole body oxygen consumption approximated values previously reported indogs under nonbypass conditions. Oxygen delivery and whole body oxygen uptakewere maintained between a hematocrit value of 39% and 25%.Significant decreases for both were seen when the hematocrit value was reducedto 18% and below.
Conclusions: Ahematocrit level greater than 18% was needed to maintain systemic oxygendelivery and consumption during warm cardiopulmonary bypass. The criticalhematocrit value may be higher under bypass than nonbypass conditions becausethe flow increases that are practical during cardiopulmonary bypass do notapproximate those seen in response to hemodilution of the intact circulation.Finally, the critical hematocrit value for the body may be higher than thatrequired for the brain during warm cardiopulmonary bypass. (J Thorac CardiovascSurg 1998;115:1203-9)

	Introduction

Top Abstract Introduction Materials and methods Results Discussion References

 
Although hemodilution is standard practice during cardiopulmonary bypass(CPB), the limits of hemodilution at differing extracorporeal temperatures havenot yet been systematically determined. ¹The purpose of this study was to define the minimal hematocrit value thatsupports whole body oxygen consumption during normothermic CPB.

The systemic response to hemodilution under non-CPB conditions is welldescribed. Under normal conditions, systemic and regional oxygen consumption isindependent of oxygen delivery. Oxygen delivery and consumption are maintainedduring moderate hemodilution by increases in cardiac output, increases in tissueblood flow, and later by an increase in tissue oxygen extraction. ^2-4However, for the individual organ and the body as a whole, there is a criticalhematocrit value at which oxygen consumption becomes delivery-dependent. In thedog, under non-CPB conditions, systemic oxygen consumption is maintained to ahematocrit value of approximately 10%. ⁵ The same physiology is applicableduring CPB, during which whole body oxygen balance is actively manipulated bychanges in hematocrit value, temperature, and pump flow.

Transfusion practice varies greatly in cardiac surgery and improvedtransfusion guidelines are needed. ^6,7 These issues are made morepressing with the shift to normothermic CPB in the past few years. ^8,9Given the higher oxygen demand associated with "warm" CPB, ¹⁰ there is a tendency to transfusemore frequently, but this practice is not based on a systematic evaluation ofhemoglobin requirements. In fact, variability in transfusion practice arises inpart because the relationship between temperature, hematocrit level, and oxygenbalance has not been adequately characterized.

In evaluating the relationships between hematocrit value, systemic oxygenconsumption, and oxygen delivery during normothermic CPB, we hope to provide amore physiologic foundation on which to make decisions on perfusion andhematocrit management during CPB.

	Materials and methods

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After review and approval by the Institutional Animal Care and UseCommittee of the Mayo Clinic, nine unmedicated fasting adult mongrel dogsweighing 17 to 20 kg were studied. The dogs were placed in an acrylic plasticbox (Plexiglas box, Rohm and Haas Company, Philadelphia, Pa.) and anesthesia wasinduced with halothane 3% to 4% inspired. After the onset ofanesthesia, peripheral intravenous access was secured, muscle relaxation wasobtained with pancuronium (0.1 mg · kg^–1), and thetrachea was intubated. Ventilation was controlled with a Harvard pump (HarvardApparatus Co., Inc., S. Natick, Mass.) set to maintain arterial carbon dioxidetension (PaCO₂) at 35 to 40 mm Hgand an arterial oxygen tension (PaO₂)greater than 150 mm Hg. Anesthesia was maintained with isoflurane 0.5% to1.5% inspired and fentanyl and midazolam (bolus: 250 µg · kg^–1fentanyl and 350 µg · kg^–1 midazolam, followed byinfusion: fentanyl 3.0 µg ·kg^–1 · min^–1and midazolam 9.6 µg · kg^–1 · min^–1).Muscle relaxation was maintained by continuous infusion of pancuronium (0.8µg · kg^–1 · min ).

A cannula was surgically inserted into a femoral artery for mean arterialblood pressure measurements and blood sampling. Body temperature was measuredwith a nasopharyngeal thermistor.

For CPB, a left-sided thoracotomy was performed. Venous drainage to theextracorporeal circuit was by a 36F cannula placed in the right atrium via theright atrial appendage. The blood was circulated by centrifugal pump through acombined heat exchanger–oxygenator (Bentley Univox, Irvine, Calif.) andreturned via a cannula (4.4 mm inner diameter) into the root of the aorta.Before aortic cannulation, intravenous heparin was given to maintain anactivated coagulation time greater than 600 seconds. The bypass machine wasprimed with blood (approximately 750 ml) from a donor dog and with salinesolution (about 250 ml). Mean arterial pressure was maintained between 55 and 70mm Hg throughout the period of bypass by altering bypass pump flow. Novasoconstrictors or vasodilators were used. Arterial hemoglobin concentration,blood temperature, and blood gas data were continuously monitored by in-linedetectors (CDI 100 and CDI 400, Cardiovascular Devices, Inc., Tustin, Calif.).Pump flow was measured with an in-line ultrasonic blood flowmeter (Sarns/3M, AnnArbor, Mich.).

After establishment of CPB, control measurements and blood samples wereobtained after the target nasopharyngeal temperature of 37.5° C to 38.5°C (low normal dog temperature) was achieved. Arterial blood was drawn from thefemoral line and mixed venous blood was drawn from the venous return line justproximal to the CPB reservoir. Arterial and venous oxygen and carbon dioxidepartial pressures (PO₂, PCO₂) and pH were measured with an IL 1306 pHand blood gas analyzer (Instrumentation Laboratories, Inc., Lexington, Mass.)with the electrodes maintained at 37° C. Hemoglobin concentration and oxygensaturation were measured by an IL 482 Co-Oximeter (Instrumentation Laboratories)with its coefficient setting selected for canine blood. Venous lactate levelswere measured with a YSI model 23A analyzer (Yellow Springs Instrumentation,Yellow Springs, Ohio).

Oxygen consumption, oxygen delivery, oxygen extraction ratio, and totalperipheral resistance were calculated by means of standard equations.

Oxygen consumption

Arteriovenous oxygen content difference (AVDO₂):
AVDO₂ = (CaO₂ – CVO₂ml · dl^–1)
Arterial or venous oxygencontent (CxO₂):
CXO₂ = 1.34 Hb(SXO₂ + 0.003 (PXO₂)
whereHb = hemoglobin concentration;SVO₂= oxygen saturation; Pxo₂ = partialpressure of oxygen; and x = arterial orvenous.
Oxygen delivery (DO₂):

An oversized (36F) venous cannula (for a 20 kg dog) was placed in theright atrium to ensure complete right heart drainage such that the centralvenous pressure could be assumed to be negligible.

Hemodilution was achieved by removing blood from the CPB circuit andreplacing it with 6% dextran 70. After each reduction in hematocritvalue, a period of hemodynamic stabilization of at least 15 minutes was allowedbefore blood samples were withdrawn and measurements recorded. Mixed venousoxygen saturation was also monitored for stability before measurement recordingand blood sampling.

Statistical analysis
All physiologic and metabolic data collected at the five levels ofhemodilution during CPB were analyzed by means of repeated-measures analysis ofvariance. Differences between the five periods (with period 1 designated ascontrol) were determined by the Student-Newman-Keuls test when necessary. Allvalues are expressed as mean ± standard deviation. Regression curvesfor oxygen delivery, oxygen consumption, and total peripheral resistance weregenerated from the 45 individual data points for each variable at each measuredhematocrit value. The data were fit to a logarithmic curve by means of theformula y = a + b (lnx). The figurespresent these curves, as well as mean values and standard deviations for eachvariable.

	Results

Top Abstract Introduction Materials and methods Results Discussion References

 
As hematocrit value was reduced from 40% to 9%, systemicphysiologic variables remained stable (Table I).Throughout CPB, temperature, mean arterial pressure, PaO₂, PaCO₂,and pH remained unchanged. The pH tended to decrease in the final hemodilutionstep, but this decrease did not reach statistical significance (Table I).

View larger version (12K): [in this window] [in a new window]   Fig. 1. Total peripheralresistance (TPR) in dynes · sec ·cm–5 versus hematocrit (Hct)during the five CPB study periods. Values are mean ± standarddeviation (n = 9). A regression curve wasgenerated from 45 individual values of TPR at individual hematocrit values.

View larger version (16K): [in this window] [in a new window]   Fig. 2. Whole body oxygenconsumption (VO2) () in ml· min–1 · m–2 and oxygendelivery (Do2) () in ml ·min–1· m–2 versus hematocrit (Hct)during the five CPB study periods. Values are mean ± standarddeviation (n = 9). Each regression curvewas generated from 45 individual values of oxygen consumption and oxygendelivery at individual hematocrit levels.

	Discussion

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The beneficial effects of hemodilution during CPB are well recognized.CPB hemodilution reduces the demand for blood therapy and may reduce theincidence of transfusion-related complications. Under both CPB and non-CPBconditions, hemodilution increases blood flow in a variety of organ beds. ^2,4,11,12This effect may be particularly advantageous during hypothermic CPB when thereduction in blood viscosity with hemodilution ¹³ counteracts the effect ofcold-induced vasoconstriction and the increased blood viscosity associated withreduced body temperature. ¹⁴

As a result of the reports of the Toronto investigators in 1991, ^8,9there has been a shift toward normothermic CPB across North America. With thisshift, there was a tendency at our institution and others to require higherhematocrit values during CPB, but this practice change was not based onsystematic physiologic data on oxygen balance. Generally, guidelines as to"temperature appropriate hematocrit" would be of practical relevancebut are largely lacking. Even for institutions not practicing warm CPB, patientsapproximate normothermia in the initial and late phases of CPB. During theseperiods hematocrit may be of particular relevance.

Typically, hemodilution during normothermic CPB results in hypotension,and it is common practice to support mean arterial pressure with avasoconstrictor. In this investigation, we chose to increase pump flow tomaintain mean arterial pressure rather than use an alpha agonist, for tworeasons. First, supporting arterial pressure with pump flow allowed us tocharacterize the relationship between hematocrit value and peripheral resistanceduring CPB. Second, under non-CPB conditions the response to hemodilution is anincrease in cardiac output rather than systemic vasoconstriction; as such, anincrease in pump flow more closely mimics the physiologic response in the intactcirculation. During CPB at equivalent blood pressures, tissue perfusion shouldbe better maintained with increases in flow than with addition of avasoconstrictor. ¹⁵

Our study was designed to identify the minimal hematocrit level thatsupports whole body oxygen consumption during normothermic CPB. We found thatsystemic oxygen consumption is maintained at a hematocrit value of 25%but was reduced at 18%. Interestingly, this range was higher than thereported "critical" hematocrit level of approximately 10%under non-CPB conditions. ⁵However, we found that during warm CPB, the critical oxygen delivery wasapproximately 10 ml · 100 gm^–1 · min^–1.This is essentially the same as the valuereported by Cain ⁵ (9.8 ml · 100 gm^–1· min^–1) under non-CPB conditions. From thisobservation, two conclusions may be drawn: First, CPB per se does not alter thecritical level of oxygen transport; second, and more important, a higherhematocrit value may be indicated under CPB than non-CPB conditions. In theintact dog, the same critical oxygen delivery is obtained at a much lowerhematocrit value (10%) because the intact animal is better able toincrease its cardiac output than we are able to increase CPB pump flow. In ourstudy, at a hematocrit value of 18%, the mean pump flow was 2.9 (or 122ml · kg^–1 · min^–1). Cain'sdogs reached the same critical oxygen delivery when the hematocrit value wasapproximately 10% because the cardiac output was 300 ml · kg^–1· min^–1, a cardiac index of about 6 L · min ¹ · m^–2.Because there are technical limitations to increasing CPB flows much above 2.6or 2.8 L · min^–1 · m^–2, oxygendelivery may be compromised by the limited "cardiac output" responseto reduced hematocrit during clinical CPB.

We also found that the critical hematocrit value for the body during warmCPB is higher than that reported for the brain under the same conditions. ¹⁶ In a different study, wedetermined that cerebral oxygen demand in dogs is met with a hematocrit value aslow as 15%. We anticipated that the body would be more tolerant ofhemodilution than the brain because of its lower oxygen demand per unit weightand higher oxidative reserve. However, the brain is very effective in increasingits flow at low hematocrit values such that cerebral perfusion is maintained byshunting flow from other organ beds. ^17,18 In this way, systemicoxygenation is compromised before cerebral oxygenation.

Our study might be criticized for several reasons. First, a pre-CPBsystemic oxygen consumption was not reported. However, our pre-hemodilutionvalue is consistent with previously reported values in dogs under non-CPBconditions. In the foundation work by Starr ¹⁹ in 1959, the same value wasdocumented before CPB. Our systemic oxygen consumption during CPB period 1 alsofalls between the values reported by Gutierrez and associates ²⁰ and Cain ⁵ under non-CPB conditions. Thereforethe systemic oxygen consumption of the initial CPB period can be expected toclosely approximate the animal's oxygen consumption before CPB.

Second, the oxygen extraction ratio was higher (41%) and oxygensaturation lower (57%) than might be expected during CPB with a wholeblood prime. Although in the normal range, the values during the initial periodof CPB (hematocrit value 39%) suggest that either the mean arterialpressure or pump flow may have been somewhat low relative to systemic oxygenconsumption. We targeted a mean arterial pressure of 60 mm Hg to reflectclinical perfusion practice. However, a dog, like the adult patient with cardiacdisease, typically has a mean arterial pressure closer to 80 mm Hg under non-CPBconditions. As such, higher mean arterial pressures or pump flows may beappropriate under normothermic conditions, particularly as hematocrit isreduced.

Most studies of this type also face a methodologic limitation. As in ourstudy, the determination of systemic oxygen consumption and oxygen delivery maybe linked mathematically as well as physiologically. This is of particularimportance when correlations are performed, and this potential problem can beminimized by determination of linked or coupled variables using independenttechniques. ²¹ Ourlaboratory, like most others reporting similar studies, is unable to providecalorimetric studies or direct measurements of systemic oxygen consumption andso is compelled to rely on the Fick method. However, we do realize the inherentlimitation of the technique.

Finally, we provide an assessment of systemic oxygen balance at fivelevels of hematocrit but cannot clearly identify the single lowest acceptablehematocrit level for warm CPB. Our data indicate that a hematocrit value of 18%is too low with conventional CPB but that 25% is adequate. Ideally,oxygen balance at a hematocrit level between these values would have beendetermined. However, on the basis of non-CPB studies, we expected that the"critical" hematocrit value would be lower than 18% and wewere surprised by the finding that critical oxygen delivery is reached at ahigher hematocrit value under CPB than non-CPB conditions. This finding suggeststhat the minimal acceptable hematocrit value is not a fixed number but will varywithin a range, in large part a function of the CPB flow. At a fixed flow, acritical hematocrit value might be more rigidly defined, but if flow adjustmentsare made, a lower (or higher) hematocrit level will be critical. Nonetheless,until certain practical limitations in CPB circuitry are overcome, the criticalhematocrit value closely approximates 18% to 20% at normothermiawith conventional flow rates.

In conclusion, we found that CPB does not appear to alter whole bodyconsumption or critical oxygen delivery values. We found that whole body oxygenconsumption is not maintained when the hematocrit value is reduced to 18%during normothermic CPB. The reason is probably that the increases in pump flowthat are practical during CPB do not approximate what would be seen undernon-CPB conditions at equivalent hematocrit levels. It is important to emphasizethat we do not define what is a "safe" hematocrit value undernormothermic conditions; many physiologic aberrations can be tolerated for briefperiods of time, but it must also be kept in mind that normal dogs will toleratea lower hematocrit value than today's older adult patient undergoing cardiacsurgery. Nonetheless, we hope these findings begin to provide a betterphysiologic framework for our clinical practice.

	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 Richard C. Daly Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Liam, B.-L. Articles by Daly, R. C. Search for Related Content PubMed PubMed Citation Articles by Liam, B.-L. Articles by Daly, R. C.