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Ann Thorac Surg 2001;72:542-547
© 2001 The Society of Thoracic Surgeons
a Department of Anesthesiology, 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 April 17, 2001.
Address reprint requests to Dr Cook, Mayo Clinic, 200 First St SW, Rochester, MN 55905
e-mail: cook.david{at}mayo.edu
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Abstract |
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Methods. Ten pigs underwent bypass at 27°C. Fluorescent microspheres were administered before and during CPB at four randomized flows: 1.9, 1.6, 1.3, and 1.0 L · min-1 · m-2. At completion, tissue samples were obtained from brain, renal cortex and medulla, pancreas, small bowel, and limb muscle for regional blood flow determination.
Results. Cerebral blood flow remained unchanged between CPB flows of 1.9 and 1.3 L · min-1 · m-2. Renal perfusion was stable between flows of 1.9 and 1.6 L · min-1 · m-2, whereas perfusion of small bowel decreased linearly with pump flow. Pancreatic perfusion was unchanged over the range of flows studied; muscle blood flow was profoundly reduced at the highest CPB flow and further decreased if pump flow was reduced below 1.6 L · min-1 · m-2.
Conclusions. This study characterizes the organ-specific hierarchy of blood flow and oxygen distribution during hypothermic CPB. These dynamics are relevant to clinical decisions for perfusion management.
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Introduction |
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TopAbstractIntroductionMaterial and methodsResultsCommentReferences |
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O2) more than delivery, the balance between oxygen (O2) supply and demand on bypass can be favorable. This reduction in oxygen demand with hypothermia can extend the range of perfusion practice. Lowered body temperature allows for a greater reduction in hematocrit or reduced bypass flows. If bypass flow is decreased, perfusion of vital organs can be maintained [3–6]. However, under these conditions blood flow to other regions may be profoundly reduced. The purpose of this study was to characterize the distribution of blood flow and oxygen delivery to different organ beds during hypothermic bypass over a range of flows that encompasses most of perfusion practice at moderate hypothermia (27°C).
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Material and methods |
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A 4-inch, 18-gauge cannula was inserted into a femoral artery for mean arterial blood pressure (MAP) measurements and blood sampling. The right atrium was catheterized through the internal jugular vein. This catheter served as the injectate port for cardiac output measurements (Oximetrix 3 SO2/CO computer, Abbott Laboratories, Chicago, IL). An EDSLAB thermocouple (Linkoping, Sweden) was placed in the pulmonary artery for determination of thermodilution cardiac outputs. Cardiac output measurements were made in triplicate before bypass.
For CPB, a left thoracotomy was performed. The bypass circuit was primed with 1000 mL of crystalloid and up to 500 mL of heparinized fresh whole blood. Venous drainage to the circuit was through a 40F, two-stage cannula placed in the right atrium by the appendage. A hard shell venous reservoir (Terumo Capiox SX 25) was used. Blood was circulated by a centrifugal pump (Sarns Centrifugal Pump, Sarns, Ann Arbor, MI) through a combined heat exchanger-oxygenator (Sarns Turbo) and returned through a 4.5-mm inner diameter cannula inserted in the root of the ascending aorta.
Animals were heparinized before bypass with at least 450 U/kg. During CPB, nasopharyngeal temperature was maintained at 27°C. Hemoglobin concentration was maintained at 7.5 to 8.5 g/dL, PaCO2 at 35 to 40 mm Hg, and PaO2 at more than 200 mm Hg, using 
-stat management. Cardiopulmonary bypass flow rates were initially adjusted to achieve a MAP of 55 to 65 mm Hg. Arterial blood gases, venous hemoglobin (Hgb) concentration, and mixed venous O2 saturation were monitored continuously by an "in-line" analyzer (CDI 500, CDI, Irvine, CA). Because vasoconstrictors may alter the splanchnic and renal perfusion [4, 7], none were used in the study to support the MAP as flow was reduced.
In the investigation, the following physiologic variables were determined:
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During the five experimental periods (before bypass and during CPB at flows of 1.9, 1.6, 1.3, and 1.0 L · min-1 · m-2) regional blood flow was determined. The order of bypass flow exposure was randomized and measured continuously by a Sarns-Delphin flowmeter. During bypass the proximal ascending aorta was cross-clamped. After each study period, CPB flow was returned to 1.9 L · min-1 · m-2 until blood gases and mixed venous O2 saturation normalized.
Organ blood flow was measured using 15-µm fluorescent-labeled polystyrene microspheres (Molecular Probes, Eugene, OR), according to the blood reference sample method [8, 9]. One million crimson (excitation/emission wavelengths: 625/645 nm), red (580/605 nm), orange (540/560 nm), yellow-green (505/515 nm), and blue-green (430/465 nm) microspheres were used. Microspheres were diluted in 6 mL of 6% Dextran 70 with 0.025% Tween 80, sonicated, vortexed, and injected over 60 seconds into the left atrial appendage through a 6F catheter (pre-CPB) or into the aortic inflow line during CPB. Beginning 30 seconds before microsphere injection, a reference blood sample was obtained over 4 minutes. Blood was drawn from the femoral artery catheter into a glass syringe by a Harvard withdrawal pump at a rate of 4.9 mL/min. This blood was transferred into labeled vials, carefully rinsing syringes and extension lines [9].
After completion of the experiment, bypass was terminated, pigs were exsanguinated, and brain, kidneys, pancreas, portions of small bowel, and deep extremity muscles were excised. Weighed tissue samples (1 to 2 g) were obtained from the following regions: cerebral cortex: left and right frontal and occipital lobes, left and right renal cortex and medulla; three samples each from pancreas and small bowel (distal duodenum, jejunum, and ileum), and one muscle sample from each extremity.
Blood and tissue samples were autolyzed in the dark for 2 weeks. Thereafter, microspheres were recovered [9]. The intensity of fluorescence in tissue and blood samples was determined by a spectrofluorometer (SLM 8100, SLM-AMINCO, Rochester, NY). The fluorescence of each sample was measured at its specific excitation/emission wavelength. The optimal excitation/emission wavelength of each color was determined before each period of spectrofluorometric analysis. Organ blood flow (OBF) was calculated from the intensity of fluorescence in blood and tissue samples using the following formula:
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Data analysis
Cerebral blood flow (CBF) was determined as the mean of the four cerebral cortical samples. For calculation of renal perfusion, the ratio between cortical and medullary flows was determined and the mean of the two was expressed. Blood flow to pancreas and small bowel was determined in three regions, and the mean value in each group was reported.
Adequate mixing and equal distribution of microspheres was determined by comparing right- and left-sided tissue samples for brain, kidney, and skeletal muscle. If there was no statistical difference between sides for any paired region (p > 0.05 by paired t test for each comparison), values are presented as a mean of the left and right sides for each paired sample.
All data were expressed as the mean ± SD. A paired t test was used in comparing before-bypass values with those of CPB (1.9 L · min-1 · m-2). Physiologic variables before bypass and the four bypass periods were compared using repeated-measures analysis of variance (ANOVA). When repeated-measures ANOVA designated significance, the Student-Newman-Keuls test was used to identify differences between periods. Values of p less than 0.05 were considered statistically significant.
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Results |
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O2 were 431 ± 80 and 95 ± 47 mL · min-1 · m-2, respectively. Oxygen delivery was greatly in excess of demand, with an oxygen extraction ratio of 0.24 ± 0.13 (Table 2).
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During hypothermic bypass at 1.9 L · min-1 · m-2, DO2 decreased by a mean of 50% ± 10% (p < 0.001). This reduction was a function of CPB hemodilution and a reduction in cardiac index relative to the pre-bypass period. However, with establishment of hypothermia, whole-body O2 demand was reduced from a mean of 95 mL · min-1 · m-2 before bypass to a mean of 52 mL · min-1 · m-2 at 27°C (Table 2). Because the reductions in O2 and DO2 were similar, the ratio of whole-body O2 supply to demand, oxygen extraction ratio, was unchanged during hypothermic CPB at 1.9 L · min-1 · m-2 (Table 2).
During hypothermia, stepwise reductions in pump flow resulted in stepwise reductions in DO2 (Table 2). DO2 at a flow of 1.6 L · min-1 · m-2 was significantly lower than before bypass or at 1.9 L · min-1 · m-2. However, whole-body O2 consumption did not significantly decrease under hypothermic CPB conditions as flow was reduced from 1.9 to 1.0 L · min-1 · m-2 (52 ± 10 mL · min-1 · m-2 versus 49 ± 8 mL · min-1 · m-2 respectively, p = 0.110). Thus, during hypothermic bypass, O2 was maintained by an increase in O2 extraction (Table 2). This is also evident in that linear decreases in SvO2 were demonstrated as pump flow was reduced (Table 1).
Figure 1 presents the regional blood flow in the pre-bypass period and during hypothermic CPB at 1.9 L · min-1 · m-2. From this figure, it is evident that blood flow to all organ beds, except small bowel, was decreased relative to the nonbypass state (p < 0.001). The reductions in blood flow that occurred with the transition to hypothermic CPB differed importantly by organ bed. Brain perfusion decreased the least (28%), kidney blood flow was next best preserved with a 42% reduction in flow, pancreatic blood flow was reduced by 62%, and skeletal muscle demonstrated a mean decrease of 77% (Fig 1).
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Figure 2 shows the regression curves relating tissue perfusion and pump flow for each of the five tissues examined. Cerebral blood flow was well preserved and remained unchanged between CPB flows of 1.9 and 1.3 L · min-1 · m-2. Cerebral blood flow was significantly decreased when pump flow was reduced to 1.0 L · min-1 · m-2. Renal perfusion was preserved between bypass flows of 1.9 and 1.6 L · min-1 · m-2, but was decreased at a flow of 1.3 L · min-1 · m-2. Blood flow to small bowel decreased linearly with pump flow, whereas pancreatic perfusion remained unchanged over the range of flows studied (Fig 2). Muscle blood flow was profoundly reduced at the highest CPB flow and further decreases were observed as pump flow was reduced below 1.6 L · min-1 · m-2.
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Comment |
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O2 with hypothermia can offset the reductions in DO2 associated with bypass hemodilution. As such, whole-body O2 balance during hypothermia may be neutral. Although this is true for the body as a whole, a variety of physiologic changes are evident. Systemic vascular resistance increases; hemodynamically, this increase is evident from an unchanged MAP in the context of a pump flow that is 27 ± 11% less than the cardiac index under nonbypass conditions. The increased systemic vascular resistance is associated with large alterations in regional blood flow. The largest changes in vascular resistance occur in muscle where blood flow is reduced by approximately 80%.
The balance between systemic O2 supply and demand is unchanged (relative to the nonbypass state) with a flow of 1.9 L · min-1 · m-2 at 27°C. However, when further flow reductions occur, an increase in oxygen extraction is required to maintain O2 and the margin between O2 supply and demand progressively narrows. Under these conditions, the flow redistribution that occurred with transition to bypass continues; and a hierarchy in the distribution of blood flow between organ beds is evident (Fig 2). Brain and pancreas perfusion are maintained over the broadest range of flows, renal perfusion is next best preserved, then skeletal muscle, and finally small bowel.
From this progression it is evident how vasoconstriction and shunting of blood from differing organ beds preserve the perfusion of "higher order" organ beds when pump flow and whole-body oxygen delivery decrease. Initially, shunting from muscle supports visceral, renal, and cerebral perfusion, then visceral perfusion is sacrificed to support renal and cerebral blood flow, and finally renal perfusion is compromised to support cerebral blood flow.
This study has several limitations, one of which is that we chose to examine the hierarchy of blood flow and O2 distribution under conditions of varying CPB flow rate without independent regulation of MAP. In clinical practice, MAP might be supported at reduced flows with the use of vasoconstrictors. We chose not to use vasoconstrictors because of their independent effects on organ perfusion [7]. The application of agents, such as phenylephrine, which have differing potencies in different organ systems, would confound the characterization of the intrinsic regulation of flow distribution during CPB.
Because of this design, it might also be argued that our investigation primarily examined the distribution of blood flow and O2 delivery under varying MAP. Although this argument can be made, this distinction is somewhat artificial. Because MAP and pump flow are coupled physiologically, our results provide comment on the distribution of blood flow and O2 delivery under conditions of either reduced flow or pressure at hypothermia and in the absence of vasoconstrictive agents.
A second limitation of this investigation was our inability to provide oxygen consumption values for each of the organ beds we examined. There are both technical and physiologic reasons these consumption values were not calculated. Technically, it is difficult to isolate the venous outflow for each of the organs we examined without potentially disturbing perfusion of that organ. Whereas catheterization of renal and skeletal muscle venous systems is straightforward, catheterization of pancreatic, small bowel, and cerebral venous systems is complex, may disturb organ perfusion, and is difficult to maintain through the course of the experiment in fully heparinized animals. Physiologically, relating venous oxygen saturation to microsphere-determined blood flow is also problematic, as the venous effluent may not necessarily represent the region where the blood flow was determined. As such, studies using microspheres for regional perfusion rarely report regional O2 consumption.
Our study differs from what has been reported previously in important ways. In the foundation study by Rudy and coworkers [10], the distribution of systemic blood flow was determined in animals undergoing profound hypothermia and circulatory arrest. Alterations in cerebral, renal, and muscle blood flow distribution were demonstrated but perfusion thresholds were not evaluated; and the presence of profound hypothermia and circulatory arrest make direct comparisons with our report difficult. Another earlier investigation by Fox and colleagues [3] showed that cerebral blood flow decreased more slowly than blood flow to other organ beds. However, that study was conducted at 20°C with CPB flows ranging from 0.25 to 1.75 L · min-1 · m-2, which are outside the range of most adult clinical practice. In contrast, we examined blood flow distribution under more commonly used bypass flow and temperature conditions.
Our study also differs from the report of Lazenby and colleagues [11], who examined organ perfusion under normothermic and hypothermic conditions. During hypothermia they identified some redistribution of blood flow with a change in CPB flow from 3.0 to 1.5 L · min-1 · m-2, but their results described primarily the effects of temperature change on regional blood flow and O2.
Our results also differ from studies by the Galveston group. Two studies [4, 5] examined the effect of either phenylephrine or dopamine on regional blood flow during normothermic CPB. Our studies differ with regard to temperature, and additionally, their use of vasoactive agents makes the results of our studies not directly comparable. Additionally, like Lazenby and colleagues [11], they examined the distribution of blood flow under only two CPB flow conditions, preventing definition of the dynamic organ-specific changes in blood flow redistribution during changes in bypass flow.
Finally, our results must be compared with those of Andersson and colleagues [12], who concluded that renal autoregulation was inoperative during CPB at 28°C because renal blood flow decreased with the decrease in pump flow. Our results contradict those findings because we showed that renal perfusion was preserved between bypass flows of 1.9 and 1.6 L · min-1 · m-2. Although we identified a significant decrease in renal perfusion with a pump flow of 1.3 L · min-1 · m-2 and below, a range of CPB flows and pressures over which renal perfusion is maintained was identified because we evaluated intermediate CPB flow and pressure conditions. Although our examination of four CPB flow conditions does not provide inflection points for the curves describing regional blood flow and O2 delivery in the five organ beds described, the assessment of multiple conditions gives a more comprehensive presentation of their physiology.
We previously characterized the redistribution and hierarchy of blood flow during normothermic CPB [2]. Although the present report and the earlier one are not directly comparable because of differing ranges of flows tested, the data suggest that the regulation and distribution of blood flow during hypothermia are not qualitatively different. Whereas the absolute blood flows to various organ beds are greater with normothermic bypass, the redistribution of blood flow that occurs with reductions in pump flow and systemic O2 delivery does not appear to differ importantly between 27°C and 37°C. We cannot speculate that the same would be true with greater degrees of hypothermia. Evidence suggests that a vasoparesis occurs with more profound hypothermia [13], which could alter blood flow distribution. However, over the range of flows and temperatures that constitute the vast majority of adult cardiac surgical practice, our observations appear applicable.
Whereas cerebral injury after cardiac operations is a major form of morbidity, a variety of mechanisms maintain cerebral O2 delivery during CPB. Under conditions common during CPB, this report and others have demonstrated that visceral and sometimes renal blood flow may be compromised. These physiologic processes may contribute to the incidence of mild to moderate renal dysfunction after CPB in adults [14]. Although ischemic injury to other viscera is rare, these complications are devastating when they occur [15–18]. Furthermore, our observations of bowel hypoperfusion may be relevant as this condition has been implicated in endotoxin translocation during bypass [19].
Our choice of CPB flow, pressure, and temperature is a function of the type of operation and surgical preferences. However, the greater prevalence of risk factors and comorbidities in today’s surgical population necessitates that we consider the physiologic effects of our perfusion management on differing organ systems. Furthermore, consideration of the patient’s primary risk profile, whether it be cerebral, renal, or other, might help us make better choices in perfusion strategy and thus improve outcomes.
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