Ann Thorac Surg 2003;75:560-565
© 2003 The Society of Thoracic Surgeons
Original article: cardiovascular
Effect of perfusion flow rate on tissue oxygenation in newborn piglets during cardiopulmonary bypass
Gregory Schears, MDb,
Steven E. Schultz, MDb,
Jennifer Creed, BAa,
William J. Greeley, MDa,
David F. Wilson, PhDa,
Anna Pastuszko, PhD*a
a Department of Biochemistry and Biophysics, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
b Anesthesiology and Critical Care, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
Accepted for publication August 21, 2002.
* Address reprint requests to Dr Pastuszko, Department of Biochemistry and Biophysics, School of Medicine, University of Pennsylvania, 264 Anatomy Chemistry Bldg, Philadelphia, PA 19104, USA
e-mail: pastuszk{at}mail.med.upenn.edu
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Abstract
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BACKGROUND: Our knowledge of the best perfusion flow rate to use during cardiopulmonary bypass (CPB) in order to maintain tissue oxygenation remains incomplete. The present study examined the effects of perfusion flow rate and patent ductus arteriosus (PDA) during normothermic CPB on oxygenation in several organ tissues of newborn piglets.
METHODS: The experiments were performed on 12 newborn piglets: 6 with PDA ligation (PDA-L), and 6 without PDA ligation (PDA-NL). CPB was performed through the chest at 37°C. During CPB, the flow rate was changed at 15-minute intervals, ranging from 100 to 250 ml/kg/min. Tissue oxygenation was measured by quenching of phosphorescence.
RESULTS: For the PDA-L group, oxygen in the brain did not change significantly with changes in flow rate. In contrast, for the PDA-NL group, oxygen was dependent upon the flow rate. Statistically significant decreases in cortical oxygen were observed with flow rates below 175 ml/kg/min. Within the myocardium, liver, and intestine, there were no significant differences in the oxygen levels between the PDA-L and PDA-NL groups. In these tissues, the oxygen decreased significantly as the flow rate decreased below 150 ml/kg/min, 125 ml/kg/min, and 175 ml/kg/min, respectively. Oxygen pressure in skeletal muscle was not dependent on either PDA ligation or flow rate.
CONCLUSIONS: In newborn piglets undergoing CPB, the presence of a PDA results in reduced tissue oxygenation to the brain but not to other organs. In general, perfusion flow rates of 175 ml/kg/min or greater are required in order to maintain normal oxygenation of all organs except muscle.
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Introduction
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Cardiopulmonary bypass (CPB) is frequently used in the repair of neonates with congenital heart disease. Due to improved surgical techniques and CPB perfusion over the last 20 years, overall survival and surgical outcome have dramatically improved [1]. As a result, the focus of many investigators has turned to the examination of the neurologic sequelae associated with CPB. The neurologic injuries seen after CPB include seizures, psychomotor delay, impaired cognition, and cerebral palsy [2, 3]. Similarly to the brain, the injury of others organs such as heart, kidney, or liver can occur in children undergoing CPB. Whether injury to the brain and others tissues is the result of hypoxic-ischemic injury from preoperative preexisting medical conditions, intraoperative events directly due to CPB, or postoperative events such as hypotension or hypoxia during the early recovery period is not fully understood [4]. An important limitation in the published studies is the lack of direct measurements of oxygen pressure during bypass and post-bypass recovery. Near-infrared spectroscopy (NIRS) is one common method for obtaining information on cerebral oxygenation but its usefulness has been questioned [5].
The present study was designed to obtain quantitative measurements of oxygen distribution in the microcirculation of multiple organs in vivo during CPB, and to determine the optimal perfusion flow rate for maintaining cerebral oxygenation. Perfusion requirements during CPB are primarily influenced by factors such as hypothermia, hemodilution, extraction reserve, and specific organ ischemic tolerance [6]. Experiments were performed on newborn piglets, the animal model used by many investigators to study the neurologic sequelae of CPB in the neonatal population. Despite the widely accepted use of this model, it is unknown whether the patent ductus arteriosus (PDA) in the newborn piglet affects the degree of cerebral oxygenation during CPB. There is also an increased risk of neurologic injury associated with aortopulmonary collaterals, such as a PDA. This is most likely the result of pulmonary runoff causing a reduction in cerebral perfusion during CPB [7].
The hypotheses of the present study were that the rate of oxygenation of different tissues in newborn piglets would be critically dependent on perfusion flow during CPB, and that the presence of a PDA would decrease brain perfusion. These hypotheses were tested by real-time measurement of tissue oxygenation.
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Material and methods
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Animal model
All animal procedures were in strict accordance with NIH Guidelines for the Care and Use of Laboratory Animals and were approved by our Institutional Animal Care Committee. Twelve newborn piglets, ages 2 to 4 days (1.4 to 2.5 kg), were anesthetized with halothane. A tracheotomy was performed and the piglets were then placed on mechanical ventilation (Sechrist Infant Ventilator, model IV-100 B, Anaheim, CA). Anesthesia and neuromuscular blockade were maintained with fentanyl (30 mcg/kg IV bolus, followed by 10 mcg/kg/h) and pancuronium (0.1 mg/kg IV), respectively. The ventilator was set with a positive inspiratory pressure of 14-cm H2O and positive end-expiratory pressure of 3-cm H2O. Respiratory rate and inspiratory oxygen were titrated to maintain a PaCO2 range of 35 to 45 mmHg and a PaO2 range of 100 to 200 mmHg. Sodium bicarbonate (8.5%) was used to maintain the base excess between -3 and 3 mmol/L. Femoral arterial and venous cannulae were placed for intravenous infusions, hemodynamic monitoring, and blood gas sampling. Temperatures were monitored throughout the study by both nasopharyngeal and rectal temperature probes (PhysiTemp Instruments, Inc, Clifton, NJ). To stabilize the piglet’s head, the head was placed in a Kopf stereotaxic holder. The scalp was then removed and a hole 10-mm in diameter was made over one parietal hemisphere for measurement of cortical oxygen pressure. Prior to CPB, the liver and small intestine were both exposed via a laparotomy and covered with warmed saline for measurement of their respective tissue oxygen pressures at a later stage in the experiment. A small area of skeletal muscle over the left forepaw was also exposed for oxygen measurements.
In all experiments, the hemodynamics as well as temperatures were continuously monitored. Blood samples were taken every 15 minutes with each change of perfusion flow rate for measurement of pH, PaCO2, PaO2, hemoglobin, and electrolytes using a RapidLab 865 blood gas machine (Bayer Corp, Diagnostics Div, Norwood, MA). Blood glucose levels were also sampled at regular intervals (Lifescan glucose monitor, Milpitas, CA). Tissue oxygenation was measured every 15 minutes within the cortex of the brain, heart, liver, intestine, and skeletal muscle correlating with each change in perfusion flow rate.
CPB technique and experimental protocol
The CPB circuit consisted of two Cobe Roller Pumps (Cobe, Lakewood, CO), a membrane oxygenator (Lilliput 1; Dideco, Mirandola, Italy) and a heater-cooler system (Sarns, Ann Arbor, MI). The pump was primed with donor packed red blood cells and plasma in order to maintain a CPB hematocrit between 20% and 25%.
Following a 2-hour baseline period while keeping the FiO2 constant at 0.3, the animals were then assigned to 1 of 2 groups: 1 group with PDA (PDA-L) ligation (n = 6) and another without PDA (PDA-NL) ligation (n = 6). Through a median sternotomy, the heart and its vascular anatomy were visualized. The PDA was identified in all experiments and a suture was placed around the vessel. In the PDA-L group, the suture was then tied to prohibit flow through the PDA. The ascending aorta was cannulated with a 10 Fr Bard catheter, and the right atrium was cannulated with an 18 Fr cannula (Research Medical, Inc, Midvale, UT). Intravenous heparin (300 units/kg) was administered prior to CPB for maintenance of activated clotting times (ACTs) greater than 400 seconds (Hemachron Jr, International Technidyne Corp, Edison, NJ).
Normothermic CPB was initiated with a perfusion flow rate of 200 ml/kg/min and a FiO2 of 0.3. After a 15-minute period of stabilization on CPB, the perfusion flow rate was changed at 15-minute intervals from 200 to 225, 250, 175, 150, 125, 100 ml/kg/min, and eventually returned to 200 ml/kg/min. During each change in perfusion flow rate, tissue oxygen was measured.
Measurements of oxygen by the oxygen-dependent quenching of phosphorescence
Cortical oxygen pressure was measured by the oxygen-dependent quenching of phosphorescence [8–10]. This is a minimally invasive optical method in which an oxygen sensitive phosphor, the two-layer glutamic acid dendrimer of Pd-meso-tetra-(4-carboxyphenyl) porphyrin (Oxyphor R2; Oxygen Enterprises, Ltd, Philadelphia, PA) was injected IV at a final concentration of 22 mg/kg prior to all procedures. The measurements were made with a frequency domain phosphorometer (PMOD 2000, Oxygen Enterprises).
Statistical analysis
All values are expressed as means ± SEM for 6 PDA-L and 6 PDA-NL experiments. Statistical significance was determined using one-way analysis of variance with repeated measures by Wilcoxon signed-rank test; p < 0.05 was considered statistically significant.
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Results
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All 12 piglets within the experimental protocol had their PDA identified. Physiologic parameters of newborn piglets during normothermic CPB are presented in Table 1.
When the perfusion flow rate was changed, there were no significant differences in the measured physiologic parameters as compared to pre-CPB values or between the PDA-L and PDA-NL groups of animals. There were no significant changes in either of the groups when perfusion flow rate was compared to mean arterial pressure.
Brain
The effects of the perfusion flow rate and PDA ligation on the cortical oxygen pressure are shown in Figure 1.
In the PDA-L group, pre-CPB cortical oxygenation was 49.2 ± 9.3 mm Hg. This did not change significantly with change in perfusion flow rate. In contrast, within the PDA-NL group, cortical oxygenation was dependent upon the rate of perfusion flow. Statistically significant decreases in cortical oxygen, compared with 200 ml/kg/min, were observed with rates of 175, 150, 125, and 100 ml/kg/min. The pre-CPB cortical oxygen within the PDA-NL group was 46.4 ± 1.4 mm Hg and decreased to 37 ± 3 (p < 0.05), 39.5 ± 2.5 (p < 0.05), 35.7 ± 2.9 (p < 0.05), and 33.5 ± 0.5 mm Hg (p < 0.01), respectively. When the perfusion flow rate was again increased to 200 ml/kg/min, the cortical oxygen pressure increased to 41 ± 3.1 mmHg, a value not significantly different from pre-CPB levels. There were significant differences in brain oxygen pressure between the PDA-L and PDA-NL groups of piglets. At the flow rates of 175, 150, 125, and 100 ml/kg/min, the oxygen pressures in the brain were significantly higher (p < 0.05 and p < 0.01) in PDA-L as compared to PDA-NL group of animals.
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Fig 1. Relationship between brain oxygenation and perfusion flow rate during cardiopulmonary bypass (CPB) in patent ductus arteriosus ligated (PDA-L) and nonligated (PDA-NL) newborn piglets. The results are expressed as the means ± SEM for six experiments. a* = p < 0.05; a** = p < 0.01 for significant difference from pre-CPB values in PDA-NL group of animals. b* = p < 0.05; b** = p < 0.01 for significant difference between PDA-L and PDA-NL groups of animals, as determined by one-way analysis of variance, followed by the Wilcoxon signed-rank test.
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Myocardium
Within the PDA-L group, pre-CPB oxygen pressure of the myocardium was 24.3 ± 2.8 mm Hg (Fig 2).
As the flow rates were decreased to 150, 125, and 100 ml/kg/min, myocardial oxygen pressures decreased significantly to 13.8 ± 2.3 mm Hg (p < 0.05), 10.2 ± 1.5 mm Hg (p < 0.005), and 8.5 ± 1.2 mm Hg (p < 0.001), respectively. When the flow rate was then returned to 200 ml/kg/min, myocardial oxygen pressure remained below the pre-CPB value (13 ± 2.5 mm Hg versus 24.3 ± 2.8 mm Hg (p < 0.05). The response of the myocardial oxygen pressure to changes in perfusion flow within the PDA-NL group was the same as that of the ligated group. There were also no significant differences in myocardial oxygen pressure between the PDA-L and PDA-NL groups of piglets.
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Fig 2. Oxygenation of the heart at different perfusion flow rates in patent ductus arteriosus ligated (PDA-L) and nonligated (PDA-NL) newborn piglets during cardiopulmonary bypass (CPB). The results are expressed as the means ± SEM for six experiments. a* = p < 0.05; a** = p < 0.005; a*** = p < 0.001 for significant difference from pre-CPB values in PDA-L group of animals. c** = p < 0.005; c*** = p < 0.001 for significant difference from pre-bypass values in PDA-NL group of animals as determined by one-way analysis of variance, followed by the Wilcoxon signed-rank test.
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Liver
Within the PDA-L group, the pre-CPB liver oxygen pressure was 31.3 ± 5.6 mm Hg (Fig 3).
A decrease in flow rates to 125 and 100 ml/kg/min caused significant decreases in oxygen pressure to 13.6 ± 3.6 mm Hg (p < 0.05) and 8.8 ± 1.9 mm Hg (p < 0.01), respectively. Increasing the perfusion flow rate again to 200 ml/kg/min resulted in liver oxygenation not significantly different from pre-CPB values. The changes in oxygenation within the liver of the PDA-NL group were the same as in the PDA-L group.
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Fig 3. Oxygenation of the liver at different perfusion flow rates in patent ductus arteriosus ligated (PDA-L) and nonligated (PDA-NL) newborn piglets during cardiopulmonary bypass (CPB). The results are expressed as the means ± SEM for six experiments. a* = p < 0.05; a** = p < 0.01 for significant difference from pre-CPB values in PDA-L group of animals. c* = p < 0.05 for significant difference from pre-bypass values in PDA-NL group of animals as determined by one-way analysis of variance, followed by the Wilcoxon signed-rank test.
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Intestine
Within the intestine, the pre-CPB oxygen pressure was 45 ± 6 mm Hg in the PDA-L group (Fig 4).
Decreasing the perfusion flow rates to 175, 150, 125, and 100 ml/kg/min resulted in significant decreases in oxygenation to 27 ± 3 mm Hg (p < 0.05), 28 ± 3.5 mm Hg (p < 0.05), 24.7 ± 4.6 mm Hg (p < 0.05), and 22.5 ± 1.9 mm Hg (p < 0.01), respectively. Returning the flow rate to 200 ml/kg/min resulted in the intestinal oxygen pressure rising again to values not significantly different from pre-CPB levels. There were no differences in intestinal oxygenation between the PDA ligated and nonligated groups.
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Fig 4. Dependence of intestine oxygenation on perfusion flow rates in the patent ductus arteriosus ligated (PDA-L) and nonligated (PDA-NL) newborn piglets during cardiopulmonary bypass (CPB). The results are expressed as the means ± SEM for six experiments. a* = p < 0.05; a** = p < 0.01 for significant difference from pre-CPB values in PDA-L group of animals. c* = p < 0.05; c** = p < 0.01 for significant difference from pre-CPB values in PDA-NL group of animals as determined by one-way analysis of variance, followed by the Wilcoxon signed-rank test.
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Skeletal muscle
In the PDA ligated group, pre-CPB oxygen was 47.3 ± 2.5 mmHg (Fig 5).
This did not significantly change when the perfusion flow rate was altered. There were also no significant differences in muscle oxygenation between the PDA ligated and nonligated groups.
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Fig 5. Effect of varying perfusion flow on oxygen pressure in the skeletal muscle of patent ductus arteriosus ligated (PDA-L) and nonligated (PDA-NL) newborn piglets during cardiopulmonary bypass. The results are expressed as the means ± SEM for six experiments.
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Comment
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Our study investigated the dependence of oxygen pressure within various organ systems of newborn piglets on the perfusion flow rate during normothermic CPB. This animal model was chosen because of the piglet’s similarity to neonates in both anatomy and physiology [11]. Factors influencing the use of a piglet model include the size and weight of the animal being comparable to that of a neonate along with the well-described and validated scores used to assess neurologic injury. In newborn piglets, the brain regions that are vulnerable to CPB include areas of the neocortex and hippocampus, and are damaged by both apoptosis and cell necrosis [12].
In our study, the oxygenation of various organ tissues of newborn piglets was determined by a minimally invasive optical method called oxygen-dependent quenching of phosphorescence. This method has been effectively used for oxygen measurements in a wide range of tissue, including the brain [13–20], as well as the retina and choroid of the eye [21–22]. At the beginning of the experimental protocol, a phosphor dye was injected into the blood where it remained dissolved in the blood plasma, and oxygen in the immediate environment of the phosphor is measured by the decrease in phosphorescence lifetime that occurs with increasing oxygen pressure. Since phosphorescence lifetime is measured, and not intensity, the measurements are not affected by the presence of tissue pigments such as hemoglobin and cytochromes or by their absorption changes. Phosphorescence quenching directly measures the oxygen dissolved within the blood plasma and is not affected by bound oxygen, such as that bound to hemoglobin. This is important, because the oxygen dissolved in the plasma is the source for oxygen diffusion from the capillaries into the surrounding tissue. For these reasons, oxygen-dependent quenching is a more reliable method for measuring tissue oxygenation compared to the less invasive technique of NIRS, which measures the volume averaged saturation of hemoglobin with oxygen. The obtained values represent the mean oxygen pressure in the plasma oxygen levels in the microcirculation of the tissue.
Our study shows that newborn piglets normally have a PDA, which markedly influences the pattern of blood flow to the brain during normothermic CPB thereby affecting cerebral oxygenation. When the PDA was not ligated, oxygenation of the brain was dependent on perfusion flow rate. In the PDA-L group, however, brain oxygen levels did not differ from pre-CPB values at flow rates between 100 and 250 ml/kg/min. Piglets with a ligated PDA are appropriate for mimicking the cerebral response of full-term infants on normothermic CPB because, in most clinical situations, the PDA is either closed or is ligated prior to CPB thereby preventing pulmonary overcirculation. Most of the reported animal studies using the piglet model, however, either do not mention PDA ligation or use a percutaneous technique for CPB in which the PDA is not ligated. Our experiments show that, when the PDA is not ligated, cerebral oxygenation is diminished when perfusion flow rates are set below 175 to 200 ml/kg/min during normothermic CPB.
Our study suggests that PDA ligation in newborn piglets protects the brain from a decrease in oxygenation with decreasing perfusion flow by eliminating a low-resistance "shunt" flow. Previous investigators have shown that a risk factor for increased neurologic injury in children undergoing CPB is heart malformations with systemic-to-pulmonary collaterals [23]. Kirshbom and colleagues showed that these types of collaterals decrease the rate of cerebral cooling and offered pH-stat CPB management as a possible solution [6, 24]. Our study would suggest that these patients would need a higher perfusion flow rate on normothermic CPB compared to patients without systemic-to-pulmonary collaterals.
The response of brain oxygenation to PDA ligation is in contrast to other tissues. In other organs such as the heart, liver, and intestine, oxygen pressure was not affected by PDA ligation. Oxygenation of these organs was, however, dependent on perfusion flow rate in both groups (PDA-L and PDA-NL). The most sensitive tissue response to a decrease in rate of perfusion flow was the heart. At the end of the experiment, when the perfusion flow was returned to 200 ml/kg/min, this was the only tissue in which oxygenation remained below control values. This is in agreement with a study of Undar and colleagues [25] who reported significantly diminished renal and myocardial blood flow during normothermic bypass in newborn piglets using a perfusion flow rate of 150 ml/kg/min. This decrease in myocardial blood flow is also consistent with the decreased oxygenation observed in this present study. In contrast to other tissue, oxygenation of skeletal muscle was not dependent on either perfusion flow rate or PDA ligation.
The observed relationship between the oxygenation of various organs of newborn piglets and perfusion flow rate is of major significance. In most published studies, investigators have used perfusion flow rates ranging between 100 and 150 ml/kg/min during normothermic CPB as representative of "full flow" CPB [26–28]. Our data show that within this range of flow, oxygenation of the liver, heart, and intestines was significantly decreased as compared to pre-CPB values even in the PDA-L group.
Our study was carried out during normothermic CPB. Although this is not commonly used clinically, we wanted to observe how perfusion flow rate affected tissue oxygenation during normothermia. We also used a pump hematocrit similar to the observed hematocrit in newborn piglets. Recent studies are now suggesting that a higher pump hematocrit may have a beneficial role in patients undergoing CPB. Finally, our study protocol did not randomly assign varying flow rates. Due to the complexity of the experiment, we used the same piglet while changing the flow rate at several points during the experiment. Now that we have a better understanding of how a wide range of flow rates affects cerebral oxygenation, our future experiments can focus on a more narrow range of rates.
In conclusion, in newborn piglets undergoing CPB, a perfusion flow rate of 175 ml/kg/min or greater is required in order to maintain normal oxygenation of the brain, liver, heart, and intestine. Muscle oxygenation, however, is not dependent on perfusion flow rate in the range of 100 and 250 ml/kg/min. The presence of a PDA results in reduced oxygenation blood flow to the brain but not to other organs.
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Acknowledgments
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This study was supported by grant HL-58669.
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References
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Abstract
Introduction
