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Ann Thorac Surg 1999;67:731-735
© 1999 The Society of Thoracic Surgeons
a Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA
b Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, USA
Address reprint requests to Dr Ungerleider, Duke University Medical Center, PO Box 3178, Durham, NC 27710
e-mail: unger002{at}mc.duke.edu
Presented at the Poster Session of the Thirty-fourth Annual Meeting of The Society of Thoracic Surgeons, New Orleans, LA, Jan 26–28, 1998.
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Abstract |
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Methods. Twenty neonatal piglets (2.5 to 3.1 kg) were randomly assigned to two groups. Group A (n = 10) underwent 90 minutes of CPB at full flow (100 mL · kg-1 · min-1) and clamping of the main pulmonary artery (PA). Group B (n = 10) underwent 90 minutes of partial CPB (66 mL · kg-1 · min-1) with continued mechanical ventilation and without clamping of the PA. All hearts were instrumented with micromanometers and a PA ultrasonic flow probe. Endothelial function was assessed by measuring endothelial-dependent relaxation (measured by change in pulmonary vascular resistance after PA infusion of acetylcholine) and endothelial-independent relaxation (measured by change in pulmonary vascular resistance after ventilator infusion of nitric oxide and PA infusion of sodium nitroprusside).
Results. All groups exhibited signs of pulmonary injury after CPB as evidenced by significantly increased pulmonary vascular resistance, increased alveolar–arterial O2 gradients, and decreased pulmonary compliance (p < 0.05); however, pulmonary injury was significantly worse in group A (p < 0.05).
Conclusions. This study suggests that although exposure to CPB alone is enough to cause pulmonary injury, cessation of PA flow during CPB contributes significantly to this pulmonary dysfunction.
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Introduction |
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Although the exact mechanism behind CPB-induced pulmonary hypertension is unclear, previous studies suggest that pulmonary vascular endothelial dysfunction plays an integral role [4, 5]. The vascular endothelium produces both vasodilators and vasoconstrictors that act to maintain vascular smooth muscle tone. Endothelial dysfunction, manifested by impairment of endothelium-dependent vasodilation in response to acetylcholine, has been well documented in children after CPB [6]. Acetylcholine is a receptor-mediated endothelium-dependent vasodilator that acts by stimulating endothelial production of vasodilator agents (the most important being nitric oxide). Nitric oxide is a potent vasodilator produced by endothelial cells from the precursor L-arginine and is an important component in the regulation of vascular smooth muscle tone. Previous studies in this laboratory have investigated the effects of CPB and circulatory arrest on pulmonary endothelium-dependent vasodilation and showed a significant impairment in receptor-mediated endothelium-dependent vasodilation after CPB [7]. The mechanism behind this endothelial impairment remains unclear, however.
During periods of CPB, delivery of oxygenated blood to the pulmonary parenchyma is completely maintained by the bronchial arteries. As a result, the lungs may experience some degree of ischemia during periods of CPB if the bronchial circulation is inadequate. The purpose of this study was to investigate the potential ischemic effects of cessation of pulmonary arterial flow on pulmonary hypertension and lung injury after CPB.
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Material and methods |
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Anesthesia was induced in all piglets with intramuscular ketamine (20 mg/kg) and acepromazine (1 mg/kg). The piglets were intubated and mechanical ventilation (Sechrist Infant Ventilator, model IV-100B, Sechrist Industries, Inc, Anaheim, CA) begun. Anesthesia was maintained with fentanyl (100 µg/kg bolus and 50 µg · kg-1 · h-1 continuous infusion) and pancuronium (0.3 µg/kg). The ventilator was set with a positive inspiratory pressure of 25 mm Hg and a positive end-expiratory pressure of 3 mm Hg. Respiratory rate and inspired oxygen fraction were titrated to maintain an arterial PCO2 of 35 to 45 mm Hg and an arterial PO2 of 150 to 250 mm Hg. Sodium bicarbonate (8.5%) was used to maintain a base excess between -3 and 3 mmol/L. Methylprednisolone (25 mg/kg) was given intravenously before the operation to all piglets.
A femoral arterial line was placed for blood pressure; monitoring and arterial blood gas sampling. A nasopharyngeal temperature probe (YSI-400; Yellow Springs Instrument Co, Yellow Springs, OH) was placed and a median sternotomy performed. The pericardium was opened and a 10-mm ultrasonic flow probe was placed around the main pulmonary artery (PA; Transonic Systems Inc, Ithaca, NY). Micromanometers (3F, Millar Instruments, Inc, Houston, TX) were placed in the PA, left atrium, and right ventricle. A 24-gauge infusion catheter was also placed in the PA and left atrium.
Pursestring sutures (5-0 Prolene, Ethicon, Inc, Somerville, NJ) were placed in the aortic root and right atrial appendage. Animals were given heparin (500 IU/kg) and cannulated with an 8F infant arterial cannula and an 18F venous cannula (DLP, Inc, Grand Rapids, MI). The CPB circuit consisted of a Stockert Shiley roller pump (model 10-10-00; Shiley Inc, Irvine, CA), a Medtronic Minimax Plus oxygenator (Medtronic Inc, Anaheim, CA), and a Bio-Cal 370 heat exchanger (Bio-Medicus, Minneapolis, MN). The pump was primed with crystalloid solution and fresh donor pig blood to maintain a circuit hematocrit value of 18% to 22%.
Group A piglets (n = 10) underwent 90 minutes of CPB at full flow (100 mL · kg-1 · min-1) and clamping of the main PA. Group B piglets (n = 10) underwent 90 minutes of partial CPB (66 mL · kg-1 · min-1) with continued flow (maintained at 33 mL · kg-1 · min-1) through the PA and continued mechanical ventilation. All piglets were kept at 37°C and weaned off CPB without the use of inotropic agents.
Baseline data were collected before CPB once the piglet was fully instrumented and arterial blood gases were within the guidelines previously mentioned. Post-CPB data were collected 15 minutes after weaning from CPB once piglets were hemodynamically stable and arterial blood gases were within the acceptable ranges stated. Data collected included pulmonary compliance, assessment of endothelial-dependent relaxation and endothelial-independent relaxation, arterial blood gases, heart rate, cardiac output, nasopharyngeal temperature, left atrial pressure, systemic arterial blood pressure, and pulmonary arterial blood pressure.
Endothelial function was assessed by measuring endothelial-dependent relaxation (measured by change in pulmonary vascular resistance (PVR) after PA infusion of acetylcholine [12.5 µg · kg-1 · min-1]) and endothelial-independent relaxation (measured by change in PVR after ventilator infusion of nitric oxide [20 ppm] and PA infusion of sodium nitroprusside [10 µg · kg-1 · min-1]). Agents were infused for 5 minutes with data acquired immediately before and at the end of each infusion period. Piglets were allowed to return to baseline conditions for 10 minutes before the administration of the next agent. The order of administration was randomized for each piglet. All animals were kept stable with respect to hematocrit, left atrial pressures, and arterial blood gases throughout the collection period. Nitric oxide concentration was monitored with a chemiluminescence nitric oxide analyzer (model 42H, Thermo Environmental Instruments, Franklin, MA). Data collected included PA flow, pulmonary arterial pressures, right ventricular pressures, left atrial pressures, systemic arterial pressures, and arterial blood gases. Pressure and flow data were collected at 500 Hz for 8 seconds with the ventilator placed at a continuous positive airway pressure of 3 mm Hg. Pulmonary vascular resistance was calculated using the formula
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where PAP is mean pulmonary artery pressure, LAP is mean left atrial pressure, CO is cardiac output in milliliters per second, and 1330 dynes/mm Hg is a constant that converts millimeters of mercury to dynes.
Alveolar–arterial O2 gradients were calculated before and 15 minutes after CPB. Alvelolar–arterial O2 gradient (in mm Hg) was calculated by the formula
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where FiO2 is the concentration of inspired oxygen, PaCO2 is the partial pressure of carbon dioxide in arterial blood, and PaO2 is the partial pressure of oxygen in arterial blood.
Static pulmonary compliance was measured before CPB and 15 minutes after CPB using a Pediatric Pulmonary Function Laboratory 2600 machine (SensorMedics, Yorba Linda, CA) once the piglet was hemodynamically stable, with the ventilator set at a positive inspiratory pressure of 25 mm Hg.
Statistical analysis was performed using two-tailed unpaired Student’s t test and Microsoft Excel. Statistical significance was taken at p < 0.05.
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Results |
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Comment |
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The increase in pulmonary injury seen in the total CPB group compared with that in the partial CPB group may be related to a number of factors in addition to a lack of pulmonary arterial flow, such as differences in pump flow rates or continued ventilation of the lungs. We looked at effects of continued ventilation during CPB compared with CPB without continued ventilation in a previous unpublished study and found no significant differences; thus, we believe the impact of continued ventilation is likely minimal.
We did not perform any direct measures of lung ischemia in this study; thus, we are unable to make comments on the degree of ischemia that results from cessation of pulmonary arterial flow. We do know, however, that ischemic injury occurs in the lungs secondary to CPB from previous work by others [8, 9]. Kuratani and associates [10] have demonstrated significant decreases in adenosine triphosphate tissue concentrations and regional blood flow in the lung as well as alveolar epithelial cell and capillary endothelial cell injury during CPB with pulmonary artery occlusion. Recently, Serraf and colleagues [11] have also shown evidence of ischemic injury to the lungs caused by CPB with increases in myeloperoxidase activity and significant decreases in adenosine triphosphate levels in the lungs after CPB.
Pulmonary endothelial-dependent relaxation is impaired during hypoxic conditions [12, 13]. Cultured endothelial cells subjected to various hypoxic conditions have also shown significant deficiencies in intracellular high-energy phosphates [14] and have been shown to lose their ability to contract [15]. The mechanism of this impairment is unknown; however, it is thought that decreased production of endothelium-derived relaxing factor is a likely cause.
It is unclear whether ischemia itself or reperfusion of an ischemic lung contributes more to the endothelial dysfunction and lung injury after CPB. Pulmonary endothelial dysfunction is a sensitive measure of pulmonary injury and has been attenuated with the use of antioxidants and free-radical scavengers in previous studies [16, 17]. Reoxygenation has been shown to produce lipid peroxidation with endothelial damage and production of reactive O2 products [18]. Adhesion molecules, important in the initiation of activated leukocyte injury to pulmonary endothelium, have also been shown to increase in an ischemia-reperfusion rat lung model and are likely contributors in the pathogenesis of ischemia-induced pulmonary injury [19, 20].
Pulmonary endothelial damage after CPB could further result in abnormalities of pulmonary compliance and A–a O2 gradients as well. Leaky alveolar capillaries secondary to free radical formation and inflammatory mediators could lead to pulmonary edema [9]. This in turn would result in decreases in pulmonary compliance and increases in A–a O2 gradients in a manner similar to acute respiratory distress syndrome. Morita and coworkers [21] found no difference in pulmonary compliance or A–a O2 gradients in groups treated with nitric oxide as a free radical scavenger. This suggests that changes in compliance and A–a O2 gradients may be a secondary effect of free radical or ischemic injury if pulmonary edema were increased secondary to free radical vascular damage.
We chose to focus on the variable of cessation of pulmonary arterial flow during CPB in this study and did not measure the inflammatory response in the two groups. It may be possible that one group experienced a greater degree of inflammation than the other; however, because both groups were exposed to the extracorporeal circuit for an identical period, the inflammatory response was most likely the same in both groups. Steroid pretreatment has routinely been given in our laboratory for a number of years in our CPB studies. Piglets experience a marked inflammatory reaction secondary to CPB. Steroid pretreatment is not necessary for animal survival but it does help to decrease the attrition rate of animals in our studies. All animals in this study received identical doses of steroids; thus, the degree of inflammation should be the same in both groups.
Partial CPB clearly results in a lesser degree of pulmonary injury and endothelial dysfunction compared with total CPB. The exact cause of increased injury caused by cessation of pulmonary arterial flow has not been specifically elucidated in this study, but these results certainly suggest that ischemia may play a significant role. Further studies delineating tissue ischemia versus tissue hypoperfusion need to be performed to clarify this issue.
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