Kirk S. Bolling

Retrograde cardioplegia does not adequately perfuse the right ventricle

UNLABELLED Surgeons often rely primarily on retrograde cardioplegia for myocardial protection, because it provides adequate left ventricular perfusion even in the presence of coronary artery disease. Clinically, however, adequate right ventricular perfusion by retrograde delivery has not been demonstrated. Using intraoperative transesophageal echocardiography, we examined retrograde delivery of cardioplegic solutions by contrast echocardiography, which directly assesses myocardial perfusion. In 15 patients (seven having coronary bypass and eight having valve operations), 4 ml of sonicated Isovue medium was injected retrograde via a coronary sinus catheter. Myocardial perfusion was assessed quantitatively by visual inspection and back-ground-subtracted videodensitometric analysis. In five patients undergoing aortic valve replacement, right and left coronary ostial drainage was estimated during retrograde infusion. Before the aortic crossclamp was removed, myocardial oxygen extraction was calculated in all 15 patients by first delivering warm blood cardioplegic solution for 2 minutes in a retrograde fashion and then taking samples from the cardioplegia line and aortic root. This determined the oxygen extraction ratio across the myocardium at the end of retrograde delivery. Warm blood cardioplegic solution was next given antegrade, and 15 seconds later samples were taken from the cardioplegia line and a right ventricular (acute marginal) vein to determine the oxygen extraction ratio across the right ventricle. As assessed by contrast echocardiography, retrograde infusion resulted in almost four times more perfusion to the left ventricular free wall and septum than to the right ventricular free wall (74 +/- 2 versus 69 +/- 2 versus 20 +/- 2, p < 0.05). In those five patients with an aortotomy the right ostial drainage was less than 5 ml/min whereas left ostial drainage was estimated at 80 ml/min during retrograde administration. Oxygen extraction across the myocardium supplied by retrograde infusion was low after 2 minutes. Conversely, when antegrade cardioplegia was started, right ventricular oxygen extraction rose fourfold (42% +/- 5% versus 11% +/- 1%, p < 0.05), demonstrating that retrograde cardioplegia had not adequately perfused the right ventricular myocardium. CONCLUSIONS 1. Retrograde cardioplegia provides poor right ventricular myocardial perfusion as assessed by contrast echocardiography and coronary ostial drainage. (2) This poor perfusion is inadequate to meet myocardial demands as demonstrated by the high right ventricular oxygen extraction after a prolonged retrograde infusion. (3) Therefore surgeons must not rely solely on retrograde cardioplegia for right ventricular myocardial protection. This concept is especially important if continuous warm blood cardioplegia is used, because myocardial requirements are then higher.

Prevention of the hypoxic reoxygenation injury with the use of a leukocyte-depleting filter

OBJECTIVES Recent studies have shown that an injury occurs when the hypoxic heart is suddenly reoxygenated (as occurs with cardiopulmonary bypass), resulting in myocardial depression, impaired oxygenation, and increased pulmonary vascular resistance. We hypothesize that this injury is, in part, due to oxygen-derived radicals produced by activated white cells and may therefore be ameliorated by limiting leukocytes in the bypass circuit. METHODS Fifteen neonatal piglets underwent 60 minutes of ventilator hypoxia (inspired oxygen fraction 8% to 10%), followed by reoxygenation with cardiopulmonary bypass at an inspired oxygen fraction of 100% for 90 minutes. In nine piglets (group 1) our routine bypass circuit was used with no modifications, and in six piglets (group 2) a leukocyte-depleting filter (Pall BC-1; Pall Biomedical Products Corporation, Glencoe, N.Y.) was inserted in the arterial line to lower the neutrophil count. Six additional piglets underwent 90 minutes of bypass without hypoxia (cardiopulmonary bypass controls). Postbypass myocardial and pulmonary function was assessed by pressure volume loops, arterial/alveolar ratio, and pulmonary vascular resistance index. Results are expressed as a percentage of control. RESULTS By comparison with group 1 piglets (reoxygenation without a filter), hypoxic piglets undergoing reoxygenation with a leukocyte-depleting filter (group 2) had improved myocardial systolic function (88% vs 52%; p < 0.05), diastolic compliance (175% vs 275%; p < 0.05), and preload recruitable stroke work (91% vs 54%; p < 0.05); had better preservation of the arterial/alveolar ratio (97% vs 74%; p < 0.05); and had less increase in pulmonary vascular resistance (229% vs 391%; p < 0.05). Furthermore, leukocyte filtration prevented adenosine triphosphate depletion or a change in tissue antioxidants. Conversely, unprotected piglets (group 1) exhibited lower levels of adenosine triphosphate and significant loss of tissue antioxidants. Indeed, the results in the leukocyte-filtered piglets (group 2) were nearly identical to those of piglets subjected to bypass without hypoxia (controls). CONCLUSIONS (1) This study demonstrates that a major component of the injury that occurs when the hypoxic heart is abruptly reoxygenated is caused by oxygen radicals produced by white blood cells; (2) this injury can be prevented by a leukocyte-depleting filter; and (3) avoidance of this injury improves postbypass myocardial and pulmonary function. These data suggest that leukocyte depletion should be used routinely in all children undergoing operations for cyanotic heart disease or extracorporeal membrane oxygenation.

Detrimental Effects of Cardiopulmonary Bypass in Cyanotic Infants: Preventing the Reoxygenation Injury

BACKGROUND Recent experimental studies have shown that acute hypoxia followed by abrupt reoxygenation using cardiopulmonary bypass (CPB) results in an unintended injury mediated by oxygen free radicals, which can be modified by initiating CPB at a lower fraction of inspired oxygen (FiO2) or by leukocyte filtration. However, the clinical relevance of these experimental studies has been questioned because chronic hypoxia may allow compensatory changes to occur. METHODS Seven acyanotic infants had CPB initiated at an FiO2 of 1.0. Of 21 cyanotic infants, 7 (group 1) had CPB initiated at an FiO2 of 1.0, 6 (group 2) at an FiO2 of 0.21, and 8 (group 3) underwent CPB using leukocyte filtration. Biopsy of right atrial tissue was performed before and 10 to 20 minutes after the initiation of CPB. The tissue was incubated in 4-mmol/L t-butylhydroperoxide (a strong oxidant), and the malondialdehyde (MDA) level was measured to determine the antioxidant reserve capacity. The more MDA produced, the greater was the depletion of tissue antioxidants secondary to oxygen free radical formation during reoxygenation. RESULTS There was no difference in the prebypass antioxidant reserve capacity between cyanotic and acyanotic hearts (492 +/- 72 versus 439 +/- 44 nmol MDA/g protein). However, after the initiation of CPB without leukocyte filtration, MDA production rose markedly in the cyanotic (groups 1 and 2) as compared with the acyanotic hearts (322% versus 40%; p < 0.05), indicating a depletion of antioxidants. In cyanotic hearts, initiating CPB at an FiO2 of 1.0 (group 1) resulted in increased MDA production (407% versus 227%) as compared with hearts in which CPB was initiated at an FiO2 of 0.21 (group 2), indicating a greater generation of oxygen free radicals in group 1. Conversely, there was only a minimal increase in MDA production in 8 of the 21 infants (group 3) in whom white blood cells were effectively filtered (19% versus 322%; p < 0.05). CONCLUSIONS First, increased amounts of oxygen free radicals are generated in cyanotic infants with the initiation of CPB. Second, this production is reduced by initiating CPB at an FiO2 of 0.21 or by effectively filtering white blood cells. Third, these changes parallel those seen in the acute experimental model, validating its use for future study.

Controlled Reperfusion After Lung Ischemia: Implications For Improved Function After Lung Transplantation

OBJECTIVES Despite improvements in organ preservation, reperfusion injury remains a major source of morbidity and mortality after lung transplantation. This pilot study was designed to investigate the effects of controlled reperfusion after lung ischemia. METHODS Twenty adult pigs underwent 2 hours of warm lung ischemia by crossclamping the left bronchus and pulmonary artery. In five (group 1), the clamp was simply removed at the end of ischemia (uncontrolled reperfusion). The 15 other pigs underwent modified reperfusion using blood from the femoral artery to perfuse the lung through the pulmonary artery (pressure 40 to 50 mm Hg) for 10 minutes before removing the pulmonary artery clamp. In five (group 2), the blood was mixed with crystalloid, resulting in a substrate-enriched, hypocalcemic, hyperosmolar, alkaline solution. In five (group 3), the blood was circulated through a leukocyte-depleting filter, and the last five (group 4) underwent reperfusion with both a modified solution and white blood cell filter. Lung function was assessed 60 minutes after reperfusion, and biopsy specimens were taken. RESULTS Controlled reperfusion with both a white blood cell filter and modified solution (group 4) completely eliminated the reperfusion injury that occurred with uncontrolled reperfusion (group 1), resulting in complete preservation of compliance (98% +/- 1% vs 77% +/- 1%; p < 0.001, and arterial/alveolar ratio (97% +/- 2% vs 27% +/- 2%; p < 0.001); no increase in pulmonary vascular resistance (106% +/- 1% vs 198% +/- 1%; p < 0.001); lowered tissue edema (82.1% +/- 0.4% vs 84.3% +/- 0.2%; p < 0.001), and myeloperoxidase activity (0.18 +/- 0.02 vs 0.35 +/- 0.02 deltaOD/min/mg protein; p < 0.001). In contrast, using either a white blood cell filter or modified solution separately improved but did not avoid the reperfusion injury, resulting in pulmonary function and tissue edema levels that were intermediate between group 1 (uncontrolled reperfusion) and group 4 (white blood cell filter and modified solution). CONCLUSION After 2 hours of warm pulmonary ischemia, (1) a severe lung injury occurs after uncontrolled reperfusion, (2) controlled reperfusion with either a modified reperfusion solution or white blood cell filter limits, but does not avoid, a lung reperfusion injury, (3) reperfusion using both a modified reperfusate and white blood cell filter results in complete preservation of pulmonary function. We therefore believe surgeons should control the reperfusate after lung transplantation to improve postoperative pulmonary function.

Myocardial protection in normal and hypoxically stressed neonatal hearts: The superiority of hypocalcemic versus normocalcemic blood cardioplegia ☆ ☆☆ ★ ★★ ♢ ♢♢ ♦

OBJECTIVES The ideal cardioplegic calcium (Ca+2) concentration in newborns continues to be debated. Most studies examining cardioplegia calcium concentrations have been done with a nonclinical model (i.e., isolated heart preparation), the results of which may not be clinically applicable, and they have not examined the effect of calcium concentration in a clinically relevant stressed (hypoxic) heart. METHODS Twenty neonatal piglets 5 to 18 days old were placed on cardiopulmonary bypass, and their aortas were crossclamped for 70 minutes with hypocalcemic or normocalcemic multidose blood cardioplegic infusions. Group 1 (n = 5; low Ca+2, 0.2 to 0.4 mmol/L) and group 2 (n = 5; normal Ca+2, 1.0 to 1.3 mmol/L) were nonhypoxic (uninjured) hearts. Ten other piglets were first ventilated at an FiO2 of 8% to 10% (O2 saturation 65% to 70%) for 60 minutes (i.e., causing hypoxia) and then reoxygenated at an FiO2 of 100% with cardiopulmonary bypass, which produces a clinically relevant stress injury. They then underwent cardioplegic arrest (as described above) with a hypocalcemic (n = 5, group 3) or normocalcemic (n = 5, group 4) blood cardioplegic solution. Myocardial function was assessed with pressure volume loops and expressed as a percentage of control values. Coronary vascular resistance was measured during each cardioplegic infusion. All values were reported as the mean +/- standard error. RESULTS In nonhypoxic hearts (groups 1 and 2), good myocardial protection was achieved at either concentration of cardioplegia calcium, as demonstrated by preservation of postbypass systolic function (104% vs 99% end-systolic elastance), minimally increased diastolic stiffness (152% vs 162%), no difference in myocardial water (78.9% vs 78.9%), and no change in adenosine triphosphate levels or coronary vascular resistance. Low-calcium blood cardioplegia solution repaired the hypoxic reoxygenation injury in stressed hearts (group 3), resulting in no statistical difference in myocardial function, coronary vascular resistance, or adenosine triphosphate levels compared with nonhypoxic hearts (groups 1 and 2). Conversely, when a normocalcemic cardioplegia solution was used in hypoxic hearts (group 4), there was marked reduction in postbypass systolic function (49% +/- 4% end-systolic elastance; p < 0.05), increased diastolic stiffness (276% +/- 9%; p < 0.05), increased myocardial water (80.1% +/- 0.2%; p < 0.05), rise in coronary vascular resistance (p < 0.05), and lower adenosine triphosphate levels compared with groups 1, 2, and 3. CONCLUSIONS This study demonstrates that, in the clinically relevant, intact animal model, good myocardial protection is independent of cardioplegia calcium concentration in nonhypoxic (noninjured) hearts; hypoxic (stressed) hearts are extremely sensitive to the cardioplegic calcium concentration; and normocalcemic cardioplegia is detrimental to neonatal myocardium subjected to a preoperative hypoxic stress.

The Importance of Cardioplegic Infusion Pressure in Neonatal Myocardial Protection

BACKGROUND Cardioplegia infusion pressure is usually not directly monitored during neonatal heart operations. We hypothesize that the immature newborn heart may be damaged by even moderate elevation of cardioplegic infusion pressure, which in the absence of direct aortic monitoring may occur without the surgeons knowledge. METHODS Twenty neonatal piglets received cardiopulmonary bypass and the heart was protected for 70 minutes with multidose blood cardioplegia infused at an aortic root pressure of 30 to 50 mm Hg (low pressure) or 80 to 100 mm Hg (high pressure). Group 1 (n = 5, low pressure), and group 2 (n = 5, high pressure) were uninjured (nonhypoxic) hearts. Group 3 (n = 5, low pressure) and group 4 (n = 5, high pressure) first underwent 60 minutes of ventilator hypoxia (FiO2 8% to 10%) before initiating cardiopulmonary bypass to produce a clinically relevant hypoxic stress before cardiac arrest. Function was assessed using pressure volume loops (expressed as a percentage of control), and coronary vascular resistance was measured with each cardioplegic infusion. RESULTS In nonhypoxic (uninjured) hearts (groups 1 and 2) cardioplegic infusion pressure did not significantly affect systolic function (end systolic elastance, 104% versus 96%), preload recruitable stroke work (102% versus 96%) diastolic compliance (152% versus 156%), or coronary vascular resistance but did raise myocardial water (78.9% versus 80.1%; p < 0.01). Conversely, if the cardioplegic solution was infused at even a slightly higher pressure in hypoxic hearts (group 4), there was deterioration of systolic function (end systolic elastance, 28% versus 106%) (p < 0.001) and preload recruitable stroke work (31% versus 103%; p < 0.001), rise in diastolic stiffness (274% versus 153%; p < 0.001), greater myocardial edema (80.5% versus 79.6%), and marked increase in coronary vascular resistance (p < 0.001) compared to hypoxic hearts given cardioplegia at low infusion pressures (group 3), which preserved function. CONCLUSIONS Hypoxic neonatal hearts are very sensitive to cardioplegic infusion pressures, such that even moderate elevations cause significant damage resulting in myocardial depression and vascular dysfunction. This damage is avoided by using low infusion pressures. Because small differences in infusion pressure may be difficult to determine without a direct aortic measurement, we believe it is imperative that surgeons directly monitor cardioplegia infusion pressure, especially in cyanotic patients.