Biomedical subjects

M Kronon

Publications and source records attributed to M Kronon.

9 recordsLinked to original sources

PubMed1998

Controlled reperfusion prevents pulmonary injury after 24 hours of lung preservation.

BACKGROUND: Posttransplantation lung reperfusion injury continues to be a major problem. We have shown that controlling the initial period of reperfusion limits this injury after 2 hours of warm lung ischemia. The effectiveness of this modality, however, is unknown after longer periods of cold ischemia, which more closely mimics the clinical situation. METHODS: After baseline measurements, 10 pigs had the left lung flushed with a modified Euro-Collins solution, explanted, stored at 4 degrees C for 24 hours, and transplanted into 10 other pigs. Five (group 1) underwent uncontrolled reperfusion created by removal of the vascular clamps after implantation of the new left lung, mimicking the clinical situation. The other five (group 2) underwent controlled reperfusion, which we performed by taking blood from the femoral artery, mixing it with a crystalloid solution (using a mixer heater) to make the blood hyperosmolar, alkalotic, and substrate-enriched, and pumping it through a leukocyte-depleting filter into the transplanted lung for 10 minutes at a pressure of 20 to 30 mm Hg before removing the pulmonary artery clamp. The right pulmonary artery and bronchus were then ligated, and left lung function was assessed each hour for 4 hours and compared with baseline. RESULTS: Controlled reperfusion (group 2) minimized the reperfusion injury, preserving posttransplant pulmonary compliance (92% +/- 1% versus 68% +/- 1%; p < 0.001), reducing the rise in pulmonary vascular resistance (27% +/- 2% versus 166% +/- 3%; p < 0.001), improving oxygenation (PO2, 425 +/- 14 versus 82 +/- 11 mm Hg; p < 0.001), and lowering myeloperoxidase activity (0.22 +/- 0.02 versus 0.45 +/- 0.02 deltaOD/mg protein per minute; p < 0.001) and tissue edema (83.0% +/- 0.3% versus 84.9% +/- 0.3%; p < 0.001) compared with uncontrolled reperfusion, which resulted in an injury so severe that 3 of 5 pigs died before the 4-hour measurements. CONCLUSIONS: After 24 hours of cold ischemia uncontrolled reperfusion results in a severe pulmonary reperfusion injury. This injury is almost completely avoided by controlling the composition (modified solution and white blood cell filter) and conditions (pressure) of the reperfusion. Because this experiment mimics the clinical situation, it suggests surgeons should begin to use this modality to limit reperfusion injury after lung transplantation.

Animals↗

PubMed1998

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 surgeon's 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.

Animals↗

PubMed1998

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.

Animals↗

PubMed1997

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.

Antioxidants↗

PubMed1997

The relationship between calcium and magnesium in pediatric myocardial protection.

OBJECTIVE: We previously demonstrated that calcium can be harmful to the hypoxic neonatal heart. Despite the fact that magnesium inhibits membrane transport of calcium, few studies have examined whether magnesium can prevent the deleterious effects of calcium in cardioplegic solutions. METHODS: Twenty neonatal piglets (5 to 18 days old) underwent 60 minutes of ventilator hypoxia (inspired oxygen fraction 8% to 10%) followed by reoxygenation with the use of cardiopulmonary bypass before cardioplegic arrest to produce a clinically relevant hypoxic "stress" injury. The aorta was then crossclamped for 70 minutes with multidose blood cardioplegia. Ten piglets received a hypocalcemic (0.2 to 0.4 mmol/L) cardioplegic solution without (group 1, n = 5) or with magnesium (10 mEq/L) (group II, n = 5) supplementation. Ten other piglets were protected with a normocalcemic (1.0 to 1.2 mmol/L) cardioplegic solution without (group III, n = 5) or with magnesium (group IV, n = 5). Myocardial function was assessed by means of pressure volume loops and expressed as a percentage of control. Coronary vascular resistance was assessed during each cardioplegic infusion. RESULTS: Adding magnesium to a hypocalcemic cardioplegic solution (groups I and II) had no effect: Both groups had complete preservation of postbypass systolic function (end-systolic elastance 101% vs 104%) and preload recruitable stroke work (101% vs 102%), minimal increase in diastolic stiffness (159% vs 153%), and no difference in myocardial tissue edema (78.8% vs 78.9%) or coronary vascular resistance. Conversely, when a normocalcemic cardioplegic solution was administered without magnesium supplementation (group III), the results were markedly poorer than results obtained with magnesium supplementation (group IV). Without magnesium, there was a marked reduction in postbypass systolic function (end-systolic elastance 49% vs 101%; p < 0.05), increased diastolic stiffness (276% vs 162%; p < 0.05), decreased preload recruitable stroke work (53% vs 102%; p < 0.05), increased myocardial tissue edema (80.0% vs 78.9%; p < 0.05), and a rise in coronary vascular resistance (p < 0.05). Magnesium supplementation of the normocalcemic cardioplegic solution, by contrast, resulted in complete functional recovery. CONCLUSIONS: This study demonstrates that (1) magnesium does not alter the cardioprotective effects of a hypocalcemic cardioplegic solution, (2) a normocalcemic cardioplegic solution is detrimental to neonatal myocardium subjected to a previous hypoxic stress, and (3) magnesium supplementation of normocalcemic cardioplegic solutions prevents the deleterious effects of calcium.

Animals↗

PubMed1997

Myocardial protection in normal and hypoxically stressed neonatal hearts: the superiority of blood versus crystalloid cardioplegia.

OBJECTIVES: Blood cardioplegia predominates in the adult because it provides superior myocardial protection, especially in the ischemically stressed heart. However, the superiority of blood over crystalloid cardioplegia in the pediatric population is unproved. Furthermore, because many pediatric hearts undergo a preoperative stress such as hypoxia, it is important to compare the different methods of protection in both normal and hypoxic hearts. METHODS: Twenty neonatal piglets were supported by cardiopulmonary bypass and subjected to 70 minutes of cardioplegic arrest. Of 10 nonhypoxic hearts, five (group 1) were protected with blood cardioplegia and five (group 2) with crystalloid cardioplegia (St. Thomas' Hospital solution). Ten other piglets underwent 60 minutes of ventilator hypoxia (inspired oxygen concentration 8% to 10%) before cardioplegic arrest. Five (group 3) were then protected with blood cardioplegia and the other five (group 4) with crystalloid cardioplegia. Myocardial function was assessed by means of pressure volume loops and expressed as a percentage of control. Coronary vascular resistance was measured with each infusion of cardioplegic solution. RESULTS: No difference was noted between blood (group 1) or crystalloid cardioplegia (group 2) in nonhypoxic hearts regarding systolic function (end-systolic elastance 104% vs 103%), diastolic stiffness (156% vs 159%), preload recruitable stroke work (102% vs 101%), or myocardial tissue edema (78.9% vs 78.9%). Conversely, in hearts subjected to a hypoxic stress, blood cardioplegia (group 3) provided better protection than crystalloid cardioplegia (group 4) by preserving systolic function (end-systolic elastance 106% vs 40%; p < 0.05) and preload recruitable stroke work (103% vs 40%; p < 0.05); reducing diastolic stiffness (153% vs 240%; p < 0.05) and myocardial tissue edema (79.6% vs 80.1%); and preserving vascular function, as evidenced by unaltered coronary vascular resistance (p < 0.05). CONCLUSION: This study demonstrates that (1) blood or crystalloid cardioplegia is cardioprotective in hearts not compromised by preoperative hypoxia and (2) blood cardioplegia is superior to crystalloid cardioplegia in hearts subjected to the preoperative stress of acute hypoxia.

Animals↗

PubMed1997

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.

Adenosine Triphosphate↗

PubMed1996

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.

Animals↗

PubMed1996

Peripheral vascular disease in spinal cord injury patients: a difficult diagnosis.

The timely detection of peripheral vascular disease (PVD) in spinal cord injury (SCI) patients is difficult because the usual symptoms of claudication and rest pain are absent. In fact, the initial manifestation of PVD in SCI patients is often advanced gangrene, so that healing, primarily or following major amputation, is either difficult and prolonged or impossible. In addition, sacral and ischial pressure sores common among SCI patients may be exacerbated and reconstruction made more difficult by PVD. Five SCI patients presented with lower extremity gangrene as the initial recognized manifestation of PVD at our institution between January 1992 and January 1994. All 5 patients had risk factors for PVD. Four out of ten limbs in these patients required amputation, either above the knee or below the knee. Three patients required concurrent vascular reconstruction of the aortoiliac segments, including an aortobiprofunda femoral bypass, an iliac embolectomy with femoral-femoral bypass, and iliac angioplasty. Three patients had ischial and/or sacral pressure sores that had recurred following multiple musculocutaneous flap reconstructions before vascular disease was recognized. The timely diagnosis of PVD involving the iliac segment in the SCI patient is sometimes overlooked and is often necessary to optimize the treatment of both lower extremity ulcers and sacral/ ischial pressure sores common among these patients.

Adult↗