Adenosine-supplemented blood cardioplegia attenuates postischemic dysfunction after severe regional ischemia.

BACKGROUND: Various studies have reported that the administration of adenosine (ADO) in cardioplegia reduces myocardial ischemic injury, but this timing may not utilize ADO's potential against myocardial reperfusion injury. This study tested the hypothesis that ADO-supplemented blood cardioplegia (BCP) or ADO administered during reperfusion reduces postischemic dysfunction after severe regional ischemia. METHODS AND RESULTS: After 75 minutes of left anterior descending coronary artery occlusion, total cardiopulmonary bypass was initiated; cold (4 degrees C) antegrade BCP (8:1 blood:crystalloid) was delivered every 20 minutes for the first 3 doses, and 27 degrees C BCP was delivered for the terminal infusion. Dogs (n=6 per group) received unsupplemented BCP, ADO (100 micromol/L/L) supplemented in all infusions of BCP (ADO-CP), or ADO (100 micromol x L(-1) x L(-1)) supplemented only in the terminal infusion of BCP followed by intravenous ADO (140 microg x kg(-1) x min(-1)) infusion for the first 30 minutes of reperfusion (ADO-R). Postischemic regional systolic shortening was significantly greater in the ADO-R group (5+/-2.0%) than in the BCP group (-3+/-1.0%), but not in the ADO-CP group (2+/-0.2%). Postischemic regional diastolic stiffness in the area at risk during end reperfusion was lower with ADO-R (1.8+/-0.3%) than with ADO-CP (2.7+/-0.3%) or BCP (4.4+/-0.5%). Infarct size was reduced in the ADO-CP (29+/-2%) and ADO-R (21+/-2%) groups compared with the BCP group (42+/-4%). Edema in the myocardial area at risk was decreased in the ADO-CP (82+/-0.2%) and ADO-R (80+/-0.4%) groups compared with the BCP group (86+/-0.7%). Adherence of fluorescently labeled neutrophils (PMNs) to postischemic coronary artery endothelium was attenuated by ADO-R (55+/-2 PMNs/mm(2)), but not by ADO-CP (114+/-5 PMNs/mm(2)), compared with BCP (118+/-3 PMNs/mm(2)). CONCLUSIONS: The results show that BCP supplemented with ADO reduces infarct size, preserves postischemic systolic and diastolic regional function but does not attenuate coronary artery endothelial dysfunction unless administered during reperfusion.

Peroxynitrite, the breakdown product of nitric oxide, is beneficial in blood cardioplegia but injurious in crystalloid cardioplegia.

BACKGROUND: Peroxynitrite (ONOO(-)) has been implicated as a primary mediator in the deleterious effects of nitric oxide (NO) in crystalloid solutions, possibly due to a lack of detoxification mechanisms, leading to the formation of.OH. In contrast, ONOO(-) may exert cardioprotective effects in blood environments secondary to detoxification and the subsequent formation of NO-donating nitrosothiols. This dichotomy in physiological effects of ONOO(-) may exist between crystalloid and blood cardioplegia (BCP) environments. In the present study, we tested the hypothesis that ONOO(-) is cardiotoxic in crystalloid cardioplegia but cardioprotective in BCP in ischemically injured hearts. METHODS AND RESULTS: In anesthetized dogs on cardiopulmonary bypass, global 37 degrees C ischemia was imposed for 30 minutes, followed by 60 minutes of intermittent 4 degrees C hyperkalemic crystalloid (Plegisol) or BCP with (+) or without (-) 5 micromol/L authentic ONOO(-). After 2 hours of reperfusion, left ventricular (LV) function (end-systolic pressure-volume relations, in percent of baseline) was 56+/-3% in Plegisol-, which was further reduced in Plegisol+ to 40+/-4%.* In contrast, postischemic systolic function was better in BCP+ groups than in BCP- groups (96+/-2%* versus 82+/-2%, respectively). Differences in functional recovery could not be attributed to differences in hemodynamics. LV end-diastolic stiffness was significantly increased with the addition of ONOO(-) in both Plegisol (298+/-26% versus 466+/-30%*) and BCP (201+/-22% versus 267+/-13%*) groups. Consistent with increased LV chamber stiffness, myocardial edema was increased in BCP+ compared with BCP- (78.9+/-0.3% versus 76.4+/-0.3%*) and in Plegisol+ compared with Plegisol- (81.1+/-0.3% versus 79.6+/-0.4%*). Creatine kinase activity was significantly increased in Plegisol+ (48+/-6) compared with that in Plegisol- (31+/-6) but was unchanged in BCP- (14+/-2) relative to BCP+ (18+/-1). Nitrotyrosine (ng/mg protein) accumulation in LV myocardial biopsy samples confirmed myocardial exposure to ONOO(-) or its metabolites (Plegisol- 1.2+/-0.1, Plegisol+ 3.31+/-0.3*, BCP- 1.4+/-0.2, BCP+ 2.9+/-0.2*). CONCLUSIONS: We conclude that (1) the postcardioplegic cardiodynamic effects of ONOO(-) depend on its environment and (2) ONOO(-) in crystalloid solution impairs postcardioplegia systolic and diastolic functional recovery, whereas (3) ONOO(-) in BCP increases functional recovery. This environment-dependent dichotomy in the effect of ONOO(-) may affect the benefits of NO-related adjuncts to crystalloid or BCP solutions (*P<0.05 versus group without ONOO(-)). :II-384-II-391.)

Recombinant human megakaryocyte growth and development factor attenuates postbypass thrombocytopenia.

BACKGROUND: Cardiopulmonary bypass contributes to platelet loss and dysfunction by exposure to shear stresses, foreign surfaces, and hypothermia. This study tested the hypothesis that pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) accelerates recovery of the platelet population after hypothermic extracorporeal circulation (HEC). METHODS: In a blinded study, subcutaneous injections of drug or placebo were given to dogs daily for 3 days preoperatively (day 0, 1, and 2) with no drug on day 3. On day 4, the animal was prepared for arteriovenous HEC. After heparinization, HEC was initiated at 30 to 40 mL x kg(-1) x min(-1). Hypothermic extracorporeal circulation (25 degrees C) was continued for 90 minutes. RESULTS: Preoperative platelet count (x10(3) platelets/microL) did not differ from predrug count in placebo (256+/-27 versus 255+/-20) or PEG-rHuMGDF (271+/-30 versus 291+/-38). During 60 minutes of HEC, the platelet count decreased to approximately 10% of baseline in placebo (29+/-5) and PEG-rHuMGDF (46+/-8), and recovered to approximately 70% of baseline after rewarming (90 minutes of HEC: placebo, 185+/-17, versus PEG-rHuMGDF, 169+/-22). After HEC, platelet count was greater in PEG-rHuMGDF-treated animals (p < 0.05) without altering function (aggregation responses). Within the first 6 hours after HEC, platelet count in PEG-rHuMGDF-treated animals was rising and increased to 260+/-29 (p < 0.01), but was unchanged in placebo animals (186+/-21). Thereafter, platelet count in placebo animals declined to a nadir of 124+/-15 (72 hours after HEC), whereas platelet count in PEG-rHuMGDF animals approximated the preoperative value (>200) at all times. CONCLUSIONS: Appropriately timed presurgical administration of PEG-rHuMGDF counteracts post-HEC relative thrombocytopenia without increasing platelet population and enhancing aggregation preoperatively or during extracorporeal circulation.

Successful treatment of empyema thoracis with polymethylmethacrylate antibiotic-impregnated beads in the guinea pig.

Two hundred nine Duncan-Harley guinea pigs had intrathoracic inoculation with 10(8) Staphylococcus aureus, accompanied by blood and umbilical tape. One hundred fifty-two animals were excluded because of clinical recovery, early death, or complications related to intrathoracic polymethylmethacrylate (PMMA) bead placement. The remaining 57 animals had clinical signs of empyema thoracis and were the subjects of this study. Group I animals (N = 24) served as the controls and had no therapy. Group II animals (N = 14) were treated by intrathoracic placement of placebo PMMA beads. Group III animals (N = 19) were treated by intrathoracic placement of tobramycin sulfate-impregnated PMMA beads. There were no differences between the groups in pleural reaction or pneumonia scores. These findings demonstrate a similar host response to the established infection. Group III, however, had a higher sterilization rate than Groups I and II (p less than 0.05), a finding underlining the therapeutic effect of tobramycin-treated PMMA beads. We conclude that intrathoracic local antimicrobial therapy with slow-release tobramycin-impregnated PMMA beads may enhance empyema treatment by increasing the rate of local sterilization. More experiments are necessary to assess the efficacy of this potentially important therapeutic arm for the treatment of thoracic empyema.

Myocardial preservation in the neonate. Beneficial effects of cardioplegia and systemic hypothermia on piglets undergoing cardiopulmonary bypass and myocardial ischemia.

This study examined anatomic differences between the adult and the newborn heart as they relate to myocardial preservation and compared standard techniques of myocardial preservation used in operations for congenital heart disease. The biventricular endocardial surface area/ventricular mass ratios were calculated in 10 neonatal (2.5 +/- 0.2:1) and 10 adult (0.6 +/- 0.1:1) pigs (p less than 0.001). Three groups of neonatal pigs underwent 1 hour of global myocardial ischemia while being supported by cardiopulmonary bypass. Myocardial protection was by deep systemic hypothermia (group 1), moderate systemic hypothermia and cardioplegia (group 2), or by deep systemic hypothermia and cardioplegia (group 3). Left ventricular end-systolic pressure-dimension and end-diastolic pressure-dimension relationships were measured before and after cardiopulmonary bypass. Septal temperatures remained below 20 degrees C in groups 1 and 3 but rose above 20 degrees C in group 2. Groups 1 and 2 had moderate and mild ventricular stiffening, respectively, whereas group 3 showed no diastolic dysfunction. Ventricular contractility was increased (p less than 0.05) in group 3. Techniques for myocardial preservation used during operations for congenital heart disease must consider the large endocardial surface area/mass ratio and the rewarming effects of systemic blood. The combination of deep systemic hypothermia and cardioplegia provided superior myocardial protection compared with the other techniques tested.

The comparative clearance rates of the pleural and peritoneal cavities.

We compared the rates of bacterial clearance from the pleural and peritoneal cavities of rats after contamination with 1 x 10(6) live Escherichia coli. Pleural clearance was enhanced beginning at 30 minutes after injection and extended to at least six hours. At 24 hours, the clearance was similar for both the pleural and peritoneal groups. Blood and organ bacterial cultures were similar between these two groups. White blood cell populations were similar at rest, but there was a greater increase in the leukocyte population in the pleural cavity six hours after E coli stimulation. We postulate that the increased clearance of E coli from the pleural cavity may be due to differences in lymphatic absorption, recruitment of leukocytes, or fibrin trapping of bacteria.

Blood flow distribution in infant pigs subjected to surface cooling, deep hypothermia, and circulatory arrest. Deleterious effects in pigs with left-to-right shunts.

Surface cooling, deep hypothermia and circulatory arrest have been used effectively for correction of congenital heart defects in infancy. Which patients are best suited for this technique has not been addressed. The addition of surface cooling to deep hypothermia and circulatory arrest provides homogeneous cooling and avoids swelling due to reperfusion injury after circulatory arrest. However, surface cooling in patients with large left-to-right shunts causes increased peripheral resistance and increased shunting which can result in decreased perfusion of vital organs. The purpose of this study is to measure the effect of a large left-to-right shunt on total organ blood flow distribution in infant piglets during surface cooling, deep hypothermia, and circulatory arrest. Eleven 2-week-old piglets had surface cooling, deep hypothermia, and circulatory arrest for 45 minutes, followed by rewarming and weaning from cardiopulmonary bypass. Microspheres (15 mu) were injected before surface cooling, at 28 degrees C, at 15 degrees C, and after weaning from cardiopulmonary bypass. Group I (five piglets) was the control. Group II (six piglets) had a large (6 mm) left-to-right aortopulmonary shunt established before microsphere injection. Cardiac outputs in both Groups I and II decreased with surface cooling. The distribution of cardiac output in Group I did not change with surface cooling; however, Group II pigs showed marked change in distribution of cardiac output, resulting in decreased renal, visceral, and pulmonary flow (p less than 0.05). Amylase determinations before and after surface cooling, deep hypothermia, and circulatory arrest were unchanged in Group I but elevated in Group II (p less than 0.05). These observations suggest altered cellular metabolism in visceral organs during the period of surface cooling which may be compounded by circulatory arrest and rewarming.