Use of nesiritide (human B-type natriuretic peptide) in infants following cardiac surgery.

We report the use of nesiritide in two infants following cardiac surgery. Both infants had increased intracardiac filling pressures postoperatively, despite traditional afterload reduction and diuretics. Both infants demonstrated clinical improvement with nesiritide therapy. There is currently limited data available describing the use of nesiritide in infants.

Neurodevelopmental outcomes in children after the fontan operation.

BACKGROUND: Previous studies of patients after the Fontan operation have reported IQ scores lower than population norms. In the past decade, changes have occurred both in surgical methods used and in the patient population undergoing Fontan palliation. The present study examined the impact of these changes on neurodevelopmental outcomes after Fontan. METHODS AND RESULTS: Neuropsychological tests were administered to 27 five-year-old children after Fontan. Mean age at repair was 2 years 4 months. The present sample was compared with an earlier Fontan group (EFG) of 133 patients who underwent surgery in the 1970s and 1980s. Mean age at repair for the EFG was 7 years 3 months. Compared with EFG, the present study sample was younger at Fontan (P=0.0001) and more likely to have undergone a Norwood procedure (P=0.02), a pre-Fontan bidirectional cavopulmonary anastomosis (P<0.001), and Fontan fenestration (P=0.001). Although mean full-scale, verbal, and performance IQ scores were within 1 SD (15 points) of the population mean of 100 (93+/-16, 95+/-15, and 91+/-17, respectively), mean full-scale and performance IQ scores were significantly lower than this population mean (P=0.03 and P=0.01, respectively). CONCLUSIONS: Compared with a historical cohort of Fontan patients from this institution, a staged approach to Fontan earlier in life is not detrimental to neurodevelopmental outcome. Neurodevelopmental outcomes in children after Fontan are in the normal range, but performance remains lower than the general population.

Effects of Hot shot on recovery after hypothermic ischemia in neonatal lamb heart.

BACKGROUND: Terminal warm blood cardioplegia, "Hot shot", is the method for providing an energy replenishment and/or early recovery of aerobic metabolism without electromechanical activity at initial reperfusion. The mechanism of beneficial effects of this Hot Shot is multifactorial. This study was designed to assess the effects of terminal warm blood cardioplegia by comparing with oxygenated terminal warm crystalloid cardioplegia. METHODS: In Group HS-B, n=8 (oxygenated blood; 37 degrees C, Ht: 20%, K+ 20 mEq/l, pH 7.237, PO2 219 mmHg) and in Group HS-C, n=8 (bloodless oxygenated (5% CO2+95%O2) crystalloid, 37 degrees C, K+ 20 mEq/l, pH 7.435, PO2 624 mmHg), terminal warm cardioplegia (20 ml/kg for 5 minutes) was studied in the isolated blood perfused neonatal lamb heart following 2 hr of cardioplegic ischemia. Another eight hearts served as control without any kind of terminal cardioplegia. After 60 min of reperfusion, LV function was measured. Coronary blood flow (CBF), oxygen content, and oxygen consumption (MVO2) were measured and the oxygen extraction ratio was calculated in Group HS-B and HS-C during terminal cardioplegia and/or reperfusion. Results are given as % recovery of preischemic values. RESULTS: HS-B as well as HS-C groups showed better functional recovery in maximum developed pressure (DP: 78.0+/-8.3 in HS-B vs 65.2+/-9.2%; p=0.018), maximum dp/dt (67.3+/-6.2 in HS-B, 65.3+/-7.4 in HS-C vs 55.8+/-5.0%; p=0.003, p=0.02), DP V10 (87.1+/-8.5 in HS-B vs 67.2+/-9.9%; p=0.0001), and peak dp/dt V10 (76.4+/-7.6 in HS-B, 69.8+/-8.1 in HS-C vs 58.6+/-6.9 %; p=0.0001) than the control group. Between the HS-B and HS-C groups, HS-B showed better functional recovery in terms of DP V10 (p=0.01). Oxygen delivery of terminal cardioplegia was almost four times higher in HS-B group (90.4+/-17.7 vs 18.7+/-1.1 mcl/ml), contrarily, HS-C group showed four times higher oxygen extraction ratio compared to HS-B group (0.78+/-0.06 vs 0.18+/-0.11), thus oxygen consumption during hot shot was maintained at the same level in both groups. CBF in the control group was lower than that in the other groups at 60 min of reperfusion. CONCLUSIONS: Reperfusion with both terminal warm cardioplegia including blood and oxygenated crystalloid cardioplegia resulted in better recovery of function and higher levels of CBF with slightly better function in terminal warm blood cardioplegia.

Cryopreserved homografts in the pulmonary position: determinants of durability.

BACKGROUND: The cryopreserved homograft has emerged as the pulmonary conduit of choice for the repair of many congenital heart defects. It is also used for pulmonary valve replacement in the Ross procedure. Because of a wide range of patient ages and diagnoses, the risk of homograft failure may vary. METHODS: We reviewed 185 consecutive pulmonary position implants performed between September 1985 and January 1999. We examined three age groups: patients less than 1 year of age (n = 53), patients 1 to 10 years of age (n = 46), and patients more than 10 years of age (n = 86). RESULTS: Five-year Kaplan-Meier homograft survival was 25%, 61%, and 81% for the groups, respectively (p < 0.02). Smaller homograft size, younger patient age, and truncus arteriosus were risk factors for homograft failure in univariate analysis (p < 0.05). Smaller homograft size was the only predictor for homograft failure in multivariate analysis (p < 0.001). Twenty of 99 implants in patients less than 10 years old underwent transcatheter intervention. The 3-year Kaplan-Meier implant survival of this group (79%) was not different from those who did not undergo intervention (77%, p = 0.84). Survival of aortic and pulmonary homografts in patients less than 10 years of age was not different (p = 0.35). Ross procedure implants appear to have optimal survival (94%) at 5 years. Non-Ross implants in patients more than 10 years of age have 76% 5-year Kaplan-Meier survival, which is not different from Ross patients (p = 0.33). CONCLUSIONS: Small homografts have limited durability. Aortic homografts perform as well as pulmonary homografts in young patients. Once patients receive an "adult-size" homograft, at approximately 10 years of age, risk for implant failure approximates that of patients undergoing the Ross procedure. Transcatheter interventions, when indicated, may prolong homograft life.

Minimally invasive cardioverter defibrillator implantation for children: an animal model and pediatric case report.

The smaller venous capacitance in infants and small children may hamper transvenous ICD lead implantation, and epicardial approaches require thoracotomy and have associated complications. The study evaluated the feasibility and performance of subcutaneous arrays and active can ICDs without transvenous shocking coils or epicardial patches. An immature and mature pig were anesthetized and ventilated. A pacing lead was inserted in the right ventricle for fibrillation induction and rate sensing. Subcutaneous arrays were positioned in the right and left chest walls. An ICD emulator was placed in abdominal and prepectoral pockets. Fluoroscopic images were acquired for each electrical vector configuration (array --> can, can --> array, array --> array, array + array --> can). Ventricular fibrillation was induced and DFT testing performed. Defibrillation was achieved in all ten trials in the immature piglet, with DFT < or = 9 J, regardless of vector configuration. Using a single subcutaneous array and active can, the shock impedance ranged from 28-36 ohms. With two arrays, shocking impedance fell to 15-22 ohms. In the adult pig, defibrillation was not accomplished with maximum energy of 40 J, using all vector configurations. Using data garnered from these experiments, this technique was then successfully performed in a 2-year-old child with VT and repaired congenital heart disease, needing an ICD. This study demonstrates the feasibility of leadless ICD implantation in an immature animal and successful implementation in a small child. A single subcutaneous array and active can resulted in excellent implant characteristics and DFTs with a minimally invasive approach. Defibrillation was not possible in a larger animal, possibly due to maximal available energy. This may be of value for small children requiring ICD implantation.

Extracorporeal membrane oxygenation for infant postcardiotomy support: significance of shunt management.

BACKGROUND: After repair of complex congenital heart defects in infants and children, postcardiotomy cardiac failure requiring temporary circulatory support can occur. This is usually accomplished with the use of extracorporeal membrane oxygenation (ECMO). ECMO management of patients with single-ventricle physiology and aorto-pulmonary shunts can be particularly challenging. We retrospectively reviewed our experience with postcardiotomy support with particular attention to those children with single-ventricle palliation. METHODS: Thirty-five consecutive children (age 1 to 820 days, median 19 days) out of 1,020 patients (3.4%) required mechanical support (ECMO) after repair of congenital cardiac lesions from February 1994 to April 1999. Twenty-five patients underwent two ventricle repairs and 10 patients had single-ventricle palliation. Various parameters analyzed included strategies of shunt management, presence of presupport cardiac arrest, and timing of support initiation. RESULTS: Overall hospital survival for these 35 patients was 61%. There were four additional late deaths. Hospital survival was the same for those patients in whom support was initiated for failure to wean from cardiopulmonary bypass in the operating room versus those patients in whom support was initiated after successful separation from cardiopulmonary bypass (6 of 10 vs 15 of 25 or 60% survival). In those patients with shunt-dependent pulmonary circulation, survival was significantly improved in those patients in which the aorto-pulmonary shunt was left open (4 of 5 with open shunt vs 0 of 4 with occluded shunt (p = 0.048). CONCLUSIONS: The ability to readily implement postcardiotomy support is vital to the management of children with complex congenital cardiac disease. Overall survival can be quite satisfactory if support is employed in a rational and expedient manner. In patients with single-ventricle physiology and aorto-pulmonary shunts, leaving the shunt open during the period of support can result in markedly improved outcomes.

Myocardial self-preservative effect of heat shock protein 70 on an immature lamb heart.

BACKGROUND: Heat shock proteins have been shown to enhance myocardial tolerance of ischemia-reperfusion injury and are induced in the myocardium of many animals by various stressors. METHODS: To assess the effects and time course of the inducible form of heat shock protein 70, we raised the rectal temperature of 15 neonatal lambs to 43 degrees C for 15 minutes. At 15, 30, 60, and 120 minutes and 24 hours after heat shock, hearts were subjected to immunoblot analysis for heat shock protein (hsp 72/73). Twenty-four hours after heat shock, neonatal lamb hearts (n = 8) were subjected to 2 hours of cold cardioplegic ischemia (HSP group). Eight neonatal lamb hearts without heat shock served as control. After 60 minutes of reperfusion, left ventricular systolic and diastolic function, coronary blood flow (CBF), myocardial oxygen consumption (MVO2), and lactate levels were measured. Endothelial function was assessed by measuring in situ coronary vascular resistance response to acetylcholine and trinitroglycerine. RESULTS: The HSP group showed a significantly higher recovery of systolic function as well as MVO, and a lower lactate level compared to the control group at 60 minutes after reperfusion. Recovery of coronary endothelial function was also significantly better in the HSP group than in the control group. Inducible form of HSP 70 was expressed 15 minutes after heat shock and continued to be observed at 24 hours after the stress. CONCLUSIONS: Heat shock stress associated with the production of inducible heat shock proteins improved the recovery of ventricular function as well as endothelial function and aerobic metabolism after hypothermic cardioplegic ischemia. Induction of heat shock proteins by any means prior to planned hypothermic ischemia may lead to a new approach for myocardial protection.

Persistent left superior vena cava and partial anomalous pulmonary venous connection: incidental diagnosis by transesophageal echocardiography during coronary artery bypass surgery.

Transesophageal echocardiography plays an important role in the intraoperative treatment of the heart surgery patient. Its utility in the description of both known and unexpected cardiac pathology is well established. We describe a patient with a previously undiagnosed partial anomalous pulmonary venous connection along with a persistent left superior vena cava scheduled for routine coronary artery bypass graft surgery (CABG).

Valve replacement for appetite suppressant-induced valvular heart disease.

Valvular heart disease associated with the use of appetite-suppressant medication is a recently described clinical entity. Although the mechanism of valvular injury remains elusive pathologically, the valvular abnormalities resemble those observed in carcinoid syndrome. The incidence of clinically evident valvular heart disease is low with short-term (less than 3 months) exposure to appetite-suppressant drugs. Prolonged exposure to higher doses in addition to combination drug therapy confers an excess risk for valvular pathologic changes. We report the case of a patient with severe mitral regurgitation who had short-term exposure (3 weeks) to the combination of fenfluramine (20 mg) and phenteramine (15 mg).

Effects of adenosine infusion with or without leukocyte depletion on recovery after hypothermic ischemia in neonatal lamb hearts.

OBJECTIVE: Leukocytes have been shown to have an important role in ischemia/reperfusion injury. Adenosine also reduced this ischemia/reperfusion injury. There is an interaction between adenosine and leukocyte via receptor mediated function. To determine whether beneficial effects of adenosine on reperfusion injury is mediated by changes in leukocyte function, we studied the effects of adenosine with and without leukocyte depletion during reperfusion on the functional recovery of the neonatal myocardium after cold cardioplegic arrest. MATERIALS AND METHODS: We infused adenosine (350 micromol/l) during the first 20 min of reperfusion for adenosine treated group and adenosine-leukocyte treated group. The other two groups were perfused with leukocyte treated blood or untreated blood. All the groups were subjected to 2 h of cold cardioplegic ischemia (n = 8 in each group). At 30 min of reperfusion, LV function was measured. Coronary blood flow and oxygen consumption (MVO2) were also measured to evaluate the metabolic recovery. RESULTS: Adenosine treated, adenosine-leukocyte treated, and leukocyte treated groups showed better functional recovery than the control group (maximum developed pressure: control = 74.6 +/- 5.6%, adenosine treated = 97.6 +/- 9.5%, adenosine-leukocyte treated = 98.5 +/- 5.6%, leukocyte treated = 82.5 +/- 6.0%. P < 0.05). Both adenosine treated and adenosine-leukocyte treated groups showed better recovery than leukocyte treated group (P < 0.05). Coronary blood flow was higher in adenosine-leukocyte treated group compared to other groups (P < 0.05). MVO2/beat was higher in adenosine treated, adenosine-leukocyte treated, and leukocyte treated groups than control group (P < 0.05). CONCLUSION: Adenosine, with or without leukocyte depletion, had similar beneficial effect on recovery of systolic and diastolic functions, which involved other mechanisms in addition to the leukocyte inhibitory effect.

Relationship of blood flow effects of adenosine during reperfusion to recovery of ventricular function after hypothermic ischemia in neonatal lambs.

BACKGROUND: Previous experiments have shown that infusion of either adenosine (ADO) or an adenosine receptor agonist during reperfusion after hypothermic ischemia improved the recovery of ventricular function in neonatal lamb hearts. Adenosine has multiple actions that might be beneficial during postischemic reperfusion, and the A2 effects include both coronary vasodilator and leukocyte inhibitory effects. In the current experiment we investigated the relationship between the coronary blood flow (CBF) effects of A2 stimulation and the recovery of postischemic ventricular function. METHODS AND RESULTS: Two hours of 10 degrees C cardioplegic ischemia was induced in 40 isolated, blood-perfused, neonatal lamb hearts (n=8 in each group). Group I had ischemia followed by unmodified reperfusion for 90 minutes. During the first 20 minutes of reperfusion, Group II received 350 micromol/L ADO, Group III received ADO and 100 nmol/L DPCPX (A1 antagonist) to achieve an A2 effect, Group IV received 0.25 micromol/L CPCA (A2 agonist), and Group V received ADO and DPCPX but CBF was limited to that of Group I levels. At 30 and 90 minutes of reperfusion, LV maximum developed pressure (DP), dP/dt, CBF, and oxygen consumption (MVO2) were measured. At 30 minutes of reperfusion Groups II, III, and IV showed better functional recovery than Group I or Group V (DP: G-I=75.7+/-7.3%, G-II=97.6+/-9.5%, G-III=88.1+/-4.8%, G-IV=86.7+/-9.0%, G-V=75.5+/-6.9%, P<.05; dP/dt: G-I=69.1+/-9.6%, G-II=94.2+/-10.7%, G-III=95.7+/-13.1%, G-IV=80.1+/-11.1%, G-V=75.2+/-8.2%, P<.05). Coronary blood flow was higher in Groups II, III, and IV compared with Group I or V (G-1=129+/-32%, G-II=183+/-36%, G-III=266+/-72%, G-IV=259+/-70%, G-V=132+/-5%, P<.05). MVO2/beat was higher in Group II than in Groups I and IV (G-I=98.3+/-21.3%, G-II=135.5+/-28.0%, G-III=126.2+/-21.9%, G-IV=102.5+/-16.7%, G-V=107.5+/-29.3%, P<.05). At 90 minutes of reperfusion, Groups II, III, and IV, as well as V, showed better recovery of DP and dP/dt compared with Group I (DP: G-I=50.6+/-11.4%, G-II=63.0+/-8.7%, G-III=69.0+/-10.8%, G-IV=72.5+/-12.7%, G-V=66.2+/-10.0%, P<.05; dP/dt: G-I=38.9+/-7.1%, G-II=53.5 +/-3.8%, G-III=61.5+/-10.8%, G-IV=59.8+/-16.3%, G-V=58.2+/-9.8%, P<.05) although only in Groups III and IV was CBF higher than in Group I (G-1=116+/-54%, G-II=116+/-27%, G-III=210+/-67%, G-IV=239+/-85%, G-V=130+/-8%, P<.05). CONCLUSIONS: Reperfusion under conditions of A2 stimulation by ADO, by an A2 agonist, or by ADO plus A1 blockade was associated with improved recovery of LV function. The early A2 effect seems to be related to coronary vasodilation because reduced CBF (equal to Group I) in Group V reduced early recovery of LV function. However, there seems to be a second effect observed at 90 minutes that is not related to CBF inasmuch as Groups II and V had CBF equal to Group I but had significantly higher DP and dP/dt. These findings suggest that mechanisms in addition to vasodilation are involved in the beneficial effects of A2 stimulation during postischemic reperfusion.

An institutional experience with second- and third-stage palliative procedures for hypoplastic left heart syndrome: the impact of the bidirectional cavopulmonary shunt.

OBJECTIVES: The aim of this study was to perform a retrospective analysis of an institutional experience with a consecutive series of patients with post-stage I palliation for hypoplastic left heart syndrome (HLHS). BACKGROUND: In a recent review of 212 consecutive patients who underwent stage I operations for HLHS at our institution between 1983 and 1993, we identified risk factors related to stage I mortality. We sought to examine the outcome for these patients at subsequent palliative procedures. METHODS: All patients who underwent stage I reconstruction between January 1983 and June 1993 and also underwent subsequent palliation at our institution were included. Seventy patients underwent palliative procedures and two underwent heart transplantation. Patient-specific factors and features of the stage II operation were analyzed for impact on stage II mortality and actuarial survival. RESULTS: The only independent risk factor for stage II mortality was the performance of a nonfenestrated Fontan operation (p < 0.001). There were nine in-hospital deaths (69%) in the 13 patients undergoing the nonfenestrated Fontan procedure at stage II. Fifty patients underwent intermediate superior vena cava to pulmonary artery anastomosis at stage II, with 4 (8%) early deaths. Pulmonary artery augmentation was performed in 19 patients (38%) at stage II, without increased operative risk. Hypoplastic left heart syndrome anatomic subtype did not influence stage II mortality. The modified fenestrated Fontan procedure has been performed as a third stage in 32 patients whose median age was 28.7 months, with one early death at a median follow-up of 24.5 months. CONCLUSIONS: A second-stage bidirectional cavopulmonary anastomosis for HLHS reduces second-stage mortality and improves intermediate survival. The modified fenestrated Fontan operation may then be performed as a final palliative stage with low operative risk.

Cerebral oxygenation measured by near infrared spectroscopy during cardiopulmonary bypass and deep hypothermic circulatory arrest in piglets.

Near infrared spectroscopy (NIRS) shows large changes in cerebral oxyhemoglobin (Hbo2), deoxyhemoglobin (Hb), and oxidation state of cytochrome aa3 (Cyto2) in infants undergoing cardiopulmonary bypass and deep hypothermic circulatory arrest (CPB-DHCA). To evaluate the physiologic significance of these clinical NIRS measurements, we applied the technique in a piglet model of CPB-DHCA. After an initial stabilization period on CPB, animals (n = 8) were cooled to 15 degrees C, subjected to DHCA for 1 h, then reperfused with rewarming and monitored for 180 min. NIRS measurements were compared with determinations of cerebral blood flow (CBF). During cooling, Cyto2 decreased markedly, whereas Hbo2 increased. DHCA was associated with a sharp decrease in Hbo2, a corresponding increase in Hb, and a smaller, less consistent further decrease in Cyto2. NIRS measurements recovered toward baseline with reperfusion. CBF decreased during cooling and recovered to baseline levels with reperfusion. These findings are consistent with existing human data and show that 1) cooling is associated with increased oxygenation of cerebral hemoglobin despite a reduction in CBF; 2) Cyto2 becomes more reduced during cooling, consistent with a net cellular oxygen deficit; and 3) DHCA is associated with rapid cerebral hemoglobin deoxygenation and a small further reduction of Cyto2.

Cerebral metabolic recovery from deep hypothermic circulatory arrest after treatment with arginine and nitro-arginine methyl ester.

BACKGROUND: Recent studies suggest that nitric oxide is important in the pathogenesis of ischemic brain injury and also has a role in controlling cerebrovascular tone. This study examines the net effects of nitric oxide on cerebral metabolic recovery after deep hypothermic circulatory arrest. METHODS: Two-week-old piglets were supported by cardiopulmonary bypass and cooled to 15 degrees C followed by 1 hour of deep hypothermic circulatory arrest, 45 minutes of reperfusion and rewarming, and then 3 hours of normothermic perfusion. Groups of 10 piglets received one of four treatments before bypass; L-nitro-arginine methyl ester, inhibitor of nitric oxide synthesis, 10 mg/kg intravenously; L-arginine, to enhance nitric oxide synthesis, 30 mg/kg intravenously before bypass and then 10 mg/kg per minute during the first hour of reperfusion; a combination of L-nitro-arginine methyl ester plus L-arginine at these same doses; and no pretreatment (controls). Cerebral high-energy phosphates and pH were measured by magnetic resonance spectroscopy in half the animals. Cerebral blood flow, metabolic rates for oxygen and glucose, and the oxidation/reduction state of cytochrome aa3 and oxygenated and deoxygenated hemoglobin measured by near-infrared spectroscopy were assessed in the other half of the piglets. RESULTS: L-nitro-arginine methyl ester significantly increased cerebral vascular resistance and markedly reduced recovery of high-energy phosphates, pH, and oxidation state of cytochrome aa3, L-arginine increased cerebral blood flow, cerebral glucose and oxygen consumption, and recovery of cytochrome aa3 oxidation and high-energy phosphates. L-Arginine did not reverse completely the effects of L-nitro-arginine methyl ester on cerebral metabolic recovery. CONCLUSION: In a piglet model of deep hypothermic circulatory arrest, L-nitro-arginine methyl ester has a deleterious effect and L-arginine has a beneficial effect on cerebral metabolic recovery. The deleterious metabolic effects of L-nitro-arginine methyl ester are only partially reversed by L-arginine. This fact suggests that there may be mechanisms in addition to inhibition of nitric oxide synthesis contributing to the neurotoxicity of L-nitro-arginine methyl ester in this model.

Influence of age on cerebral recovery after deep hypothermic circulatory arrest in piglets.

BACKGROUND: In the first weeks of life there are important maturational changes in the central nervous system in many species in energy metabolism, synapse number, and concentration of neuronal excitatory receptors. METHODS: Four groups of 10 piglets (aged 1, 2, 4, and 10 weeks) underwent 1 hour of deep hypothermic circulatory arrest at 15 degrees C, with cooling and rewarming on cardiopulmonary bypass. Cerebral blood flow and metabolic rate measurements and electroencephalographic recordings were obtained from 5 animals per group. The remaining animals underwent cerebral magnetic resonance spectroscopy. RESULTS: Preoperative cerebral blood flow and glucose consumption were higher at 4 and 10 weeks than at 1 and 2 weeks. Cerebral adenosine triphosphate content decreased more rapidly during deep hypothermic circulatory arrest at 4 and 10 weeks. Phosphocreatine recovery was greater at 30 minutes of reperfusion at 10 weeks compared with 1 week. Recovery of cerebral phosphocreatine/ adenosine triphosphate ratio and intracellular pH was remarkably uniform at all ages. Latency to recovery of electroencephalographic activity decreased with increasing age (p = 0.04). CONCLUSIONS: Differences in acute recovery of brain energy metabolism and electroencephalogram after cardiopulmonary bypass and 1 hour of deep hypothermic circulatory arrest in piglets between 1 and 10 weeks of age are small. Further studies are required to correlate these acute findings with subsequent neurologic outcome.

Effects of endothelin-1 and L-arginine after cold ischemia in lamb hearts.

BACKGROUND: Prior studies from our laboratory have suggested an important role for the coronary endothelium in the injury resulting from hypothermic ischemia and reperfusion. A decreased endothelial response to intraarterial acetylcholine occurs after ischemia/reperfusion, implying a reduced release of the vasodilator nitric oxide by endothelial cells, but the role of endothelial-derived vasoconstrictor endothelin-1 in ischemia/reperfusion and interactions between endothelin-1 and nitric oxide in ischemia/reperfusion are still unclear. METHODS: We examined the effects of endothelin-1 and L-arginine, the precursor for nitric oxide, on functional recovery of isolated, blood-perfused neonatal lamb hearts undergoing 2 hours of ischemia at 10 degrees C. One group (n = 8) received 10 pmol/L endothelin-1 before reperfusion, and a second group (n = 8) received a continuous infusion of 3 mmol/L L-arginine during the initial 20 minutes of reperfusion. The third group (n = 8) received both endothelin-1 and L-arginine in the same way as in the endothelin-1 and L-arginine groups. The fourth group underwent the same period of hypothermic ischemia without interventions during reperfusion. RESULTS: After 30 minutes of reperfusion, the endothelin-1-treated hearts showed significantly reduced recovery of left ventricular systolic function (positive maximum dP/dt and volume normalized [V10] dP/dt) and diastolic function (negative maximum dP/dt), coronary blood flow, and myocardial oxygen consumption compared with the control group (p < 0.05). These effects of endothelin-1 were offset to equal the values observed in controls having unmodified reperfusion by adding L-arginine. The L-arginine group had significantly greater recovery of left ventricular systolic function (positive maximum dP/dt, maximum developed pressure, dP/dt at V10, and developed pressure at V10) and diastolic function (negative maximum dP/dt), coronary blood flow, and myocardial oxygen consumption compared with the control group (p < 0.05). CONCLUSION: These results, combined with our previous observations that endothelin-1 levels are unchanged by hypothermic ischemia and reperfusion, suggest that there is an imbalance between the endothelial production of endothelin-1 and nitric oxide, which affects postischemic coronary blood flow and the recovery of ventricular function. Interventions that modify this imbalance of endothelially derived substances could favorably influence the outcome after a period of hypothermic ischemia and reperfusion.

University of Wisconsin cerebroplegia in a piglet survival model of circulatory arrest.

BACKGROUND: Previous acute studies in immature piglets at our institution have demonstrated improved recovery of cerebral blood flow, intracellular pH, and high-energy phosphates with the administration of multidose University of Wisconsin solution as cerebroplegia during a period of deep hypothermic circulatory arrest (HCA). In an effort to define further the clinical applicability of this technique, we have developed a survival model of swine cardiopulmonary bypass (CPB) and HCA. METHODS: 12 Yorkshire pigs (age 4 to 5 weeks) were placed on CPB via the right femoral artery and right atrium. Animals were cooled to a rectal temperature of 15 degrees C and submitted to 90 minutes of HCA. Group UW (n = 6) received a single infusion of 50 mL/kg of 4 degrees C University of Wisconsin solution delivered antegrade to the cerebral circulation. The control group (n = 6) received no intervention. Animals were reperfused, rewarmed to 35 degrees C, and weaned from CPB. Neurologic assessments using neurologic deficit scoring (0 = normal, 500 = brain death) and overall performance categories (1 = normal, 5 = brain death) were performed at 24-hour intervals for 5 days. On the 5th postoperative day all brains were perfusion-fixed and examined for histologic evidence of neuronal injury (0 = normal, 5 = severe injury). RESULTS: All animals were extubated 18 to 20 hours postoperatively. There was no significant difference between the mean neurologic score of the two groups. The mean day 5 neurologic deficit score was 108 for the UW group and 68 for the control group (p > 0.05). The day 5 overall performance category was 2.8 for the UW group and 2.0 for the control group (p > 0.05). Three of the UW animals but none of the control animals experienced generalized seizures. Histologic examination revealed more severe damage in UW animals, primarily in the cerebral cortex. Injury was more widespread in UW animals, involving cerebellum and hippocampus. The mean histologic injury score was 3.8 for UW animals and 2.4 for the control group (p = 0.06). CONCLUSIONS: A clinically relevant survival model of CPB with HCA in immature swine is feasible. Cold UW solution as single-dose cerebroplegia is not beneficial, and may be injurious to the immature swine brain subjected to CPB and HCA. Further studies are indicated to determine optimal composition and administration of cerebroplegic solutions.

Effect of L-arginine cardioplegia on recovery of neonatal lamb hearts after 2 hours of cold ischemia.

BACKGROUND: Despite hypothermia and cardioplegia, myocardial ischemia followed by reperfusion results in both ventricular and endothelial dysfunction. The endothelial dysfunction is characterized by a reduced response to acetylcholine, which implies a reduced ability of the endothelium to release nitric oxide after hypothermic ischemia and reperfusion. We have previously demonstrated that infusion of the nitric oxide precursor L-arginine only during reperfusion after hypothermic ischemia significantly improves the recovery of ventricular function and results in an increased vasodilator response to the infusion of acetylcholine. In contrast, other investigators have found that nitric oxide has deleterious effects during postischemic reperfusion. METHODS: In the current experiments we have further examined the role of endothelial production of nitric oxide by adding 10 mmol/L L-arginine to cardioplegia in isolated, blood-perfused neonatal lamb hearts having 2 hours of cold cardioplegic ischemia. In another group 10 mmol/L D-arginine, an inactive enantiomer of L-arginine, was added to the cardioplegia. Controls received only cardioplegia (dextrose-potassium). RESULTS: At 30 minutes of reperfusion, the L-arginine group showed a significantly improved recovery in left ventricular systolic function (maximum developed pressure, developed pressure at a constant balloon volume [V10] resulting in an end-diastolic pressure of 10 mm Hg before ischemia, positive maximum dP/dt, and dP/dt at V10), diastolic function (negative maximum dP/dt and end-diastolic pressure at V10), coronary blood flow, endothelial function (assessed by the coronary vascular resistance response to acetylcholine), and myocardial oxygen consumption compared with the control group (p < 0.05). There were no significant differences in the recovery of any variables between the D-arginine and control groups. CONCLUSIONS: These results suggest that provision of more substrate for the endothelial production of nitric oxide during ischemia has an important salutary effect on the recovery of postischemic myocardial and endothelial function and provide further evidence for an important role for the endothelial production of nitric oxide in the response to hypothermic ischemia and reperfusion in the neonatal lamb heart.

Anti-CD11b monoclonal antibody improves myocardial function after six hours of hypothermic storage.

BACKGROUND: The shortage of pediatric heart donors often necessitates considerable travel time and, as a result, prolonged donor heart ischemia. This excessive hypothermic storage may contribute markedly to myocardial dysfunction in the recipient. METHODS: We investigated the role of leukocyte-endothelial interactions in this dysfunction in an isolated, immature (mean age, 11.8 +/- 1.6 days) swine heart model using a monoclonal antibody against a leukocyte adhesion molecule. We studied a total of 20 hearts subjected to 6 hours of cardioplegic arrest at 4 degrees C. Group M1/70 (n = 6) received at reperfusion 15 micrograms/mL of a monoclonal antibody F(ab')2 fragment to CD11b, the alpha-subunit of the leukocyte adhesion molecule Mac-1. Group MB10.6 (n = 8) received 15 micrograms/mL of the swine unreactive F(ab')2 MB10.6, and the third group received saline vehicle. RESULTS: Administration of M1/70 resulted in improved postischemic recovery of ventricular function compared with the two control groups (p < 0.05). CONCLUSIONS: These data implicate leukocyte-endothelial interactions mediated by the leukocyte adhesion molecule CD11b in myocardial dysfunction after long-term hypothermic ischemia. Specific antiadhesion strategies such as this may safely extend storage time for pediatric donor hearts.