Selective inhibition of receptor-mediated pulmonary vasorelaxation in endotoxin-induced acute lung injury.

We hypothesized that pulmonary vasorelaxation mediated by receptors that require generation of cyclic adenosine monophosphate (cAMP) is impaired in endotoxin-induced acute lung injury. The purpose of this study was to determine the effect of endotoxin on the following pathways of pulmonary vasorelaxation that require the generation of cAMP: 1) beta-adrenoreceptor stimulation (response to isoproterenol, ISO), 2) P2 purinoreceptor stimulation (response to adenosine diphosphate, ADP), 3) H2-histamine receptor stimulation (response to dimaprit), 4) adenosine A2 receptor stimulation (response to adenosine, ADO), 5) type 2 E prostaglandin (EP2) receptor stimulation (response to prostaglandin E1, PGE1), and 6) direct adenylate cyclase stimulation (response to forskolin, FSK). We used isolated pulmonary artery rings harvested from rats injected with endotoxin or saline. We found that endotoxin impaired the response to beta-adrenoreceptor stimulation (ISO) and P2 purinoreceptor stimulation (ADP). Endotoxin converted the vasorelaxant effect of H2-histamine receptor stimulation (dimaprit) to vasoconstriction. On the other hand, the response to A2 receptor stimulation (ADO) and EP2 receptor stimulation (PGE1), was normal. The dose response to direct adenylate cyclase stimulation (FSK) was the same as control except at a single concentration (10(-7) M). These data suggest that endotoxin causes selective impairment of pulmonary vasorelaxation through receptors coupled to cAMP generation. This impaired pulmonary vasorelaxation may contribute to the increased pulmonary vascular resistance seen in acute lung injury. These data may lead to therapy that will prevent or improve the pathophysiologic pulmonary circulation in acute lung injury.

Nitric oxide synthase is not involved in cardiac contractile dysfunction in a rat model of endotoxemia without shock.

Endotoxin and proinflammatory cytokines induce nitric oxide synthase (NOS), and nitric oxide (NO) plays an important role in promoting endotoxin shock. However, the role of NOS in endotoxemic cardiac contractile dysfunction is not defined. To determine whether endotoxemic cardiac contractile dysfunction involves NOS, the present study used a rat model of endotoxemia without shock and examined the effects of glucocorticoids (dexamethasone, a potent inhibitor of inducible NOS, iNOS, expression), isoform nonselective NOS inhibitor (NG-monomethyl-L-arginine, L-NMA) and iNOS selective inhibitor (S-methylisothiourea sulfate, SMT) on cardiac contractile dysfunction. A sublethal dose of endotoxin (from Salmonella typhimurium, .5 mg/kg, i.p.) was given to adult rats, and left ventricular developed pressure (LVDP) examined by Langendorff technique was attenuated in hearts isolated at 4 or 6 h (66.7 +/- 3.4 and 60.3 +/- 5.5 mmHg, respectively, p < .05 vs. 102 +/- 2.4 mmHg in saline control) after endotoxin treatment. Pretreatment of rats with dexamethasone (4.0 mg/kg, i.v., -30 min) partially abolished endotoxin-induced contractile dysfunction at 6 h (LVDP 87.6 +/- 6.8 mmHg, p < .05 vs. endotoxin alone at 6 h). However, pretreatment with L-NMA (30 mg/kg, i.v., -5 min) or SMT (5.0 mg/kg, i.v., -1 min) failed to prevent the contractile dysfunction. Moreover, infusion of L-NMA or SMT in vitro could not restore contractile function in hearts isolated at 6 h after endotoxin treatment. In contrast, inhibition of NOS with L-NMA or SMT in vitro further attenuated coronary flow in endotoxin-treated hearts. Thus, endotoxemic cardiac contractile dysfunction in this non-shock rat model may not involve NOS, and inhibition of NOS may deteriorate coronary perfusion in endotoxemic heart.

Endotoxin stuns cGMP-mediated pulmonary vasorelaxation.

Net pulmonary vascular tone is determined by the balance of pulmonary vasorelaxation and vasoconstriction. In endotoxemic rats, cGMP-mediated pulmonary vasorelaxation is impaired through neutrophil-dependent mechanisms, yet agonist stimulated vasoconstriction remains intact. Endotoxin-induced lung neutrophil accumulation is a transient response. In models of myocardial ischemia-reperfusion injury, "stunning" or reversible cardiac dysfunction is also associated with a reversible neutrophil presence. We hypothesized that lung neutrophil accumulation and dysfunction of cGMP-mediated pulmonary vasorelaxation is reversible after an endotoxin challenge. Our purpose was to examine lung neutrophil accumulation and endothelium-dependent and -independent mechanisms of cGMP-mediated pulmonary vasorelaxation 4 and 48 h after endotoxin challenge. Rats (n = 5 per group) were studied 4 and 48 h after injection of saline or endotoxin (500 micrograms/kg, intraperitoneal). Endothelium-dependent relaxation by receptor-dependent (acetylcholine) and -independent (A23187) mechanisms and endothelium-independent (sodium nitroprusside) relaxation were studied in isolated pulmonary artery rings preconstricted with phenylephrine. Lung neutrophil accumulation was examined by lung myeloperoxidase assay. Lung neutrophil accumulation was increased at 4 h (p < .05 vs. control) and was attenuated by 48 h (p < .05 vs. endotoxin x 4 h) following endotoxin challenge. Similarly, the endotoxin-induced dysfunction of endothelium-dependent and -independent cGMP-mediated pulmonary vasorelaxation at 4 h normalized by 48 h. Endotoxin appears to induce reversible dysfunction of pulmonary vasorelaxation through stunning of vascular endothelial and smooth muscle cells.

Vinblastine attenuates endotoxin-induced impairment of CGMP-mediated pulmonary vasorelaxation.

We tested the hypothesis that neutrophils contribute to endotoxin-induced impairment of endothelium-dependent and -independent cyclic guanosine monophosphate (cGMP)-mediated pulmonary vascular smooth muscle relaxation. Rats were studied 6 h after endotoxin (20 mg/kg, intraperitoneal) or saline (1 cc, intraperitoneal). Neutrophil-depleted rats were studied 4 days after administration of vinblastine (750 micrograms/kg, intravenous). Concentration-response curves were generated for acetylcholine and sodium nitroprusside in isolated pulmonary arterial rings (10(-9) M to 10(-6) M). The absolute neutrophil count of controls was 1050 +/- 206 neutrophils/mL, and the absolute neutrophil count of vinblastine-treated rats was 100 +/- 41 neutrophils/mL (p < .05 versus controls) and 25 +/- 25 neutrophils/mL in vinblastine-treated rats receiving endotoxin (p < .05 versus control and endotoxin). Endotoxin-induced impairment of endothelium-dependent and -independent cGMP-mediated pulmonary vasorelaxation was significantly attenuated by prior treatment with vinblastine. We conclude that neutrophils contribute to the pathogenesis of endotoxin-induced impairment of cGMP-mediated pulmonary vascular smooth muscle relaxation.

The influence of respiratory acid-base status on adult pulmonary vascular resistance before and after cardiopulmonary bypass.

Respiratory acid-base status has recently been shown to affect pulmonary vascular resistance (PVR) in adults following cardiac surgery. The purpose of this study was to examine what influence cardiopulmonary bypass has on the pulmonary vascular response to changes in respiratory acid-base status. Fifteen consecutive patients undergoing aortocoronary bypass were studied under general anesthesia both before and after cardiopulmonary bypass. Arterial PCO2 was manipulated by the addition of 5 percent carbon dioxide to the breathing circuit. Both before and after bypass, PVR increased significantly as PCO2 rose from 30 mm Hg to 50 mm Hg (p < 0.05). The PVR returned to baseline as PCO2 was returned to 30 mm Hg. These data suggest that increased PVR induced by hypercarbic acidemia is not simply a result of the effects of cardiopulmonary bypass on the pulmonary circulation. Instead, we conclude that respiratory acid-base status is an important determinant of adult PVR. We believe these data may be helpful in the treatment of mechanically ventilated patients, since patients are at particular risk of having abnormalities develop in respiratory acid-base status.

Conduit reconstruction of the right ventricular outflow tract. Lessons learned in a twelve-year experience.

From September 1979 to July 1991, a total of 163 patients have undergone valved conduit reconstruction of the right ventricular outflow tract when a right ventricle-pulmonary artery connection was absent or right ventricular outflow tract enlargement was required. From September 1979 through October 1984, 24 porcine valved conduits were implanted with an operative mortality of 38% (9/24). There were no early failures, but by 9 years after the operation 9 of 15 survivors (60%) had severe conduit obstruction, which resulted in death in 2 patients and reoperation in 6. From May 1985 to June 1991, 24 patients received cryopreserved aortic allografts to correct congenital anomalies. Operative mortality was 25% (6/24) and, again, early conduit function was good. There were 4 (22%) late deaths that were not related to the aortic allograft. At a mean follow-up of 3.4 years, 11 of the 13 survivors (85%) had allograft calcification and 8 of the 13 (62%) had mild to moderate conduit stenosis or regurgitation, or both; two of them required conduit replacement. Distal anastomotic problems that might have been avoided with bifurcated pulmonary allografts were apparent in 4 (36%) patients. Cryopreserved pulmonary allografts were placed in 115 patients between April 1985 and January 1991, with 18 (16%) operative deaths. Late deaths that were not allograft related occurred in 7 of 97 surviving patients (7%). Six patients (6%) underwent reoperation, 2 because of primary pulmonary allograft failure. The 84 remaining patients are free of symptoms with little or no allograft calcification or echocardiographic evidence of significant conduit stenosis or regurgitation. Experience with porcine valved conduits and aortic and pulmonary allografts suggests that pulmonary allografts are the conduit of choice for right ventricular outflow tract reconstruction.

Influence of hydrogen ion concentration versus carbon dioxide tension on pulmonary vascular resistance after cardiac operation.

Disturbances of respiratory acid-base status are common in patients supported with mechanical ventilation of the lungs after cardiac operations. This study was conducted with two protocols. The purpose was to determine whether respiratory acid-base status influences pulmonary vascular resistance in adults after cardiac operations and whether the influence is mediated by hydrogen ion concentration or carbon dioxide tension. Patients were studied while under general anesthesia immediately after aorta-coronary bypass. In the first protocol, with seven patients, arterial carbon dioxide tension was manipulated by the addition of 5% carbon dioxide to the breathing circuit. Pulmonary vascular resistance index was determined as arterial carbon dioxide tension rose from 30 mm Hg to 50 mm Hg and back to 30 mm Hg. In the second protocol, with 10 different patients, hydrogen ion concentration was manipulated by the addition of 0.2N hydrochloric acid, sodium bicarbonate, or both as arterial carbon dioxide tension was held constant. We used analysis of variance for statistical data. The results of the first protocol showed that pulmonary vascular resistance index rose by 44% (p < 0.05) as arterial carbon dioxide tension rose from 30 to 50 mm Hg. The results of the second protocol showed that changes in pulmonary vascular resistance index were parallel to changes in hydrogen ion concentration as arterial carbon dioxide tension was held constant (p < 0.05). These data demonstrate that respiratory acid-base status is an important determinant of pulmonary vascular resistance in the adult after cardiac operations. Furthermore, these data suggest the effect is mediated by hydrogen ion concentration, not carbon dioxide tension.

Pulmonary vasomotor dysfunction is produced with chronically high pulmonary blood flow.

This study examined the hypothesis that chronic high pulmonary blood flow produces dysfunction of the mechanisms of pulmonary vasorelaxation. A 3:1 left-to-right shunt was created in dogs by bilateral femoral artery-femoral vein shunts with use of 6 mm polytetrafluoroethylene grafts. Isolated pulmonary artery rings were studied at the following times: 3 days (n = 2), 2 weeks (n = 4), and 5 months (n = 6). Control animals had no shunt. The following mechanisms of pulmonary vasorelaxation were studied in isolated pulmonary artery rings (4 rings from each dog): (1) endothelium-dependent cyclic guanosine monophosphate-mediated relaxation (response to acetylcholine), (2) endothelium-independent cyclic guanosine monophosphate-mediated relaxation (response to sodium nitroprusside), and (3) beta-adrenergic cyclic adenosine monophosphate-mediated relaxation (response to isoproterenol). Statistical analysis was done by analysis of variance. This model of high pulmonary flow did not produce an increase in pulmonary arterial pressure or transpulmonary gradient. However, chronic high pulmonary flow produced progressive dysfunction of all three of these mechanisms of pulmonary vasorelaxation. By 5 months of high pulmonary flow, acetylcholine produced only 36% +/- 6% relaxation versus 95% +/- 5% in control animals (p < 0.05). Likewise, sodium nitroprusside produced only 69% +/- 6% relaxation versus 100% in control animals (p < 0.05). Finally, isoproterenol produced only 55% +/- 5% relaxation versus 94% +/- 6% in control animals (p < 0.05). We conclude that dysfunction of the mechanisms of pulmonary vasorelaxation may contribute to exaggerated perioperative pulmonary vasoconstriction in the setting of chronic high pulmonary blood flow.

Adenosine is a selective pulmonary vasodilator in cardiac surgical patients.

OBJECTIVE: The purpose of this study was to examine and compare the systemic and pulmonary hemodynamic effects of a central venous infusion of adenosine in cardiac surgical patients. DESIGN: Prospective; each subject served as his/her own control. SETTING: University Hospital and Veteran's Affairs Medical Center. PATIENTS: Ten cardiac surgical patients (age 56 +/- 6 years) were studied in the operating room under general anesthesia after weaning from cardiopulmonary bypass. Pulmonary vascular resistance (PVR), systemic vascular resistance (SVR), mean pulmonary arterial pressure (MPAP), and mean systemic arterial pressure (MAP) were determined before, during, and after central venous infusion of adenosine (50 micrograms/kg/min) for 15 min. Statistical analysis was by analysis of variance; significance was accepted at p < 0.05. RESULTS: Adenosine produced selective vasodilation of the pulmonary vascular bed: both PVR and MPAP were significantly reduced during adenosine infusion without changes in either SVR or MAP. PVR and MPAP returned to preinfusion levels after cessation of the infusion. Adenosine effectively reduced PVR and pulmonary arterial pressure without decreasing SVR or systemic arterial pressure. CONCLUSIONS: Adenosine may be used clinically as a selective pulmonary vasodilator to optimize pulmonary hemodynamics without adverse systemic hemodynamic effects in cardiac surgical patients. It may be particularly valuable in patients with right heart dysfunction by selectively lowering right ventricular afterload.

Lung transplantation with cardiopulmonary bypass exaggerates pulmonary vasomotor dysfunction in the transplanted lung.

Pulmonary vascular resistance is significantly increased in the transplanted lung. If cardiopulmonary bypass is required, the transplanted lung is reperfused with activated blood elements, which might exacerbate the reperfusion injury. The purpose of this study was to examine the influence of cardiopulmonary bypass on the following mechanisms of pulmonary vasomotor control in a dog model of autologous lung transplantation: (1) endothelium-dependent cyclic guanosine monophosphate-mediated relaxation (response to acetylcholine), (2) endothelium-independent cyclic guanosine monophosphate-mediated relaxation (response to nitroprusside), and (3) beta-adrenergic cyclic adenosine monophosphate-mediated relaxation (response to isoproterenol). Autologous right lung transplants were performed with (n = 4 dogs) and without (n = 5 dogs) bypass. Lungs were stored in cold saline solution (4 degrees C, 3 hours) before reimplantation. Pulmonary vasomotor control mechanisms were studied in isolated pulmonary arterial rings immediately after harvest and 1 hour after reimplantation. Ten rings were studied in each group at each time. Statistical analysis was by analysis of variance. Without bypass, endothelium-dependent cyclic guanosine monophosphate-mediated relaxation and beta-adrenergic cyclic adenosine monophosphate-mediated relaxation were significantly impaired, although endothelium-independent cyclic guanosine monophosphate-mediated relaxation was not. Use of bypass produced significantly greater impairment of both endothelium-dependent cyclic guanosine monophosphate-mediated relaxation and beta-adrenergic cyclic adenosine monophosphate-mediated relaxation. In addition, use of bypass produced significant dysfunction of endothelium-independent cyclic guanosine monophosphate-mediated relaxation as well. We conclude that using cardiopulmonary bypass to perform lung transplantation greatly exaggerates pulmonary vasomotor dysfunction in the transplanted lung. This dysfunction may contribute to significantly higher pulmonary vascular resistance in the transplanted lung if cardiopulmonary bypass is used.

Independent ventilation and ECMO for severe unilateral pulmonary edema after SLT for primary pulmonary hypertension.

Single lung transplantation (SLT) is now accepted therapy for selected cases of severe pulmonary hypertension. A recognized complication is the postoperative development of reperfusion edema in the graft, a potentially fatal cause of respiratory failure. Because reperfusion edema may be a reversible process, temporizing support measures can be life-saving. We report the case of a 48-year-old woman who developed severe reperfusion edema following right SLT for primary (unexplained) pulmonary hypertension. Extracorporeal membrane oxygenation (ECMO) was instituted. Independent lung ventilation was later begun and resulted in markedly improved oxygenation allowing withdrawal of ECMO. We conclude that reperfusion edema following SLT for pulmonary hypertension may be uniquely amenable to treatment with independent lung ventilation and ECMO if needed.

Effective control of refractory pulmonary hypertension after cardiac operations.

OBJECTIVES: Inhaled nitric oxide is a promising therapy to control pulmonary hypertension. However, pulmonary hypertension caused by valvular heart disease is often refractory to inhaled nitric oxide. The objective of this study was to determine whether the combination of inhaled nitric oxide plus dipyridamole will cause a response in patients with pulmonary hypertension undergoing cardiac operations who had not responded to inhaled nitric oxide alone. METHODS: Responses in 10 patients (62 +/- 7 years) with pulmonary hypertension caused by aortic or mitral valvular disease (mean pulmonary artery pressure, > or = 30 mm Hg) were studied in the operating room after valve replacement. The effect of inhaled nitric oxide alone (40 ppm) on pulmonary vascular resistance, mean pulmonary artery pressure, cardiac output, and mean arterial pressure was determined. Inhaled nitric oxide administration was then stopped and patients were given dipyridamole (0.2 mg/kg intravenously); the effect of inhaled nitric oxide plus dipyridamole was then examined. RESULTS: Dipyridamole effected a response in patients who had not responded to nitric oxide. Pulmonary vascular resistance and mean pulmonary artery pressure were significantly reduced and cardiac output was increased without change in mean arterial pressure. CONCLUSIONS: Patients with refractory pulmonary hypertension in whom inhaled nitric oxide alone fails to cause a response may respond to combined therapy of inhaled nitric oxide plus dipyridamole. This therapy may be particularly valuable in patients with dysfunction of the right side of the heart as a result of pulmonary hypertension because of its effective lowering of right ventricular afterload.

Effective control of pulmonary vascular resistance with inhaled nitric oxide after cardiac operation.

Increased pulmonary vascular resistance may greatly complicate the perioperative management of cardiac surgical patients. Inhaled nitric oxide may be a promising new therapy to selectively lower pulmonary vascular resistance. The purpose of this study was to examine the effects of inhaled nitric oxide on pulmonary and systemic hemodynamics in cardiac surgical patients. Twenty patients (age 57 +/- 6 years) were studied in the operating room after weaning from cardiopulmonary bypass. Mean pulmonary artery pressure, pulmonary vascular resistance, systemic vascular resistance, and mean aortic pressure were determined at four points of data collection: before nitric oxide, with 20 ppm nitric oxide, with 40 ppm nitric oxide, and after nitric oxide. Statistical analysis was by analysis of variance; significance was accepted for p < 0.05. Inhaled nitric oxide produced selective pulmonary vasorelaxation. Pulmonary vascular resistance was lowered from 343 +/- 30 before nitric oxide to 233 +/- 25 dynes.sec-1.cm-5 with 20 ppm nitric oxide. Pulmonary vascular resistance was not further lowered by 40 ppm nitric oxide (p < 0.05). Mean pulmonary arterial pressure was 29 +/- 1 mm Hg before nitric oxide and was lowered to 22 +/- 1 mm Hg by 20 ppm nitric oxide and 21 +/- 1 mm Hg by 40 ppm nitric oxide (p < 0.05). Both pulmonary vascular resistance and mean pulmonary arterial pressure returned to baseline after withdrawal of inhaled nitric oxide. Inhaled nitric oxide produced no changes in either systemic vascular resistance or mean aortic pressure. We conclude that nitric oxide may be used as an effective pulmonary vasodilator after cardiac operations. It may be particularly valuable for selectively lowering right ventricular afterload in patients with right ventricular dysfunction.

The effects of donor-recipient size disparity in infant and pediatric heart transplantation.

To determine the effect of heart donor and recipient size mismatches in infant and pediatric heart transplantation, we studied all 69 patients (age 1 day to 11 years) having 71 orthotopic heart transplants from 1985 to 1989. Patients were divided into three groups based on donor to recipient weight ratios. Group I comprised 13 heart transplants with a donor to recipient weight ratio less than 0.95 (mean 0.81, range 0.48 to 0.94); group II comprised 29 heart transplants with a weight ratio between 0.95 and 1.60 (mean 1.28); and group III had 27 heart transplants with weight ratios greater than 1.60 (mean 2.2, range 1.61 to 3.09). All chests were closed primarily. The cardiothoracic ratio by chest radiography was significantly larger in group III (p = 0.0002); 75% of group III patients had periods of lobar or complete lung collapse by chest radiography compared with 28% of group II and 19% of group I patients (p < 0.05). Despite this, there was no difference in the number of days of ventilator support for any group (p = 0.92). There was no difference in graft ischemic time or inotropic drug use among groups, nor were differences found in the cardiac systolic function parameters of left ventricular preejection time (p = 0.975), left ventricular ejection time (p = 0.975), left ventricular fiber shortening (p = 0.97), and left ventricular fractional shortening (p = 0.596). Thus despite a high incidence of transient lobar or complete lung collapse in high donor to recipient weight ratio transplants, large donor heart size produces very little clinical impairment in recipient lung function. Size mismatches do not influence cardiac systolic function. Overall, large size mismatches appear to be very well tolerated in infant and pediatric heart transplantation.

Cold ischemia and reperfusion each produce pulmonary vasomotor dysfunction in the transplanted lung.

Pulmonary vascular resistance is significantly increased in the transplanted lung. We hypothesized that the ischemic or reperfusion injuries incurred by the transplanted lung may produce pulmonary vasomotor dysfunction, which in turn may produce increased pulmonary vascular resistance. In a dog model of autologous lung transplantation, the purpose of this study was to examine the following mechanisms of pulmonary vasomotor control and to relate each of them to cold ischemia and to reperfusion: (1) endothelium-dependent cyclic guanosine monophosphate-mediated vasorelaxation (response to acetylcholine 10(-6) mol/L), (2) endothelium-independent cyclic guanosine monophosphate-mediated vasorelaxation (response to sodium nitroprusside 10(-6) mol/L), and beta-adrenergic cyclic adenosine monophosphate-mediated vasorelaxation (response to isoproterenol 10(-6) mol/L). Autologous right lung transplantation was performed in five dogs. At each of three times, two third-order pulmonary arteries were dissected from each transplanted lung and studied: control (immediately after harvest), cold ischemia (3 hours in 4 degrees C saline solution), and cold ischemia plus reperfusion (1 hour after lung reimplantation). The vasorelaxing effects of acetylcholine, sodium nitroprusside, and isoproterenol were studied in isolated pulmonary arterial rings, suspended on fine wire tensiometers in individual organ chambers. Statistical analysis was by analysis of variance. Results demonstrated significant dysfunction of beta-adrenergic cyclic adenosine monophosphate-mediated relaxation after cold ischemia alone, and this dysfunction was exacerbated by reperfusion. Endothelium-dependent cyclic guanosine monophosphate-mediated relaxation was not impaired by cold ischemia alone but was significantly impaired by reperfusion. Endothelium-independent cyclic guanosine monophosphate-mediated relaxation was not impaired by cold ischemia or reperfusion. We conclude that cold ischemia and reperfusion each produce different patterns of pulmonary vasomotor dysfunction. Cumulatively, such dysfunction may contribute to increased pulmonary vascular resistance in the transplanted lung.

Infant heart transplantation: improved intermediate results.

OBJECTIVES: Our objectives were to (1) review our experience with heart transplants in infants (age < 6 months), (2) delineate risk factors for 30-day mortality, and (3) compare outcomes between our early and recent experience. METHODS: Records of all infants listed for transplantation in our center before September 1996 were analyzed. Early and recent comparisons were made between chronologic halves of the accrual period. Univariate analysis was used to analyze potential risk factors for 30-day mortality (categorical variables, Fisher's exact test; continuous variables, nonparametric Wilcoxon rank-sum test). Multivariable analysis included univariate variables with p values < or = 0.10. Actuarial survivals were estimated (Kaplan-Meier) and compared by the log-rank test. RESULTS: Fifty-one of the 60 infants listed for transplantation were operated on (waiting list mortality 15%). Thirty-day mortality was 18% overall, 30% in the first 3 years and 10% in the last 3 years (p = 0.07). Sepsis was the commonest cause of early death (4/9). Univariate analysis suggested four potential risk factors for early death: preoperative mechanical ventilation (p = 0.01), prior sternotomy (p = 0.002), preoperative inotropic drugs (p = 0.08), and warm ischemia time (p = 0.08). Multivariable analysis indicated that prior sternotomy (p = 0.01) was an independent risk factor for 30-day mortality. Actuarial survivals were 80%, 78%, and 70% at 1, 2, and 3 years, and these figures improved between early and recent groups (p = 0.05). Late deaths were most commonly due to acute rejection (3/5). CONCLUSIONS: Results of heart transplantation in infancy improve with experience. Prior sternotomy increases initial risk. Intermediate-term survival for infants with end-stage heart disease is excellent.

Indications and contraindications for heart transplantation in infancy.

Heart transplantation uniquely offers infants with irreversible myopathies and complex congenital heart disease (CCHD) the potential for survival. Heart transplantation in the first year of life has an actuarial 1-year survival rate of 85%. Controlling for the variables that lead to perioperative death can improve 1-year survival rates to 95%. Mortality is also accrued before transplantation, with 15% to 20% of infants dying before a donor organ is available. Because of this cumulative mortality, an algorithm was developed to maximize pre- and posttransplantation survival and thus increase the likelihood that the limited donor supply would have the greatest impact. The risk factors considered in the algorithm include: (1) hemodynamic stability, (2) central venous access/prostaglandin requirements, (3) need for ventilator support, (4) pulmonary blood flow dependent on a critically restricted atrial septal defect, (5) risk for pulmonary hypertension, (6) anomalous pulmonary venous return, and (7) history of sepsis. Overall, patient survival would be maximized by only using transplantation for patients with CCHD who have moderate or less risk of pre- or posttransplantation death (< 20%). Donor organ utilization could be maximized by reserving transplantation for patients without options (myopathies) and for patients with CCHD who have a low predicted risk of death (< 10%). Because the risks of death at transplantation or in the first year after transplantation are low and relatively fixed, changes in risks of palliative surgery or donor availability can be easily used to adjust the decision algorithm.

Prolonged preservation of human pediatric hearts for transplantation: correlation of ischemic time and subsequent function.

Ninety-one infants and children, aged 0 days to 12 years, who received 93 hearts from donors aged 2 days to 24 years between November 1985 and September 1990 were retrospectively studied. Forty-three children were less than 1 month of age; 31 children were between 1 month and 6 months of age, and 19 children were between 6 months and 12 years of age. The donor heart ischemic time ranged from 51 minutes to 8 hours 17 minutes (mean, 4 hours 2 minutes). Fifty-one hearts had an ischemic time of less than 4 hours (group 1), and 42 hearts, more than 4 hours (group 2). No significant difference was noted in the age of donor or recipient or in donor/recipient weight ratio. No correlation was found between ischemic time and number of primary graft failures between groups. Inotropic support was required for 3.9 +/- 3.3 and 5.2 +/- 3.7 days for group 1 versus group 2 (not significant). Ventilator status was the same between the groups. A significant decrease of posterior wall movement in diastole (p < 0.01) occurred among patients of group 2 at 1 week after transplantation, but no difference was found between groups at 2 weeks, 1 month, and 3 months after operation. Posterior wall movement of group 2 heart grafts recovered completely by week 2. No difference was noted in the fractional shortening between the groups; but in both groups, fractional shortening significantly increased from week 1 to week 2. We conclude that ischemic times up to nearly 8 1/2 hours are well tolerated by donor hearts used in pediatric transplantation.

Mechanistic imbalance of pulmonary vasomotor control in progressive lung injury.

BACKGROUND: Pulmonary hypertension is the major hemodynamic feature of progressive lung injury. We hypothesized that the mechanisms of pulmonary vasorelaxation become progressively impaired in progressive lung injury. The purpose of this study was to examine the following mechanisms of pulmonary vasorelaxation in a rat model of monocrotaline-induced progressive lung injury: endothelial-dependent cyclic guanosine monophosphate-mediated relaxation (response to acetylcholine), endothelial-independent cyclic guanosine monophosphate-mediated relaxation (response to nitroprusside), beta-adrenergic cyclic adenosine monophosphate-mediated relaxation (response to isoproterenol), and hypoxic pulmonary vasoconstriction. METHODS: Rats were studied 2, 7, and 14 days after monocrotaline injection (100 mg/kg intraperitoneally). Pulmonary vasomotor control mechanisms were studied in isolated pulmonary artery rings. Controls were studied 14 days after saline injection. Statistical analysis was by ANOVA; p < 0.05 was considered significant. RESULTS: A progressive impairment of pulmonary vasorelaxation was observed. By 14 days after monocrotaline injection acetylcholine produced only 25% +/- 5% relaxation versus 95% +/- 5% in controls (p < 0.05), nitroprusside produced 46% +/- 5% relaxation versus 100% in controls (p < 0.05), and isoproterenol produced only 18% +/- 5% relaxation versus 94% +/- 4% in controls (p < 0.05). At the same time hypoxic pulmonary vasoconstriction became progressively exaggerated. CONCLUSIONS: Progressive dysfunction of pulmonary vasomotor control may contribute to the pulmonary hypertension seen in progressive lung injury.

Intracellular mechanisms of pulmonary vasomotor dysfunction in acute lung injury caused by mesenteric ischemia-reperfusion.

BACKGROUND: A major hemodynamic feature of adult respiratory distress syndrome is pulmonary hypertension secondary to avid pulmonary vascular smooth muscle constriction. This study was undertaken to study the hypothesis that this pulmonary vasoconstriction may derive from pulmonary vasomotor dysfunction. METHODS: A rat model of acute lung injury was studied after 2 hours of superior mesenteric arterial occlusion followed by 4 hours reperfusion. Lung neutrophil accumulation was assessed by myeloperoxidase assay, and lung leak was assessed by iodine 125-labeled albumin lung/blood ratio. The following mechanisms of pulmonary vascular smooth muscle relaxation were studied in isolated pulmonary arterial rings: (1) endothelial-dependent cyclic guanosine monophosphate-mediated, (2) endothelial-independent cyclic guanosine monophosphate-mediated, (3) beta-adrenergic cyclic adenosine monophosphate-mediated. Control rats underwent sham laparotomy. Statistical analysis was done with unpaired Student t test. RESULTS: Lung myeloperoxidase increased from 6.2 +/- 2 to 42 +/- 5 units/gm (p < 0.05), and 125I-labeled albumin lung/blood ratio increased from 0.028 +/- 0.02 to 0.063 +/- 0.03 (p < 0.05) after mesenteric ischemia-reperfusion. beta-adrenergic cyclic adenosine monophosphate-mediated pulmonary vascular smooth muscle relaxation was dysfunctional in the lung-injured rats (62% +/- 5% relaxation versus 95% +/- 3% in controls) (p < 0.05). CONCLUSIONS: These data suggest a mechanistic imbalance of pulmonary vascular smooth muscle contraction and relaxation in acute lung injury. Such imbalance may contribute to the pulmonary hypertension found in adult respiratory distress syndrome.