Type 1 growth factor receptor expression in node positive breast cancer: adverse prognostic significance of c-erbB-4.

BACKGROUND: There is a clear need to define biological markers that will predict the response to treatment in breast cancer, and several recent studies suggest that the expression of type 1 growth factor receptors may prove important in this regard. The type 1 growth factor receptors are a family of transmembrane receptors comprising epidermal growth factor receptor (EGFR), c-erbB-2, c-erbB-3, and c-erbB-4. Both EGFR and c-erbB-2 are associated with poor prognosis in certain tumours. AIMS: There is very little information concerning expression patterns of the full range of type 1 growth factor receptors, especially with respect to c-erbB-3 and c-erbB-4. Therefore, this study was designed to compare the expression of each, and to assess whether expression of any of the factors was related to patient survival in a clinical series. METHODS: Type 1 growth factor receptor expression was investigated by means of immunohistochemistry in a series of node positive patients with breast cancer (n = 66), and statistical analysis was carried out to determine associations between variables and survival analysis for each variable. RESULTS: There were several correlations between variables, and overexpression of EGFR, c-erbB-2, and c-erbB-4 was found to be associated with adverse clinical outcome, although the results were significant only for c-erbB-4 (p = 0.002). CONCLUSION: Although patient numbers are small, this is the first report describing c-erbB-4 as an adverse prognostic marker. These findings are in contrast to previous investigations and may relate to the fact that the patients studied all had advanced stage disease and had undergone similar chemotherapy regimens in the context of a clinical trial.

Topoisomerase II alpha and II beta expression in childhood acute lymphoblastic leukaemia: relation to prognostic factors and clinical outcome.

BACKGROUND/AIMS: Many regimens used in the treatment of childhood acute lymphoblastic leukaemia (ALL) include Daunorubicin or Etoposide, which act as topoisomerase poisons. It has been suggested that there may be a relation between topoisomerase expression and response to topoisomerase poisons, based mainly on results from in vitro studies. Therefore, the aim of this study was to investigate this relation in a clinical setting and determine whether topoisomerase II alpha and II beta might be of predictive value in ALL. METHODS: Cellular expression of topoisomerases II alpha and II beta was assessed in 177 cases of ALL by immunohistochemistry using monoclonal antibodies to the two enzymes. The percentages of cell nuclei showing positive staining for topoisomerase II alpha and II beta expression were assessed. RESULTS: Taking the series as a whole, a clear separation of survival curves was seen with the established prognostic markers white blood cell (WBC) count, CD10 status, and sex. However, topoisomerase II alpha and II beta expression showed no relation to survival. No association was found between the topoisomerases and the prognostic markers CD10 and WBC count; however, topoisomerase II alpha expression was found to be related to sex, with expression being lower in girls (p = 0.002). CONCLUSIONS: These results suggest that the response to topoisomerase poisons cannot be predicted by the assessment of topoisomerase II alpha and II beta expression as defined by immunohistochemistry.

Vascular control for resection of suprahepatic intracaval Wilms' tumor: technical considerations.

The surgical resection of Wilms' tumor can be complicated by tumor thrombus extension into the inferior vena cava. In cases of suprahepatic Wilms' tumor thrombus that may extend into the right atrium, a median sternotomy and cardiopulmonary bypass (CPB) are used to facilitate tumor resection. However, if the tumor can be localized and controlled below the atrium, resection without the use of cardiopulmonary bypass may limit morbidity. The authors describe a novel approach to tumor thrombectomy for a Wilms' tumor extending to the suprahepatic vena cava without the use of CPB. The authors used transesophageal echocardiography to localize the tumor thrombus and detect any tumor or air embolization and a minimal lower sternotomy to obtain intrapericardial control of the inferior vena cava. This technique may be useful in selected cases of Wilms' tumor as an alternative to median sternotomy and use of cardiopulmonary bypass.

Expression of topoisomerase IIIalpha in normal and neoplastic tissues determined by immunohistochemistry using a novel monoclonal antibody.

Topoisomerases are nuclear enzymes that modulate the topological structure of DNA in order to facilitate cellular events such as replication and transcription. These enzymes are also the cellular targets of certain classes of chemotherapeutic agents termed topoisomerase poisons. A new human topoisomerase isoform, IIIa, was discovered in 1996, which is thought to have roles in genome stability and possibly chromosome separation during mitosis. It is possible that novel or existing anti-topoisomerase agents target topoisomerase IIIa, suggesting that this enzyme may have potential as a prognostic marker and chemotherapeutic target. In order to study expression patterns of topoisomerase IIIa we have produced a novel monoclonal antibody to human topoisomerase IIIa (TOPO3a-1A4), and used it to assess topoisomerase IIIa expression in a wide range of normal and neoplastic tissues. We have found that topoisomerase IIIa is expressed in a wide range of tissue types, with especially high concentrations in endothelial cells and stromal fibroblasts. No general relationship was observed between expression of topoisomerase IIIa and proliferation. Expression in neoplastic tissues often paralleled their normal counterparts, although certain tumours showed either increased (e.g. colonic adenoma) or reduced (e.g. gastric carcinoma, small cell carcinoma of bronchus) expression. If topoisomerase IIIa is found to be a target for chemotherapeutic agents, clinical response in different tumour types may be related to topoisomerase IIIa expression, which may be assessed using TOPO3a-1A4.

The role of antibodies in dysfunction of pig-to-baboon pulmonary transplants.

OBJECTIVE: Pulmonary transplantation has become the preferred treatment for end-stage lung disease, but application of the procedure is limited because of a paucity of donors. One way to solve donor limitations is to use animal organs as a donor source or xenotransplantation. The current barrier to pulmonary xenotransplantation is the rapid failure of the pulmonary xenograft. Although antibodies are known to play a role in heart and kidney xenograft rejection, their involvement in lung dysfunction is less defined. This project was designed to define the role of antibodies in pulmonary graft rejection in a pig-to-baboon model. METHODS: Orthotopic transgenic swine left lung transplants were performed in baboons depleted of antibodies by one of three techniques before transplantation: (1) ex vivo swine kidney perfusion, (2) total immunoglobulin-depleting column perfusion, and (3) ex vivo swine lung perfusion. Results were compared with those of transgenic swine lung transplants in unmodified baboons. RESULTS: All three techniques of antibody removal resulted in depletion of xenoreactive antibodies. Only pretransplantation lung perfusion improved pulmonary xenograft function compared with lung transplantation in unmodified baboons. CONCLUSIONS: The pathogenesis of pulmonary injury in a swine-to-primate transplant model is different from that in renal and cardiac xenografts. Depletion of antibodies alone does not have a beneficial effect and may actually be detrimental.

Intermittent perfusion protects the brain during deep hypothermic circulatory arrest.

BACKGROUND: Deep hypothermic circulatory arrest (DHCA) has been shown to cause impairment in recovery of cerebral blood flow (CBF) and cerebral metabolism (CMRO2) proportional to the duration of the DHCA period. This effect on CMRO2 may be a marker for brain injury, because CMRO2 recovers normally after cardiopulmonary bypass (CPB) when DHCA is not used. The aim of this study was to investigate the effects of intermittent perfusion during DHCA on the recovery of CMRO2 after CPB and to correlate these findings with electron microscopy (EM) of the cerebral microcirculatory bed. METHODS: Fifteen neonatal piglets were placed on CPB and cooled to 18 degrees C. Each animal then underwent either: (1) 60 minute continuous CPB (control), (2) 60 minute uninterrupted DHCA (UI-DHCA), or (3) 60 minute DHCA with intermittent perfusion (1 minute every 15 minutes) (I-DHCA). All animals were then rewarmed and weaned from CPB. Measurements of CBF and CMRO2 were taken before and after CPB. A further 9 animals underwent CPB without DHCA (2 animals) or with DHCA (7 animals), under various conditions of arterial blood gas management, intermittent perfusion, and reperfusion time. RESULTS: UI-DHCA resulted in significant impairment to recovery of CMRO2 after CPB (p < 0.05). Regardless of the blood gas strategy used, the EM after UI-DHCA revealed extensive damage characterized by perivascular intracellular and organelle edema, and vascular collapse. I-DHCA, on the other hand, produced a pattern of normal CMRO2 recovery identical to controls, and the EM was normal for both these groups. CONCLUSIONS: Intermittent perfusion during DHCA is clinically practical and results in normal cerebral metabolic and ultrastructural recovery. Furthermore, the correlation between brain structure and CMRO2 suggests that monitoring CMRO2 during the operation may be an outstanding way to investigate new strategies for neuroprotection designed to reduce cerebral damage in children undergoing correction of congenital cardiac defects.

Effects of ischemia on pulmonary dysfunction after cardiopulmonary bypass.

BACKGROUND: Pulmonary hypertension and lung injury secondary to cardiopulmonary bypass (CPB) are probably caused by a combination of ischemia and inflammation. This study was undertaken to investigate the potential ischemic effects of cessation of pulmonary arterial flow during CPB on pulmonary injury. METHODS: Twenty neonatal piglets (2.5 to 3.1 kg) were randomly assigned to two groups. Group A (n = 10) underwent 90 minutes of CPB at full flow (100 mL x kg(-1) x min(-1)) and clamping of the main pulmonary artery (PA). Group B (n = 10) underwent 90 minutes of partial CPB (66 mL x kg(-1) x min(-1)) with continued mechanical ventilation and without clamping of the PA. All hearts were instrumented with micromanometers and a PA ultrasonic flow probe. Endothelial function was assessed by measuring endothelial-dependent relaxation (measured by change in pulmonary vascular resistance after PA infusion of acetylcholine) and endothelial-independent relaxation (measured by change in pulmonary vascular resistance after ventilator infusion of nitric oxide and PA infusion of sodium nitroprusside). RESULTS: All groups exhibited signs of pulmonary injury after CPB as evidenced by significantly increased pulmonary vascular resistance, increased alveolar-arterial O2 gradients, and decreased pulmonary compliance (p<0.05); however, pulmonary injury was significantly worse in group A (p<0.05). CONCLUSIONS: This study suggests that although exposure to CPB alone is enough to cause pulmonary injury, cessation of PA flow during CPB contributes significantly to this pulmonary dysfunction.

Methylprednisolone reduces the inflammatory response to cardiopulmonary bypass in neonatal piglets: timing of dose is important.

INTRODUCTION: Cardiopulmonary bypass produces an inflammatory response that can cause significant postoperative pulmonary dysfunction and total body edema. This study evaluates the efficacy of preoperative methylprednisolone administration in limiting this injury in neonates and compares the effect of giving methylprednisolone 8 hours before an operation to the common practice of adding methylprednisolone to the cardiopulmonary bypass circuit prime. METHODS: A control group of neonatal pigs (control; n = 6) received no preoperative medication. One experimental group (n = 6) received methylprednisolone sodium succinate (30 mg/kg) both 8 and 1.5 hours before the operation. A second experimental group received no preoperative treatment, but methylprednisolone (30 mg/kg) was added to the cardiopulmonary bypass circuit prime. All animals underwent cardiopulmonary bypass and 45 minutes of deep hypothermic circulatory arrest. Hemodynamic and pulmonary function data were acquired before cardiopulmonary bypass and at 30 and 60 minutes after bypass. RESULTS: In the control group, pulmonary compliance, alveolar-arterial gradient, and pulmonary vascular resistance were significantly impaired after bypass (P <.01 for each by analysis of variance). In the group that received methylprednisolone, compliance (P =.02), alveolar-arterial gradient (P =.0003), pulmonary vascular resistance (P =.007), and extracellular fluid accumulation (P =.003) were significantly better after bypass when compared with the control group. Results for the group that received no preoperative treatment fell between the control group and the group that received methylprednisolone. CONCLUSIONS: When given 8 hours and immediately before the operation, methylprednisolone improves pulmonary compliance after bypass, alveolar-arterial gradient, and pulmonary vascular resistance compared with no treatment. The addition of methylprednisolone to the cardiopulmonary bypass circuit prime is beneficial but inferior to preoperative administration.

NCL-CD10-270: a new monoclonal antibody recognizing CD10 in paraffin-embedded tissue.

CD10 (CALLA) antigen is expressed in a wide variety of epithelial and nonepithelial tissues, but its most significant application is in the diagnosis and classification of certain types of malignant lymphoma and leukemia. CD10 is expressed in a high percentage of cases of acute lymphoblastic leukemia (ALL), follicular lymphoma, Burkitt's lymphoma, and some hematopoietic tumors. Although the antigen is not lineage specific, CD10 expression is widely used to define subgroups within B-ALL and is a useful tool for detecting the presence of leukemic blasts in the bloodstream. Currently available monoclonal antibodies to CD10 have been found to be effective only in fresh-frozen tissue and for techniques such as flow cytometry. We have used a recombinant protein corresponding to the whole of CD10 to generate a monoclonal antibody that is effective in paraffin-embedded tissue sections. We have used this antibody to assay for the presence of CD10 on a range of normal and pathological tissues. Strong staining was seen in lymphoid germinal centers, renal tubules, glomeruli, syncytiotrophoblast, hepatic parenchymal canaliculi, B-lineage ALL, follicle center cell lymphoma, and a proportion of cases of large-B-cell lymphoma. We believe that this antibody will be of value in the characterization of malignant lymphoma, in particular the differential diagnosis of small-B-cell lymphoma and subtyping of lymphoblastic leukemia, as well as the investigation of the significance of expression of CD10 in other normal and pathological tissues.

The type of aortic cannula and membrane oxygenator affect the pulsatile waveform morphology produced by a neonate-infant cardiopulmonary bypass system in vivo.

Although the debate still continues over the effectiveness of pulsatile versus nonpulsatile perfusion, it has been clearly proven that there are several significant physiological benefits of pulsatile perfusion during cardiopulmonary bypass (CPB) compared to nonpulsatile perfusion. However, the components of the extracorporeal circuit have not been fully investigated regarding the quality of the pulsatility. In addition, most of these results have been gathered from adult patients, not from neonates and infants. We have designed and tested a neonate-infant pulsatile CPB system using 2 different types of 10 Fr aortic cannulas and membrane oxygenators in 3 kg piglets to evaluate the effects of these components on the pulsatile waveform produced by the system. In terms of the methods, Group 1 (Capiox 308 hollow-fiber membrane oxygenator and DLP aortic cannula with a very short 10 Fr tip [n = 2]) was subjected to a 2 h period of normothermic pulsatile CPB with a pump flow rate of 150 ml/kg/min. Data were obtained at 5, 30, 60, 90, and 120 min of CPB. In Group 2 (Capiox 308 hollow-fiber membrane oxygenator and Elecath aortic cannula with a very long 10 Fr tip [n = 7]) and Group 3 (cobe VPCML Plus flat sheet membrane oxygenator and DLP aortic cannula with a very short 10 Fr tip [n = 7]), the subjects' nasopharyngeal temperatures were reduced to 18 degrees C followed by 1 h of deep hypothermic circulatory arrest (DHCA) and then 40 min rewarming. Data were obtained during normothermic CPB in the pre- and post-DHCA periods. The criteria of pulsatility evaluations were based upon pulse pressure (between 30 and 40 mm Hg), aortic dp/dt (greater than 1000 mm Hg/s), and ejection time (less than 250 ms). The results showed that Group 1 produced flow which was significantly more pulsatile than that of the other 2 groups. Although the same oxygenator was used for Group 2, the quality of the pulsatile flow decreased when using a different aortic cannula. Group 3 did not meet any of the criteria for physiologic pulsatility. In conclusion these data suggest that in addition to a pulsatile pump, the aortic cannula and the membrane oxygenator must be chosen carefully to achieve physiologic pulsatile flow during CPB.

Modified ultrafiltration versus conventional ultrafiltration: a randomized prospective study in neonatal piglets.

UNLABELLED: Cardiopulmonary bypass in neonates generates large increases in inflammatory mediators, causing edema formation that may lead to multiple organ dysfunction. Clinical strategies aimed at removing inflammatory mediators, reducing edema formation, and improving organ function include conventional and modified ultrafiltration. OBJECTIVE: This study examines the effectiveness of conventional and modified ultrafiltration in preventing weight gain, myocardial edema formation, and left ventricular dysfunction in neonatal piglets undergoing cardiopulmonary bypass. METHODS: In this randomized prospective study, 18 1-week-old piglets were supported with cardiopulmonary bypass at 100 ml kg(-1) x min(-1), cooled to 25 degrees C, exposed to 75 minutes of cardioplegic arrest, rewarmed to 37 degrees C, and weaned from bypass. Left ventricular myocardial contractility was assessed by the preload-recruitable stroke work method, with the use of a sonomicrometric two-dimensional cylindrical model, before bypass and at 10, 60, and 120 minutes after separation from bypass. RESULTS: Total body weight gain was significantly less in the modified ultrafiltration group than in either the conventional ultrafiltration group or the control group (no filtration). Myocardial wet/dry ratios were also improved with modified ultrafiltration, but not with conventional ultrafiltration, when compared with no filtration (control group). Hemodynamically, modified ultrafiltration was superior to conventional ultrafiltration and no filtration (control) in raising the mean arterial pressure and increasing the left ventricular preload-recruitable stroke work after bypass. CONCLUSION: Modified ultrafiltration is superior to conventional ultrafiltration and no filtration in reducing the total body weight gain, lessening myocardial edema, raising mean arterial pressure, and improving left ventricular contractility in neonatal piglets undergoing cardiopulmonary bypass and cardioplegic arrest.

The role of endothelial nitric oxide synthase expression in the development of pulmonary hypertension in chronically hypoxic infant swine.

OBJECTIVE: Our goal was to determine the role of pulmonary endothelial nitric oxide synthase expression in the development of pulmonary hypertension in infants with congenital cyanotic heart disease. METHODS: Two groups of 4-week-old piglets were studied. In one group, the piglets were raised in an environment of 10% oxygen from 2 days of age (cyanotic, n = 6), and in the other group the piglets were raised at room air (control, n = 5). Pulmonary hemodynamics were measured in vivo for each animal, and peripheral lung biopsy specimens were obtained for Western blot analysis with the use of antiendothelial nitric oxide synthase antibody and for activity analysis with the use of the tritiated L-arginine assay. RESULTS: The piglets in the chronically hypoxic group had significant increases in mean pulmonary arterial pressure (44.0 +/- 3.8 mm Hg vs 14.8 +/- 1.2 mm Hg in controls, p = 0.0007) and pulmonary vascular resistance (7272.0 +/- 871.1 dyne x cm x sec(-5) vs 1844.5 +/- 271.2 dyne x cm x sec(-5) in controls, p = 0.002). These changes in the pulmonary hemodynamics of the hypoxic piglets were accompanied by a twofold increase in the expression of pulmonary endothelial nitric oxide synthase (p = 0.0043) but no corresponding increase in nitric oxide synthase activity. CONCLUSIONS: Raising infant piglets in an environment of 10% oxygen for 4 weeks results in significant pulmonary arterial hypertension accompanied by increased expression of nitric oxide synthase within the lung endothelium. Furthermore, the increased levels of nitric oxide synthase within the lungs of the hypoxic swine were not accompanied by a proportional increase in enzyme activity. These findings suggest that the development of pulmonary hypertension in infants with congenital cyanotic disease is not due to decreased expression of endothelial nitric oxide synthase, but instead may be related to a decreased ability of the enzyme to produce sufficient nitric oxide.

Total respiratory support from swine lungs in primate recipients.

UNLABELLED: The use of nonhuman lung donors, such as swine, has the potential to provide an unlimited supply of organs. However, hyperacute rejection has prevented pulmonary xenotransplantation. OBJECTIVE: Our aim was to test the hypothesis that immunodepletion by pretransplantation swine lung perfusion will prevent hyperacute swine-to-primate pulmonary xenograft rejection and allow for a functional swine pulmonary xenograft. METHODS: Seven baboons underwent left pneumonectomy followed by orthotopic transplantation of the swine left lung. Four baboons received immunodepletion by perfusion with swine lungs before transplantation, and three received no treatment before transplantation. RESULTS: After transplantation, pulmonary xenografts from immunodepleted baboons had a low pulmonary vascular resistance and a high pulmonary blood flow compared with control animals, which had a high pulmonary vascular resistance and a low pulmonary blood flow. After 60 minutes of reperfusion, three of four immunodepleted animals also tolerated complete occlusion of the right pulmonary artery, with the baboon relying completely on the swine pulmonary xenograft for respiratory function for 11 hours. Pathologic analysis of peripheral lung biopsy specimens taken from control lungs displayed alveolar disruption and hemorrhage within small vessels, whereas swine lungs transplanted into immunodepleted baboons displayed little histologic evidence of injury. Furthermore, pulmonary xenografts transplanted into immunodepleted baboons demonstrated excellent respiratory function and adequate hemodynamics during occlusion of the right pulmonary artery. CONCLUSION: Hyperacute pulmonary xenograft rejection can be prevented by pretransplantation swine lung perfusion. Swine pulmonary xenografts can provide complete respiratory support in primates when rejection is prevented.

Error associated with the choice of an aortic cannula in measuring regional cerebral blood flow with microspheres during pulsatile CPB in a neonatal piglet model.

The effectiveness of an infant pulsatile cardiopulmonary bypass (CPB) system on maintaining regional cerebral blood flow (CBF) using two different types of aortic cannulae in 3 kg piglets has been investigated. The University of Texas Neonatal Pulsatile Pump was used with either a DLP (Group I, n = 6) or an Elecath (Group II, n = 7) 10Fr aortic cannula. In all the subjects, nasopharyngeal temperature was reduced to 18 degrees C, followed by 1 hr of deep hypothermic circulatory arrest (DHCA), then 45 min of rewarming. During cooling and rewarming, alpha-stat blood gas management was used. The radionuclide labeled microsphere technique was used to determine blood flows in the cerebellum, basal ganglia, brainstem, right and left hemispheres, as well as global CBF (ml/100 g/min). When the DLP aortic cannula was used, regional and global CBF appeared to be higher pre- and post DHCA. In both groups regional CBF was significantly decreased following DHCA. Although better pulsatile flow was attained using the DLP cannula and this may have resulted in higher regional CBF, these results must be interpreted in light of the large standard deviations noted when this cannula was chosen for the studies. These results demonstrate the importance of choosing an appropriate aortic cannula for measuring regional CBF with a pulsatile neonate-infant CPB system.

Regional blood flow during pulsatile cardiopulmonary bypass and after circulatory arrest in an infant model.

BACKGROUND: Pulsatile perfusion systems have been proposed as a means of improving end-organ perfusion during and after cardiopulmonary bypass. Few attempts have been made to study this issue in an infant model. METHODS: Neonatal piglets were subjected to nonpulsatile (n = 6) or pulsatile (n = 7) cardiopulmonary bypass and 60 minutes of circulatory arrest. Cerebral, renal, and myocardial blood flow measurements were obtained at baseline, on bypass before and after circulatory arrest, and after bypass. RESULTS: Cerebral blood flow did not differ between groups at any time and was diminished equally in both groups after circulatory arrest. Renal blood flow was diminished in both groups during bypass but was significantly better in the pulsatile group than in the nonpulsatile group prior to, but not after, circulatory arrest. Myocardial blood flow was maintained at or above baseline in the pulsatile group throughout the study, but in the nonpulsatile group, it was significantly lower than baseline during CPB prior to circulatory arrest and lower compared with baseline and with the pulsatile group 60 minutes after CPB. CONCLUSIONS: Pulsatile bypass does not improve recovery of cerebral blood flow after circulatory arrest, may improve renal perfusion during bypass but does not improve its recovery after ischemia, and may have beneficial effects on myocardial blood flow during bypass and after ischemia compared with nonpulsatile bypass in this infant model.

Swine lungs expressing human complement-regulatory proteins are protected against acute pulmonary dysfunction in a human plasma perfusion model.

UNLABELLED: Pulmonary transplantation is currently limited by the number of suitable cadaver donor lungs. For this reason, pulmonary xenotransplantation is currently being investigated. OBJECTIVE: Our goal was to assess the role of complement in pulmonary xenograft dysfunction. METHODS: The pulmonary function of swine expressing human decay accelerating factor and human CD59 (n = 6) was compared with that of the lungs from nontransgenic (control) swine (n = 6) during perfusion with human plasma. RESULTS: After 2 hours of perfusion, the pulmonary vascular resistance was 1624 +/- 408 dynes.sec.cm-5 in control lungs and 908 +/- 68 dynes.sec.cm-5 in transgenic lungs (p < 0.05). Control lungs had a venous oxygen tension of 271 +/- 23 mm Hg with a ratio of venous oxygen tension to inspired oxygen fraction of 452 +/- 38 at 2 hours of perfusion; transgenic lungs had a venous oxygen tension of 398 +/- 11 mm Hg and a ratio of venous oxygen tension to inspired oxygen fraction of 663 +/- 18 (p < 0.05). Control lungs showed a decrease of 79.8% +/- 3.7% in static pulmonary compliance by 2 hours, versus a 12.0% +/- 8.1% decrease by the transgenic lungs (p < 0.05). The control lungs also developed 561.7 +/- 196.2 ml of airway edema over 2 hours, in contrast to 6.5 +/- 1.7 ml in transgenic lungs (p < 0.05). CONCLUSION: Lungs from swine expressing human decay accelerating factor and human CD59 functioned better than nontransgenic swine lungs when perfused with human plasma. These results suggest that complement activation is involved in producing acute pulmonary xenograft dysfunction and demonstrate that lungs from swine expressing human decay accelerating factor and human CD59 are protected against pulmonary injury when perfused with human plasma.

Low-flow cardiopulmonary bypass produces greater pulmonary dysfunction than circulatory arrest.

BACKGROUND: Deep hypothermic circulatory arrest (DHCA) is used during the repair of congenital heart disease in neonates. However, because of concern about neurologic injury after DHCA, there is increasing use of continuous deep hypothermic low-flow cardiopulmonary bypass (DHCPB). This study examines the effects of DHCPB versus DHCA on pulmonary dynamics in 1-week-old piglets (weight range, 2.5 to 3.5 kg). METHODS: Animals were placed on CPB (37 degrees C) at 100 mL.kg-1.min-1, cooled to 18 degrees C, and then assigned to one of two groups: DHCPB (n = 7), 25 to 50 mL.kg-1.min-1 DHCPB for 90 minutes; or DHCA (n = 8), DHCA for 90 minutes. Animals were rewarmed to 37 degrees C, weaned from CPB, and observed for 30 minutes. Static pulmonary compliance and pulmonary vascular resistance index were assessed before CPB, 5 minutes after CPB, and 30 minutes after CPB. RESULTS: There was greater impairment of static pulmonary compliance after DHCPB compared with 90 minutes of DHCA. There was a trend toward higher pulmonary vascular resistance index in the DHCPB group; however, significance was not reached. CONCLUSIONS: Deep hypothermic low flow cardiopulmonary bypass produces greater pulmonary dysfunction than DHCA, manifested by decreased static pulmonary compliance. If DHCPB is used in place of DHCA in congenital heart operations, close attention to ventilatory and fluid management is mandatory in the postoperative period to prevent further worsening of pulmonary dysfunction.

Design and performance of a physiologic pulsatile flow neonate-infant cardiopulmonary bypass system.

The authors have designed an alternative infant cardiopulmonary bypass (CPB) system using the University of Texas neonatal pulsatile pump, which produces physiologic pulsatile flow and allows a low priming volume. This system has been tested with normothermic CPB (n = 8), and deep hypothermic circulatory arrest (n = 14) in 3 kg piglets. Data obtained during these studies suggest that this system can produce flow characteristics that approximate normal physiologic values. Unlike other pulsatile pumps, this pump can produce a very small stroke volume, ranging from 0.5 to 7.1 ml with a pump rate of 120 beats/min. These stroke volumes correspond to our target value of 1 ml/kg body weight. This system is designed to cause minimal hemodilution and minimal exposure of blood to foreign surface areas. The pump does not produce negative pressure, and therefore the venous reservoir is not essential, and only a cardiotomy reservoir is required. Conclusions after in vivo testing are, first, that physiologic pulsatile flow can be achieved readily with this system using a 10 Fr aortic cannula in 3 kg piglets; and second, that a significant reduction in priming volume and hemodilution can be obtained using this system.

Myocardial function is normal after rapid cooling of the in vivo neonatal heart.

Rapid cooling (RC) on cardiopulmonary bypass (CPB) has been reported to be injurious to the neonatal myocardium when compared with slow cooling (SC). However, previous studies have been performed on isolated heart preparations using asanguineous perfusates and may not represent clinically valid conclusions. In this study, the effect of RC versus SC on post-CPB cardiac function in an in vivo neonatal heart model using a blood perfusate was investigated. Thirteen neonatal piglets underwent median sternotomy. Left ventricular ultrasonic dimension transducers were placed in the minor and major axis diameters, and an intraventricular micromanometer was placed. Baseline left ventricular pressure-dimension data were obtained during transient vena caval occlusion. Animals were then placed on CPB (blood prime; mean hematocrit, 25%) with the prime temperature at either 18 degrees C (RC) or 37 degrees C (SC) and perfusion cooled either quickly (RC) or gradually (SC) such that within 2 minutes of cooling the average myocardial temperature was 23.5 degrees C in the RC group versus 33.8 degrees C in the SC group (p = 0.0001). Animals were cooled to 20 degrees C, rewarmed to 37 degrees C, and then weaned from CPB. Left ventricular pressure-dimension data were obtained 30 minutes after CPB and compared with baseline. The slope (MW) and x-intercept (Vo) of the linear stroke work-end-diastolic volume relationship were used as load-insensitive indices of left ventricular function at baseline and after CPB. There was no statistically significant difference in baseline versus postbypass MW or Vo in the RC or SC groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Cerebral metabolic effects of sequential periods of hypothermic circulatory arrest.

During repair of congenital heart defects, extended periods of hypothermic circulatory arrest (CA) have been shown to cause short-term cerebral metabolic and flow abnormalities as well as long-term neuropsychologic dysfunction. Occasionally, a second period of CA is required during the same operative setting to revise a complicated repair. However, the metabolic effects of two consecutive periods of CA on the brain are unclear. In this study, we compared the recovery of cerebral metabolism after 60 minutes of CA with that after two sequential 30-minute periods of CA separated by a brief period of rewarming (30'SEQ). Fifteen neonatal piglets (2 to 3 kg) were placed on cardiopulmonary bypass at 100 mL.kg-1 x min-1 and cooled to 18 degrees C. Each animal then underwent either 60 minutes of uninterrupted cardiopulmonary bypass at 18 degrees C, 60 minutes of CA, or two 30-minute periods of CA separated by a brief period of rewarming. After these experimental periods, animals were rewarmed to 37 degrees C and weaned from cardiopulmonary bypass. Data were obtained before cardiopulmonary bypass and after cardiopulmonary bypass at 37 degrees C and included measurements of cerebral blood flow by xenon 133 clearance, arterial and sagittal sinus blood gases, and cerebral metabolism (mL O2.100 g-1 x min-1). Our results demonstrated that acute recovery of cerebral metabolism was significantly impaired after 60 minutes of CA and that recovery of cerebral metabolism after two sequential 30-minute periods of CA was significantly better than after 60 minutes of continuous CA.(ABSTRACT TRUNCATED AT 250 WORDS)