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Drug repurposing can be cheaper and faster than developing new compounds. Yet, it remains underused, partially because of regulatory and intellectual property challenges. Policy-makers in the United States and Europe have created seven drug development programs that aim to overcome these challenges using a variety of different strategies.

Biobanks are repositories that collect, store and distribute large quantities of biological samples and associated data (collectively called biobank `material'). Although biobanks have different modes of operation, all face a variety of similar challenges. Some of these challenges, such as donor consent and privacy, have been rigorously debated, but comparatively less attention has been paid to biobanks' intellectual property (IP) practices. IP rights (particularly patents) are integral to the translation of research into clinically relevant outcomes and, therefore, are key features in the business models of many biobanks. As a foundation for such research, commentators have identified five IP clauses of interest: (i) non-obstruction clauses; (ii) march-in clauses; (iii) grant-back clauses; (iv) return-of-results clauses and (v) reach-through clauses (also commonly called `reach-through rights'). In the limited literature that discusses the five clauses, commentators have largely debated their advantages and disadvantages in the abstract. The IP terms that biobanks actually use have not been empirically examined, apart from some small case studies. In particular, no industry-wide evidence exists on three points of biobanks' IP practice: (i) if and how biobanks implement these five types of IP clauses, (ii) whether any norms or standards have emerged, and (iii) whether the norms and standards align with commentators' recommendations for using the five IP clauses. To address these three gaps, the authors conducted a systematic, global survey of the IP clauses used by large, human biobanks. The results indicate that biobanks draft bespoke policies to meet their own needs, and probably do so without knowledge of the gamut of IP terms available. This study also revealed that, in general, biobanks are using IP terms differently from the advice of the commentators. On reviewing the differences, we encourage the use of march-in and grant-back clauses, discourage biobanks from using redundant non-obstruction clauses, and call for more research on return-of-results clauses. We also encourage the use of reach-through clauses to claim royalties (not IP), but only in limited circumstances; for example, where user access fees do not cover a biobanks' operational costs., (© The Author(s) 2021. Published by Oxford University Press on behalf of Duke University School of Law, Harvard Law School, Oxford University Press, and Stanford Law School. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

This review explores the recent divergence in international patent law relating to genes and associated subject matter. This divergence stems primarily from decisions of the highest courts in the United States and Australia on the eligibility of patent claims relating to the BRCA gene sequences. Patent offices, courts, and policy makers have struggled for many years to clearly articulate the bounds of patent claims on isolated and synthetic DNA and related products and processes, including methods for their use in genetic diagnostics. This review provides context to the current divergence by mapping key events in the gene patent journey from the early 1980s onward in five key jurisdictions: the United States, the member states of the European Patent Convention, Australia, Canada, and China. Early approaches to gene patenting had some commonalities across jurisdictions, which makes exploration of the recent divergence all the more interesting.There is insufficient empirical evidence to date to confidently predict the consequences of this recent divergence. However, it could potentially have a significant effect on local industry and on consumer access.

Recent US Supreme Court decisions have invalidated patent claims on isolated genomic DNA, and testing methods that applied medical correlations using conventional techniques. As a consequence, US genetic testing laboratories have a relatively low risk of infringing patents on naturally occurring DNA or methods for detecting genomic variants. In Europe, however, such claims remain patentable, and European laboratories risk infringing them. We report the results from a survey that collected data on the impact of patents on European genetic testing laboratories. The results indicate that the proportion of European laboratories that have refrained from providing associated testing services owing to patent protection has increased over the last decade (up from 7% in 2008 to 15% in 2017), and that the non-profit sector was particularly strongly affected (up from 4% in 2008 to 14% in 2017). We renew calls for more readily available legal support to help public sector laboratories deal with patent issues, but we do not recommend aligning European law with US law at present. Watchful monitoring is also recommended to ensure that patents do not become a greater hindrance for clinical genetic testing laboratories.

Whereas biological materials were once transferred freely, there has been a marked shift in the formalisation of exchanges involving these materials, primarily through the use of Material Transfer Agreements (MTAs). This paper considers how risk aversion dominates MTA negotiations and the impact it may have on scientific progress. Risk aversion is often based on unwarranted fears of incurring liability through the use of a material or loss of control or missing out on commercialisation opportunities. Evidence to date has suggested that complexity tends to permeate even straightforward transactions despite extensive efforts to implement simple, standard MTAs. We argue that in most cases, MTAs need do little more than establish provenance, and any attempt to extend MTAs beyond this simple function constitutes stifling behaviour. Drawing on available examples of favourable practice, we point to a number of strategies that may usefully be employed to reduce risk-averse tendencies, including the promotion of simplicity, education of those engaged in the MTA process, and achieving a cultural shift in the way in which technology transfer office (TTO) success is measured in institutions employing MTAs., Competing Interests: We have read the journal's policy and the authors of this manuscript have the following competing interests: Joanne Kamens reports receiving salary from Addgene.

Genome editing using clustered regularly interspersed short palindromic repeats (CRISPR) and CRISPR-associated proteins offers the potential to facilitate safe and effective treatment of genetic diseases refractory to other types of intervention. Here, we identify some of the major challenges for clinicians, regulators, and human research ethics committees in the clinical translation of CRISPR-mediated somatic cell therapy.

In genetic diagnostics testing, what are the boundaries of the global patent problem, and is there a real risk that patents and licensing practices could impede access to tests?

Objective: Health policy and law reform agencies lack a sound evidence base of the impacts of patents on innovation and access to healthcare to assist them in their deliberations. This paper reports the results of a survey of managers of Australian genetic testing laboratories that asked a series of questions relating to the tests they perform, whether they pay to access patented inventions and whether they have received notifications from patent holders about patents associated with particular tests., Results: Some diagnostics facilities are exposed to patent costs, but they are all located in the private sector. No public hospitals reported paying licence fees or royalties beyond those included in the price of commercial test kits. Some respondents reported having received enforcement notices from patent holders, but almost all related to the widely known breast cancer-associated patents. Respondents were also asked for their views on the most effective mechanisms to protect their ability to provide genetic tests now and in the future. Going to the media, paying licence fees, ignoring patent rights and relying on the government to take action were widely seen as most effective. Litigation and applications for compulsory licences were seen as some of the least effective mechanisms., Conclusion: These results provide an evidence base for development of health policy and law reform. What is known about the topic? The impact of patents on the delivery of genetic testing services remains unclear in Australia. What does this paper add? The survey reported in this paper suggests that, aside from well-known enforcement actions relating to the breast cancer associated patents, there is little evidence that providers of genetic testing services are being exposed to aggressive patent-enforcement practices. What are the implications for practitioners? Although patent-enforcement actions may increase in the future, a range of strategies are available to providers of testing services to protect them against adverse consequences of such actions. There are ongoing law reform activities aimed at improving these strategies.

Papillary fibroelastomas are rare and benign cardiac tumors that typically affect the cardiac valves. To the best of our knowledge, the English literature contains only 1 case report of pulmonary valve fibroelastoma diagnosed by echocardiogram and confirmed by surgical resection. There is a paucity of pathology literature on this subject. We describe an additional case of pulmonary valve fibroelastoma diagnosed by transesophageal echocardiography and magnetic resonance imaging confirmed by pathologic examination in a patient who also had a thymoma.

Background: The proportion of patients in their ninth decade of life undergoing complex cardiovascular procedures has increased over the past decade. The purpose of this study is to quantify the potential for stroke and mortality associated with deep hypothermic circulatory arrest (DHCA) in this age group., Methods: At our institution, 251 adult patients had cardiovascular procedures that required DHCA since 1989. This included 20 patients 80 years of age or older (group I) and 231 patients less than 80 years (group II). Additionally, we analyzed 632 patients 80 years of age or older who underwent a variety of cardiovascular procedures since 1989 that required cardiopulmonary bypass but not DHCA (group III). Neurologic outcomes have been maintained in our database prospectively since 1991., Results: The 30-day mortality in group I was 5%, in group II 15.2%, and in group III 8.2%. The stroke rate was 20% in group I, 8.8% in group II, and 6.5% in group III., Conclusions: DHCA can be performed with acceptable early mortality in patients in their ninth decade of life, but they are at an increased risk of stroke. Follow-up shows satisfactory late survival.

Background: Fetal cardiac bypass causes placental dysfunction, characterized by increased placental vascular resistance, decreased placental blood flow, hypoxia, and acidosis. Vasoactive factors produced by the vascular endothelium, such as nitric oxide and endothelin 1, are important regulators of placental vascular tone and may contribute to this placental dysfunction., Methods: To investigate the role of the vascular endothelium in placental dysfunction related to fetal cardiac bypass, we studied 3 groups of fetal sheep. In the first group (n = 7) we determined placental hemodynamic responses before and after bypass to an endothelium-dependent vasodilator (acetylcholine), an endothelium-independent vasodilator (nitroprusside), and endothelin 1. In the second group (n = 8) a nonspecific endothelin receptor blocker (PD 145065) was administered and placental hemodynamic values were measured before and after bypass. In the third group (n = 5) endothelin 1 levels were measured before and after bypass., Results: Before fetal cardiac bypass exogenous endothelin 1 decreased placental blood flow by 9% and increased placental resistance by 9%. After bypass endothelin 1 decreased placental flow by 47% and increased resistance by 106%. There was also a significant attenuation of the placental vascular relaxation response to acetylcholine after bypass, whereas the response to nitroprusside was not significantly altered. In fetuses that received the PD 145065, placental vascular resistance increased significantly less than in control fetuses (28% versus 62%). Similarly, placental blood flow decreased significantly more (from 6. 3 +/- 3.1 to 28.3 +/- 10.4 pg/mL; P =.01) in control fetuses than in fetuses receiving PD 145065 (33% versus 20%). Umbilical venous endothelin 1 levels increased significantly in fetuses exposed to fetal bypass but did not change in control fetuses., Conclusions: The basal endothelial regulatory mechanisms of placental vascular tone were deranged after fetal cardiac bypass. Endothelin receptor blockade, which substantially reduced postbypass placental dysfunction, and other interventions aimed at preserving endothelial function may be effective means of optimizing fetal outcome after cardiac bypass.

The Cardiothoracic Surgery Network is an international collaborative effort among cardiothoracic surgeons that provides a common platform for the exchange of information. The Cardiothoracic Surgery Network website provides peer-reviewed journals, multimedia applications, and a database repository.

Objective: Cryopreserved aortic allograft can be used for aortic valve replacement in congenital, rheumatic, degenerative, and infected native valve conditions, as well as failed prosthetic valves. This study was conducted to determine the long-term results of aortic valve replacement with cryopreserved aortic allografts., Methods: Aortic valve replacement with cryopreserved aortic allografts was performed in 117 patients from July 1985 until August 1996. All patients requiring aortic valve replacement regardless of valve disease were considered for allograft replacement; the valve was preferentially used in patients under age 55 years and in the setting of bacterial endocarditis. Four operative techniques involving cryopreserved aortic allografts were used: freehand aortic valve replacement with 120-degree rotation, freehand aortic valve replacement with intact noncoronary sinus, aortic root enlargement with intact noncoronary sinus, and total aortic root replacement. Valve function was assessed by echocardiography during the operation in 78 patients (66%) and after the operation in 77 patients (65%)., Results: One-hundred eighteen aortic valve replacements with cryopreserved aortic allografts were performed on 117 patients; mean age was 45.6 years (range 15 to 83 years) and mean follow-up was 4.6 years (range up to 11 years). Intraoperative echocardiography disclosed no significant aortic valve incompetence. There were four operative deaths (3%) and seven late deaths; freedom from valve-related mortality at 10 years was 9:3% +/- 4.55%. New York Heart Association functional status at latest follow-up was normal in 98 (94%) patients. On postoperative echocardiography, 90% had no or trivial aortic valve incompetence. Freedom from thromboembolism at 10 years was 100% and from endocarditis, 98% +/- 2.47%. Seven (6%) patients required valve explantation, four for structural deterioration. At 10 years, freedom from reoperation for allograft-related causes was 92% +/- 3.47%., Conclusions: Aortic valve replacement with cryopreserved aortic allografts can be performed with low perioperative and long-term mortality. Most patients have excellent functional status, and reoperation for valve-related causes is unusual. Aortic valve replacement with cryopreserved aortic allografts demonstrates excellent freedom from thromboembolism, endocarditis, and progressive valve incompetence.

Background: Increasing the heart rate of the fetus with cardiac failure caused by complete AV block (CAVB) may allow delivery of a full-term, stable neonate with preserved ventricular function. Direct fetal pacing may be a feasible method to achieve this, but the effect of pacing on the structure and function of the rapidly developing fetal heart is unknown., Methods and Results: CAVB was created in fetal lambs at 80% gestation by cryoablating the AV node. Epicardial ventricular pacing at 130 bpm was achieved by use of a pacemaker placed under the pectoral muscles. The fetus was returned to the uterus and allowed to continue to term. Ventricular function was assessed 1 week after birth in 7 lambs with CAVB and 10 control lambs. By use of the conductance catheter technique, the end-systolic pressure-volume relationship was determined at different heart rates, pacing conditions, and inotropic states. The contractility was not different between the two groups at their baseline heart rates and rhythms or when they were paced synchronously compared with asynchronously. Also, both groups responded significantly and similarly to inotropic manipulation, indicating preserved contractile reserve. Finally, in both groups, increased heart rates were associated with increased contractility, indicating an intact force-frequency relationship., Conclusions: We conclude that chronic epicardial ventricular pacing is well tolerated by the fetus, can be successfully applied as a treatment for CAVB, and does not adversely affect myocardial function in the rapidly developing, immature heart.

Background: This study examined the ability of autopsy to confirm or dispute presumptive cause of death among cardiac surgery patients., Methods: Autopsy reports were compared with mortality conference notes that were dictated prospectively before autopsy results were available. Between January 1985 and December 1995, there were 600 hospital deaths among 13,029 adult cardiac surgery patients (4.6% mortality). Of these 600 deaths, 147 (24.5%) had postmortem examination., Results: Annual autopsy rate remained constant over the course of the study. Autopsied patients were younger (60.4 +/- 15 versus 66.7 +/- 13 years [mean +/- standard error of the mean]; p < 0.0001), but their race and sex distributions were similar to deceased patients not having autopsy. Autopsy confirmed clinical presumptive cause of death in 52% (76), disputed clinical diagnosis in 9.5% (14), provided definitive diagnosis in the absence of clinical diagnosis in 13.6% (20), and failed to provide definitive diagnosis in 25% (37). One third of autopsies (39%; 57) provided information that was clinically unrecognized and might have altered therapy and outcome if known premortem. As determined by autopsy, common causes of death were cardiac (27%; 39), unknown (25%; 37), sepsis (14%; 21), stroke (8.8%; 13), cholesterol embolism (4.1%; 6), pulmonary embolism (4.1%; 6), and adult respiratory distress syndrome (4.1%; 6)., Conclusions: Autopsy reveals or confirms cause of death in nearly three quarters of cardiac surgical deaths and provides information that differs significantly from premortem clinical impression more than 20% of the time. As such, the autopsy remains important to quality assurance in cardiac surgical care.

Objectives: A reproducible fetal animal model of single-ventricle physiology was created to examine the effects of pharmacologic agents commonly used in the perinatal and perioperative intensive care management of patients with a single ventricle., Background: Single-ventricle physiology is characterized by parallel pulmonary and systemic circulations, with effective blood flow to each determined by the relative resistances in the pulmonary and systemic vascular beds. Perinatal and perioperative management of these patients is largely based on empiric observations and differs considerably between institutions and is further complicated by the transitional physiology of the newborn. The lack of animal models of single-ventricle physiology has hindered the understanding of this problem., Methods: A 10-mm, Damus-Kaye-Stansel-type aortopulmonary anastomosis was created in 10 fetal sheep at 140 +/- 1.2 days of gestation. The main pulmonary artery was ligated distally, and pulmonary blood flow (Qp) was provided through a 5-mm aortopulmonary shunt. Eight lambs were delivered at term and placed on cardiopulmonary bypass (30 min) 48 to 72 h after birth. Pharmacologic interventions (0.1 microgram/kg body weight per min of epinephrine, 2 mEq/kg of sodium bicarbonate and 10 mg/kg of calcium chloride) were performed before and after bypass, and hemodynamic responses were observed. The response to the epinephrine bolus was determined only in the postbypass study., Results: Both before and after bypass, epinephrine infusion and calcium and bicarbonate administration increased Qp and systemic blood flow (Qs) (total cardiac output) but produced only small changes in the Qp/Qs ratio (-0.5% to -7.3% change). With the epinephrine bolus, Qp increased enormously, and the Qp/Qs ratio increased by 584% (p < 0.001)., Conclusions: In neonatal lambs with single-ventricle physiology created in utero, epinephrine infusion and calcium and bicarbonate administration increased total cardiac output without significantly compromising the Qp/Qs ratio. However, epinephrine bolus seems to be hemodynamically detrimental in circumstances of single-ventricle physiology and should be used with caution and probably in relatively lower doses in the resuscitation of patients with single-ventricle physiology. Further investigation of the dose-dependent effects and the effects of prolonged administration of common pharmacologic agents will enable better management of patients with single-ventricle physiology.

Background: Progressive metabolic acidosis, hypoxia, and hypercarbia develop rapidly after fetal cardiac bypass mainly as a result of an increase in placental vascular resistance and a decrease in placental blood flow. A number of factors including fetal stress, priming substances, and extracorporeal surfaces have been identified as possible stimuli causing this placental dysfunction. The purpose of this study was to examine the effects of avoiding priming volume and minimizing extracorporeal surface area on placental hemodynamics and function., Methods: Fetal sheep (n = 16) at 118 to 122 days of gestation were subjected to cardiac bypass for 30 minutes using either an in-line axial-flow pump (Hemopump group: n = 8, no prime) or a roller pump with a venous reservoir (control group: n = 8, priming volume = 150 mL). After bypass, the fetuses were observed for 90 minutes. Placental blood flow and combined ventricular output were continuously measured with ultrasonic flow probes, and fetal blood gases were measured at specific intervals., Results: Three fetuses in the control group died during the study, whereas all 8 fetuses in the Hemopump group remained in stable condition throughout the study period. During and after bypass, placental blood flow was significantly higher (p < 0.0001) and placental vascular resistance was significantly lower (p < 0.0001) in the Hemopump group than in the control group. Arterial pH and partial pressure of arterial oxygen declined significantly less (p < 0.0001), and partial pressure of arterial carbon dioxide increased significantly less (p = 0.0002) in the Hemopump group than in the control group., Conclusions: Reducing the extracorporeal surface area and avoiding external priming substances preserves placental hemodynamics after fetal cardiac bypass. An in-line axial-flow pump is useful in miniaturizing the bypass circuits for potential use in fetal cardiac surgery.

Background: In patients with single ventricle physiology, the distribution of flow to the systemic and pulmonary circulations, which are in parallel, largely depends on the relative resistances in the respective vascular beds. Although neonatal palliation in patients with single ventricle physiology has become more common, medical management during the perinatal and perioperative periods is often based primarily on personal and institutional experience and is complicated by the transition to postnatal life and the effects of cardiopulmonary bypass. The lack of an animal model that suitably mimics single ventricle physiology has impeded progress in this area., Objective: The purpose of the current study was to investigate the effects of respiratory manipulations on pulmonary hemodynamics in the early neonatal period in a reproducible model of single ventricle physiology created in utero., Methods: A 10 mm Damus-Kaye-Stansel aortopulmonary anastomosis was created in fetal sheep (n = 14) at 140 +/- 1.2 days' gestation, with pulmonary blood flow provided through a 5 mm aortopulmonary shunt after ligation of the main pulmonary artery distally. Two to 3 days after delivery at term, lambs (n = 11) underwent an open sternotomy and 30 minutes of deep hypothermic circulatory arrest. Both before and after bypass, respiratory manipulations, including administration of nitric oxide (80 ppm), 100% oxygen, 10% oxygen, and 5% carbon dioxide, were performed and hemodynamic variables were measured., Results: Nitric oxide and oxygen caused a decrease in pulmonary vascular resistance and an increase in the pulmonary/systemic blood flow ratio, both before and after bypass. Hypoxia and carbon dioxide produced a significant rise in pulmonary vascular resistance and a significant drop in the ratio of pulmonary to systemic blood flow., Conclusions: Oxygen, nitric oxide, and carbon dioxide all appear to be useful means of manipulating pulmonary vascular resistance and pulmonary/systemic blood flow ratio in neonatal lambs with single ventricle physiology, but further investigation is necessary to understand their dose responsive effects and the effects of prolonged administration.

Background: Earlier work suggests that fetal cardiac bypass is technically feasible but results in significant placental dysfunction. Many of the stimuli that initiate this placental dysfunction have been identified in the past several years and these involve fetal stress, extracorporeal surfaces, priming substances (maternal blood), and flow characteristics. Fetal survival with conventional methods of bypass has been far less than optimal. A novel fetal bypass circuit requiring no priming volume was designed incorporating an in-line axial flow pump (Hemopump, Johnson & Johnson Interventional Systems, Rancho Cordova, Calif.) and was demonstrated to have a marked beneficial effect on placental function., Objective: The purpose of this study was to investigate the effect of this newly developed customized fetal bypass circuit on fetal survival and developing fetal organs., Methods and Results: Nine fetuses at 122 to 126 days of gestation were subjected to fetal cardiac bypass via a transsternal approach, with a 16F single right atrial venous cannula and a 12F arterial cannula. Normothermic cardiac bypass was continued for 30 minutes at flow rates of 320 +/- 32 ml/kg. Of the nine fetuses, one fetus was stillborn 4 days after bypass and eight (89%) were delivered alive after progressing to term gestation. One lamb died of blunt trauma 1 day after birth. All other lambs (n = 7) thrived normally, and at 1 week of age they were subjected to autopsy. No gross hemorrhagic or thromboembolic lesions were detected in the organs examined including the brain. Microscopic examination of representative sections from all organs revealed mild pleural reaction in two lambs, and in two other lambs the hepatocytes showed evidence of mild increase in glycogen content, the significance of which is unknown in relation to fetal bypass. In one fetus that was aborted there was evidence of mild to moderate neuronal loss in the cerebral cortex., Conclusion: This study demonstrates that with improvements in fetal extracorporeal circuitry and techniques very favorable fetal outcome can be achieved. Further studies are necessary to evaluate the effects of bypass on fetal brain in an appropriate animal model. Advances in extracorporeal circuitry to suit the unique fetal physiology increase the possibility of future clinical application.

Background: Although primary repair of tetralogy of Fallot is increasingly undertaken in infancy, complete repair is generally performed in only selected symptomatic neonates., Methods: From July 1992 through March 1995, 30 consecutive neonates and young infants with tetralogy of Fallot underwent routine primary repair. Group I (n = 10) consisted of patients with tetralogy of Fallot and pulmonary atresia (n = 5) or severe pulmonary stenosis (n = 5) who were duct dependent and were repaired in the neonatal period. Group II (n = 11) consisted of patients who were asymptomatic with arterial oxygen saturation between 75% and 90% (adequate pulmonary blood flow). Group III (n = 9) consisted of patients with "pink" tetralogy of Fallot (arterial oxygen saturation > 90%). Patients in groups II and III were electively scheduled for repair at about 2 months of age., Results: The postrepair peak systolic right ventricular-to-peak systolic left ventricular pressure ratio did not correlate (p = 0.96) with the branch pulmonary artery size. One patient died 2 months after operation, despite good hemodynamics, of uncontrollable diffuse subcutaneous edema due to familial distichiasis lymphedema syndrome. There were no late deaths. At a median follow-up of 19 months, 1 patient underwent balloon dilation of branch pulmonary arteries. Follow-up echocardiography revealed a 30 to 60 mm Hg right ventricle-to-pulmonary artery gradient in 3 patients., Conclusions: Excellent early and midterm results can be accomplished with routine primary repair of tetralogy of Fallot in early infancy regardless of age, symptomatic status, coronary anatomy, and the size of branch pulmonary arteries as long as they arborize normally.

Background: The development of pulmonary hypertension and its associated increased vascular reactivity is a common accompaniment of congenital heart disease with increased pulmonary blood flow. Although the morphology of the pulmonary vascular changes is well described, the mechanisms of vascular remodeling and increased reactivity remain incompletely understood., Methods and Results: To elucidate these mechanisms, we established an accurate and reliable experimental model of pulmonary hypertension with increased pulmonary blood flow. An aortopulmonary shunt was created with an 8.0-mm expanded polytetrafluoroethylene vascular graft in 11 late-gestation fetal lambs. At 1 month of age, shunted lambs had a pulmonary-to-systemic blood flow ratio of 2.2 +/- 1.2. Compared with 11 age-matched control lambs, mean pulmonary arterial pressure (44.8 +/- 11.7 versus 16.2 +/- 2.9 mm Hg) and the ratio of pulmonary to systemic arterial pressure were significantly increased (P < .05). Pulmonary vascular resistance was not significantly increased. The pulmonary vasoconstricting response to the infusion of U46619 (a thromboxane A2 mimic) or acute alveolar hypoxia also was augmented in the shunted lambs. Morphometric analysis of the barium-filled pulmonary artery bed revealed medial hypertrophy, abnormal extension of muscle distally into the walls of the intra-acinar arteries, and increased numbers of barium-filled intra-acinar arteries., Conclusions: In utero placement of aortopulmonary shunts reproduces the aberrant hemodynamic state of children with cogenital heart disease with left-to-right shunts; postnatal pulmonary hypertension, increased pulmonary blood flow, and vascular remodeling. In addition, the lambs have a unique paradoxical increase in pulmonary vascular volume that attenuates an increase in pulmonary vascular resistance. This experimental preparation provides a useful and consistent model for the study of the pathogenesis of pulmonary hypertension.

The performance of a primary bidirectional superior cavopulmonary shunt procedure in early infancy is attractive because it minimizes the number of operations needed before a Fontan procedure, avoids ventricular volume overload and its sequelae, and eliminates pulmonary artery distortion. However, concerns over elevated or labile pulmonary vascular resistance have limited its use in the first few months of life. Nine patients aged 1 to 4 months (5 patients, < 2 months) have undergone a primary bidirectional superior cavopulmonary shunt procedure between October 1992 and March 1994. Primary diagnoses were tricuspid atresia (n = 4), asplenia syndrome (n = 2), polysplenia syndrome (n = 1), double-outlet right ventricle (n = 1), and double-inlet left ventricle (n = 1). Associated lesions of immediate surgical importance were total anomalous pulmonary veins (n = 2), a restrictive atrial septum (n = 4), bilateral superior venae cavae (n = 5), and patent ductus arteriosus (n = 5). The surgical procedure consisted of unilateral (n = 4) or bilateral (n = 5) bidirectional superior cavopulmonary shunt and the repair of associated lesions. Of significance, in 4 of our first 5 patients a very limited additional source of pulmonary blood flow was provided because of a low arterial oxygen tension immediately after cardiopulmonary bypass. Pleural effusions developed in 2 of these 4 patients. In subsequent patients cardiopulmonary bypass was not used whenever possible or, if it was needed, use of an extra source of pulmonary blood flow was avoided.(ABSTRACT TRUNCATED AT 250 WORDS)

Traditionally patients with pulmonary atresia, ventricular septal defect, diminutive or absent central pulmonary arteries, and multiple aortopulmonary collaterals have been managed by staged procedures necessitating multiple operations. We have taken a different approach to this lesion. Between August 1992 and March 1994, ten patients aged 1.43 months to 37.34 years (median 2.08 years) at the severe end of the morphologic spectrum of this lesion underwent a one-stage complete unifocalization and repair from a midline sternotomy approach. The median Nakata index of true pulmonary arteries was 50.0 (range 0 to 103.13) and they provided vascular supply to up to nine lung segments (median 5 segments). The number of collaterals per patient ranged from two to five with a median of four. The collaterals provided vascular supply to a median of 15 lung segments per patient (range 11 to 20). Complete unifocalization was achieved in all patients with emphasis on native tissue-to-tissue connections via anastomosis of collaterals to other collaterals and to the native pulmonary arteries. In only one patient (37.34 years old) was it necessary to use a non-native conduit for peripheral pulmonary artery reconstruction. The ventricular septal defect was left open in one patient (5 years old) because of diffuse distal hypoplasia and stenosis of the pulmonary arteries and the collaterals. The postrepair peak systolic right ventricular/left ventricular pressure ratio ranged from 0.31 to 0.58 (median 0.47). There were no early deaths. Complications were bleeding necessitating reexploration in one patient, phrenic nerve palsy in three patients, and severe bronchospasm in three patients. Follow-up (median 8 months, range 2 to 19 months) was complete in all patients. One patient was reoperated on for pseudoaneurysm of the central homograft conduit and then again for stenosis of the left lower lobe collateral. After this last operation at 13 months after the initial repair she died of a preventable cardiac arrest caused by pneumothorax. The patient with open ventricular septal defect underwent balloon dilation of the unifocalized pulmonary arteries, with a current pulmonary/systemic flow ratio of 1.4 to 1.8:1, and is awaiting ventricular septal defect closure. One other patient underwent balloon dilation of the reconstructed right pulmonary artery, with a good result. All survivors (9/10) are clinically doing well. This approach establishes normal cardiovascular physiology early in life, eliminates the need for multiple systemic-pulmonary artery shunts and use of prosthetic material, and minimizes the number of operations required.(ABSTRACT TRUNCATED AT 400 WORDS)

Interrupted aortic arch can be associated with transposition of the great arteries with ventricular septal defect and with the Taussig-Bing anomaly. This usually results in a marked disparity between the hypoplastic ascending aorta and the dilated main pulmonary artery. Currently, standard arterial switch and arch repair is a widely applied approach to the surgical management of these lesions. Though the morphology of the great vessels in these lesions does not preclude this approach, the great-vessel mismatch can result in difficulties at and beyond the proximal neo-aortic to ascending aortic suture line that cause excessive bleeding, obstruction, tension, distortion, and the need of patch augmentation of the ascending aorta or arch with nonviable material. We present an alternative surgical approach used in 2 patients, 1 with Taussig-Bing anomaly and interrupted aortic arch and the other with transposition of the great arteries, ventricular septal defect, and interrupted aortic arch, that greatly simplifies the reconstruction of the neo-aorta and repair of the interrupted arch and avoids these potential hazards.

The initial experience with cardiac bypass in fetal lambs resulted in early fetal death from placental insufficiency. Subsequent work in our laboratory indicated that vasoactive cyclooxygenase products were released as mediators of this response. The placental dysfunction could be blocked by the administration of indomethacin, allowing longer fetal survival. This unmasked a more subacute (but fatal) problem: fetal surgical stress resulted in diminished fetal cardiac output and progressive metabolic acidosis and contributed to the placental vasoconstriction. In acute studies, when indomethacin was given and the stress response was inhibited by the use of total spinal anesthesia, the fetus maintained normal blood gas levels, cardiac output, placental blood flow, and acid-base status for several hours after bypass. We hypothesized that beyond this point, no further fetal or placental compromise would occur and that this management technique would thus allow long-term fetal survival. With the use of total spinal anesthesia and sterile technique for long-term study, 12 fetal lambs at 120 days (80%) gestation underwent exposure, line placement, and cannulation for fetal cardiac bypass. Indomethacin was given intravenously on obtaining venous access. After 20 minutes of normothermic cardiac bypass at flow rates of 250 to 300 ml/kg/min, the fetus was weaned from bypass, the cannulas and lines were removed, the uterus and abdomen were closed, and the ewe and fetus were allowed to recover. There was one maternal death (pneumonia) and one early abortion (of twins); the remaining 10 ewes progressed to term. At term, five healthy lambs that had undergone fetal cardiac bypass were delivered (including one twin), four ewes delivered a mummified study fetus and one or two healthy siblings, and one delivered a dead term fetus. With the use of techniques that inhibit fetal stress and block placental vasoconstriction, cardiac bypass can be performed in single-gestation fetal lambs with a high degree of recovery and survival (80% in this study). The cause of the elevated abortion rate associated with twin gestation is unclear.

Cardiac bypass in late-gestation fetal lambs causes severe placental vasoconstriction, which leads to fetal death from hypoxemia and respiratory acidosis. This response can be blocked by the administration of indomethacin; however, a fatal metabolic acidosis then gradually develops in the fetus. Because the fetus is known to mount an intensive catecholamine response to stress, and because the fetal myocardium is particularly sensitive to increased afterload, we hypothesized that elevated afterload as a result of fetal stress contributes to diminished cardiac output after bypass. Twenty fetal lambs at 80% gestation underwent 30 minutes of normothermic cardiac bypass at flow rates of 200 to 500 ml/kg per minute. All ewes received general anesthesia with ketamine. In 10 fetuses general anesthesia was specifically designed not to inhibit the release of stress-related catechols (ketamine); the remaining 10 fetuses received a "high" (cisterna magna) total spinal anesthetic with tetracaine, to block the fetal stress response. In each anesthetic group, 5 of the 10 lambs received indomethacin. During operation, normal hemodynamics were preserved in the spinal anesthetic group. Cardiac output, placental blood flow, and arterial carbon dioxide tension were all improved relative to results in the ketamine group. When spinal anesthesia and indomethacin are both given, hemodynamics also approach normal after bypass, and gas exchange is further improved. These data suggest that the inhibition of the stress response by spinal anesthesia improves the hemodynamic status of the fetus during operation and, in combination with indomethacin, allows maintenance of near-normal placental function after fetal cardiac bypass. Similar responses may also be possible in human fetuses with use of a high-dose narcotic technique.

We investigated the effects of cryopreservation, immunosuppression, and antibiotic treatment on the patency and histologic appearance of venous conduits in the arterial circulation. Twenty-eight dogs received arterial replacements with autograft vein, fresh allograft, and two types of cryopreserved allograft vein implanted into both carotid and both femoral arteries. All animals were given aspirin, and half were given cyclosporine. After 3 months the vein grafts were harvested. Patency and light, transmission, and scanning electron microscopic criteria were scored to evaluate quality of preservation of the endothelium, the appearance of rejection, and the effects of cryopreservation with and without antibiotic pretreatment. The results show that patency is not statistically different based on graft type or treatment modality. The histologic appearance among the various vein types was remarkably similar at 3 months, with the exception of a cellular infiltrate present most prominently in the fresh allografts and least in the fresh autografts. Cyclosporine, even at a low dose, decreased the incidence of cellular infiltration. Preservation of endothelium was generally good in the cryopreserved allografts both with and without antibiotic pretreatment. In general, the effects of cryopreservation, cyclosporine, and antibiotics ameliorated the effects of venous allografting into an arterial position.

Retrograde cardioplegia has gained popularity in coronary and noncoronary cardiac operations. We have used contrast echocardiography in the open-chest canine model to compare the distribution of cardioplegia delivered antegrade in the aortic root versus retrograde through the coronary sinus, and to determine the effect of coronary occlusion on that delivery. With no coronary occlusion, antegrade cardioplegia was distributed to the entire left ventricle and septum whereas retrograde cardioplegia was distributed to the left ventricular free wall but had inconsistent delivery to the septum. Acute occlusion of the left circumflex coronary artery resulted in 57.06% +/- 9.52% of the left ventricle not being perfused by antegrade cardioplegia and occlusion of both the left circumflex and anterior descending coronary arteries caused a 65.46% +/- 18.5% reduction in perfusion by antegrade cardioplegia. Acute coronary occlusion had no effect on retrograde cardioplegia distribution. We conclude that retrograde cardioplegia is less homogeneous than antegrade cardioplegia in the intact coronary circulation but that retrograde cardioplegia preserves cardioplegia distal to acutely occluded coronary arteries. Furthermore, contrast echocardiography is a useful method of assessing myocardial perfusion and may have useful clinical applications.

Aneurysms of the ascending aorta, if undiagnosed or untreated, may result in left ventricular failure from aortic valvular insufficiency. Aortic rupture, dissection, or compression of adjacent vital structures may also occur. The application of refined cardiopulmonary bypass devices, prosthetic heart valves, and synthetic grafts now allows successful surgical management of this disorder. This report presents our current diagnostic methods, surgical techniques, and the early and late results of 100 consecutive patients undergoing surgical treatment of aneurysms of the ascending aorta. There were 72 males and 28 females, ranging in age from 25 to 72 (ave 51.2) years. All patients had angiographic studies to demonstrate precisely the location of the aneurysm and the presence or absence of aortic valvular insufficiency. Sixty-three patients required concomitant aortic valve replacement, and the remaining 37 patients had only aneurysm resection and replacement. Pathological studies revealed 69 aneurysms were atherosclerotic, 22 were secondary to cystic medial necrosis, with the remaining 9 considered to be possibly leutic in origin. Despite the magnitude of the surgery and the advanced ages of some of these patients, the overall operative and hospital mortality rates were 4% and 9%. Survival rates by actuarial representation in 82 patients at 2, 4, 6, and 8 years were 82.9%, 78%, 70%, and 69.5%, respectively.

A 55-year-old man underwent insection of a Hufnagel valve into his descending thoracic aorta for aortic valve insufficiency 18 years ago. He remained asymptomatic for 16 years. Because of progressive left ventricular failure his incompetent aortic valve was replaced with a De Bakey carbon ball aortic valve prosthesis 2 years later. Currently, 21 months after the operation, he is doing well with two aortic valves. Review of the literature suggests that he is the first patient reported with two aortic valves functioning concomitantly and one of the longest surviving patients with a Hufnagel valve.

Minor technical errors may jeopardize the patency of femoral-popliteal bypass grafts. In an attempt to detect such errors, intraoperative arteriography has been routinely employed. It allows immediate recognition and correction of the most common abnormal findings: intraluminal debris, intimal dissection, distal thrombosis, arterial spasm, and kinking of the graft.

Early clinical application of technetium 99m labeled pyrophosphate for cardiac imaging has revealed a safe noninvasive method of determining areas of impaired myocardial perfusion in patients with atherosclerotic occlusive coronary artery disease. Using this method, we were able to demonstrate improvement in myocardial blood supply following coronary artery bypass surgery.

Numerous studies have demonstrated the superiority of membrane oxygenators (MO) over the bubble oxygenators (BO) when used for prolonged cardiopulmonary support. However, there is little information available evaluating the MO for routine, short-term cardiopulmonary bypass. In this study the 5MO314 Modulung-Teflo (MO) was compared to 5M30314 Miniprime Variflo (BO). The data of 91 patients (46 MO and 45 BO) were analyzed according to the duration of cardiopulmonary bypass (Group I less than 60 min., Group II 60-90 min. and Group III greater than 90 min.). Hemodynamic parameters, fluid and blood balance, as well as hematologic and blood gas studies were used for comparing the two oxygentors. The hemodynamic parameters were better, and the arterial blood gases were more physilogic with the MO. The postoperative blood loss was significantly less when using the MO. The other measurements documented the stability of the MO. All statements were based on statistical analysis with a DEC PDP-9 computer, using the MIIS language and operating system. Consequently, we are now using this MO for routine cardiopulmonary bypass.

Following "vein stripping" for varicosities, two patients were referred to our service for evaluation of arterial insufficiency of the lower extremities. Both patients had had surgical interruption of the femoral arterial system which required reconstruction. This paper emphasizes the importance of understanding surgical anatomy and presents the techniques of successful surgical management of both cases.