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I n the last decade, refinement of surgical techniques, evolution of immunosuppression, and advances in infection and rejection management after heart and/or lung transplantation have produced improvements in survival rates. Because transplantation is recognised as the best therapeutic option for an expanding number of patients with end-stage heart and lung diseases, the number of patients referred for transplantation is increasing. Before 1980, less than 350 heart transplantations were performed annually worldwide. Numbers steadily increased through the 1980s to almost 4,000 per annum by 1990 (Fig l).’ Thereafter, the number of heart and lung transplantations reached a plateau and started to decline in the last few years. Conversely, in the United Kingdom alone, 100,000 new cases of heart failure are reported each year.* The limited availability ofdonor organs results in a steady increase in both waiting times and the number of patients dying while on the waiting lists. High standards of donor care are required to ensure the maximum yield of organs for transplantation from all potential donors. The active management of donors is therefore an essential part of every transplant program. Donor selection criteria have long been established.3 The absolute contraindications to organ donation remain unchanged. These include septicaemia, extracranial malignancy, hepatitis B or C, and infection with human immunodeficiency virus. A previous myocardial infarction precludes the use of the heart for transplantation. Evidence of chronic obstructive airways disease, significant lung trauma, infection, neurogenic pulmonary oedema, and previous thoracic surgery are exclusion criteria for the use of lungs for transplantation. In an attempt to increase the donor pool; many centres have relaxed the classic donor criteria. Hearts from donors aged up to 65 years have been used, as

Transbronchial biopsies (TBBs) are useful to diagnose acute rejection and infection in patients with lung transplants. The value of routine surveillance biopsies (S-TBBs) is not known, and such biopsies with a clinical indication are not without risk and are expensive. One hundred twenty-six 6-mo survivors of heart-lung transplantation (HLT) were studied to determine the effect of stopping S-TBBs on the development of bronchiolitis obliterans syndrome (BOS) and subsequent survival. Fifty-one received transplants while S-TBB was part of routine care (group A), and 75 received transplants after this practice was stopped (group B). There was no difference in patient characteristics. Group A had shorter graft ischemia (p < 0.01) and longer postoperative ventilation (p < 0.01). Maintenance immunosuppression was similar, but group A had more steroid pulses in the second 6 mo after HLT (p < 0.01). The number of patients free from any functional deterioration at 49 to 60 mo after HLT declined to 39% in group A and 64% in group B. The risk of developing BOS grade 1 in group A relative to group B was 1.63 (95% confidence intervals: 0.96-2.79, p = 0.07). Patient survival was similar in the two groups. A total of 86 TBBs were taken in the absence of any signs or symptoms and had low diagnostic yield. In summary, there was no increased incidence of BOS after stopping S-TBBs.

Lung volumes after heart-lung transplantation (HLT) were recorded and compared with measurements at the time of assessment for surgery and the predicted values for recipients. The influence of donor lung size and recipients' underlying lung disease was evaluated. All patients underwent HLT between April 1984 and April 1991, and only those 82 who survived for at least 6 mo were studied. Mean total lung capacity (TLC) at preoperative assessment was 112% (SD = 28%) of the value predicted for recipients. One month after HLT, mean TLC was 83% (SD = 15%) of the predicted value but increased to 100% (SD = 15%) after 9 mo. No further change in average TLC occurred for 5 yr subsequently. The mean TLC of patients with emphysema before surgery was 164% (SD = 26%) of the predicted value and fell to the predicted value within 1 mo of HLT. The TLC in patients with primary pulmonary hypertension before surgery was close to the predicted value, but postoperative predicted TLC was achieved later than in emphysema patients. A donor-versus-recipient difference in TLC of more than 1L at the time of assessment did not influence the adaptation to the predicted value. FEV1 and vital capacity (VC) rose from means of 70% (SD = 25%) and 63% (SD = 20%) at 1 mo to 96% (SD = 27%) and 91% (SD = 18%), respectively, at 9 mo after HLT. After HLT, TLC returns to the predicted value for the recipient, and not to the preoperative TLC.(ABSTRACT TRUNCATED AT 250 WORDS)

Traditional clinical assessment of cardiac function has relied on the indirect measurement of systemic blood pressure, heart rate and rhythm, and central venous pressure. However, because the circulation comprises complex interactions between flow and impedance in two hydraulic systems coupled in series, the usual assumptions drawn from the measurement of only a representative sample of this system can lead to serious errors in interpretation. This is particularly significant in conditions leading to physiologic distortions. Patients undergoing major surgery, or with suspected cardiac dysfunction, can only be adequately managed with a knowledge of both right and left heart pressures, together with the measurement of cardiac output. This report presents a rationale for the use of a simple method for interpreting these data and a guide to optimizing management. For those patients with heart failure who are unable to be sustained with conventional pharmacology, criteria are suggested that may help the clinician decide when more aggressive intervention, such as mechanical assist, is required.

By audit from January to June 1989 to quantify, separately for hearts, kidneys, liver, lungs and corneas, the possible increases in transplantable organs from brain stem dead potential donors in intensive care units and to compare them with the increases achieved in October-November 1989, during intense, national publicity about transplantation.Prospective audit of all deaths in intensive care units in England from 1 January to 30 June 1989 and subsequent case study of the impact of publicity on offers and donations during October-November 1989.15 regional and special health authorities in England.5803 patients dying in intensive care units, of whom 497 were confirmed as brain stem dead and had no general medical contraindication to organ donation.Organ specific suitability for transplantation (as reported by intensive care units); consent for donation of specific suitable organs; and procurement of specific organs reported as suitable for transplantation and offered.In the 497 (8.6%) brain stem dead potential donors were estimated the organ specific suitability for heart as 63%, kidneys 95%, liver 70%, lungs 29%, and corneas 91%. Refusal of relatives (30%) accounted for major losses of suitable organs of all types. For kidneys the loss was equivalent to 44% of brain stem dead actual kidney donors. No discussion of organ donation was the second most important reason for missed kidney donors, the loss being equivalent to 10% of brain stem dead actual donors. Non-procurement or difficulties with allocating organs was the second most notable cause of missed suitable liver and lung donors; 29% (55) of the offered total of 189 liver donors and 27% (21) of 78 offered suitable lung donors in six months. Non-procurement of suitable, offered organs was rare for kidneys and modest, of the order of 13% and 10% respectively, for heart and corneas. Corneal donation from brain stem dead potential donors might be improved nearly as much (that is, a 78% increase in brain stem dead actual corneal donors) by specific measures to promote corneal donation when other organs are offered as by reducing the overall refusal rate. Restricted offers, non-procurement, and no discussion of donation accounted for nearly equal numbers of lost donations of hearts (each equivalent to 15% of donated hearts). During October-November 1989 when there was intense, positive publicity about transplantation the rates of refusal and non-discussion fell compared with during January-June (22%, 36/163 v 30%, 138/460; 7%, 33/497 v 2%, 4/167 respectively). Offers of suitable donors increased significantly (p less than 0.02) compared with the first six months of 1989, most notably for heart donors (80 v 60.1 expected) and kidney donors (122 v 102.1 expected) but only for kidneys was there a noticeable 17% increase in actual donors (118 actual audited donors v 100.8 expected donors; p = 0.09).Four strategies to increase the supply of transplantable organs from brain stem dead potential donors in intensive care units were identified: (a) reducing refusal of relatives (b) avoiding non-procurement of actually suitable organs (by logistical initiatives) and deterioration of initially suitable organs (by donor care initiatives); (c) converting restricted offers to unrestricted offers; and (d) ensuring discussion with families. Early referral to the transplant team or coordinator gives time for discussion about donor care and agreement on medical suitability for donation of specific organs. Solving some of the logistical problems of non-procurement may be a prerequisite for increased offers to be translated into increased donations. The impact of publicity therefore needs to be measured on offers of suitable donors as well as by actual donations.Setting -- 15 regional and special health authorities in England... Conclusions -- four strategies to increase the supply of transplantable organs from brain stem dead potential donors in intensive care units were identified: (a) reducing refusal of relatives; (b) avoiding non-procurement of actually suitable organs (by logistical initiatives) and deterioration of initially suitable organs (by donor care initiatives); (c) converting restricted offers to unrestricted offers; and (d) ensuring discussion with families. Early referral to the transplant team or coordinator gives time for discussion about donor care and agreement on medical suitability for donation for specific organs. Solving some of the logistical problems for non-procurement may be a prerequisite for increased offers to be translated into increased donations. The impact of publicity therefore needs to be measured on offers of suitable donors as well as by actual donations.

Sixty transbronchial biopsies have been performed in eight children after heart-lung transplantation. The selection of fiber-optic bronchoscope or a small (4 mm; 30 cm) rigid bronchoscope was made according to the size of endotracheal tube required at surgery. If the endotracheal tube was size 7.5 or greater, a fiber-optic bronchoscope was used, whereas if the endotracheal tube size was below 7, a rigid bronchoscope was used. For the diagnosis of lung rejection, the histology of biopsies revealed a sensitivity of 91% and specificity of 69% (similar to the result in adults). The histology also distinguished lung infection from rejection. Complications included three pneumothoraces and two clinically significant episodes of hemorrhage, one of which led to a cardiorespiratory arrest, which may have been caused by hypoxia. As a result, arterial oxygen saturation is now monitored during the procedure using a pulse oximeter.

Neural cell adhesion molecule (N-CAM) has been implicated in cellular interactions involved in cardiac morphogenesis and innervation. Immunohistochemical techniques and Western blot analysis were used to determine the localization and isoforms of N-CAM in the developing and extrinsically denervated human heart. Myocardial and conducting cells in the fetal heart (7-24 wk gestation) exhibited sarcolemmal immunoreactivity, the major desialo N-CAM isoforms being 150, 145, 120, 115, and 110 kD. N-CAM expression appeared to be downregulated in the myocardium during adult life, with relatively little sarcolemmal immunoreactivity being detected in normal donor tissues. In contrast to the temporal changes observed in the myocardium, both the developing and mature cardiac innervation displayed N-CAM immunofluorescence staining, localized to neuronal cell bodies, nerve fascicles and fibres. Extrinsically denervated cardiac allografts, obtained 2 d to 91 mo after transplantation, showed extensive sarcolemmal and intercalated disc immunostaining and expression of 125-, 120-, and 115-kD isoforms. Tissues from explanted recipient hearts and atrial appendage samples obtained during coronary bypass graft operations were also examined and displayed varying amounts of N-CAM immunoreactivity. We conclude that the expression of N-CAM immunoreactivity and isoforms in the human heart is developmentally regulated and may be modulated by factors such as cardiac innervation and myocardial hypertrophy.

Endothelium-dependent vasorelaxation mediated by endothelium-derived relaxing factors (EDRF) has been extensively studied in animals but only limited studies in man are available. Demonstration of EDRF-mediated dilatation of human vessels is fundamental for understanding the mechanisms of vascular diseases in man. We have investigated endothelium-dependent relaxation of isolated human pulmonary arteries. Vascular segments, taken from uninvolved regions of resected lung from eight patients undergoing lobectomy for lung carcinoma, were cut into rings. In rings precontracted with phenylephrine, both acetylcholine (ACh) and adenosine diphosphate (ADP) induced dose-dependent relaxation in the presence of endothelium but not when the endothelium had been carefully removed. The rings without endothelium relaxed completely with sodium nitroprusside, a vasodilator agent acting directly on vascular smooth muscle. Pre-incubation with indomethacin, a cyclo-oxygenase inhibitor which blocks production of prostacyclin, did not alter the vasorelaxant responses to ACh and ADP, suggesting that one (or several) non-prostanoid EDRF(s) are responsible for the endothelium-dependent relaxation of isolated human pulmonary arteries.

The introduction of cyclosporine as a highly effective immunosuppressive agent and the development of new techniques for heart-lung and lung transplantation have led to a new treatment for a wide range of fatal cardiopulmonary diseases. Indications for surgery are now becoming clear, together with major contra-indications. Suppurative lung disease, such as cystic fibrosis, can be effectively treated by heart-lung transplant (HLT). A whole new field of pulmonary medicine is emerging to provide the physiological monitoring and diagnostic techniques for major complications such as opportunistic lung infection and pulmonary rejection. Obliterative bronchiolitis, a consequence of frequent and severe rejection, still provides a major challenge to the immunological scientist and respiratory physician. Lung transplantation, by disrupting the vascular supply and innervation of the lung, is raising major questions about the generally accepted beliefs of regulation of breathing and pulmonary mechanics. Finally, as the survival rate improves beyond the current 50% at 3 yrs, lung transplantation will perhaps present further challenges to our understanding of the pathogenesis of various diseases such as asthma and cystic fibrosis.

Knowledge about the distribution and origins of peptide-containing nerves in the innervated and transplanted heart is lacking. Immunohistochemical and histochemical techniques were used to visualize human cardiac innervation before and after transplantation. In the recipient heart cardiac nerve fibers and fascicles displayed immunoreactivity for general neural (protein gene product 9.5 and synaptophysin) and Schwann cell markers (S-100). A major proportion of cardiac nerves displayed neuropeptide tyrosine and tyrosine hydroxylase immunofluorescence staining. Subpopulations of nerves contained somatostatin, vasoactive intestinal polypeptide, calcitonin gene-related peptide, substance P- or neurokinin-like immunoreactivity, and acetylcholinesterase activity. Tissues from cardiac allografts (5 weeks to 63 months after transplantation) contained nerves and ganglion cells that were acetylcholinesterase positive and immunoreactive for the general neural markers. These nerves were less numerous than in recipient hearts and rarely displayed neuropeptide immunostaining. Atrial natriuretic peptide immunoreactivity was localized to myocardial cells in transplanted hearts as well as explanted recipient and postmortem hearts. While most human cardiac allografts remain functionally extrinsically denervated, they appear to contain viable intrinsic nerves, and myocardial cells retain the capacity to produce atrial natriuretic peptide.

Patients restored to a normal healthy life after heart-lung transplantation have grossly abnormal physiology. Review of recent pathophysiological observations in this group of patients has led to new ideas on the mechanism of bronchoconstriction and control of ventilation during exercise and question the role of vagal reflexes in regulation of breathing at rest.

Hypertension may be associated with an increase in oxidative stress as a possible mechanism for the increased vascular tone and organ injury. Previously, we reported an increased production of reactive oxygen species and endothelial cell death in the microcirculation of hypertensive rats. We hypothesize that xanthine oxidase (XO) may be a potential source of oxidants induced by glucocorticoid-induced hypertension. Male Wistar rats were administered dexamethasone (0.5 mg/kg/day) for 5 days to induce hypertension. After general anesthesia, cremaster muscle was collected for analysis of XO and xanthine dehydrogenase (XDH) activities. The mean blood pressure and XO levels in cremaster muscle were significantly increased in the dexamethasone-treated rats compared with controls. There was a strong age-dependent rise in total XO + XDH activity in all groups. To inhibit XO, we administered allopurinol (ALLO, 0.4 mg/mL) in the drinking water to a subset of control and dexamethasone-treated rats during a 5-day treatment. The ALLO significantly reduced the mean arterial blood pressure in the dexamethasone-treated rats. Although in the cremaster muscle the total XO + XDH levels were not completely reduced with ALLO, the XO levels of the dexamethasone-treated + ALLO rats were reduced to levels of the control + ALLO group. These results suggest that dexamethasone induces an elevated level of XO activity in the cremaster muscle. The enhanced XO activity can be attenuated by chronic allopurinol treatment.

Obliterative bronchiolitis (OB) continues to be a major cause of morbidity and mortality following heart-lung transplantation. We compared the incidence of death from obliterative bronchiolitis in 19 children and 72 adults following heart-lung transplantation at our institutes. The incidence of death from OB at 2 years was 38% for children compared with 17% for adults, this difference was significant (Cox-Mantel Z value = 2.243, P < 0.05). The frequency of acute lung rejection and persistent lung rejection, previously described as risk factors for OB in adults, were significantly more common in children, P = 0.004 and P = 0.001, respectively. Average forced expiratory volume in 1 s was lower in children than in adults for each 3-month period after transplantation (P < 0.001). In conclusion, identified risk factors for the development of OB were more common, and the risk of death from OB was greater in children than in adults following heart-lung transplantation.

More than 1,200 patients have now undergone thoracic transplantation at Papworth Hospital and about 90 transplants are performed annually. Papworth remains one of the largest transplant units in the UK. Unique activities include a very large heart-lung transplant program: 247 patients have now undergone heart-lung transplants and 73 domino heart transplants have been performed. The 5-year survival rates are 71% for heart transplants, 48% for heart-lung and 41% for lung transplants, respectively. Chronic obliterative bronchiolitis remains an important limitation for heart-lung and lung transplant survival.

Increases in blood eosinophil counts (EOS) beyond 0.06 x 10(9)/liter precede treated heart allograft rejection. An oral prednisolone dose of 0.35 mg/kg/day usually suppresses EOS below this threshold.We designed a randomized trial to compare our empirical protocol for steroid dose adjustment with a novel protocol guided by EOS monitoring during the first 3 months after heart transplantation. Eighty patients were randomized to either have their EOS reported and used for steroid dose adjustment (RG; n=40), or not reported (NG; n=40). RG patients had their steroid dosage increased if EOS exceeded 0.06 x 10(9)/liter.RG patients had an 83% lower risk of treated rejection (P=0.035) and lower median intravenous dose of methyl-prednisolone (P=0.017) than NG during the first 6 postoperative weeks. The proportion of diagnostic increases in EOS that were followed within 2 weeks by treated rejection was 42% greater in NG than RG (P=0.0001), compatible with a direct impact of EOS-guided prednisolone dose adjustment on the risk of subsequent rejection. Overall, RG had less than half the risk of rejection of any grade (P0.001) and significantly more rejection-free biopsies than NG (P=0.001). The mean oral prednisolone dosage was significantly greater in RG than NG during the first (P=0.014) and second (P=0.001) 6 weeks of follow-up. This did not increase the incidence of serious steroid-related side effects.EOS monitoring is a simple, cheap, and effective means of optimizing steroid immunosuppression. Restriction of the EOS-guided steroid dosing protocol to periods of prolonged hospitalisation during the first 3 postoperative months should limit the requirement for higher prednisolone dosage without affecting immunosuppressive efficacy.

A group of 284 patients who underwent orthotopic heart transplantation between April 1986 to June 1991 and who were followed up for at least five years was analyzed in this paper. Patients were divided into three groups according to the presence or absence of cytomegalovirus infection or disease: patients without infection, patients with serologycaly proven infection and patients with cytomegalovirus disease. The analysis of survival was performed with respect to all major factors that influence survival: age and sex of a donor and a recipient, number of rejection episodes, perioperative ischemic time and pulmonary vascular resistence. A recipient's age was shown to be a significant factor. Patients who experienced at least one episode of cytomegalovirus disease had significantly worse long-term survival compared to those with the infection only or without the infection. That difference was caused by the increased incidence of coronary atherosclerosis, which caused deaths in patients with a previous episode of cytomegalovirus disease. A possible mechanism responsible for this phenomenon is discussed.

To review and compare our results for single lung transplantation (SLT) and double lung transplantation (DLT).One hundred twenty-three patients transplanted between September 1988 and July 1997 (99 SLT and 24 DLT) were reviewed. Mean follow-up was 749 days.The following variables were significantly different for the two recipient populations: the most common indication was restriction for SLT and sepsis for DLT; mean ages were 50.3 +/- 9.2 and 40.6 +/- 14.3 for SLT and DLT, respectively; and nutritional status measured as body mass index was 21.5 +/- 4 for SLT and 18.6 +/- 2.7 for DLT. DLT patients experienced longer periods of ischemia during surgery (287 +/- 75 min versus 242 +/- 65 min for SLT, p = 0.01) and more of them required extracorporeal circulation (67% versus 37%, p = 0.005). Early postoperative morbidity after DLT was greater because of bleeding (1,046 +/- 848 ml versus 690 +/- 503 ml; p = 0.01) and time of intubation (9 hours, interquartile range 7 to 13 for DLT patients versus 5 hours, interquartile range 1 to 10 for SLT; p = 0.001). DLT recipients also suffered more respiratory infections during the first 3 months after surgery. Long term, DLT patients had greater pulmonary function capacity than did SLT patients, a difference that was maintained over the three years of follow-up. Readmission was more frequent among DLT patients because of infection (0.40 versus 0.26 readmissions per patient per 100 days; p0.02).Both unilateral and bilateral lung transplants are valid therapeutic options for patients with terminal phase lung disease. DLT offers more hope of long term functional recovery without negatively affecting survival.

In lung transplantation, obliterative bronchiolitis is the major factor limiting long-term survival. Bronchiolitis obliterans syndrome (BOS), defined as staged decline in pulmonary function has proved a reproducible and sensitive marker of obliterative bronchiolitis.The incidence of, and risk factors for, BOS were investigated in 230 lung transplant recipients who underwent transplantation from April 1984 to December 1995 and who survived at least 3 months after operation. Progression and prognosis was investigated in the 109 cases with development of BOS.Actuarial BOS-free probability at 5 years was 36%. Post-BOS onset survival was 51% at 3 years. BOS onset conferred increased risk of death (hazard ratio [HR], 5.96; 95% confidence interval [CI], 3.61, 9.83). Donor and recipient characteristics such as sex, age, underlying disease, type of transplant, and graft ischemic time did not affect BOS onset, progression, or prognosis. Cytomegalovirus serologic status and early acute rejection were risk factors for BOS onset in multivariate modeling. In univariate analysis, other risk factors were lung infection, cytomegalovirus episodes, organizing pneumonia, and human leukocyte antigen mismatch. Later transplantation era (1991 to 1995) was associated with decreased risk of BOS (HR, 0.64; 95% CI, 0.44, 0.92). Acute rejection affected post-BOS progression (HR, 1.28/episode; 95% CI, 1.12, 1.45) and survival (HR, 1.20/episode; 95% CI, 1.05, 1.37). Post-BOS lung infection was an independent prognostic factor (HR, 1.12/episode; 95% CI, 1.01, 1.24). BOS onset in the later half of the series (1992 to 1997) was associated with decreased risk of progression (HR, 0.52; 95% CI, 0.33, 0.82).This study confirms that BOS is a major problem in lung transplantation, with a high incidence, rapid progression, and poor survival. It affects all modes of lung transplantation, regardless of sex, age, or underlying diagnosis. Acute rejection is a major prognostic factor. Lung infections after BOS onset worsen survival rates.

Isolated pig hearts, subsequently perfused with pig or human blood, were prepared for the cytochemical demonstration of sites of hydrogen peroxide generation and increased vascular permeability. Oxidant stress was associated with ultrastructural changes commonly seen following myocardial reperfusion. In addition, the precipitation of cerium perhydroxide following perfusion with physiological saline containing cerium chloride suggested the vascular endothelium and leukocytes as sources of oxidants. This was associated with rapid penetration of horseradish peroxidase through the intercellular clefts of the vascular endothelium into the interstitial space, suggesting increased vascular leakiness at these sites. The rapid penetration of horseradish peroxidase was observed at all monitored periods of reperfusion with pig or human blood. This indicates that the increased permeability occurred during the ischaemic period and continued during reperfusion. Morphological damage was greatest in pig hearts reperfused with whole human blood and this was attenuated if the blood was preabsorbed to remove antibodies prior to reperfusion. We conclude that oxidant stress was initiated during ischaemia and continued during reperfusion in this model.

Previous studies demonstrated that hearts from transgenic pigs expressing human decay-accelerating factor (hDAF) were not hyperacutely rejected when transplanted heterotopically into the abdomen of cynomolgus monkeys. This study examines orthotopic transplantation of hDAF transgenic pig hearts into baboon recipients.Orthotopic xenogeneic heart transplantation was performed using piglets, transgenic for hDAF, as donors. Ten baboons were used as recipients and were immunosuppressed with a combination of cyclophosphamide, cyclosporine, and steroids.Five grafts failed within 18 hr without any histological signs of hyperacute rejection. Pulmonary artery thrombosis induced by a size mismatch was observed in two of these animals. The other three recipients died because of failure to produce even a low cardiac output and/or dysrhythmia. The remaining five animals survived between four and nine days. One animal died of bronchopneumonia on day 4. Three xenografts stopped beating on day 5 due to acute vascular rejection. The longest survivor was killed on day 9 with a beating, histologically normal xenograft, because of pancytopenia.The results reported here demonstrate that hDAF transgenic pig hearts are not hyperacutely rejected when transplanted into baboon recipients. Orthotopically transplanted transgenic pig hearts are capable of maintaining cardiac output in baboons. An optimum immunosuppressive regimen is the subject of ongoing research.

Peripheral blood eosinophilia is a particularly early and specific marker of both renal and hepatic allograft rejection. Therefore we evaluated the relationship between blood eosinophil counts and cardiac and pulmonary allograft rejection.Differential blood counts were available within 3 days before 383 endomyocardial biopsy specimens in 56 heart transplant recipients. Blood counts were also available before 84 treated rejection episodes and 28 transbronchial biopsy specimens showing no rejection in 58 lung transplant recipients.Cardiac allograft rejection: There was a significant association between the mean maximum blood eosinophil count and treated acute rejection (p0.01) and a linear relationship between this eosinophil count and the histologic grade of rejection (p0.01). The first increase in eosinophils occurred at a median of 4 days before treated rejection. Pulmonary allograft rejection: The mean maximum blood eosinophil count was 0.14 x 10(9)/L (95% confidence interval = 0.10, 0.18) preceding treated rejection, and this was significantly greater than the mean maximum blood eosinophil count of 0.07 x 10(9)/L (confidence interval = 0.05, 0.09) measured when there was no rejection or during infection (p = 0.01). The first increase in eosinophil occurred at a median of 5 days before treated rejection. There was no relationship between blood neutrophil counts and either cardiac or pulmonary allograft rejection.An increase in peripheral blood eosinophils but not neutrophils is a specific and early marker of clinically significant rejection of both cardiac and pulmonary allografts. Furthermore, the maximum blood eosinophil count measured in the 3 days before rejection is linearly related to the severity of cardiac allograft rejection.

The physiology of hyperacute rejection of pig lung by human blood and the role of antispecies antibody and complement in this phenomenon have not previously been characterized.Human blood was perfused through an ex vivo pig heart-lung preparation. In the treatment groups, blood was either unmodified or modified to deplete alternative pathway complement (heat treatment), anti-pig antibody, or both. Control experiments were performed with unmodified and heat-treated pig blood. Physiologic parameters, organ survival, and immunohistology were the primary outcome measures assessed.Pig lung was consistently damaged by human blood within 45 min (median 20 min), as evidenced by elevated pulmonary vascular resistance and parenchymal injury. Immunohistologic studies of perfused lungs showed prominent deposition of IgM and classical pathway component, C4, and weaker deposition of alternative pathway component, properdin. Heat treatment did not impede the rise in pulmonary vascular resistance or significantly prolong survival. Depletion of anti-pig antibody prolonged survival (median 90 min) and attenuated the rise in pulmonary vascular resistance. Antibody absorption, combined with heat treatment of plasma, prevented the elevation in pulmonary vascular resistance and yielded median graft survival (210 min) similar to pig blood perfusion (approximately 240 min).These results show that elevated pulmonary vascular resistance and pulmonary parenchymal injury are mediated at least in part by antispecies antibody and heat-sensitive pathways. They are consistent with the hypothesis that complement activation contributes significantly to acute lung damage in the pig-to-human species combination.

Hyperacute rejection currently prevents clinical application of discordant lung xenografts. Pigs transgenic for human regulators of complement activation offer one promising potential solution to this problem.Using fresh human blood in an ex vivo lung perfusion model, we studied eight different strains of pigs transgenic for human decay accelerating factor. Survival (by blood flow and gas transfer criteria) were correlated with immunohistologic evidence of pulmonary human decay accelerating factor expression and complement activation.With human blood perfusion, blood flow through the unmodified pig lung rapidly falls and is not restored by continuous infusion or high-dose bolus of prostacyclin. Airway pressure also rises rapidly and is followed promptly by loss of gas transfer. Four of the transgenic pig strains showed no difference from this pattern. Immunohistochemistry for human decay accelerating factor revealed low or no pulmonary expression in these lungs. In contrast, two of five transgenic pig lungs that had significant decay accelerating factor expression demonstrated recovery of pulmonary blood flow within 1 hour, and rejection was delayed, from less than 20 minutes in controls to about 1 hour. Complement activation, particularly the alternative pathway, was inhibited in lungs with high levels of endothelial decay accelerating factor expression.Lungs from some strains of pig transgenic for human decay accelerating factor demonstrate incomplete physiologic and histologic protection from hyperacute rejection. Although complement-independent pathogenic mechanisms may present a formidable obstacle, pig lungs transgenic for human complement regulatory proteins may facilitate discordant lung transplantation in human beings.

We have attempted to quantify the optimal clinical use of cyclosporine during the first 3 months after heart-lung transplantation. We used multiple logistic regression to investigate the influence of blood cyclosporine concentrations and other potential risk factors on histologically confirmed acute lung rejection in 50 heart-lung transplant recipients. A 50% increase in cyclosporine concentration was associated with a 25% reduction in risk of rejection in the subsequent 5 days (P=0.008). Increasing oral corticosteroid dose also protected against rejection (P=0.006). Rejection was over 4 times more likely to occur during the first 20 postoperative days (P=0.002). After 20 days, an FEV1or = 70% of the age-, sex-, and height-adjusted expected score was associated with a 4-fold increase in risk of rejection (P=0.01). Patients who had multiple previous rejection episodes were also predisposed to further rejection (P=0.005). An investigation of threshold levels for the cyclosporine concentration-effect relationship suggested that cyclosporine concentrations above 500 microg L(-1) provide optimal protection against acute lung allograft rejection. This result provides an objectively defined therapeutic threshold for targeting early cyclosporine concentrations following heart-lung transplantation.

We have attempted to determine the optimal clinical use of cyclosporine during the first 3 months after heart transplantation. We used multiple logistic regression to quantify how blood cyclosporine concentrations and other potential risk factors influence the risk of histologically confirmed acute rejection in 111 heart transplant recipients. A 50% increase in cyclosporine concentration was associated with a 15% reduction in risk of rejection in the subsequent 5 days (P=0.002). Increasing oral corticosteroid dose also protected against rejection (P=0.01). Rejection was over 2.5 times more likely during the first 20 postoperative days, and patients with 2 HLA-DR mismatches who were transplanted for cardiomyopathy or who had multiple previous rejection episodes were predisposed to further rejection (P0.01). High short-term variability in cyclosporine concentrations was weakly associated with risk of rejection (P=0.1). Investigation of threshold levels for the cyclosporine concentration-effect relationship suggested that concentrations above 375 microgram L(-1) provide optimal protection against acute cardiac allograft rejection. This result yields an objectively defined therapeutic threshold for targeting early cyclosporine concentrations following heart transplantation, although the upper end of the range will depend on the individual's susceptibility to nephrotoxicity and infection.

The measurement of the quality of the outcome of treatment as viewed by patients is becoming increasingly recognized as an important aspect of decision making in all health services. This major study, which set out to measure the health-related quality of life outcomes of heart and lung transplantation, developed from the experience gained in the United Kingdom and United States studies of the cost and benefits of heart transplantation in the 1980s.The design was prospective with a cohort of patients completing a variety of generic and specific health-related quality of life questionnaires at intervals before and after heart and lung transplantation. The sample size was not prescribed; one of the aims of the project was to test the feasibility of introducing routine monitoring of health-related quality of life outcomes as an integral part of a developing transplant service.Before the operation, there was evidence of deterioration over time in all dimensions of the Nottingham Health Profile. In comparing Profile scores at less than 3 months before with those at 3 to 6 months after transplantation, statistically significant improvements were evident (p0.001). Mean scores at intervals up to 2 years after transplantation showed little change over time and compared well with those from a general population sample. Hospital Anxiety and Depression Scale scores were reduced significantly (p0.01) by 1 year after heart and lung transplantation. In the pretransplantation period, at least 90% of 101 patients had some level of restriction in home and leisure activities, reducing to between 2% and 24% at 1 year after transplantation. Similarly, 79 patients (78%) had chest pain, and 101 (100%) were breathless before transplantation, reducing to 54% and 39%, respectively, at 1 year after surgery; by which time, for 8 of 10 patients, the problem was occasional.Highly significant improvements were observed in the physical, social, and emotional dimensions of health-related quality of life of patients after heart-lung transplantation. The advantages and feasibility of combining generic and condition-specific questionnaires are shown together with the need to develop new measures with greater sensitivity to the smaller peaks and troughs of recovery.

Ostial stenosis of the left main coronary artery is a serious condition with a dismal prognosis. The treatment is surgical, with the two viable options being coronary artery bypass grafting and surgical angioplasty of the left main coronary artery.We describe the use of surgical angioplasty to treat 3 patients (2 women and 1 man) with left main ostial stenosis using the posterior approach. Patency of the angioplasty was demonstrated subsequently with magnetic resonance imaging.All 3 patients were free of angina 12, 18, and 24 months after operation. Magnetic resonance imaging scans in all 3 patients demonstrated the widely patent left main coronary artery.Surgical angioplasty is an effective alternative to coronary artery bypass grafting in patients with left main ostial stenosis. Magnetic resonance imaging is an excellent noninvasive method for monitoring the patency of the left main coronary artery.

We report three patients with cystic fibrosis and one patient with primary biliary cirrhosis and plexogenic pulmonary hypertension who have undergone heart-lung-liver transplantation as a combined procedure. Liver transplantation was necessary in the three patients with cystic fibrosis because of portal hypertension secondary to either hepatic fibrosis or established cirrhosis in addition to their advanced lung disease. Three of the four patients were alive at 20, 50, and 100 months after transplantation (one patient with cystic fibrosis died on day 16 of pneumonia) with well-preserved pulmonary function (forced expiratory volume in 1 second 110%, 49%, and 100% predicted, respectively), normal hepatic function and New York Heart Association class 1 performance status. Heart-lung and concurrent liver transplantation is a feasible and successful procedure with a satisfactory long-term outcome in selected patients with advanced pulmonary and hepatic disease.

The presence of a systemic disease has traditionally been considered a contraindication to lung transplantation.We present a retrospective review of 19 patients undergoing lung transplantation for end-stage pulmonary disease associated with a systemic illness since 1984. There were 11 male and 8 female patients, aged from 23 to 59 years (median 43 years) with end-stage pulmonary involvement by sarcoidosis (11 patients), Langerhan's cell histiocytosis (three patients), systemic vasculitis (four patients: three with systemic lupus erythrematosis, one with Churg-Strauss), and common variable immunodeficiency (one patient). Ten patients received a heart-lung transplant, and eight patients received a single lung transplant. One patient underwent single lung transplantation after an earlier heart-lung transplant.The 30-day mortality was 5.3%. Nine patients died overall. Two of these had systemic lupus erythrematosis with anticardiolipin antibodies and died from complications of their underlying vasculitis. The mean 1- and 2-year actuarial survivals for all patients were 71% (standard error +/- 10.8%) and 64% (standard error +/- 11.9%), respectively. All patients surviving longer than 3 months achieved an improvement in functional status to New York Heart Association class I or II, and a significant increase occurred in mean forced expiratory volume in 1 second and forced vital capacity. Disease recurrence without clinical significance occurred in two patients with sarcoidosis. Of the nine patients who died, seven had autopsies and none showed evidence of disease recurrence in the lungs.Patients with systemic diseases can be considered for lung transplantation and each case should be judged on its individual merits. However, patients with systemic lupus erythrematosis (particularly when associated with anticardiolipin antibodies) should probably not be offered lung transplantation because they are likely to develop further complications of their underlying vasculitis.

With the increasing number of successfully performed lung transplants and a longer follow up of patients, there is an interest in the analysis of long-term complications and their impact on patient survival. Heart-lung transplantation was performed in 157 patients with 126 patients surviving at least 6 months. Early death was mainly caused by bacterial and viral infection. Long-term patient survival was decisively influenced by obliterative bronchiolitis. With the new international definition of bronchiolitis obliterans syndrome (BOS) based on an irreversible decline of FEV1 from baseline values, it became possible to analyse the incidence of BOS and the impact on patient mortality in long-term survivors. FEV1 reached a peak value of 102% predicted at a median of 219 days. In 106 of 126 patients (84%), FEV1 showed no decline within the first year. A total of 60 patients (47.6%) developed BOS grade 1 with progression to BOS grade 2 in 85% of these patients. The incidence of BOS was 12.6% at 1 year increasing to more than 50% 5 years after transplantation. Patient mortality due to obliterative bronchiolitis increased from 1% at 1 year to 18% more than 5 years after transplantation. Almost all deaths (86%; 32/37) more than 1 year after HLT were associated with bronchiolitis obliterans. In summary, bronchiolitis obliterans decisively contributes to long-term patient morbidity and mortality after heart-lung transplantation. Clinical and research efforts should be directed towards avoiding this important complication.

Lung transplantation is performed for an increasing range of pulmonary conditions in which the diagnosis is often clinical or based on limited biopsy material. Diagnosis may be made late in the course of the disease where specific features are no longer present. Posttransplantation complications and disease recurrence may relate to the primary disease, and accurate diagnosis is therefore essential.A pathologic review of 183 explanted lungs over a 10-year period (heart-lung = 109, single lung = 65, double lung = 9) showed 29 significant discrepancies or additional features likely to effect outcome. The final pathologic diagnosis was cystic fibrosis (n = 66), emphysema (59), bronchiectasis (17), pulmonary fibrosis (19), sarcoidosis (10), Langerhans cell histiocytosis (3), pulmonary veno-occlusive disease (3), posttransplantation obliterative bronchiolitis (2), primary hemosiderosis (1), rheumatoid obliterative bronchiolitis (1), extrinsic allergic alveolitis (1), pneumoconiosis (1). Unsuspected diagnoses included tuberculosis (8) (four cases of which were active and in single lung recipients requiring antituberculous chemotherapy), sarcoidosis (9), (of which, six were unsuspected primary diagnoses and three were additional diagnoses), veno-occlusive disease (3), carcinoma (1), pneumoconiosis (1), and pulmonary fibrosis (2). Aspergillus infection (2) and bronchocentric granulomatosis (3) were found in patients with cystic fibrosis. One active tuberculosis case also showed an aspergilloma. Unsuspected infections requiring therapy in immunosuppressed patients and previously unsuspected sarcoidosis, which is known to recur in the graft, were the major novel diagnoses. Discrepancy rate was 12 of 65 in single lungs (19%) and 17 of 109 in heart-lungs (16%).These results emphasize the need for accurate preoperative diagnosis especially when the similarly diseased native lung remains in situ.

Vascular grafts continue to evolve. Recent developments have been aimed at decreasing porosity, increasing strength of prosthesis, increasing ease of handling and suturing and optimising flow characteristics. This study describes results with a recently developed collagen impregnated polyester prosthesis Hemashield Woven Double Velour, which does not require pre-clotting. Between January 1988 and December, 1991 such prostheses were used in 90 patients at Papworth Hospital. Fifty-eight, were used to replace the ascending aorta, 10 for the arch of the aorta and 28 for the descending aorta seven of whom were for coarctation and four for traumatic transections. In 60 cases the underlying disease was a dissected or ruptured aorta requiring emergency operation. There were 66 survivors with X-ray and CT follow-up of 6-52 months. Median blood loss was 630 ml range 380-1800 ml. There was no leakage from any of the grafts during surgery despite full perioperative heparinisation. For emergency/elective operations (N = 60/30) early mortality was 25%/10% (15/3) and late mortality 5%/6.6% (3/2). Of 15 patients who had interposition grafts for Type A dissection CT scans at 5-47 months showed one with chronic dissection proximal to the repair and 11 with persistent distal dissection. There was no evidence of late bleeding, seroma impaired healing or thickened neointima formation. It is concluded that there are no clinical disadvantages associated with collagen impregnation to set against the notable convenience of initial impermeability.

A retrospective serologic study was made of 67 heart-lung and 295 heart transplant recipients (with transplantations at Papworth Hospital, Cambridge, England) to determine the incidence and clinical impact of Epstein-Barr virus infection.Epstein-Barr virus capsid antigen immunofluorescence tests were performed, and the antibody avidity was determined by modifying the washing procedure to include a mild reducing agent (8M urea).This testing showed that 6.0% of the patients had primary Epstein-Barr virus infections, whereas 17.4% had the reactivation of a past infection. Primary infections were only detected in patients who were Epstein-Barr virus antibody-negative before transplantation, who had received an organ from an Epstein-Barr virus antibody-positive donor. Of the patients with serologically proven Epstein-Barr virus infections, 52.9% had symptoms. Although these were generally mild, five heart and two heart-lung transplant recipients had malignant lymphoma and one heart and one heart-lung transplant recipient had lymphoproliferative disease after Epstein-Barr virus infection. Additional four heart transplant recipients had lymphoma after transplantation. None of these four patients had evidence of active Epstein-Barr virus infection; one was Epstein-Barr virus antibody-negative during the study period and three had stable Epstein-Barr virus virus capsid antigen immunoglobulin G titers throughout.Epstein-Barr virus infection in organ transplant recipients may lead on to life-threatening lymphoproliferative disease or lymphoma. For this reason it may be beneficial to monitor patients after transplantation for evidence of Epstein-Barr virus infection and to follow the progress of those affected.

Donor management remains one of the most neglected areas of transplantation. A comprehensive donor management regimen has been developed. The results of the application of this strategy form the basis of this report.Full hemodynamic data were collected from 150 multiorgan donors between October 1990 and August 1993. The data were collected at the time of donor team arrival, after insertion of a pulmonary artery floatation catheter and immediately before cardiac excision.Fifty-two donors (35%) fell well outside our minimum acceptance criteria on arrival. Twenty-one of fifty-two had a mean arterial pressure less than 55 mm Hg (mean 47 mm Hg) despite inotropic support in most cases; 10 of 52 had a central venous pressure greater than 15 mm Hg (mean 18.0 mm Hg); 2 of 52 had a high inotrope requirement greater than 20 micrograms/kg/min (mean 25 micrograms/kg/min). After the insertion of a pulmonary artery floatation catheter, an additional 13 of 52 donors were found to have a pulmonary capillary wedge pressure greater than 15 mm Hg (mean 19.8 mm Hg), and the final 6 of 52 had a low left ventricular stroke work index, less than 15 gm (mean 12.8 gm). After optimal management, including hormone replacement 44 of 52 donors yielded transplantable organs (29 hearts, 15 heart and lung blocks). Thirty-seven of forty-four patients (84%) were alive and well from 13 to 48 months after transplantation. There were five early deaths (11%) caused by infection (heart), adult respiratory distress syndrome (heart), arrhythmia (heart), cerebrovascular event (heart and lung), and infection (heart, lung, and liver). Two late deaths (5%) occurred as a result of tamponade (3 months, heart) and infection (14 months, heart and lung). Eight of fifty-two organs were still unsuitable for transplantation after optimum management during the splanchnic dissection as a result of inotrope dependency (n = 4), left ventricular hypertrophy (n = 2), and coronary artery disease (n = 2).The data indicate that, of the organs which initially fall outside our transplant acceptance criteria, 92% are capable of functional resuscitation. Conversely, superficial assessment may not show compromised function. Optimizing cardiovascular performance also has important implications for the viability of all transplantable organs. This aggressive approach to donor management has resulted in the transplantation of 44 donor hearts that may otherwise have been turned down or inappropriately managed.