Empirical supportive therapy in the hypotensive donor - best guess or worst option?
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Journal Article↗
Biomedical subjects
J Wallwork
Publications and source records attributed to J Wallwork.
Atrial transplantation for recurrent cardiac sarcoma.
Cardiac transplantation for sarcomas has met with little success and the surgical treatment remains controversial. We describe the case of a 56-year-old woman who was referred for transplantation after two procedures in which undifferentiated atrial sarcoma was locally excised successfully. The patient underwent atrial homograft transplantation, the first reported to date. Advantages of the procedure include wide atrial resection and no need for immune suppression.
Female↗
Randomized trial of blood eosinophil count monitoring as a guide to corticosteroid dosage adjustment after heart transplantation.
BACKGROUND: 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. METHODS: 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. RESULTS: 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 (P<0.001) 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. CONCLUSIONS: 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.
Adrenal Cortex Hormones↗
Long-term survival of nonhuman primates receiving life-supporting transgenic porcine kidney xenografts.
BACKGROUND: Recently, there has been a resumed interest in clinical xenotransplantation using pig organs. However, no data are available yet regarding the capacity of porcine organs to sustain the life of a primate beyond the first month. We have attempted to obtain long-term survival of nonhuman primates using human decay-accelerating factor (hDAF) transgenic pig organs and an immunosuppressive strategy particularly aimed at neutralizing the humoral component of the immune response. METHODS: hDAF transgenic or control kidneys were transplanted into 14 bilaterally nephrectomized cynomolgus monkeys (Macaca fascicularis) that underwent splenectomy and were immunosuppressed with cyclosporine A, cyclophosphamide, and steroids. All animals also received recombinant erythropoietin. Postoperatively, the primates were monitored daily. Laboratory evaluations included serum biochemistry, hematology, and measurements of hemolytic antipig antibodies. To assess the role of splenectomy in the control of humoral response, historical data were also used from a group of monkeys (n=7) that received the same immunosuppressive regimen and an hDAF transgenic porcine kidney but did not have splenectomy or receive recombinant erythropoietin. RESULTS: This immunosuppressive approach obtained the longest survival time (78 days) described to date of a primate receiving a life-supporting porcine renal xenograft. Furthermore, four of nine animals in this series survived for 50 days or more. Most biochemical measurements in this study (including plasma urea, creatinine, sodium, and potassium concentrations) remained within normal ranges for several weeks in all of the longest-surviving animals. CONCLUSIONS: Normalization of renal function (urea and creatinine) in primate recipients of porcine renal xenografts suggests that pig kidneys may be suitable for future clinical xenotransplantation. Additional immunosuppressive approaches, specifically designed to prevent humorally mediated immunological damage, should be explored to further prolong survival of primates that have received porcine xenografts.
Animals↗
Life supporting function for over one month of a transgenic porcine heart in a baboon.
BACKGROUND: Inhibition of hyperacute rejection (HAR) and sustained graft survival have been demonstrated in a pig-to-primate model of heterotopic cardiac xenotransplantation using pigs transgenic for human Decay Accelerating Factor (hDAF). Building on this work, an orthotopic model has been developed. This case records 39-day cardiac xenograft function in a life-supporting capacity with clinically applicable immunosuppression. METHODS: Using a heart from an hDAF transgenic pig, an orthotopic cardiac transplant was performed on an adult baboon. The immunosuppressive regimen consisted of induction with a short course of cyclophosphamide, followed by maintenance therapy with cyclosporine A, mycophenolate mofetil and a tapering course of corticosteroids. Post-operative monitoring included daily anti-pig hemolytic antibody titer surveillance and endomyocardial biopsy. RESULTS: The animal survived 39 days and was active and energetic throughout its postoperative course, remaining free of signs of cardiopulmonary failure. Endomyocardial biopsy performed on post-operative Day 36 revealed only patches of sub-endocardial fibrosis with no signs of active rejection. The baboon succumbed to an acute cardiopulmonary decompensation immediately following administration of medication via oral gavage. Post-mortem histopathology demonstrated well-preserved myocardial architecture with small foci of mild humoral rejection. CONCLUSIONS: This case documents the longest survival recorded to date of a discordant orthotopic cardiac xenograft and illustrates that the hDAF transgene combined with a clinically acceptable maintenance immunosuppressive regimen enables sustained, life-supporting function of porcine cardiac xenografts in non-human primates. The inhibition of hyperacute rejection and the subsequent control of humoral and cellular rejection for over 1 month demonstrated in this experiment represent significant progress in the development of a viable strategy for clinical xenotransplantation.
Animals↗
Is the secretion of atrial natriuretic peptide in man under neural control?
AIMS: Previous work has described short-term variation in the circulating plasma level of atrial natriuretic peptide (ANP), but the mechanism remains unknown. Our aim was to investigate the role of cardiac innervation in this variability. METHODS AND RESULTS: Blood samples were obtained from the right atrium via a pulmonary artery flotation catheter every 2 min over a 90 min period. Seven patients who underwent cardiac transplantation by the standard biatrial technique (partial innervation) and ten patients who underwent transplantation by the bicaval technique (total denervation) were studied. ANP levels were measured by radioimmunoassay. The median ANP levels were somewhat higher in the biatrial group compared to the bicaval group [470 (150-1095) vs. 216 (100-605) pg. ml(-1); median (range); P = ns], and both were much higher than normal levels in the pulmonary artery (40 (24, 56) pg ml(-1); median and interquartile range). In both transplant groups circulating plasma ANP levels showed considerable variability. The median number of 'peaks' and 'troughs', as counted by visual inspection, were not significantly different between the two groups. Computer analysis identified 12-16 and 6-15 'pulses' in the biatrial and bicaval group, respectively. Further analysis revealed that pulse amplitude, height and area were significantly higher in the biatrial compared to the bicaval group. CONCLUSION: It would appear that variability of circulating plasma levels of ANP is preserved despite complete or partial cardiac denervation, and so a neural mechanism does not appear to account for such variation.
Adult↗
An ethical problem for discussion (transplantation research): a response to Stone and Fulbrook.
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Biopsy↗
Transmyocardial laser revascularisation in clinical practice.
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Angina Pectoris↗
Transmyocardial laser revascularisation in patients with refractory angina: a randomised controlled trial.
BACKGROUND: Transmyocardial laser revascularisation (TMLR) is used to treat patients with refractory angina due to severe coronary artery disease, not suitable for conventional revascularisation. We aimed in a randomised controlled trial to assess the effectiveness of TMLR compared with medical management. METHODS: 188 patients with refractory angina were randomly assigned TMLR plus normal medication or medical management alone. At 3 months, 6 months, and 12 months after surgery (TMLR) or initial assessment (medical management) we assessed exercise capacity with the treadmill test and the 12 min walk. FINDINGS: Mean treadmill exercise time, adjusted for baseline values, was 40 s (95% CI -15 to 94) longer in the TMLR group than in the medical-management group at 12 months (p=0.152). Mean 12 min walk distance was 33 m (-7 to 74) further in TMLR patients than medical-management patients (p=0.108) at 12 months. The differences were not significant or clinically important. Perioperative mortality was 5%. Survival at 12 months was 89% (83-96) in the TMLR group and 96% (92-100) in the medical-management group (p=0.14). Canadian Cardiovascular Society score for angina had decreased by at least two classes in 25% of TMLR and 4% of medical-management patients at 12 months (p<0.001). INTERPRETATION: Our findings show that the adoption of TMLR cannot be advocated. Further research may be appropriate to assess any potential benefit for sicker patients.
Angina Pectoris↗
Intravenous ganciclovir prophylaxis for cytomegalovirus in heart, heart-lung, and lung transplant recipients.
Cytomegalovirus (CMV) disease has had a significant clinical impact on the heart, heart-lung and lung transplant recipients in our centre. CMV disease has been so severe with CMV antibody-negative heart-lung transplant patients receiving organs from CMV antibody-positive donors (CMV-mismatched patients) that in 1986 we adopted the policy of not transplanting CMV-positive organs into CMV-negative heart-lung or lung recipients. In December 1992, we instituted a policy of providing intravenous ganciclovir (5 mg/kg twice a day for 28 days) during the immediate postoperative period for CMV-mismatched heart recipients and CMV antibody-positive heart-lung and lung patients, who have been the patients at greatest risk of severe CMV disease in our centre. A placebo group was not employed because of ethical considerations, ganciclovir having been shown to be effective for the treatment of CMV infections among transplant patients. Compared with a historical control group of patients receiving no prophylaxis, prophylactic ganciclovir reduced the incidence of CMV infection (39 % vs 91 %, P = 0.0006) and CMV disease (17 % vs 74 %, P = 0.0004) among CMV antibody-positive heart-lung recipients. Prophylactic ganciclovir did not significantly reduce the incidence of CMV infection or disease among heart or isolated lung recipients. Ganciclovir was well tolerated, with few adverse reactions. In the case of heart-lung transplant patients, one month of intravenous prophylactic ganciclovir significantly reduced the incidence of both CMV infection and disease when compared with patients who received no prophylaxis. With the lung transplant and heart transplant patients, there were no significant differences between the prophylaxis and nonprophylaxis groups, although there was a consistent trend towards less infection and disease in the prophylaxis groups.
Adolescent↗
HLA antigen frequencies in end-stage idiopathic and ischaemic cardiomyopathy.
We investigated the distribution of HLA antigens among 413 patients with ischaemic heart disease or dilated cardiomyopathy referred for cardiac transplantation to determine if possession of certain HLA antigens predisposed to end-stage heart failure. Of the patients studied, 234 had ischaemic heart disease (218 males), mean age 49 years (SD 7.1) and 179 patients had dilated cardiomyopathy (150 males), mean age 39 years (12.8). The control group comprised 2041 kidney donors reported to the United Kingdom Transplant Service between July and August 1985. We found a significant excess of HLA DR1 (odds ratio 1.64, 95% CI 1.16-2.33, attributable risk 5.0%) and DR5 antigens (odds ratio 1.47, 95% CI 0.99-2.18, attributable risk) among patients with dilated cardiomyopathy but not of HLA DR4 as previously reported. We found a lower frequency than expected of HLA B21 (10.44 expected, none observed) among patients with ischaemic heart disease but no other significant differences. This study provides some support for the concept of the risk of developing end-stage heart failure due to dilated cardiomyopathy being associated with possession of HLA DR1 and DR5, but no such evidence in ischaemic heart disease. Larger multi-centre studies are required to confirm the validity of these findings.
Adult↗
[Lung transplantation at the Papworth Hospital: 9-year experience].
OBJECTIVE: To review and compare our results for single lung transplantation (SLT) and double lung transplantation (DLT). METHODS: 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. RESULTS: 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; p < 0.02). CONCLUSIONS: 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.
Adolescent↗
The contribution of donor management and modified cold blood lung perfusate to post-transplant lung function.
BACKGROUND: Donor organ availability remains the major limiting factor in the treatment of patients with end-stage lung disease by lung transplantation. Maximising the use of available organs is therefore crucial. Details available at the time of organ referral may give a misleading impression of their quality. Intensive donor management may improve the quality of the organs thereby improving the quality of the outcome. METHODS: We performed 56 heart-lung and 5 double lung transplants between November 1990 and September 1993; 49 had adequate documentation for analysis. All organs were preserved with modified cold blood solution with an ischemic time of 197 (117-297) minutes. Assessment of lung function post-implantation was performed using an acute lung injury score as this gives a more accurate indication of overall lung function. Donors were treated intensively by bronchoscopy, optimal fluid management and appropriate lung expansion. RESULTS: Careful management improved donor quality so that the alveolar-arterial oxygen gradient fell significantly from 185 (+/-20) mmHg at arrival to 80 (+/-11) mmHg (p < .0001) immediately prior to harvesting 190 minutes later. This improvement was maintained following harvesting using the modified cold blood preservation solution so that lung injury was assessed as "mild" according to the acute lung injury criteria post-transplantation. There was one instance of primary lung failure following transplantation which was neither related to the quality of the organ at harvesting nor to the method of lung preservation. CONCLUSIONS: Intensive donor management significantly improves the quality of donor organs, providing an improvement in immediate post-transplantation lung function. This improvement is maintained using modified cold blood lung preservation solution.
Adolescent↗
A prospective randomized trial of complete atrioventricular transplantation versus ventricular transplantation with atrioplasty.
BACKGROUND: The standard technique of ventricular transplantation with atrioplasty (SOHT) distorts atrial anatomy. This may compromise diastolic ventricular function, impair atrioventricular valve competence and elevate resting ANP secretion. In contrast, complete atrioventricular anastomosis (CAVT) preserves atrial geometry. METHODS: We evaluated long term outcome in a prospective randomized trial of CAVT vs. SOHT. The primary outcome measures were peak oxygen uptake, atrioventricular valve regurgitation and ANP secretion. RESULTS: 58 recipients (median age 49 years; range 21-64) were consecutively randomized (29 CAVT; 29 SOHT). There were no differences in total ischaemic time, cardiopulmonary bypass time, postoperative bleeding or immunosuppression. Cardiopulmonary exercise tolerance testing was performed by 29 recipients at 742 to 1825 days. Pulmonary function was equivalent. Peak oxygen consumption expressed as a percentage of predicted maximum was 53.5% with CAVT and 63.8% with SOHT (p = 0.14). Echocardiography was performed on 41 recipients at 944 to 1665 days. There was less tricuspid regurgitation with CAVT (3/22 [13.6%] CAVT vs. 10/19 [52.6%] SOHT; p = 0.019). The incidence of mitral regurgitation was similar (5/22 [22.7%] CAVT vs. 4/19 [21.1%] SOHT; p = 0.803). Resting ANP secretion was assessed in 17 recipients at 1013 to 1812 days. All were hemodynamically stable and none had concurrent rejection. Resting ANP secretion was less with CAVT (CAVT: 283 pg/ml; SOHT: 521.4; p = 0.041). CONCLUSIONS: Peak oxygen consumption was not influenced by implantation technique. However, CAVT reduced the incidence of tricuspid regurgitation and attenuated the elevation in resting ANP secretion.
Adult↗
Assessing low volume, high cost, potentially life saving surgical interventions: how and when? Left ventricular assist devices (LVADs) as a case study.
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Cardiac Surgical Procedures↗
The transmyocardial laser revascularization international registry report.
AIMS: This report aimed to provide an analysis of the data submitted from Europe and Asia on transmyocardial laser revascularization. METHODS AND RESULTS: Prospective data was recorded on 967 patients with intractable angina not amenable to conventional revascularization in 21 European and Asian centres performing transmyocardial laser revascularization using the PLC Medical Systems CO2 laser. Patient characteristics, operative details and early complications following transmyocardial laser revascularization were recorded. The in-hospital death rate was 9.7% (95% confidence interval 7.8% to 11.6%). Other early complications were consistent with similar cardiothoracic surgical procedures. There was a decrease of two or more Canadian Cardiovascular Score angina classes in 47.3%, 45.4% and 34.0% of survivors at 3, 6 and 12 months follow-up, respectively (P=0.001 for each). Treadmill exercise time increased by 42 s at 3 months (P=0.008), 1 min 43 s at 6 months (P<0.001) and 1 min 50 s at 12 months (P<0.001) against pre-operative times of 6 min. CONCLUSION: Uncontrolled registry data suggest that transmyocardial laser revascularization may lead to a decrease in angina and improved exercise tolerance. It does, however, have a risk of peri-operative morbidity and mortality. Definitive results from randomized controlled trials are awaited.
Adult↗
Randomized, trough blood cyclosporine concentration-controlled trial to compare the pharmacodynamics of Sandimmune and Neoral in de novo lung transplant recipients.
The greater and more consistent absorption of cyclosporine from the microemulsion formulation (Neoral; Novartis Pharmaceuticals Ltd., Frimley, UK) when compared with that from the original form (Sandimmune; Novartis Pharmaceuticals Ltd., Frimley, UK) results in greater systemic exposure. Lung transplant recipients could particularly benefit from this enhanced exposure, but not at the expense of excessive cyclosporine toxicity. We compared the pharmacodynamics of Neoral and Sandimmune over the first postoperative year in 50 lung transplant recipients. Twenty-eight patients were randomly selected to receive Neoral and 22 to receive Sandimmune. Nine patients with cystic fibrosis (CF) were randomly selected independently (5, Neoral; 4, Sandimmune). Patients were maintained on similar trough blood cyclosporine concentrations (C0) throughout the 12-month follow-up. A limited blood sampling strategy was adopted to compare the pharmacokinetics of the two formulations at the end of weeks 1 to 4, and of weeks 13, 26, 39, 52. The influence of any difference between the pharmacokinetics of Neoral and Sandimmune on either efficacy or toxicity of the drug was investigated during the follow-up period. Patients in the Neoral and the Sandimmune groups were matched demographically. There were no differences in dose-normalized blood cyclosporine concentrations measured predose (C0) or 6 hours postdose between the two groups. However, the measurement at 2 hours postdose (C2) and the total AUC0-6 were significantly greater in the Neoral group in both CF and non-CF patients at all visits (p < 0.001). Non-CF patients required 9% lower doses of Neoral to achieve comparable C0 measurements to those patients receiving Sandimmune. However, patients with CF required 2 to 3 times the dose of both Neoral and Sandimmune to achieve the same C0 as non-CF patients. The linear rejection rate in the Sandimmune group was 1.87 episodes per patient year, which was similar to the rejection rate of 1.97 episodes per patient year in the Neoral group. Serial lung function, blood biochemistry and hematology, mortality and the incidence of severe renal dysfunction, hypertension, infection, seizures, and new-onset diabetes were all similar in the two groups. Despite equivalent C0, those in the Neoral group were consistently exposed to greater blood cyclosporine concentrations during the dosing interval than those in the Sandimmune group. This did not increase the incidence of serious cyclosporine-associated side effects or influence the rate of acute rejection either. When data from the Neoral and Sandimmune groups were combined, measurements of C0 but not C2 or C6 were associated with the risk of acute lung allograft rejection.
Adult↗