Cardiovascular effects of cyclosporine in heart transplant recipients.
Explore the source record for details and available documents.
Biomedical subjects
Publications and source records attributed to J Wallwork.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Fifty-one patients underwent heart-lung transplantation between April 1984 and October 1988. The first five donor organs were removed in an adjacent operating theatre. Organs were subsequently removed from distant centres. The method of preservation consisted of cold cardioplegic arrest of the heart using St. Thomas' solution, followed by a simple, cold pulmonary artery flush of a lung perfusate developed at Papworth Hospital. Administration of the solution was preceded by an infusion of prostacyclin into the pulmonary artery during preliminary dissection of the donor organs. The total ischaemic time ranged from 48 to 51 min (mean 49.6 min) for the near procurement group and from 70 to 249 min (mean 154.2 min) for the distant procurement group. There were no primary organ failures. Function of the lungs was assessed by gas exchange, pulmonary function tests, time to extubation, and survival data. Serial radiological studies were used to monitor graft performance in the postoperative period. We report here on our clinical experience of early graft function following heart and lung transplantation.
Explore the source record for details and available documents.
We have studied the contribution of vagal pulmonary receptors to the stability of breathing during postural changes in humans. Quiet breathing was quantified in the seated and the supine postures in 10 patients with chronic pulmonary denervation due to heart-lung transplantation and 10 age and sex matched normal controls. In the vast majority of patients and normal subjects frequency histograms for tidal volume and mean inspiratory flow rate were virtually superimposed seated and supine. There were no significant differences in the mean levels of respiratory variables between postures in either group (except for mean inspiratory flow rate in the patients which was slightly greater seated than supine). Experiments performed on a tilt table in two additional patients showed that the ventilatory response to postural changes was immediate. In addition, the response was maintained after blockade of intact tracheal stretch receptors with aerosolized lidocaine. These results indicate that adequate ventilatory compensation during postural changes does not depend on vagal afferent information arising in intrapulmonary or tracheal airway stretch receptors. The appropriate receptors may be diaphragmatic Golgi tendon organs.
Combined heart-lung transplantation has been performed in 51 patients since 1984. A pulmonary preservation fluid preceded by prostacyclin infusion has allowed distant procurement. Early organ function has been good in all cases. Maintenance immunosuppression is cyclosporine and azathioprine. Steroids are given to treat rejection episodes. Transbronchial biopsy has allowed the accurate, early and safe diagnosis of rejection. Acute cardiac rejection has not occurred in these patients. Thirty-seven patients are alive between 1 and 54 months following transplantation. The actuarial survival at 1 year is 76% and 68% at 2 years. Four patients died in the early postoperative period as a result of primary Cytomegalovirus (CMV). Other causes of early death were bacterial infection (4), cerebrovascular event (1), tracheal dehiscence (1) and small bowel infarction following retransplantation for obliterative bronchiolitis. Three other patients have died as a result of obliterative bronchiolitis. Patients and donors have been carefully selected to ensure that this scarce resource is utilised most effectively.
Evaluation of the functional condition of the heart prior to its removal from the donor or after transport to the recipient is difficult. Biopsies of the myocardium allow serial assessments to be made throughout this period, but suffer from the disadvantage that the average analysis of biopsies has only a tenuous connection with physiological function. Quantitative birefringence measurements (QBM), on the other hand, assess the ability of myocardial fibres to respond to ATP and calcium and have been shown to correlate well with measurements of cardiac function (P less than 0.001). A prospective study of myocardial biopsies before excision, after transport and again after transplantation, using quantitative birefringence measurement of biopsies of the heart has recently been completed. These studies have shown evidence of impaired myocardial function in 73 (43%) of 172 donor hearts studied prior to excision, with a further 27% showing significant deterioration during storage and transport to the recipient. Biopsy assessments therefore indicated that at the moment of implantation, only 30% of the donor hearts were normal. Functional assessment of the biopsies by QBM correlated with early clinical outcome of transplantation (P less than 0.001). Longer term follow-up of the recipients (up to 5 years) has shown that the mortality of recipients of hearts with impaired function before transplantation is significantly increased (44% of 120) compared with that of recipients of undamaged hearts (6% of 52, P less than 0.001).
Over the last eight years a completely new form of treatment has been introduced for end-stage pulmonary vascular disease and chronic lung disease, including cystic fibrosis. Lung transplantation and heart-lung transplantation have moved from an experimental and innovative stage to clinical treatments. The exclusion criteria for selecting potential recipients have become relaxed whilst preservation techniques have improved to allow ischaemic times of donor organs to be extended beyond 4 h. Monitoring of graft function with daily spirometry and use of transbronchial lung biopsy have enabled early diagnosis of lung rejection or infection and thus effective treatment. Lung transplantation and heart-lung transplantation, by their success, are providing new insight into lung disease and pulmonary physiology.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
We report our experience of heart-lung transplantation for the treatment of children with terminal respiratory disease. Between May 1987 and October 1988 we performed heart-lung transplantation in five children under the age of 16 (age range 11-15). All the patients were severely disabled by dyspnoea and hypoxia. Two had primary pulmonary hypertension, two cystic fibrosis, and one had Eisenmenger's syndrome. All five children are alive and well five to 17 months after operation and have returned to activities normal for their age. Three of the five patients had episodes of infection after operation. These were staphylococcal pneumonia, herpes simplex pneumonitis and, in one of the patients with cystic fibrosis, persistent purulent sputum. The mean number of episodes of rejection per child was 2.7 per half year. Heart-lung transplantation is a practical treatment for children in these disease groups with terminal respiratory failure.
Serial myocardial biopsy specimens, taken up to the time of serological evidence of primary cytomegalovirus (CMV) infection in 22 heart transplant patients, were examined and compared with those taken over similar times after transplantation in 21 patients who did not develop CMV infection. None of these 43 patients had serological evidence of CMV infection before their heart transplantation. There was no evidence of an increased cellular infiltrate in the myocardium at the time of the active CMV infection, even though the donor heart is the likeliest source of infection, nor was there any change in myocyte, interstitial cell, or vascular endothelial cell nuclei to identify active CMV infection.
Of the first 250 heart and 35 heart and lung transplant recipients at Papworth Hospital, Cambridge, who survived for more than one month after transplantation, 217 heart and 33 heart and lung patients were investigated serologically for evidence of Toxoplasma gondii infection. Six patients acquired primary T gondii infection, most probably from the donor organ. Five patients experienced T gondii recrudescence, two of whom had recovered from primary infection a few years earlier. Two patients died from primary T gondii infection and the severity of symptoms in the other patients with primary infection was related to the amount of immunosuppressive treatment. Prophylaxis with pyrimethamine (25 mg a day for six weeks) was introduced for T gondii antibody negative transplant recipients who received a heart from a T gondii antibody positive donor after the first four cases of primary toxoplasmosis. Of the seven patients not given pyrimethamine, four (57%) acquired primary T gondii infection. This compared with two of the 14 patients (14%) given prophylaxis.
Acute denervation of the lungs occurs after heart-lung transplantation (HLT), affecting both afferent and efferent nerves below the tracheal anastomosis. After surgery, the carina and main bronchi are perfused by mediastinal collaterals derived from the coronary arteries, and the intrapulmonary airways by retrograde blood flow from pulmonary artery collaterals. During acute rejection, the lungs are subjected to inflammation, particularly perivascular lymphocytic infiltrates. Rejection can be diagnosed by transbronchial biopsy (TBB). We report the bronchial responses to inhaled methacholine and ultrasonically nebulized distilled water (USNDW) in 16 HLT patients 2 wk to 43 months after surgery, relating them to the lung histopathology from concurrent TBB. Methacholine bronchial hyperresponsiveness was common, but it was not associated with airway epithelial or submucosal inflammation or perivascular lymphocytic infiltration. Six patients had a modest response to USNDW (fall in FEV1 greater than 10%). The responsiveness to USNDW was not associated with enhanced methacholine responsiveness or epithelial and mucosal inflammation. However, it was more commonly seen in patients with lung rejection and perivascular infiltrates. Methacholine hyperresponsiveness in HLT patients could therefore reflect denervation hypersensitivity of airway smooth muscle muscarinic receptors. The modest response to USNDW in some patients cannot be a result of a vagal reflex but could reflect a pathologic vascular response associated with lung rejection. These observations offer insight into the possible mechanisms of bronchial hyperresponsiveness in disease.
As a result of clinical heart-lung transplantation, the lungs are denervated below the level of the tracheal anastomosis. It has been questioned whether afferent vagal reinnervation occurs after surgery. Here we report the cough frequency, during inhalation of ultrasonically nebulized distilled water, of 15 heart-lung transplant patients studied 6 wk to 36 months after surgery. They were compared with 15 normal subjects of a similar age and sex. The distribution of the aerosol was studied in five normal subjects using 99mtechnetium diethylene triamine pentaacetate (99mTc-DTPA) in saline. In seven patients, the sensitivity of the laryngeal mucosa to instilled distilled water (0.2 ml) was tested at the time of fiberoptic bronchoscopy by recording the cough response. Ten percent of the aerosol was deposited onto the larynx and trachea, 56% on the central airways, and 34% in the periphery of the lung. The cough response to the aerosol was strikingly diminished in the patients compared with normal subjects (p less than 0.001), but all seven patients coughed when distilled water was instilled onto the larynx. As expected, the laryngeal mucosa of heart-lung transplant patients remains sensitive to distilled water. However, the diminished coughing when the distilled water is distributed by aerosol to the central airways supports the view that vagal afferent nerves do not reinnervate the lungs after heart-lung transplantation, up to 36 months after surgery.
Thirty-two patients underwent combined heart and lung transplantation at Papworth Hospital between 1984 and 1987. The clinical and physiologic observations made at the time of episodes of infection and rejection together with the histopathology of lung tissue obtained by transbronchial lung biopsy were compared with pre- and postepisode chest radiographs. There were 45 episodes of rejection in 20 patients: 23 episodes during the first month after transplantation, and 22 after 1 month. Twenty-six episodes of infection occurred in 15 patients. The causative organisms included Aspergillus fumigatus, cytomegalovirus (CMV), herpes simplex, Pneumocystis carinii, and Staphylococcus aureus. When an abnormal chest radiograph is common during the first month after transplantation during acute rejection (74%), it may alternatively be due to lung infection (most commonly CMV pneumonitis). The chest radiograph during this period provides a useful indication for transbronchial biopsy and bronchial lavage. The chest radiograph is abnormal in the minority (23%) of episodes of rejection occurring later than 1 month after transplantation. Pulmonary function tests (FEV1 and VC) offered a more useful indication for transbronchial biopsy during this period.