Brain death, triiodothyronine depletion, and inhibition of oxidative phosphorylation: relevance to management of organ donors.
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Animals↗
Biomedical subjects
D Novitzky
Publications and source records attributed to D Novitzky.
Interpretation of endomyocardial biopsy after heart transplantation. Potentially confusing factors.
Histological examination of the myocardium by endomyocardial biopsy is a standard method of monitoring the presence of acute rejection in the transplanted heart. The histopathological consequences of the biopsy procedure itself have been investigated in non-transplanted hearts in the baboon. Organization of thrombus, necrosis of myocytes adjacent to the biopsy site, and mononuclear cells (including T lymphocytes) surrounding the biopsy site appear after biopsy; should a subsequent biopsy be taken from this area, these appearances may be confused with the appearances associated with acute or resolving cardiac rejection. This problem has been encountered in the clinical transplant programme. Observations on the myocardial histopathological changes resulting from brain death and from parasitic infestation, both of which may also lead to confusion in the interpretation of endomyocardial biopsies, are also presented. Awareness of these factors in patients with heart transplants should lead to caution in the interpretation of the histopathological features and may avoid unnecessary extra immunosuppression early after transplantation. Observations indicate that endomyocardial biopsy should not be the sole method of monitoring for the development of acute rejection.
Animals↗
Surgery in patients with heart transplants. Anaesthetic and operative considerations.
As cardiac transplantation becomes more common, so an increasing number of patients with functioning heart transplants may require surgery for related or unrelated non-cardiac conditions. Fifteen patients who have undergone a total of 39 operations (excluding retransplantation) since heart transplantation were reviewed; 36% were for infective conditions and 23% each for gastro-intestinal and vascular lesions. There was one postoperative death in a patient undergoing leg amputation for overwhelming Clostridium welchii infection. There were no major non-fatal complications. The conditions for which operation may be necessary, the specific problems of anaesthesia and surgery in such patients, and the prophylactic measures which may be undertaken to ensure an uncomplicated clinical course are discussed. A clear understanding of the physiology and pharmacology of the denervated heart is essential if these patients are successfully to undergo major operations requiring general anaesthesia.
Adolescent↗
Forty-eight hours hypothermic perfusion storage of pig and baboon hearts.
A system has been developed for the continuous hypothermic perfusion of isolated hearts using a clear fluid perfusate. Myocardial viability has been maintained after periods of storage of up to 48 hr. Pig hearts stored in this way showed almost normal hemodynamic performance on subsequent functional testing. Orthotopic allotransplantation or autotransplantation of baboon hearts stored for 48 hr was followed by good immediate and long-term function. Baboons receiving allotransplants survived until rejection. Three of four of those autotransplanted survived until electively sacrificed at 1, 3, and 12 months; all showed normal hemodynamic function on cardiac catheterization and normal myocardial histology.
Animals↗
Acute isolated pulmonary rejection following transplantation of the heart and both lungs: experimental and clinical observations.
Early observations following transplantation of the heart and both lungs have suggested that acute rejection occurs simultaneously in both organs. Endomyocardial biopsy could, therefore, be used to monitor rejection in both heart and lungs. We present here our experience with heart-lung transplantation in the baboon, and in two recently observed human patients. The evidence we provide suggests that acute rejection may occur earlier in the lungs than in the heart, and that monitoring the heart alone may prove inadequate. Of 12 baboons that survived heart and lung transplantation, 11 died from acute isolated pulmonary rejection; 10 of these 11 animals showed no features of cardiac rejection. In 2 of 6 human patients who have undergone this operation, an episode of acute pulmonary rejection is believed to have occurred in the absence of cardiac rejection. There is no easy method of confirming pulmonary rejection directly (other than open-lung biopsy, which is clearly contraindicated as a routine procedure). We suggest that more attention be directed toward developing tests that indicate acute rejection but are not organ specific, rather than relying on techniques that diagnose cardiac rejection only.
Acute Disease↗
Prevention of myocardial injury during brain death by total cardiac sympathectomy in the Chacma baboon.
In a previous study, structural myocardial damage was found to occur in 60% of baboons after brain death had been induced by a rapid increase in intracranial pressure. In the present study, we attempt to clarify the causative mechanisms involved in the development of such injury. Three groups of baboons were subjected to brain death: group A, the control; group B, those with previous surgical or pharmacological cardiac sympathectomy or cardiac denervation; and group C, those with bilateral vagotomy, incomplete sympathectomy, or bilateral adrenalectomy. Electrocardiographic and hemodynamic responses to brain death were greatly modified in group B baboons compared with responses in groups A and C. Groups A and C showed a high incidence of myocardial necrosis, whereas no myocyte damage was seen in the hearts of group B baboons. The histological appearance of innervated hearts following brain death (groups A and C) may closely resemble that seen during an acute rejection episode following cardiac transplantation. We suggest that myocardial damage occurring during the process of dying may be related to endogenous catecholamine release (possibly resulting in increased calcium uptake by the myocardial cells), inducing various forms of myocyte necrosis. This may result in early failure in a donor heart following cardiac transplantation.
Animals↗
Are there indications for heterotopic heart transplantation in 1986? A 2- to 11-year follow-up of 49 consecutive patients undergoing heterotopic heart transplantation.
In the 9-year period between November 1974 and December 1983, 49 patients underwent heterotopic heart transplantation at Groote Schuur Hospital. Eight patients subsequently underwent a further transplant procedure, and one of these a third transplant (58 transplants in 49 patients). Conventional immunosuppressive therapy (azathioprine, corticosteroids, and rabbit antithymocyte globulin) was used in 47 cases (81%), and cyclosporine and conventional immunosuppression in 11 (19%). Follow-up (to 1st January 1986) has been for a minimum of 2 and a possible maximum of 11 years. Forty-one of the 49 patients (85%) have subsequently died, mean survival of this group being 18.5 months. Mean survival of the 8 patients alive is 74 months. One-year survival has been 55% and 5-year survival 22%. In light of this experience, it would seem to us that the indications for heterotopic transplantation have now greatly diminished. There would still appear to be a place for it, however, when the donor heart is small in relation to the mass of the recipient, when there is a possibility of myocardial recovery following the resolution of a myocarditis, and when there is an elevated pulmonary vascular resistance which may make orthotopic transplantation hazardous. Heterotopic heart transplantation may also be indicated when the recipient circulation is failing rapidly despite maximal medical support, and therefore transplantation is urgent.
Adolescent↗
Impairment of renal slice function following brain death, with reversibility of injury by hormonal therapy.
The effects of the agonal period and subsequent donor management on renal slice function, using the K+ - Na+ ratio, have been studied in the pig. Brain ischaemia or death resulted in a reduction in renal slice function, whether the pig was maintained normovolemic or hypovolemic by i.v. fluid and dobutamine therapy. This deterioration in function was, however, reversed or prevented by a period of therapy with thyroxine (T3), insulin, and cortisol. A period of 24 hr storage of the kidney slice in a low ionic strength solution in ice resulted in a further deterioration in slice function in all groups studied.
Animals↗
Endomyocardial biopsy site morphology. An experimental study in baboons.
Endomyocardial biopsy (EMB) is widely used, but the effects on the endocardium have not been studied in detail. If repetitive biopsies are performed, as in the monitoring of cardiac transplants, there is a chance of sampling a previous EMB site. This study investigates changes in EMB site morphology over a period of 0 to 30 days in a primate model. Organization of thrombus, necrosis of myocytes adjacent to the biopsy site, and the presence of mononuclear cells (including T lymphocytes) surrounding the biopsy site indicated a potential for confusion with the appearances associated with acute or resolving cardiac rejection. We have encountered this problem in clinical practice. Knowledge of EMB site morphology aids in the interpretation of EMB specimens.
Animals↗
The effects of brain death and 24 hours' storage by hypothermic perfusion on donor heart function in the pig.
The effects on the myocardium of the agonal period and subsequent management have been studied in the pig. Acute ischemia of the brain led to major temporary hemodynamic changes. Brain death, with or without hemodynamic support of the circulation, led to a significant reduction in subsequent myocardial function, associated with some depletion of the myocardial high-energy phosphate and glycogen reserves, although the rate of this depletion was reduced by anaerobic glycolysis. Although 24 hours' storage by continuous hypothermic perfusion of hearts taken from control animals led to only a minimal reduction in myocardial function, storage increased the reduction in function associated with brain death when intravenous fluid and dobutamine support had been given to maintain the brain dead pig in a normotensive state. Storage, however, reduced the anaerobic metabolism seen in hearts functioning in hypotensive brain dead pigs and led to replenishment of the glycogen stores.
Adenosine Triphosphate↗
A successful method of administering cyclosporin A to the chacma baboon.
Cyclosporin A (CYA) is a powerful immunosuppressant. Hitherto, it has proved difficult to maintain therapeutic whole-blood levels of the drug in the chacma baboon, making this animal unsuitable for transplantation studies if CYA is used. A successful method of maintaining adequate therapeutic levels after the intramuscular injection of CYA in a mixture of alcohol and Intralipid (Saphar) is described.
Administration, Oral↗
Transplantation of the heart and both lungs. Experimental and clinical experience and review of the literature.
Transplantation of the heart and both lungs is the only therapy that can be offered to certain patients with end-stage pulmonary vascular disease. Our experimental experience with the baboon is presented. Fourteen allotransplants were performed, 12 recipients (inadequately immunosuppressed with cyclosporin A and azathioprine) surviving between 4 and 29 days. In 11 cases death resulted from acute rejection which predominantly involved the lungs, the heart being spared in 10 cases; the remaining death was from bronchopneumonia. Two autotransplanted baboons survived until sacrificed at 6 months. Indications for the operation, selection of both the recipient and the donor, and recent results at other centres are briefly reviewed. It would seem that this operation is recommended in selected patients with idiopathic pulmonary hypertension or Eisenmenger's syndrome whose condition is deteriorating and in whom no other form of therapy is applicable.
Animals↗
An airlift pump device for low pressure perfusion storage of the isolated heart.
A portable apparatus for the continuous hypothermic perfusion of the isolated heart is described. The system has been used successfully to store pig and baboon hearts for periods of up to 48 hr, and to store human donor hearts for periods of 7 to 17 hr before being transplanted. The perfusate is both oxygenated and circulated by gas flow from a pressurized oxygen cylinder, using the air-lift pump principle. The apparatus has no moving parts and requires no electrical energy supply; malfunction is, therefore, extremely unlikely. A regulator has been incorporated which can be adjusted to increase or decrease the myocardial perfusion pressure. The system and environmental variables which can affect flow and pressure within the apparatus are discussed. The storage time allowed by this system will enable transportation of donor hearts between most of the world's major cities.
Cold Temperature↗
Further cardiac transplant procedures in patients with heterotopic heart transplants.
Seven patients with heterotopic heart transplants have undergone further heart transplant procedures. In 5, the first heterotopically placed donor heart was excised and replaced with the second donor heart. In 2, the first heterotopic donor heart was left in situ and the patient's own heart (then nonfunctioning) was excised and replaced by the second donor heart; thus, these patients underwent orthotopic transplantation and were left with two donor hearts. The decision to perform retransplantation in a patient undergoing irreversible acute rejection is usually straightforward, but the timing of a further transplant procedure in a patient with advanced graft arteriosclerosis may present a difficult problem. Two of the 7 patients in this series died of infectious complications within the first 3 months after retransplantation. A third patient acutely rejected the second donor heart within 5 days, but survived an additional 17 months with the support of his own cardiomyopathic heart. Four patients remain alive and well between 5 and 36 months following the second transplant and between 17 and 54 months following the first transplant procedure.
Acute Disease↗
The significance of left ventricular volume measurement after heart transplantation using radionuclide techniques.
Multigated equilibrium blood pool scanning using Technetium 99m labeled red blood cells was used to measure left ventricular volumes in three heterotopic and one orthotopic heart transplant recipient(s). Simultaneously, an endomyocardial biopsy was performed and the degree of acute rejection was assessed by a histological scoring system. The scores were correlated to changes in ejection fraction and heart rate. Technetium 99m scanning data were pooled according to the endomyocardial biopsy score: no rejection; mild rejection; moderate rejection, and severe rejection. In each group, the median of the left ventricular volume parameters was calculated and correlated with the endomyocardial biopsy score, using a non-parametric one-way analysis of variance. A decrease in stroke volume correlated best with the endomyocardial biopsy score during acute rejection. A decrease in end-diastolic left ventricular volumes did not correlate as well. Changes in the end-systolic left ventricular volumes were not statistically significant, but using a simple correlation between end-systolic left ventricular volumes and endomyocardial biopsy the correlation reached significance. Changes in left ventricular volumes measured by Technetium 99m scanning may be useful to confirm the presence or absence of acute rejection in patients with heart grafts.
Adolescent↗
Preformed lymphocytotoxic antibodies disappear following cyclosporine therapy.
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Adolescent↗
Cyclosporin A in the management of patients with heart transplants. Initial experience at Groote Schuur Hospital.
During the year February 1983 - February 1984 10 patients received immunosuppressive therapy with cyclosporin A (CYA) and methylprednisolone (MP) after either heterotopic or orthotopic heart transplantation. Two of these patients were undergoing severe acute rejection episodes (intractable to conventional immunosuppressive therapy) when CYA administration was initiated; both episodes were reversed and neither patient suffered further rejection. The remaining 8 patients received CYA from the time of transplantation. Two patients died 7 and 9 days postoperatively from multi-organ failure; in retrospect, excessively high dosages of CYA were administered, resulting in very high blood levels of the drug, which may have contributed to renal failure. One patient died (while living abroad) of a possible septicaemia 8 months after transplantation, having otherwise done well. Seven patients remain alive and active 3 1/2 - 15 months after operation. The incidence of both severe acute rejection episodes and life-threatening infection would appear to be lower in patients receiving CYA and MP when compared with earlier patients at our institution who received conventional immunosuppression. Frequent monitoring of whole-blood levels of CYA is necessary to ensure that the nephrotoxic effect of the drug is minimized.
Adult↗
Primary cardiac haemangiomas. A report of 2 cases.
Primary heart tumours are extremely rare. Over a period of 25 years 22 primary cardiac tumours were diagnosed clinically or at autopsy at Groote Schuur Hospital. Fourteen patients with myxomas, 1 with lymphocytic lymphoma and 2 with haemangiomas underwent surgery. A further 4 myxomas and 1 histiocytoma were found at autopsy. In both the cases of haemangioma the diagnosis of a vascular tumour was made before surgery. One tumour had infiltrated the lateral wall of the left ventricle and was unresectable; only a biopsy specimen was taken. The patient, however, remains well some 6 years later. In the second patient the haemangioma was situated in the outflow tract of the right ventricle and was successfully excised. The clinical history, pathological features and management of both cases are presented.
Child, Preschool↗