Dose-related Phenomenon Research Articles

Methoxyflurane and Renal Function

To the Editor.— Another study of methoxyflurane and renal function has recently appeared (218:841, 1971). The findings indicate temporary renal dysfunction in patients receiving methoxyflurane. It is of note that the duration of anesthesia was 187 ± 42 minutes and that the inhalation anesthetic was administered with the vaporizer setting usually less than 0.8%. To achieve tolerance of the endotrachael tube by means of methoxyflurane, nitrous oxide, and oxygen, for this length of time, the total dose of methoxyflurane administered would be excessive. While one accepts the fact that temporary renal dysfunction may occasionally follow administration of methoxyflurane, and that this temporary dysfunction may progress to a more severe impairment under certain circumstances, it seems that this is clearly a dose-related phenomenon. It would be irresponsible to claim that anesthetic agents are in themselves beneficial to the human organism; they have all been implicated in one or another postanesthetic

RADIATION-INDUCED HEART DISEASE: Clinical and Experimental Aspects

The heart traditionally was considered to be radioresistant; however, careful analysis of a large number of patients treated at Stanford Medical Center has revealed examples of radiation-induced heart disease. In Hodgkin's disease, the incidence was 6.6 per cent and in breast carcinoma 4.5 per cent. The pathology of radiation-induced heart disease is distinctive but by no means specific. The hallmark of the late lesions in the pericardium and myocardium is fibrosis. On clinical grounds, we have attempted to classify syndromes, realizing that there is considerable overlap in the course of many patients. Particularly, either of the late pericardial syndromes, acute pericarditis or chronic pericardial effusion, may progress to cardiac tamponade or constriction. It is of utmost importance to remain alert to the occurrence of radiation-induced pericardial disease because it is often satisfactorily treatable. The signs and symptoms accompanying radiation pericarditis often are similar to those produced by advancing neoplasm within the thorax, but careful clinical study will reveal the correct diagnosis in the majority of cases. Our policy of treatment has been conservative because in approximately half the patients we have seen pericarditis has cleared spontaneously. Pericardiocentesis may be urgently indicated in the presence of tamponade, and several patients have been cured by pericardiectomy. The occurrence of late radiation pericarditis is related to the dose of radiation, its fractionation, and also to the volume of heart irradiated. When large volumes of the heart must be treated, pericardial tolerance is approximately 1500 rets fractionated radiation. If only a small volume is included, pericardial tolerance is approximately 1850 rets. Pancarditis, the most severe form of radiation-induced heart disease, will be rare if these tolerance limits are not exceeded. In planning radiation therapy, as much of the cardiac silhouette as possible should be excluded by careful treatment planning and port shielding. Although the incidence of pericarditis is related to dose, one must guard against a systematic policy of reduced dosage insufficient to control the neoplasm. Our animal studies have added helpful information concerning the nature of radiation-induced heart disease and have shown that pericarditis is a dose-related phenomenon which does not depend on underlying malignancy for its production. The sharp rise in incidence with increasing dose is similar to that observed in humans. Therefore, the concept of pericardial tolerance developed from the clinical data appears validated in the animal model. Our experiments revealed that the pathogenesis of the myocardial fibrosis is related to capillary endothelial cell injury, leading to a quantitative loss of capillaries, failure of the microcirculation, and ischemia.

Bleomycin-induced interstitial pneumonia in dogs.

The intravenous administration of Bleomycin to 10 dogs at different dosages resulted in varying degrees of interstitial pneumonia in all cases and a lower incidence of nephrosis, foot pad excoriation and ulceration, onychoptosis, and alopecia. Pulmonary changes did not occur as a simple dose-related phenomenon. The lesions required at least 38 days to become apparent and appeared to increase in severity with time. Even at the lowest dose used (0·625 mg/kg body weight) very severe changes were seen 128 days after cessation of therapy. Morphological features of interstitial pneumonia were subpleural localization, focal mesothelial hyperplasia, marked hyperplasia and metaplasia of type II pneumocytes, fetalization of alveoli, and a pleomorphic inflammatory infiltrate. In cross-sections of lung lobes selected for histology approximately 1 to 22% of the parenchyma contained lesions. Involved areas showed marked elastosis, excess of reticular fibres, fibrosis, and increased acid mucopolysaccharides. The administration of Bleomycin produced pulmonary changes similar in many respects to those reported in busulphan-treated patients and desquamative interstitial pneumonia. The finding of interstitial pneumonia and pulmonary fibrosis in dogs treated with low doses over prolonged periods points the need to monitor pulmonary function in humans treated with Bleomycin.

Acquired immunological tolerance of male skin isografts in adult female mice injected with whole blood.

SummaryPermanent acquired immunological tolerance has been established in adult C57B1/1 female mice to isologous male skin graft using pooled whole blood obtained from C57B1/1 males as a pre-conditioning material. Tolerance using this technic is a dose related phenomenon. Doses of 0.25 cc of whole blood or greater produce a long lasting tolerance.