- Email: [email protected]
FIBRINOLYSIS AND PULMONARY EMBOLISM
1079 increased incidence of bradycardia twelve hours after initiation of therapy in the propranolol-treated patients as a whole gives no information about drug absorption by the shocked patients. Dr. Balcon and his colleagues state " that the risks of using propranolol intravenously in the acute phase of myocardial infarction would be too great ", but surely, if they wish to study the effects of any pharmacological agent in this situation, intravenous administration of known quantities of the drug is the only acceptable technique. Unless evidence of satisfactory absorption of propranolol from the bowel of patients in cardiogenic shock can be produced, it appears that the beneficial or harmful effects of p-adrenergic blockade during acute mvocardial infarction remain in doubt. The General Hospital, B. L. PENTECOST. Birmingham 4.
laboratory evidence of digestion or depletion of the circulating coagulation factors during this time or later. On the rationale that the fibrinolysis would be beneficial to the state of cardiopulmonary embarrassment we deliberately refrained from using antifibrinolytic agents, while continuing to monitor the level of coagulation factors. The pulmonary symptoms in fact disappeared and the patient recovered. This case4 and these problems 5are discussed more fully elsewhere. Even in obstetric emergencies fibrinolysis may on occasion be beneficial and does not necessarily require to be inhibited.
SIR,-In your leading article (Oct. 29, p. 950) you doubt " whether any so-called coronary vasodilators depend on this action for their therapeutic value in coronary-artery disease...." In this respect, we think it important to distinguish between the therapy of angina and that of acute myocardial infarction. We have evidence, using a technique of xenon-133 clearance, that coronary vasodilators, particularly dipyridamole, increase collateral blood-flow within 24 hours of experimental myocardial infarction in dogs. An increase of 50% in anastomotic blood-flow is achieved during the first 10 days of healing. This somewhat surprising but encouraging finding has initiated appropriate double-blind trials with dipyridamole in patients with acute myocardial infarction. Though the drug has been available for some years, its therapeutic value remains uncertain; we know of no adequate trials in this condition. Department of Cardiology, V. J. REDDING Westminster Hospital, London S.W.1. J. RUSSELL REES. a controlled trial of in acute myocardial infarction. Our results were similar to those of Dr. Balcon and his colleagues (Oct. 29, p. 917) and Dr. Clausen and his colleagues (Oct. 29, p. 920), though we used a higher dosage of propranolol-40 mg. sixhourly. The criterion of success was survival at 4 weeks. There were 52 patients on propranolol and 47 on placebo. The death-rate was 19-4% in the treated patients and 25-5% in the control group. No serious side-effect was encountered, and the incidence of heart-failure was similar in the two groups.
SIR,-We have recently completed
propranolol
The results will be published. North Downs Hospitals Group, and Department of Medical Statistics, Queen’s University of Belfast.
J. M. BARBER F. M. MURPHY J. D. MERRETT.
FIBRINOLYSIS AND PULMONARY EMBOLISM SIR,-Your annotation discussing the beneficial effect of fibrinolytic activity on the resolution of pulmonary emboli (Oct. 29, p. 953) may have relevance also to another type of clinical situation-namely, amiotic-fluid embolism. Activation of the fibrinolytic system is well documented in this obstetric complication.1-s If this activity is confined to the dissolution of the fibrin content of emboli (i.e., fibrinolysis) it will be wholly beneficial to the patient. If, however, the fibrinolytic activity
generalised hyperplasminxmic state with circulating coagulation factors (i.e., fibrinogenolysis), a severe hwmorrhagic state will supervene. We have seen a patient who appeared to fit into the first of these two categories. The clinical picture, radiological findings, and circulation disturbances were almost certainly those of amnioticfluid embolism. In-vitro fibrinolysis was confirmed in two blood-samples collected 11/4 hours apart, but there was no
progresses to a digestion of the
Ratnoff, O. D., Vosburgh, G. J. New Engl. J. Med. 1952, 247, 626. Beller, F. K., Douglas, G. W., Debrovner, G. H., Robinson, R. Am. J. Obstet. Gynec. 1963, 87, 48. 3. Skjodt, P. Acta obstet. gynec. scand. 1965, 44, 437.
1. 2.
Department of Haematology, Queen Mother’s Hospital, Glasgow C.3.
M. L. N. WILLOUGHBY J. WILLOCKS.
CHOLESTYRAMINE AND PORPHYRIN-BINDING SIR,-The clinical response to cholestyramine administration which Dr. Stathers describes (Oct. 8, p. 780) in patients with porphyria cutanea tarda (P.C.T.) is similar to that which my co-workers and I have reportedin erythropoietic protoporphyria (E.P.). We are gratified that Dr. Stathers was able to obtain objective evidence of in-vivo porphyrin binding by cholestyramine with resulting increased fxcal elimination of porphyrin. We have conducted almost identical tests in E.P., but could not clearly demonstrate in-vivo porphyrin binding. It is likely that the difference between our results and those of Dr. Stathers is related to the chemical properties of the porphyrins involved-primarily coproporphyrin in P.C.T., and almost exclusively protoporphyrin, a less stable compound, in E.P. I summarise briefly here our own findings in a child with unusually severe E.P.
Existence of
porphyrin
was
a significant enterohepatic shunt of protostrongly suspected in our patient when it was the amount of protoporphyrin in a 1-hour
observed that collection of bile from a duodenal tube was 3 times the mean hourly rate of faecal elimination of protoporphyrin during the same period. It was hoped that reabsorption of protoporphyrin in the gastrointestinal tract could be prevented by the binding action of cholestyramine. The child weighed 27 kg. and was given 9-18 g. per day of the drug for periods of 2 and 4 months with no significant side-effects except mild hypoprothrombinaemia on one occasion. Supplementary fat-soluble vitamins were thereafter given once a week. There was improvement in all clinical and laboratory indices during the periods of therapy. But the manifestations of the disease in this patient were found to vary so dramatically in response to many known and unknown stimuli that it was impossible to be sure that the improvement was not fortuitous.
Protoporphyrin could be quantitatively eluted from cholestyramine in vitro by 3N-5N mineral acids or O.1N-0°5N ammonium hydroxide, and it could be partially eluted by
ether/acetic-acid or ethyl-acetate/acetic-acid mixtures. The amount of protoporphyrin extracted from stool specimens with ethyl-acetate/acetic-acid fell 2 to 10 fold during cholestyramine therapy of the patient, a mildly involved sibling, and a normal adult. Extraction of the fxcal residues with mineral acids yielded only insignificant amounts of in distinct contrast to Dr. Stathers’ results in We have not been able to detect increased f2ecal protoporphyrin or breakdown products by other methods.
protoporphyrin, P.C.T.
Our results suggest, but do
not
prove, that
to
cholestyramine in the
protoporphyrin
as the which accumulate in P.C.T. It appears likely that increased fscal protoporphyrin was not detected during cholestyramine therapy of E.P. because the protoporphyrin was in some way modified or destroyed in the gastrointestinal
is bound
same
manner
porphyrins
Willocks, J., Mone, J. G., Thomson, W. J. Br. med. J. (in the press). Willoughby, M. L. N. J. Obstet. Gynœc. Br. Commonw. (in the press). Willoughby, M. L. N. in Coagulation Disorders in Obstetrics (edited by J. C. de Neef and G. J. H. den Ottolander); p. 87. Excerpta Medica Foundation, International Congress series no. 123, 1966. 7. Lischner, H. W., Purugganan, H. B., Valdes-Dapena, M. A., Watts, H. G., McElfresh, A. E. Seventy-sixth Annual Meeting of the American Pediatric Society, Inc., Atlantic City, New Jersey, April, 1966; Program and Abstracts, p. 48.
4. 5. 6.
laboratory evidence of digestion or depletion of the circulating coagulation factors during this time or later. On the rationale that the fibrinolysis would be beneficial to the state of cardiopulmonary embarrassment we deliberately refrained from using antifibrinolytic agents, while continuing to monitor the level of coagulation factors. The pulmonary symptoms in fact disappeared and the patient recovered. This case4 and these problems 5are discussed more fully elsewhere. Even in obstetric emergencies fibrinolysis may on occasion be beneficial and does not necessarily require to be inhibited.
SIR,-In your leading article (Oct. 29, p. 950) you doubt " whether any so-called coronary vasodilators depend on this action for their therapeutic value in coronary-artery disease...." In this respect, we think it important to distinguish between the therapy of angina and that of acute myocardial infarction. We have evidence, using a technique of xenon-133 clearance, that coronary vasodilators, particularly dipyridamole, increase collateral blood-flow within 24 hours of experimental myocardial infarction in dogs. An increase of 50% in anastomotic blood-flow is achieved during the first 10 days of healing. This somewhat surprising but encouraging finding has initiated appropriate double-blind trials with dipyridamole in patients with acute myocardial infarction. Though the drug has been available for some years, its therapeutic value remains uncertain; we know of no adequate trials in this condition. Department of Cardiology, V. J. REDDING Westminster Hospital, London S.W.1. J. RUSSELL REES. a controlled trial of in acute myocardial infarction. Our results were similar to those of Dr. Balcon and his colleagues (Oct. 29, p. 917) and Dr. Clausen and his colleagues (Oct. 29, p. 920), though we used a higher dosage of propranolol-40 mg. sixhourly. The criterion of success was survival at 4 weeks. There were 52 patients on propranolol and 47 on placebo. The death-rate was 19-4% in the treated patients and 25-5% in the control group. No serious side-effect was encountered, and the incidence of heart-failure was similar in the two groups.
SIR,-We have recently completed
propranolol
The results will be published. North Downs Hospitals Group, and Department of Medical Statistics, Queen’s University of Belfast.
J. M. BARBER F. M. MURPHY J. D. MERRETT.
FIBRINOLYSIS AND PULMONARY EMBOLISM SIR,-Your annotation discussing the beneficial effect of fibrinolytic activity on the resolution of pulmonary emboli (Oct. 29, p. 953) may have relevance also to another type of clinical situation-namely, amiotic-fluid embolism. Activation of the fibrinolytic system is well documented in this obstetric complication.1-s If this activity is confined to the dissolution of the fibrin content of emboli (i.e., fibrinolysis) it will be wholly beneficial to the patient. If, however, the fibrinolytic activity
generalised hyperplasminxmic state with circulating coagulation factors (i.e., fibrinogenolysis), a severe hwmorrhagic state will supervene. We have seen a patient who appeared to fit into the first of these two categories. The clinical picture, radiological findings, and circulation disturbances were almost certainly those of amnioticfluid embolism. In-vitro fibrinolysis was confirmed in two blood-samples collected 11/4 hours apart, but there was no
progresses to a digestion of the
Ratnoff, O. D., Vosburgh, G. J. New Engl. J. Med. 1952, 247, 626. Beller, F. K., Douglas, G. W., Debrovner, G. H., Robinson, R. Am. J. Obstet. Gynec. 1963, 87, 48. 3. Skjodt, P. Acta obstet. gynec. scand. 1965, 44, 437.
1. 2.
Department of Haematology, Queen Mother’s Hospital, Glasgow C.3.
M. L. N. WILLOUGHBY J. WILLOCKS.
CHOLESTYRAMINE AND PORPHYRIN-BINDING SIR,-The clinical response to cholestyramine administration which Dr. Stathers describes (Oct. 8, p. 780) in patients with porphyria cutanea tarda (P.C.T.) is similar to that which my co-workers and I have reportedin erythropoietic protoporphyria (E.P.). We are gratified that Dr. Stathers was able to obtain objective evidence of in-vivo porphyrin binding by cholestyramine with resulting increased fxcal elimination of porphyrin. We have conducted almost identical tests in E.P., but could not clearly demonstrate in-vivo porphyrin binding. It is likely that the difference between our results and those of Dr. Stathers is related to the chemical properties of the porphyrins involved-primarily coproporphyrin in P.C.T., and almost exclusively protoporphyrin, a less stable compound, in E.P. I summarise briefly here our own findings in a child with unusually severe E.P.
Existence of
porphyrin
was
a significant enterohepatic shunt of protostrongly suspected in our patient when it was the amount of protoporphyrin in a 1-hour
observed that collection of bile from a duodenal tube was 3 times the mean hourly rate of faecal elimination of protoporphyrin during the same period. It was hoped that reabsorption of protoporphyrin in the gastrointestinal tract could be prevented by the binding action of cholestyramine. The child weighed 27 kg. and was given 9-18 g. per day of the drug for periods of 2 and 4 months with no significant side-effects except mild hypoprothrombinaemia on one occasion. Supplementary fat-soluble vitamins were thereafter given once a week. There was improvement in all clinical and laboratory indices during the periods of therapy. But the manifestations of the disease in this patient were found to vary so dramatically in response to many known and unknown stimuli that it was impossible to be sure that the improvement was not fortuitous.
Protoporphyrin could be quantitatively eluted from cholestyramine in vitro by 3N-5N mineral acids or O.1N-0°5N ammonium hydroxide, and it could be partially eluted by
ether/acetic-acid or ethyl-acetate/acetic-acid mixtures. The amount of protoporphyrin extracted from stool specimens with ethyl-acetate/acetic-acid fell 2 to 10 fold during cholestyramine therapy of the patient, a mildly involved sibling, and a normal adult. Extraction of the fxcal residues with mineral acids yielded only insignificant amounts of in distinct contrast to Dr. Stathers’ results in We have not been able to detect increased f2ecal protoporphyrin or breakdown products by other methods.
protoporphyrin, P.C.T.
Our results suggest, but do
not
prove, that
to
cholestyramine in the
protoporphyrin
as the which accumulate in P.C.T. It appears likely that increased fscal protoporphyrin was not detected during cholestyramine therapy of E.P. because the protoporphyrin was in some way modified or destroyed in the gastrointestinal
is bound
same
manner
porphyrins
Willocks, J., Mone, J. G., Thomson, W. J. Br. med. J. (in the press). Willoughby, M. L. N. J. Obstet. Gynœc. Br. Commonw. (in the press). Willoughby, M. L. N. in Coagulation Disorders in Obstetrics (edited by J. C. de Neef and G. J. H. den Ottolander); p. 87. Excerpta Medica Foundation, International Congress series no. 123, 1966. 7. Lischner, H. W., Purugganan, H. B., Valdes-Dapena, M. A., Watts, H. G., McElfresh, A. E. Seventy-sixth Annual Meeting of the American Pediatric Society, Inc., Atlantic City, New Jersey, April, 1966; Program and Abstracts, p. 48.
4. 5. 6.