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EFFECT OF BETA-ADRENERGIC BLOCKADE ON PLASMA-RENIN ACTIVITY AND INTRACTABLE HYPERTENSION IN PATIENTS RECEIVING REGULAR DIALYSIS TREATMENT
67
recorded on placebo (table i) (p<0.001, X2 Of =13-99). the twenty-eight cramps which occurred on placebo, six were severe, five were moderate, and seventeen were mild. Of the ten cramps on quinine, two were severe, two were moderate, and six were mild (table II). Thus, quinine sulphate significantly reduced the frequency of cramps on haemodialysis but did not appear to alter their severity. All patients denied symptoms of vertigo, tinnitus, nausea, vomiting, or diarrhoea. None were found to have disturbances of vision or eighth-nerve damage on physical examination. All patients had normal audiograms at the end of the study. Haemolytic anaemia, agranulocytosis and thrombocytopenia were not observed. A transient rise in serum-glutamic-oxaloacetictransaminase and serum-glutamic-pyruvic-transaminase was noted in two patients in whom HBAg-positive hepatitis developed simultaneously. All other patients had normal liver profiles. cramps
were
Discussion
Chillar and Desforges5 observed a significant drop in red-blood-cell (R.B.C.) 2-3-diphosphoglycerate (2-3-D.P.G.) and a significant rise in arterial pH from normal or acidotic predialysis values to alkalotic values after dialysis. Since both the fall in R.B.C. 2-3-D.P.G. and the rise in pH would increase haemoglobin oxygen affinity it was proposed that cramps during hsemodialysis may be a manifestation of reduced tissue oxygen delivery during 5
h3emodialysis/
However, Stewart
et al. suggested that blood-volume the basis for cramps on haemodialysis.66 Higher dialysate sodium concentration (140 mmol/1) and ingestion of 140 mmol of sodium in the form of slow-release tablets have been shown to relieve cramps on haemodialysis.7 More recently, an intravenous bolus of hypertonic saline solution containing 40-45 mmol sodium has been used to treat cramps in a small number of patients on haemodialysis.8 All these treatments involved the administration of large amounts of sodium (60-140 mmol) which may exacerbate the hypertension and heart-failure which affect a very high percentage of dialysis patients. It seemed appropriate, therefore, to explore alternative treatments which did not involve the administration of sodium. Quinine sulphate increased the threshold of stimulation of the motor end plate, with reduction in response to repetitive nerve stimulation.Quinine sulphate also prolonged the refractory period of the muscle, resulting in diminished response to tetanic stimulation.1 Wolfz reported in 1936 that quinine sulphate was successful in relieving muscle cramps in myotonia congenita. Moss and Hermann3 administered this drug to fifteen patients with nocturnal cramps and reported uniform improvement. Gootnick4 reported successful results with this drug in twenty-eight out of thirty patients with night cramps. Although these were not controlled studies, quinine sulphate was subsequently extensively used with variable effectiveness to control night cramps.24We reasoned that quinine sulphate might be useful in controlling dialysis-induced muscle cramps, particularly in view of its extra-renal detoxification and ease of administration. We observed a significant reduction in the frequency of cramps in patients receiving quinine sulphate as com-
contraction
was
pared to placebo. In the small dose used, none of the sideeffects usually attributed to quinine sulphate were observed. Thus, quinine sulphate was found to be a safe and effective agent for reducing the frequency of muscle cramps in patients on haemodialysis. Ten cramps did occur in patients receiving quinine. This could be due to inadequate blood concentrations of quinine sulphate in some patients, because of poor absorption, enhanced degradation, or higher individual requirements. In view of the paucity of data on this drug in uraemia, we were unwilling to give higher doses even in selected patients. With monitoring of blood concentrations of quinine sulphate and tailoring the dose to individual requirements, the results might prove even more striking. In any event, our experience with this drug is encouraging and demonstrates the efficacy of quinine sulphate in reducing the frequency of cramps during hsemodialysis. Further trials are needed with larger patient populations to determine the pharmacokinetics of quinine sulphate in renal failure. Quinine sulphate could be valuable in treating dialysis-induced cramps, especially in patients with hypertention or heart-failure in whom increasing the sodium content of the bath, increasing oral sodium intake, or administrating intravenous sodium could be deleterious. Requests for reprints should be addressed to D.M.K., Renal Section, Veterans Administration Hospital, 130 West Kingsbridge Road, Bronx, New York 10468, U.S.A. REFERENCES 1. Goodman, L., Gilman, A. The Pharmacological Basis of Therapeutics. p. 1105. New York, 1970. 2. Wolf, A. Archs Neurol. Psychiat. 1936, 36, 382. 3. Moss, H. K., Hermann, L. G. J. Am. med. Ass. 1940, 115, 1358. 4. Gootnick, A. Archs intern. Med. 1943, 71, 555. 5. Chillar, R. K., Desforges, J. F. Lancet, 1972, ii, 285. 6. Stewart, W. K., Fleming, L. W., Manuel, M. A. ibid. 1972, i, 1049. 7. Catto, G. R. D., Smith, F. W., MacLeod, M. Br. med. J. 1973, iii, 389. 8. Jenkins, P., Dreher, W. Trans. Am. Soc. artif. intern. organs, 1975, iv, 30.
EFFECT OF BETA-ADRENERGIC BLOCKADE ON PLASMA-RENIN ACTIVITY AND INTRACTABLE HYPERTENSION IN PATIENTS RECEIVING REGULAR DIALYSIS TREATMENT S. B. MOORE*
F.
J. GOODWIN
Medical Unit, The London Hospital, London El 1BB
The effect of propranolol has been studied in two patients with chronic renal failure and hypertension which remained refractory despite the removal of excess sodium and water by dialysis. Measurements of plasma-renin, exchangeable sodium, and blood-volume demonstrated that in both patients hypertension was due to excess renin. The administration of propranolol was followed by a rapid fall in bloodpressure to normal, thereby obviating the need for bilateral nephrectomy. In both patients the fall in blood-pressure was accompanied by a striking fall in plasma-renin, and in one there was a highly significant association between plasma-renin activity and mean arterial pressure.
Summary
*Present address: Ontario, Canada.
Peterborough Clinic,
327 Charlotte Street,
Peterborough,
68 Plasma-renin
Introduction
activity was measured in samples collected at patients having been out of bed throughout the morning. Blood-pressure was measured every four hours; measurements shown in the figures and used for statistical analysis are means of all readings made during the day in the supine position, excluding those made during dialysis. These measurements were continued for five and eleven days respectively in the two patients, following which plasma-volume, redcell mass, and exchangeable sodium were measured by isotope dilution methods previously described’ (study 1). Bloodvolume was derived from the sum of plasma-volume and red-
noon, the
HYPERTENSION is a common complication of advanced chronic renal failure and is related to both hypervolaemia, occurring as a result of sodium retention, and the prevailing level of plasma-renin,’ which may be raised inappropriately in relation to exchangeable sodium and sodium excretion.2 In a small minority of patients bloodpressure cannot be controlled solely by the removal of the excess sodium by dialysis,3 and for them bilateral nephrectomy has been advocated.4-9 In such patients, preoperative plasma-renin is invariably raised, often to very high levels, and it is generally agreed that their intractability by removal of sodium and water is due directly to increased activity of the renin-angiotensin system. 10 11 Apart from the general risks attending bilateral nephrectomy, an additional disadvantage is the fall in hxmoglobin concentration which usually follows, leading to loss of energy and a greater requirement for blood
cell
mass.
then started, with no other changes in further seven days (patient 1) and fourteen days (patient 2) plasma-volume, red-cell mass, and exchangeable sodium were again measured (study 2). Both patients were discharged from hospital, each taking propranolol 20 mg four times a day, and remained normotensive. Patient 1 was readmitted two months later for a further set of the same
Propranolol
treatment.
measurements
transfusion.5 12 Renin release is increased by p-adrenergic stimulation and may be inhibited in man13 14 and in animals15 by propranolol. We describe here two patients with chronic renal failure whose hypertension failed to respond to removal of sodium and water by dialysis, but whose blood-pressure fell promptly following the administration of propranolol. In both cases, control of the hypertension was associated with marked falls in the level of
plasma-renin activity.
was
After
a
(study 3). Results
In each
patient (figs. 1 and 2) blood-pressure, which particularly high in patient 1, fell to normal within a few days following the administration of quite small doses of propranolol (40-80 mg/day). This fall in bloodpressure was accompanied by a striking fall in plasmarenin activity, the levels of which were extremely high before propranolol treatment. Throughout the period of the first two studies body-weight remained relatively constant: in the case of patient 1, who was studied two
was
Case-reports Case 1 A
34-year-old
presented with malignant hypertenAugust, 1972. Her hypertension to drug treatment, including daily in-
woman
sion and renal failure in
proved highly resistant jections of diazoxide, and her renal function deteriorated further. Dialysis treatment with a modified Kiil dialyser thrice weekly was started in January, 1973, and she continued on a diet containing only 20 mmol sodium per day. During the first eight weeks of treatment her weight fell from 46-5to 36.1kg as a result of fluid removal, but despite this and the continuation of hypotensive drug therapy, she remained severely hypertensive. She was clinically dehydrated and experienced episodes of severe postural hypotension during dialysis. Case 2
41-year-old woman with an eleven-year history of urinary infection and proteinuria was admitted to hospital in April, 1971, with malignant hypertension and chronic renal failure. Her blood-pressure proved difficult to control by drugs and her renal function deteriorated. Dialysis A
recurrent
started in October, 1972, and she continued on diet containing 50 mmol sodium daily. During the first eight weeks of treatment her weight fell from 48-5to 40-0 kg as a result of fluid removal, with poor control of her blood-pressure, episodes of pulmonary oedema, severe nausea, vomiting, and headache. Attempts to remove more fluid were frustrated by precipitous falls in blood-pressure during, and postural hypotension after, dialysis. Her hypertension persisted and at a weight of approximately 40 kg she appeared clinically
treatment was a
dehydrated. Protocol and Methods Each patient was admitted to the metabolic ward, given diet containing 20 mmol sodium daily, and maintained at
a
pre-dialysis body-weight. Dialysis treatment conand neither patient received hypotensive drug therapy.
constant
tinued
uays a
Fig. I-Response of blood-pressure and plasma-renin activity to propranolol in patient 1. Triangles indicate times at which exchangeable sodium and bloodvolume were measured.
69
Fig. 3-Relationship activity in patient
between 1.
mean
arterial pressure and
plasma-renin
Angio=angiotensinIogp.R.A. (plasma-renin activity )==0-039+0-1027 (mean arterial pressure) r=09; r<00005.
M.A.P.
both plasma-renin activity and mean arterial pressure fell markedly in patient 2 after propranolol, there were insufficient intermediate measurements of
Although
both to justify the conclusion that existed between them.
a
linear correlation
uays
of
Fig. 2-Response blood-pressure pranolol in patient 2.
Triangles indicate times
at
and
which
plasma-renin activity
exchangeable
to
pro-
sodium and
blood-volume were measured.
months
allowed
later, still normotensive, body-weight had been to rise approximately 3 kg before the third set
of measurements. The results of exchangeable sodium and blood volume measurements, which did not change appreciably in either patient during the study, are shown in the accompanying table. In neither case was either exchangeable sodium or blood-volume increased when compared with published data for normal subjects.16 17 An excess of body-sodium or blood-volume did not therefore appear to be the cause of either patient’s hypertension. The relationship between mean arterial pressure and plasma-renin activity between days 0 and 14 in patient 1 is shown in fig. 3. The administration of propranolol was associated with a highly significant linear correlation (r=0.9; P<0.0005) between mean arterial pressure and the logarithm of plasma-renin activity.
Discussion In order to identify the minority of patients with chronic renal failure whose hypertension is due largely to increased activity of the renin-angiotensin system and cannot be corrected by dialysis alone, a raised level of plasma-renin in the presence of a normal exchangeable sodium and blood-volume must be demonstrated. Although the methods of measurement of the latter two are well established, there is no entirely satisfactory means of expressing the values obtained in order to compare them with normality. Ways must be found of using parameters such as weight, height, and surface area which minimise the errors which are most liable to occur when expressing these measurements in grossly obese or emaciated patients. In the patients described, both of whom were emaciated, the results were therefore compared with predicted values for normal subjects using the "leanness index" method’6 ’a for exchangeable sodium and a computer-corrected formula 17 for bloodvolume. In both patients exchangeable sodium and blood-volume were consistently normal when compared with predicted values for normal subjects.
EXCHANGEABLE SODIUM AND BLOOD-VOLUME WITH PREDICTED VALUES IN PATIENTS
"From data of Davies et al.16 17 7From data of Nadler et al."
1
AND
2
70 In normal subjects plasma-renin activity is related to the prevailing state of sodium balance 16 ’9 and ranges between 0.5 and 2.0 ng/ml/h in samples collected at noon and when they are receiving a sodium intake of 80-120 mmol/day.2O Higher levels occur after dietary sodium restriction.19 Although both patients studied were receiving low-sodium diets, normal or only moderately raised levels of plasma-renin might have been anticipated since exchangeable sodium and blood-volume were normal. However, plasma-renin levels were enormously increased to 25-50 times those found in normal subjects. There is little doubt therefore that the hypertension in both patients was solely renin-dependent. Buhler et al. 21 showed in a group of patients with hypertension of mixed aetiology that those whose plasma-renin activity was raised responded well to propranolol, whereas those with low levels responded poorly. The response of the blood-pressure was related to the reduction in plasma-renin activity, a finding which was not confirmed by Birkenhager et al. 22 who studied a group of patients with essential hypertension and failed to find such a relationship. Differences such as these may be due in part to different patient selection and the probability remains that certain groups of hypertensive patients with raised plasma-renin levels, such as those described here, may respond particularly well to p-blocking drugs with dramatic falls in both plasma-renin and blood-pressure. The highly significant correlation between mean arterial pressure and plasmarenin in patient 1 suggests that the fall in blood-pressure induced by propranolol was mediated via its effect upon renin release. Most patients with malignant hypertension and hypertension associated with chronic renal failure have angiotensin n levels above the normal range when related to exchangeable odium. 16 In these cases p-blocking drugs may lower blood-pressure by inhibiting renal renin release rather than by central inhibition of sympathetic outflow.23 It would be of interest to study in patients with chronic renal failure the effect of other -blocking drugs such as pindolol, which has been shown to lower the blood-pressure of patients with normal or only slightly impaired renal function without lowering plasma-renin.24 If pindolol failed to lower blood-pressure in patients with chronic renal failure one might conclude that in this situation only those -blocking drugs which interfered with renin release would be effective
hypotensive agents. In both patients the administration of propranolol radically changed the course of their progress. Bloodpressure remained under good control, severe postural hypotension during dialysis ceased, weight-gain occurred (patient 1, 15 kg; patient 2, 6 kg) and a feeling of wellbeing returned. Finally, the use of this drug obviated the need for either patient to undergo bilateral nephrectomy. It is suggested therefore that patients receiving dialysis treatment and whose blood-pressure remains refractory despite the removal of sodium and water should be given a trial of propranolol before bilateral nephrectomy is considered. Requests for reprints should
be addressed
to
F.
J. G.
BACTEROIDES: AN UNUSUAL CAUSE OF BREAST ABSCESS
J. E. HALE
R. M. PERINPANAYAGAM G. SMITH
Departments of Surgery and Bacteriology, Westminster and Queen Mary’s Hospitals, London Three cases of breast abscess from which the non-sporing anaerobe Bacteroides was isolated are described. This organism has apparently not previously been reported as a cause of abscess in a breast without underlying malignancy.
Summary
Case-reports FIRST CASE
45-year old nulliparous woman complained of a painful left breast. Examination revealed an irregular lobulated swelling beneath the nipple, and mammography showed an ill-defined density but no evidence of malignancy. A giant fibroadenoma was diagnosed, but at operation an abscess containing foul-smelling pus was found. Culture yielded a pure growth of Bacteroidesfragilis, sensitive to clindamycin and erythromycin, resistant to penicillin and tetracycline. During the ensuing weeks a foul discharge persisted, so clindamycin 300 mg was given four times daily for ten days. This had little effect, and B. fragilis with sensitivities similar to the original isolate was cultured on numerous occasions. Metronidazole 200 mg thrice daily was substituted for the clindamycin. This resulted in rapid improvement with loss of tenderness, but an inA
Dathan, J. R. E., Johnson, D. B., Goodwin, F. J. Clin. Sci. molec. Med. 1973, 45, 77. 2. Goodwin, F. J., Dathan, J. R. E., Greenwood, R. H., Ledingham, J. M. Proc. Int. Congr. Nephrol. 1972, 3, 81. 3. Blumberg, A., Nelp, W. B., Hegstrom, R. M., Scribner, B. H. Lancet, 1967, ii, 69. 4. Vertes, V., Cangiano, J. L., Berman, L. B., Gould, A. New Engl. J. Med. 1969, 280, 978. 5. Wilkinson, R., Scott, D. F., Uldhall, P. R., Kerr, D. N. S., Swinney, J. Q. Jl Med. 1970, 39, 377. 6. Onesti, G., Swartz, C., Ramirez, O., Brest, A. N. Trans. Am. Soc. artif. intern. Organs, 1968, 14, 361. 7. Kolff, W. J., Nakamoto, S., Poutasse, E. F., Straffon, R. A., Figueroa, J. E. Circulation, 1964, 30, suppl. n, 23. 8. Schupak, E., Sullivan, J. F., Lee, D. Y. Ann. intern. Med. 1967, 67, 708. 9. Medina, A., Bell, P. R. F., Briggs, J. D., Brown, J. J., Fine, A., Lever, A. F., Morton, J. J., Paton, A. M., Robertson, J. I. S., Tree, M., Waite, M. A., Weir, R., Winchester, J. Br. med. J. 1972, iv, 694. 10. Ledingham, J. M. J. R. Coll. Physns, 1971, 5, 103. 11. Brown, J. J., Dusterdieck, G., Fraser, R., Lever, A. F., Robertson, J. I. S., Tree, M., Weir, R. J. Br. med. Bull. 1971, 27, 128. 12. Rao, T. K. S., Manis, T., Delano, G., Friedman, E. A. Trans. Am. Soc. artif. intern. Organs, 1973, 19, 340. 13. Winer, N., Chokshi, D. S., Yoon, M. S., Freedman, A. D. J. clin. Endocr. Metab. 1969, 29, 1168. 14. Michelakis, A. M., McAllister, R. G. ibid. 1972, 34, 386. 15. Assaykeen, T. A., Clayton, P. L., Goldfien, A., Ganong, W. F. Endocrinology, 1970, 87, 1318. 16. Davies, D. L., Beevers, D. G., Briggs, J. D., Medina, A. M., Robertson, J. I. S., Schalekamp, M. A., Brown, J. J., Lever, A. F., Morton, J. J., Tree, M. Lancet, 1973, i, 683. 17. Nadler, S. B., Hidalgo, J. U., Bloch, T. Surgery, 1962, 51, 224. 18. Nicholson, J. P., Zilva, J. F. Clin. Sci. 1964, 27, 97. 19. Ledingham, J. G. G., Bull, M. B., Laragh, J. H. Circulation Res. 1967, 21, 1.
suppl. ii, 177. 20. Newton, M. A., Laragh, J. K. J. clin. Endocr. Metab. 1968, 28, 1006. 21. Bühler, F. R., Laragh, J. H., Baer, L., Vaughan, E. D., Brunner, H. R. New Engl. J. Med. 1972, 287, 1209. 22. Birkenhäger, W. H., Krauss, X. H., Schalekamp, M. A. D. H., Kolsters, G., Kroon, B. J. M. Folia med. neerl. 1971, 14, 67. 23. Lewis, P. J., Myers, M. G., Reid, J. L., Dollery, C. T. New Engl. J. Med 1973, 288, 689. 24. Stokes, G. S., Weber, M. A., Thornell, I. R. Br. med. J. 1974, i, 60.
recorded on placebo (table i) (p<0.001, X2 Of =13-99). the twenty-eight cramps which occurred on placebo, six were severe, five were moderate, and seventeen were mild. Of the ten cramps on quinine, two were severe, two were moderate, and six were mild (table II). Thus, quinine sulphate significantly reduced the frequency of cramps on haemodialysis but did not appear to alter their severity. All patients denied symptoms of vertigo, tinnitus, nausea, vomiting, or diarrhoea. None were found to have disturbances of vision or eighth-nerve damage on physical examination. All patients had normal audiograms at the end of the study. Haemolytic anaemia, agranulocytosis and thrombocytopenia were not observed. A transient rise in serum-glutamic-oxaloacetictransaminase and serum-glutamic-pyruvic-transaminase was noted in two patients in whom HBAg-positive hepatitis developed simultaneously. All other patients had normal liver profiles. cramps
were
Discussion
Chillar and Desforges5 observed a significant drop in red-blood-cell (R.B.C.) 2-3-diphosphoglycerate (2-3-D.P.G.) and a significant rise in arterial pH from normal or acidotic predialysis values to alkalotic values after dialysis. Since both the fall in R.B.C. 2-3-D.P.G. and the rise in pH would increase haemoglobin oxygen affinity it was proposed that cramps during hsemodialysis may be a manifestation of reduced tissue oxygen delivery during 5
h3emodialysis/
However, Stewart
et al. suggested that blood-volume the basis for cramps on haemodialysis.66 Higher dialysate sodium concentration (140 mmol/1) and ingestion of 140 mmol of sodium in the form of slow-release tablets have been shown to relieve cramps on haemodialysis.7 More recently, an intravenous bolus of hypertonic saline solution containing 40-45 mmol sodium has been used to treat cramps in a small number of patients on haemodialysis.8 All these treatments involved the administration of large amounts of sodium (60-140 mmol) which may exacerbate the hypertension and heart-failure which affect a very high percentage of dialysis patients. It seemed appropriate, therefore, to explore alternative treatments which did not involve the administration of sodium. Quinine sulphate increased the threshold of stimulation of the motor end plate, with reduction in response to repetitive nerve stimulation.Quinine sulphate also prolonged the refractory period of the muscle, resulting in diminished response to tetanic stimulation.1 Wolfz reported in 1936 that quinine sulphate was successful in relieving muscle cramps in myotonia congenita. Moss and Hermann3 administered this drug to fifteen patients with nocturnal cramps and reported uniform improvement. Gootnick4 reported successful results with this drug in twenty-eight out of thirty patients with night cramps. Although these were not controlled studies, quinine sulphate was subsequently extensively used with variable effectiveness to control night cramps.24We reasoned that quinine sulphate might be useful in controlling dialysis-induced muscle cramps, particularly in view of its extra-renal detoxification and ease of administration. We observed a significant reduction in the frequency of cramps in patients receiving quinine sulphate as com-
contraction
was
pared to placebo. In the small dose used, none of the sideeffects usually attributed to quinine sulphate were observed. Thus, quinine sulphate was found to be a safe and effective agent for reducing the frequency of muscle cramps in patients on haemodialysis. Ten cramps did occur in patients receiving quinine. This could be due to inadequate blood concentrations of quinine sulphate in some patients, because of poor absorption, enhanced degradation, or higher individual requirements. In view of the paucity of data on this drug in uraemia, we were unwilling to give higher doses even in selected patients. With monitoring of blood concentrations of quinine sulphate and tailoring the dose to individual requirements, the results might prove even more striking. In any event, our experience with this drug is encouraging and demonstrates the efficacy of quinine sulphate in reducing the frequency of cramps during hsemodialysis. Further trials are needed with larger patient populations to determine the pharmacokinetics of quinine sulphate in renal failure. Quinine sulphate could be valuable in treating dialysis-induced cramps, especially in patients with hypertention or heart-failure in whom increasing the sodium content of the bath, increasing oral sodium intake, or administrating intravenous sodium could be deleterious. Requests for reprints should be addressed to D.M.K., Renal Section, Veterans Administration Hospital, 130 West Kingsbridge Road, Bronx, New York 10468, U.S.A. REFERENCES 1. Goodman, L., Gilman, A. The Pharmacological Basis of Therapeutics. p. 1105. New York, 1970. 2. Wolf, A. Archs Neurol. Psychiat. 1936, 36, 382. 3. Moss, H. K., Hermann, L. G. J. Am. med. Ass. 1940, 115, 1358. 4. Gootnick, A. Archs intern. Med. 1943, 71, 555. 5. Chillar, R. K., Desforges, J. F. Lancet, 1972, ii, 285. 6. Stewart, W. K., Fleming, L. W., Manuel, M. A. ibid. 1972, i, 1049. 7. Catto, G. R. D., Smith, F. W., MacLeod, M. Br. med. J. 1973, iii, 389. 8. Jenkins, P., Dreher, W. Trans. Am. Soc. artif. intern. organs, 1975, iv, 30.
EFFECT OF BETA-ADRENERGIC BLOCKADE ON PLASMA-RENIN ACTIVITY AND INTRACTABLE HYPERTENSION IN PATIENTS RECEIVING REGULAR DIALYSIS TREATMENT S. B. MOORE*
F.
J. GOODWIN
Medical Unit, The London Hospital, London El 1BB
The effect of propranolol has been studied in two patients with chronic renal failure and hypertension which remained refractory despite the removal of excess sodium and water by dialysis. Measurements of plasma-renin, exchangeable sodium, and blood-volume demonstrated that in both patients hypertension was due to excess renin. The administration of propranolol was followed by a rapid fall in bloodpressure to normal, thereby obviating the need for bilateral nephrectomy. In both patients the fall in blood-pressure was accompanied by a striking fall in plasma-renin, and in one there was a highly significant association between plasma-renin activity and mean arterial pressure.
Summary
*Present address: Ontario, Canada.
Peterborough Clinic,
327 Charlotte Street,
Peterborough,
68 Plasma-renin
Introduction
activity was measured in samples collected at patients having been out of bed throughout the morning. Blood-pressure was measured every four hours; measurements shown in the figures and used for statistical analysis are means of all readings made during the day in the supine position, excluding those made during dialysis. These measurements were continued for five and eleven days respectively in the two patients, following which plasma-volume, redcell mass, and exchangeable sodium were measured by isotope dilution methods previously described’ (study 1). Bloodvolume was derived from the sum of plasma-volume and red-
noon, the
HYPERTENSION is a common complication of advanced chronic renal failure and is related to both hypervolaemia, occurring as a result of sodium retention, and the prevailing level of plasma-renin,’ which may be raised inappropriately in relation to exchangeable sodium and sodium excretion.2 In a small minority of patients bloodpressure cannot be controlled solely by the removal of the excess sodium by dialysis,3 and for them bilateral nephrectomy has been advocated.4-9 In such patients, preoperative plasma-renin is invariably raised, often to very high levels, and it is generally agreed that their intractability by removal of sodium and water is due directly to increased activity of the renin-angiotensin system. 10 11 Apart from the general risks attending bilateral nephrectomy, an additional disadvantage is the fall in hxmoglobin concentration which usually follows, leading to loss of energy and a greater requirement for blood
cell
mass.
then started, with no other changes in further seven days (patient 1) and fourteen days (patient 2) plasma-volume, red-cell mass, and exchangeable sodium were again measured (study 2). Both patients were discharged from hospital, each taking propranolol 20 mg four times a day, and remained normotensive. Patient 1 was readmitted two months later for a further set of the same
Propranolol
treatment.
measurements
transfusion.5 12 Renin release is increased by p-adrenergic stimulation and may be inhibited in man13 14 and in animals15 by propranolol. We describe here two patients with chronic renal failure whose hypertension failed to respond to removal of sodium and water by dialysis, but whose blood-pressure fell promptly following the administration of propranolol. In both cases, control of the hypertension was associated with marked falls in the level of
plasma-renin activity.
was
After
a
(study 3). Results
In each
patient (figs. 1 and 2) blood-pressure, which particularly high in patient 1, fell to normal within a few days following the administration of quite small doses of propranolol (40-80 mg/day). This fall in bloodpressure was accompanied by a striking fall in plasmarenin activity, the levels of which were extremely high before propranolol treatment. Throughout the period of the first two studies body-weight remained relatively constant: in the case of patient 1, who was studied two
was
Case-reports Case 1 A
34-year-old
presented with malignant hypertenAugust, 1972. Her hypertension to drug treatment, including daily in-
woman
sion and renal failure in
proved highly resistant jections of diazoxide, and her renal function deteriorated further. Dialysis treatment with a modified Kiil dialyser thrice weekly was started in January, 1973, and she continued on a diet containing only 20 mmol sodium per day. During the first eight weeks of treatment her weight fell from 46-5to 36.1kg as a result of fluid removal, but despite this and the continuation of hypotensive drug therapy, she remained severely hypertensive. She was clinically dehydrated and experienced episodes of severe postural hypotension during dialysis. Case 2
41-year-old woman with an eleven-year history of urinary infection and proteinuria was admitted to hospital in April, 1971, with malignant hypertension and chronic renal failure. Her blood-pressure proved difficult to control by drugs and her renal function deteriorated. Dialysis A
recurrent
started in October, 1972, and she continued on diet containing 50 mmol sodium daily. During the first eight weeks of treatment her weight fell from 48-5to 40-0 kg as a result of fluid removal, with poor control of her blood-pressure, episodes of pulmonary oedema, severe nausea, vomiting, and headache. Attempts to remove more fluid were frustrated by precipitous falls in blood-pressure during, and postural hypotension after, dialysis. Her hypertension persisted and at a weight of approximately 40 kg she appeared clinically
treatment was a
dehydrated. Protocol and Methods Each patient was admitted to the metabolic ward, given diet containing 20 mmol sodium daily, and maintained at
a
pre-dialysis body-weight. Dialysis treatment conand neither patient received hypotensive drug therapy.
constant
tinued
uays a
Fig. I-Response of blood-pressure and plasma-renin activity to propranolol in patient 1. Triangles indicate times at which exchangeable sodium and bloodvolume were measured.
69
Fig. 3-Relationship activity in patient
between 1.
mean
arterial pressure and
plasma-renin
Angio=angiotensinIogp.R.A. (plasma-renin activity )==0-039+0-1027 (mean arterial pressure) r=09; r<00005.
M.A.P.
both plasma-renin activity and mean arterial pressure fell markedly in patient 2 after propranolol, there were insufficient intermediate measurements of
Although
both to justify the conclusion that existed between them.
a
linear correlation
uays
of
Fig. 2-Response blood-pressure pranolol in patient 2.
Triangles indicate times
at
and
which
plasma-renin activity
exchangeable
to
pro-
sodium and
blood-volume were measured.
months
allowed
later, still normotensive, body-weight had been to rise approximately 3 kg before the third set
of measurements. The results of exchangeable sodium and blood volume measurements, which did not change appreciably in either patient during the study, are shown in the accompanying table. In neither case was either exchangeable sodium or blood-volume increased when compared with published data for normal subjects.16 17 An excess of body-sodium or blood-volume did not therefore appear to be the cause of either patient’s hypertension. The relationship between mean arterial pressure and plasma-renin activity between days 0 and 14 in patient 1 is shown in fig. 3. The administration of propranolol was associated with a highly significant linear correlation (r=0.9; P<0.0005) between mean arterial pressure and the logarithm of plasma-renin activity.
Discussion In order to identify the minority of patients with chronic renal failure whose hypertension is due largely to increased activity of the renin-angiotensin system and cannot be corrected by dialysis alone, a raised level of plasma-renin in the presence of a normal exchangeable sodium and blood-volume must be demonstrated. Although the methods of measurement of the latter two are well established, there is no entirely satisfactory means of expressing the values obtained in order to compare them with normality. Ways must be found of using parameters such as weight, height, and surface area which minimise the errors which are most liable to occur when expressing these measurements in grossly obese or emaciated patients. In the patients described, both of whom were emaciated, the results were therefore compared with predicted values for normal subjects using the "leanness index" method’6 ’a for exchangeable sodium and a computer-corrected formula 17 for bloodvolume. In both patients exchangeable sodium and blood-volume were consistently normal when compared with predicted values for normal subjects.
EXCHANGEABLE SODIUM AND BLOOD-VOLUME WITH PREDICTED VALUES IN PATIENTS
"From data of Davies et al.16 17 7From data of Nadler et al."
1
AND
2
70 In normal subjects plasma-renin activity is related to the prevailing state of sodium balance 16 ’9 and ranges between 0.5 and 2.0 ng/ml/h in samples collected at noon and when they are receiving a sodium intake of 80-120 mmol/day.2O Higher levels occur after dietary sodium restriction.19 Although both patients studied were receiving low-sodium diets, normal or only moderately raised levels of plasma-renin might have been anticipated since exchangeable sodium and blood-volume were normal. However, plasma-renin levels were enormously increased to 25-50 times those found in normal subjects. There is little doubt therefore that the hypertension in both patients was solely renin-dependent. Buhler et al. 21 showed in a group of patients with hypertension of mixed aetiology that those whose plasma-renin activity was raised responded well to propranolol, whereas those with low levels responded poorly. The response of the blood-pressure was related to the reduction in plasma-renin activity, a finding which was not confirmed by Birkenhager et al. 22 who studied a group of patients with essential hypertension and failed to find such a relationship. Differences such as these may be due in part to different patient selection and the probability remains that certain groups of hypertensive patients with raised plasma-renin levels, such as those described here, may respond particularly well to p-blocking drugs with dramatic falls in both plasma-renin and blood-pressure. The highly significant correlation between mean arterial pressure and plasmarenin in patient 1 suggests that the fall in blood-pressure induced by propranolol was mediated via its effect upon renin release. Most patients with malignant hypertension and hypertension associated with chronic renal failure have angiotensin n levels above the normal range when related to exchangeable odium. 16 In these cases p-blocking drugs may lower blood-pressure by inhibiting renal renin release rather than by central inhibition of sympathetic outflow.23 It would be of interest to study in patients with chronic renal failure the effect of other -blocking drugs such as pindolol, which has been shown to lower the blood-pressure of patients with normal or only slightly impaired renal function without lowering plasma-renin.24 If pindolol failed to lower blood-pressure in patients with chronic renal failure one might conclude that in this situation only those -blocking drugs which interfered with renin release would be effective
hypotensive agents. In both patients the administration of propranolol radically changed the course of their progress. Bloodpressure remained under good control, severe postural hypotension during dialysis ceased, weight-gain occurred (patient 1, 15 kg; patient 2, 6 kg) and a feeling of wellbeing returned. Finally, the use of this drug obviated the need for either patient to undergo bilateral nephrectomy. It is suggested therefore that patients receiving dialysis treatment and whose blood-pressure remains refractory despite the removal of sodium and water should be given a trial of propranolol before bilateral nephrectomy is considered. Requests for reprints should
be addressed
to
F.
J. G.
BACTEROIDES: AN UNUSUAL CAUSE OF BREAST ABSCESS
J. E. HALE
R. M. PERINPANAYAGAM G. SMITH
Departments of Surgery and Bacteriology, Westminster and Queen Mary’s Hospitals, London Three cases of breast abscess from which the non-sporing anaerobe Bacteroides was isolated are described. This organism has apparently not previously been reported as a cause of abscess in a breast without underlying malignancy.
Summary
Case-reports FIRST CASE
45-year old nulliparous woman complained of a painful left breast. Examination revealed an irregular lobulated swelling beneath the nipple, and mammography showed an ill-defined density but no evidence of malignancy. A giant fibroadenoma was diagnosed, but at operation an abscess containing foul-smelling pus was found. Culture yielded a pure growth of Bacteroidesfragilis, sensitive to clindamycin and erythromycin, resistant to penicillin and tetracycline. During the ensuing weeks a foul discharge persisted, so clindamycin 300 mg was given four times daily for ten days. This had little effect, and B. fragilis with sensitivities similar to the original isolate was cultured on numerous occasions. Metronidazole 200 mg thrice daily was substituted for the clindamycin. This resulted in rapid improvement with loss of tenderness, but an inA
Dathan, J. R. E., Johnson, D. B., Goodwin, F. J. Clin. Sci. molec. Med. 1973, 45, 77. 2. Goodwin, F. J., Dathan, J. R. E., Greenwood, R. H., Ledingham, J. M. Proc. Int. Congr. Nephrol. 1972, 3, 81. 3. Blumberg, A., Nelp, W. B., Hegstrom, R. M., Scribner, B. H. Lancet, 1967, ii, 69. 4. Vertes, V., Cangiano, J. L., Berman, L. B., Gould, A. New Engl. J. Med. 1969, 280, 978. 5. Wilkinson, R., Scott, D. F., Uldhall, P. R., Kerr, D. N. S., Swinney, J. Q. Jl Med. 1970, 39, 377. 6. Onesti, G., Swartz, C., Ramirez, O., Brest, A. N. Trans. Am. Soc. artif. intern. Organs, 1968, 14, 361. 7. Kolff, W. J., Nakamoto, S., Poutasse, E. F., Straffon, R. A., Figueroa, J. E. Circulation, 1964, 30, suppl. n, 23. 8. Schupak, E., Sullivan, J. F., Lee, D. Y. Ann. intern. Med. 1967, 67, 708. 9. Medina, A., Bell, P. R. F., Briggs, J. D., Brown, J. J., Fine, A., Lever, A. F., Morton, J. J., Paton, A. M., Robertson, J. I. S., Tree, M., Waite, M. A., Weir, R., Winchester, J. Br. med. J. 1972, iv, 694. 10. Ledingham, J. M. J. R. Coll. Physns, 1971, 5, 103. 11. Brown, J. J., Dusterdieck, G., Fraser, R., Lever, A. F., Robertson, J. I. S., Tree, M., Weir, R. J. Br. med. Bull. 1971, 27, 128. 12. Rao, T. K. S., Manis, T., Delano, G., Friedman, E. A. Trans. Am. Soc. artif. intern. Organs, 1973, 19, 340. 13. Winer, N., Chokshi, D. S., Yoon, M. S., Freedman, A. D. J. clin. Endocr. Metab. 1969, 29, 1168. 14. Michelakis, A. M., McAllister, R. G. ibid. 1972, 34, 386. 15. Assaykeen, T. A., Clayton, P. L., Goldfien, A., Ganong, W. F. Endocrinology, 1970, 87, 1318. 16. Davies, D. L., Beevers, D. G., Briggs, J. D., Medina, A. M., Robertson, J. I. S., Schalekamp, M. A., Brown, J. J., Lever, A. F., Morton, J. J., Tree, M. Lancet, 1973, i, 683. 17. Nadler, S. B., Hidalgo, J. U., Bloch, T. Surgery, 1962, 51, 224. 18. Nicholson, J. P., Zilva, J. F. Clin. Sci. 1964, 27, 97. 19. Ledingham, J. G. G., Bull, M. B., Laragh, J. H. Circulation Res. 1967, 21, 1.
suppl. ii, 177. 20. Newton, M. A., Laragh, J. K. J. clin. Endocr. Metab. 1968, 28, 1006. 21. Bühler, F. R., Laragh, J. H., Baer, L., Vaughan, E. D., Brunner, H. R. New Engl. J. Med. 1972, 287, 1209. 22. Birkenhäger, W. H., Krauss, X. H., Schalekamp, M. A. D. H., Kolsters, G., Kroon, B. J. M. Folia med. neerl. 1971, 14, 67. 23. Lewis, P. J., Myers, M. G., Reid, J. L., Dollery, C. T. New Engl. J. Med 1973, 288, 689. 24. Stokes, G. S., Weber, M. A., Thornell, I. R. Br. med. J. 1974, i, 60.