784
THE LANCET, OCTOBER
ing,!4 it is likely that more cases of M.E.A. will also be reported. Some clinicians have adopted a "wait and see" policy in the management of asymptomatic hypercalcemia, believing that it generally runs an indolent course, 15 both in patients with M.E.A. and in those without M.E.A. However, fifteen of our twenty-one patients had important renal or skeletal disease with their hyperparathyroidism, even though many of them were symptomfree. They were 10-20 years older (mean 48 years) when hyperparathyroidism was diagnosed than M.E.A. patients in reported series with asymptomatic hypercalcemia." !6 This may imply a long symptom-free interval before hypercalcemia produces organ damage. But in a prospective study of patients with asymptomatic hypercalcemia," 20% of patients came to surgery within the first 5-year follow-up. The likelihood of renal damage in such patients is unpredictable, its onset insidious, and its progress may not be halted by parathyroidectomy. For these reasons we strongly recommend parathyroidectomy in patients in whom asymptomatic hyperparathyroidism is diagnosed. The clinical features of hyperparathyroidism in our twenty-one patients with M.E.A. did not distinguish them from other hyperparathyroid patients. The age and sex, the degree of hypercalcemia, and the number with renal or skeletal complications were similar in both groups. We found three patients with a family history of hyperparathyroidism, but our information as to familial morbidity has been scanty and we have not screened any relatives for hypercalcemia, There is, however, a significant increase in the number of patients with several diseased parathyroid glands in the M.E.A. group--twelve of our twenty-one patients (57%) having several diseased parathyroids compared with only sixteen out of ninety-eight (16·5%) of the other hyperparathyroid patients. In all, twentyeight of a hundred and nineteen patients had two or more diseased parathyroid glands, and twelve of these (43%) had M.E.A. The high frequency of multiple parathyroid involvement in our M.E.A. patients accords fully with earlier reports.' 4 We thank the physicians of the endocrine department at Hammersmith Hospital who originally investigated most of these patients. Their notes and data greatly helped us during this study. Requests for reprints should be addressed to S.T. REFERENCES I. Underdahl, L. 0., Woolner, L. B., Black, B. M.]. din. Endocr. 1953, 13, 20. 2. Wenner, P. Am.]. Med. 1954,16,363. 3. Steiner, A. L., Goodman, A. D., Powers, S. R. Medicine, Baltimore, 1968, 47,371. 4. Ballard, H. 5., Frame, B., Hartsock, R. J. ibid. 1964,43,481. 5. Johnson, G. J., Summerskill, W: H. J., Anderson, V. E., Keating, F. R. Jr. New Engl.]. Med.1967,277, 1379. 6. Craven, D. E., Goodman, A. D., Carter, J. H. Arch, intern. Med. 1972~ 129,567. 7. Cope, 0., Keynes, W. M., Roth, S. I., Castleman, B. Ann. Surg. 1958,148, 375. 8. Hellstrom, J., Ivemark, B. I. Acta chir. scand. 1962, suppl. 294, 79. 9. Krementz, E. T., Yeager, R., Hawley, W., Weicnen, R. Ann. Surg. 1971, 173,872. 10. Mallette, L. E., Bilezikian, J. P., Heath, D. A., Aurbach, G. D. Medicine, Baltimore, 1974,53,127. II. Dutra, P., Wallace, M. R. Proc. R. Soc. Med. 1968,61,658. 12. Child, D. F., Nader, S., Mashiter, K., Kjeld, M., Banks, L.,.Fraser, T. R. Hr. med.]. 1975, i, 604. 13. Snyder, N. Ill, Scurry, M. T., Deiss, W. P., Jr. Ann. intern. Med. 1972, 76,53. 14. Jackson, C. E., Boonstra, C. E. Am.]. Med. 1967,43,727. 15. Purnell, D. C., Scholz, D. A., Smith, L. H., Sizemore, G. W., Black, B. M., Goldsmith, R. S., Arnaud, C. D. ibid. 1974,56,800. 16. Ptak, T., Kirsner, J. B.AdfJ. intern. Med. 1970,16,213.
25, 1975
SARALASIN BOLUS TEST Rapid Screening Procedure for Renin-mediated Hypertension LEONARD
S.
MARKS
Department of Surgery/Urology, University of California at Los Angeles School of Medicine, Los Angeles, Caltfornia 90024, U.S.A. MORTON
H.
MAXWELL
Department of Medicine, University of Caltfornia at Los Angeles School of Medicine, and the Hypertension/Nephrology Service, Cedars-Sinai Medical Center, 8720 Beverly Blod., Los Angeles, Caltfornia 90048 JOSEPH J. KAUFMAN
Department of Surgery/Urology, University of California at Los Angeles School of Medicine
The angiotensin-blocking agent, saralasin, was given by rapid intravenous (bolus) injection to 21 hypertensive patients. A marked depressor response (average blood-pressure decrease of 30 mm Hg systolic and 20 mm Hg diastolic at 10 minutes after injection) was noted in 13 patients, of whom 11 had renovascular hypertension and 2 had high-renin essential hypertension. No change from prebolus blood-pressure was apparent at 10 minutes in 8 control patients with essential hypertension and normal or low peripheral plasma-renin activity. In all patients, blood-pressure response to saralasin bolus (10 mg) correlated with blood-pressure response to subsequent infusion of saralasin (10 I-lg/kg/min). Blood-pressure response to rapid intravenous injection of saralasin-the "saralasin bolus test"-has many characteristics of an ideal screening procedure for renin-mediated hypertension. Summary
Introduction ANGIOTENSIN blockade with saralasin (l-sar-Bsala-angiotensin II) has been suggested as a means of detecting hyperactivity of the renin-angiotensin system in hypertension.' 2 The sole action of saralasin is thought to be specific, competitive inhibition of angiotensin 1I. 3 4 In human studies, a blood-pressure-lowering effect of saralasin has been shown to correlate both with evidence of renal ischemia" and with elevated renin levels in peripheral blood.' 4 A depressor response to saralasin has been demonstrated in some patients with surgically correctable renovascular disease but with normal peripheral plasma-renin levels," 5 suggesting that the presence of renovascular hypertension may correlate better with saralasin response than with elevated levels of renin in peripheral blood. The usual method of saralasin administration-i.e., continuous, pump-controlled intravenous infusion-is obviously not applicable for widespread screening of large populations. In the present report, we show for the first time that the procedure may be greatly simplified by the use of a single, rapid bolus injection of the drug. The "saralasin bolus' test" may be rapidly and easily performed with standard officeequipment.
Patients and Methods 21 Caucasian adults with moderate diastolic hypertension
THE LANCET, OCTOBER
25,1975
were included in the study. 10 patients had well-defined essential hypertension and no renal or renovascular lesions, as judged by rapid-sequence intravenous pyelograms (LV.P.), renal scan/renogram, and, in 5 patients, renal arteriography. 11 patients had renal-artery stenosis and were studied 1-30 days before nephrectomy or bypass of a stenotic lesion. Antihypertensive and diuretic medication was stopped 2 weeks before admission to the V.C.L.A. Clinical Research Center, where each test was performed. Arterial pressures on admission varied from 144/104 to 210/130 mm Hg; the pressures were somewhat lower 2 days later at the time of the test (see table). All patients consumed approximately 150 meq/day of sodium for the 2 weeks until the evening before the test. Each test was conducted as follows. At 5P.M. the preceding evening, the patient was given furosemide (frusemide) by mouth (approximately 1 mg/kg body-weight). No salt intake was allowed thereafter until the test was concluded. On the morning of the test, a blood-sample was obtained for plasmarenin activity after an hour of ambulation. The patient then remained supine until his blood-pressure was stable for at least 30 minutes. Arterial pressures were recorded every 2 minutes for the duration of the experiment, using an automatic bloodpressure recorder." A 10 mg bolus of saralasin was hand-injected over 2 minutes into the tubing of an indwelling venous catheter. 30 minutes after the bolus was injected, a constant infusion of saralasin (10 p.g/kg/min) was administered over a 90-minute period. Each study was supervised by the same physician (L.S.M.), and was performed by the same two research nurses who were unaware of the patient's diagnosis at the time of the test. Plasma-renin activity was determined by radio-immunoassay,' and all samples were run in duplicate. In our laboratory, this test has a within-assay variation of ±5.6% S.D. 8 Assignment of "high," "normal," or "low" to individual renin determinations was based on normal values established in healthy young adults, who were studied previously under conditions identical to those on the morning of the test. Thus, the range of normal values for plasma-renin activity was 673-3155 ng/ 100 mV3h incubation (95% confidence interval) under the stated conditions of salt depletion, morning collection, and l-hour ambulation.
785 response (among the responders) was 15 mm Hg systolic and 10 mm Hg diastolic in a patient whose pre-bolus blood-pressure was 135/95. Beginning at 6 minutes after the bolus, a statistically significant depressor effect persisted throughout the 30 minutes after the bolus for the group of 13 responders (p-
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THE LANCET, OCTOBER
ing,!4 it is likely that more cases of M.E.A. will also be reported. Some clinicians have adopted a "wait and see" policy in the management of asymptomatic hypercalcemia, believing that it generally runs an indolent course, 15 both in patients with M.E.A. and in those without M.E.A. However, fifteen of our twenty-one patients had important renal or skeletal disease with their hyperparathyroidism, even though many of them were symptomfree. They were 10-20 years older (mean 48 years) when hyperparathyroidism was diagnosed than M.E.A. patients in reported series with asymptomatic hypercalcemia." !6 This may imply a long symptom-free interval before hypercalcemia produces organ damage. But in a prospective study of patients with asymptomatic hypercalcemia," 20% of patients came to surgery within the first 5-year follow-up. The likelihood of renal damage in such patients is unpredictable, its onset insidious, and its progress may not be halted by parathyroidectomy. For these reasons we strongly recommend parathyroidectomy in patients in whom asymptomatic hyperparathyroidism is diagnosed. The clinical features of hyperparathyroidism in our twenty-one patients with M.E.A. did not distinguish them from other hyperparathyroid patients. The age and sex, the degree of hypercalcemia, and the number with renal or skeletal complications were similar in both groups. We found three patients with a family history of hyperparathyroidism, but our information as to familial morbidity has been scanty and we have not screened any relatives for hypercalcemia, There is, however, a significant increase in the number of patients with several diseased parathyroid glands in the M.E.A. group--twelve of our twenty-one patients (57%) having several diseased parathyroids compared with only sixteen out of ninety-eight (16·5%) of the other hyperparathyroid patients. In all, twentyeight of a hundred and nineteen patients had two or more diseased parathyroid glands, and twelve of these (43%) had M.E.A. The high frequency of multiple parathyroid involvement in our M.E.A. patients accords fully with earlier reports.' 4 We thank the physicians of the endocrine department at Hammersmith Hospital who originally investigated most of these patients. Their notes and data greatly helped us during this study. Requests for reprints should be addressed to S.T. REFERENCES I. Underdahl, L. 0., Woolner, L. B., Black, B. M.]. din. Endocr. 1953, 13, 20. 2. Wenner, P. Am.]. Med. 1954,16,363. 3. Steiner, A. L., Goodman, A. D., Powers, S. R. Medicine, Baltimore, 1968, 47,371. 4. Ballard, H. 5., Frame, B., Hartsock, R. J. ibid. 1964,43,481. 5. Johnson, G. J., Summerskill, W: H. J., Anderson, V. E., Keating, F. R. Jr. New Engl.]. Med.1967,277, 1379. 6. Craven, D. E., Goodman, A. D., Carter, J. H. Arch, intern. Med. 1972~ 129,567. 7. Cope, 0., Keynes, W. M., Roth, S. I., Castleman, B. Ann. Surg. 1958,148, 375. 8. Hellstrom, J., Ivemark, B. I. Acta chir. scand. 1962, suppl. 294, 79. 9. Krementz, E. T., Yeager, R., Hawley, W., Weicnen, R. Ann. Surg. 1971, 173,872. 10. Mallette, L. E., Bilezikian, J. P., Heath, D. A., Aurbach, G. D. Medicine, Baltimore, 1974,53,127. II. Dutra, P., Wallace, M. R. Proc. R. Soc. Med. 1968,61,658. 12. Child, D. F., Nader, S., Mashiter, K., Kjeld, M., Banks, L.,.Fraser, T. R. Hr. med.]. 1975, i, 604. 13. Snyder, N. Ill, Scurry, M. T., Deiss, W. P., Jr. Ann. intern. Med. 1972, 76,53. 14. Jackson, C. E., Boonstra, C. E. Am.]. Med. 1967,43,727. 15. Purnell, D. C., Scholz, D. A., Smith, L. H., Sizemore, G. W., Black, B. M., Goldsmith, R. S., Arnaud, C. D. ibid. 1974,56,800. 16. Ptak, T., Kirsner, J. B.AdfJ. intern. Med. 1970,16,213.
25, 1975
SARALASIN BOLUS TEST Rapid Screening Procedure for Renin-mediated Hypertension LEONARD
S.
MARKS
Department of Surgery/Urology, University of California at Los Angeles School of Medicine, Los Angeles, Caltfornia 90024, U.S.A. MORTON
H.
MAXWELL
Department of Medicine, University of Caltfornia at Los Angeles School of Medicine, and the Hypertension/Nephrology Service, Cedars-Sinai Medical Center, 8720 Beverly Blod., Los Angeles, Caltfornia 90048 JOSEPH J. KAUFMAN
Department of Surgery/Urology, University of California at Los Angeles School of Medicine
The angiotensin-blocking agent, saralasin, was given by rapid intravenous (bolus) injection to 21 hypertensive patients. A marked depressor response (average blood-pressure decrease of 30 mm Hg systolic and 20 mm Hg diastolic at 10 minutes after injection) was noted in 13 patients, of whom 11 had renovascular hypertension and 2 had high-renin essential hypertension. No change from prebolus blood-pressure was apparent at 10 minutes in 8 control patients with essential hypertension and normal or low peripheral plasma-renin activity. In all patients, blood-pressure response to saralasin bolus (10 mg) correlated with blood-pressure response to subsequent infusion of saralasin (10 I-lg/kg/min). Blood-pressure response to rapid intravenous injection of saralasin-the "saralasin bolus test"-has many characteristics of an ideal screening procedure for renin-mediated hypertension. Summary
Introduction ANGIOTENSIN blockade with saralasin (l-sar-Bsala-angiotensin II) has been suggested as a means of detecting hyperactivity of the renin-angiotensin system in hypertension.' 2 The sole action of saralasin is thought to be specific, competitive inhibition of angiotensin 1I. 3 4 In human studies, a blood-pressure-lowering effect of saralasin has been shown to correlate both with evidence of renal ischemia" and with elevated renin levels in peripheral blood.' 4 A depressor response to saralasin has been demonstrated in some patients with surgically correctable renovascular disease but with normal peripheral plasma-renin levels," 5 suggesting that the presence of renovascular hypertension may correlate better with saralasin response than with elevated levels of renin in peripheral blood. The usual method of saralasin administration-i.e., continuous, pump-controlled intravenous infusion-is obviously not applicable for widespread screening of large populations. In the present report, we show for the first time that the procedure may be greatly simplified by the use of a single, rapid bolus injection of the drug. The "saralasin bolus' test" may be rapidly and easily performed with standard officeequipment.
Patients and Methods 21 Caucasian adults with moderate diastolic hypertension
THE LANCET, OCTOBER
25,1975
were included in the study. 10 patients had well-defined essential hypertension and no renal or renovascular lesions, as judged by rapid-sequence intravenous pyelograms (LV.P.), renal scan/renogram, and, in 5 patients, renal arteriography. 11 patients had renal-artery stenosis and were studied 1-30 days before nephrectomy or bypass of a stenotic lesion. Antihypertensive and diuretic medication was stopped 2 weeks before admission to the V.C.L.A. Clinical Research Center, where each test was performed. Arterial pressures on admission varied from 144/104 to 210/130 mm Hg; the pressures were somewhat lower 2 days later at the time of the test (see table). All patients consumed approximately 150 meq/day of sodium for the 2 weeks until the evening before the test. Each test was conducted as follows. At 5P.M. the preceding evening, the patient was given furosemide (frusemide) by mouth (approximately 1 mg/kg body-weight). No salt intake was allowed thereafter until the test was concluded. On the morning of the test, a blood-sample was obtained for plasmarenin activity after an hour of ambulation. The patient then remained supine until his blood-pressure was stable for at least 30 minutes. Arterial pressures were recorded every 2 minutes for the duration of the experiment, using an automatic bloodpressure recorder." A 10 mg bolus of saralasin was hand-injected over 2 minutes into the tubing of an indwelling venous catheter. 30 minutes after the bolus was injected, a constant infusion of saralasin (10 p.g/kg/min) was administered over a 90-minute period. Each study was supervised by the same physician (L.S.M.), and was performed by the same two research nurses who were unaware of the patient's diagnosis at the time of the test. Plasma-renin activity was determined by radio-immunoassay,' and all samples were run in duplicate. In our laboratory, this test has a within-assay variation of ±5.6% S.D. 8 Assignment of "high," "normal," or "low" to individual renin determinations was based on normal values established in healthy young adults, who were studied previously under conditions identical to those on the morning of the test. Thus, the range of normal values for plasma-renin activity was 673-3155 ng/ 100 mV3h incubation (95% confidence interval) under the stated conditions of salt depletion, morning collection, and l-hour ambulation.
785 response (among the responders) was 15 mm Hg systolic and 10 mm Hg diastolic in a patient whose pre-bolus blood-pressure was 135/95. Beginning at 6 minutes after the bolus, a statistically significant depressor effect persisted throughout the 30 minutes after the bolus for the group of 13 responders (p-
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