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Use of continuous saralasin infusion to control hypertension
PEDIATRIC AND
PHARMACOLOGY
THERAPEUTICS
Paul S. Lietman,Editor
Use o f continuous saralasin infusion to control hypertension Saralasin acetate, a competitive inhibitor of angiotensin 11, was administered as a continuous infusion to two pediatric patients for 8 and 13 days, respectively, to control hypertension. Both patients had become refractory to parenterally administered antihypertensive medications and had an ileus that precluded drug treatment orally. Both patients had a reduction in blood pressure o f 30 % in response to intravenous infusion of saralasin as a diagnostic test. In the patient with renal failure, neither saralasin nor ultrafiltration was effective alone, but blood pressure was controlled when their use was combined. In these two patients the continuous infusion of saralasin proved to be an effective means for blood pressure control and was unassociated with any recognized adverse effects.
Edward J. Ruley, M.D., Glenn H. Boek, M.D., and Douglas Smith, Pharm.D., Washington, D.C.
SARALASIN ACETATE (Sarenin, N o r w i c h - E a t o n Pharmaceuticals, Norwich, N.Y.), a specific competitive inhibtor of angiotensin II, was approved recently for diagnostic use in detecting renin-maintained hypertension. TM In this report we document the use of a continuous saralasin infusion in two pediatric patients to control elevated blood pressure. CASE R E P O R T S
Patient 1. An 800 gm white male infant of 24 to 26 weeks' gestation was born to a 15-year-old primigravida. The postnatal course was complicated by respiratory distress syndrome with the gradual development of bronchopulmonary dysplasia, intraventricular hemorrhage, two episodes of staphylococcal sepsis, and acidosis. At age 38 days the infant was transferred to Children's Hospital National Medical Center because of these problems and the occurrence of a right-sided inguinal hernia. At the time of transfer the infant's weight was 980 gm, the heart rate was 148 bpm, and the blood pressure as measured by oscillometry (Dinamap, Criticon Inc., Tampa, Fla.) was 87/61 mm Hg with a mean blood pressure of 76 mm Hg. The trachea was intubated, and the infant was given clindamycin, ampicillin, gentamicin, and dexamethasone. After stabilization the infant underwent a surgical reduction of From the Departments of Nephrology and Pharmacy Services, Children's Hospital National Medical Center. Reprint address: Edward J. Ruley, M.D., Department o f Nephrology, Children's Hospital National Medical Center, 111 Michigan Ave., N.W., Washington, D.C. 20010.
0022-3476/82/121013+05500.50/0 9 1982 The C. V. Mosby Co.
the inguinal hernia and placement of a central venous catheter for parenteral nutrition. The blood pressure remained elevated, so intravenous doses of furosemide (1 mg/kg) were begun on day 44. When the blood pressure failed to respond to diuretic therapy alone, the infant was given hydralazine intravenously (increased stepwise to 6 mg/kg/day), methyldopa (20 mg/kg/day intravenously), and larger doses of furosemide (2mg/kg). None of these therapies was effective (Fig. 1). Plasma renin and aldosterone values obtained on day 48 were eventually reported as 432 ng/ml/hour and > 50 mg/dl, respectively. Throughout this period the infant had an ileus that precluded the use of orally administered antihypertensive therapy. On day 51 a saralasin test was performed using a serially titrated intravenous infusion that began at 0.05 ~g/kg/minute and ended at 20 t~g/kg/minute. To minimize the volume of fluid administered to the infant, two different concentrations of saralasin were used. Infusions were continued for 30 minutes at the initiation of each infusion to allow time for the new concentration to clear the dead space of the needle. Subsequent increases in saralasin were achieved by increasing the rate of infusion, using an observation period of 10 minutes. Blood pressure began to decline at a saralasin dose of 5 #g/kg/minute and was maximally reduced at 20/~g/kg/minute, by which time the systolic blood pressure and diastolic BP had decreased by approximately 30 mm Hg to normal values. Because of the continued ileus, the failure of conventional parenterally administered antihypertensive medications, and the response to the saralasin test, emergency approval was obtained from the Human Research Committee to use a continuous saralasin infusion to control the elevated blood pressure. After obtaining informed consent, saralasin therapy was begun on day 51 and was followed by a prompt reduction of blood pressure.
The Journal o f P E D I A T R I C S Vol. 101, No. 6, pp. 1013-1017
1013
10 14
Ruley, Bock, and Smith
BLOOD
110-
The Journal of Pediatrics December 1982
PRESSURE
1 O0 -A
r--
9 0 - - "~
B
80--
E 70-E
~--
60-50-40-
r \
E
9, 876543-
SODIUM
INTAKE
loo
I I
I9
Furosemide
+ ++ +
+ + + + | ~ | | | + Methyldopa I I ~
|
I |
I Fur~
. ICapt~
N Hydralazine _xA. :::: :::::::::::::::::::::::::: Sara as n........ :: ::::::::::::::::::::::: . . . . . . ............... I I I I ' I I I t I I I I I I I I I I I I I I I I 11 I I I I I I I I I I 11 I I 11 I 11 i i i i I I 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 D A Y S O F LIFE
Fig. !. Clinical course of patient 1. Results are expressed as the mean of 12-hour values, BP as the mean of all measurements, sodium as total milliequivalents, and fluid as total milliliters. Furosemide administration: ~ = 1 m g / k g as a single dose, | = 2 m g / k g as a single dose. See text for explanation of points A and B.
Over the next 13 days the dose varied from a high of 9.1 to a low of 2.8 # g / k g / m i n u t e . The mean + 1 SD systolic BP (68.7 +_ 6.2 m m Hg), mean BP (54.2 _+ 6.3 m m Hg), and diastolic BP (41.8 + 6.2 m m Hg) during saralasin treatment were significantly lower ( P < 0.001) than the pre-saralasin systolic BP (86.9 _+ 7.7 m m Hg), mean BP (72.3 ___ 6.2 m m Hg), and diastolic BP (59.3 + 6.3 m m Hg). During the constant saralasin infusion BP became elevated on only two occasions: on day 59, when t h e saralasin infusion was discontinued for eight hours (Fig. 1, point A) and on day 60, when there was a marked increase in intravenous fluid administration (Fig. 1, point B). On day 63, with resumption of bowel function, treatment with captopril was begun (0.25 m g orally three times a day), and the saralasin infusion was gradually discontinued over the next two days. Blood pressure remained well controlled with oral eaptopril therapy alone. Patient 2. An 8-year-old black girl was admitted with a 50% second- and third-degree immersion burn to the lower trunk and legs. At the time of admission her BP was 210/140 m m Hg. By history she was receiving phenobarbital (30 mg each morning and 40 m g at bedtime) and hydralazine (10 mg every six hours). This child had been hospitalized elsewhere at 19 months of age, with BP 250/210 m m H g and hypertensive encephalopathy.
Multiple caf6-au-lait spots were noted and neurofibromatosis was suspected. Two 24-hour urine collections for eatecholamines and vanillylmandelic acid were normal. Excretory urography demonstrated an enlarged left kidney with no function on the right. Selective renal angiography demonstrated a small right renal artery with a poorly perfused right kidney. The left kidney was reported tO be normal. A right nephrectomy was done. No neurofibromas were noted at the time of surgery. At discharge the BP remained elevated at 138/84 m m H g without antihypertensive medications. Subsequent follow-up was erratic, although her BP was noted to be elevated three months prior to the present admission, necessitating the reinstitution of antihypertensive medications. A serum creatinine concentration 22 months prior to her admission for the burn was 0.4 mg/dl. Initial management included standardized fluid therapy for her burn and diazoxide, nitroprusside, and diuretics to control her hypertension. The patient remained oliguric from the time of admission. Blood urea nitrogen and creatinine concentrations on admission were 25 and 2.8 mg/dl, respectively. Her progressive acute renal failure was thought to be secondary to malignant hypertension superimposed on preexisting renal disease. A radionuclide renal scan demonstrated poor blood flow and no extraction
Volume 101 Number 6
Continuous saralasin infusion to control hypertension
] 0 15
200 190-
~
180-
E E 170160150-
FLUIDSTATUS +1.5-
+.I ~2 + . 5 0 -ff
ULTRAFILTRATION
~.~
SARALASIN
'E 1 0 v ~.
5.
'
I
2
'
I
4
'
I
6
'
8
10
12
14
16
18
20
22
24
26
28
30
32
HOURS Fig. 2. Reduction of blood pressure produced by ultrafiltration and saralasin infusion in patient 2. No rebound was observed, and BP slowly rose as the vascular space (fluid status) became reexpanded.
of the radionuclide. Her serum creatinine concentration continued to rise, and there was virtually no urine output. A continuous intravenous infusion of nitroprusside was used to decrease systolic BP to approximately 150 mm Hg. An ileus, present from the time of admission, precluded the use of any antihypertensive medications orally. Over several days her BP became progressively unresponsive to increasing doses of nitroprusside. At this time plasma renin activity was 169.4 ng/ml/hour and aldosterone concentration was 40 ng/dl. The presence of anuria, rising BUN and creatinine values, poorly controlled hypertension, and rising pulmonary arterial wedge pressure necessitated the institution of sequential dialysis and ultrafiltration with a Scribner shunt. Ultrafiltration resulted in an exacerbation of hypertension despite normalization of the wedge pressure. A saralasin test was performed at a starting dose of 0.05 ~g/ kg/minute with a stepwise increase to 0.35 ttg/kg/minute. The systolic BP, as measured by intra-arterial catheter, dropped from a pretest value of 200 mm Hg (while the patient was receiving 10 ug/kg/minute nitroprusside) to 138 mm Hg (when nitroprusside was discontinued). As a result of the response to saralasin and in consideration of her lack of response to nitroprusside and the continued ileus, emergency approval for the therapeutic use of saralasin was obtained from the Human Research Committee. After obtaining informed consent, a continuous infusion of saralasin was begun. The blood pressure was successfully controlled
with a combination of saralasin and ultrafiltration, the latter being necessary to manage the volume expansion associated with parenteral nutrition (Fig. 2). After eight days of saralasin infusion (ranging from 0.05 to 15 ~zg/kg/minute) the ileus resolved. Subsequently, BP was controlled with oral captopril therapy, and the saralasin was discontinued. No recognized adverse effects directly attributable to saralasin occurred during the treatment period. DISCUSSION Saralasin acetate is now approved for general use as a screening test for suspected renovascular hypertension, a l t h o u g h there is some d e b a t e as to its clinical v a l u e 5 6 To our knowledge only Z a w a d a et al 7 have reported the use of a continuous infusion of saralasin to control BP. Their patient was a 40-year-old m a n who developed hypertension refractory to multiple antihypertensive drugs including nitroprusside given intravenously following renal transplantation. Saralasin was infused for 14 hours with satisfactory blood pressure control, permitting the performance of a renal angiogram. O u r experience with two pediatric patients indicates t h a t the continuous saralasin infusion for blood pressure control m a y be safe and effective. Both patients had
10 1~
Rule)), Bock, and Smith
become unresponsive to conventional intravenously administered antihypertensive medications, and medications could not be given orally because of an ileus. Although plasma samples for renin activity were obtained prior to the saralasin test, the results were not available at the time of the initiation of the continuous saralasin infusion in either patient. The decreased BP in response to the test infusion of saralasin in each patient suggested that the renin-angiotensin pathway played an important role in the hypertension. This was the basis for the choice of a continuous saralasin infusion to control BP. Subsequently, the plasma renin values were reported to be elevated, supporting a role for renin mediation in the hypertension in these patients. However, it should be noted that in each case blood for renin determination was obtained after the patient had received antihypertensive d r u g s k n o w n to increase renin activity. Thus the absolute value of renin does not reflect the pretreatment state. Administration of saralasin, however, acts as a functional test for the role of renin in the etiology of hypertension. In the absence of renin-maintained hypertension, saralasin is either ineffective or acts as an agonist causing a rise in BP. In these two children the reduction in BP as a result of the saralasin test proved to be a valuable predictor of the subsequent response to the continued use of this medication and to captopril, another agent that is effective in renin-mediated hypertension. The principal reported adverse reactions with intravenous administration of saralasin have been excessive reduction or elevation of BP during the test infusion. Exaggerated changes in BP are less likely to occur if the serially titrated infusion method is used for the test procedure. Occasionally extrasystotes have been noted in patients with preexisting electrocardiographic abnormalities, and a small number of minor adverse reactions, including nausea, sweating, anxiety, and flushing of the skin, have been reported, s Neither patient had any recognized adverse effect from the continous saralasin infusion. Furthermore, in neither was the blood pressure reduced below the normal range to hypotensive levels, a situation that has been described when intravenously administered nitroprusside has been used for blood pressure control. Laragh 9 has proposed a vasoconstriction-volume model as a simplified concept of the pathogenesis of hypertension. In brief, BP is a function of effective blood volume (largely determined by sodium balance) and arteriolar vasoconstriction (largely determined by the renin-angiotension system). In this model elevated BP is maintained by the predominant effect of either one or the other of these factors. Reducing the effect of one factor (e.g., reducing fluid volume by the use of diuretics) causes the other factor to become the predominant determinant of BP elevation.
The Journal of Pediatrics December 1982
Such a relationship was evident in patient 2. Fluid administration to this child with oliguric renal failure produced hypertension that was more volume dependent and less dependent on the renin-angiotensin system. Clinically this was evidenced by the ineffectiveness of saralasin in controlling BP until volume reduction occurred. Similarly, BP control was lost in patient 1 when an increased amount of fluids was administered intravenously. Increased sodium intake in this infant did not induce tachyphylaxis to saralasin, as might be expected. However, saralasin effectiveness may have been preserved by the continued use of diuretic therapy. ~~ The cause of moderate hypertension in patient 1 is unclear. Radionuclide and sonographic studies showed the kidneys to be normal. Dexamethasone, which was administered for bronchopulmonary dysplasia, may have contributed to the elevated BP; corticosteroids are known to increase the hepatic production of renin substrate. H The severe hypertension in patient 2 was presumed to be caused by neurofibromatosis. The association of renovascular hypertension resulting from intrinsic renal artery hyperplasia and neurofibromatosis is well described. ~2 This diagnosis was suspected when the child had hypertensive encephalopathy at age 19 months. In the period preceding the thermal burn there was a gradual rise in her BP, necessitating the reinstitution of antihypertensive medications. In addition the severe hypertension associated with burns ~3 may have contributed to the development of malignant hypertension in this child. Continuous infusion of saralasin proved to be effective in controlling blood pressure in two pediatric patients who had BP reduction in response to a saralasin test and in whom drugs could not be given orally and conventional parenteral antihypertensive agents were ineffective. Although conventional antihypertensive medications administered orally or intravenously remain the principal means to control BP, we believe that saralasin may be a valuable agent for parenteral administration in selected patients with hypertension. ADDENDUM Since the submission of this report we have treated an 8-month-old male infant for hypertension caused by coarctation of the thoracic aorta. Despite conventional antihypertensive therapy including nitroprusside, the infant had BP in excess of 230/130 mm Hg. Continuous saralasin infusion was started after the BP decreased in response to a test dose. By titrating the saralasin infusion it was possible to lower the BP to 160 mm Hg, a value that assured perfusion distal to the coarctation. The infusion was continued through surgery (20 hours) without recognized adverse effects.
Volume 101 Number 6 REFERENCES
1. Wilson HM, Wilson JP, Slaton PE, et al: Saralasin infusion in the recognition of renovascular hypertension, Ann Intern Med 87:36, 1977. 2. Favre L, Boerth RC, Braren V, et al: Angiotension II blockade by saralasin in the evaluation of hypertension in children, Kidney Int 15(suppl 9):$75, 1979. 3. Gillespie L, Ehrlich RM, Marks LS, et al: Use of saralasin to detect renovascular hypertension in childhood, Urology 16:453, 1980. 4. Weber MA: Saralasin testing for renin-dependent hypertension, Arch Intern Med 139:93, 1979. 5. Braren V, and Boerth RC: Saralasin testing in pediatric hypertension, Urology 17:512, 1981. 6. Saralasin for diagnosis of renovascular hypertension, Med Lett Drugs Ther 24:3, 1982. 7. Zawada ET, Maxwell MH, Marks LS, et al: The diagnostic and therapeutic uses of saralasin in renal transplant hypertension, J Urol 123:148, 1980.
Continuous saralasin infusion to control hypertension
10 17
8. Horne ML, Conklin VM, Keenan RE, et al: Angiotensin II profiling with saralasin: Summary of Eaton collaborative study, Kidney Int 15(suppl 9):S115, 1979. 9. Laragh JH: Vasoconstriction-volume analysis for understanding and treating hypertension: The use of renin and aldosterone profiles, Am J Med 55:261, 1973. 10. Thananopavarn C, Golub MS, Eggena P, et al: Angiotensin II, plasma renin and sodium depletion as determinants of blood pressure response to saralasin in essential hypertension, Circulation 61:920, 1980. 11. Lazar J, and Hoobler SW: Studies on the role of the adrenal in renin kinetics, Proc Soc Exp Biol Med 138:614, 1971. 12. Stanley JC, and Fry WJ: Pediatric renal artery occlusive disease and renovaseular hypertension, Arch Surg 116:669, 1981. 13. Popp MB, Silberstein EB, Srivastava LS, et al: A pathophysiologic study of the hypertension associated with burn injury in children, Ann Surg 193:817, 1981.
PHARMACOLOGY
THERAPEUTICS
Paul S. Lietman,Editor
Use o f continuous saralasin infusion to control hypertension Saralasin acetate, a competitive inhibitor of angiotensin 11, was administered as a continuous infusion to two pediatric patients for 8 and 13 days, respectively, to control hypertension. Both patients had become refractory to parenterally administered antihypertensive medications and had an ileus that precluded drug treatment orally. Both patients had a reduction in blood pressure o f 30 % in response to intravenous infusion of saralasin as a diagnostic test. In the patient with renal failure, neither saralasin nor ultrafiltration was effective alone, but blood pressure was controlled when their use was combined. In these two patients the continuous infusion of saralasin proved to be an effective means for blood pressure control and was unassociated with any recognized adverse effects.
Edward J. Ruley, M.D., Glenn H. Boek, M.D., and Douglas Smith, Pharm.D., Washington, D.C.
SARALASIN ACETATE (Sarenin, N o r w i c h - E a t o n Pharmaceuticals, Norwich, N.Y.), a specific competitive inhibtor of angiotensin II, was approved recently for diagnostic use in detecting renin-maintained hypertension. TM In this report we document the use of a continuous saralasin infusion in two pediatric patients to control elevated blood pressure. CASE R E P O R T S
Patient 1. An 800 gm white male infant of 24 to 26 weeks' gestation was born to a 15-year-old primigravida. The postnatal course was complicated by respiratory distress syndrome with the gradual development of bronchopulmonary dysplasia, intraventricular hemorrhage, two episodes of staphylococcal sepsis, and acidosis. At age 38 days the infant was transferred to Children's Hospital National Medical Center because of these problems and the occurrence of a right-sided inguinal hernia. At the time of transfer the infant's weight was 980 gm, the heart rate was 148 bpm, and the blood pressure as measured by oscillometry (Dinamap, Criticon Inc., Tampa, Fla.) was 87/61 mm Hg with a mean blood pressure of 76 mm Hg. The trachea was intubated, and the infant was given clindamycin, ampicillin, gentamicin, and dexamethasone. After stabilization the infant underwent a surgical reduction of From the Departments of Nephrology and Pharmacy Services, Children's Hospital National Medical Center. Reprint address: Edward J. Ruley, M.D., Department o f Nephrology, Children's Hospital National Medical Center, 111 Michigan Ave., N.W., Washington, D.C. 20010.
0022-3476/82/121013+05500.50/0 9 1982 The C. V. Mosby Co.
the inguinal hernia and placement of a central venous catheter for parenteral nutrition. The blood pressure remained elevated, so intravenous doses of furosemide (1 mg/kg) were begun on day 44. When the blood pressure failed to respond to diuretic therapy alone, the infant was given hydralazine intravenously (increased stepwise to 6 mg/kg/day), methyldopa (20 mg/kg/day intravenously), and larger doses of furosemide (2mg/kg). None of these therapies was effective (Fig. 1). Plasma renin and aldosterone values obtained on day 48 were eventually reported as 432 ng/ml/hour and > 50 mg/dl, respectively. Throughout this period the infant had an ileus that precluded the use of orally administered antihypertensive therapy. On day 51 a saralasin test was performed using a serially titrated intravenous infusion that began at 0.05 ~g/kg/minute and ended at 20 t~g/kg/minute. To minimize the volume of fluid administered to the infant, two different concentrations of saralasin were used. Infusions were continued for 30 minutes at the initiation of each infusion to allow time for the new concentration to clear the dead space of the needle. Subsequent increases in saralasin were achieved by increasing the rate of infusion, using an observation period of 10 minutes. Blood pressure began to decline at a saralasin dose of 5 #g/kg/minute and was maximally reduced at 20/~g/kg/minute, by which time the systolic blood pressure and diastolic BP had decreased by approximately 30 mm Hg to normal values. Because of the continued ileus, the failure of conventional parenterally administered antihypertensive medications, and the response to the saralasin test, emergency approval was obtained from the Human Research Committee to use a continuous saralasin infusion to control the elevated blood pressure. After obtaining informed consent, saralasin therapy was begun on day 51 and was followed by a prompt reduction of blood pressure.
The Journal o f P E D I A T R I C S Vol. 101, No. 6, pp. 1013-1017
1013
10 14
Ruley, Bock, and Smith
BLOOD
110-
The Journal of Pediatrics December 1982
PRESSURE
1 O0 -A
r--
9 0 - - "~
B
80--
E 70-E
~--
60-50-40-
r \
E
9, 876543-
SODIUM
INTAKE
loo
I I
I9
Furosemide
+ ++ +
+ + + + | ~ | | | + Methyldopa I I ~
|
I |
I Fur~
. ICapt~
N Hydralazine _xA. :::: :::::::::::::::::::::::::: Sara as n........ :: ::::::::::::::::::::::: . . . . . . ............... I I I I ' I I I t I I I I I I I I I I I I I I I I 11 I I I I I I I I I I 11 I I 11 I 11 i i i i I I 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 D A Y S O F LIFE
Fig. !. Clinical course of patient 1. Results are expressed as the mean of 12-hour values, BP as the mean of all measurements, sodium as total milliequivalents, and fluid as total milliliters. Furosemide administration: ~ = 1 m g / k g as a single dose, | = 2 m g / k g as a single dose. See text for explanation of points A and B.
Over the next 13 days the dose varied from a high of 9.1 to a low of 2.8 # g / k g / m i n u t e . The mean + 1 SD systolic BP (68.7 +_ 6.2 m m Hg), mean BP (54.2 _+ 6.3 m m Hg), and diastolic BP (41.8 + 6.2 m m Hg) during saralasin treatment were significantly lower ( P < 0.001) than the pre-saralasin systolic BP (86.9 _+ 7.7 m m Hg), mean BP (72.3 ___ 6.2 m m Hg), and diastolic BP (59.3 + 6.3 m m Hg). During the constant saralasin infusion BP became elevated on only two occasions: on day 59, when t h e saralasin infusion was discontinued for eight hours (Fig. 1, point A) and on day 60, when there was a marked increase in intravenous fluid administration (Fig. 1, point B). On day 63, with resumption of bowel function, treatment with captopril was begun (0.25 m g orally three times a day), and the saralasin infusion was gradually discontinued over the next two days. Blood pressure remained well controlled with oral eaptopril therapy alone. Patient 2. An 8-year-old black girl was admitted with a 50% second- and third-degree immersion burn to the lower trunk and legs. At the time of admission her BP was 210/140 m m Hg. By history she was receiving phenobarbital (30 mg each morning and 40 m g at bedtime) and hydralazine (10 mg every six hours). This child had been hospitalized elsewhere at 19 months of age, with BP 250/210 m m H g and hypertensive encephalopathy.
Multiple caf6-au-lait spots were noted and neurofibromatosis was suspected. Two 24-hour urine collections for eatecholamines and vanillylmandelic acid were normal. Excretory urography demonstrated an enlarged left kidney with no function on the right. Selective renal angiography demonstrated a small right renal artery with a poorly perfused right kidney. The left kidney was reported tO be normal. A right nephrectomy was done. No neurofibromas were noted at the time of surgery. At discharge the BP remained elevated at 138/84 m m H g without antihypertensive medications. Subsequent follow-up was erratic, although her BP was noted to be elevated three months prior to the present admission, necessitating the reinstitution of antihypertensive medications. A serum creatinine concentration 22 months prior to her admission for the burn was 0.4 mg/dl. Initial management included standardized fluid therapy for her burn and diazoxide, nitroprusside, and diuretics to control her hypertension. The patient remained oliguric from the time of admission. Blood urea nitrogen and creatinine concentrations on admission were 25 and 2.8 mg/dl, respectively. Her progressive acute renal failure was thought to be secondary to malignant hypertension superimposed on preexisting renal disease. A radionuclide renal scan demonstrated poor blood flow and no extraction
Volume 101 Number 6
Continuous saralasin infusion to control hypertension
] 0 15
200 190-
~
180-
E E 170160150-
FLUIDSTATUS +1.5-
+.I ~2 + . 5 0 -ff
ULTRAFILTRATION
~.~
SARALASIN
'E 1 0 v ~.
5.
'
I
2
'
I
4
'
I
6
'
8
10
12
14
16
18
20
22
24
26
28
30
32
HOURS Fig. 2. Reduction of blood pressure produced by ultrafiltration and saralasin infusion in patient 2. No rebound was observed, and BP slowly rose as the vascular space (fluid status) became reexpanded.
of the radionuclide. Her serum creatinine concentration continued to rise, and there was virtually no urine output. A continuous intravenous infusion of nitroprusside was used to decrease systolic BP to approximately 150 mm Hg. An ileus, present from the time of admission, precluded the use of any antihypertensive medications orally. Over several days her BP became progressively unresponsive to increasing doses of nitroprusside. At this time plasma renin activity was 169.4 ng/ml/hour and aldosterone concentration was 40 ng/dl. The presence of anuria, rising BUN and creatinine values, poorly controlled hypertension, and rising pulmonary arterial wedge pressure necessitated the institution of sequential dialysis and ultrafiltration with a Scribner shunt. Ultrafiltration resulted in an exacerbation of hypertension despite normalization of the wedge pressure. A saralasin test was performed at a starting dose of 0.05 ~g/ kg/minute with a stepwise increase to 0.35 ttg/kg/minute. The systolic BP, as measured by intra-arterial catheter, dropped from a pretest value of 200 mm Hg (while the patient was receiving 10 ug/kg/minute nitroprusside) to 138 mm Hg (when nitroprusside was discontinued). As a result of the response to saralasin and in consideration of her lack of response to nitroprusside and the continued ileus, emergency approval for the therapeutic use of saralasin was obtained from the Human Research Committee. After obtaining informed consent, a continuous infusion of saralasin was begun. The blood pressure was successfully controlled
with a combination of saralasin and ultrafiltration, the latter being necessary to manage the volume expansion associated with parenteral nutrition (Fig. 2). After eight days of saralasin infusion (ranging from 0.05 to 15 ~zg/kg/minute) the ileus resolved. Subsequently, BP was controlled with oral captopril therapy, and the saralasin was discontinued. No recognized adverse effects directly attributable to saralasin occurred during the treatment period. DISCUSSION Saralasin acetate is now approved for general use as a screening test for suspected renovascular hypertension, a l t h o u g h there is some d e b a t e as to its clinical v a l u e 5 6 To our knowledge only Z a w a d a et al 7 have reported the use of a continuous infusion of saralasin to control BP. Their patient was a 40-year-old m a n who developed hypertension refractory to multiple antihypertensive drugs including nitroprusside given intravenously following renal transplantation. Saralasin was infused for 14 hours with satisfactory blood pressure control, permitting the performance of a renal angiogram. O u r experience with two pediatric patients indicates t h a t the continuous saralasin infusion for blood pressure control m a y be safe and effective. Both patients had
10 1~
Rule)), Bock, and Smith
become unresponsive to conventional intravenously administered antihypertensive medications, and medications could not be given orally because of an ileus. Although plasma samples for renin activity were obtained prior to the saralasin test, the results were not available at the time of the initiation of the continuous saralasin infusion in either patient. The decreased BP in response to the test infusion of saralasin in each patient suggested that the renin-angiotensin pathway played an important role in the hypertension. This was the basis for the choice of a continuous saralasin infusion to control BP. Subsequently, the plasma renin values were reported to be elevated, supporting a role for renin mediation in the hypertension in these patients. However, it should be noted that in each case blood for renin determination was obtained after the patient had received antihypertensive d r u g s k n o w n to increase renin activity. Thus the absolute value of renin does not reflect the pretreatment state. Administration of saralasin, however, acts as a functional test for the role of renin in the etiology of hypertension. In the absence of renin-maintained hypertension, saralasin is either ineffective or acts as an agonist causing a rise in BP. In these two children the reduction in BP as a result of the saralasin test proved to be a valuable predictor of the subsequent response to the continued use of this medication and to captopril, another agent that is effective in renin-mediated hypertension. The principal reported adverse reactions with intravenous administration of saralasin have been excessive reduction or elevation of BP during the test infusion. Exaggerated changes in BP are less likely to occur if the serially titrated infusion method is used for the test procedure. Occasionally extrasystotes have been noted in patients with preexisting electrocardiographic abnormalities, and a small number of minor adverse reactions, including nausea, sweating, anxiety, and flushing of the skin, have been reported, s Neither patient had any recognized adverse effect from the continous saralasin infusion. Furthermore, in neither was the blood pressure reduced below the normal range to hypotensive levels, a situation that has been described when intravenously administered nitroprusside has been used for blood pressure control. Laragh 9 has proposed a vasoconstriction-volume model as a simplified concept of the pathogenesis of hypertension. In brief, BP is a function of effective blood volume (largely determined by sodium balance) and arteriolar vasoconstriction (largely determined by the renin-angiotension system). In this model elevated BP is maintained by the predominant effect of either one or the other of these factors. Reducing the effect of one factor (e.g., reducing fluid volume by the use of diuretics) causes the other factor to become the predominant determinant of BP elevation.
The Journal of Pediatrics December 1982
Such a relationship was evident in patient 2. Fluid administration to this child with oliguric renal failure produced hypertension that was more volume dependent and less dependent on the renin-angiotensin system. Clinically this was evidenced by the ineffectiveness of saralasin in controlling BP until volume reduction occurred. Similarly, BP control was lost in patient 1 when an increased amount of fluids was administered intravenously. Increased sodium intake in this infant did not induce tachyphylaxis to saralasin, as might be expected. However, saralasin effectiveness may have been preserved by the continued use of diuretic therapy. ~~ The cause of moderate hypertension in patient 1 is unclear. Radionuclide and sonographic studies showed the kidneys to be normal. Dexamethasone, which was administered for bronchopulmonary dysplasia, may have contributed to the elevated BP; corticosteroids are known to increase the hepatic production of renin substrate. H The severe hypertension in patient 2 was presumed to be caused by neurofibromatosis. The association of renovascular hypertension resulting from intrinsic renal artery hyperplasia and neurofibromatosis is well described. ~2 This diagnosis was suspected when the child had hypertensive encephalopathy at age 19 months. In the period preceding the thermal burn there was a gradual rise in her BP, necessitating the reinstitution of antihypertensive medications. In addition the severe hypertension associated with burns ~3 may have contributed to the development of malignant hypertension in this child. Continuous infusion of saralasin proved to be effective in controlling blood pressure in two pediatric patients who had BP reduction in response to a saralasin test and in whom drugs could not be given orally and conventional parenteral antihypertensive agents were ineffective. Although conventional antihypertensive medications administered orally or intravenously remain the principal means to control BP, we believe that saralasin may be a valuable agent for parenteral administration in selected patients with hypertension. ADDENDUM Since the submission of this report we have treated an 8-month-old male infant for hypertension caused by coarctation of the thoracic aorta. Despite conventional antihypertensive therapy including nitroprusside, the infant had BP in excess of 230/130 mm Hg. Continuous saralasin infusion was started after the BP decreased in response to a test dose. By titrating the saralasin infusion it was possible to lower the BP to 160 mm Hg, a value that assured perfusion distal to the coarctation. The infusion was continued through surgery (20 hours) without recognized adverse effects.
Volume 101 Number 6 REFERENCES
1. Wilson HM, Wilson JP, Slaton PE, et al: Saralasin infusion in the recognition of renovascular hypertension, Ann Intern Med 87:36, 1977. 2. Favre L, Boerth RC, Braren V, et al: Angiotension II blockade by saralasin in the evaluation of hypertension in children, Kidney Int 15(suppl 9):$75, 1979. 3. Gillespie L, Ehrlich RM, Marks LS, et al: Use of saralasin to detect renovascular hypertension in childhood, Urology 16:453, 1980. 4. Weber MA: Saralasin testing for renin-dependent hypertension, Arch Intern Med 139:93, 1979. 5. Braren V, and Boerth RC: Saralasin testing in pediatric hypertension, Urology 17:512, 1981. 6. Saralasin for diagnosis of renovascular hypertension, Med Lett Drugs Ther 24:3, 1982. 7. Zawada ET, Maxwell MH, Marks LS, et al: The diagnostic and therapeutic uses of saralasin in renal transplant hypertension, J Urol 123:148, 1980.
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8. Horne ML, Conklin VM, Keenan RE, et al: Angiotensin II profiling with saralasin: Summary of Eaton collaborative study, Kidney Int 15(suppl 9):S115, 1979. 9. Laragh JH: Vasoconstriction-volume analysis for understanding and treating hypertension: The use of renin and aldosterone profiles, Am J Med 55:261, 1973. 10. Thananopavarn C, Golub MS, Eggena P, et al: Angiotensin II, plasma renin and sodium depletion as determinants of blood pressure response to saralasin in essential hypertension, Circulation 61:920, 1980. 11. Lazar J, and Hoobler SW: Studies on the role of the adrenal in renin kinetics, Proc Soc Exp Biol Med 138:614, 1971. 12. Stanley JC, and Fry WJ: Pediatric renal artery occlusive disease and renovaseular hypertension, Arch Surg 116:669, 1981. 13. Popp MB, Silberstein EB, Srivastava LS, et al: A pathophysiologic study of the hypertension associated with burn injury in children, Ann Surg 193:817, 1981.