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Differential diagnosis of diabetes insipidus: Use of DDAVP to terminate the seven-hour water deprivation test
244
Brief cfinical and laboratory observations
litis, and is unusual because of his age, as well as his gender. Although antimalarial agents are the therapy of choice of lupus panniculitis, intermittent therapy with prednisone may be a reasonable alternative, as evidenced by our patient's favorable response. REFERENCES
1. Nelson WE, Vaughan III, VC, McKay, Jr., RJ and Behrman RE, editors. Textbook of pediatrics, Philadelphia, 1979, W B Saunders Company. 2. Rudolph AM, Barnett HL, and Einhorn AH, editors: Pediatrics, ed 16, New York, 1977, Appleton-CenturyCrofts. 3. Irgang S: Lupus erythematosus profundus. Report of an example with clinical resemblance to Darier-Roussy sarcoid, Arch Dermatol 42:97, 1940. 4. Fountain RB: Lupus erythematosus profundus, Br J Dermatol 80:571, 1968.
The Journal of Pediatrics February 1981
5. Harris RB, Duncan SC, Ecker RI, and Winkelmann RK: Lymphoid follicles in subcutaneous inflammatory disease, Arch Dermatol 115:442, 1979. 6. Diaz-Juanen E, Dehoratius RJ, Alarcon-Segovia D, and Messner RP: Systemic lupus erythematosus presenting as panniculitis (lupus profundus), Ann Intern Med 82:376, 1975. 7. Tuffanelli DL: Lupus erythematosus panniculitis (profundus)-clinical and immunologic studies, Arch Dermatol 103:231, 1971. 8. Winkelmann RK, and Padilha-Goncalves A: Connective tissue panniculitis, Arch Dermatol 116:291, 1980. 9. Winkelmann RK: Chronic discoid lupus erythematosus in childhood, JAMA 205:675, 1968. 10. Zweiman B, Tomar RH, and Gross P: Lupus erythematosus profundus followingthrombocytopenia purpura, Arch Dermatol 3:347, 1975.
Differential diagnosis of diabetes insipidus: Use of DDA VP to terminate the seven-hour water deprivation test S. Anne Hendricks, M.D.,* Barbara Lippe, M.D., Solomon A. Kaplan, M.D., and W-N. Paul Lee, M.D., Los Angeles, Calif.
IN PATIENTS with diabetes insipidus, testing shows a failure of antidiuresis in the face of induced serum hyperosmolarity~ and failure to excrete a concentrated urine following water deprivation.2, 3 Once the diagnosis is established, differentiation between vasopressin-sensifive DI and nephrogenic DI depends on the response to administered vasopressin. The Carter-Robbins modification of the Hicky-Hare test I included a method for the administration of aqueous pitressin intravenously at the end of the test following an initial period of intravenous infusion of hypertonic sodium chloride. In children, however, this test is cumbersome and often technically difficult because it requires intravenous fluid and vasopressin administration, timed urine collections over precise time periods, and the potential necessity of bladder catheterization. The seven-hour water deprivation test, as described by Frasier and coworkers) has proven effective and safe in our experience. Although water deprivation for seven hours only does not permit assessment of the From the Department of Pediatrics, UCLA Hospital and Clinics. *Reprint address: Department of Pediatrics, Division of Endocrinology and Metabolism, UCLA Hospital and Clinics, Los Angeles, CA 90024.
maximal concentrating power of the kidney, the criteria established for normal renal function after this short period of time serve to distinguish patients with a significant concentrating defect from those with normal renal function.2" Depriving children with impaired renal concentrating power of water for longer periods of time is not only unpleasant for the patient, nurses, and physician, but may be hazardous. However, a method to terminate this test using a vasopressin preparation to distinguish vasopressin sensitivity from nephrogenic DI or hyposthenuric renal disease was not described. Abbreviations used DI: diabetes insipidus SG: specificgravity This report reviews our recent experience in terminating the seven-hour water deprivation test with intranasal administration of vasopressin. Our data indicate that l-desamino-8-D-arginine vasopressin (DDAVP) can be used to demonstrate pitressin sensitivity following the demonstration of DI, thereby expanding the usefulness of the seven-hour water deprivation test to include a means and criteria for the differential diagnosis between pitressin-sensitive and pitressin-resistant DI.
0022-3476/81/020244+03500.30/0 9 1981 The C. V. Mosby Co.
Volume 98 Number 2
Brief clinical and laboratory observations
24 5
Table
Patient 1
2
3
4 5 6
7
Idiopathic diabetes insipidus Idiopathic diabetes insipidus Idiopathic diabetes insipidus Craniopharyngioma Hypothalamic hypopituitarism Nephrogenic diabetes insipidus Nephrogenic diabetes insipidus
Values after vasopressin
Values after water deprivation
U,
S~
U~ S~
Urine SG
U~
S~.
U~ $2
Urine SG
U~
S~
Ua S~
Vasopressin U r i n e preparation SG used
95
293
0.32
1.002
219
308
0.69
1.005
552
300
1.84
1.019 DDAVP
105
298
0.35
1.004
160
304
0.53
1.006
590
301
1.96
104
284
0.36
1.002
87
293
0.30
1.000
688
289
2.38
1.017 DDAVP
40 80
294 293
0.14 0.3
1.004 1.002
152 232
308 306
0.49 0.75
1.002 1.005
552 548
300 304
1.84 1.8
1.020 DDAVP 1.017 DDAVP
68
297
0.23
1.005
107
329
0.33
*
68 110
330 320
0.21 0.34
60
275
0.22
1.002
103
284
0.36
1.005
124
284
0.44
1.004 DDAVP 1.007 pitressinin-oil 1.006 DDAVP
Initial values
*
DDAVP
SG ~ Specificgravity. *Not obtained. Urine and serum osmolarity (U,. U~, U~, S~, S:, S~) expressed as mOsm/L and urine specific gravity at various times during the test as described in the text. METHODS
AND MATERIALS
Seven previously untreated patients with polyuria and polydipsia were studied. Patients ranged in age from 4 to 20 years. A seven-hour water deprivation test was initiated according to the protocol o f Frasier et a12 The protocol was modified to include bedside recording of urine volume and specific gra~,ity hourly (when cooperation of subject could be obtained) during the test and for four hours afterward. Osmolarity of the urine ( U 0 and of the serum (SO were measured at the beginning of the test and after completion of the seven-hour deprivation period (U~, S~). DDAVP, 10 to 20 /tg, was then administered intranasally with the calibrated Rhinyle distributed by the manufacturer. The patients were then monitored for up to another four hours, and serum (Ss) and urine (U~) osmolarity determined. If the urine SG obtained in the hourly monitoring rose to 1.014 or greater, the test was terminated early and $3 and U3 samples obtained at that time. During the period following vasopressin administration, oral fluids were permitted hourly at volumes equal to the urine output of the previous hour. After the U3 and S~ samples were obtained, oral .fluids were permitted in larger quantities, but close monitoring was continued over the next 12 hours in order to prevent water intoxication.
The ratios U1 U2 U3 S, ' S~ ' $3 ' were calculated. A ratio U2 --< $2
!.5
was considered indicative of abnormal urinary concentrating ability, whereas that ~ i.5 indicated normal renal function. A positive response to D D A V P was defined by criteria similar to those used ~ to define normal function after water deprivation: a ratio U3 --> S~
1.5,
a final urine osmolarity of >_--450 mOsm, or an increase in the urine to serum osmolarity ratio of 1.0 or more. An increase in urine SG to 1.014 or greater less than four hours after vasopressin administration was used as an indication of a probable response to D D A V P so that Us and $3 could be obtained sooner. RESULTS The Table shows the data obtained in the seven patients studied. The ratio U1/S~ was less than 0.5 in all patients.
24 6
Brief clinical and laboratory observations
Following seven hours of water deprivation, all patients failed to increase the U~/S~ ratio to greater than 1.0, thereby meeting the criteria for DI. In Patients 1 to 5 vasopressin responsiveness was clinically evident within two hours after administration of DDAVP, as marked antidiuresis ensued. By four hours all had
U3 5:2
-->
1.5.
Subsequently, these five patients have continued to respond to DDAVP, continued administration of which has been necessary to prevent polyuria. Patient 6, a male, failed to respond to DDAVP within four hours; he was subsequently given pitressin tannatein-oil, to which he also failed to respond. Subsequent renal evaluation showed no evidence of impairment of other renal functions and he is considered to have nephrogenic DI. Patient 7, also a male, was referred with the diagnosis of nephrogenic DI because his polyuria had failed to respond to intramuscular administration of pitressin preparations on numerous previous occasions. He did not demonstrate renal concentrating ability after seven hours of water deprivation and also did not respond to administration of DDAVP. Intravenous urography showed distention of the urinary collecting system without signs of obstruction, findings commonly reported in nephrogenic D I ? '~ DISCUSSION The diagnosis of DI can be made effectively in children with a seven-hour water deprivation test, without resorting to more complicated and potentially hazardous protocols. The distinction between vasopressin-sensitive and vasopressin-resistant forms of DI necessitates assessment of a positive response to administered vasopressin. Our data suggest that the administration of intranasal DDAVP at the end of the seven-hour water deprivation test is a simple and effective way to demonstrate vasopressin sensitivity. Since its introduction, D D A V P has been shown to be a potent and effective antidiuretic agent which is considered the therapeutic agent of choice for central diabetes insipidus. 7'~ Additionally, its usefulness in evaluating renal concentrating ability in both children and adults has been established. T M A dose of 20 ~g in children and 10 #g in infants has been demonstrated to result in maximum urine osmolarities similar to those resulting from 22 hours of water deprivation or from the administration of pitressin tannate. This study indicates that initial responsiveness to D D A V P may be assessed within four hours after its administration. Although maximum concentrating ability is not achieved in this short a
The Journal of Pediatrics February 198 !
period, criteria which otherwise characterize pitressin sensitivity can be applied to the use of this preparation in this test. We used the criteria established by Frasier et al 3 to define normal concentrating ability after water deprivation. Five of our seven patients met one or more of these criteria within four hours of D D A V P administration and have all subsequently continued to require DDAVP to control their polyuria. The two patients who did not meet the criteria were subsequently treated with other vasopressin preparations and failed to respond. Although the n u m b e r of patients reported in this study is small, we have subsequently treated 12 more patients with known neurogenic DI with DDAVP. At a time when their previous pitressin preparation was discontinued, the administration of a single dose of D D A V P always produced a significant antidiuretic response with four hours. The seven-hour water deprivation test and measurement of the U~/S~ osmolarity ratio followed by administration of D D A V P and additional measurements of U3/$3 osmolarity ratios within four hours seem to provide a systematic and effective approach to the diagnosis of polyuria and polydipsia in children. REFERENCES I. Carter AC, and Robbins J: The use of hypertonic saline infusion in the differential diagnosis of diabetes insipidus and psychogenic polydipsia, J Clin Endocrinol 7:753, 1947. 2. Dashe AM, Cramm RE, Crist CA, Habener JF, and Solomon DH: A water deprivation test for the differential diagnosis of polyuria, JAMA 185:699, 1963. 3. Frasier SD, Kutnik LA, Schmidt RT, and Smith FG Jr: A water deprivation test for the diagnosis of diabetes insipidus in children, Am J Dis Child 114:157, 1967. 4. Price JDE, and Lauener RN: Serum and urine osmolalities in the differential diagnosis of polyuric states, J Clin Endocrinol 26:143, 1966. 5. ten Bensel RW, and Peters ER: Progressive hydronephrosis, hydroureter and dilatation of the bladder in siblings with congenital nephrogenic diabetes insipidus, J P~DIAa'R 77:439, 1970. 6. Carter RD, and Goodman AD: Nephrogenic diabetes insipidus accompanied by massive dilatation of the kidneys, ureters, and bladder, J Urol 89:366, 1963. 7. Lee WNP, Lippe BM, LaFi'anchi SH, and Kaplan SA: Vasopressin analog DDAVP in the treatment of diabetes insipidus, Am J Dis Child 130:166, 1976. 8. Becker DJ, and Foley TP Jr: l-Desamino-8-D-arginine vasopressin in the treatment of central diabetes insipidus in childhood, J PEDIAXR92:1011, 1978. 9. Delin K, Aurell M, and Ewald J: Urinary concentration test with Desmopressin, Br Med J 951:757, 1978. t0. Somerfield SD, and Hocken AG: Desamino arginine vasopressin (DDAVP) as a diagnostic agent, NZ Med J 86:472, 1977. 11. Aronson AS, and Svenningsen NW: DDAVP test for estimation of renal concentrating capacity in infants and children, Arch Dis Child 49:654, 1974.
Brief cfinical and laboratory observations
litis, and is unusual because of his age, as well as his gender. Although antimalarial agents are the therapy of choice of lupus panniculitis, intermittent therapy with prednisone may be a reasonable alternative, as evidenced by our patient's favorable response. REFERENCES
1. Nelson WE, Vaughan III, VC, McKay, Jr., RJ and Behrman RE, editors. Textbook of pediatrics, Philadelphia, 1979, W B Saunders Company. 2. Rudolph AM, Barnett HL, and Einhorn AH, editors: Pediatrics, ed 16, New York, 1977, Appleton-CenturyCrofts. 3. Irgang S: Lupus erythematosus profundus. Report of an example with clinical resemblance to Darier-Roussy sarcoid, Arch Dermatol 42:97, 1940. 4. Fountain RB: Lupus erythematosus profundus, Br J Dermatol 80:571, 1968.
The Journal of Pediatrics February 1981
5. Harris RB, Duncan SC, Ecker RI, and Winkelmann RK: Lymphoid follicles in subcutaneous inflammatory disease, Arch Dermatol 115:442, 1979. 6. Diaz-Juanen E, Dehoratius RJ, Alarcon-Segovia D, and Messner RP: Systemic lupus erythematosus presenting as panniculitis (lupus profundus), Ann Intern Med 82:376, 1975. 7. Tuffanelli DL: Lupus erythematosus panniculitis (profundus)-clinical and immunologic studies, Arch Dermatol 103:231, 1971. 8. Winkelmann RK, and Padilha-Goncalves A: Connective tissue panniculitis, Arch Dermatol 116:291, 1980. 9. Winkelmann RK: Chronic discoid lupus erythematosus in childhood, JAMA 205:675, 1968. 10. Zweiman B, Tomar RH, and Gross P: Lupus erythematosus profundus followingthrombocytopenia purpura, Arch Dermatol 3:347, 1975.
Differential diagnosis of diabetes insipidus: Use of DDA VP to terminate the seven-hour water deprivation test S. Anne Hendricks, M.D.,* Barbara Lippe, M.D., Solomon A. Kaplan, M.D., and W-N. Paul Lee, M.D., Los Angeles, Calif.
IN PATIENTS with diabetes insipidus, testing shows a failure of antidiuresis in the face of induced serum hyperosmolarity~ and failure to excrete a concentrated urine following water deprivation.2, 3 Once the diagnosis is established, differentiation between vasopressin-sensifive DI and nephrogenic DI depends on the response to administered vasopressin. The Carter-Robbins modification of the Hicky-Hare test I included a method for the administration of aqueous pitressin intravenously at the end of the test following an initial period of intravenous infusion of hypertonic sodium chloride. In children, however, this test is cumbersome and often technically difficult because it requires intravenous fluid and vasopressin administration, timed urine collections over precise time periods, and the potential necessity of bladder catheterization. The seven-hour water deprivation test, as described by Frasier and coworkers) has proven effective and safe in our experience. Although water deprivation for seven hours only does not permit assessment of the From the Department of Pediatrics, UCLA Hospital and Clinics. *Reprint address: Department of Pediatrics, Division of Endocrinology and Metabolism, UCLA Hospital and Clinics, Los Angeles, CA 90024.
maximal concentrating power of the kidney, the criteria established for normal renal function after this short period of time serve to distinguish patients with a significant concentrating defect from those with normal renal function.2" Depriving children with impaired renal concentrating power of water for longer periods of time is not only unpleasant for the patient, nurses, and physician, but may be hazardous. However, a method to terminate this test using a vasopressin preparation to distinguish vasopressin sensitivity from nephrogenic DI or hyposthenuric renal disease was not described. Abbreviations used DI: diabetes insipidus SG: specificgravity This report reviews our recent experience in terminating the seven-hour water deprivation test with intranasal administration of vasopressin. Our data indicate that l-desamino-8-D-arginine vasopressin (DDAVP) can be used to demonstrate pitressin sensitivity following the demonstration of DI, thereby expanding the usefulness of the seven-hour water deprivation test to include a means and criteria for the differential diagnosis between pitressin-sensitive and pitressin-resistant DI.
0022-3476/81/020244+03500.30/0 9 1981 The C. V. Mosby Co.
Volume 98 Number 2
Brief clinical and laboratory observations
24 5
Table
Patient 1
2
3
4 5 6
7
Idiopathic diabetes insipidus Idiopathic diabetes insipidus Idiopathic diabetes insipidus Craniopharyngioma Hypothalamic hypopituitarism Nephrogenic diabetes insipidus Nephrogenic diabetes insipidus
Values after vasopressin
Values after water deprivation
U,
S~
U~ S~
Urine SG
U~
S~.
U~ $2
Urine SG
U~
S~
Ua S~
Vasopressin U r i n e preparation SG used
95
293
0.32
1.002
219
308
0.69
1.005
552
300
1.84
1.019 DDAVP
105
298
0.35
1.004
160
304
0.53
1.006
590
301
1.96
104
284
0.36
1.002
87
293
0.30
1.000
688
289
2.38
1.017 DDAVP
40 80
294 293
0.14 0.3
1.004 1.002
152 232
308 306
0.49 0.75
1.002 1.005
552 548
300 304
1.84 1.8
1.020 DDAVP 1.017 DDAVP
68
297
0.23
1.005
107
329
0.33
*
68 110
330 320
0.21 0.34
60
275
0.22
1.002
103
284
0.36
1.005
124
284
0.44
1.004 DDAVP 1.007 pitressinin-oil 1.006 DDAVP
Initial values
*
DDAVP
SG ~ Specificgravity. *Not obtained. Urine and serum osmolarity (U,. U~, U~, S~, S:, S~) expressed as mOsm/L and urine specific gravity at various times during the test as described in the text. METHODS
AND MATERIALS
Seven previously untreated patients with polyuria and polydipsia were studied. Patients ranged in age from 4 to 20 years. A seven-hour water deprivation test was initiated according to the protocol o f Frasier et a12 The protocol was modified to include bedside recording of urine volume and specific gra~,ity hourly (when cooperation of subject could be obtained) during the test and for four hours afterward. Osmolarity of the urine ( U 0 and of the serum (SO were measured at the beginning of the test and after completion of the seven-hour deprivation period (U~, S~). DDAVP, 10 to 20 /tg, was then administered intranasally with the calibrated Rhinyle distributed by the manufacturer. The patients were then monitored for up to another four hours, and serum (Ss) and urine (U~) osmolarity determined. If the urine SG obtained in the hourly monitoring rose to 1.014 or greater, the test was terminated early and $3 and U3 samples obtained at that time. During the period following vasopressin administration, oral fluids were permitted hourly at volumes equal to the urine output of the previous hour. After the U3 and S~ samples were obtained, oral .fluids were permitted in larger quantities, but close monitoring was continued over the next 12 hours in order to prevent water intoxication.
The ratios U1 U2 U3 S, ' S~ ' $3 ' were calculated. A ratio U2 --< $2
!.5
was considered indicative of abnormal urinary concentrating ability, whereas that ~ i.5 indicated normal renal function. A positive response to D D A V P was defined by criteria similar to those used ~ to define normal function after water deprivation: a ratio U3 --> S~
1.5,
a final urine osmolarity of >_--450 mOsm, or an increase in the urine to serum osmolarity ratio of 1.0 or more. An increase in urine SG to 1.014 or greater less than four hours after vasopressin administration was used as an indication of a probable response to D D A V P so that Us and $3 could be obtained sooner. RESULTS The Table shows the data obtained in the seven patients studied. The ratio U1/S~ was less than 0.5 in all patients.
24 6
Brief clinical and laboratory observations
Following seven hours of water deprivation, all patients failed to increase the U~/S~ ratio to greater than 1.0, thereby meeting the criteria for DI. In Patients 1 to 5 vasopressin responsiveness was clinically evident within two hours after administration of DDAVP, as marked antidiuresis ensued. By four hours all had
U3 5:2
-->
1.5.
Subsequently, these five patients have continued to respond to DDAVP, continued administration of which has been necessary to prevent polyuria. Patient 6, a male, failed to respond to DDAVP within four hours; he was subsequently given pitressin tannatein-oil, to which he also failed to respond. Subsequent renal evaluation showed no evidence of impairment of other renal functions and he is considered to have nephrogenic DI. Patient 7, also a male, was referred with the diagnosis of nephrogenic DI because his polyuria had failed to respond to intramuscular administration of pitressin preparations on numerous previous occasions. He did not demonstrate renal concentrating ability after seven hours of water deprivation and also did not respond to administration of DDAVP. Intravenous urography showed distention of the urinary collecting system without signs of obstruction, findings commonly reported in nephrogenic D I ? '~ DISCUSSION The diagnosis of DI can be made effectively in children with a seven-hour water deprivation test, without resorting to more complicated and potentially hazardous protocols. The distinction between vasopressin-sensitive and vasopressin-resistant forms of DI necessitates assessment of a positive response to administered vasopressin. Our data suggest that the administration of intranasal DDAVP at the end of the seven-hour water deprivation test is a simple and effective way to demonstrate vasopressin sensitivity. Since its introduction, D D A V P has been shown to be a potent and effective antidiuretic agent which is considered the therapeutic agent of choice for central diabetes insipidus. 7'~ Additionally, its usefulness in evaluating renal concentrating ability in both children and adults has been established. T M A dose of 20 ~g in children and 10 #g in infants has been demonstrated to result in maximum urine osmolarities similar to those resulting from 22 hours of water deprivation or from the administration of pitressin tannate. This study indicates that initial responsiveness to D D A V P may be assessed within four hours after its administration. Although maximum concentrating ability is not achieved in this short a
The Journal of Pediatrics February 198 !
period, criteria which otherwise characterize pitressin sensitivity can be applied to the use of this preparation in this test. We used the criteria established by Frasier et al 3 to define normal concentrating ability after water deprivation. Five of our seven patients met one or more of these criteria within four hours of D D A V P administration and have all subsequently continued to require DDAVP to control their polyuria. The two patients who did not meet the criteria were subsequently treated with other vasopressin preparations and failed to respond. Although the n u m b e r of patients reported in this study is small, we have subsequently treated 12 more patients with known neurogenic DI with DDAVP. At a time when their previous pitressin preparation was discontinued, the administration of a single dose of D D A V P always produced a significant antidiuretic response with four hours. The seven-hour water deprivation test and measurement of the U~/S~ osmolarity ratio followed by administration of D D A V P and additional measurements of U3/$3 osmolarity ratios within four hours seem to provide a systematic and effective approach to the diagnosis of polyuria and polydipsia in children. REFERENCES I. Carter AC, and Robbins J: The use of hypertonic saline infusion in the differential diagnosis of diabetes insipidus and psychogenic polydipsia, J Clin Endocrinol 7:753, 1947. 2. Dashe AM, Cramm RE, Crist CA, Habener JF, and Solomon DH: A water deprivation test for the differential diagnosis of polyuria, JAMA 185:699, 1963. 3. Frasier SD, Kutnik LA, Schmidt RT, and Smith FG Jr: A water deprivation test for the diagnosis of diabetes insipidus in children, Am J Dis Child 114:157, 1967. 4. Price JDE, and Lauener RN: Serum and urine osmolalities in the differential diagnosis of polyuric states, J Clin Endocrinol 26:143, 1966. 5. ten Bensel RW, and Peters ER: Progressive hydronephrosis, hydroureter and dilatation of the bladder in siblings with congenital nephrogenic diabetes insipidus, J P~DIAa'R 77:439, 1970. 6. Carter RD, and Goodman AD: Nephrogenic diabetes insipidus accompanied by massive dilatation of the kidneys, ureters, and bladder, J Urol 89:366, 1963. 7. Lee WNP, Lippe BM, LaFi'anchi SH, and Kaplan SA: Vasopressin analog DDAVP in the treatment of diabetes insipidus, Am J Dis Child 130:166, 1976. 8. Becker DJ, and Foley TP Jr: l-Desamino-8-D-arginine vasopressin in the treatment of central diabetes insipidus in childhood, J PEDIAXR92:1011, 1978. 9. Delin K, Aurell M, and Ewald J: Urinary concentration test with Desmopressin, Br Med J 951:757, 1978. t0. Somerfield SD, and Hocken AG: Desamino arginine vasopressin (DDAVP) as a diagnostic agent, NZ Med J 86:472, 1977. 11. Aronson AS, and Svenningsen NW: DDAVP test for estimation of renal concentrating capacity in infants and children, Arch Dis Child 49:654, 1974.