- Email: [email protected]
Syndrome of inappropriate secretion of antidiuretic hormone produced by vincristine toxicity (with bioassay of ADH level)
90
Brie[ clinical and laboratory observations
old incubator. Using a Zeiss monochromator, M U Q 11 with a P M Q 11 Detector, we measured the energy transmission of 10 nm. inter-
The Journal o[ Pediatrics July 1972
ing, the Plexiglas not only maintains its transmission of visible light, but also lessens the transmission of ultraviolet radiation.
vals. A sharp cut-off around 360 nm. was noted for the new Plexiglas G, whereas with the aged section there was a 90 nm. shift toward the lower spectrum, thus decreasing ultraviolet transmission (Fig. 1). Total transmittance of the visible spectra was approximately 90 per cent for each test material; aging thus does not reduce the transmitting properties of Plexiglas. SUMMARY
Plexiglas G, the ultraviolet absorbing plastic used in commercial incubators, does not alter the transmission of the visible spectra and does not affect phototherapy. With ag-
Syndrome of inappropriate secretion of antidiuretic hormone produced by vincristine toxicity (with bioassay of ADH level) R. M. Suskind, M.D;, S. W. Brusilow, M.D., ~" Baltimore, Md., and J. Zehr, Ph.D., Seattle, Wash. T H E A S S O C I A T I O 51 of ,hyponatremia with vincristine therapy was first reported by Fine and associates 1 and by Slater and associates 2 and later by C u t t i n g ? All of these authors felt that the syndrome resulted from
From the Department oi Pediatrics o[ the Johns Hopkins University School of Medicine. Reprint address: S. W. Brusilow, M.D., The Johns Hopkins Hospital, Baltimore, Md. 21205. "~Aided by Research Grant 5 ROI A M 12934-02 from the National Institutes o/ Health. Dr. Brusitow occupies the Eudowood Chair in Pulmona~-y Disease.
REFERENCES
1. Transmittance and Exposure Stability of Colorless Plexiglas Cast Sheet. Bulletin: PL-53f. Rohm and Haas, Philadelphia, Pa., May, 1965, pp. 1-7. 2. Sisson, T. R. C., Kendall, N., Davies, R., and Berger, D.: The photobiological effects of hyperbilirubinemia, Seventy-ninth Annual Meeting, the American Pediatric Society, Atlantic City, April 30-May 2, 1969. 3. Cremer, R. J., Perryman, P. W., and Richards, D. H.: Influence of light on the hyperbilirubinemia of infants, Lancet 1: 1094, 1958. 4. Sisson, T. R. C., Kendall, N., Davies, R. E., and Berger, D.: Factors influencing the effectiveness of phototherapy in neonatal hyperbilirubinemia. Bilirubin metabolism in the newborn, Birth Defects: Original Article Series 6 (2): 100, 1970.
the inappropriate secretion of antidiuretic h o r m o n e ( A D H ) . A 3-year-old Negro girl is described here, who inadvertently received ten times the recommended dose of vincristine, and five days later developed a clinical state characterized by hypoosmolality. Her extracellular fluid volume was not contracted, and her urine was not maximally dilute. At this time the concentration of A D H in her blood was more than four times the normal value. CASE REPORT
Patient B. H. (Johns Hopkins Hospital No. 131 86 56) was a 3 89 Negro girl, who two months previously had undergone a left nephrectomy for removal of a Wilms' tumor. She had received Daunomycin for five days, as well as radiation therapy to the operated area. There was no clinical evidence of metastasis, although histopathology revealed that the tumor had invaded the renal capsule. Two days prior to admission , the patient inadvertently was given 0.5 mg. per kilogram (10 times the recommended dose) of vincristine intravenously. She returned to the clinic with anorexia, vomiting, diarrhea, and lethargy.
Volume 81 Number 1
At the time of admission, the patient appeared to be chronically ill, lethargic, and somewhat dehydrated but in no acute distress. Vital signs were unremarkable. The weight was 12.3 Kg. Positive physical findings included loss of hair, nuchat rigidity, ulcerations of the buccal mucosa and pharynx, a diffusely tender abdomen without rebound tenderness or rigidity, and moderate weakness with decreased deep tendon reflexes. Laboratory studies. The white blood count was 3,500 per cubic millimeter, platelets 77,000 per cubic millimeter, hematocrit 30, and serum sodium and chloride concentrations 141 and 102 mEq. per liter, respectively. The urine specific gravity was 1.027 and urine ketones, 2+. The chest radiograph was normal. Blood, cerebrospinal fluid, and urine cultures were negative. Hospital course. Initially, the patient was thought to be mildly salt depleted and was treated over an 8 hour period with 650 ml. of water (as 5 per cent glucose), 40 mEq. of sodium, and 8 mEq. of potassium. By the third hospital day, the patient had gained 1.1 Kg. and had a temperature of 38.4 ~ C. Physical examination revealed no evidence of contracted extracellular volume; the skin turgor was normal, tile eyes were not sunken, and the mucous membranes were moist. Cultures of the stool, throat, and blood were negative. The serum sodium concentration was 120 mEq. per liter, serum urea nitrogen concentration 7 rag. per 100 ml., and the urine specific gravity 1.014. An attempt to correct the hyponatremia was made by giving 400 ml. of isotonic saline. On the fourth hospital day, the blood pressure was 160/120. Another infusion of isotonic saline was given but the serum sodium concentration fell from 123 mEq. per liter to 118 mEq. per liter over an 8 hour period. Serum urea nitrogen concentration remained 7 mg. per 100 ml. The specific gravity of the urine on several occasions was never below 1.010. She was given 10 per cent mannitol intravenously, following which she voided 250 ml. of urine with a specific gravity of 1.015. Shortly thereafter she had a grand real seizure which was treated with diazepam. Blood pressure was 150/130. Again there was no clinical evidence of a contracted extracellular volume. Later that day the serum and urine osmolalities were 240 and 400 mOsm., respectively, and the serum ADH level~ (patient recumbent) was 4.1 /~U per milliliter (normal adult values 0.4 + 0.6). On tile fifth hospital day her fluid intake was
Brie[ clinical and laboratory observations
91
restricted. The serum sodium concentration slowly rose to 138 mEq. per liter on the sixteenth hospital day. DISCUSSION T h e p a t i e n t described above h a d the k n o w n side effects of vincristine toxicity, including epilation, loss of deep tendon reflexes, a b d o m i n a l pain, neuritic pain, leukopenia, muscle wasting, weight loss, fever, oral ulceration, vomiting, diarrhea, b l a d d e r atonia, a n d depression. She also experienced a less well-known side effect of vincristine toxi c i t y - - t h e syndrome of i n a p p r o p r i a t e secretion of A D H . I n 1966, F i n e a n d associates ~ described the first case of h y p o n a t r e m i a associated with vincristine therapy. A n l 1-month-old child with r h a b d o m y o s a r c o m a of t h e spermatic cord, who received 3 weekly doses of 0.5 mg. of vincristine followed by 8 weekly doses of 0.075 rag. p e r kilogram, developed h y p o n a t r e m i a with a h y p e r t o n i c urine and without evidence of r e n a l t u b u l a r damage. T h e p a tient h a d a seizure a n d b e c a m e comatose at the onset of the h y p o n a t r e m i a . T h e syndrome a b a t e d with fluid restriction. Slater a n d associates ~ described a 7-year-old Caucasian boy with acute l y m p h a t i c leukemia, w h o was t r e a t e d with 1.8 mg. of vincristine twice in a 9 day period. F o u r days after the second dose, the p a t i e n t developed a seizure a n d became comatose. T h e serum sodium concentration was 125 mEq. p e r liter. A n a d u l t case was recently r e p o r t e d by C u t t i n g ? T h e s e patients a n d ours fulfill the criteria for diagnosis of the syndrome of i n a p p r o p r i ate secretion of A D H : hypoosmolality of extracellular fluid, clinically n o r m a l extracellular volume, a n d absence of a m a x i m a l l y dilute urine. I n o u r patient, the d e m o n s t r a t i o n of an elevated blood A D H concentration confirmed the clinical impression. T h e p a t h o physiology of vincristine-induced i n a p p r o p r i ate secretion of A D H is p r o b a b l y similar to t h a t p r o d u c e d by o t h e r central nervous system diseases, since the three r e p o r t e d cases all h a d o t h e r manifestations of central nervous system disease. However, a specific ef-
9 2
Brie.[ clinical and laboratory observations
fect of vincristine on A D H release cannot be completely excluded. I t is also possible t h a t vincristine itself has an A D H - l i k e activity, a l t h o u g h the f r a c t i o n a t i o n p r o c e d u r e employed p r i o r to bioassay of the serum should have removed vincristine.
REFERENCES
The Journal o[ Pediatrics July 1972
2. Slater, L. M., Wainer, R. A., and Serpick, A. A.: Vincristine neurotoxicity with hyponatre. mia, Cancer 23" 122, 1971. 3. Cutting, H. O.: Inappropriate secretion of antidiuretic hormone secondary to vincristine therapy, Am. J. Med. 51: 269, 1971. 4. Segar, W. E., and Moore, W. W.: The regulation of antidiuretic hormone release in man, J. Clin. Invest. 47: 2143, 1968.
1. Fine, R. N., Clarke, R. R., and Shore, N. A.: Hyponatremia and vincristine therapy, Am. J. Dis. Child. 112: 256, 1966.
A partial defect in antidiuretic hormone secretion--cb lorpropa m ide rgy_Don.fg
John I. Malone, M.D., H. L a w r e n c e Vallet, M . D . , a n d A l f r e d M . Bongiovanni, M.D., Philadelphia, Pa.
c h l o r p r o p a m i d e on the isolated u r i n a r y bladd e r of the toad, suggest t h a t some A D H m u s t be present for c h l o r p r o p a m i d e to affect w a t e r transport. A l t h o u g h a direct m e t h o d of measuring A D H is n o t presently available, M i l l e r and associates 7 have defined a n indirect m e t h o d of differentiating a p a r t i a l from a complete deficiency of A D H . This test was employed to evaluate a p a t i e n t with diabetes insipidus before starting t h e r a p y w i t h chlorpropamide. T h e atypical response to the w a t e r deprivation test, a n d the effect of c h l o r p r o p a m i d e in this p a t i e n t are reported.
CASE REPORT T H E ~. F F I C A C Y of c h l o r p r o p a m i d e in the t r e a t m e n t of vasopressin-sensitive diabetes insipidus has been well demonstrated. 1-a T h e m e c h a n i s m of action i s presently unknown. M o s t evidence suggests t h a t c h l o r p r o p a m i d e acts either by e n h a n c i n g p i t u i t a r y release of antidiuretic h o r m o n e ( A D H ) 4 or by enh a n c i n g renal sensitivity to A D H ? Ingelfinger a n d Hays, 6 studying the effect of From the Department o[ Pediatrics, University o[ Pennsylvania School o[ Medicine,,and The Children's Hospital of Philadelphia. Supported by a Research Grant [rom the United States Public Health Service, HD-O0371, Training Grant AM-05197, and HD-215, and support [or the General Clinical Research Center o[ the Children's Hospital o[ Philadelphia FR-O0240. Reprint address: Al[red M. Bongiovannl, M.D., Children's Hospital o[ Philadelphia, 1740 Balnbridge St., Philadelphia, Pa. 19146.
Patient D. B. was a 13-year-old girl in whom the diagnosis of diabetes insipidus was first considered when she developed polyuria and polydipsia at 6 years of age. The initial values for serum and urine osmolallty were 275 and 511 mOsm. per kilogram, respectively. After 10 hours of water deprivation her urine osmolality rose to 640 mOsm. per kilogram. She was discharged with the diagnosis of psychogenic polydipsia. At the age of 12 years she was evaluated again according to the protocol of Frasier and associates, s The initial ratio of urine to serum osmolality was 0.15 (49 mOsm.:325 mOsm.), and after 8 hours of water deprivation the ratio was 0.25 (80 mOsm.:320 mOsm.). Since both ratios were less than 1.0, they fulfilled the criteria of Frasier and associates, and tile diagnosis of diabetes insipidus was made. The patient then responded to 5 units of aqueous vasopressin with a rise in urine osmolality from
Brie[ clinical and laboratory observations
old incubator. Using a Zeiss monochromator, M U Q 11 with a P M Q 11 Detector, we measured the energy transmission of 10 nm. inter-
The Journal o[ Pediatrics July 1972
ing, the Plexiglas not only maintains its transmission of visible light, but also lessens the transmission of ultraviolet radiation.
vals. A sharp cut-off around 360 nm. was noted for the new Plexiglas G, whereas with the aged section there was a 90 nm. shift toward the lower spectrum, thus decreasing ultraviolet transmission (Fig. 1). Total transmittance of the visible spectra was approximately 90 per cent for each test material; aging thus does not reduce the transmitting properties of Plexiglas. SUMMARY
Plexiglas G, the ultraviolet absorbing plastic used in commercial incubators, does not alter the transmission of the visible spectra and does not affect phototherapy. With ag-
Syndrome of inappropriate secretion of antidiuretic hormone produced by vincristine toxicity (with bioassay of ADH level) R. M. Suskind, M.D;, S. W. Brusilow, M.D., ~" Baltimore, Md., and J. Zehr, Ph.D., Seattle, Wash. T H E A S S O C I A T I O 51 of ,hyponatremia with vincristine therapy was first reported by Fine and associates 1 and by Slater and associates 2 and later by C u t t i n g ? All of these authors felt that the syndrome resulted from
From the Department oi Pediatrics o[ the Johns Hopkins University School of Medicine. Reprint address: S. W. Brusilow, M.D., The Johns Hopkins Hospital, Baltimore, Md. 21205. "~Aided by Research Grant 5 ROI A M 12934-02 from the National Institutes o/ Health. Dr. Brusitow occupies the Eudowood Chair in Pulmona~-y Disease.
REFERENCES
1. Transmittance and Exposure Stability of Colorless Plexiglas Cast Sheet. Bulletin: PL-53f. Rohm and Haas, Philadelphia, Pa., May, 1965, pp. 1-7. 2. Sisson, T. R. C., Kendall, N., Davies, R., and Berger, D.: The photobiological effects of hyperbilirubinemia, Seventy-ninth Annual Meeting, the American Pediatric Society, Atlantic City, April 30-May 2, 1969. 3. Cremer, R. J., Perryman, P. W., and Richards, D. H.: Influence of light on the hyperbilirubinemia of infants, Lancet 1: 1094, 1958. 4. Sisson, T. R. C., Kendall, N., Davies, R. E., and Berger, D.: Factors influencing the effectiveness of phototherapy in neonatal hyperbilirubinemia. Bilirubin metabolism in the newborn, Birth Defects: Original Article Series 6 (2): 100, 1970.
the inappropriate secretion of antidiuretic h o r m o n e ( A D H ) . A 3-year-old Negro girl is described here, who inadvertently received ten times the recommended dose of vincristine, and five days later developed a clinical state characterized by hypoosmolality. Her extracellular fluid volume was not contracted, and her urine was not maximally dilute. At this time the concentration of A D H in her blood was more than four times the normal value. CASE REPORT
Patient B. H. (Johns Hopkins Hospital No. 131 86 56) was a 3 89 Negro girl, who two months previously had undergone a left nephrectomy for removal of a Wilms' tumor. She had received Daunomycin for five days, as well as radiation therapy to the operated area. There was no clinical evidence of metastasis, although histopathology revealed that the tumor had invaded the renal capsule. Two days prior to admission , the patient inadvertently was given 0.5 mg. per kilogram (10 times the recommended dose) of vincristine intravenously. She returned to the clinic with anorexia, vomiting, diarrhea, and lethargy.
Volume 81 Number 1
At the time of admission, the patient appeared to be chronically ill, lethargic, and somewhat dehydrated but in no acute distress. Vital signs were unremarkable. The weight was 12.3 Kg. Positive physical findings included loss of hair, nuchat rigidity, ulcerations of the buccal mucosa and pharynx, a diffusely tender abdomen without rebound tenderness or rigidity, and moderate weakness with decreased deep tendon reflexes. Laboratory studies. The white blood count was 3,500 per cubic millimeter, platelets 77,000 per cubic millimeter, hematocrit 30, and serum sodium and chloride concentrations 141 and 102 mEq. per liter, respectively. The urine specific gravity was 1.027 and urine ketones, 2+. The chest radiograph was normal. Blood, cerebrospinal fluid, and urine cultures were negative. Hospital course. Initially, the patient was thought to be mildly salt depleted and was treated over an 8 hour period with 650 ml. of water (as 5 per cent glucose), 40 mEq. of sodium, and 8 mEq. of potassium. By the third hospital day, the patient had gained 1.1 Kg. and had a temperature of 38.4 ~ C. Physical examination revealed no evidence of contracted extracellular volume; the skin turgor was normal, tile eyes were not sunken, and the mucous membranes were moist. Cultures of the stool, throat, and blood were negative. The serum sodium concentration was 120 mEq. per liter, serum urea nitrogen concentration 7 rag. per 100 ml., and the urine specific gravity 1.014. An attempt to correct the hyponatremia was made by giving 400 ml. of isotonic saline. On the fourth hospital day, the blood pressure was 160/120. Another infusion of isotonic saline was given but the serum sodium concentration fell from 123 mEq. per liter to 118 mEq. per liter over an 8 hour period. Serum urea nitrogen concentration remained 7 mg. per 100 ml. The specific gravity of the urine on several occasions was never below 1.010. She was given 10 per cent mannitol intravenously, following which she voided 250 ml. of urine with a specific gravity of 1.015. Shortly thereafter she had a grand real seizure which was treated with diazepam. Blood pressure was 150/130. Again there was no clinical evidence of a contracted extracellular volume. Later that day the serum and urine osmolalities were 240 and 400 mOsm., respectively, and the serum ADH level~ (patient recumbent) was 4.1 /~U per milliliter (normal adult values 0.4 + 0.6). On tile fifth hospital day her fluid intake was
Brie[ clinical and laboratory observations
91
restricted. The serum sodium concentration slowly rose to 138 mEq. per liter on the sixteenth hospital day. DISCUSSION T h e p a t i e n t described above h a d the k n o w n side effects of vincristine toxicity, including epilation, loss of deep tendon reflexes, a b d o m i n a l pain, neuritic pain, leukopenia, muscle wasting, weight loss, fever, oral ulceration, vomiting, diarrhea, b l a d d e r atonia, a n d depression. She also experienced a less well-known side effect of vincristine toxi c i t y - - t h e syndrome of i n a p p r o p r i a t e secretion of A D H . I n 1966, F i n e a n d associates ~ described the first case of h y p o n a t r e m i a associated with vincristine therapy. A n l 1-month-old child with r h a b d o m y o s a r c o m a of t h e spermatic cord, who received 3 weekly doses of 0.5 mg. of vincristine followed by 8 weekly doses of 0.075 rag. p e r kilogram, developed h y p o n a t r e m i a with a h y p e r t o n i c urine and without evidence of r e n a l t u b u l a r damage. T h e p a tient h a d a seizure a n d b e c a m e comatose at the onset of the h y p o n a t r e m i a . T h e syndrome a b a t e d with fluid restriction. Slater a n d associates ~ described a 7-year-old Caucasian boy with acute l y m p h a t i c leukemia, w h o was t r e a t e d with 1.8 mg. of vincristine twice in a 9 day period. F o u r days after the second dose, the p a t i e n t developed a seizure a n d became comatose. T h e serum sodium concentration was 125 mEq. p e r liter. A n a d u l t case was recently r e p o r t e d by C u t t i n g ? T h e s e patients a n d ours fulfill the criteria for diagnosis of the syndrome of i n a p p r o p r i ate secretion of A D H : hypoosmolality of extracellular fluid, clinically n o r m a l extracellular volume, a n d absence of a m a x i m a l l y dilute urine. I n o u r patient, the d e m o n s t r a t i o n of an elevated blood A D H concentration confirmed the clinical impression. T h e p a t h o physiology of vincristine-induced i n a p p r o p r i ate secretion of A D H is p r o b a b l y similar to t h a t p r o d u c e d by o t h e r central nervous system diseases, since the three r e p o r t e d cases all h a d o t h e r manifestations of central nervous system disease. However, a specific ef-
9 2
Brie.[ clinical and laboratory observations
fect of vincristine on A D H release cannot be completely excluded. I t is also possible t h a t vincristine itself has an A D H - l i k e activity, a l t h o u g h the f r a c t i o n a t i o n p r o c e d u r e employed p r i o r to bioassay of the serum should have removed vincristine.
REFERENCES
The Journal o[ Pediatrics July 1972
2. Slater, L. M., Wainer, R. A., and Serpick, A. A.: Vincristine neurotoxicity with hyponatre. mia, Cancer 23" 122, 1971. 3. Cutting, H. O.: Inappropriate secretion of antidiuretic hormone secondary to vincristine therapy, Am. J. Med. 51: 269, 1971. 4. Segar, W. E., and Moore, W. W.: The regulation of antidiuretic hormone release in man, J. Clin. Invest. 47: 2143, 1968.
1. Fine, R. N., Clarke, R. R., and Shore, N. A.: Hyponatremia and vincristine therapy, Am. J. Dis. Child. 112: 256, 1966.
A partial defect in antidiuretic hormone secretion--cb lorpropa m ide rgy_Don.fg
John I. Malone, M.D., H. L a w r e n c e Vallet, M . D . , a n d A l f r e d M . Bongiovanni, M.D., Philadelphia, Pa.
c h l o r p r o p a m i d e on the isolated u r i n a r y bladd e r of the toad, suggest t h a t some A D H m u s t be present for c h l o r p r o p a m i d e to affect w a t e r transport. A l t h o u g h a direct m e t h o d of measuring A D H is n o t presently available, M i l l e r and associates 7 have defined a n indirect m e t h o d of differentiating a p a r t i a l from a complete deficiency of A D H . This test was employed to evaluate a p a t i e n t with diabetes insipidus before starting t h e r a p y w i t h chlorpropamide. T h e atypical response to the w a t e r deprivation test, a n d the effect of c h l o r p r o p a m i d e in this p a t i e n t are reported.
CASE REPORT T H E ~. F F I C A C Y of c h l o r p r o p a m i d e in the t r e a t m e n t of vasopressin-sensitive diabetes insipidus has been well demonstrated. 1-a T h e m e c h a n i s m of action i s presently unknown. M o s t evidence suggests t h a t c h l o r p r o p a m i d e acts either by e n h a n c i n g p i t u i t a r y release of antidiuretic h o r m o n e ( A D H ) 4 or by enh a n c i n g renal sensitivity to A D H ? Ingelfinger a n d Hays, 6 studying the effect of From the Department o[ Pediatrics, University o[ Pennsylvania School o[ Medicine,,and The Children's Hospital of Philadelphia. Supported by a Research Grant [rom the United States Public Health Service, HD-O0371, Training Grant AM-05197, and HD-215, and support [or the General Clinical Research Center o[ the Children's Hospital o[ Philadelphia FR-O0240. Reprint address: Al[red M. Bongiovannl, M.D., Children's Hospital o[ Philadelphia, 1740 Balnbridge St., Philadelphia, Pa. 19146.
Patient D. B. was a 13-year-old girl in whom the diagnosis of diabetes insipidus was first considered when she developed polyuria and polydipsia at 6 years of age. The initial values for serum and urine osmolallty were 275 and 511 mOsm. per kilogram, respectively. After 10 hours of water deprivation her urine osmolality rose to 640 mOsm. per kilogram. She was discharged with the diagnosis of psychogenic polydipsia. At the age of 12 years she was evaluated again according to the protocol of Frasier and associates, s The initial ratio of urine to serum osmolality was 0.15 (49 mOsm.:325 mOsm.), and after 8 hours of water deprivation the ratio was 0.25 (80 mOsm.:320 mOsm.). Since both ratios were less than 1.0, they fulfilled the criteria of Frasier and associates, and tile diagnosis of diabetes insipidus was made. The patient then responded to 5 units of aqueous vasopressin with a rise in urine osmolality from