The syndrome of inappropriate antidiuretic hormone secretion as a cause of hyponatremia in cystic fibrosis

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April 1977 The Journal o f P E D I A T R I C S

The syndrome of inappropriate antidiuretic hormone secretion as a cause of hyponatremia in cystic fibrosis The syndrome of inappropriate secretion of antidiuretic hormone was observed in two patients with cystic fibrosis during acute exacerbation o f chronic pulmonary disease. It was diagnosed by the accepted clinical and laboratory criteria and confirmed in one case by values for immunoreactive vasopressin that were inappropriately high for plasma osmolality. The severe hyponatremia was corrected by fluid restriction, alone or combined with intravenous treatment with a diuretic and hypertonic saline solution. In addition, there was simultaneous therapy of the pulmonary disease. S I A D H thus must be added to salt loss as a cause of hyponatremia in CF, and may be more common than realized in patients with CF and severe pulmonary disease.

Lawrence F. Cohen, M.D., Paul A. di Sant'Agnese, M.D., Dr. Med. Sc.,* Addison Taylor, M.D., Ph.D., and John R. Gill, Jr., M.D., Bethesda, Md.

HYPONATREMIA AND VASCULAR COLLAPSE from excessive loss of sweat electrolytes as a complication of cystic fibrosis has been recognized for over 20 years.' We now report two patients with CF who developed severe hyponatremia and fluid retention as a result of the syndrome of inappropriate secretion of antidiuretic hormone during an acute exacerbation of their chronic pulmonary disease. The diagnosis of SIADH ~-~ requires hyponatremia and hypo-osmolality of body fluids (serum) with simultaneous inappropriate osmolality of urine, which contains appreciable amounts of sodium, in a patient who shows no signs of hypovolemia. Improvement of the renal loss of sodium and hyponatremia by fluid restriction corroborates the clinical impression. After recovery, adrenal and renal functions should be shown to be normal. The recently developed radioimmunoassay for A D H .... is a useful tool in confirming the diagnosis, if available.

From the Pediatric Metabolism Branch, National Institute o f Arthritis, Metabolism and Digestive Diseases, and Hypertension Endocrinology Branch, National Heart and Lung Institute, National Institutes of Health. *Reprint address: National Institutes of Health, Building 10, Room 8N250, Bethesda, MD 20014. Vol. 90, No. 4, pp. 574-578

The SIADH was first described in 1957 in association with bronchogenic carcinoma. ~ In recent years both acute and chronic SIADH have been shown to occur as a complication of a variety of disorders, not only in adults but in children, 7 including acute and chronic pneumonias, meningitis, pulmonary tuberculosis, hypothyroidism, and treatment with various drugs? In most instances, the pathophysiology of SIADH is elusive.

Abbreviations used ADH: antidiuretic hormone, vasopressin cystic fibrosis CF: National Institutes of Health NIH: SIADH: syndrome of inappropriate secretion of ADH BUN: blood urea nitrogen SCOT: serum glutamic oxalacetic transaminase serum glutamic pyruvic transaminase SGPT: partial pressure of oxygen Poz: partial pressure of carbon dioxide PCO,:

CASE REPORTS Case 1. A 28-year-old white man with known CF (chronic lung disease, pancreatic insufficiency, sweat chloride 125, and sodium 115 mEq/l, respectively) and an N1H Clinical Score of 48 *~ was

*With this system, maximal score = 100; a score ~ 50 = very severe.

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S I A D H as cause o f hyponatremia in C F

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Table I. Course o f two patients with cystic fibrosis

Case I

Case 2

Day of hospitalization

Day of hospitalization 23

1

2

3

4

5

6

21

Plasma ADH levels* (pg/ml) Serum Na (mEq/l)

5 AM [ 8 PM

24

3.5 128

114

Serum osmolalityt (mOsm/kg) Urine osmolality (mOsm/kg)

406

Urine Na excretion (mEq/24 hr) Body weight (kg)

22

46.6

Treatment Intravenous hypertonic saline Intravenous furosemide Fluid restriction

45.6

116

120 126

130

133

126

115 117

241

263

272

274

257

240

329

210

533

420

337

195

88

186

292

127

46.6

45.0

43.6

43.9

None None

38.2

36.4

25

26

1.5 115

330

34.8

130

133

134

137

287

279

270

284

826

667

279 68

167

71

123

33.9

35.4

36.0

36.3

§247 §162 11

*Plasma ADH levels should be appropriate to plasma osmolatityand interpreted according to the nomogram of Robertson'" (see text). tNormal serum osmolality: 285-295 mOsm. Each arrow represents a dose of furosemide or an infusion of hypertonicsaline. admitted to the NIH Clinical Center on January 2, 1975, because of a relapse in pulmonary disease. Weight was 46.6 kg; height, 168 cm. Serum Na concentration was 128, K 4.7, C1 83, and COs content 32 mEq/1, BUN 7 mg/dl; results of tests for fasting glucose, creatinine, SGPT, SGOT, total protein, and albumin were normal. Arterial blood gas values in room air were Po~ 47 and Pco~ 36 mm Hg and pH 7.47. Treatment was started with intravenous sodium carbenicillin (Na = 64 mEq/24 hours) and gentamicin, and postural drainage. To reduce the viscosity of pulmonary secretions, facilitate their evacuation, and replace respiratory losses, he was given intravenous fluids equivalent to 2.5 1/m ~ on Day 1. Oral intake of fluid and dietary sodium was not restricted. The following morning, he complained of nausea and vomiting. The serum Na concentration had decreased to 114 mEq/1; the simultaneously determined osmolality of urine was 406 mOsm/kg (Table I). BUN was 5 mg/dl; the concentration of plasma cortisol was 17 ~g/dl. There was no evidence of congestive heart failure. On the third day after admission, on the basis of serum sodium values and serum and urine osmolalities (Table I), SIADH was diagnosed and fluids were restricted to 600 ml/24 hours. On this regimen, serum sodium and osmolality increased and body weight and urine osmolality gradually decreased. Nine days after admission, intravenous antibiotics were replaced by orai tetracycline and cloxacillin, and fluid restriction was discontinued. Body weight and serum Na concentration remained stable thereafter. After recovery, adrenal function was normal; excretion of 17hydroxy-corticosteroids increased from 4.5 mg/24 hours in the control period to 39.0 mg/24 hours on the third day of Cortrosyn

stimulation (025 mg/day). The response to a restricted sodium intake of plasma renin activity, plasma aldosterone, and sodium excretion were within normal limits) ~ Water load test after recovery was normaW TM with 97% of the water challenge excreted within 2 hours (normal > 70%), decreased urine osmolality and maintenance of normal serum sodium levels and osmolality. Plasma ADH level by radioimmunoassay was < 0.5 pg/ml appropriate to the serum osmolalities of 295 and 288 mOsm/kg 1 hour before and 2 hours following the water load." ~5 Case 2. A 23-year-old white woman with CF (chronic pulmonary disease, pancreatic insufficiency; sweat C1 124 and Na 126 mEq/1, respectively) and NIH Clinical Score of 34 was admitted to the NIH on March 14, 1975, with evidence of respiratory distress. Weight was 38.1 kg and height 155 cm. Serum Na concentration was 136; K, 4.2; C1, 89; and COs content, 36 mEq/1; BUN was 11 mg/dl; results of tests for fasting glucose, creatinine, alkaline phosphatase, SGPT, SGOT, total protein, and albumin were normal. Creatinine clearance was 71 ml/minute/ 1.73 m~..Arterial blood gases in room air showed Po2 45, Pco~ 59 mm Hg, and pH 7.41. Therapy was begun with intravenous gentamicin and aminophylline, and postural drainage. However, her condition deteriorated and six days after admission gentamicin was replaced by intravenous tobramycin and carbenicillin. Forty-eight hours later, the appearance of hepatic tenderness and edema suggested the development of congestive heart failure. Administration of digoxin was followed by a weight loss of 2.2 kg. After recovery from this episode, the patient averaged a fluid intake of 2.000 to 2.500 ml/24 hours, with a similar output.

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However, on the twenty-first day after admission after a weight gain of 0.9 kg in 24 hours with a fluid intake of 2.465 and output of 1.390 ml/day, she complained of blurred vision and the next day became stuporous. On fundoscopy there was blurring of the optic disc margins, but otherwise neurologic examination was normal. Arterial blood gas values in 30% oxygen were Po~ 31, Pco~ 79 mm Hg, and pH 7.42. Her symptoms were attributed at first to respiratory failure. However, on the next day, on the basis of the serum sodium concentration and serum and urine osmolalities (Table I) with BUN of 4 mg/dl, SIADH was diagnosed, fluids were restricted to 500 ml/24 hours and two doses of furosemide were administered intravenously. Despite this regimen she became comatose and, at 5 AM on the twenty-third day of hospitalization, she had a generalized convulsion. In addition to the chemistries listed in Table I, at this time blood glucose was 154 mg/dl, serum calcium 9.0 mg/dl, BUN 9 mg/dl, Po~ 65, Pco~ 95 mm Hg (on 30% oxygen), pH 7.21, plasma cortisol 20 mg/dl, urinary 17-ketosteroids 14 mg/day, and urinary 17-hydroxycorticosteroids 16 mg/day. Over the next 8 hours she was given two infusions of hypertonic sodium chloride solution with 146 mEq/Na in 250 ml water over 80 minutes, as well as two other doses of furosemide intravenously. Her sensorium improved and by 6 PM she was oriented. At 8 I'M serum Na concentration was 130 mEq/l and osmolality 287 mOsm/kg (Table I), Po~ 63, Pco2 81, and pH 7.44. Her weight decreased 3.3 kg in four days. Over the next month her pulmonary condition gradually improved and body weight and serum sodium remained stable. After recovery, adrenal function was normal, with 17-hydroxycorticosteroids of 6.6 mg/24 hours in the control period and 48.0 mg/24 hours on the third day of Cortrosyn stimulation (0.25 mg/ 24 hours). Response to a restricted oral sodium intake of plasma renin activity, plasma aldosterone, and sodium excretion were normal. When her dietary fluids were increased to 5 liters day as a challenge, she responded normally, with increased urinary output, decreased urine osmolality, and maintenance of normal serum Na concentration and osmolality. During the episode of congestive heart failure, plasma ADH determinations of 0.9 and 0.8 pg/ml were appropriate to the plasma osmolalities of 277 and 273 mOsm/kg, respectively. Conversely, during the period of SIADH when plasma osmolality was 240 mOsm/kg, plasma ADH was 3.5 pg/ml (Table I), and therefore inappropriately high. (This ADH level would have been appropriate for an osmolality of 285 to 295 mOsm/kg.) ~6 These data confirm the occurrence of SIADH during the second episode of fluid retention and are consistent with congestive heart failure during the first. DISCUSSION On the basis of the case histories of the two patients reported, SIADH must be added to the causes of hyponatremia in CF, in addition to salt loss in sweat 1 and dilutional hypervolemia due to cor pulmonale. 17 We are not aware of any previous report of SIADH in CF, but it may not be a rare occurrence in this disorder, as we have seen it as an acute complication of chronic pulmonary

The Journal of Pediatrics April 1977

disease in two patients with CF in a three-month period. It is especially important to recognize SIADH promptly in CF, since the treatment is the exact opposite of that of the hyponatremia due to salt loss from sweating: fluid restriction instead of administration. Since each complication may represent a medical emergency, prompt and correct diagnosis may have important therapeutic consequences. The two patients reported also illustrate the clinician's therapeutic dilemma between giving fluid therapy sufficient to maintain adequate hydration of bronchial secretions and avoiding overloading the circulation resulting in heart failure or precipitation of severe hyponatremia, if SIADH is impending. The presenting picture of SIADH is one of water intoxication with continued natriuresis despite the low serum sodium levels. The clinical manifestations reflect the degree of hyponatremia, ranging from mild (vomiting, irritability, personality changes) to severe (focal neurologic signs, coma and convulsions). Because the sweat has an abnormally high salt concentration, hyponatremia in CF patients raises the possibility of massive salt loss through sweating? 1~In this situation, however, due to the rapidity of the process, the extracellular fluid volume is primarily affected; the serum Na concentration is usually only moderately decreased (126 to 130 mEq/1) before serious or even fatal cardiovascular collapse, and there is clinical and laboratory evidence for dehydration. SIADH is characterized instead by normal or expanded extracellular fluid volume, absence of dehydration, and a low or normal BUN; it is usually associated with symptoms when the serum sodium concentration is below 120 mEq/l. Salt loss in sweating in patients with C F may contribute to the hyponatremia of SIADH, although sweat gland function per se is not affected by vasopressin. I~ A slight but significant reduction in the capacity to excrete solute-free water in response to a water load has been observed in patients with CF, and is most marked in those in whom the disease is most severe. ~~Yet even these patients were able to dilute their urine to a value of 84 m O s m / k g H~O or lower during a high or low sodium intake. Thus, it is unlikely that hyponatremia would result from such a small decrease in maximal urinary dilution. In any event, urine osmolality in both of our patients was considerably higher than 84 m O s m / k g H~O during their episodes of hyponatremia and, following recovery, both patients responded normally to a large fluid intake. In patients with bronchogenic carcinoma and chronic pulmonary tuberculosis who develop SIADH, the affected tissue has been found to contain an antidiuretic

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substance. ~l Whereas one cannot exclude the possibility that the diseased pulmonary tissue of patients with CF may also produce an antidiuretic substance, the transient nature of SIADH in these patients would argue against such a possibility. A n alternative explanation is that A D H is released as a consequence of deranged cardiopulmonary physiology such as occurs in p n e u m o n i a and which may give rise to SIADH in that disorder. In CF, acute and chronic hypoxia, as well as hypercapnea, may produce pulmonary artery hypertension and cor pulmonale. ~..... This increase in pulmonary vascular resistance may cause a decrease in cardiac output in patients with CF similar to that documented in p n e u m o n i a in patients with other disorders. '-'4The reduced blood flow to the left atrium that results may cause reflex stimulation of A D H secretion TM '-"~ and promote fluid retention and expand plasma volume which, in turn, inhibits the secretion of aldosterone. The end result would be hyponatremia with excretion of sodium in the urine. Intermittent positive pressure breathing, frequently used in the treatment of pulmonary disorders, can impede left atrial filling and may itself lead to a release o f A D H . ~ Consequently, this therapy could be a factor in the induction of SIADH, and should be used with caution. Treatment of SIADH should be directed simultaneously to correction of the hyponatremia and therapy of the basic disease. Since all of the symptoms in uncomplicated SIADH are due to excessive retention of water, restriction of the fluid intake is the cardinal principle of treatment. In cases of greater clinical severity, rapid negative water balance may be induced by rapidly acting diuretics (e.g., furosemide) in conjunction with infusion of hypertonic saline to replace salt loss produced by diuresis. '-'~Without some contraction of the expanded extracellular fluid by a diuretic, the infused hypertonic saline may be rapidly excreted, with little change in the concentration of serum sodium. Therapy of the basic disease is also imperative, especially in the case of bacterial infections. Effective correction of the severe hyponatremia caused by SIADH may afford the margin of safety until therapy of the underlying disease takes effect. We are grateful to Dr. Gary Robertson for performing the assay for immunoreactive vasopressin. We also appreciate the participation of Drs. Gordon Strewler, James Thorpe, and John Vierling in the care of these patients, and Jacquelyn Friedlander for secretarial help. REFERENCES

1. di Sant'Agnese PA, Darling RC, Perera GA, and Shea E: Abnormal electrolyte composition of sweat in cystic fibrosis of the pancreas. Clinical significance and relationship to the disease, Pediatrics 12:549, 1953.

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2. Schwartz WB, Bennet W, Curelop S, and Bartter FC: A syndrome of renal sodium loss and hyponatremia probably resulting from inappropriate secretion of antidiuretic hormone, Am J Med 23:529, 1957. 3. Bartter FC, and Schwartz WB: The syndrome of inappropriate secretion of antidiuretic hormone, Am J Med 42:790, 1967. 4. Klenk EL, and Winters RW: Disorders of antidiuretic hormone secretion, in The body fluids in pediatrics, Boston, 1973, Little, Brown & Company, p 415. 5. Robertson GL, Mahr EA, Athar S, and Tusher S: Development and clinical application of a new method for the radioimmunoassay of arginine vasopressin in human plasma, J Clin Invest 52:2340, 1973. 6. Miller M, and Moses AM: Urinary antidiuretic hormone in polyuric disorders and in inappropriate ADH syndrome, Ann Intern Med 77:715, 1972. 7. Mor J, Ben-Galim E, and Abramahov A: Inappropriate antidiuretic hormone secretion in an infant with severe pneumonia, Am J Dis Child 129:!33, 1975. 8. Bartter FC: Syndrome of inappropriate secretion of antidiuretic hormone, Disease-a-Month, 11/73. 9. Taussig LM, Kattwinkel J, Freidewald WT, and di Sant'Agnese PA: A new prognostic score and clinical evaluation system for cystic fibrosis, J PEmATR 82:380, 1973. 10. Haber E, Koerner T, Page LB et al.: Application of angiotensin I to the physiologic measurement of plasma renin activity in normal human subjects, J Clin Endocrinol Metab 29:134, 1969. 11. Ito T, Woo J, Haning R, and Horton R: A radioimmunoassay for aldosterone in human peripheral plasma including a comparison of alternate techniques, J Clin Endocrinol Metab 34:106, 1972. 12. Rollins DE, Mitchell JR, Taylor AA, Snodgrass WR, et al.: Heterogeneity of patients with low renin hypertension diagnosed by renin-sodium index. Clin Res 24:238A, 1976. 13. DeWardner HE: The kidney, ed 3, Boston, 1967, Little, Brown & Company, p 53. 14. Derubertis FR, Michelis MF, Bloom ME, et al.: Impaired water excretion in myxedema, Am J Med 31:41, 1971. 15. Miller M, and Moses MA: Radioimmunoassay of urinary antidiuretic hormone in man: response to water load and dehydration in normal subjects, J Clin Endocrinol Metab 34:537, 1972. 16. Robertson GL: Vasopressin in osmotic regulation in man, Am Rev Med 25:315, 1974. 17. Strober W, Peter (3, and Schwartz RH: Albumin metabolism in cystic fibrosis, Pediatrics 43:416, 1969. 18. di Sant'Agnese PA, and Powell GF: Eccrine sweat defect in cystic fibrosis of the pancreas (mucoviscidosis), Ann NY Acad Sci 93:555, 1962. 19. Taussig LM, and Braunstein GD: Effects of vasopressin on sweat rate and composition in patients with diabetes insipidus and normal controls, J Invest Dermatol 60:197, 1973. 20. Robson AM, Tateishi S, Ingelfinger Jr, Strominger DB, and Klahr S: Renal function in patients with cystic fibrosis, J PEDIATR 79:(12, 1971. 21. Bower BF, Mason DM, and Forsham PH: Bronchogenic carcinoma with inappropriate antidiuretic activity in plasma and tumor, N Engl I Med 271:934, 1964.

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22. Goldring RM, Fishman AP, Turino GM, Cohen HI, Denning RC, and Andersen DH: Pulmonary hypertension and cor pulmonale in cystic fibrosis, J PEDIATR 65:501, 1964. 23. Siassi B, Moss A J, and Dooley RR: Clinical recognition of cor pulmonale in cystic fibrosis, J PEDIATR78:784, 1971. 24. Benson H, Mohammed A, Adler LN, and Abelmann WH: Hemodynamic effects of pneumonia. I: Normal and hypodynamic responses, J Clin Invest 49:791, 1970.

The Journal of Pediatrics April 1977

25. Schrier RW, and Bed T: Nonosmolar factors affecting renal water excretion, N Engl J Med 292:81,141, 1975. 26. Goetz KL, Bond GC, and Bloxham DD: Atrial receptors and renal function, Physiol Rev 55:157, 1975. 27. Hantman D, Rossier B, Zehlman R, and Schrier R: Rapid correction of hyponatremia in the syndrome of inappropriate secretion of antidiuretic hormone, Ann Intern Med 78:870, 1973.