Hyponatremia due to cerebral salt-wasting syndrome: Combined cerebral and distal tubular lesion

A 76-year-old white man was evaluated for a syndrome of hyponatremia, hypotension, and high urinary sodium excretion. There was evidence of inappropriate secretion of antidiuretic hormone and renal salt wasting in the presence of a normal glomerular filtration rate. He had a distal tubular acidification defect and unresponsiveness to standard doses of mineralocorticoids. The renin aldosterone axis was normal, as were thyroid and adrenal function. The patient could not dilute the urine, nor excrete a standard water load. Renal concentrating ability was normal, but there was no additional response to exogenous vasopressin. With modest salt restitution, the patient continued to lose large quantities of sodium in the urine, resulting in severe postural hypotension. Renal biopsy showed normal glomeruli with distinct degeneration of the distal tubules. There was no evidence of an acute inflammatory interstitial nephritis. The patient did not respond to therapeutic doses of mineralocorticoid (fludrocortisone), but treatment with water restriction, increased salt intake, and large doses of mineralocorticoids resulted In a normal serum sodium level and blood pressure. This case falls in the category of “cerebral salt wasting” syndrome. The cause was a combination of idiopathic secretion of antidiuretic hormone and distal tubular degeneration resulting in pseudohypoaldosteronism.     

Focal segmental glomerulosclerosis

Renal and hepatic function were studied in 20 patients with cirrhosis and ascites, before and during infusion of prostaglandin A₁ (PG-A₁), and in 7 patients during infusion of furosemide, with and without PG-A₁. Liver function was evaluated by using 10 clinically related criteria to determine a liver function profile. A significant negative correlation was found between the liver function profile and both glomerular filtration rate (GFR) (r = ?0.74, p < 0.01) and effective renal plasma flow (ERPF) (r = ?0.71, p < 0.01). Patients were then grouped according to their ERPF: Group I (450 ml/min), group II (150 to 450 ml/min) and group III (< 150 ml/min). During PG-A₁ infusion, ERPF increased significantly only in groups I and II, by (±SE) 138 ± 67 ml/min and 131 ± 40 ml/ min, respectively. The GFR and sodium excretion also increased only in groups I and II. During furosemide infusion, there were highly significant increases in urine volume and sodium excretion but no consistent change in either GFR or ERPF. The effects of PG-A₁ and furosemide were not additive.The results show that in cirrhotic patients with ascites, PG-A₁ infusion can significantly increase both GFR and ERPF in all patients but those with the most severe liver impairment. Furosemide consistently increased urine volume and sodium excretion but did not affect GFR or ERPF. Both GFR and ERPF could be related to the extent of hepatic impairment by means of a liver function profile.     

Neurologic manifestations of diabetic comas: Correlation with biochemical alterations in the brain

Coma and other neurologic abnormalities are present in patients with either diabetic ketoacidosis (DKA) or nonketotic coma (NKC), and the cause of such phenomena are not known. Patients with NKC also manifest seizures and focal neurologic changes. Treatment of diabetic coma with insulin may induce cerebral edema by as yet undefined mechanism(s). In patients with DKA, cerebral oxygen utilization is impaired, and there is hyperviscosity of the blood. A substantial part of the brain's energy source is derived from ketones, which in themselves can depress sensorium. Extracellular hyperosomolality is present, which may also contribute to the genesis of coma. In addition, most keto-acidotic patients have associated medical conditions, which may further impair consciousness. Biochemical changes in the brains of animals with DKA include impairment of both phosphofructokinase activity and pyruvate oxidation, and accumulation of citrate. The net effect upon sensorium in ketoacidotic patients probably represents the interaction of most of the above factors and differs markedly among individuals. Patients with NKC manifest not only depression of sensorium, but also focal motor seizures, hemiparesis, and other neurologic changes, such as aphasia, hypereflexia, sensory defects, autonomic changes, and brainstem dysfunction. Most of the aforementioned changes revert to normal after correction of hyperosomolality. Gamma amino butyric acid, which has been shown to elevate the seizure threshold, is normal in brains of ketoacidotic animals, but may be low in nonketotic coma. Also, hyperosomolality per se may produce seizures. Cerebral edema may complicate the treatment of either DKA or NKC. The available experimental evidence suggests that many of the commonly held theories for the production of such brain swelling probably do not occur. There is no breakdown of the sodium pump, sorbitol or fructose do not accumulate in brain, and brain glucose is only about 25% of that in plasma. Cerebral edema is probably produced largely by a direct action of insulin on brain at a time when plasma glucose is approaching normal values. Cerebral edema can thus theoretically be avoided by stopping insulin when plasma glucose has been lowered to values approaching normal.     

Central nervous system manifestations of hyperparathyroidism

Prospective neurologic and psychologic studies were thus undertaken in 19 patients who were to undergo major neck operations either for parathyroidectomy (seven for primary hyperparathyroidism and six for secondary hyperparathyroidism) or other reasons (six control subjects). A complete physical and neurologic examination, laboratory tests (calcium, PTH), roentgenograms, a standard electroencephalogram and psychologic testing were carried out in patients before and three and a half months after neck operation.The preoperative electroencephalograms were abnormal in groups with both primary and secondary hyperparathyroidism. For the patients with primary hyperparathyroidism, the preoperative electroencephalogram revealed a percentage electroencephalographic power below 5 Hz (± SE) of 4.2 ± 2.2 per cent (normal = 2.4 ± 1.0 per cent), and the percentage of electroencephalographic frequencies below 7 Hz was 14.7 ± 3.2 per cent (normal = 6.0 ± 1.6 per cent). Postoperatively, however, there were significant (p < 0.01) decrements in these measurements to normal values. The percentage electroencephalographic power below 5 Hz was 1.5 ± 0.6 per cent, whereas the percentage of electroencephalographic frequencies below 7 Hz was 5.2 ± 1.1 per cent. In patients with secondary hyperparathyroidism, both the percentage electroencephalographic power below 5 Hz (9.7 ± 2.5 per cent, p < 0.01) and the percentage electroencephalographic frequencies below 7 Hz (22.2 ± 4.2 per cent, p < 0.01), were significantly higher than normal values. There were significant decrements in all the abnormal electroencephalographic values postoperatively. The percentage electroencephalographic power below 5 Hz decreased to 3.4 ± 2.4 per cent, and the percentage electroencephalographic frequencies below 7 Hz decreased to 17.4 ± 3.1 per cent. Electroencephalograms in control patients did not change.Patients with primary hyperparathyroidism showed no significant postoperative improvement in any of the psychologic parameters tested. By contrast, patients with secondary hyperparathyroidism showed improvement in several areas of testing after undergoing surgery when compared to control subjects.The brain calcium in four other patients with secondary hyperparathyroidism who died of miscellaneous causes was 38.3 ± 5.7 meq/kg dry wt, versus the normal value of 25.2 ± 0.7 meq/kg dry wt (p < 0.03).These data show that in patients with either primary or secondary hyperparathyroidism, the electroencephalogram is abnormal and shows significant improvement following parathyroidectomy. There is also improvement in several tests of intellectual function in patients with secondary hyperparathyroidism. Brain calcium content was significantly higher than normal in patients with secondary hyperparathyroidism.     

Thiazide-induced hyponatremia associated with death or neurologic damage in outpatients

Seven elderly patients were encountered who had been taking thiazides or thiazide-like diuretics (hydrochlorothiazide, polythiazide or metolazone) for less than 16 days and who presented with severe symptomatic hyponatremia (serum SODIUM = 105 ± 6 meq/liter). In five patients, urine sodium + potassium was 156 meq/liter whereas that in serum was 108 meq/liter (P < 0.01). All patients had central nervous manifestations of hyponatremia (seizures, stupor, coma, extensor plantar response) and all but one were treated with 3 percent sodium chloride to raise the serum sodium level above 130 meq/liter within 44 hours. Three patients died, two had permanent paralysis, and two recovered. Other causes of the neurologic dysfunction were ruled out by negative lumbar punctures, brain scan and computerized axial tomography (CAT) scan. In all, serum creatinine was below 1.1 mg/dl.

The patients who recovered were studied. In two patients, the administration of oral metolazone (10 mg/day for two days) or hydrochlorothiazide (100 mg/day for two days) with ad libitum water intake resulted in decrements in serum sodium of 13 to 18 meq/liter in 36 hours. In both, serum sodium levels fell below 125 meq/liter with resultant symptoms. In one patient, the response to a standard oral water loading test was studied before and after 10 mg of metolazone administration. After metolazone therapy, the percent excretion of a standard oral water load in 4 hours fell from 65 percent to 15 percent, minimal urine osmolality, which had been 130 to 371 mosmol/kg, increased to 371 mosmol/kg, free water clearance fell from 2.25 to −0.25 ml/min and urine sodium excretion increased from 62 to 159 μeq/min. Plasma antidiuretic hormone (ADH) levels were undetectable before and after the administration of metolazone but rose after overnight dehydration. Thus, metolazone resulted in impaired ability to dilute the urine and excrete a water load, with 256 percent increase in urine sodium loss. Therefore, in a susceptible subgroup of outpatients, thiazides may rapidly induce severe hyponatremia with permanent neurologic damage or death.     

Lactic acidosis: an experimental model.

A model of spontaneous lactic acidosis was developed in alloxan diabetic rabbits by infusing intravenously beta-hydroxybutyric acid followed by a continuous infusion of NaHCO3. In half of the animals, the arterial lactate/pyruvate ratio rose from 2.5 mM/0.19mM to 20.4 mM/0.28 mM, and arterial pH fell to 7.16. In animals with lactic acidosis, the calculated ratio in blood of NAD/NADH was 1437 +/- 230, versus a normal value of 6754 +/- 1250. Both arterial PO2 and blood pressure were normal. Continued infusion of NaHCO3 led to increased blood lactate levels, with cardiorespiratory arrest in 36% of animals. Lactic acidosis did not develop in normal rabbits who were similarly treated. It is concluded that spontaneous lactic acidosis can be produced in diabetic, but not in normal, rabbits by infusion of beta-hydroxybutric acid followed by infusion of NaHCO3.