Severe Hypernatremia From a Urea-Induced Diuresis due to Body Protein Wasting in an Insulin-Resistant Type 2 Diabetic Patient

Abstract

Context:

Hypernatremia is encountered after pituitary or hypothalamic surgery and typically is secondary to vasopressin deficiency resulting in increased free water clearance with inadequate water replacement.

Objective:

We report a type 2 diabetic patient with severe hypernatremia (Na⁺ = 161 mEq/L) after hypothalamic surgery. Unexpectedly, this was accompanied by persistent urinary hypertonicity and negative total but positive electrolyte free water clearance.

Main Outcome Measure:

Measurement of urinary electrolytes and urea revealed that an osmotic diuresis induced by urea derived principally by breakdown of endogenous protein was causative. Body protein losses over 48 hours were estimated to exceed 2 kg of lean mass. High-dose glucocorticoid, insulin resistance, and a postsurgical catabolic stress likely contributed.

Conclusion:

In surgically severely stressed individuals, proteolysis of endogenous protein can strongly impact body water metabolism and contribute to severe hypernatremia.

Disordered renal water handling with resulting alterations of serum sodium commonly occurs after pituitary surgery and with hypothalamic lesions (eg, craniopharyngioma, sarcoid, histiocytosis). Deficient or excess arginine vasopressin (AVP) secretion is nearly uniformly causative, and treatment consists of AVP replacement for polyuric and fluid restriction for hyponatremic patients. Here we present a patient who developed severe hypernatremia after hypothalamic surgery. Unexpectedly, investigation revealed that an osmotic diuresis, fueled principally by breakdown of body protein, was causative.

History and Examination

A 47-year-old male with a history of obesity, type 2 diabetes, and hypertension was hospitalized after a syncopal episode. He was found to have a suprasellar mass on a noncontrast head computed tomography scan as well as hydrocephalus. He was transferred to the University of Virginia where magnetic resonance imaging revealed a well-circumscribed 3.1 × 4.5 × 2.3-cm enhancing mass centered in the hypothalamus above the optic chiasm. The infundibulum and pituitary appeared intact. A frontal/parietal craniotomy was performed, and a grade 2 choroid glioma was partially resected. After surgery, the patient remained obtunded, occasionally following simple commands. His speech was unintelligible. On postoperative day 1, the serum sodium was 140 mEq/L (Table 1). There was a significant increase in urine output overnight between postoperative days 1 and 2. Enteral feeding was begun on postoperative day 2 with 65 cc/h of Promote (Abbott Laboratories, Abbott Park, Illinois). Serum sodium and urine osmolality had risen before beginning the enteral feeding. The endocrine department was consulted on postoperative day 2 when the serum sodium reached 161 mEq/L. At that time, the urine specific gravity was 1.014 and the urine osmolality, measured several hours later, was 717 mOsm/kg (Table 1). The patient remained in the neurosurgical intensive care unit for the next 7 days.

Table 1.

Serum and Urinary Chemistries and Fluid Balance for the First 6 Days After Surgery

	POD 1	POD 2 (1 am)	POD 2 (5 pm)	POD 3	POD 4	POD 5	POD 6
Serum sodium, mEq/L	140	149	161	158	154	143	143
Serum osmolality, mOsm/L			333	334 (average of 5 readings)	342 (average of 3 readings)	309	305
Urine osmolality, mOsm/L		719/608/799	849/683/783	848	799	874
Specific gravity, g/cm3		1.013	1.014	1.025	1.023	1.026	1.020
Serum creatinine, mg/dL	0.9		0.8	0.9	0.8	0.8	0.9
Blood urea nitrogen, mg/dL	19		20	29	33	23	27
Urine sodium (mEq/L)			98	92		106	104
Urine urea (mg/dL)				1374	1930		1427
24-h average plasma glucose (mg/dL)	162	151		176	171	171	157
I/O (24 h)	4.48 L NS/ 4840	3.04 L NS/4100		1.4 L NS, 1.7 L D5W/ 3995	2913 ½ NS/ 2550	3543 ¼ NS/ 2640	2727 ¼ NS/ 2655

Abbreviations: D5W, 5% dextrose in water; I/O, input and output; NS, normal saline; POD, postoperative day.

Results and Discussion

The time course for serum and urine sodium and osmolality and the daily fluid balances over the first 6 days after surgery are shown in Table 1. Throughout this time, the patient received a continuous iv insulin infusion that maintained his plasma glucose concentration in the 100–200 mg/dL range, and he was never glycosuric.

The urine specific gravity measured on postoperative day 2 provided the first indication that the evolving hypernatremia and hyperosmolarity were not due to AVP deficiency, as commonly occurs after hypothalamic surgery. Rather, it suggested that an osmotic diuresis was involved. However, the patient at no time received an osmotic diuretic (mannitol or urea), and there was no significant osmolar gap in the serum or urine. The patient was maintained on 4–6 mg of dexamethasone every 6 hours over the course of these 6 days. The urinary urea concentration was markedly elevated repeatedly (Table 1) and could fully account for the elevated urine osmolality observed. The urinary osmolar load of urea averaged 1858 mOsm/24 h on postoperative days 3 and 4. The urea-induced diuresis resulted in a negative free water clearance (FWC = [V − V (Uosm/Sosm)]/t) which raised the serum sodium. Electrolyte FWC remained positive whether estimated by the classical (EFWC = [V − V (UNa⁺ + K⁺/SNa⁺ + K⁺)]/t) or modified (mEFWC = V [1 − 1.03 [UNa⁺ + K⁺/(Na⁺ + 23.8)]]) formulae (1).

Considering sources for the excess urea, the daily protein intake was 1560 cc of Promote, with 14.8 g of protein/250 cc which amounts to 92 g of protein/24 h. If entirely catabolized, this could produce approximately 526 mOsm of urea in 24 hours ([92 g protein × 16 g nitrogen/100 g protein]/28 mg nitrogen/mOsm urea). We estimated the total (48 h) protein catabolism from the measured urea nitrogen excretion on postoperative days 3 (54.9 g) and 4 (51.4 g) (106.3 g N/48 h × 6.25 g protein/g protein N). Thus 664 g of protein must be catabolized to provide this amount of urea nitrogen. The protein available from the Promote (180 g/48 h) if entirely catabolized could provide only approximately 27% of the urinary urea nitrogen excreted daily. The other > 70% or 484 g would be derived from endogenous proteolysis.

Lean body tissues (eg, liver and muscle) are approximately 20% protein by weight (2). To supply the 484 g of protein for catabolism would require that more than 2.4 kg of lean body tissue undergo net proteolysis over 48 hours to supply the nitrogen found in the observed urea excretion.

The etiology of the highly catabolic state observed here is likely multifactorial. First, the postoperative state and the accompanying immobility promote protein loss (3, 4). Second, the patient was receiving pharmacological doses of dexamethasone (4–6 mg every 6 h) (5). Third, the patient was obese, with type 2 diabetes and marked insulin resistance (6, 7). His iv insulin requirements on postoperative days 2 through 6 ranged between 3 and 7.5 U/h.

Despite these potential precipitants, we were surprised at the dramatic electrolyte abnormalities. Review of the literature yielded surprisingly little information on osmotic diuresis produced by this type of endogenous protein wasting. A single recent report suggested that urea-induced diuresis might account for up to 10% of hypernatremia encountered in the intensive care unit setting (8). Of the 7 patients included in that report, all were on enteral nutrition and intubated. Five of the 7 patients were on glucocorticoids, and 6 of the 7 were on pressors. The contribution of catabolism of endogenous vs exogenous protein was not addressed in that study. An antinaturetic action of urea may also contribute to the hypernatremia seen here (9). It is worth recognizing that giving 1-desamino-β-d-arginine vasopressin would be of no value in this setting (none was given) because the renal concentrating mechanism appears to be near maximal already. We conclude that catabolism of endogenous protein can, in the setting of postoperative stress, insulin resistance, and high-dose glucocorticoids, produce dramatic protein wasting accompanied by an osmotic diuresis that can cause severe hypernatremia and hyperosmolarity.