Isolated second-phase diabetes insipidus post-transsphenoidal surgery

Abstract

A 57-year-old woman presented with severe lethargy, dizziness and nausea 1 week after transsphenoidal resection of a growth hormone secreting pituitary adenoma. She was found to have severe hyponatremia of 115 mmol/L. Importantly, she was neurologically intact and clinically euvolaemic. Her fluid intake was restricted and her sodium levels increased to 131 mmol/L over 4 days. She made a full recovery.

She was diagnosed with isolated second-phase diabetes insipidus, a state of symptomatic hypoosmolar hyponatremia that usually occurs 7–10 days after transsphenoidal surgery. The sodium levels improve with fluid restriction.

Background

Postoperative isolated second-phase diabetes insipidus is an important clinical entity to recognise. Patients are usually well and clinically euvolaemic soon after their pituitary surgery and are discharged home. They may then present a few days later with collapse or seizures due to an underlying severe hyponatremia.

Case presentation

A 57-year-old woman known case of type 2 diabetes and hypertension underwent transsphenoidal surgery (TSS) for a growth hormone secreting pituitary microadenoma in October 2019. The adenoma was completely removed. There were no intraoperative complications. Her fluid status was strictly monitored postoperatively. Serum sodium, serum and urine osmolality were monitored every 12 hours. Serum cortisol was 516 nmol/L on day 2. Her serum sodium kept within normal limits, she was euvolaemic and was well enough to be discharged home on day 3 postoperatively.

She presented to her prescheduled review 7 days later with nausea, dizziness and severe lethargy. Her serum sodium was 115 mmol/L. Her 9 am cortisol and thyroid function tests were within normal limits. She was neurologically intact, clinically euvolaemic and not passing excessive amounts of urine. She was admitted for further monitoring of her fluid intake, urine output and clinical status. Serum sodium, serum and urine osmolality were checked regularly. Her fluid intake was restricted to 1.5 L/day.

Her serum sodium continued to drop reaching a lowest value of 107 mmol/L on the first day postadmission. After 2 days, her serum sodium started rising slowly increasing to 131 mmol/L 4 days later (figure 1). She remained clinically well throughout and was discharged home on day 4 postadmission.

Figure 1.

Sodium trends over 4 days of admission with fluid restriction.

Investigations

Investigations included a full blood count, renal function, paired serum and urine electrolyte levels, paired serum and urine osmolality, a 9 am serum cortisol, glucose and thyroid function tests. Serum sodium was 115 (135–145 mmol/L) in the context of a low serum osmolality of 245 (282–300 mOsm/kg) and an inappropriately high urine osmolality 808 (50–1200 mOsm/kg). A full blood count, thyroid function tests, serum glucose, 9 am cortisol and lipid profile were within normal limits (table 1).

Table 1.

Initial investigations on admission

Test	Level	Range
Serum sodium	115	135–145 mmol/L
Serum osmolality	245	282–300 mOSm/kg
Urine osmolality	808	50–1200 mOsm/kg
Urine sodium	141	54–190 mmol/L
TSH	1.65	0.3–3 μIU/L
T4	16.41	11–18 pmol/L
9 am serum cortisol	998	145–619 nmol/L
Glucose	8.74	3.88–6.38 mmol/L
Total cholesterol	3.21	2–5 mmol/L

TSH, thyroid stimulating hormone.

The sodium level of 115 mmol/L can be explained by a surge in antidiuretic hormone (ADH) release from damaged axons that course to the posterior pituitary gland. This leads to fluid retention and hyponatremia if excess intravenous fluids are administered or if the patient ingests large amounts of hypotonic fluids such as water.

The patient’s cortisol was checked as hypocortisolemia may lead to hyponatremia. Thyroid function tests confirmed euthyroidism. Hypothyroidism can also be a cause of hyponatremia. Glucose and lipid levels were also collected to exclude a pseudohyponatremia.

Differential diagnosis

The initial evaluation of hyponatremia starts with a thorough clinical assessment. Patients presenting with severe symptoms such as vomiting, seizures, Glasgow Coma Scale≤8 or cardiorespiratory arrest warrant immediate administration of 3% hypertonic saline, irrespective of the cause.¹

If the patient presents with mild or moderate symptoms that include nausea, confusion or headache, the cause of hyponatremia should be established for adequate management. Initially, the patients’ clinical hydration status must be assessed. Second, a paired serum and urine osmolality and urine sodium level are taken. A true hyponatremia is confirmed if there is hypoosmolar hyponatremia. In our case, our patient was euvolaemic and had hypoosmolar hyponatremia with an inappropriately high urine osmolality. This suggests that she was not releasing free water.

Hyponatremia postpituitary surgery presents a wide differential diagnosis. These include hypocortisolaemia, excess fluid administration, concurrent medications, cerebral salt wasting (CSW) and hypothyroidism.

Hypocortisolaemia is an important differential for euvolaemic hyponatremia occurring in the initial postoperative days.² Low cortisol leads to an increase in corticotropic releasing hormone, which is an ADH secretagogue. Cortisol is also a direct inhibitor of ADH, thus ADH levels are increased when cortisol levels are low.³

Another possible cause of early postoperative hyponatremia is excess fluid administration intraoperatively or postoperatively. This leads to hypotonic polyuria. Vasopressin is released in response to surgical stress resulting in fluid retention. Intravenous fluids should be stopped as soon as patients are able to drink. Medications that cause syndrome of inappropriate ADH secretion (SIADH) are other potential causes. These include diuretics, antipsychotics, selective serotonin receptor inhibitors, tricyclic antidepressants and non steroidal antiinflammatory drugs.

Hyponatremia may also develop due to excess desmopressin administration used to treat postoperative diabetes insipidus (DI). Postoperative DI is often transient and can often be managed with just fluid replacement. Hypothyroidism may be another cause of hyponatremia. In such cases, patients are usually either undiagnosed or undertreated. Patients with hypothyroid are euvolaemic but may have excess ADH in view of decreased clearance or excess secretion due to decreased cardiac output.²

CSW may develop postpituitary surgery. It usually occurs at 1 week postsurgery or later. The pathogenesis may be due to release of natriuretic peptides, which lead to excretion of excess water and sodium. Decreased renin, aldosterone and ADH levels cause a net sodium loss. Loss of sympathetic input to the kidney in CSW causes less sodium reabsorption at the proximal tubule and more sodium excretion.⁴

CSW presents very similarly to the SIADH with low serum sodium, a low serum osmolality, inappropriately high urine osmolality and high urine sodium loss. The urinary sodium excretion is higher than the intake in CSW resulting in a negative net sodium balance with polyuria. In SIADH, urinary sodium excretion equates sodium intake.⁴

In CSW, there is a decrease in extracellular volume, body weight, central venous pressure and haemoconcentration resulting in a higher urea, uric acid, haemoglobin, potassium and low plasma aldosterone. SIADH presents with euvolaemia or mild extracellular expansion.² Patients with SIADH have a low plasma renin, low haematocrit, low plasma urea and uric acid.⁴

Treatment

The patient was treated with fluid restriction and this was effective over a few days. Her fluid intake and output were strictly monitored. Serum sodium, serum and urine osmolality were monitored frequently.

Hypertonic saline was not administered as there was no clinical indication. Treatment of hyponatremia depends on the severity of symptoms. In all cases, sodium correction should not exceed 10–12 mmol/L sodium per day or 18 mmol/L in 48 hours.

Outcome and follow-up

The sodium levels increased to normal over 4 days. The patient was followed up at outpatients clinic and the sodium levels remained stable. There was no sign of residual tumour on MRI postoperatively.

Discussion

Thirteen to thirty-five per cent of patients undergoing TSS develop hyponatremia postoperatively. 2%–7% are symptomatic.² It is most commonly due to excess ADH secretion postoperatively but may be due to surgical complications such as meningitis or bleeding.²

The term ‘isolated second-phase diabetes insipidus’ may mislead the clinician as patients present with euvolaemic hyponatremia rather than polyuria and hypernatremia as expected in DI. This phenomenon is due to excess ADH rather than its absence. The term originates from the possible triphasic response that may occur post-TSS or head injury. Triphasic DI occurs when there is complete pituitary stalk transection and consists of the following sequence of events:

First phase

The first phase presents with polyuria in the first 24 hours postsurgery/head injury. It is postulated to occur due to the failure of action potentials to pass from the hypothalamus to the posterior pituitary. Thus, there is a decrease in ADH secretion causing polyuria up to 6–8 L.

Second phase

During the second phase, there is a rapid decrease in urine output associated with hyponatremia. The axon terminals in the posterior pituitary degenerate causing a release of the preformed and stored ADH. This surge of ADH leads to an SIADH-like state if excess fluids are administered. This phase occurs 7–10 days postoperatively. In addition, surgical stress also induces ADH secretion from the posterior pituitary gland. This may last 3–5 days and further exacerbate the SIADH-like state. Patients therefore need to be counselled to limit their oral intake of hypotonic fluids such as water, so as not to induce hyponatremia.⁵

Third phase

The third phase represents with polyuria due to complete exhaustion of ADH stores. A clinical picture suggesting DI recurs.

Triphasic DI occurs in 1%–2% of patients undergoing TSS.⁶ Isolated second phase occurs in 8%–21% of patients postpituitary surgery.⁴ Isolated second phase DI occurs when some but not all of the axons passing from the hypothalamus to the posterior pituitary are damaged. The remaining functioning axons still produce enough vasopressin to avoid the first and third phases of DI.

Release of excess ADH leads to plasma volume expansion and sodium and water excretion via the functioning kidneys. Thus, a euvolaemic state is maintained.² During this phase, any excess fluid intake results in hyponatremia. Patients present with collapse, nausea, headaches or seizures usually 7–10 days postsurgery/head injury. Fluid restriction results in resolution of the hyponatremia within a few days.

In a study by Kristof et al, 75.4% of patients post-TSS developed water and electrolyte disturbances. 21% of these patients had isolated hyponatremia with a nadir of 132 mmol/L at day 9. Serum ADH level was not low. 42.8% were treated with fluid restriction.⁷

There have been numerous studies investigating any predictive causes for hyponatremia postpituitary surgery. Women are more likely to develop transient hyponatremia and are three times more likely to have severe hyponatremia.^{6 8}

Patients who have previous transient diabetes insipidus are two times more likely to develop hyponatremia postoperatively.^8–10 There is still a debate whether micro or macroadenomas are more likely to cause hyponatremia postoperatively. Macroadenomas were more likely to cause hyponatremia in a study by Kelly et al.¹¹ However in other studies, macroadenomas were more likely.⁸

Learning points.

• Serum electrolytes and osmolality together with urine osmolality should be checked and monitored in post-transsphenoidal surgery (TSS) patients as a screening tool for the triphasic effect or isolated second phase diabetes insipidus.

• Patients should be advised to avoid excess fluid intake post-TSS.

• Post-TSS/head injury patients should be instructed to report to their physician if any symptoms suggestive of hyponatremia are noted.

• Checking patients’ serum electrolytes 1 week postoperative is an effective way to pick up these electrolyte imbalances.