What are the Endocrine causes of hyponatremia following Traumatic brain injury ?

Original Case by Taylor et al

Review by Dr. Om J Lakhani (Endocrinologist)

A 44-year-old male with no substantial medical history was injured falling off his road bike at 25 mph and sustained a traumatic brain injury resulting in a marked expressive dysphasia. CT brain demonstrated a small left subdural haematoma, left temporal contusion and right petrous temporal bone fracture. He did not require surgical intervention. Forty eight hours after injury he developed a lower motor neurone facial weakness secondary to the temporal bone fracture, therefore dexamethasone was commenced.

Q Define traumatic brain injury ?

TBI is a non-degenerative, non-congenital insult to the brain from an external mechanical force causing temporary or permanent neurological dysfunction, which may result in impairment of cognitive, physical and psychosocial functions

Q What are the Endocrine problems associated with traumatic brain injury ?

  1. Post traumatic hypopituitarism (PTHP)
  2. Diabetes Insipidus
  3. Hyponatremia (SIADH , Cerebral salt wasting)

Q Which are the risk factors associated with Pituitary dysfunction after traumatic brain injury ?

  • Diffuse axonal injury
  • Fracture of skull base
  • Older age

Q Does the severity of GCS (Glasgow common scale) associated with pituitary dysfunction ?

  • Yes
  • Lower post resuscitation GCS is associated with more severe pituitary dysfunction

Q Which inflammatory mediator is related involvement leads to SIADH in TBI ?

  • IL6 increases release of Vasopressin
  • It leads to SIADH after TBI

Q Which type of forces damage the Hypothalamic pituitary unit ?

  • Shearing forces tend to cause damage to midline structure- more likely to be involved in Hypothalamic pituitary damage

Q What type of skull fracture can cause direct pituitary damage ?

  • Basal skull fractures

Q Which pituitary hormones increase and which reduce after an acute traumatic event ?

  • ACTH, GH, Prolactin – increase
  • FSH/LH and TSH- reduce

Q When does diabetes insipidus occur in Acute TBI ?

  • It generally manifests on day 5-10
  • It is often transient

Q In what period after brain injury does post traumatic hypopituitarism occur ?

  • Time period is variable from 1 months to 23 years
  • In 75% of patients it occurs within the first year
  • 35% cases within first 3 months

Q What type of damage predominantly leads to PTHP ?

  1. Vascular damage
  2. Shearing axonal injuries

Q Which part of the blood system of pituitary is most vulnerable to damage ?

  • The damage most predominantly occurs in the long hypophyseal portal system that goes through the sellar diaphragm
  • This part is most vulnerable to mechanical damage

Q Describe the percentage of various hormonal injuries following PTHP ?

  1. GHD – 30%
  2. Gonadotropin deficiency – 28%
  3. ACTH Deficiency – 18%
  4. Thyrotropin deficiency – 18%
  5. Diabetes insipidus- 2.7 %
  6. Hyperprolactinemia- 0-12%
  7. Hypoprolactinemia- also reported

Q When should pituitary evaluation be done after TBI ?

  • Generally done 3- 6 months after head injury

On Day 5 of admission his sodium level fell.

Q What are the causes of Hyponatremia following Traumatic brain injury ?

  1. SIADH
  2. Cerebral salt wasting
  3. Central Adrenal insufficiency

Q What are the Diagnostic criteria for SIADH ?

  1. Serum osmolality <280 mom/kg
  2. Urine osmolality >100 mom/kg
  3. Urinary sodium >30 meq/l
  4. Euvoluemic patient
  5. Adrenal insufficiency and hypothyroidism ruled out
  6. Low uric acid
  7. No acid base balance
  8. Normal potassium

Q Describe the management of SIADH ?

  • The management of SIADH deals mainly with management of Hyponatremia.
  • Before correction of hyponatremia you need to answer following questions :
    • How Rapidly did the hyponatremia develop ?
    • How severe is the hyponatremia ?
    • Is the patient symptomatic ?
  • In most cases of asymptomatic chronic , mild to moderate hyponatremia, free fluid restriction is mainstay of treatment.

Initially attributed to SIADH, his sodium continued to fall rapidly despite fluid restriction and slow sodium tablets. Baseline paired serum and urine osmolality were 265 and 595 respectively with urine sodium of 191 mmol/L. He was referred to endocrinology who suspected a diagnosis of CSW on the basis of failure of resolution with fluid restriction, low JVP and high urine output.


Q What are the essential features of Cerebral salt wasting ?


  • Low circulating volume
  • Low serum sodium
  • Sodium loss in urine

Q What are the theories for pathophysiology of this disorder ?

Two theories

  • Due to BNP increases urine sodium loss and suppresses renin (more likely theory)
  • Due to reduced central sympathetic outflow prevents activation for RAS in state of hypovoluemia loss of Sodium in urine

Q Which is more common SIADH or CSW ?

  • SIADH is more common

Q When is CSW generally seen after neurosurgical procedure ?

  • Generally seen 10 days after neurosurgical procedure

Q What are the CF of CSW  ?

  • Hyponatremia à cerebral edema à altered sensorium
  • Dehydration
  • Polyuria

Q What are the diagnostic criteria for CSW  ?

  • In patient with CNS disorder
  • Serum sodium <135
  • Urine osmolality >100
  • Urine sodium >40
  • Reduced serum uric acid
  • Clinical evidence of hypovolaemia

Q Which is the most important feature to distinguish SIADH and CSW  ?

  • It is the status of circulating volume – which is low in CSW

Q What are the essential points to differentiate Cerebral salt wasting from SIADH ?

  • CSW: With Infusion of fluids there is improvement in hyponatremia and reduction in urine osmolality
  • SIADH- Infusion of fluid à no improvement in hyponatremia and urine remains concentratedà this is because ADH is not suppressed

Urine output assessment was challenging to interpret initially due to extreme confusion, and agitation preventing catheterisation but his urine output was in excess of 3 L a day at this point despite a 1.5 L fluid restriction. During this time the patient recalls having excessive thirst and a craving for the salt tablets, which he later found unpalatable.

Despite hypertonic saline (1.8% saline) being commenced, his sodium continued to fall, with increased cerebral oedema and worsening confusion. This combination necessitated admission to intensive care with a sodium nadir of 116 mmol/L. A graph of his serum sodium, urine sodium and daily intravenous sodium is shown in Fig. 1.


Q Why is differentiating CSW and SIADH important from treatment point of view ?

  • Because treatment is opposite
  • SIADH – there is need for fluid restriction
  • CSW- there is need for fluid infusion and not restriction
  • Doing the opposite in both the condition can worsen each of the condition

Q What type of fluid is generally given in CSW ?

  • Generally isotonic fluid
  • This is not the case in SIADH where isotonic fluid will worsen the patient

Q Which Pharmacological agent is used in treatment of Cerebral Salt wasting ?

  • Fludrocortisone

Infusion of 5% saline (>950 mEq of sodium required in first 24 h in ITU) restored serum sodium to low normal levels within 72 h (sodium 134 mmol/L). During his intensive care admission he also required inotropic support which further highlights the extent of his volume depletion. Following the stabilisation of his sodium levels he was stepped back down to the neurosurgical high dependency unit. However, his urinary sodium remained persistently elevated peaking at 254 mmol/L, (urine osmolality 710 mmol/kg) serum sodium fell to 125 mmol/L despite hypertonic saline and he required substantial volume replacement (equivalent of more than 4 L/day of 1.8% saline). Urine output remained persistently high between 3 and 5 L a day over this time.

Fludrocortisone was therefore introduced at 75 µg bd and ultimately increased to 150 µg bd, which resulted in a substantial (threefold) fall in requirements for hypertonic saline that was still required for another 7 days. His sodium remained stable around 130 mmol/L on fludrocortisone alone and he was discharged home 25 days post injury. Fludrocortisone was continued for the next four months.

The dexamethasone initiated at 48 hours was continued for a 1-week course. As a baseline cortisol taken 24 h post the final dexamethasone was 94 nmol/L, he was maintained on hydrocortisone 10 mg bd which was continued until after discharge. A post discharge short synacthen test was normal and hydrocortisone was then stopped.

It took four months to wean him off the fludrocortisone without the occurrence of rebound hyponatraemia suggestive of on-going, albeit mild, CSW. Intriguingly, the attempt in the week after he developed peripheral oedema on fludrocortisone was successful and he has remained stable off fludrocortisone for three months.

Learning points

  1. Post-traumatic hypopituitarism, Diabetes Insipidus, SIADH and Cerebral salt wasting are important Endocrine disorders following traumatic brain injury
  2. Treatment of SIADH and Cerebral salt wasting is different, hence it is important to differentiate the two conditions in patients who present with hyponatremia following TBI
  3. Isotonic fluids with or without fludrocortisone is the treatment of choice in patients with CSW.




Original case by Óscar Aramburu-Bodas et al 

A 67-year-old woman was hospitalized with a 2-month history of asthenia without weight loss, neurologic, or respiratory symptoms. Her medical history included hypertension. Her medications at admission were enalapril and lorazepam. The physical examination revealed the patient to be alert, clinically euvolemic, and with a blood pressure of 147/90 mm Hg.
Laboratory tests showed a serum sodium (SNa) level of 112 mmol/L; low plasma osmolality (POSM), 250 mOsm/kg; high urine osmolality (UOSM), 562 mOsm/kg; and urine sodium (UNa) level of 88 mmol/L. Potassium was 4.9 mmol/L; urea, 12 mg/dL; creatinine, 0.4 mg/dL; and glucose, 95 mg/dL.
Q. What is your interpretation of these reports ?
Since the patient is euvolemic my differentials for the hyponatremia would be
2. Adrenal insufficiency
3. Hypothyroidism
Q. What are the criteria for SIADH ?

1. Serum osmolality <280 mom/kg
2. Urinary osmolality >100 mom/kg
3. Urinary sodium > 30 meq/l
4. Clinically euvolemic
5. Hypothyroidism and Adrenal insufficiency have been ruled out
Q. What would be your approach to treating hyponatremia in this case ?
This is based in European society of endocrinology protocol
1. 3% NaCl @75-100 ml/hr
2. Recheck Sodium after 4 hrs. If Serum sodium raise by 4 meq/l – I would go to next step else continue the 3% NaCl and recheck every 4 hours. Sodium should not raise by >10 meq/l in 24 hrs
3. Next I would search for the cause of SIADH
4. I would advice free fluid restriction additionally
5. Furosemide may be added if urine osmolality remains > 500 mom/kg

Upon admission, uric acid was 2.1 mg/dL; cortisol, 12.2 μg/dL; and thyroid-stimulating hormone, 2.28 mU/L. Tumor markers were within reference range. A computed tomography (CT) scan of the brain, chest, and abdomen revealed small nodes located in the mediastinum as the only finding.

Q. Can Adrenal insufficiency be ruled out with this baseline cortisol ?

Yes. Some guidelines suggest cortisol >10.8 ug/dl generally rules out adrenal insufficiency.

During hospitalization, enalapril was replaced with amlodipine, since angiotensin-converting enzyme (ACE) inhibitors are a potential cause of SIADH. The patient began with fluid restriction. Despite severe hyponatremia and a Furst formula of 1.09, there was only slight improvement in sodium level (from 112 to 126 mmol/L), but the symptoms disappeared. The patient was discharged with the recommendation to limit fluid intake and referred for outpatient follow-up.

Read : ACEI leading to SIADH (http://www.ncbi.nlm.nih.gov/pubmed/12087354)

Q. What is Furst formula ?
Furst formula gives the estimate of how much free fluid is lost and helps estimate the degree of free water restriction to be prescribed.
The formula is in a spot sample of urine – Urine Na + Urine K / Plasma Na
If the interpretation is as follows:
1. Value > 1.0- patient is not excreting any free water- advised 0 litre of free fluid
2. Value 0.5-1.0 – 500 ml of free fluid allowed
3. <0.5- good free fluid excretion- upto 1 litre of free fluid allowed
Q. What can explain the improvement in Sodium ?

Probably because of stopping of ACEI which can cause SIADH

Chest CT scan and laboratory tests were repeated 6 months later. CT revealed nonspecific mediastinal lymph nodes only (similar to the previous scan). New blood tests were within normal range, except for a SNa of 127 mmol/L and POSM of 250 mOsm/kg. Uric acid was 2.3 mg/dL. The patient remained asymptomatic. After a 2-year follow-up, she presented with marked weakness. Physical examination was normal. A chest X-ray was similar to the previous one. She was therefore prescribed tolvaptan 15 mg/day, and the dose was progressively increased to 60 mg daily. SNa rose to 136 mmol/L, with an excellent tolerance and clinical response. The evolution of laboratory variables is showed in Table 1.
One year after tolvaptan was initiated, she complained of progressive asthenia once more. SNa was 115 mmol/L despite receiving tolvaptan at the maximum recommended dose, and without changes in dietary habits, fluid intake, or medication. The patient was admitted to the hospital for further evaluation. The patient was euvolemic. Hypothyroidism and adrenal insufficiency were ruled out. Renal function, potassium, and tumor markers were normal. UNa was 109 mmol/L; urine potassium, 26 mmol/L; POSM, 249 mOsm/kg; and UOSM, 410 mOsm/kg. The diagnosis was made of SIADH of unknown origin resistant to tolvaptan treatment. A chest X-ray revealed that the mediastinum was slightly widened. A chest CT scan (Fig. 1) showed an anterosuperior mediastinal mass located in thymus gland. Plasma AVP concentration was determined, revealing extremely high levels (63.5 pg/mL; normal, <7.6 pg/mL).
The patient was treated with continuous 3% hypertonic saline (27 mL/hour) and the maximum dose of tolvaptan, which resulted in a marked improvement in SNa, although hyponatremia persisted throughout the hospitalization. She was discharged 10 days after admission, asymptomatic, with sodium levels of 130 mmol/L and was referred to thoracic surgery. Before surgery, she continued treatment with 60 mg of tolvaptan and sodium supplements daily (a salt diet with approximately 10 g of sodium). The patient underwent video thoracoscopy with total thymectomy.
Macroscopically, the tumor measured 7.2 × 6 × 4 cm. It was encapsulated, showing a heterogeneous cut surface with areas of necrosis, hemorrhage, and punctate calcifications. Microscopically, it consisted of a diffuse growth of small uniform cells with hyperchromatic nuclei, arranged in an eosinophilic fibrillar matrix consistent with a neuropil and vascular pattern. Immunohistochemical analysis was performed using the Ventana Benchmark System (Roche Laboratories, Basel, Switzerland) on formalin-fixed paraffin-embedded tissue sections cut to a thickness of 4 μm. The following antibodies were used: chromogranin A, synaptophysin, neuronal-specific enolase, CD56, S100 protein (prediluted, Roche Labs), and AVP (1:100, Merck-Millipore, Billerica, MA). AVP was positive in neuropil and cytoplasms of neuroblasts. Molecular analysis revealed no amplification of N-Myc and c-Myc.
SNa levels (140 mmol/L), blood osmolality, and plasma AVP concentration (<1.2 pg/mL) completely normalized 2 weeks after tumor removal. The treatment with tolvaptan was withdrawn

Q. What is the importance of measuring plasma AVP levels ?

Plasma AVP levels help determine etiology of SIADH. Very high AVP levels are generally seen in patients with cancer causing SIADH as in this case. Also in cancer patients it can be help to monitor response to therapy

Q. What is the side effect with chronic tolvaptan therapy ?
It can cause liver enzyme elevation and potential liver failure

Q. What are the two trials which have studied Tolvaptan use ?
1. EVEREST trial for heart failure
2. SALTWATER trial

Learning points from this case
1. Measurement of AVP may be useful to define etiology in patient with SIADH
2. Tolvaptan may be ineffective in patients with SIADH with very high AVP levels due to cancer.