J Neurol Neurosurg Psychiatry 83:510-512 doi:10.1136/jnnp-2011-300576
  • Neurosurgery
  • Short report

Syndrome of inappropriate secretion of antidiuretic hormone in traumatic brain injury: when tolvaptan becomes a life saving drug

  1. Carlo Selmi4
  1. 1Department of Medicine, Nephrology and Dialysis Unit, Istituto Clinico Humanitas IRCCS, Rozzano, Milan, Italy
  2. 2Department of Medicine, Nephrology and Dialysis Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
  3. 3Department of Neurology, Neurosurgery Unit, Istituto Clinico Humanitas IRCCS, Rozzano, Milan, Italy
  4. 4Department of Medicine, Autoimmunity and Metabolism Unit, IRCCS Istituto Clinico Humanitas, Rozzano, Milano, Italy
  1. Correspondence to Professor G Graziani, Istituto Clinico Humanitas IRCCS, Via Manzoni, 56 20089 Rozzano, MI, Italy; giorgio.graziani{at}
  1. Contributors GG: followed the patient, wrote the article and coordinated the coworkers. DC: wrote the article, collected the data and searched for bibliographic references. AA: collected data and searched for bibliographic references. CA: followed the patient and revised the manuscript. PG: followed the patient and collected the data. CS: revised the manuscript.

  • Received 27 May 2011
  • Revised 5 December 2011
  • Accepted 17 January 2012
  • Published Online First 9 February 2012


Objective To outline the role of a new drug, tolvaptan, in treating severe and chronic hyponatraemia. Tolvaptan decreases aquaporin expression in renal collecting ducts, by inhibiting antidiuretic hormone (ADH)-V2 receptors, to promote free water clearance. Given its mechanism of action, this drug seems the ideal treatment for the syndrome of inappropriate antidiuretic hormone secretion (SIADH) when the osmotic imbalance leads to life threatening complications.

Data sources A case is described of severe hyponatraemia deriving from SIADH secondary to meningoencephalitis in a patient admitted to hospital for traumatic brain injury.

Data extraction Clinical, laboratory and radiological data at presentation and for a 1 year of follow-up were analysed.

Data synthesis Tolvaptan ameliorated hyponatraemia, brain oedema and consciousness, and drug withdrawal led to recurrence of hyponatraemia and coma.

Conclusions In patients with SIADH, which is not self-limited, and is associated with severe cognitive impairment, the use Tolvaptan may prove life saving and should be rigorously evaluated.


Hypotonic hyponatraemia is a common finding among patients in a neurosurgery ward, with prevalence rates as high as 50%,1 defined by a sodium concentration <135 mmol/l associated with reduced plasma osmolarity (<280 mosmol/l). Such a decrease in plasma osmolarity causes intracellular oedema, a potentially fatal condition for the brain, where cell swelling exceeding 8% poses a serious risk for brainstem herniation.2 In this clinical setting, hyponatraemia may be induced by two major mechanisms: the syndrome of inappropriate antidiuretic hormone secretion (SIADH) and the cerebral salt wasting syndrome (CSW) (table 1). Both of these conditions may complicate brain diseases, particularly traumatic brain injury (TBI) or infections, and may follow neurosurgery. Therapy is commonly based on the careful management of water and electrolyte balance and involves fluid restriction or replacement depending on the diagnosis of SIADH or CSW.

Table 1

Features of the syndrome of inappropriate secretion of antidiuretic hormone and cerebral salt wasting syndrome

A new drug, tolvaptan (Samsca; Otsuka, Tokyo, Japan), has recently been introduced. This is a selective arginine–vasopressin V2 receptors antagonist, thought to be beneficial for hyponatraemia in SIADH patients.

We report the case of a patient with SIADH induced severe hyponatraemia following TBI. In this case, tolvaptan administration was followed by restoration of normal plasma sodium levels and coma regression. During the 16 week follow-up, an attempt to interrupt the medical treatment was associated with immediate relapse of SIADH, which rapidly regressed after tolvaptan re-introduction. This observation suggests that an irreversible lesion of the hypothalamus or pituitary gland occurred and, therefore, chronic treatment was started to avoid more episodes of coma.

Case report

A 47-year-old Caucasian man was admitted to the department of emergency medicine at our institute with severe head injury due to an assault. The patient was classified as having a Glasgow Coma Scale score of 6 (E2, V1, M3) and intubated for ventilation. A CT scan revealed multiple lacerative cerebral lesions with significant perilesional brain oedema. Plasma electrolytes were as follows: Na+ 140 mmol/l, K+ 3.4 mmol/l and Cl 87 mmol/l. An intracranial device for intracranial pressure monitoring (ICP) (Codman ICP Express, Raynham, Massachusetts, USA) was applied and ICP values ranged between 20 and 35 mm Hg in the days following admission. To reduce ICP the patient was first treated with mannitol, diuretics and hyperventilation without significant benefit and, subsequently, 4 days after admission, underwent a wide frontal bilateral craniotomy with drainage of the haemorrhagic components.

The postoperative days were uneventful with slow but progressive recovery of neurological functions and the patient became gradually alert and able to answer simple questions. Nevertheless, marked hemiparesis remained and for this reason, 2 months after the acute event, he was transferred to the local neurological rehabilitation unit. Two weeks after admission, meningoencephalitis due to Enterobacter cloacae was diagnosed following progressive impairment of consciousness, along with fever, headache and neck rigidity. CSF analysis showed hypoglycorrhachia (41 mg/dl), hyperproteinorrhachia (185.5 mg/dl) and 250/μl white blood cells. C reactive protein was 14.48 mg/dl, associated with absolute neutrophilia (9200/μl). In this setting, plasma sodium concentration suddenly decreased (119 mmol/l) without signs of hypovolaemia. Laboratory values of thyroid stimulating hormone (0.68 mIU/l), cortisol (13 μg/dl), prolactin (318 mIU/l) and gonadotropins were in the normal range, ruling out anterior pituitary dysfunction. Plasma osmolarity, based on sodium, blood urea nitrogen and glucose concentrations, was estimated to be 250 mosmol/l, along with a concomitant natriuresis of 270 mmol over 24 h, a picture consistent with SIADH (table 1).

Another brain CT scan demonstrated severe cerebral oedema (figure 1). Antibiotic therapy with ceftazidime and vancomycin, based on CSF culture, and hypertonic solution administration were started. Although CSF cultures became negative and C reactive protein levels declined to 1.34 mg/dl in 1 week, the patient remained comatose with a stable sodium level of approximately 120 mmol/l. As the hyponatraemia was resistant to electrolyte infusion, tolvaptan treatment was started at a dose of 15 mg/day. We observed a rapid rise in plasma sodium levels, which increased from 124 to 136 mmol/l in 24 h. The patient became progressively alert and a subsequent brain CT scan documented resolution of the brain oedema (figure 1), allowing the performance (7 months after admission) of a definitive custom made cranioplasty. After 2 months of stable plasma sodium levels and a stable clinical condition, we attempted to discontinue tolvaptan but observed a sudden decrease in plasma sodium associated with generalised seizures and lethargy. The drug was therefore reintroduced and prompt normalisation of the electrolyte profile and state of consciousness were observed.

Figure 1

Morphological changes in the brain detected at CT scan before and after tolvaptan administration.

After 6 months the patient remains on the same dose of tolvaptan, without major side effects, and neuromuscular function is slowly improving. At present, no other attempts to stop drug administration are foreseen.


Hyponatraemia may be a consequence of CNS lesions or may occur as a complication of heart failure, liver cirrhosis and other non-neurological diseases. The severity of this condition depends on both the rapidity of onset and the degree of hyponatraemia per se. An acute decrease in sodium levels below 125 mmol/l is a life threatening condition, rapidly inducing seizures, hypo-osmolar coma and cardiorespiratory arrest.3

In patients with mild to moderate hyponatraemia, where plasma sodium ranges from 125 to 135 mmol/l, the disequilibrium syndrome may be apparently asymptomatic. Nevertheless, it has been reported that neurological disturbances resembling acute alcohol intoxication may appear.4 In older patients, gait and reflex alterations may increase the risk of falls and bone fractures.5 Other symptoms related to hyponatraemia include lethargy, headache, restlessness, nausea, vomiting, muscle cramps and reflex reduction.

The most common cause of hyponatraemia among neurosurgical patients is SIADH, with a prevalence of approximately 60%.6 Surgical procedures, trauma, vascular accidents and infections may cause stimulation of neurons located in supraoptic and paraventricular nuclei of the hypothalamus with abnormal release of oxytocin and vasopressin (ADH) from the pituitary neural lobe. The non-osmotic ADH hypersecretion is followed by increased aquaporin expression at renal collecting ducts. Free water clearance inhibition causes water retention and extracellular volume expansion. However, patients do not become hypervolaemic because sodium handling mechanisms are intact: plasma renin activity is suppressed and brain natriuretic peptide secretion is enhanced.7 The consequent natriuresis restores euvolaemia but worsens hyponatraemia. In the setting of brain lesions, CSW may also induce hyponatraemia, which is associated with renal salt wasting and extracellular volume depletion (table 1). The differential diagnosis of CSW and SIADH is essential because water restriction is indicated for SIADH whereas salt and fluid resuscitation is mandatory in the latter.

The plasma sodium level at which hyponatraemia should be further evaluated and treated is not well defined. Recently, Rahman et al1 proposed that it should be <131 mmol/l. If hyponatraemia causes brain oedema and affects the patient's state of consciousness, an aggressive treatment is mandatory. Nevertheless, rapid correction of natraemia may lead to osmotic demyelination, a condition as dangerous as brain oedema, resulting in dysarthria, affective changes, quadriplegia, pseudobulbar palsy, respiratory paralysis and, ultimately, coma.8

A new family of drugs, the vaptans, has recently become available to treat hyponatraemia in patients with SIADH. These drugs reduce aquaporin expression at collecting duct cells, promoting free water clearance. Given this pharmacological action, this medication appears to be the ideal treatment for SIADH.

The use of vaptans in neurosurgical patients is poorly documented and recent reports have demonstrated an effective role for another drug in this family, conivaptan, used as an intravenous bolus for increasing natraemia in the intensive care unit setting.9 The authors documented its effectiveness in raising sodium levels for at least 72 h after administration.

We have described the benefits associated with oral tolvaptan for prolonged use in SIADH in a patient with severe hyponatraemia resulting in brain oedema and coma. Tolvaptan allowed normalisation of plasma sodium and restoration of consciousness. Moreover, when the drug was later discontinued, hyponatraemia relapsed, causing generalised seizures and lethargy. This observation suggests that the patient suffered irreversible damage to the hypothalamus or neurohypophysis and became dependent on the drug. The direct dependence of consciousness on hyponatraemia correction is clearly demonstrated by the morphological changes in the brain detected at CT scan. In fact, parenchymal oedema reversed after drug administration when the patient regained consciousness (figure 1). To prevent the risk of myelinolysis, a gradual dosage of the drug is essential. At the onset of treatment we recommend a dose of 15 mg/day, which on follow-up may be gradually increased to 60 mg/day. Side effects commonly observed are thirst, dry mouth, asthenia, polyuria, constipation and hyperglycaemia, but the occurrence of pontine myelinolysis is a catastrophic eventuality that physicians must prevent with cautious dosage of the drug and continuous monitoring of sodium concentration.


We believe this is the first published case of an irreversible tolvaptan dependent hyponatraemia deriving from TBI induced meningoencephalitis where the drug proved to be life saving. When chronic SIADH develops, the physician should take into account the fact that patients may be effectively managed with this new type of drug, taken orally once a day. Clinical trials are needed to better demonstrate the effectiveness of tolvaptan in neurosurgical patients in whom hyponatraemia could impair prognosis and neurological recovery.


  • Competing interests None.

  • Patient consent Obtained.

  • Provenance and peer review Not commissioned; externally peer reviewed.


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