Why siadh hyponatremia

She has normal orthostatic vital signs. Her mucus membranes are moist and she has no jugular venous distension, edema, or ascites. Additional labs include serum thyroid stimulating hormone 1. She receives 2 L isotonic saline intravenously over 24 hours, with resulting P Na of Hyponatremia is a state of excess water compared with the amount of solute in the extracellular fluid.

To aid in diagnosing the etiology of hypotonic hyponatremia, the differential is traditionally divided into categories based on extracellular fluid volume ECV status, as shown in Table 1 below , with syndrome of inappropriate antidiuretic hormone secretion SIADH being the most common cause of euvolemic hyponatremia.

The gold standard for assessing ECV status is by radioisotope, which is not practically feasible. Another challenge lies in the interpretation of U Na , which frequently is used as a surrogate for extra-arterial blood volume EABV status. In these situations, measurement of the change in P Na concentration after a test infusion of isotonic saline is helpful. Given these challenges, recommendations to use an algorithmic approach for the evaluation and diagnosis of hyponatremia have surfaced.

Management of acute and symptomatic hyponatremia. When hyponatremia develops acutely, urgent treatment is required see Figure 2, below. Small case reviews in the s began to associate postoperative deaths with the administration of hypotonic fluids. Acute hyponatremia or neurologically symptomatic hyponatremia regardless of duration requires the use of hypertonic saline. Recent observations focused on the initial four hours from onset of hyponatremia suggest a higher rate of correction can be tolerated without complications.

Subsequent treatment with hypertonic fluid might not be needed if symptoms resolve. Management of chronic hyponatremia. Hyponatremia secondary to SIADH improves with the treatment of the underlying cause, thus an active search for a causative medication or condition should be sought see Table 1, p.

Water restriction. The severity of fluid restriction is guided by the concentration of the urinary solutes. Saline infusion. The infusion of normal saline theoretically worsens hyponatremia due to SIADH because the water is retained while the salt is excreted.

However, a trial of normal saline sometimes is attempted in patients in whom the differentiation between hypovolemia and euvolemia is difficult. However, the hyponatremia following pituitary surgery can also be due to cortisol deficiency and CSW. Patients with CSW are usually volume depleted and further fluid restriction in CSW can lead to dangerous consequences. Use of vasopressin, desmopressin or oxytocin can cause SIADH by increasing the activity of vasopressor-2 V2 vasopressin receptor.

Two genetic syndromes, one affecting the gene for renal V2 receptor and the other affecting osmolality sensing in hypothalamus, have been identified. The former is called nephrogenic syndrome and the latter is termed as hypothalamic syndrome.

In the nephrogenic syndrome, a gain-of-function mutation in the gene for V2 receptor, which is located on the X chromosome, has been identified[ 20 ] V2 vasopressor receptor is responsible for water reabsorption in the renal collecting duct.

Gain-of-function mutation in the gene for V2 receptor results in persistent activation of receptor. In the hypothalamic syndrome, mutation in the transient receptor potential vanilloid type 4 TRPV4 gene has been identified.

Loss of function nonsynonymous polymorphism in this gene affects the sensing of hypo-osmolality. This interferes with appropriate suppression of ADH release in the presence of hypo-osmolality. Adrenal insufficiency, opportunistic infections and malignant diseases associated with HIV infection may also contribute to the development of hyponatremia.

Certain basic principles of fluid and electrolyte balance need to be kept in mind when analyzing a case of hyponatremia. Two-thirds of total body water is intracellular and one-third is extracellular.

When the sodium concentration in the ECF changes, it is the water which moves across membranes to maintain stable osmolality across the two compartments. Hence, irrespective of the etiology, hyponatremia indicates swollen cells.

This is initiated by downregulation of Na channels in the proximal tubules of the kidneys. Hyponatremia in SIADH is a result of excess water and is not primarily due to serum sodium deficiency. It is the combination of water retention together with secondary solute loss, which results in reduction in serum sodium. Hyponatremia is mediated initially by ADH-induced water retention that results in volume expansion which activities secondary natriuretic mechanisms causing sodium and water loss and restoration of euvolemia.

This euvolemia should not be confused with normal water content of the body. The dynamic nature of the natriuresis in the acute states creates problems in management. The role of natriuretic peptides in patients with SIADH has been a topic of discussion, and at least in a selected group of patients the natiuretic peptides do seem to play a role, albeit minor, when compared to their dominant role in CSW.

However, the clinical assessment of volume status is often inaccurate when done even by experienced physicians. In chronic hyponatremia, the water retention and sodium loss are well balanced and the serum Na is usually stable.

There are several clinical conditions, which manifest as hyponatremia, and SIADH should be differentiated from such disorders. Table 2 enlists few of these conditions. Pseudohyponatremia is associated with normal serum osmolality. In these situations, the measured sodium concentration in total plasma volume will be reduced as it contains less plasma water.

In fact, the plasma water as such will have normal sodium content and normal osmolality. Serum glucose levels must be monitored to rule out hyperglycemia, which results in decrease in the measured serum sodium levels as the osmotic effect of glucose draws water into the intravascular space. Chest X-ray and in selected cases, computed tomography CT scan of head may be appropriate to reveal an underlying cause. Identify whether the hyponatremia is acute or chronic.

This is the time that the brain cells take to generate osmotically active particles in response to the cellular swelling. As a general rule, if the patient is completely asymptomatic, the hyponatremia is most likely a chronic one.

If clearly known to be acute, correction can be fast. The source of retained effective water has to be identified and stopped. If possible, the underlying cause should be treated. Reviewing the medication chart and drugs prior to admission is worthwhile and is often rewarding. Dextrose based intravenous fluids which are commonly used in postoperative setting can result in hyponatremia. Treatment of chronic hyponatremia varies from that of acute hyponatremia.

Hyponatremia correction should be done cautiously to avoid the risk of inducing osmotic central pontine myelinolysis especially in chronic hyponatremia.

There are two formulas which are commonly used for calculating the deficit, and there are few issues associated with using these formulas, which should be taken into account:. What are the problems associated with this formula? It assumes constant total body water and also fails to take into account the volume of fluid infused. SIADH is associated with water retention, and hence the total body water is higher in the hyponatremic state. Secondly, it assumes a closed system.

We have to make assumptions about the amount of Na excreted and this has to be added to the deficit to determine the amount to be infused in 24 hours. This is especially problematic in acute hyponatremia when there may be significant alterations due to the sodium loss in the urine. This formula is better in that the infusate volume is taken into account. Again, it fails to take into account the increase in ICF in the hyponatremic state.

The above-mentioned fallacies explain the unsatisfactory results obtained sometimes on using these formulae. Treatment should be tailored on individual basis and these formulas should only act as rough guides. Alternate approaches based on the principles of tonicity balance are available.

This can be a bit laborious at times, but probably is worth mentioning. The principles are outlined[ 28 ] here briefly.

The number of osmotically active particles in the ICF is relatively constant. This, divided by the current low serum Na, gives the current ICF volume. This allows calculation of the fluid that has to be lost by water restriction.

The Na deficit has to be calculated separately. Always consider the urine Na concentration. Use a fluid with concentration of Na above that in the urine to bring up the Na levels. There are several online calculators [ Table 3 ] available to help physicians with the sodium correction in hyponatremia.

Again, these should be used only as guides. It must be remembered that each patient is unique and an individualized treatment plan is often needed. Fluid restriction to less than the urine output is the primary therapy in hyponatremia. In the setting where hyponatremia is associated with head trauma, subarachnoid hemorrhage, etc.

These patients are usually volume depleted and further fluid restriction can be dangerous to the patient. It should be noted that aldosterone is unaffected in SIADH and the sodium balance will be usually normal. If isotonic saline is administered, the water will be retained and sodium will be excreted in urine, leading to possible worsening of hyponatremia. Hypertonic saline raises serum sodium, but the response will partially dissipate over time. The effect of salt tablets can be enhanced by administration of a loop diuretic like furosemide which interferes with the countercurrent concentrating mechanism by decreasing sodium chloride reabsorption in the thick ascending limb of loop of Henle.

This results in excretion of isotonic urine and considerable fluid loss. The usual dose is 9 g salt daily with 20 mg oral furosemide twice a day. Antidiuretic response is mediated by V2 receptor, while V1a and V1b receptors cause vasoconstriction and adrenocortcotropic hormone ACTH hormone release. Vasopressin receptor antagonists produce a selective water diuresis without interfering with sodium and potassium excretion.

Tolvaptan, satavaptan and lixivaptan are selective V2 receptor antagonists, while conivaptan blocks both V1 and V1a receptors. In a randomized controlled trial, intravenous conivaptan significantly raised serum sodium concentration. The use of V2 receptor antagonists is limited due to increased thirst,[ 35 ] rapid correction of hyponatremia as demonstrated in SALT trials and the high cost. Vasopressin receptor antagonists should not be used in hyponatremic patients who are volume depleted.

It is a tetracycline derivative which induces drug-induced diabetes insipidus by acting on the collecting tubule cell to diminish its responsiveness to ADH.

Rapid correction of hyponatremia can lead to central pontine myelinolysis. The risk is highest in premenopausal women. Osmotic demyelination syndrome ODS occurs with rapid correction of severe hyponatremia.

There are several risk factors for ODS which include serum sodium concentration at presentation, duration of hyponatremia and rapid rate of correction, alcoholism, malnutrition, liver disease and hypokalemia. Clinical features can be delayed by a few days after rapid sodium correction. Symptoms include neurological manifestations like dysarthria, dysphagia, paraparesis, quadriparesis, confusion, coma, etc. Seizures are very rare.

Locked-in syndrome can occur when there is bilateral pontine demyelination. ODS can be detected by magnetic resonance imaging MRI scan, but it may take up to 4 weeks to become positive. Hence, a negative study earlier in the course does not rule out ODS.

Hyponatremia is a common feature in oncology practice [ 37 ], occurring most frequently in patients with SCLC [ 38 ]. Type A is characterized by an unregulated, erratic, secretion independent of the prevailing plasma osmolality. Type B is characterized by an elevated basal secretion of vasopressin, despite normal regulation by osmolality. Type D is characterized by undetectable vasopressin levels some of these patients may have gain-of-function mutations in the vasopressin V 2 receptor [ 15 , 45 , 46 ].

Patterns of plasma vasopressin levels where compared with plasma sodium levels in patients with SIADH [ 15 ]. The shaded area represents normal values of plasma vasopressin. Many of these patients respond to the administration of vasopressin receptor antagonists with an aquaresis, suggesting that they have low levels of inappropriate vasopressin secretion despite the difficulty measuring such low levels.

An exception is a patient group with gain-of-function mutations in the vasopressin V 2 receptor—identified in infants with clinical and laboratory features consistent with the presence of SIADH but with undetectable vasopressin levels—who do not appear to respond to the administration of vasopressin receptor antagonists [ 45 , 48 ]. Although this mutation appears to be a rare cause of hyponatremia at this time, the term SIAD would comprise these patients.

It is therefore important to continuously monitor sodium levels carefully in such patients as vasopressin levels can increase randomly. Although this patient was treated with fluid restriction, it is nowadays likely that therapy with an oral vasopressin V 2 receptor antagonist, i. Tolvaptan acts by antagonizing the effects of endogenous vasopressin at the V 2 receptors in the renal collecting duct. Urine excretion of sodium and potassium is not significantly affected.

The effects of tolvaptan on this patient are shown in Figure Case 4: response to tolvaptan therapy. This overcorrection was likely influenced by the patient continuing to limit his fluid intake following the initiation of tolvaptan despite feeling thirsty. Consequently, it is important to advise patients that they can, and should, drink fluid in response to thirst during tolvaptan therapy.

A year-old man previously in good health except for hyperlipidemia was found unconscious in his bathroom. After awakening, he complained of a severe headache. On transfer to a university hospital, he was awake and oriented with no focal neurological deficits but was noted to be drowsy and lethargic with intermittent nausea and vomiting. The patient was admitted to the neurosurgical ICU, where his blood pressure was controlled with labetalol and hydralazine drips.

A cerebral angiogram revealed an anterior communicating artery aneurysm, which was successfully occluded by insertion of a coil by interventional neuroradiology. He was started on nimodipine for vasospasm prophylaxis and diphenylhydantoin for seizure prophylaxis. An external ventricular drain was placed to control intracranial pressure.

Triple-H therapy i. On evaluation by the endocrinology department, the patient was clinically euvolemic. BUN was 2. Thyroid function was normal: free T4 was Analysis of the intakes and outputs showed that the patient had been in a positive fluid balance each day over the first week of hospitalization. Based on the patient's physical exam, laboratory values and clinical course, he was assessed to have euvolemic hyponatremia that was unresponsive to NaCl administration, which met the criteria for a diagnosis of SIADH Table 1.

Although fluid restriction was relatively contraindicated in this case, it likely would not have been effective even if employed in view of the high urine to plasma electrolyte ratio that ranged from 0.

Patients with acute neurological disorders, such as SAH, represent an especially challenging group of patients with hyponatremia. This is because the mild degrees of cerebral edema produced by hyponatremia that would not cause significant neurological symptoms in normal brains, can worsen both symptoms and recovery from already damaged brain tissue as a result of increased intracranial pressure [ 50 ]. Consequently, both avoidance of hyponatremia, and prompt and effective treatment of hyponatremia, when it occurs, is a crucial aspect of management in patients with acute neurological disorders.

The degree to which hyponatremia occurs primarily as a result of natriuresis has remained controversial for many years. Cerebral salt wasting CSW was first proposed by Peters in [ 51 ] as an explanation for the natriuresis and hyponatremia that sometimes accompanies intracranial disease, particularly SAH, in which up to one-third of patients often develop hyponatremia.

Following the first clinical description of SIADH in [ 25 ], such patients were generally assumed to have hyponatremia secondary to vasopressin hypersecretion with a secondary natriuresis [ 52 ]. However, over the last decade, clinical and experimental data have suggested that some patients with SAH and other intracranial diseases may actually have a primary natriuresis leading to volume contraction rather than SIADH [ 53 — 56 ]; in which case, the elevated measured plasma vasopressin levels may actually be physiologically appropriate for the degree of volume contraction present.

The major clinical question as to the frequency of CSW as a cause of hyponatremia is dependent on the criteria used to assess the extracellular fluid ECF volume status of these patients; opponents argue that there is insufficient evidence of true hypovolemia despite ongoing natriuresis [ 57 ], whereas proponents argue that the combined measures that have traditionally been used to estimate ECF volume do in fact support the presence of hypovolemia in many cases [ 58 , 59 ].

With regard to the potential mechanisms underlying the natriuresis, in both plasma and cerebrospinal fluid CSF , atrial natriuretic peptide ANP and brain natriuretic peptide BNP , levels are clearly elevated in many patients with SAH [ 56 , 60 — 62 ] and have been found to correlate variably with hyponatremia in patients with intracranial diseases [ 56 , 62 , 63 ]. But, characteristic of these disorders, normalization of ECF volume with isotonic NaCl infusions restores plasma tonicity to normal ranges by virtue of shutting off the secondary vasopressin secretion.

If hyponatremia in patients with SAH occurred via a similar mechanism, it should also respond to this therapy. However, studies indicate that it does not. In contrast, other studies have demonstrated that mineralocorticoid therapy to inhibit natriuresis can reduce the incidence of hyponatremia in patients with SAH [ 65 ]; such results are not unique to patients with intracranial diseases, since a subset of elderly patients with SIADH have also been shown to respond favorably to mineralocorticoid therapy [ 66 ].

Although seemingly disparate, these types of results support the existence of disordered vasopressin secretion as well as a coexisting stimulus to increased natriuresis in many such patients.

It seems most likely that SAH and other intracranial diseases represent a mixed disorder in which some patients have both exaggerated natriuresis and inappropriate vasopressin secretion; which effect predominates in terms of the clinical presentation will depend on their relative intensities, as well as the effects of concomitant therapy.

This patient was initially assumed to have CSW as a result of hyponatremia with an elevated urine sodium excretion. However, the patient never actually met criteria for a diagnosis of CSW, since volume depletion resulting from natriuresis was never documented.

Subsequent therapy with the vasopressin receptor antagonist tolvaptan produced correction of the hyponatremia as a result of the induced aquaresis, thereby documenting vasopressin-induced water retention as the major etiological factor causing this patient's hyponatremia. Treatment of hyponatremia in patients with acute neurological injury is challenging.

Patients with SAH have been shown to have worse outcomes with fluid restriction, presumably as a result of vasospasm [ 54 ]. This has led to the widespread use of triple-H therapy to decrease the risk of vasospasm [ 49 ], though definitive evidence in support of this therapy is lacking [ 67 ]. Based on these findings, treatment of patients with true CSW using vaptans would be contraindicated, since such patients are by definition hypovolemic, which is a contraindication to the use of vaptans because of the risk of worsening volume depletion with resulting hemodynamic instability, hypotension and, in this group of patients, increased risk of vasospasm.

However, the widespread employment of triple-H therapy effectively eliminates the possibility of CSW in most patients as a result of the volume expansion produced by NaCl administration, whether as oral, isotonic or hypertonic NaCl administration, or all three as in this case. When hyponatremia persists in the face of volume expansion, then it can only be due to vasopressin-induced water retention, which was proved by the favorable response to tolvaptan in this case.

Consequently, even if this patient had a component of salt wasting due to CSW, his clinical picture was clearly one of euvolemic hyponatremia from SIADH, thereby making vaptan therapy an appropriate choice. This case illustrates three additional important aspects of clinical use of vaptans. First, caution must be used when using vaptans in combination with other therapies for the treatment of hyponatremia.

Extra caution should be employed if fluid restriction is used in combination with vaptan therapy to ensure that dehydration does not occur patients should have access to drinking water , and concomitant use with hypertonic saline is not recommended in order to avoid the possibility of overly rapid correction of the hyponatremia with subsequent risk of precipitating the ODS [ 17 ].

Secondly, effective therapy of hyponatremia is often a major determinant of patient discharge from ICUs and hospitals. In this case, continued use of ineffective therapies such as excessive NaCl administration would very likely have further prolonged this patient's hospital stay. Finally, many cases of hyponatremia are transient and resolve following treatment of the underlying disease process causing the hyponatremia. SAH is a classic example of this situation, in which the hyponatremia typically resolves 2—4 weeks after the clearance of blood products from the CSF.

Which patients should be discharged on vaptans to maintain normonatremia, and for how long, therefore depends critically upon the underlying etiology of the hyponatremia Figure 12 [ 68 ]. Estimated probability of need for long-term treatment of SIADH depending on underlying etiology [ 68 ]. Adapted from Verbalis [ 68 ]. As stated in the introduction to this article, among the many reasons why the diagnosis and treatment of hyponatremia remains far from optimal is the heterogeneous nature of the disorder, including a wide variety of possible etiologies, variable symptomology and differing fluid volume status.

The five cases presented here abundantly illustrate the marked heterogeneity in the presentations of hyponatremia. As always is the case in medical practice, therapy in each case must be individualized to the patient. But despite their many differences, the cases presented here also illustrate that adherence to accepted guidelines for the diagnosis of SIADH and rational decision-making among the available therapeutic options for treating hyponatremia, importantly including the new class of vasopressin receptor antagonists, can achieve desirable outcomes in the majority of cases.

The case emphasizes several important points about management of hyponatremia. As discussed by Dr Burst, employment of simple calculations such as the urine to plasma electrolyte ratio can identify patients in whom fluid restriction is likely to be ineffective, or even dangerous by virtue of negative electrolyte-free water clearance, as summarized in Table 5 [ 27 ].

Rather than assuming that all patients with SIADH should have an initial trial of fluid restriction, intelligent decision-making in should employ a careful analysis of which patients are likely to respond, and to what degree, before choosing an initial therapy.

This case raises the important issue of the appropriate choice of initial therapy of patients with SIADH; a careful assessment of the patient's likelihood of responding to individual therapies is clearly superior to choosing treatments simply because they are typically employed in such patients. A second important point made by this case is that not all patients with malignancies have tumor-induced hyponatremia.

There is no question that this patient met standard criteria for SIADH as shown in Table 1 , but the list of potential etiologies of SIADH is long Table 7 , and one must consider many possibilities in patents with malignancies.

The finding that this patient more likely had a pneumonia-induced SIADH had important implications for her long-term therapy, since it allowed discontinuation of the tolvaptan after successful therapy of the pneumonia; had this truly been tumor-associated SIADH, the patient would likely have required more chronic therapy for the hyponatremia Figure Case 2 represents another common cause of SIADH, namely both acute and chronic neurological disorders.

There is no question that this is the appropriate therapy for patients with severe symptomatic hyponatremia, as in this case.

However, even in the best hands at advanced academic medical centers, overly rapid correction of hyponatremia remains a potential risk using hypertonic saline [ 69 ]. The most likely reason is that this was an acute hyponatremia. Studies in experimental animals have shown that the brain adapts to chronic hyponatremia by loss of solute, both as electrolytes and organic osmolytes.

Because the degree of osmotic brain shrinkage is greater in animals that are maintained chronically hyponatremic than in normonatremic animals undergoing similar increases in plasma osmolality [ 70 — 72 ]; by analogy, the brains of human patients adapted to hyponatremia are likely to be particularly susceptible to dehydration following subsequent increases in osmolality, which in turn can lead to pathological demyelination in some patients.

MRI studies have shown that chronic hypo-osmolality predisposes rats to opening of the blood—brain barrier following rapid correction of hyponatremia [ 73 ], and that the disruption of the blood—brain barrier is highly correlated with subsequent demyelination [ 74 ]; a potential mechanism by which blood—brain barrier disruption might lead to subsequent myelinolysis via an influx of complement, which is toxic to the oligodendrocytes that manufacture and maintain the myelin sheaths of neurons into the brain [ 75 ].

Of the factors that clearly influence the susceptibility to demyelination following correction of hyponatremia, perhaps most important are the severity and duration of the pre-existing hyponatremia. Both of these risk factors likely relate to the degree of brain volume regulation that has occurred prior to the correction: the more severe the hyponatremia and the longer it has been maintained, the greater the degree of solute loss that will have occurred during the process of brain volume regulation.

Clinical implications of this pathophysiological mechanism are that ODS should not occur in cases of either mild or very acute hyponatremia. Both of these findings have been found to be true. However, there is no clinical evidence to support the recommendation of this for cases of acute hyponatremia, as in this case. Typical scenarios in which hyponatremia develops acutely are water intoxication from severe polydipsia in psychiatric patients, hyponatremia that occurs 24—48 h postoperatively, especially in neurosurgical patients, and exercise-associated hyponatremia following marathon and ultramarathon endurance events.

However, it occurred in a patient who represents the patient population at greatest risk of hyponatremia, namely the elderly.

Many different factors are responsible for the high prevalence of hyponatremia in the elderly, including drugs, particularly thiazide diuretics and selective serotonin reuptake inhibitors antidepressants, low solute diets, underlying co-morbidities such as heart failure and lung disease, and SIADH of multiple etiologies. Unexplained or idiopathic causes of SIADH account for a relatively small proportion of all cases of SIADH, and the numbers of patients in whom an apparent cause cannot be established after consistent follow-up over time are relatively few.

However, an exception to this appears to be elderly patients who sometimes develop SIADH without any apparent underlying etiology [ 87 — 89 ]. Coupled with the significantly increased incidence of hyponatremia in geriatric patients [ 1 , 85 , 86 , 90 — 92 ], this suggests that the normal ageing process may be accompanied by abnormalities of regulation of vasopressin secretion that predispose to SIADH. Such an effect could potentially account for the fact that virtually all causes of drug-induced hyponatremia occur much more frequently in elderly patients [ 93 — 95 ].

Infusion of isotonic saline was shown to be ineffective in the first patients described to have SIADH by Schwartz et al. Given what has long been known about the futility of using isotonic saline in patients with SIADH, it remains surprising how often this therapy is employed as the initial therapy of such patients. Luckily, in this case, the patient was treated more efficaciously following an appropriate evaluation that documented a diagnosis of SIADH.

In contrast to case 1, utilization of the urine to plasma electrolyte ratio Table 5 prevented subsequent employment of fluid restriction as a second ineffective treatment, and therapy with tolvaptan allowed the patient to be discharged sooner than undoubtedly would have been the case had a fluid restriction been employed.

Case 4 illustrates a case of SIADH produced by small-cell carcinoma of the lung, the disease of the index cases of SIADH and still the most common tumor associated with inappropriately elevated vasopressin levels and hyponatremia. It is of interest that this patient was admitted with a normal sodium level and only became hyponatremic following admission to the hospital.

Peri hypothesizes that this may have been due to the production of more severe SIADH with the institution of opiate therapy. This is certainly possible, and would fit the time course of the hyponatremia. This is especially true of the elderly, who are known to have a decreased thirst response [ ]; in effect, they have a self-imposed fluid restriction, but when subjected to intravenous fluids as well as medications that further reduce free water excretion, they manifest the hyponatremia characteristic of SIADH.

Evidence in support of a disordered thirst mechanism in this patient is the development of hypernatremia with tolvaptan therapy. Case 5 illustrates a case of hyponatremia accompanying SAH, one of the most common causes of hyponatremia with acute neurological injury. Although in some ways similar to case 2, this case highlights why CSW cannot account for the development of hyponatremia in most cases with neurological injury.

Typical of many such cases, the patient was initially assumed to have CSW as a result of hyponatremia with an elevated urine sodium excretion, but never actually met criteria for a diagnosis of CSW since volume depletion resulting from natriuresis was never documented [ ].

When this occurs, therapy with vaptans is an appropriate consideration to correct the hyponatremia and prevent potentially detrimental increases in intracranial pressure. Although not specifically illustrated via a case study in this supplement, a careful drug history is essential in patients with SIADH as hundreds of different medications can potentially cause hyponatremia Table 8 [ 35 ].

Discontinuation of treatment with these agents and avoidance of readministration is an effective management strategy in such cases Figure 3. Despite the heterogeneous nature of these five cases, including age, disease process, acuity of hyponatremia and symptomatology, there are significant commonalities across all of the presented cases that deserve emphasis:. In all cases, the necessary clinical and laboratory evaluations were eventually, though not always initially, obtained to make a definitive diagnosis of SIADH Table 1.

Too often, treatment for hyponatremia is started without performing the analyses needed to confirm the correct diagnosis Figure 3.

In most of the cases, initial therapies were chosen that were ineffective, or actually worsened the hyponatremia, including isotonic saline administration, NaCl tablets and fluid restriction. These errors could have been avoided, for the most part, by the evaluation of the patient's initial presentation.

More careful initial analysis of the clinical scenario, importantly including consideration of the urine and plasma laboratory values, could have led to employment of more effective therapies sooner, as was demonstrated in case 4. Treatment with vaptan therapy was successful in cases that were refractory to other therapies, usually leading to quicker hospital and ICU discharge. Obviously, the above characteristics will not be applicable to all cases, nor will the treatment decisions made be the same.

However, the cases in aggregate emphasize that paying attention to known principles of diagnosis and treatment can result in better outcomes for patients with hyponatremia from SIADH by choosing initial therapies according to a careful analysis of the patient's presenting clinical characteristics, rather than indiscriminate employment of typical therapies that are too often ineffective or deleterious.

Ltd, and has received a research grant from Otsuka America, Inc. This supplement was commissioned by Otsuka Pharmaceutical Europe Ltd. The authors have not received any honorarium in relation to this supplement. The authors would like to thank apothecom for editorial assistance in the preparation of this supplement. National Center for Biotechnology Information , U.

Journal List Clin Kidney J v. Clin Kidney J. Verbalis 5. Joseph G. Author information Copyright and License information Disclaimer. Correspondence and offprint requests to: M. Laville; E-mail: rf.

All rights reserved. For permissions, please email: journals. For commercial re-use, please contact journals. This article has been cited by other articles in PMC. Introduction M. Rationale for the treatment of hyponatremia Hyponatremia at admission has been shown to be associated with increased length of stay LOS and cost of care for hospitalized patients [ 6 ]. Open in a separate window. Figure The syndrome of inappropriate secretion of antidiuretic hormone Approximately one-third of all cases of hyponatremia are accounted for by the syndrome of inappropriate secretion of antidiuretic hormone SIADH [ 13 ], a condition first described by Bartter and Schwartz [ 14 ].

Table 1. The management of SIADH Owing to a relative lack of randomized controlled trials, the treatment of SIADH is largely based on expert opinion and uses agents commonly approved for indications other than for hyponatremia [ 16 ]. Table 2. The advent of vasopressin receptor antagonists The recent introduction of orally available tolvaptan and parenteral conivaptan antagonists to the renal vasopressin receptor represents a new era in the management of SIADH.

Tolvaptan In the European Union, tolvaptan—the only orally administered vaptan—is approved for use in adults with hyponatremia secondary to SIADH [ 20 ].

Upcoming guidelines for the management of hyponatremia With the development of the vaptans, it has been suggested that these agents may become the mainstay of treatment for SIADH. A review of real-life cases For a condition that is frequently encountered in clinical practice and has the clinical consequences that hyponatremia does, its suboptimal diagnosis and management are a serious cause for concern. Case 1: year-old woman with a medulloblastoma V. Burst A year-old woman with a known medulloblastoma diagnosed 2 years previously went to see her oncologist for a scheduled check-up.

Table 3. Case 1: physical and laboratory data at scheduled check-up. Discussion When a patient presents with hyponatremia, there is a need to make a careful assessment of the volume status of the patient.

Table 4. Matrix for the differential diagnosis of the underlying etiology of hyponatremia. Table 5. Recommendations for fluid restriction. Case 2: year-old man with possible anaplastic oligoastrocytoma recurrence V. Burst A year-old man was transferred from a secondary hospital to a university hospital following suspicious magnetic resonance imaging MRI findings, which suggested a recurrence of his known anaplastic oligoastrocytoma and intracerebral bleeding Figure 4.

Case 2: treatment response and patient progress. ICU, intensive care unit. Discussion When considering the management of hyponatremia, the benefits of treatment must be balanced against the potential risks. Case 3: year-old woman presenting with mental confusion A. Peri An year-old Caucasian woman was brought in to the emergency department of the University Hospital in Florence suffering from mental confusion.

Table 6. Case 3: laboratory values at admission and diagnostic work-up. Discussion Chronic hyponatremia is associated with increased patient morbidity. Table 7. Table 8. Drugs affecting sodium and water homeostasis Diuretics Drugs affecting water homeostasis Antidepressants, antipsychotic drugs, opioids, antiepileptic drugs, anticancer agents Potentiation of vasopressin effect Antiepileptic drugs, antidiabetic drugs anticancer agents, non-steroidal anti-inflammatory drugs Reset osmostat Antidepressants, antiepileptic drugs Rare causes of drug-induced hyponatremia Antihypertensive agents, immune globulin intravenous , 3,4-methylenedioxymethamphetamine ecstasy , antibiotics, antiarrhythmic, theophylline, proton pump inhibitors, bromocriptine, terlipressin, duloxetine, fluorescein angiography, bupropion.

Case 4: year-old man presenting with a cough and hemoptysis A. Peri A year-old Caucasian man presented with a cough and hemoptysis, with which he had been suffering for the last 3 months.