Syndrome of inappropriate antidiuretic hormone secretion | Medicina Clínica (English Edition)

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Ku: urinary potassium; Nap: plasma or serum sodium; Nau: urinary sodium." ] ] ] "textoCompleto" => "Definition and pathogenesisSyndrome of inappropriate antidiuretic hormone secretion (SIADH) is a disorder of the regulation of renal excretion of free water. It is caused by the inability to suppress antidiuretic hormone (ADH) secretion, although it is not always associated with increased secretion of this hormone, which is why it has also been called syndrome of inappropriate antidiuresis (see below).Under normal conditions, ADH, also known as vasopressin, regulates the variable excretion of water from the kidney. It is synthesized in the hypothalamus and released from the posterior pituitary gland into the bloodstream. There are several receptors for ADH. V1 receptors are located mainly in the vascular smooth muscle fibre and are responsible for vasoconstrictor action (non-osmotic action). On the other hand, V2 receptors are located mainly in the renal collecting tubule and are the mediators of the osmotic ADH action. When activated, they are responsible for the insertion of the aquaporin 2 channel in the apical membrane of the collecting tubule, which allows the reabsorption of free water. Thus, ADH plays a fundamental role in the regulation of body water and, therefore, of plasma osmolality. When plasma osmolality (determined largely by plasma sodium) rises above 284 mOsm/kg, ADH is stimulated to concentrate urine (increase urine osmolality), prevent body water loss, and thus return plasma osmolality to its normal level. In contrast, an osmolality below 275 mOsm/kg, reflecting diluted plasma, should, under normal conditions, completely suppress ADH secretion.<a class="elsevierStyleCrossRef" href="#bib0005">1</a>SIADH should be suspected in any patient with hypoosmotic hyponatremia (low plasma osmolality) and urine osmolality >100 mOsm/kg. This urine osmolality reflects the action of ADH, which is inadequate in this case, as it should be suppressed due to the state of plasma hypoosmolality. SIADH has been considered an exclusive disorder of plasma water, with extracellular fluid volume expansion dilutional hyponatremia. However, the transient expansion of blood volume it produces promotes urinary sodium excretion, a phenomenon known as desalination. This process favours the restoration of blood volume, but, on the other hand, it worsens hyponatremia. Although there is an increase in blood volume in SIADH, patients do not usually experience oedema, because total body sodium is normal or low, the increase in blood volume does not usually exceed 4 L, and finally, the increase in total body water is concentrated in the intracellular space. The expansion of blood volume is not unlimited, as it would have catastrophic clinical consequences, and ceases to occur at a certain level due to what is known as vasopressin escape, which appears to be mediated by a reduction in the expression of aquaporin 2 channels in the collecting tubule.<a class="elsevierStyleCrossRef" href="#bib0010">2</a>Clinical evaluation and diagnostic criteriaHyponatremia is the most common electrolyte disorder in clinical practice, occurring in between 15% and 30% of hospitalized patients.<a class="elsevierStyleCrossRef" href="#bib0015">3</a> In addition, it is associated with high morbidity and mortality in different clinical contexts.<a class="elsevierStyleCrossRef" href="#bib0020">4</a> Therefore, the clinician must be acquainted with the detection and management of this disorder. When plasma sodium is found to be below 135 mmol/L and the cause is not obvious, measurement of osmolality is very useful (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). If elevated, the presence of active osmoles in plasma must be ruled out, such as excess glucose, mannitol or high amounts of contrast, which cause translocation hyponatremia. If plasma osmolality is normal, pseudohyponatremia, which is mainly caused by excess plasma triglycerides, which reduce plasma water, should be ruled out because it will affect the measurement when the laboratory method includes sample dilution. This does not apply if the sodium determination is carried out directly with ion-sensitive electrodes. Another cause of pseudohyponatremia is the accumulation of gamma globulins (they are cationic) in the case of paraproteins or the administration of large amounts of gamma globulins (2 g/kg in 2–5 days).<a class="elsevierStyleCrossRefs" href="#bib0025">5,6</a><elsevierMultimedia ident="fig0005"></elsevierMultimedia>A reduced effective plasma osmolality defines true hyponatremia. The effective plasma osmolality is obtained by subtracting the urea nitrogen concentration in mmol/L from the measured osmolality or dividing it by 2.8 if it is expressed in mg/dL. In this case, measurement of urinary osmolality will help to identify primary polydipsia or low solute intake when it is less than 100 mOsm/kg. True hyponatremia with urine osmolality above 100 can have a variety of causes. In this case, a recent low urine sodium identifies volume depletion of extrarenal origin and oedematous states with decreased effective arterial volume. A urine sodium above 20 or 30 mEq/L reasonably rules out volume depletion of extrarenal origin and, if the use of diuretics or renal failure is ruled out and the patient is normovolemic, the most likely diagnosis is of SIADH. The presence of hypovolemia with elevated urinary sodium should lead to suspicion of renal loss of water and salt, either due to aldosterone deficiency, aldosterone resistance, or salt-losing nephropathy.The diagnosis of SIADH is one of exclusion, but a number of criteria must be met which, at present, are still the original ones described by Schwartz and Bartter in the publication of the first cases, re-issued by Schwartz et al.<a class="elsevierStyleCrossRef" href="#bib0035">7</a>. The most important criteria are urine osmolality >100 mOsm/kg and the presence of clinical euvolemia<a class="elsevierStyleCrossRef" href="#bib0040">8</a> (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). This urine osmolality is a surrogate marker of elevated ADH levels, which in a hyponatraemic and normovolemic patient is totally inadequate. In hypovolemic states, the activation of ADH is appropriate and in hypervolemic states this hormone is part of the neurohumoral activation typical of these conditions. Therefore, ADH levels are not essential for diagnosis, since urine osmolality >100 mOsm/kg already indicates a circulating excess.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Copeptin, a precursor of ADH, has been postulated as a useful tool in the diagnosis of water disorders as a marker of ADH, as it reflects ADH levels reliably, has a higher molecular stability than ADH and is easier and more reliable to measure. However, its value in the diagnosis of hypoosmolar states, such as SIADH, is low, since the levels are usually erratic.<a class="elsevierStyleCrossRef" href="#bib0045">9</a> It seems that its usefulness is much greater in the diagnosis of nephrogenic diabetes insipidus.<a class="elsevierStyleCrossRef" href="#bib0045">9</a>Since it is sometimes difficult to discern between clinical euvolemia and hypovolaemia because of the poor sensitivity of physical examination in the assessment of hyponatraemia,<a class="elsevierStyleCrossRef" href="#bib0050">10</a> laboratory data are a useful support but not diagnostic in themselves. Although a urine sodium ≤30 mEq/L identifies most patients who will respond to saline because they are depleted, it can sometimes be greater than 30 in these patients. In these cases, a fractional excretion (FE, excreted to filtered ratio) of sodium (FENa) <0.5% identifies all volume-depleted patients. In contrast, a FENa > 1% supports euvolemia and thus SIADH, although there is some overlap.<a class="elsevierStyleCrossRef" href="#bib0030">6</a> As there is an expansion of blood volume in SIADH, at least in the first days, before being “compensated” by desalination, there is an increase in FE of urea and uric acid, so we will find low concentrations of uric acid and of BUN (although this is more typical than common or constant). Therefore, it is worth emphasizing that additional laboratory data only serve to support the essential criteria. As for oral overload, it is not commonly used in clinical practice because of the potential danger of worsening hyponatraemia.To complicate matters somewhat, a patient with SIADH, especially in chronic and severe cases, may manifest as salt-depleted and thus not exhibit the diagnostic features from the onset.<a class="elsevierStyleCrossRef" href="#bib0030">6</a> In addition, a patient with SIADH may have a low urine Na if they are on a very low sodium diet.When in doubt about the hypovolaemic or euvolemic state of a patient, isotonic saline perfusion at a rate of 2 L over 24 or 48 h can be tried, provided the patient can tolerate it, followed by analysis of the response (serum Na and FENa).<a class="elsevierStyleCrossRefs" href="#bib0025">5,6,8</a> In patients with salt depletion, including cerebral salt wasting syndrome (CSW, see below), serum sodium will be high with minimal increase in FENa (less than 0.5), as these patients tend to avidly retain all the sodium administered to them. In contrast, the serum sodium response in SIADH patients is variable, but typically increase FENa by more than 0.5%, as they are usually in sodium balance and excrete almost all of the salt they receive. This is critically important as the administration of isotonic saline may worsen hyponatremia and have adverse clinical consequences in patients with SIADH. In this sense, urinary osmolality is essential to predict the response to saline in a patient with suspected SIADH. If it is close to 300 mOsm/kg, the serum sodium is likely to increase somewhat or remain unchanged and the patient will excrete the administered salt (308 mOsm in a litre of isotonic saline) in a volume of urine similar to that administered. However, if urinary osmolality is greater than 500 mOsm/kg, the 308 mOsm of salt administered will be eliminated in 600 mL of urine, with retention of 400 mL of free water due to the action of ADH and, therefore, with a worsening of hyponatraemia. Thus, the saline test should not be performed if SIADH is suspected, and urine osmolality is above 500 mOsm/kg.<a class="elsevierStyleCrossRef" href="#bib0025">5</a>Among the diagnostic criteria, it is established that cases of hyponatremia associated with glucocorticoid deficiency and severe hypothyroidism must be ruled out by means of hormone determinations,<a class="elsevierStyleCrossRef" href="#bib0055">11</a> as they can produce euvolemic hyponatraemia that is clinically and biochemically indistinguishable from SIADH.Although SIADH is the most common cause of euvolemic hyponatremia, the clinical reality is that it is underdiagnosed in most cases. Thus, an international registry including 1,524 patients with euvolemic hyponatraemia found that, of the patients with physician-diagnosed SIADH, only 47% met the original Schwartz and Bartter criteria (serum and urine osmolality, urine sodium), while 21% also had TSH and cortisol hormone determinations. Most strikingly, 11% of cases with a clinical diagnosis of SIADH had not had a single test performed.<a class="elsevierStyleCrossRef" href="#bib0060">12</a> Therefore, there is much room for improvement in the diagnosis of this syndrome which, as we shall see, is essential for the correct treatment of hyponatraemia.AetiologySIADH is a clinical manifestation of a wide variety of disorders and the use of certain drugs, and is the most common cause of euvolemic hyponatraemia in hospital practice. The most common causes of SIADH are tumours, central nervous system diseases, lung diseases, and drugs (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>).<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>Among the neoplasms that cause SIADH, small cell lung carcinoma is the most common. SIADH is the most common cause of hyponatremia in cancer patients: it is estimated to account for around 30% of all causes. The relationship between cancer in various organs and SIADH is so strong that any patient with SIADH hyponatremia and a suspicious sign or symptom, such as weight loss, should prompt a search for an underlying neoplasm. Hyponatremia impacts the morbidity and mortality of cancer patients, as occurs in the general population. Thus, a study conducted among cancer patients found that those with hyponatraemia had a mortality rate of 19.5% compared to 6.3% in those with normal blood sodium levels.<a class="elsevierStyleCrossRef" href="#bib0065">13</a> Hyponatremia also has a predictive value on the response to treatment or patient outcome. In a cohort study of 120 patients with advanced renal carcinoma, the possibility of using hyponatremia as an independent predictive factor was evaluated and it was statistically significant in their cohort of patients.<a class="elsevierStyleCrossRef" href="#bib0070">14</a> In the case of ectopic ADH production, the treatment of choice is that of neoplastic disease. Thus, in response to chemotherapy, hyponatraemia is usually corrected after a median of 4 weeks.<a class="elsevierStyleCrossRef" href="#bib0075">15</a>Central nervous system disease is a relatively common cause of SIADH, especially traumatic brain injury, haemorrhages, tumours, and sphenoid surgery. 35% of patients with subarachnoid haemorrhage present with hyponatraemia during the first week, 70% of which correspond to SIADH.<a class="elsevierStyleCrossRef" href="#bib0080">16</a> In the case of transsphenoidal pituitary surgery, the incidence can range from 25 to 35%.<a class="elsevierStyleCrossRef" href="#bib0085">17</a>Central nervous system disease can be a cause of SIADH, as well as CSW, also called renal salt wasting, as it can occur as a complication of CNS and non-CNS conditions. CSW has an unclear pathophysiology and manifests as hyponatremia, plasma hypo-osmolarity, high urine osmolarity, and excessive natriuresis, which favours volume depletion. Its differential diagnosis with SIADH is complex, since both conditions initially present with euvolemic hyponatremia. Although well described, it appears that the incidence of CSW in neurocritical patients with hyponatraemia is rather residual: 5% compared to more than 60% in SIADH.<a class="elsevierStyleCrossRef" href="#bib0090">18</a> In addition, CSW may coexist with SIADH in a small percentage of patients (3%). It should be noted that the routine infusion of saline solutions to prevent cerebral oedema and vasospasm in neurocritical patients results in increased natriuresis and diuresis, which should not be confused with CSW. The absence of volume depletion, in this case, rules out CSW.Regarding respiratory diseases, hyponatremia can occur in around 10% of cases with community-acquired pneumonia and is a factor of morbidity and mortality and longer hospital stay.<a class="elsevierStyleCrossRef" href="#bib0095">19</a> Almost any pulmonary infection, whether bacterial, viral or fungal, has been associated with hyponatraemia associated with SIADH. Recently, it has been associated with SARS-CoV-2 lung infection.<a class="elsevierStyleCrossRef" href="#bib0100">20</a>Finally, drugs are a relatively common cause of hyponatremia. Diuretics are probably the most common cause of drug-induced hyponatremia, with an estimated incidence of 11%.<a class="elsevierStyleCrossRef" href="#bib0105">21</a> The main agents causing hyponatraemia are thiazides<a class="elsevierStyleCrossRef" href="#bib0110">22</a> and must be ruled out as a cause before diagnosing a patient with SIADH, because the clinical and biochemical findings are often indistinguishable: patients with thiazide hyponatraemia are usually euvolemic due to water gain, either by ingestion or by an effect of the drug on the collecting tubule.<a class="elsevierStyleCrossRef" href="#bib0110">22</a>Unlike diuretics, all other drugs can cause hyponatraemia due to SIADH, as they affect only water homeostasis and not sodium homeostasis. As described in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>, the mechanisms include an increase in ADH production by the hypothalamus, a potentiation of the effect of ADH on the collecting tubule and, finally, a readjustment of osmoregulation whereby the osmolality threshold for ADH stimulation is lowered. Antidepressants and antipsychotics stand out in the first group. Among antidepressants, selective serotonin reuptake inhibitors (SSRIs) are the most commonly involved. The incidence of hyponatremia, generally due to SIADH, varies according to the studies, it can range from 0.5% to 32%, it usually occurs a few weeks after starting treatment and is usually corrected about 2 weeks after drug withdrawal.<a class="elsevierStyleCrossRef" href="#bib0115">23</a> With regard to antipsychotics, the situation is more complex, due to the common association of SIADH with primary polydipsia and with abundant water intake because of the dry mouth sensation induced by these drugs. Antiepileptics are another class of drugs associated with hyponatremia, especially carbamazepine and, more recently, lamotrigine, the latter by sensitizing the renal tubule to ADH action.<a class="elsevierStyleCrossRef" href="#bib0120">24</a> Advanced age and the joint use of other hyponatraemia-inducing drugs, such as diuretics, are risk factors.Among the antineoplastic drugs, vinca alkaloids (vincristine rather than vinblastine) have been reported to be associated with hyponatraemia. Platinum compounds (more cisplatin than carboplatin) are also associated with hyponatremia.<a class="elsevierStyleCrossRefs" href="#bib0125">25,26</a> The mechanism involves an increase in ADH secretion, although in the case of platinum compounds we must add their toxic effect on the renal tubule, which often causes hypomagnesemia, hypocalcaemia, and hypokalaemia. The incidence of hyponatremia secondary to cisplatin can reach up to 43%.<a class="elsevierStyleCrossRef" href="#bib0130">26</a> Cyclophosphamide, especially at high intravenous doses, can cause severe hyponatraemia by potentiation of the renal effect of ADH and probably increased synthesis, exacerbated by intensive hydration of these patients to prevent haemorrhagic cystitis.<a class="elsevierStyleCrossRef" href="#bib0130">26</a> It usually appears a few hours after the drug is administered and usually subsides within 24–48 h.Treatment of hyponatremia due to the syndrome of inappropriate antidiuretic hormone secretionIn general, the treatment of hyponatremia will depend, above all, on the cause and the accompanying symptoms. The clinical manifestations of hyponatremia are not specific and will depend on the speed of onset and the magnitude of the decrease in serum sodium levels. Neurological manifestations reflect cerebral oedema formation and range from headache, nausea, vomiting and gait instability to seizures, coma and death by brain herniation.<a class="elsevierStyleCrossRef" href="#bib0040">8</a> Intracellular oedema is a reflection of plasma hypoosmolality and, in this situation, cells adapt by expelling osmoles, first inorganic, especially potassium, and then inorganic such as myo-inositol; this process usually takes about 48 h until intracellular osmolality is brought into balance with plasma hypoosmolality and cell oedema is reduced.<a class="elsevierStyleCrossRefs" href="#bib0135">27,28</a> Because of this adaptation, hyponatraemia is considered acute when it has developed within the previous 48 h and chronic when it has persisted for more than 48 h. This consideration is critical when deciding the rate of correction of hyponatremia.<a class="elsevierStyleCrossRef" href="#bib0145">29</a>If the correction of chronic hyponatraemia is too fast and exceeds the ability of astrocytes to recover their osmolytes, this can lead to what is known as osmotic demyelination, pontine and extrapontine myelinolysis or osmotic demyelination syndrome (ODS).<a class="elsevierStyleCrossRefs" href="#bib0145">29–31</a> The clinical presentation of the syndrome usually follows an initial improvement in the symptoms of hyponatremia, only to develop new focal neurologic signs within a few days, mainly motor, which are often irreversible and whose white matter lesions can be detected within a few days or weeks by MRI.<a class="elsevierStyleCrossRef" href="#bib0155">31</a> The risk of developing ODS is variable; serum sodium concentration ≤ 105 mmol/L, coexisting hypokalaemia and a number of unquantified comorbidities such as alcoholism, malnutrition and advanced liver disease have been described as risk factors.<a class="elsevierStyleCrossRef" href="#bib0145">29</a> In contrast, the likelihood of ODS is very low in patients with a documented hyponatraemia of less than 24 h of progression or with sodium levels of 120 mmol/L or more. Several multidisciplinary clinical guidelines on the diagnosis and treatment of hyponatraemia became available in the middle of the last decade.<a class="elsevierStyleCrossRefs" href="#bib0145">29,32,33</a> They emphasise that the maximum increase in serum sodium in the first 24 h (10–12 mmol/L) and 48 h (18 mmol/L) are limits, not targets. Thus, the goal of treatment of severe acute hyponatraemia is to reduce cerebral oedema and decrease symptoms, which is usually achieved with an increase in sodium levels by 4–5 mmol/L, thus setting treatment targets in the first 24 h at an increase of 4–8 mmol/L in subjects at low risk of ODS and 4–6 mmol/L in subjects at high risk.<a class="elsevierStyleCrossRef" href="#bib0145">29</a>Symptomatic hyponatremia is treated with infusion of 3% hypertonic saline (513 mmol/L). The administration of hypertonic saline is done by means of a bolus of 100 mL in 10 min, which can be repeated 2 more times, or by continuous infusion at a rate of 0.5 to 2 mL/kg per hour, depending on severity.<a class="elsevierStyleCrossRefs" href="#bib0145">29,32,34</a> Furosemide (20–40 mg) to treat or prevent hypervolemia. There are several formulas to estimate the expected increase in sodium levels with the infusion, but the most used is that of Verbalis, which estimates that an infusion of, for example, 1 ml/kg per hour will increase sodium levels by 1 mmol/L in one hour.<a class="elsevierStyleCrossRef" href="#bib0040">8</a> In general, these formulas do not take into account changes in ADH or volume, or extra sodium gains and losses. Therefore, a continuous infusion requires close follow-up and monitoring, with sodium level checks every 2 h to adjust the rhythm (for more details, see Runkle et al.<a class="elsevierStyleCrossRef" href="#bib0205">34</a>).Several retrospective studies have shown that overcorrection with hypertonic saline administration is relatively common: up to 41%<a class="elsevierStyleCrossRefs" href="#bib0175">35–37</a>; however, severe complications, such as ODS, are less than 1%. The main risk factors for overcorrection were being a young woman, having psychiatric disorders (schizophrenia), a lower Charlson index, lower baseline sodium levels and urine sodium less than 30 mmol/L.<a class="elsevierStyleCrossRef" href="#bib0175">35</a> This reflects that, on occasion, a misdiagnosis can lead to a situation of overcorrection, such as failure to identify potomania or volume depletion, a causal drug that has ceased to have an effect, hypokalaemia, or the onset of rapid water diuresis.In the event that there is an overcorrection of sodium levels above the recommended values, we must lower sodium levels with 5% dextrose serum (6 ml/kg per hour for 2 h with sodium level control) with the administration of desmopressin (1–2 μg subcutaneously or intravenously every 6–8 h) or without it.<a class="elsevierStyleCrossRefs" href="#bib0145">29,34</a>Treatment of chronic hyponatremia or asymptomatic or paucisymptomatic hyponatremia should not be done with hypertonic saline. If we do not know the time of onset of hyponatremia, it is highly recommended to treat it as if it were chronic. Treatment should always be directed at the cause of the hyponatremia, such as the correction of adrenocortical failure or hypothyroidism. In the case of SIADH, the mainstay of treatment is fluid restriction, understood to include not only water restriction, but all oral fluids and intravenous fluids. In general, the volume of fluid intake accepted would be 500 mL below the daily diuresis. The effect of fluid restriction on sodium concentration is slow, usually taking at least 48 h and will depend on the ability to excrete electrolyte-free water. This capacity can be estimated using the Furst formula or the ratio between the sum of urine Na+ and K+ and plasma Na+.<a class="elsevierStyleCrossRef" href="#bib0190">38</a> It should be noted that if it is ≤0.5, it will result in watery diuresis and therefore restriction will be reflected in an increase in sodium levels, but if it is ≥1, there will be no capacity to excrete free water and therefore water restriction will be ineffective.<a class="elsevierStyleCrossRefs" href="#bib0145">29,34</a>Established predictors of water restriction failure are urine osmolality >500 mOsm/kg, diuresis less than 1.5 L per day, and increase in sodium levels of less than 2 mmol/L after 24 h of fluid restriction to less than one litre per day. In case of urinary osmolality above 350 mOsm/kg, 20–40 mg/d of oral furosemide can be added due to its urinary dilution-limiting effect.<a class="elsevierStyleCrossRef" href="#bib0170">34</a> A recent prospective study shows that out of a cohort of 183 patients with a diagnosis of SIADH, 59% met one criterion for non-response to water restriction, 37% met 2 criteria and 3% met 3 criteria. This underlines that the main measure recommended by the guidelines has, a priori, a very high probability of primary failure.<a class="elsevierStyleCrossRef" href="#bib0195">39</a>In addition, the volume of diuresis depends on the amount of osmoles that the kidney is forced to excrete. Therefore, a high osmole intake is recommended, either in the form of common salt (2 g/8 h), if there is no contraindication, with a diet rich in protein or urea (15–60 g/day). The use of oral urea has been controversial, since it was initially proposed by a small group of researchers<a class="elsevierStyleCrossRefs" href="#bib0200">40,41</a> and finally included in the European guidelines as a second option after fluid restriction,<a class="elsevierStyleCrossRef" href="#bib0160">32</a> aspect not contemplated in the American guidelines.<a class="elsevierStyleCrossRef" href="#bib0145">29</a> Urea induces osmotic diuresis, which increases free water excretion. Although it does not eliminate the risk of overcorrection or hypernatremia, it seems that a priori should produce less brain damage, as seen in animal experimentation,<a class="elsevierStyleCrossRef" href="#bib0210">42</a> and because of the known protection conferred by renal failure (uraemia) against the brain effects of overcorrection.The drug therapy of SIADH approved by the different drug agencies is tolvaptan, an ADH V2-receptor antagonist and, therefore, an inhibitor of water reabsorption in the collecting tubule, which acts on the physio-disease target of SIADH. In the pivotal SALT studies, tolvaptan was shown to be effective in correcting sodium versus placebo in hypervolemic and euvolemic hyponatremia, with the ability to maintain corrected sodium concentrations long-term, although without modifying survival.<a class="elsevierStyleCrossRefs" href="#bib0215">43,44</a> However, due to its efficacy and safety profile, different guidelines and experts recommend it as a second line in the treatment of SIADH, once fluid restriction fails.<a class="elsevierStyleCrossRefs" href="#bib0145">29,33,34</a> It should always be considered in patients without severe symptoms and with initial sodium concentrations not less than 120 mmol/L, since there is a risk of overcorrection due to the induction of a rapid water diuresis. Also, for this reason, treatment should be started in the context of hospital admission to ensure close monitoring.<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a> illustrates the treatment algorithm for chronic hyponatremia, adapted from Runkle et al.,<a class="elsevierStyleCrossRef" href="#bib0170">34</a> in which the different options can be followed sequentially according to the result of electrolytes in urine and the sequential response to the different interventions. The outline is indicative, since the characteristics of the patient and the adverse reactions on nutrition and quality of life that strict water restriction can cause in susceptible patients (cancer and elderly) must be taken into account. While the initial dose was initially 15 mg, many physicians started with lower doses to avoid overcorrection, and today the 7.5 mg presentation is also available.<elsevierMultimedia ident="fig0010"></elsevierMultimedia>Another aspect is that tolvaptan should not be started immediately after finishing a hypertonic infusion to avoid overcorrection. Due to the fact that after the first dose there is an abundant water diuresis in the first hours, it is necessary to insist on the intake of abundant water according to thirst. Overcorrection with the use of vaptans is variable and can be as high as 25%, as described in a small series with a mean baseline sodium concentration of 120.6 mmol/L.<a class="elsevierStyleCrossRef" href="#bib0225">45</a> The duration of treatment should be adjusted to the expected duration of SIADH, since in many cases it is reversible.Conflicts of interestThe authors have no conflicts of interest to declare in relation to this paper." "textoCompletoSecciones" => array:1 [ "secciones" => array:10 [ 0 => array:3 [ "identificador" => "xres1761443" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1549056" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1761442" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1549055" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Definition and pathogenesis" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Clinical evaluation and diagnostic criteria" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Aetiology" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Treatment of hyponatremia due to the syndrome of inappropriate antidiuretic hormone secretion" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "Conflicts of interest" ] 9 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2021-10-05" "fechaAceptado" => "2022-02-17" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1549056" "palabras" => array:5 [ 0 => "Hyponatremia" 1 => "Sodium" 2 => "Antidiuretic hormone" 3 => "Vaptans" 4 => "Vasopressin" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1549055" "palabras" => array:5 [ 0 => "Hiponatremia" 1 => "Sodio" 2 => "Hormona antidiurética" 3 => "Vaptanes" 4 => "Vasopresina" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Hyponatremia is the most frequent electrolytic disorder in hospitalized patients, and the syndrome of inappropriate secretion of antidiuretic hormone (SIADH), the most frequent cause of hiponatremia with clinically normal extracellular volume. It consists of a disorder of the regulation of body water that obeys to different causes, mainly cancer, pulmonary illnesses, disorders of the central nervous system and diverse drugs. As in any hiponatremia it a physiological knowledge of the regulation of body water and sodium is essential as well as the applicatin of precise diagnostic criteria in order to manage the problem with an effective treatment. The available data until the moment show that the clinical diagnosis of SIADH made by professionals is mainly not supported on the established criteria drawn by experts and this lack of accuracy probably hits in the therapeutic result. The basis of the treatment of the SIADH is to correct its cause, water restriction, solutes (sodium chloride) and the use of vaptans in case of failure of the previous measures." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "La hiponatremia es el trastorno electrolítico más frecuente en pacientes hospitalizados, y el síndrome de secreción inadecuada de hormona antidiurética (SIADH), la causa más frecuente de hiponatremia con volumen extracelular clínicamente normal. Se trata de un trastorno de la regulación del agua corporal que obedece a diferentes causas, entre las que destacan las neoplasias, las enfermedades pulmonares, los trastornos del sistema nervioso central y diversos fármacos. Como en cualquier hiponatremia es importante un conocimiento fisiológico de la regulación del agua y del sodio corporal y aplicar unos criterios diagnósticos precisos de cara a poder realizar un tratamiento eficaz. Los datos disponibles hasta el momento demuestran que el diagnóstico clínico de SIADH realizado por profesionales no se sustenta sobre los criterios establecidos por expertos y esta carencia probablemente impacta en los resultados terapéuticos. La base del tratamiento del SIADH es corregir su causa, la restricción hídrica con el aporte de solutos (cloruro sódico) y el uso de vaptanes en caso de falta de respuesta a las medidas anteriores." ] ] "multimedia" => array:4 [ 0 => array:8 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 3772 "Ancho" => 2925 "Tamanyo" => 536738 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Diagnostic algorithm for hyponatremia. * In primary polydipsia, water intake exceeds the renal excretory capacity for water. An inhibition of ADH occurs, which is why urine osmolality is very low. ** In chronic kidney disease there is initially an inability to concentrate urine (Na is lost) and, in advanced stages, difficulty in dilution. Nap: plasma or serum sodium; Nau: urinary sodium; Osmp: plasma osmolality; Osmu: urinary osmolality." ] ] 1 => array:8 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 2630 "Ancho" => 2925 "Tamanyo" => 454703 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0010" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Algorithm for correction of hyponatremia with the use of tolvaptan in the context of SIADH. Ku: urinary potassium; Nap: plasma or serum sodium; Nau: urinary sodium." ] ] 2 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0015" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "ADH: antidiuretic hormone; BUN: blood urea nitrogen; FE: fractional excretion; mOsm: milliosmoles." "tablatextoimagen" => array:1 [ 0 => array:1 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Criteria \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Major \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Plasma sodium < 135 mEq/L \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Urine sodium > 30 mEq/L with normal-sodium diet \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Effective plasma osmolality (without urea) < 275 mOsm/kg \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Osmolality in urine > 100 mOsm/kg \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Clinical euvolemia (no signs of hypervolemia or hypovolemia) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No treatment with diuretics \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Absence of adrenal failure or hypothyroidism \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Ancillary \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Uricemia < 4 mg/dL, uric FE > 12% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">BUN < 10 mg/dL \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">FENa > 1%; FEUrea > 55% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Failure to correct hyponatremia with infusion of isotonic saline (0.9%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Correction of hyponatremia with fluid restriction \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pathological fluid overload test. Excretion < 90% of a 20 mL/kg water overload in 4 h or inadequate urine dilution (Osm < 100 mOsm/kg) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Elevated ADH level despite hypotonicity and euvolemia \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] ] ] ] "descripcion" => array:1 [ "en" => "Diagnostic criteria for the syndrome of inappropriate antidiuretic hormone secretion (SIADH)." ] ] 3 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0020" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "Diuretics are not included, as they are an exclusion criterion for the diagnosis of SIADH. However, given the high incidence of diuretic-induced hyponatraemia, it is briefly discussed in the text.ADH: antidiuretic hormone; TCA: tricyclic antidepressants; COPD: chronic obstructive pulmonary disease; SAH: subarachnoid haemorrhage; MAOI: monoamine oxidase inhibitors; SSRIs: selective serotonin reuptake inhibitors; SOL: space-occupying lesions; TBI: traumatic brain injury; HIV: human immunodeficiency virus infection." "tablatextoimagen" => array:1 [ 0 => array:1 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Tumors \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Carcinomas: lung (especially small cell), oropharynx, gastrointestinal, genitourinary \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Lymphomas and sarcomas \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pulmonary disorders \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Infections, especially Legionella, Mycoplasma, tuberculosis, abscesses \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">COPD, asthma \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cystic fibrosis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Non-invasive mechanical ventilation \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Vasculitis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Central nervous system disorders \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Infections: encephalitis, myelitis, abscess \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Haemorrhages and masses: SAH, TBI, SOL \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Neurological disorders: Guillain-Barré syndrome, multiple sclerosis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Vasculitis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Drugs and toxic substances \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Stimulate the release of ADH: \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Antidepressants: SSRIs, TCAs, MAOIs \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Antipsychotics: phenothiazines, haloperidol \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Antiepileptics: carbamazepine, levetiracetam, valproate \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NSAIDs \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Opiates \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cytotoxic agents: vincristine, vinblastine, cyclophosphamide, cisplatin, carboplatin \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Nicotine \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3,4, methylenedioxymethamphetamines \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Opiates \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Potentiate the antidiuretic effect of ADH: vasopressin, oxytocin, carbamazepine, lamotrigine, chlorpropamide, tolbutamide \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Prostaglandin synthesis inhibitors \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Produce a reset of ADH osmoregulation \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Venlafaxine \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Carbamazepine \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Miscellaneous \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">HIV \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Postoperative \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pain, nausea and vomiting \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Prolonged exercise \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Idiopathic \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] ] ] ] "descripcion" => array:1 [ "en" => "Most common causes of syndrome of inappropriate antidiuretic hormone secretion (SIADH)." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:45 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Disorders of body water homeostasis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "JG Verbalis" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Best Pract Res Clin Endocrinol Metab [Internet]" "fecha" => "2003" "volumen" => "17" "paginaInicial" => "471" "paginaFinal" => "503" ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Role of renal aquaporins in escape from vasopressin-induced antidiuresis in rat" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "C.A. 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Syndrome of inappropriate antidiuretic hormone secretion

Síndrome de secreción inadecuada de hormona antidiurética

Esteban Pocha,b,c,

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epoch@clinic.cat

Corresponding author.

, Alicia Molinaa, Gastón Piñeiroa

a Servicio de Nefrología y Trasplante Renal, Hospital Clínic, Barcelona, Spain

b IDIBAPS

c Departamento de Medicina, Universidad de Barcelona, Barcelona, Spain

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This does not apply if the sodium determination is carried out directly with ion-sensitive electrodes&#46; Another cause of pseudohyponatremia is the accumulation of gamma globulins &#40;they are cationic&#41; in the case of paraproteins or the administration of large amounts of gamma globulins &#40;2&#8239;g&#47;kg in 2&#8211;5 days&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;6</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0025" class="elsevierStylePara elsevierViewall">A reduced effective plasma osmolality defines true hyponatremia&#46; The effective plasma osmolality is obtained by subtracting the urea nitrogen concentration in mmol&#47;L from the measured osmolality or dividing it by 2&#46;8 if it is expressed in mg&#47;dL&#46; In this case&#44; measurement of urinary osmolality will help to identify primary polydipsia or low solute intake when it is less than 100&#8239;mOsm&#47;kg&#46; True hyponatremia with urine osmolality above 100 can have a variety of causes&#46; In this case&#44; a recent low urine sodium identifies volume depletion of extrarenal origin and oedematous states with decreased effective arterial volume&#46; A urine sodium above 20 or 30&#8239;mEq&#47;L reasonably rules out volume depletion of extrarenal origin and&#44; if the use of diuretics or renal failure is ruled out and the patient is normovolemic&#44; the most likely diagnosis is of SIADH&#46; The presence of hypovolemia with elevated urinary sodium should lead to suspicion of renal loss of water and salt&#44; either due to aldosterone deficiency&#44; aldosterone resistance&#44; or salt-losing nephropathy&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">The diagnosis of SIADH is one of exclusion&#44; but a number of criteria must be met which&#44; at present&#44; are still the original ones described by Schwartz and Bartter in the publication of the first cases&#44; re-issued by Schwartz et al&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a>&#46; The most important criteria are urine osmolality &#62;100&#8239;mOsm&#47;kg and the presence of clinical euvolemia<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; This urine osmolality is a surrogate marker of elevated ADH levels&#44; which in a hyponatraemic and normovolemic patient is totally inadequate&#46; In hypovolemic states&#44; the activation of ADH is appropriate and in hypervolemic states this hormone is part of the neurohumoral activation typical of these conditions&#46; Therefore&#44; ADH levels are not essential for diagnosis&#44; since urine osmolality &#62;100&#8239;mOsm&#47;kg already indicates a circulating excess&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0035" class="elsevierStylePara elsevierViewall">Copeptin&#44; a precursor of ADH&#44; has been postulated as a useful tool in the diagnosis of water disorders as a marker of ADH&#44; as it reflects ADH levels reliably&#44; has a higher molecular stability than ADH and is easier and more reliable to measure&#46; However&#44; its value in the diagnosis of hypoosmolar states&#44; such as SIADH&#44; is low&#44; since the levels are usually erratic&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> It seems that its usefulness is much greater in the diagnosis of nephrogenic diabetes insipidus&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">Since it is sometimes difficult to discern between clinical euvolemia and hypovolaemia because of the poor sensitivity of physical examination in the assessment of hyponatraemia&#44;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> laboratory data are a useful support but not diagnostic in themselves&#46; Although a urine sodium &#8804;30&#8239;mEq&#47;L identifies most patients who will respond to saline because they are depleted&#44; it can sometimes be greater than 30 in these patients&#46; In these cases&#44; a fractional excretion &#40;FE&#44; excreted to filtered ratio&#41; of sodium &#40;FENa&#41; &#60;0&#46;5&#37; identifies all volume-depleted patients&#46; In contrast&#44; a FENa&#8239;&#62;&#8239;1&#37; supports euvolemia and thus SIADH&#44; although there is some overlap&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> As there is an expansion of blood volume in SIADH&#44; at least in the first days&#44; before being &#8220;compensated&#8221; by desalination&#44; there is an increase in FE of urea and uric acid&#44; so we will find low concentrations of uric acid and of BUN &#40;although this is more typical than common or constant&#41;&#46; Therefore&#44; it is worth emphasizing that additional laboratory data only serve to support the essential criteria&#46; As for oral overload&#44; it is not commonly used in clinical practice because of the potential danger of worsening hyponatraemia&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">To complicate matters somewhat&#44; a patient with SIADH&#44; especially in chronic and severe cases&#44; may manifest as salt-depleted and thus not exhibit the diagnostic features from the onset&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> In addition&#44; a patient with SIADH may have a low urine Na if they are on a very low sodium diet&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">When in doubt about the hypovolaemic or euvolemic state of a patient&#44; isotonic saline perfusion at a rate of 2&#8239;L over 24 or 48&#8239;h can be tried&#44; provided the patient can tolerate it&#44; followed by analysis of the response &#40;serum Na and FENa&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;6&#44;8</span></a> In patients with salt depletion&#44; including cerebral salt wasting syndrome &#40;CSW&#44; see below&#41;&#44; serum sodium will be high with minimal increase in FENa &#40;less than 0&#46;5&#41;&#44; as these patients tend to avidly retain all the sodium administered to them&#46; In contrast&#44; the serum sodium response in SIADH patients is variable&#44; but typically increase FENa by more than 0&#46;5&#37;&#44; as they are usually in sodium balance and excrete almost all of the salt they receive&#46; This is critically important as the administration of isotonic saline may worsen hyponatremia and have adverse clinical consequences in patients with SIADH&#46; In this sense&#44; urinary osmolality is essential to predict the response to saline in a patient with suspected SIADH&#46; If it is close to 300&#8239;mOsm&#47;kg&#44; the serum sodium is likely to increase somewhat or remain unchanged and the patient will excrete the administered salt &#40;308 mOsm in a litre of isotonic saline&#41; in a volume of urine similar to that administered&#46; However&#44; if urinary osmolality is greater than 500&#8239;mOsm&#47;kg&#44; the 308&#8239;mOsm of salt administered will be eliminated in 600&#8239;mL of urine&#44; with retention of 400&#8239;mL of free water due to the action of ADH and&#44; therefore&#44; with a worsening of hyponatraemia&#46; Thus&#44; the saline test should not be performed if SIADH is suspected&#44; and urine osmolality is above 500&#8239;mOsm&#47;kg&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">Among the diagnostic criteria&#44; it is established that cases of hyponatremia associated with glucocorticoid deficiency and severe hypothyroidism must be ruled out by means of hormone determinations&#44;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> as they can produce euvolemic hyponatraemia that is clinically and biochemically indistinguishable from SIADH&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">Although SIADH is the most common cause of euvolemic hyponatremia&#44; the clinical reality is that it is underdiagnosed in most cases&#46; Thus&#44; an international registry including 1&#44;524 patients with euvolemic hyponatraemia found that&#44; of the patients with physician-diagnosed SIADH&#44; only 47&#37; met the original Schwartz and Bartter criteria &#40;serum and urine osmolality&#44; urine sodium&#41;&#44; while 21&#37; also had TSH and cortisol hormone determinations&#46; Most strikingly&#44; 11&#37; of cases with a clinical diagnosis of SIADH had not had a single test performed&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> Therefore&#44; there is much room for improvement in the diagnosis of this syndrome which&#44; as we shall see&#44; is essential for the correct treatment of hyponatraemia&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Aetiology</span><p id="par0065" class="elsevierStylePara elsevierViewall">SIADH is a clinical manifestation of a wide variety of disorders and the use of certain drugs&#44; and is the most common cause of euvolemic hyponatraemia in hospital practice&#46; The most common causes of SIADH are tumours&#44; central nervous system diseases&#44; lung diseases&#44; and drugs &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0070" class="elsevierStylePara elsevierViewall">Among the neoplasms that cause SIADH&#44; small cell lung carcinoma is the most common&#46; SIADH is the most common cause of hyponatremia in cancer patients&#58; it is estimated to account for around 30&#37; of all causes&#46; The relationship between cancer in various organs and SIADH is so strong that any patient with SIADH hyponatremia and a suspicious sign or symptom&#44; such as weight loss&#44; should prompt a search for an underlying neoplasm&#46; Hyponatremia impacts the morbidity and mortality of cancer patients&#44; as occurs in the general population&#46; Thus&#44; a study conducted among cancer patients found that those with hyponatraemia had a mortality rate of 19&#46;5&#37; compared to 6&#46;3&#37; in those with normal blood sodium levels&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> Hyponatremia also has a predictive value on the response to treatment or patient outcome&#46; In a cohort study of 120 patients with advanced renal carcinoma&#44; the possibility of using hyponatremia as an independent predictive factor was evaluated and it was statistically significant in their cohort of patients&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> In the case of ectopic ADH production&#44; the treatment of choice is that of neoplastic disease&#46; Thus&#44; in response to chemotherapy&#44; hyponatraemia is usually corrected after a median of 4 weeks&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">Central nervous system disease is a relatively common cause of SIADH&#44; especially traumatic brain injury&#44; haemorrhages&#44; tumours&#44; and sphenoid surgery&#46; 35&#37; of patients with subarachnoid haemorrhage present with hyponatraemia during the first week&#44; 70&#37; of which correspond to SIADH&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> In the case of transsphenoidal pituitary surgery&#44; the incidence can range from 25 to 35&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">Central nervous system disease can be a cause of SIADH&#44; as well as CSW&#44; also called <span class="elsevierStyleItalic">renal salt wasting</span>&#44; as it can occur as a complication of CNS and non-CNS conditions&#46; CSW has an unclear pathophysiology and manifests as hyponatremia&#44; plasma hypo-osmolarity&#44; high urine osmolarity&#44; and excessive natriuresis&#44; which favours volume depletion&#46; Its differential diagnosis with SIADH is complex&#44; since both conditions initially present with euvolemic hyponatremia&#46; Although well described&#44; it appears that the incidence of CSW in neurocritical patients with hyponatraemia is rather residual&#58; 5&#37; compared to more than 60&#37; in SIADH&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> In addition&#44; CSW may coexist with SIADH in a small percentage of patients &#40;3&#37;&#41;&#46; It should be noted that the routine infusion of saline solutions to prevent cerebral oedema and vasospasm in neurocritical patients results in increased natriuresis and diuresis&#44; which should not be confused with CSW&#46; The absence of volume depletion&#44; in this case&#44; rules out CSW&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">Regarding respiratory diseases&#44; hyponatremia can occur in around 10&#37; of cases with community-acquired pneumonia and is a factor of morbidity and mortality and longer hospital stay&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> Almost any pulmonary infection&#44; whether bacterial&#44; viral or fungal&#44; has been associated with hyponatraemia associated with SIADH&#46; Recently&#44; it has been associated with SARS-CoV-2 lung infection&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">Finally&#44; drugs are a relatively common cause of hyponatremia&#46; Diuretics are probably the most common cause of drug-induced hyponatremia&#44; with an estimated incidence of 11&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> The main agents causing hyponatraemia are thiazides<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> and must be ruled out as a cause before diagnosing a patient with SIADH&#44; because the clinical and biochemical findings are often indistinguishable&#58; patients with thiazide hyponatraemia are usually euvolemic due to water gain&#44; either by ingestion or by an effect of the drug on the collecting tubule&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">Unlike diuretics&#44; all other drugs can cause hyponatraemia due to SIADH&#44; as they affect only water homeostasis and not sodium homeostasis&#46; As described in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#44; the mechanisms include an increase in ADH production by the hypothalamus&#44; a potentiation of the effect of ADH on the collecting tubule and&#44; finally&#44; a readjustment of osmoregulation whereby the osmolality threshold for ADH stimulation is lowered&#46; Antidepressants and antipsychotics stand out in the first group&#46; Among antidepressants&#44; selective serotonin reuptake inhibitors &#40;SSRIs&#41; are the most commonly involved&#46; The incidence of hyponatremia&#44; generally due to SIADH&#44; varies according to the studies&#44; it can range from 0&#46;5&#37; to 32&#37;&#44; it usually occurs a few weeks after starting treatment and is usually corrected about 2&#8239;weeks after drug withdrawal&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> With regard to antipsychotics&#44; the situation is more complex&#44; due to the common association of SIADH with primary polydipsia and with abundant water intake because of the dry mouth sensation induced by these drugs&#46; Antiepileptics are another class of drugs associated with hyponatremia&#44; especially carbamazepine and&#44; more recently&#44; lamotrigine&#44; the latter by sensitizing the renal tubule to ADH action&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> Advanced age and the joint use of other hyponatraemia-inducing drugs&#44; such as diuretics&#44; are risk factors&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">Among the antineoplastic drugs&#44; vinca alkaloids &#40;vincristine rather than vinblastine&#41; have been reported to be associated with hyponatraemia&#46; Platinum compounds &#40;more cisplatin than carboplatin&#41; are also associated with hyponatremia&#46;<a class="elsevierStyleCrossRefs" href="#bib0125"><span class="elsevierStyleSup">25&#44;26</span></a> The mechanism involves an increase in ADH secretion&#44; although in the case of platinum compounds we must add their toxic effect on the renal tubule&#44; which often causes hypomagnesemia&#44; hypocalcaemia&#44; and hypokalaemia&#46; The incidence of hyponatremia secondary to cisplatin can reach up to 43&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> Cyclophosphamide&#44; especially at high intravenous doses&#44; can cause severe hyponatraemia by potentiation of the renal effect of ADH and probably increased synthesis&#44; exacerbated by intensive hydration of these patients to prevent haemorrhagic cystitis&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> It usually appears a few hours after the drug is administered and usually subsides within 24&#8211;48&#8239;h&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Treatment of hyponatremia due to the syndrome of inappropriate antidiuretic hormone secretion</span><p id="par0105" class="elsevierStylePara elsevierViewall">In general&#44; the treatment of hyponatremia will depend&#44; above all&#44; on the cause and the accompanying symptoms&#46; The clinical manifestations of hyponatremia are not specific and will depend on the speed of onset and the magnitude of the decrease in serum sodium levels&#46; Neurological manifestations reflect cerebral oedema formation and range from headache&#44; nausea&#44; vomiting and gait instability to seizures&#44; coma and death by brain herniation&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> Intracellular oedema is a reflection of plasma hypoosmolality and&#44; in this situation&#44; cells adapt by expelling osmoles&#44; first inorganic&#44; especially potassium&#44; and then inorganic such as myo-inositol&#59; this process usually takes about 48&#8239;h until intracellular osmolality is brought into balance with plasma hypoosmolality and cell oedema is reduced&#46;<a class="elsevierStyleCrossRefs" href="#bib0135"><span class="elsevierStyleSup">27&#44;28</span></a> Because of this adaptation&#44; hyponatraemia is considered acute when it has developed within the previous 48&#8239;h and chronic when it has persisted for more than 48&#8239;h&#46; This consideration is critical when deciding the rate of correction of hyponatremia&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">If the correction of chronic hyponatraemia is too fast and exceeds the ability of astrocytes to recover their osmolytes&#44; this can lead to what is known as osmotic demyelination&#44; pontine and extrapontine myelinolysis or osmotic demyelination syndrome &#40;ODS&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">29&#8211;31</span></a> The clinical presentation of the syndrome usually follows an initial improvement in the symptoms of hyponatremia&#44; only to develop new focal neurologic signs within a few days&#44; mainly motor&#44; which are often irreversible and whose white matter lesions can be detected within a few days or weeks by MRI&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a> The risk of developing ODS is variable&#59; serum sodium concentration&#8239;&#8804;&#8239;105&#8239;mmol&#47;L&#44; coexisting hypokalaemia and a number of unquantified comorbidities such as alcoholism&#44; malnutrition and advanced liver disease have been described as risk factors&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> In contrast&#44; the likelihood of ODS is very low in patients with a documented hyponatraemia of less than 24&#8239;h of progression or with sodium levels of 120&#8239;mmol&#47;L or more&#46; Several multidisciplinary clinical guidelines on the diagnosis and treatment of hyponatraemia became available in the middle of the last decade&#46;<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">29&#44;32&#44;33</span></a> They emphasise that the maximum increase in serum sodium in the first 24&#8239;h &#40;10&#8211;12&#8239;mmol&#47;L&#41; and 48&#8239;h &#40;18&#8239;mmol&#47;L&#41; are limits&#44; not targets&#46; Thus&#44; the goal of treatment of severe acute hyponatraemia is to reduce cerebral oedema and decrease symptoms&#44; which is usually achieved with an increase in sodium levels by 4&#8211;5&#8239;mmol&#47;L&#44; thus setting treatment targets in the first 24&#8239;h at an increase of 4&#8211;8&#8239;mmol&#47;L in subjects at low risk of ODS and 4&#8211;6&#8239;mmol&#47;L in subjects at high risk&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">Symptomatic hyponatremia is treated with infusion of 3&#37; hypertonic saline &#40;513&#8239;mmol&#47;L&#41;&#46; The administration of hypertonic saline is done by means of a bolus of 100&#8239;mL in 10&#8239;min&#44; which can be repeated 2 more times&#44; or by continuous infusion at a rate of 0&#46;5 to 2&#8239;mL&#47;kg per hour&#44; depending on severity&#46;<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">29&#44;32&#44;34</span></a> Furosemide &#40;20&#8211;40&#8239;mg&#41; to treat or prevent hypervolemia&#46; There are several formulas to estimate the expected increase in sodium levels with the infusion&#44; but the most used is that of Verbalis&#44; which estimates that an infusion of&#44; for example&#44; 1&#8239;ml&#47;kg per hour will increase sodium levels by 1&#8239;mmol&#47;L in one hour&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> In general&#44; these formulas do not take into account changes in ADH or volume&#44; or extra sodium gains and losses&#46; Therefore&#44; a continuous infusion requires close follow-up and monitoring&#44; with sodium level checks every 2&#8239;h to adjust the rhythm &#40;for more details&#44; see Runkle et al&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">34</span></a>&#41;&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">Several retrospective studies have shown that overcorrection with hypertonic saline administration is relatively common&#58; up to 41&#37;<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">35&#8211;37</span></a>&#59; however&#44; severe complications&#44; such as ODS&#44; are less than 1&#37;&#46; The main risk factors for overcorrection were being a young woman&#44; having psychiatric disorders &#40;schizophrenia&#41;&#44; a lower Charlson index&#44; lower baseline sodium levels and urine sodium less than 30&#8239;mmol&#47;L&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a> This reflects that&#44; on occasion&#44; a misdiagnosis can lead to a situation of overcorrection&#44; such as failure to identify potomania or volume depletion&#44; a causal drug that has ceased to have an effect&#44; hypokalaemia&#44; or the onset of rapid water diuresis&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">In the event that there is an overcorrection of sodium levels above the recommended values&#44; we must lower sodium levels with 5&#37; dextrose serum &#40;6&#8239;ml&#47;kg per hour for 2&#8239;h with sodium level control&#41; with the administration of desmopressin &#40;1&#8211;2&#8239;&#956;g subcutaneously or intravenously every 6&#8211;8&#8239;h&#41; or without it&#46;<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">29&#44;34</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">Treatment of chronic hyponatremia or asymptomatic or <span class="elsevierStyleItalic">paucisymptomatic</span> hyponatremia should not be done with hypertonic saline&#46; If we do not know the time of onset of hyponatremia&#44; it is highly recommended to treat it as if it were chronic&#46; Treatment should always be directed at the cause of the hyponatremia&#44; such as the correction of adrenocortical failure or hypothyroidism&#46; In the case of SIADH&#44; the mainstay of treatment is fluid restriction&#44; understood to include not only water restriction&#44; but all oral fluids and intravenous fluids&#46; In general&#44; the volume of fluid intake accepted would be 500&#8239;mL below the daily diuresis&#46; The effect of fluid restriction on sodium concentration is slow&#44; usually taking at least 48&#8239;h and will depend on the ability to excrete electrolyte-free water&#46; This capacity can be estimated using the Furst formula or the ratio between the sum of urine Na<span class="elsevierStyleSup">&#43;</span> and K<span class="elsevierStyleSup">&#43;</span> and plasma Na<span class="elsevierStyleSup">&#43;</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a> It should be noted that if it is &#8804;0&#46;5&#44; it will result in watery diuresis and therefore restriction will be reflected in an increase in sodium levels&#44; but if it is &#8805;1&#44; there will be no capacity to excrete free water and therefore water restriction will be ineffective&#46;<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">29&#44;34</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">Established predictors of water restriction failure are urine osmolality &#62;500&#8239;mOsm&#47;kg&#44; diuresis less than 1&#46;5&#8239;L per day&#44; and increase in sodium levels of less than 2&#8239;mmol&#47;L after 24&#8239;h of fluid restriction to less than one litre per day&#46; In case of urinary osmolality above 350&#8239;mOsm&#47;kg&#44; 20&#8211;40&#8239;mg&#47;d of oral furosemide can be added due to its urinary dilution-limiting effect&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> A recent prospective study shows that out of a cohort of 183 patients with a diagnosis of SIADH&#44; 59&#37; met one criterion for non-response to water restriction&#44; 37&#37; met 2 criteria and 3&#37; met 3 criteria&#46; This underlines that the main measure recommended by the guidelines has&#44; <span class="elsevierStyleItalic">a priori</span>&#44; a very high probability of primary failure&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a></p><p id="par0140" class="elsevierStylePara elsevierViewall">In addition&#44; the volume of diuresis depends on the amount of osmoles that the kidney is forced to excrete&#46; Therefore&#44; a high osmole intake is recommended&#44; either in the form of common salt &#40;2&#8239;g&#47;8&#8239;h&#41;&#44; if there is no contraindication&#44; with a diet rich in protein or urea &#40;15&#8211;60&#8239;g&#47;day&#41;&#46; The use of oral urea has been controversial&#44; since it was initially proposed by a small group of researchers<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">40&#44;41</span></a> and finally included in the European guidelines as a second option after fluid restriction&#44;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> aspect not contemplated in the American guidelines&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> Urea induces osmotic diuresis&#44; which increases free water excretion&#46; Although it does not eliminate the risk of overcorrection or hypernatremia&#44; it seems that <span class="elsevierStyleItalic">a priori</span> should produce less brain damage&#44; as seen in animal experimentation&#44;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a> and because of the known protection conferred by renal failure &#40;uraemia&#41; against the brain effects of overcorrection&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">The drug therapy of SIADH approved by the different drug agencies is tolvaptan&#44; an ADH V<span class="elsevierStyleInf">2</span>-receptor antagonist and&#44; therefore&#44; an inhibitor of water reabsorption in the collecting tubule&#44; which acts on the physio-disease target of SIADH&#46; In the pivotal SALT studies&#44; tolvaptan was shown to be effective in correcting sodium versus placebo in hypervolemic and euvolemic hyponatremia&#44; with the ability to maintain corrected sodium concentrations long-term&#44; although without modifying survival&#46;<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">43&#44;44</span></a> However&#44; due to its efficacy and safety profile&#44; different guidelines and experts recommend it as a second line in the treatment of SIADH&#44; once fluid restriction fails&#46;<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">29&#44;33&#44;34</span></a> It should always be considered in patients without severe symptoms and with initial sodium concentrations not less than 120&#8239;mmol&#47;L&#44; since there is a risk of overcorrection due to the induction of a rapid water diuresis&#46; Also&#44; for this reason&#44; treatment should be started in the context of hospital admission to ensure close monitoring&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a> illustrates the treatment algorithm for chronic hyponatremia&#44; adapted from Runkle et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> in which the different options can be followed sequentially according to the result of electrolytes in urine and the sequential response to the different interventions&#46; The outline is indicative&#44; since the characteristics of the patient and the adverse reactions on nutrition and quality of life that strict water restriction can cause in susceptible patients &#40;cancer and elderly&#41; must be taken into account&#46; While the initial dose was initially 15&#8239;mg&#44; many physicians started with lower doses to avoid overcorrection&#44; and today the 7&#46;5&#8239;mg presentation is also available&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0155" class="elsevierStylePara elsevierViewall">Another aspect is that tolvaptan should not be started immediately after finishing a hypertonic infusion to avoid overcorrection&#46; Due to the fact that after the first dose there is an abundant water diuresis in the first hours&#44; it is necessary to insist on the intake of abundant water according to thirst&#46; Overcorrection with the use of vaptans is variable and can be as high as 25&#37;&#44; as described in a small series with a mean baseline sodium concentration of 120&#46;6&#8239;mmol&#47;L&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">45</span></a> The duration of treatment should be adjusted to the expected duration of SIADH&#44; since in many cases it is reversible&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Conflicts of interest</span><p id="par0160" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare in relation to this paper&#46;</p></span></span>"
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          "titulo" => "Treatment of hyponatremia due to the syndrome of inappropriate antidiuretic hormone secretion"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Hyponatremia is the most frequent electrolytic disorder in hospitalized patients&#44; and the syndrome of inappropriate secretion of antidiuretic hormone &#40;SIADH&#41;&#44; the most frequent cause of hiponatremia with clinically normal extracellular volume&#46; It consists of a disorder of the regulation of body water that obeys to different causes&#44; mainly cancer&#44; pulmonary illnesses&#44; disorders of the central nervous system and diverse drugs&#46; As in any hiponatremia it a physiological knowledge of the regulation of body water and sodium is essential as well as the applicatin of precise diagnostic criteria in order to manage the problem with an effective treatment&#46; The available data until the moment show that the clinical diagnosis of SIADH made by professionals is mainly not supported on the established criteria drawn by experts and this lack of accuracy probably hits in the therapeutic result&#46; The basis of the treatment of the SIADH is to correct its cause&#44; water restriction&#44; solutes &#40;sodium chloride&#41; and the use of vaptans in case of failure of the previous measures&#46;</p></span>"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">La hiponatremia es el trastorno electrol&#237;tico m&#225;s frecuente en pacientes hospitalizados&#44; y el s&#237;ndrome de secreci&#243;n inadecuada de hormona antidiur&#233;tica &#40;SIADH&#41;&#44; la causa m&#225;s frecuente de hiponatremia con volumen extracelular cl&#237;nicamente normal&#46; Se trata de un trastorno de la regulaci&#243;n del agua corporal que obedece a diferentes causas&#44; entre las que destacan las neoplasias&#44; las enfermedades pulmonares&#44; los trastornos del sistema nervioso central y diversos f&#225;rmacos&#46; Como en cualquier hiponatremia es importante un conocimiento fisiol&#243;gico de la regulaci&#243;n del agua y del sodio corporal y aplicar unos criterios diagn&#243;sticos precisos de cara a poder realizar un tratamiento eficaz&#46; Los datos disponibles hasta el momento demuestran que el diagn&#243;stico cl&#237;nico de SIADH realizado por profesionales no se sustenta sobre los criterios establecidos por expertos y esta carencia probablemente impacta en los resultados terap&#233;uticos&#46; La base del tratamiento del SIADH es corregir su causa&#44; la restricci&#243;n h&#237;drica con el aporte de solutos &#40;cloruro s&#243;dico&#41; y el uso de vaptanes en caso de falta de respuesta a las medidas anteriores&#46;</p></span>"
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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Diagnostic algorithm for hyponatremia&#46;</p> <p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">&#42; In primary polydipsia&#44; water intake exceeds the renal excretory capacity for water&#46; An inhibition of ADH occurs&#44; which is why urine osmolality is very low&#46;</p> <p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">&#42;&#42; In chronic kidney disease there is initially an inability to concentrate urine &#40;Na is lost&#41; and&#44; in advanced stages&#44; difficulty in dilution&#46;</p> <p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Na<span class="elsevierStyleInf">p</span>&#58; plasma or serum sodium&#59; Na<span class="elsevierStyleInf">u</span>&#58; urinary sodium&#59; Osm<span class="elsevierStyleInf">p</span>&#58; plasma osmolality&#59; Osm<span class="elsevierStyleInf">u</span>&#58; urinary osmolality&#46;</p>"
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          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Algorithm for correction of hyponatremia with the use of tolvaptan in the context of SIADH&#46;</p> <p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">K<span class="elsevierStyleInf">u</span>&#58; urinary potassium&#59; Na<span class="elsevierStyleInf">p</span>&#58; plasma or serum sodium&#59; Na<span class="elsevierStyleInf">u</span>&#58; urinary sodium&#46;</p>"
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          "leyenda" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">ADH&#58; antidiuretic hormone&#59; BUN&#58; blood urea nitrogen&#59; FE&#58; fractional excretion&#59; mOsm&#58; milliosmoles&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Criteria&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Major&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Plasma sodium&#8239;&#60;&#8239;135&#8239;mEq&#47;L&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Urine sodium&#8239;&#62;&#8239;30&#8239;mEq&#47;L with normal-sodium diet&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Effective plasma osmolality &#40;without urea&#41;&#8239;&#60;&#8239;275&#8239;mOsm&#47;kg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Osmolality in urine&#8239;&#62;&#8239;100&#8239;mOsm&#47;kg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Clinical euvolemia &#40;no signs of hypervolemia or hypovolemia&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">No treatment with diuretics&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Absence of adrenal failure or hypothyroidism&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ancillary&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Uricemia&#8239;&#60;&#8239;4&#8239;mg&#47;dL&#44; uric FE&#8239;&#62;&#8239;12&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">BUN&#8239;&#60;&#8239;10&#8239;mg&#47;dL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">FENa&#8239;&#62;&#8239;1&#37;&#59; FEUrea&#8239;&#62;&#8239;55&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Failure to correct hyponatremia with infusion of isotonic saline &#40;0&#46;9&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Correction of hyponatremia with fluid restriction&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Pathological fluid overload test&#46; Excretion&#8239;&#60;&#8239;90&#37; of a 20&#8239;mL&#47;kg water overload in 4&#8239;h or inadequate urine dilution &#40;Osm&#8239;&#60;&#8239;100&#8239;mOsm&#47;kg&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Elevated ADH level despite hypotonicity and euvolemia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Diagnostic criteria for the syndrome of inappropriate antidiuretic hormone secretion &#40;SIADH&#41;&#46;</p>"
        ]
      ]
      3 => array:8 [
        "identificador" => "tbl0010"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at0020"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Diuretics are not included&#44; as they are an exclusion criterion for the diagnosis of SIADH&#46; However&#44; given the high incidence of diuretic-induced hyponatraemia&#44; it is briefly discussed in the text&#46;</p><p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">ADH&#58; antidiuretic hormone&#59; TCA&#58; tricyclic antidepressants&#59; COPD&#58; chronic obstructive pulmonary disease&#59; SAH&#58; subarachnoid haemorrhage&#59; MAOI&#58; monoamine oxidase inhibitors&#59; SSRIs&#58; selective serotonin reuptake inhibitors&#59; SOL&#58; space-occupying lesions&#59; TBI&#58; traumatic brain injury&#59; HIV&#58; human immunodeficiency virus infection&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:1 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Tumors&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Carcinomas&#58; lung &#40;especially small cell&#41;&#44; oropharynx&#44; gastrointestinal&#44; genitourinary&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Lymphomas and sarcomas&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pulmonary disorders&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Infections&#44; especially <span class="elsevierStyleItalic">Legionella</span>&#44; <span class="elsevierStyleItalic">Mycoplasma</span>&#44; tuberculosis&#44; abscesses&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">COPD&#44; asthma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cystic fibrosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Non-invasive mechanical ventilation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Vasculitis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Central nervous system disorders&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Infections&#58; encephalitis&#44; myelitis&#44; abscess&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Haemorrhages and masses&#58; SAH&#44; TBI&#44; SOL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Neurological disorders&#58; Guillain-Barr&#233; syndrome&#44; multiple sclerosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Vasculitis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Drugs and toxic substances&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Stimulate the release of ADH&#58;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Antidepressants&#58; SSRIs&#44; TCAs&#44; MAOIs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Antipsychotics&#58; phenothiazines&#44; haloperidol&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Antiepileptics&#58; carbamazepine&#44; levetiracetam&#44; valproate&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NSAIDs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Opiates&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cytotoxic agents&#58; vincristine&#44; vinblastine&#44; cyclophosphamide&#44; cisplatin&#44; carboplatin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Nicotine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#44;4&#44; methylenedioxymethamphetamines&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Opiates&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Potentiate the antidiuretic effect of ADH&#58; vasopressin&#44; oxytocin&#44; carbamazepine&#44; lamotrigine&#44; chlorpropamide&#44; tolbutamide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Prostaglandin synthesis inhibitors&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Produce a reset of ADH osmoregulation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Venlafaxine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Carbamazepine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Miscellaneous&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">HIV&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Postoperative&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pain&#44; nausea and vomiting&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Prolonged exercise&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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