what should i do to avoid my body depleting my sodium while living in tucson, arizona
Oncologist. 2012 Jun; 17(6): 756–765.
Diagnosis and Management of Hyponatremia in Cancer Patients
Jorge J. Castillo
aSectionalisation of Hematology and Oncology, The Warren Alpert Medical School of Brown Academy, Providence, Rhode Island, USA;
Marc Vincent
bOtsuka America Pharmaceutical, Inc., Rockville, Maryland, The states;
Eric Justice
cBioScience Communications, New York, New York, Usa
Received 2011 November fifteen; Accepted 2012 April 18.
Abstract
Hyponatremia, a common electrolyte abnormality in oncology practice, may be a negative prognostic factor in cancer patients based on a systematic assay of published studies. The largest trunk of evidence comes from small-cell lung cancer (SCLC), for which hyponatremia was identified equally an contained take chances factor for poor outcome in six of 13 studies. Hyponatremia in the cancer patient is normally caused by the syndrome of inappropriate antidiuretic hormone (SIADH), which develops more than frequently with SCLC than with other malignancies. SIADH may be driven by ectopic production of arginine vasopressin (AVP) by tumors or by effects of anticancer and palliative medications on AVP production or action. Other factors may cause hypovolemic hyponatremia, including diarrhea and vomiting acquired by cancer therapy. Hyponatremia may be detected on routine laboratory testing before or during cancer treatment or may be suggested by the presence of mostly neurological symptoms. Treatment depends on several factors, including symptom severity, onset timing, and extracellular book status. Appropriate diagnosis is important considering treatment differs by etiology, and choosing the incorrect approach can worsen the electrolyte aberration. When hyponatremia is acquired by SIADH, hypertonic saline is indicated for acute, symptomatic cases, whereas fluid restriction is recommended to reach a slower rate of correction for chronic asymptomatic hyponatremia. Pharmacological therapy may exist necessary when fluid restriction is insufficient. The orally active, selective AVP receptor 2 (V2)-receptor adversary tolvaptan provides a mechanism-based option for correcting hyponatremia acquired by SIADH or other conditions with inappropriate AVP elevations. By blocking AVP effects in the renal collecting duct, tolvaptan promotes aquaresis, leading to a controlled increment in serum sodium levels.
Keywords: Cancer, Hyponatremia, Syndrome of inappropriate antidiuretic hormone, Arginine vasopressin, Tolvaptan
Introduction
Hyponatremia is an electrolyte abnormality commonly encountered in oncology practice and is usually defined by a serum sodium level <135 mEq/L [ane, 2]. Although many cases are asymptomatic, hyponatremia may crusade neurological symptoms, specially when serum sodium declines rapidly or by a substantial extent [three]. The incidence and prevalence of hyponatremia vary profoundly, depending on the cancer type, clinical setting, and serum sodium cutoff point. Among cancer patients, hyponatremia occurs most oft with small cell lung cancer (SCLC). In an analysis of 9 sequent clinical trials conducted jointly at 4 hospitals in Denmark and Sweden, a serum sodium level <136 mEq/Fifty was identified in 415 of one,684 SCLC patients (24.6%) [4]. Rates of 25%–44% were reported in smaller SCLC cohorts when a like serum sodium cutoff was used [five–vii], whereas rates of ∼15% were institute when a serum sodium level <130 mEq/50 was used equally the cutoff [8, 9].
Near cases of hyponatremia are caused by the syndrome of inappropriate antidiuretic hormone (SIADH), with college rates of SIADH found with SCLC than with other malignancies [2, 10]. However, hyponatremia—whether precipitated by SIADH, cancer handling, or other underlying causes—may occur with other solid tumor types too SCLC, too as with hematological malignancies. This commodity identifies the rationale for diagnosis and management of hyponatremia in cancer patients, reviews its primary causes, and then discusses treatment options, with a focus on the applied apply of the arginine vasopressin (AVP) antagonist tolvaptan.
Rationale for Diagnosis and Chiliadanagement of Hyponatremia in Cancer Patients
A systematic search using PubMed and MEDLINE from inception through December 2011 was conducted to identify English language-language studies that investigated the impact of hyponatremia on outcome in cancer patients. Thirteen studies were identified in SCLC, including six prospective and seven retrospective studies (Table 1) [4–9, xi–17]. Report sizes were in the range of 76–1,960 patients, with dissimilar serum sodium cutoff points used to define hyponatremia. Hyponatremia was significantly associated with a shorter survival elapsing on univariate analysis of the study cohorts in vii of the 13 studies (54%) and on multivariate analysis in six studies (46%). The prognostic value of hyponatremia varied amid studies depending on the patient population; it was prognostic for a shorter survival fourth dimension in patients with extensive affliction simply not in patients with limited disease in a Japanese cohort [14], whereas the opposite was suggested in a Danish cohort [five]. In the largest study, pretreatment hyponatremia was independently associated with a shorter survival fourth dimension, especially in the 6- to 24-month menstruation after starting handling [13]. Failure to normalize serum sodium was a negative prognostic factor in 1 study, in which the baseline serum sodium level was likewise prognostic for outcome [7]. A subset of 61 patients had baseline serum sodium levels <130 mEq/L and received at least two cycles of chemotherapy; patients whose serum sodium levels failed to normalize by the second wheel had poorer survival outcomes in both univariate and multivariate analyses than those who had serum sodium levels ≥136 mEq/L.
Table one.
Prognostic value of hyponatremia for survival of patients with modest-cell lung cancer
Several studies were identified that explored the affect of a low serum sodium level on survival outcomes in patients with malignancies other than SCLC (Tabular array 2). Hyponatremia was identified as a negative prognostic factor in both univariate and multivariate analyses in two of three studies of non-pocket-sized cell lung cancer [16, 18, nineteen], two studies of renal cell carcinoma [20, 21], and in separate studies of gastric cancer [22, 23] and non-Hodgkin'due south lymphoma [24].
Table ii.
Prognostic value of hyponatremia for survival of patients with cancer, other than small cell lung cancer
Three large studies explored the prognostic role of hyponatremia at infirmary admission (Table 2). The start written report assessed 7,689 patients with hematological malignancies who were admitted to intensive intendance units in the U.K. in 1995–2007 [25]. A serum sodium level <130 mEq/Fifty was identified in 4.2% of 6,766 patients who had assessments at access, and this was independently associated with a significantly greater risk for in-hospital bloodshed (odds ratio [OR], 2.47; 95% confidence interval [CI], 1.seventy–three.60). The 2d study included six,612 patients with metastatic cancer admitted to ii Boston teaching hospitals in 2000–2002 [26]. A serum sodium level <135 mEq/L was identified in 10.8% of these patients, and this was also significantly associated with a greater risk for in-hospital mortality (OR, 2.05; 95% CI, 1.67–two.53). Of note, the chance for in-hospital bloodshed increased every bit serum sodium levels declined, with an OR of 4.eight (95% CI, 1.3–18.2) for patients with a serum sodium level ≤120 mEq/L. The third report evaluated the impact of hyponatremia amidst iii,357 cancer patients admitted to the M.D. Anderson Cancer Center during a 3-month period in 2006 [27]. Hyponatremia (defined every bit a serum sodium level <135 mEq/L) was identified in 47% of patients (23% at admission and 24% acquired during hospitalization), and this was independently associated with a poorer xc-day survival probability. Of note, patients whose serum sodium levels did not meliorate following access had a higher 90-24-hour interval bloodshed chance than those whose serum sodium improved (risk ratio [HR], ii.09; 95% CI, one.twoscore–3.fifteen).
Unfortunately, the data from the SCLC studies cannot exist combined and subjected to a meta-assay, given that almost did not study HRs for survival outcomes. Moreover, the bear upon of hyponatremia on issue in patients with other cancer types has been evaluated in only a express number of studies. Even so, when these data are considered together, they support the hypothesis that hyponatremia is a negative prognostic gene in cancer patients.
Causes of Hyponatremia in Cancer Patients
Hyponatremia typically develops in the presence of excessive water relative to existing sodium stores in the body [three]. Most cases reflect impaired water excretion, in which the capacity of the kidneys to eliminate water does not go along up with water intake, only in a minority of cases hyponatremia is driven by excessive h2o intake. Hyponatremia is often acquired by SIADH in cancer patients [2, x]. In this setting, ectopic secretion of AVP (also known an antidiuretic hormone [ADH]) by tumor cells appears to be important in driving the hyponatremic state. Under normal conditions, AVP is secreted by the posterior pituitary in response to increases in plasma osmolality detected by osmoreceptors located in the anterior hypothalamus, or by reductions in blood volume or pressure level detected by baroreceptors located in the carotid sinus, aortic arch, atria, and pulmonary venous system [28]. AVP then activates AVP receptor 2 (52) receptors located on the basolateral membrane of renal collecting duct cells to promote movement of aquaporin-ii containing vesicles from the cytoplasm to the upmost membrane and, in turn, enhance the h2o permeability of the upmost membrane [29]. Through this mechanism, AVP promotes h2o reabsorption and consequently reduces plasma osmolality. Further AVP secretion is usually suppressed one time plasma osmolality falls below a genetically defined threshold [28]. In SIADH, notwithstanding, AVP secretion is not fully suppressed despite the low plasma osmolality, and instead persistently elevated AVP levels are maintained by nonosmotic factors including ectopic product of AVP. In some cases, other neurohormones, such equally atrial natriuretic peptide, may also contribute to the persistence of depression plasma osmolality [30, 31].
SIADH is nearly commonly institute in patients with SCLC, occurring at a frequency of 11%–15% [32, 33]. SIADH has been reported in ∼3% of patients with caput and neck cancer (HNC) [34], virtually often in patients with lesions in the oral cavity and less oftentimes in those with lesions in the larynx, nasopharynx, hypopharynx, or other sites [35]. SIADH has also been identified in patients with a broad variety of other solid tumors and hematological malignancies, only at lower rates than those found with SCLC or HNC [2, 10]. Too cancer, SIADH may be caused by a diversity of other atmospheric condition, including cardinal nervous system (CNS) disorders (e.thou., inflammatory or demyelinating diseases, subarachnoid hemorrhage, head trauma), pulmonary disorders (due east.k., tuberculosis, pneumonia, acute respiratory failure, positive-pressure ventilation), HIV infection, and prolonged strenuous exercise [3, 28].
Drugs used in the treatment and palliation of cancer may also crusade hyponatremia by inducing SIADH (Table 3). Vincristine and, to a lesser extent, vinblastine induce SIADH by altering normal osmotic command of ADH secretion through a neurotoxic issue on the hypothalamic–pituitary axis [36–38]. Cyclophosphamide induces SIADH past potentiating the deportment of AVP in the kidneys, and possibly past stimulating AVP secretion [38]. This tin atomic number 82 to water intoxication, even when moderate doses of cyclophosphamide are used, because patients are encouraged to drink large amounts of fluids in an effort to foreclose chemical cystitis [39, twoscore]. Similarly, opioids and antidepressants, including tricyclics and selective serotonin reuptake inhibitors, stimulate AVP secretion, whereas nonsteroidal anti-inflammatory drugs potentiate the furnishings of AVP in the renal tubules [38].
Table 3.
Drugs known to cause hyponatremia by affecting arginine vasopressin (AVP) production or activeness
The development of hyponatremia during cisplatin therapy bears special mention. Cisplatin stimulates AVP secretion to cause SIADH, only information technology can too directly damage renal tubules to interfere with sodium reabsorption, which in rare cases may lead to hyponatremia via table salt wasting nephropathy [41]. Similarly, excessive sodium loss resulting from cognitive salt wasting may develop in patients with encephalon metastases, head trauma, or meningitis, or after CNS surgery [42]. These common salt wasting syndromes are often difficult to distinguish from SIADH because each is characterized by low plasma and sodium osmolality, high urine sodium concentration, and higher urine than plasma osmolality. Still, the distinction is important considering their management differs, and choosing the incorrect management approach can pb to worsening of the hyponatremia, with potential adverse consequences [2].
Diagnosis of Hyponatremia
Hyponatremia may be detected incidentally on routine laboratory testing before or during cancer treatment, or it may be suggested by the presence of mostly neurological symptoms (due east.g., headache, nausea, airsickness, muscle cramps, lethargy, disorientation, depressed reflexes) [3]. Serious neurological complications may be evident following large or rapid declines in serum sodium, including seizures, coma, respiratory arrest, or brain-stem herniation. The symptoms associated with hyponatremia are owing to water motility in the brain caused past the low plasma osmolality. Water moves across an osmotic gradient from intravascular spaces into brain cells, thereby raising intracranial pressure level. However, adaptive mechanisms are activated to initially extrude inorganic solutes (eastward.g., sodium and potassium salts) and then organic solutes (east.m., glutamate, myoinositol) from the brain cells in order to limit cognitive edema [43]. The encephalon's adaptive mechanisms are generally completed within ∼48 hours, which explains why dull serum sodium declines may not crusade symptoms. All the same, these adaptive mechanisms may be overwhelmed by large or rapid serum sodium decreases, thereby accounting for the appearance of symptoms in such cases. On the basis of the encephalon adaptation fourth dimension frame, hyponatremia is classified every bit acute if it develops within 48 hours or chronic if it develops over >48 hours [44].
The differential diagnosis of hyponatremia is important for selecting advisable handling to correct the abnormality and is based on clinical and laboratory assessments (Fig. i) [1, 45]. The beginning step is to make up one's mind plasma osmolality; it will be depression (<280 mOsm/kg) in most cases. Normal or high plasma osmolality is suggestive of the presence of an osmotically active substance, such as glucose (i.e., hyperglycemia). For patients with low plasma osmolality, the next step is to appraise urine osmolality in guild to decide if renal diluting mechanisms are intact. Normal kidneys elaborate a maximally dilute urine (<100 mOsm/L) in the face of hyponatremia, and this scenario suggests excessive water intake as a cause. Impaired water excretion is suggested by inappropriately concentrated urine (>100 mOsm/L) in the presence of hyponatremia. For patients with inappropriately concentrated urine, it is critical to assess the extracellular fluid book status. Volume depletion (hypovolemia) is suggested by orthostatic hypotension or tachycardia, dry fungus membranes, and poor skin turgor, whereas volume expansion (hypervolemia) is suggested by the presence of s.c. edema or ascites [28]. Patients without clinical bear witness of hypovolemia or hypervolemia are considered to be euvolemic.
Algorithm for the differential diagnosis of hyponatremia.
Abbreviations: ECF, extracellular fluid; SIADH, syndrome of inappropriate antidiuretic hormone.
Modified from Palmer BF, Gates JR, Lader Thousand. Causes and management of hyponatremia. Ann Pharmacother 2003;37:1694–1702 and Douglas I. Hyponatremia: Why it matters, how it presents, how we can manage it. Clev Clin J Med 2006;73(suppl 3):S4–S12.
Additional clues virtually volume status may be obtained from measurements of urine sodium, blood urea nitrogen (BUN), serum uric acid, and serum potassium [28, 45, 46]. Urine sodium >30 mEq/L in the absence of diuretic employ or renal disease is supportive of a euvolemic land, whereas a depression urine sodium level (<30 mEq/Fifty) is supportive of hypovolemia because the kidneys reabsorb sodium to conserve volume. However, the urine sodium level may be high if the kidneys are responsible for the sodium loss, as in salt wasting syndromes, or in elderly patients who adapt slowly to rapid volume depletion. Low BUN and serum uric acrid levels are as well supportive of euvolemia, whereas high values are supportive of hypovolemia; variations in the levels of these substances reverberate changes in their proximal reabsorption based on volume status.
Potassium depletion may be suggestive of diuretic-induced hyponatremia [45]. In addition, assessment of the acrid–base of operations and potassium remainder may be useful in patients in whom the diagnosis is non apparent; for example, metabolic alkalosis and hypokalemia suggest diuretic use or vomiting, metabolic acidosis and hypokalemia suggest diarrhea or laxative abuse, and metabolic acidosis and hyperkalemia suggest adrenal insufficiency [47]. On the other hand, plasma bicarbonate and potassium concentrations are typically normal in patients with SIADH [48]. Volume depletion with a high urine sodium level and accompanying hyperkalemia should enhance suspicion for mineralocorticoid deficiency; a low urine potassium level or transtubular potassium slope can provide confirmation [28].
Equally noted previously, hyponatremia in the oncology setting is ordinarily caused by SIADH—which is characterized by an substantially normal extracellular volume (euvolemia). Euvolemic hyponatremia may also be associated with hypothyroidism (in patients with myxedema or panhypopituitarism) or adrenal insufficiency, and therefore assessment of thyroid and adrenal function may exist considered in the differential diagnosis [3, 28, 46, 49]. Hypovolemic hyponatremia can be caused by either renal or extrarenal sodium loss; the erstwhile may be a effect of diuretic therapy, cerebral salt wasting, or mineralocorticoid deficiency, whereas the latter may reflect gastrointestinal sodium loss caused by vomiting or diarrhea, third-space losses acquired by bowel obstruction, pancreatitis, muscle trauma, or burns, or excessive sweating during endurance exercising. Hypervolemic hyponatremia is associated with congestive heart failure, liver cirrhosis, nephrotic syndrome, and acute and chronic renal failure.
Treatment Options
Formalized guidelines for the direction of hyponatremia in oncology patients have non been established. In general terms, the treatment of hyponatremia depends on whether or not symptoms are present, their severity and time of onset, and the extracellular volume condition of the patient [1, 3, 28]. Symptomatic patients crave prompt attention in social club to prevent serious complications. Even so, the adaptive mechanisms that control brain swelling during the development of chronic hyponatremia also brand the brain susceptible to osmotic demyelination if serum sodium is corrected in an overly rapid mode. Therefore, the serum sodium level should be raised in a controlled fashion: the charge per unit of correction should be kept <12 mEq/L in 24 hours and <18 mEq/50 in 48 hours [28]. Patients with acute onset of hyponatremia are less susceptible to osmotic demyelination with rapid serum sodium increases considering the initial adaptive mechanisms are not fully established. However, when it is difficult to pinpoint the timing of onset, it is prudent to assume a chronic course and correct serum sodium levels in a controlled fashion.
The correction of severely symptomatic hyponatremia in patients with SIADH or other euvolemic states or hypervolemia is achieved by administration of hypertonic (three%) saline via a continuous infusion or bolus [28]. Symptoms of severe hyponatremia, such as seizures, dumb mental status, or coma, are usually seen with strenuous exercise, use of iii,4-methylenedioxymethamphetamine (ecstasy), chief polydipsia, and postoperatively in patients with known intracerebral pathology. Treatment with hypertonic saline should be stopped once symptoms resolve, a safe serum sodium concentration is accomplished, or the maximum sodium correction limits are approached. The treatment approach to salt wasting and other hypovolemic conditions differs: isotonic (0.ix%) saline is typically administered until the volume deficit is corrected and the patient returns to a euvolemic state [28].
Asymptomatic patients with euvolemic or hypervolemic hyponatremia are usually managed initially by fluid restriction, with the goal of achieving a negative water remainder [3, 28]. Fluid (but not sodium) should be restricted to approximately 500 ml below the average daily urine output, and any drug known to cause SIADH should exist discontinued whenever possible and replaced with another agent that does non cause hyponatremia. Fluid brake normally takes several days earlier significant increases in serum sodium levels are achieved. Fluid brake poses a item challenge in oncology patients requiring urgent treatment with cisplatin because patients must exist adequately hydrated when receiving this amanuensis. One potential approach is to right the hyponatremia equally chop-chop as possible and and so proceed with cisplatin therapy (a more likely scenario in patients with severe hyponatremia). A second pick is to care for the cancer kickoff—which could also yield improvement in the sodium status—while monitoring carefully for hyponatremia (a likely scenario if cancer therapy is deemed to be more urgent). The approach to these patients should be dictated past the specific clinical scenario and by the treating doctor's best medical judgment.
Patient compliance with fluid restriction is oftentimes poor, and therefore pharmacological interventions may be considered in patients with euvolemic or hypervolemic hyponatremia who do not reply adequately. When SIADH is caused by a tumor, pharmacological handling should be avoided initially because successful treatment of the malignancy may eliminate or reduce the inappropriate AVP secretion [28]. Still, pharmacological intervention may be necessary, and several options are available.
Older medications such equally demeclocycline, urea, and lithium are limited by variable efficacy, poor palatability, and/or toxicity. The tetracycline derivative demeclocycline induces nephrogenic diabetes insipidus, but it has an unpredictable onset and only works in ∼sixty% of patients [28, fifty]. Monitoring of renal function is necessary because demeclocycline causes reversible azotemia and nephrotoxicity, particularly in patients with, or at risk for, renal compromise (eastward.g., those with cirrhosis or congestive heart failure). Lithium also induces nephrogenic diabetes insipidus, but information technology works in a smaller proportion of patients than demeclocycline [50]. Lithium toxicity includes gastrointestinal and CNS side effects, renal toxicity, hypothyroidism, and antianabolic furnishings. Urea is an osmotic diuretic that increases h2o excretion and decreases urinary sodium excretion [28]. Although information technology is generally effective, urea has the potential to cause azotemia, liver failure, and hypersensitivity. A convenient dosage form is unavailable, and because of its unpleasant taste, it needs to be dissolved in a strongly flavored liquid. Urea is currently used merely in some European countries where palatability is not deemed to be an issue.
The limitations of fluid restriction and these older pharmacological interventions propose the need for newer, more constructive handling strategies. The V2 receptor on renal collecting duct cells represents an attractive molecular target considering AVP is elevated in patients with euvolemic and hypervolemic hyponatremia despite the presence of low plasma osmolality, and AVP activates the V2 receptor to stimulate water reabsorption, with consequent dilution of serum sodium concentrations [51]. The use of vasopressin receptor antagonists to accost hyponatremia in cancer patients has ii potential benefits: (a) patients tin undergo chemotherapy with platinum-based regimens without concerns for further hyponatremia and (b) in patients who volition not be treated with chemotherapy, these agents may reduce the risks and mitigate the symptoms associated with hyponatremia.
Iii vasopressin antagonists (conivaptan, tolvaptan, mozavaptan) have been introduced into clinical practice and others (eastward.k., lixivaptan, satavaptan) have undergone clinical testing. Mozavaptan is an oral vasopressin V2-receptor antagonist approved in Nippon as an orphan drug for employ in cancer patients with ectopic ADH syndrome (i.e., excessive AVP secretion by cancer cells leading to hyponatremia). Short-term (7-day) treatment of 16 patients with ectopic ADH syndrome yielded significant increases in sodium concentrations, resulting in improvements in hyponatremia symptoms [52]. Conivaptan is an i.5. administered vasopressin V1A- and V2-receptor antagonist that has been shown to increase serum sodium levels in hospitalized patients with euvolemic or hypervolemic hyponatremia [53], and it is approved for employ in this patient population in the U.S. Treatment with this agent is limited to two–4 days. Tolvaptan, which is approved in Europe for the handling of hyponatremia secondary to SIADH, in the U.S. for handling of euvolemic or hypervolemic hyponatremia, and in Japan for treatment of excess water retention in patients with cardiac failure, is an oral vasopressin Fivetwo-receptor adversary that is administered once daily and can be continued after patients are discharged from the hospital [54]; appropriately, it may exist of more practical value for treating hyponatremia in cancer patients. The post-obit section reviews the clinical contour and applied utilise of tolvaptan.
Tolvaptan
Tolvaptan increases urine water excretion by blocking the effects of endogenous AVP at V2 receptors in the renal collecting duct, thereby increasing free water clearance (aquaresis), reducing urine osmolality, and consequently raising serum sodium concentrations [55, 56]. In the Study of Ascending Levels of Tolvaptan in Hyponatremia-1 (SALT-i) and Salt-2 trials (n = 448), tolvaptan (starting dose, fifteen mg/day; maximum dose, 60 mg/twenty-four hour period) was significantly meliorate at increasing serum sodium levels than placebo in patients with euvolemic or hypervolemic hyponatremia during the first four days of treatment and during the entire 30-mean solar day study period (both p < .001) [57]. Significantly more patients achieved normal serum sodium concentrations with tolvaptan than with placebo on day four (twoscore% versus 13% in the Table salt-one trial and 55% versus 11% in the Table salt-2 trial; both p < .001) and on day 30 (53% versus 25% and 58% versus 25%, respectively; both p < .001). Importantly, correction of the serum sodium level by tolvaptan was achieved without the use of fluid restriction during the first 24 hours of handling, and it was brought near in a controlled manner: only four of 223 patients (ane.eight%) had an overly rapid serum sodium correction on 24-hour interval 1 and iv of 223 patients (1.eight%) had a serum sodium level >146 mEq/L at some bespeak during the study catamenia. Tolvaptan was mostly well tolerated: thirst (14% versus 5%), dry mouth (thirteen% versus 4%), and increased urination (7% versus 3%) were the most common adverse events that occurred more oftentimes with tolvaptan than with placebo. Tolvaptan was discontinued at the finish of the xxx-day study period. When measured 7 days afterward, serum sodium levels had declined to levels found in placebo-treated patients.
The SALT trials enrolled patients with hyponatremia resulting from a variety of underlying causes, including SIADH, heart failure, and liver cirrhosis. In each of these subsets, as well as in the subgroups with baseline serum sodium levels <130 mEq/L or <125 mEq/L, the efficacy of tolvaptan was comparable to that observed in the entire study population [54, 58, 59]. As shown in Effigy 2, tolvaptan was significantly better at improving serum sodium levels than placebo over the starting time 4 days and during the entire 30-solar day handling period (both p < .0001) in the subset of 110 patients with a master diagnosis of SIADH [58]. Higher rates of normalized serum sodium were observed at both fourth dimension points (day 4, threescore% versus 11.5%; day thirty, 66.6% versus 26.8%; both p < .05). The inclusion criteria for the Table salt trials did not exclude patients with oncology-induced SIADH; however, results in this subpopulation have not been reported. Prospective studies are needed to confirm the hypothesis that improving hyponatremia leads to ameliorate outcomes.
Serum sodium levels in SIADH patients during handling with tolvaptan or placebo in the SALT trials. Investigator-diagnosed patients received a primary diagnosis of SIADH from the investigator; lab-diagnosed patients received a primary diagnosis of SIADH from the investigator and had a urine sodium concentration >20 mEq/L during the first day of treatment.
a p < .0001, tolvaptan (investigator-diagnosed) versus placebo (investigator-diagnosed).
b p < .001, tolvaptan (lab-diagnosed) versus placebo (lab-diagnosed).
c p < .029, tolvaptan (lab-diagnosed) versus placebo (lab-diagnosed).
Error bars are ± standard error of the mean.
Abbreviations: BSL, baseline; FU, 7-day follow-up visit; PBO-I, placebo (investigator-diagnosed); PBO-L, placebo (lab-diagnosed), TLV-I; tolvaptan (investigator-diagnosed); TLV-L, tolvaptan (lab-diagnosed); SALT, Study of Ascending Levels of Tolvaptan in Hyponatremia; SIADH, syndrome of inappropriate antidiuretic hormone.
Reproduced with permission from Verbalis JG, Adler Southward, Schrier RW et al. Efficacy and safety of oral tolvaptan therapy in patients with the syndrome of inappropriate antidiuretic hormone secretion. Eur J Endocrinol 2011;164:725–732. ©Society of the European Periodical of Endocrinology (2011).
Tolvaptan is indicated by the European Medicines Agency for the handling of hyponatremia secondary to SIADH [threescore], whereas it is indicated for the treatment of clinically significant hypervolemic or euvolemic hyponatremia (serum sodium <125 mEq/L or less marked hyponatremia that is symptomatic and has resisted correction with fluid brake) in the U.S. [54]. Information technology is contraindicated in patients with hypovolemic hyponatremia, volume depletion, and anuria, and in those who cannot perceive or respond accordingly to thirst, and information technology should not exist used in patients whose serum sodium levels need to be urgently raised [54, 60]. Tolvaptan is also contraindicated in Europe in women who are pregnant or breastfeeding, whereas it carries pregnancy category C labeling in the U.S. [54, threescore].
Tolvaptan therapy should exist started while patients are in a hospital to permit monitoring of the therapeutic response and ensure that serum sodium is corrected in a controlled manner [54, 60]. The starting dose is 15 mg once daily, which can be given without regard to the timing of meals. Dose increases to 30 mg once daily and subsequently to a maximum of 60 mg one time daily may be made at 24-60 minutes intervals if serum sodium is not raised to the desired level. Patients should be provided with access to sufficient amounts of water to ensure that they do not become overly dehydrated. Dose adjustments based on age, gender, race, mild or moderate renal impairment, and mild or moderate hepatic impairment are not necessary. If the serum sodium level rises at an overly rapid rate (>12 mEq/L in 24 hours), tolvaptan should be discontinued and treatment with hypotonic fluid should be considered. Following completion of tolvaptan therapy, fluid restriction should be resumed, and changes in serum sodium and volume status should exist monitored [54]. If boosted tolvaptan is needed, handling should be restarted in a infirmary setting in order to monitor the therapeutic response. In an open-label extension of the SALT trials, reinitiation of tolvaptan raised serum sodium levels to levels comparable to those seen to initial therapy, and these levels were maintained by connected daily therapy for ≥ane year [61].
Conclusions
Hyponatremia is a negative prognostic factor in cancer patients, and it is usually caused by SIADH. In the oncology setting, SIADH may be a result of ectopic AVP production by tumor cells or may be a result of stimulation of AVP secretion or potentiation of AVP effects by anticancer drugs or palliative medications. Distinguishing SIADH from other underlying causes of hyponatremia, peculiarly salt wasting syndromes and other hypovolemic states, is of import for selecting advisable treatment and ensuring that the serum sodium abnormality is not worsened. Laboratory assessments, including measurements of plasma osmolality, urine osmolality, and urine sodium, and clinical cess of extracellular volume status are critical to the differential diagnosis of hyponatremia. Symptomatic patients with hyponatremia caused by SIADH are treated initially with hypertonic saline, whereas asymptomatic patients are by and large managed with fluid restriction. Notwithstanding, fluid restriction is associated with poor patient compliance and is less likely to be constructive with greater elevations in urine osmolality (indicative of higher plasma AVP levels) [28]. Older pharmacological medications, such as demeclocycline, urea, and lithium, are limited by their variable efficacy, poor palatability, and meaning toxicity, thus underscoring the demand for new treatment approaches. Past selectively blocking V2 receptors in the renal collecting duct, tolvaptan provides a mechanism-based approach for treating hyponatremia secondary to SIADH, including in patients for whom fluid restriction was ineffective. In the oncologic setting, the use of vasopressin receptor antagonists could improve hyponatremia and allow patients to receive acceptable therapies or palliate symptoms. Further studies are needed to evaluate the prognostic value of hyponatremia and its handling in cancer patients.
Acknowledgments
Eric Justice of BioScience Communications, New York, NY, provided writing and editing support, copyediting back up, and editorial and production assistance for the development of this manuscript (supported by Otsuka America Pharmaceutical, Inc., Rockville, MD).
Footnotes
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- Consulting/advisory relationship
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- Research funding
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- Employment
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- Honoraria received
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- Ownership interests
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- Intellectual property rights/inventor/patent holder
- (SAB)
- Scientific informational board
Author Contributions
Formulation/Pattern: Jorge J. Castillo, Marc Vincent
Collection and/or assembly of data: Jorge J. Castillo, Marc Vincent, Eric Justice
Information analysis and interpretation: Jorge J. Castillo, Marc Vincent
Manuscript writing: Eric Justice
Final approval of manuscript: Jorge J. Castillo, Marc Vincent, Eric Justice
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