Journal of Critical Care (2013) 28, 219.e1–219.e12

Hyponatremia in critical care patients: Frequency, outcome,characteristics, and treatment with the vasopressinV2-receptor antagonist tolvaptan

☆

Bruce Friedman MD, CNSP, FCCP, FCCMa,b,⁎, Joshua Cirulli PharmD c,⁎

aCritical Care and Assistant Director of the JM Still Burn Center, Doctor's Hospital, Augusta, GA, USAbMedical College of Georgia, Augusta, Georgia, USAcOtsuka America Pharmaceutical, Inc., Rockville, Maryland, USA

PInP

26N

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Keywords:Critical care;Hyponatremia;ICU;SIADH;Tolvaptan

Abstract Hyponatremia is a common problem in critical care patients and is associated with increasedduration of hospital stay and increased morbidity and mortality. The prevalence of hyponatremia in theintensive care unit (ICU) has been reported to be as high as 30% to 40%. Recent studies have foundhyponatremia at ICU admission in up to 14% of patients in unselected groups; patients withhyponatremia were at elevated risk of mortality vs normonatremic patients. Most cases in the ICU areeuvolemic or hypervolemic hyponatremia, with the syndrome of inappropriate secretion of antidiuretichormone being a predominant cause. The oral selective vasopressin V2-receptor antagonist tolvaptan iseffective in treating euvolemic and hypervolemic hyponatremia and may be useful in the management ofhyponatremic critical care patients. Tolvaptan treatment increases serum sodium via aquaresis—ie,increased electrolyte-free water excretion—and thus presents an advantage in patients with syndrome ofinappropriate secretion of antidiuretic hormone or other euvolemic states or hypervolemichyponatremia. This article provides a review of hyponatremia and of the potential use of tolvaptan incritical care settings. Case reports provide examples of tolvaptan use in correcting severe hyponatremiaand associated abnormal mental status and in resolving hyponatremia prior to surgery.© 2013 Elsevier Inc. All rights reserved.

☆ Conflicts of interest: BF is on Speakers' Bureaus for Otsuka Americaharmaceutical, Inc (manufacturer of tolvaptan) and Astellas Pharma US,c (manufacturer of conivaptan). JC is an employee of Otsuka Americaharmaceutical, Inc, which manufactures tolvaptan.⁎ Corresponding authors. Bruce Friedman is to be contacted at P.O. Box

12503, Martinez, GA 30907, USA. Tel.: +1 706 339 3975; fax: +1 70651 3179. Joshua Cirulli, Otsuka America Pharmaceutical, Inc., Princeton,J 08540.E-mail address: brucefriedman.md@gmail.com (B. Friedman).

883-9441/$ – see front matter © 2013 Elsevier Inc. All rights reserved.ttp://dx.doi.org/10.1016/j.jcrc.2012.06.001

1. Introduction

Hyponatremia is common in the critical care populationand is associated with significantly increased risk of mortality[1-9]. Many factors contribute to the high frequency ofhyponatremia in critical care settings, including use ofhypotonic fluids in patients with compromised ability tomaintain water balance, surgery, trauma, numerous medica-tions, and numerous disease states. Hypotonic hyponatremia(excess water relative to solute in extracellular fluid) is of the

219.e2 B. Friedman, J. Cirulli

greatest relevance to the critical care setting, with some dataindicating that approximately three quarters of intensive careunit (ICU) hyponatremia cases are hypervolemic or euvo-lemic hyponatremia [2,10]. Most patients with hyponatremiahave clinical euvolemia, in part because of the large numberof diseases associated with the syndrome of inappropriatesecretion of antidiuretic hormone (SIADH) [11]. SIADH isthe most common cause of euvolemic hyponatremia in thecritical care setting [10] and is associated with numerousfactors, including many commonly used medications, centralnervous system (CNS) disorders, carcinomas, and pulmonarydisorders [3,10,12,13]. Most hyponatremia is hospital-acquired in association with nonosmotic stimuli for produc-tion of arginine vasopressin (AVP; also known as antidiuretichormone). Because hospitalized patients have numerousstimuli for AVP production, all should be considered at riskfor hyponatremia [3].

Tolvaptan is an orally available, selective vasopressin V2-receptor antagonist indicated in the United States fortreatment of clinically significant hypervolemic and euvo-lemic hyponatremia (serum sodium b125 mEq/L) or less-marked hyponatremia that is symptomatic and resistant tocorrection by fluid restriction, including patients with SIADHand those with heart failure or cirrhosis. It is not indicated forthe treatment of hypovolemic hyponatremia. Vasopressin V2-receptor antagonism acts to increase electrolyte-free waterexcretion and increase sodium concentration in SIADH andin edema-forming conditions such as heart failure andcirrhosis and is thus an appropriate treatment modality formany cases of hyponatremia in the critical care setting [5].

2. Prevalence and outcome of hyponatremia incritical care settings

The prevalence of hyponatremia in the ICU can be as highas 30% to 40% [4,14,15], and the frequency at admission hasbeen reported at 14% (for serum sodium b130 mEq/L) in onestudy [2] and at 13.8%, 2.7% and 1.2% (for serum sodium of130–134, 125–129, and b125 mEq/L, respectively) inanother [7]. Several studies have shown that mortality issignificantly increased in ICU patients with hyponatremiacompared with normonatremic patients [2,6-9]. Bennani etal, for example, reported that in-hospital mortality in patientswith hyponatremia (serum sodium b130 mEq/L) was 38%,and severe hyponatremia (b125 mEq/L) at admission was anindependent predictor of mortality (relative risk 2.10, P b.001). Significant prolongation of ICU stays has also beenreported in ICU patients with hyponatremia [6,7].

3. Benefits of hyponatremia resolution

In a prospective cohort study of 98411 adults hospitalizedbetween 2000 and 2003 at 2 teaching hospitals in Boston,

MA, patients with hyponatremia (serum sodium concentra-tion b135 mEq/L) had an increased risk of death in hospital(odds ratio, 1.47; 95% CI, 1.33-1.62), at 1 year (hazard ratio,1.38; 95% CI, 1.32-1.46), and at 5 years (hazard ratio, 1.25;95% CI, 1.21-1.30) [16]. The increased risk of death wasevident even in those with mild hyponatremia (130–134mEq/L; odds ratio, 1.37; 95% CI, 1.23–1.52). A total of52468 patients in the study with hypo- or normonatremiahad 2 or more sodium determinations, enabling analyses ofthe relationship between change in serum sodium concen-tration and outcomes. Most of the patients were normona-tremic at both measurements (42176/52468; 80.4%); for theremainder, hyponatremia resolved in 3794 (7.2%), persistedin 4524 (8.6%), and was acquired during hospitalization in1974 (3.8%). Mortality in hospital was highest in those withpersistent hyponatremia (6.2%; multivariate-adjusted oddsratio vs normonatremia, 2.37 [95%, CI, 2.03–2.77]) oracquired hyponatremia (5.9%; odds ratio, 2.44 [1.97–3.03]vs normonatremia), lower in those with hyponatremia thatresolved (3.9%; odds ratio, 1.26 [1.03–1.52] vs normona-tremia), and lowest in those with normonatremia at bothfirst and last serum sodium measurements (1.8%). One- and5-year mortality data followed a similar pattern.

4. Characteristics of hyponatremia incritical care

Hyponatremia may be the consequence of chronic heart orliver disease, diuretic use, SIADH, adrenal insufficiency,impaired thyroid function, or cerebral or renal salt wasting. Itmay reflect increased, decreased, or normal body sodiumconcentrations, necessitating evaluation of serum osmolality;fluid volume must also be assessed since hypo-osmolarhyponatremia can be hypovolemic, euvolemic, or hypervo-lemic [12]. AVP secretion appears to be a central componentin the reduction of sodium concentrations in all of thesesettings [1,5,17]. Common conditions associated withhypovolemic, euvolemic, and hypervolemic hyponatremiaare shown in Fig. 1 [12].

A diagnostic algorithm for hyponatremia is presented inFig. 2 [3]. Signs and symptoms of hyponatremia are oftennonspecific, with most being related to change in serumosmolality and fluid shifts in the CNS. Signs and symptomsmay include headache, lethargy, disorientation, restlessness,nausea, vomiting, muscle cramps or weakness, depressedreflexes, seizures, coma, permanent brain damage, respira-tory arrest, brain stem herniation, and death [12,18].Delirium is ubiquitous in the ICU, with various studiesreporting rates of 81% in a population that includedmechanically ventilated and nonventilated patients [19],82% and 83% in ventilated patients [20,21], 62% during ICUstay in patients aged 65 years or older [22], and 48% innonventilated patients [23]. Delirium is associated withincreased morbidity, length of stay, and mortality [19-23].

Fig. 1 Classification and common etiologies of hyponatremia. Originally published Am J HealthSyst Pharm. 2005;62:1663-82. ©2005,American Society of Health-System Pharmacists, Inc. All rights reserved. Reprinted with permission [12]. (R1114).

219.e3Hyponatremia in critical care patients

Hyponatremia is a common cause of delirium in the ICU,with one study reporting an odds ratio of 8.2 for delirium inpatients with hyponatremia [24]; thus, the potential forhyponatremia should be assessed in all patients withdelirium.

Many different disease states present with euvolemichyponatremia, and this type has been consistently reported asthe predominant form in unselected populations of patientswith critical illness [1,2,10]. In euvolemic hyponatremia(near-normal body sodium concentration), there should be noevidence of extracellular fluid volume depletion or excess—ie, no peripheral edema, ascites, pulmonary congestion, orpleural effusion. SIADH is a major cause of hyponatremia inthe ICU [3,10]. As indicated in Fig. 2, the diagnosis of

SIADH is largely one of exclusion, and can be made only inthe setting of normal renal, thyroid, and adrenal function[10]. In general, SIADH is characterized by mild volumeexpansion with low-to-normal creatinine, urea, uric acid, andpotassium levels; impaired free water excretion with normalsodium excretion that reflects sodium intake; and hypona-tremia that is relatively unresponsive to sodium administra-tion in the absence of fluid restriction [3].

Common etiologies of SIADH are shown in Table 1 andinclude neoplastic diseases, pulmonary diseases/disorders,CNS disorders, and numerous commonly used drugs,including those that stimulate AVP release and those thathave direct renal effects or potentiate AVP antidiureticeffects [3,10,12].

Serum Na <135 mEq/LAccompanying signs/symptoms may include headache, lethargy, disorientation, restlessness, delirium, nausea,

vomiting, muscle cramps or weakness, depressed reflexes; more severe signs, such as seizures, coma,

permanent brain damage, respiratory arrest, brain stem

>280 mOsm/kg H2O• Hyperglycemia• Mannitol• Pseudohyponatremia

• Hyperlipidemia• Hyperproteinemia

<280 mOsm/kg H2O

Plasma osmolality

herniation, may be apparent in severe hyponatremia

<100 mOsm/kg H2O• Psychogenic polydipsia• Water intoxication in infants• Reset osmostat

Urine osmolality

>100 mOsm/kg H2O

YesEffective circulatory volume depletion

No

Urine Na <25 mEq/L• Extrarenal losses• Edematous states

Urine Na >25 mEq/L• Salt wasting nephropathy• Mineralocorticoid deficiency• Cerebral salt wasting• Diuretics

Renal insufficiencyHypothyroidGlucocorticoid deficiencyPostoperativeSpinal fusionPain/stress/nausea • Diuretics

• Osmotic diuresisPain/stress/nauseaPositive pressure ventilation

No

Urine Na >25 mEq/L• SIADH• Reset osmostat

Urine Na <25 mEq/L• Repeat algorithm

Fig. 2 Evaluation for hyponatremia. NA indicates sodium. Reproduced from Contrib Nephrol. 2004;144:132-57 [3], with permission fromS Karger AG, Basel.

219.e4 B. Friedman, J. Cirulli

There are few specific data on the frequency ofhyponatremia by disease/condition in the ICU. Recentlarge studies have, however, identified patient factorsassociated with increased likelihood of hyponatremia onadmission to the ICU or during an ICU stay. In a studyreported by Funk and colleagues, factors significantlyassociated with hyponatremia at admission to the ICUincluded patient age, medical admission, number of organfailures, and sodium-corrected Simplified Acute Physiolo-gy Score II [7]. In the study reported by Stelfox andcolleagues [6], factors associated with ICU-acquired

hyponatremia included higher Acute Physiology andChronic Health Evaluation (APACHE) II scores, longerICU stay, body temperature disturbance (hypothermia orfever), higher serum potassium, older age, neurologic/trauma or surgical admitting diagnosis, lower level ofconsciousness, and higher serum glucose level (Table 2).Similarly, in their study of cardiovascular ICU-acquiredhyponatremia, significant factors were higher APACHE IIscore, greater ICU length of stay, mechanical ventilation,older age, higher glucose or potassium level, and diabetes(Table 2) [9].

Table 2 Multivariable analyses of patient characteristicsassociated with ICU-acquired hyponatremia a

Acquire hyponatremia

Odds ratio (95% CI) P

Medical-Surgical ICUs [6]Age (each 10-y increase) 0.93 (0.89-0.98) .004Baseline creatinine N100 μmol/L NS NSAdmitting diagnosis categoryMedical 1.00Neurologic/trauma 1.33 (1.06-1.65) .012Surgical 1.26 (1.04-1.52) .017APACHE II score(each additional unit)

1.08 (1.06-1.09) b.001

Mechanical ventilation NS NSDay of ICU stay(each additional log unit day)

1.95 (1.81-2.10) b.001

Minimum Glasgow Coma Scale(each additional unit)

1.06 (1.03-1.08) b.001

219.e5Hyponatremia in critical care patients

5. Management of hyponatremia in critical care

Hyponatremia is particularly difficult to prevent and treatin critical care. Patients frequently have multiorgan systemdysfunction in which access to fluids and renal waterhandling are impaired [3]. Incorporation of fluid manage-ment into the management of severe acute and chronicillnesses can be difficult. Further, the most severe cases ofhyponatremia (those with CNS involvement) are likely to bemanaged in the ICU, necessitating prompt diagnosis andtreatment.

Hypovolemic hyponatremia is typically treated withisotonic saline (0.9%) until correction of the volume deficitis achieved [11]. Hypertonic saline may be used initially toraise serum sodium in patients with significant neurologicsymptoms; however, care must be taken not to exceedmaximum daily correction rates. Sterns et al have suggested

Table 1 Etiologies of syndrome of inappropriate secretion ofantidiuretic hormone (SIADH)

Tumors

Pulmonary/mediastinal: bronchogenic carcinoma,mesothelioma, thymoma, oat cell of the lung

Others: duodenal, pancreatic, ureteral/prostate, uterine, andnasopharyngeal carcinomas, neuroblastoma, leukemia

Pulmonary disordersInfections: tuberculosis, acute bacterial/viral pneumonia,aspergillosis, empyema

Others: acute respiratory failure, chronic obstructive pulmonarydisease, positive pressure ventilation, asthma, pneumothorax

CNS disordersMass lesions: tumor, abscess, subdural hematomaInflammatory conditions: encephalitis, meningitis, lupus, acuteintermittent porphyria, multiple sclerosis

Degenerative/demyelinative disorders: Guillain-Barrésyndrome, spinal cord lesions

Others: vascular abnormalities, subarachnoid hemorrhage, headtrauma, psychosis, delirium tremens, hydrocephalus, pituitarysurgery, transsphenoidal adenectomy

MedicationsACE inhibitors, antineoplastic agents (eg, cyclophosphamide,vincristine), antipsychotic agents (eg, haloperidol,thioridazine, thiothixene, clozapine, phenothiazines),carbamazepine and oxcarbazepine, chlorpropamide,clofibrate, desmopressin, ecstasy (3,4-methylenedioxymethamphetamine), nicotine, NSAIDs,omeprazole, opiates (eg, morphine, meperidine), oxytocin,prostaglandin synthesis inhibitors, selective serotoninreuptake inhibitors, tricyclic antidepressants

OthersAdvanced HIV disease, prolonged strenuous exercise, senileatrophy, trauma, idiopathic pain

ACE indicates angiotensin-converting enzyme; NSAIDs, nonsteroidalanti-inflammatory drugs.Adapted from Contrib Nephrol. 2004;144:132-57, Endocrinol MetabClin North Am. 2006;35:873-94, and Am J HealthSyst Pharm.2005;62:1663-82.

Glucose level (each additional1 mmol/L)

1.07 (1.06-1.09) b.001

Temperature35.0-37.3°C 1.00N37.3°C 1.36 (1.10-1.69) .005b35.0°C 1.36 (1.08-1.70) .008Serum potassium3.5-5.0 mmol/L 1.00N5.0 mmol/L 1.67 (1.42-1.97) b.001b3.5 mmol/L 1.01 (0.90-1.14) NSLevel of care b NS NS

Cardiovascular ICU [9]Age (each 10-y increase) 0.85 (0.82-0.97) .01Diabetes 1.29 (1.06-1.55) .009APACHE II score(each additional unit)

1.04 (1.03-1.06) b.001

Mechanical ventilation 0.35 (0.29-0.42) b.001Day of ICU stay(each additional log unit day)

2.95 (2.64-3.28) b.001

Glucose level (each additional1 mmol/L)

1.10 (1.08-1.13) b.001

Serum potassium3.5-5.0 mmol/L 1.00N5.0 mmol/L 1.82 (1.57-2.11) b.001b3.5 mmol/L 0.63 (0.51-0.78) b.001

CPR indicates cardiopulmonary resuscitation; NS, not significant.a Patient population consisted of 8142 consecutive adults with

normal sodium admitted to medical-surgical intensive care units(ICUs) and 6727 consecutive adults with normal sodium admitted to acardiovascular ICU following cardiac surgery. Adapted from CritCare 2008;12:R162 and Can J Anaesth. 2010;57:650-8.

b Level of care categories included full care, full care but no CPR,and comfort care.

that overcorrection of serum sodium in cases of chronichyponatremia be defined as 10 mEq/L in 24 hours, 18 mEq/Lin 48 hours, and 20 mEq/L in 72 hours, and recommendedtherapeutic targets of 6–8 mEq/L in 24 hours, 12–14 mEq/Lin 48 hours, and 14–16 mEq/L in 72 hours (and lower forpatients with advanced liver disease/severe malnutrition who

219.e6 B. Friedman, J. Cirulli

are at high risk for osmotic demyelination) [25]. In patientswith acute hyponatremia, who do not share the sameneurologic risk, a 4- to 6-mEq/L/hour increase is appropriate,they noted. When hyponatremia is caused by excessivediuretic use, diuretics should be withheld until restoration ofeuvolemia [11]. Diuretics may then be reintroduced, asneeded, in the context of frequent serum sodium levelmonitoring over the following few weeks. If hyponatremia iscaused by diarrhea or vomiting, isotonic saline may be used(in conjunction with antidiarrheal or antiemetic agents asneeded). For patients presenting with mineralocorticoiddeficiency, isotonic saline should be used initially, withsubsequent administration of replacement therapy (hydro-cortisone and fludrocortisone).

The treatment of euvolemic hyponatremia is principallydriven by presence or absence of symptoms [11,18]. Acutesymptomatic hyponatremia (ie, symptomatic hyponatremiadeveloping within 48 hours) should be treated withhypertonic saline (3%) via continuous infusion and concom-itant loop diuretics (eg, furosemide 20–40 mg administeredintravenously [IV]) with the aim of limiting volumeexpansion. The initial saline infusion rate can be estimatedby multiplying the patient's body weight (in kg) by thedesired serum sodium correction (in mEq/L per hour).Hypertonic saline should be discontinued when symptomsare resolved, when a safe serum sodium level is attained, orwhen maximum daily sodium correction limits areapproached. Patients with chronic hyponatremia (onsetover a period N48 hours), who are typically asymptomatic,are usually managed by fluid restriction. The targeted degreeof restriction should be 500 mL below average daily urineoutput, with the goal of achieving negative water balance[11]. Fluid restriction may not yield significant increases inserum sodium for several days. Because fluid is beingrestricted rather than sodium, patients with SIADH andnegative total body sodium balance should have adequatesodium chloride intake unless this is contraindicated. Fluidrestriction is less likely to succeed in patients with greaterelevations in urine osmolality, which suggest the presence ofhigher plasma AVP levels [11].

Pharmacologic interventions include older medicationssuch as demeclocycline and urea and the more recentlyintroduced AVP antagonists such as the selective vasopres-sin V2-receptor antagonist tolvaptan and the V1A/V2

antagonist conivaptan. Among the older pharmacologicoptions, demeclocycline induces a nephrogenic diabetesinsipidus, reducing urine concentration despite elevatedAVP levels [11,26]. It is effective in only ~60% of patients,with an unpredictable onset, often—but not always—takingeffect within 2 to 5 days. Demeclocycline use alsonecessitates renal function monitoring on a regular basis,as it may cause reversible azotemia and nephrotoxicity,especially in those already at risk for renal compromise (eg,patients with cirrhosis or congestive heart failure). Urea (30g/d) is an osmotic diuretic that increases water excretion anddecreases urinary sodium excretion. This effect potentially

enables patients to maintain a less strict fluid restrictionregimen. Clinical data for urea are limited to a few Europeanstudies [27-29], and use of the oral formulation of this agentis limited by poor palatability; in addition, urea is not areceptor-targeted agent; there is a limited understanding of itsmechanism of action; and it has been clinically associatedwith many side effects (azotemia, nausea/vomiting, allergicdermatologic reactions, renal toxicity). Loop diuretics mayexacerbate sodium and water imbalance and worsenhyponatremia, and other older pharmacologic options suchas lithium are inconsistent in their effects or associated withsignificant adverse events [11].

Hypervolemic hyponatremia is generally treated bydietary sodium restriction and diuretic therapy [11], similarto the treatment protocols used for euvolemic hyponatremia.Cases generally have a chronic onset; as a result, fluidrestriction is initially employed to produce a negative solute-free water balance. This is often difficult to achieve inclinical practice, however. Loop diuretics may exacerbatesodium and water imbalance and worsen hyponatremia [30],and demeclocycline and urea, which may be considered foruse in chronic heart failure patients, have unfavorableadverse event profiles. Demeclocycline is also contra-indicated in patients with liver cirrhosis due to its potentialtoxic effects on the kidneys [31].

The limitations of fluid restriction and older pharmaco-logic agents have prompted the development of newapproaches in the treatment of euvolemic and hypervolemichyponatremia. Aquaresis—ie, increased electrolyte-freewater excretion—is a desirable mechanism for treatingthese conditions, and presents an advantage over diuresis,in that removal of water is not accompanied by elimination ofsodium and other electrolytes. Because AVP is inappropri-ately elevated in many patients with euvolemic and hyper-volemic hyponatremia, AVP receptors represent promisingtargets for the development of drug that promote aquaresis.

AVP interacts with three subtypes of G-coupled receptors[11,32].V1A and V1B receptors are coupled to phosphoino-sitol signaling, with intracellular calcium acting as a secondmessenger: V1A mediates multiple physiologic processes(eg, vasoconstriction, glycogenolysis, and platelet aggrega-tion), and V1B exists mainly in the anterior pituitary, where itregulates adrenocorticotropic hormone secretion.V2 recep-tors, by contrast, are coupled to adenylate cyclase, and theiractivation increases cyclic adenosine monophosphate levelsand protein kinase A signaling. V2 receptors are foundprimarily in renal collecting duct cells, where activation ofprotein kinase A induces a cascade of events leading tophosphorylation of aquaporin-2 water channels located inintracellular vesicles. Following phosphorylation, the vesi-cles move to the apical membrane, and the aquaporin-2channels are inserted into the membrane, promoting waterreabsorption and, as a result, lowering plasma osmolality.

Two vasopressin receptor antagonists—tolvaptan andconivaptan—have been approved for treatment of euvolemicand hypervolemic hyponatremia. The intravenous agent

219.e7Hyponatremia in critical care patients

conivaptan is the preferred option in hospitalized patientswho cannot tolerate oral medications; however, it is limitedto in-hospital use for a maximum of 4 days. Tolvaptan, bycontrast, is an can be used in patients able to tolerate oralmedications on an out-patient basis following initiation oftherapy in a hospital. No head-to-head comparisons havebeen conducted with these agents, but trial data for each drugis reviewed in the sections below. Other agents of this class(lixivaptan, satavaptan) have also been evaluated fortreatment of hyponatremia in clinical trials. Becausevasopressin receptor antagonists correct hyponatremia byremoval of electrolyte-free water, it should be noted, theyshould not be used in patients who are already volumedepleted or have hypovolemic hyponatremia.

6. Conivaptan treatment for hyponatremia

Conivaptan is a dual V1A/V2-receptor antagonist that isadministered via an IV loading dose over 30 minutes,followed by 24-hour continuous infusion for up to 4 days[33]. The effect of conivaptan on serum sodium wasdemonstrated in a double-blind, placebo-controlled, random-ized, multicenter study involving 84 patients with euvolemic(n = 56) or hypervolemic (n = 28) hyponatremia (serumsodium, 115-130 mEq/L; mean, 123.3 mEq/L) from a varietyof underlying causes (malignant or nonmalignant diseases ofthe central nervous system, lung, or abdomen; congestiveheart failure; hypertension; myocardial infarction; diabetes;osteoarthritis; or idiopathic) [33,34]. The study participantswere randomized to conivaptan 40 mg/day IV (n = 29), orconivaptan 80 mg/day IV (n = 26), or IV placebo (n = 29),and daily fluid intake was restricted to 2 L. Conivaptan orplacebo was administered as a continuous infusion after a 30-minute IV loading dose on the first treatment day andpatients were treated for a total of 4 days. Serum or plasmasodium concentrations were assessed pre-dose (hour 0) andat 4, 6, 10, and 24 hours post-dose on all treatment days.

After 24 hours during the treatment phase, the least-squares (LS) mean increase in serum sodium from baselinewas significantly higher with conivaptan 40 mg/day (6.4mEq/L) vs placebo (0.4 mEq/L; P b .001). Similar resultswere observed after 48 hours of treatment (mean changefrom baseline in serumsodium concentration with conivaptan40 mg/d, 5.3 mEq/L; mean concentration, 128.6 mEq/L). Atthe end of the 4-day treatment period, the mean change frombaseline with conivaptan 40 mg/day was 6.5 mEq/L (meanconcentration, 129.8 mEq/L) vs 0.8 with placebo (P b .001).In addition, after 2 days and 4 days of treatment withconivaptan 40 mg/day, 41% (after 2 days), and 69% (after 4days) of patients achieved a ≥6 mEq/L increase in serumsodium concentration or a normal serum sodium of ≥135mEq/L. Conivaptan 80 mg/day was not significantly moreeffective than the 40 mg/day dosage and was associated witha higher incidence of infusion site reactions and a higher rateof discontinuations for adverse events.

The most common adverse reactions across the con-ivaptan clinical trials program (incidence ≥10%) wereinfusion site reactions (including phlebitis), pyrexia, hypo-kalemia, headache, and orthostatic hypotension [33]. An oralformulation has been evaluated in clinical studies but is notapproved for use [35,36]. Conivaptan is contraindicated foruse in patients with hypovolemic hyponatremia, in patientswith anuria, in patients receiving potent cytochrome P3A(CYP3A) inhibitors, and in those with known allergy to cornor corn products [33].

7. Tolvaptan treatment for hyponatremia

Tolvaptan is an oral, selective vasopressin V2-receptorantagonist that blocks the effects of AVP, resulting inincreased electrolyte-free water excretion and, thus, in-creased serum sodium concentration. Unlike diuretics,tolvaptan does not significantly affect urinary sodium orpotassium excretion or serum potassium concentration. It iscurrently indicated for treatment of clinically significanthypervolemic and euvolemic hyponatremia (serum sodiumb125 mEq/L) or less-marked hyponatremia that is symp-tomatic and resistant to correction by fluid restriction,including treatment of patients with SIADH and those withheart failure or cirrhosis [37].

In a phase II study, tolvaptan was more effective thanfluid restriction, a primary treatment modality in hypona-tremia, in increasing serum sodium in 28 patients witheuvolemic or hypervolemic hyponatremia (serum sodiumb135 mEq/L; tolvaptan, n = 17; fluid restriction, n = 11)[38]. Changes in serum sodium concentrations were 1.6 vs−0.8 mEq/L (P= .016), respectively, at 4 hours after the firstdose, 5.2 vs 0.7 mEq/L after 5 days (P = .019), and 5.7 vs 1.0at last visit (day 27, P = .0065). In a single-dose, open-label,crossover study comparing tolvaptan vs furosemide in 14patients with congestive heart failure, both agents producedsimilar diuresis, with furosemide but not tolvaptan increasingurinary sodium and potassium excretion and reducing renalblood flow [39].

Tolvaptan was shown to be effective in reversingeuvolemic and hypervolemic hyponatremia (serum sodiumb135 mEq/L) in the Study of Ascending Levels ofTolvaptan in Hyponatremia (SALT)-1 and SALT-2 trials,2 randomized, double-blind, placebo-controlled, phase IIItrials with similar designs [40]. A total of 448 patients wererandomly assigned to receive tolvaptan (n = 225; 15 mgonce daily on day 1, increased at 1-day intervals to 30 mgand 60 mg if necessary during the first 4 days) or placebo(n = 223) in addition to the patients' standard therapy for30 days. After stopping study treatment, patients resumedprevious therapies and were followed for an additional 7days. In total, 138 patients (31%) hadhyponatremia due toheart failure, 120 (27%) had hyponatremia due to cirrhosis,and 190 (42%) had SIADH or other causes of hypona-tremia. Tolvaptan was administered with the goal of

219.e8 B. Friedman, J. Cirulli

achieving a controlled correction of hyponatremia to aserum sodium concentration of ≥135 mEq/L. Fluidrestriction was to be avoided if possible during the first24 hours of treatment to avoid overly rapid correction inserum sodium, which can cause osmotic demyelinationsyndrome; 87% of patients had no fluid restriction duringthis period [37]. Patients could then be put on fluidrestriction (defined as intake ≤1 L daily) as clinicallyindicated. The primary end point of both studies was theaverage daily area under the curve (AUC) for change inserum sodium from baseline to day 4 and day 30.

Tolvaptan treatment resulted in a significantly greaterincrease in serum sodium during both periods in both studies(P b .0001 for all comparisons) (Fig. 3) [37,40]. Pooledresults for all patients showed changes in average dailyserum sodium AUC of 4.0 mEq/L for tolvaptan vs 0.4 mEq/Lfor placebo at day 4 and 6.2 vs 1.8 mEq/L at day 30 (both P b.0001), with 14% vs25% (P b .01) requiring fluid restriction,respectively [37]. A significantly greater increase in serumsodium was observed as early as 8 hours after the first dose oftolvaptan. For the subgroup with baseline sodium b130mEq/L, changes were 4.8 vs 0.7 mEq/L at day 4 and 7.9 vs2.6 mEq/L at day 30 (both P b .0001), with 19% vs 36%requiring fluid restriction (P b .01), respectively. For thesubgroup with baseline sodium b125 mEq/L, changes were5.7 vs 1.0 mEq/L at day 4 and 10.0 vs 4.1 mEq/L at day 30(both P b .0001), with 35% vs 50% requiring fluid restriction(P = .14). During the 7-day follow-up after stopping studytreatment, serum sodium concentrations in the tolvaptangroup decreased to levels similar to those in the placebogroup. Results in the SIADH subgroup (tolvaptan = 58,placebo = 52) were similar to those in the total studypopulation [41]. Changes in average daily serum sodiumAUC for the tolvaptan vs the placebo group were 5.3 vs 0.5mEq/L at day 4 and 8.1 vs 1.9 mEq/L at day 30 (both P b.0001), respectively. Fluid restriction was required in 7.8%of tolvaptan patients vs 13.7% of placebo patients.

Fig. 3 Mean serum sodium concentrations in patients with euvolemic o(■) in the SALT-1 and SALT-2 trials. Treatment was administered oncdotted line). *P b .001, tolvaptan versus placebo. Adapted with permissi

In an open-label study (SALTWATER), 111 patients (94with serum sodium b135 mEq/L) who had previouslyreceived tolvaptan or placebo in the SALT trials were treatedwith tolvaptan after having returned to standard care for atleast 7 days. By this time, their baseline mean serum sodiumconcentration had fallen to between their original baselineand post-placebo therapy level. Upon initiation of tolvaptantherapy, average serum sodium levels increased to approx-imately the same levels as those previously observed withtolvaptan treatment in the SALT trials and were maintainedfor at least 1 year [37,42].

A post hoc analysis of the phase III Efficacy ofVasopressin Antagonism in Heart Failure: Outcome Studywith Tolvaptan (EVEREST) trial demonstrated that patientshospitalized for heart failure with a baseline serum sodiumconcentration b135 mEq/L (n = 216) who received tolvaptanhad an adjusted mean length of stay that was 1.72 daysshorter (9.72 vs11.44 days) compared with that for patientsreceiving placebo, a nonsignificant difference [43]. Inpatients with a serum sodium concentration b130 mEq/L(n = 48), tolvaptan recipients had an adjusted mean length ofstay 2.12 days shorter vs those receiving placebo (also anonsignificant difference) [44]. Tolvaptan was also shown toreduce hospital length of stay vs placebo among patients withSIADH in the SALT-1 and -2 trials (4.98 vs 6.19 days, anonsignificant difference of 1.21 days) [45].

Adverse events in the SALT-1 and SALT-2 trials weresimilar in the tolvaptan and placebo groups [40]. The mostcommon adverse events in tolvaptan patients were thirstand dry mouth. Desirable rates of sodium correction (N0.5mEq/L/h)were exceeded in 4 of 233 tolvaptan patientsduring the 24 hours after the first dose; the range ofdesirable increase was exceeded (N146 mEq/L) in 4tolvaptan patients. In the subgroup of 110 patients withSIADH, adverse effects were consistent with the overallpopulation; the most common events were increased thirst,dry mouth, headache, peripheral edema, and excessive

r hypervolemic hyponatremia treated with tolvaptan (◯) or placeboe daily for 30 days and then discontinued (depicted by the verticalon from N Engl J Med. 2006;355:2099-2112 [40].

219.e9Hyponatremia in critical care patients

urination [41]. Three (5.9%) tolvaptan patients had overlyrapid correction of sodium; none exhibited neurologicsymptoms suggestive of osmotic demyelination.

8. Potential uses of tolvaptan in criticalcare settings

Tolvaptan may have significant utility in treatinghyponatremia in patients in a critical care setting(as notedpreviously, IV conivaptan is the preferred option forhospitalized patients who cannot tolerate oral medications;its use, however, is limited to a total of 4 days). In patientsrequiring surgical procedures that may be impacted due tohyponatremia, correction of the abnormality can potentiallyreduce length of hospital stay and thereby reduce risk ofinfection following surgery. Tolvaptan use was shown toreduce hospital length of stay vs placebo among patients withSIADH in the SALT-1 and -2 trials [45] and among patientwith heart failure in the EVEREST trial [43].

Tolvaptan can be used to reverse the hyponatremiaassociated with thiazide diuretics in the euvolemic patient, aswell as hyponatremia associated with selective serotoninreuptake inhibitors and can also potentially correct thehyponatremia associated with congestive heart failure that isresistant to diuretics, providing a brisk aquaresis withoutadditional loss of solute or clinically relevant effects onblood urea nitrogen or creatinine levels. Tolvaptan treatmentcan also be used to address hyponatremia associated withmany disease states seen in critically ill patients that aredirect causes of SIADH, including serious infections,pneumonias or other lung injuries, and pain. Finally, itshould be noted that, whereas delirium manifesting inassociation with symptomatic hyponatremia—a seriousproblem in the ICU—may potentially be reversed bycorrection of the hyponatremic state, tolvaptan is notindicated for use in this patient population (ie, patientsrequiring urgent intervention to prevent or treat seriousneurological symptoms), nor has it been proved to providesymptomatic benefits.

Tolvaptan should be started in a hospital setting at 15mg and can be increased to 30 mg and 60 mg after 24hours at each prior dose level to achieve target sodiumlevels [37]. Overly rapid correction of hyponatremia mustbe avoided due to the risk of osmotic demyelination. Asnoted above, patients requiring urgent increases in serumsodium to prevent or treat serious neurologic symptomsshould not be treated with tolvaptan. During initiation andtitration of tolvaptan to reach the sodium target, changes inserum electrolytes and volume should be monitored. Fluidrestriction should be avoided during the first 24 hours afterinitiating tolvaptan, and patients should be advised that theycan ingest fluid in response to thirst. Hypertonic saline useshould be avoided in patients receiving tolvaptan. Follow-ing discontinuation of tolvaptan, patients may resume fluidrestriction, if indicated, and should be monitored for

changes in serum sodium and volume. If tolvaptan therapymust be restarted, it should be done in a hospital so thatserum sodium levels can be monitored. Tolvaptan iscontraindicated in patients with anuria, in those unable tosense or respond appropriately to thirst, and in thosereceiving potent CYP3A inhibitors.

Two case studies from Dr. Friedman's clinical practiceillustrate potential uses of tolvaptan in critical care patients(see Sidebar).

9. Conclusions

Hyponatremia is common in critical care patients and isassociated with a prolonged hospital stay and increasedmorbidity and mortality. Vigilance for both hyponatremia atICU admission and hyponatremia acquired during the ICUstay should be high. Hyponatremia should be investigated asa cause of delirium in ICU patients. Euvolemic hypona-tremia, and SIADH in particular, may be the most commonform of hyponatremia in critically ill patients, withhypervolemic hyponatremia also being quite common.Loop diuretic use may exacerbate the imbalance of sodiumand water in euvolemic and hypervolemic states. Aquaresiswith tolvaptan or other vasopressin antagonists mayconstitute optimal treatment for correcting hyponatremia ineuvolemic and hypervolemic patients by increasing aquar-esis (electrolyte-free water excretion). The V1A/V2-receptorantagonist conivaptan is the preferred option in hospitalizedpatients with euvolemic or hypervolemic hyponatremia whocannot tolerate oral medications; however, it is limited to in-hospital use as an IV product for a maximum of 4 days. Bycontrast, the oral vasopressin V2-receptor antagonist tolvap-tan can be used on an out-patient basis following initiationof therapy in a hospital. Tolvaptan has been found to be aviable option for correcting hyponatremia associated withSIADH and in patients with hypervolemic hyponatremiaassociated with heart failure and cirrhosis; it should not beused in patients requiring urgent intervention to raise serumsodium levels.

10. SIDEBAR. Tolvaptan Case Histories

Case 1. A 65-year-old man who was being treated withmany (predominantly psychiatric) medications was admittedwith altered mental status after a fall that resulted in fractureof the wrist. The treatment goal was to stabilize the patient'scondition prior to psychiatric evaluation. His medical historyincluded dementia, depression, delirium tremens, alcoholabuse, and, recently, Parkinson's disease. He also had ahistory of hypertension, rheumatoid arthritis, osteoporosis,peptic ulcer, and anemia. His medications consisted of once-daily venlafaxine 75 mg, rivastigmine 4.5 mg, oxcarbazepine150 mg, lisinopril 10 mg, sertraline 50 mg, primidone 50 mg,sodium chloride 1g, and various daily vitamins, and twice-

219.e10 B. Friedman, J. Cirulli

daily risperidone 0.5 mg and clonazepam 0.25 mg.Evaluation during admission showed normal body temper-ature, blood pressure of 128/74 mm Hg, heart rate of 80beats per minute, normal S1 and S2 heart sounds with nomurmurs or gallops, and no jugular venous distention orcarotid bruits. Laboratory evaluation revealed severehyponatremia with a serum sodium level of 104 mEq/L,potentially explaining the patient's confused state. Since thehyponatremia might be caused by the multiple psychiatricmedications, venlafaxine, rivastigmine, oxcarbazepine, ser-traline, risperidone, clonazepam, and primidone werediscontinued; lisinopril was also temporarily withheld,given the patient's normal blood pressure. Intravenouslorazepam was started to prevent seizures secondary toalcohol withdrawal and hyponatremia. The patient wasadmitted to the ICU, where he received hypertonic (3%)saline infusion at 15 mL/h and had serum sodium measuredevery 4 hours and urine sodium every 6 hours.

The patient remained somnolent after 1 day of receivinghypertonic saline infusion, with improvement of serumsodium to 115 mEq/L. The saline infusion was stopped and3 hours later the patient was given a 15-mg dose oftolvaptan. On day 3, the patient's serum sodium hadincreased to 120 mEq/L and his mental status had improved.The patient was given another 15-mg dose of tolvaptan andwas transferred out of the ICU. He received 2 more dailydoses of tolvaptan, with serum sodium continuing toincrease, and he was discharged from the hospital on day6 with a serum sodium concentration of 131 mEq/L andresolution of the neurologic symptoms.

This case shows the development of SIADH in a patientwith extensive exposure to psychotropic medications andsuccessful management of hyponatremia with hypertonicsaline followed by 4 daily doses of tolvaptan. The very lowserum sodium level observed in the patient is fairly typicalof drug-induced SIADH. Discontinuation of the psychotro-pic medications was likely an important step in managingthe condition. Although the patient responded to thehypertonic saline infusion, it was beneficial to be able todiscontinue this often-unpredictable measure and initiatetolvaptan treatment. Tolvaptan was selected over conivap-tan in this case, as it is more cost-efficient, both from theperspective of direct drug cost (average wholesale prices of$300/d vs $573/d, respectively) [46] and of indirect costs(nursing time, costs of IV set-ups); furthermore, given thattolvaptan is more selective for the V2 receptor, it provides atargeted physiologic and pharmacologic option for thetreatment of SIADH. It is important to note that patientsshould be closely monitored during the transition fromhypertonic saline to tolvaptan.

Case 2. A 24-year-old, morbidly obese woman with type2 diabetes was admitted to the emergency department withprogressive abdominal-pelvic necrotizing fasciitis. Thepatient had been briefly pressor-dependent and had under-gone two debridements before admission. The treatment goalwas to stop progression of the extensive infection and

administer preventive and supportive care. Evaluation duringadmission showed that the patient's abdominal-pelvic woundwas clean, with minimal purulence. Renal and pulmonaryfunction were normal, but the patient was uncooperative andappeared ill and confused. She had a fever of 101.8º F, bloodpressure of 136/68 mmHg, and general edema. Laboratoryevaluation showed a serum sodium level of 130 mEq/L,indicating hyponatremia. Urine osmolality was 390 mOsm/kg H2O and urine sodium was 200 mEq/L; urine output was40 mL/h, consistent with a diagnosis of SIADH. The whiteblood cell count was 25,000/μL and left-shifted, indicatingongoing infection. Wound culture was positive for methicil-lin-resistant Staphylococcus aureus and Candida.

The patient's infection was treated with telavancin,doripenem, and micafungin sodium. Nutritional andsupportive measures and prophylaxis for deep veinthrombosis were initiated, and the patient underwent fluidrestriction to 1000 mL/d for 24 hours to treat hyponatremia.After 24 hours, the patient's serum sodium level remainedunchanged and the patient was extremely uncooperative.Treatment with tolvaptan 15 mg/d was initiated and fluidrestriction was discontinued for the first 24 hours after thefirst dose. At 24 hours after the first dose of tolvaptan, thepatient's serum sodium level had increased to 136 mEq/L,urine osmolality had decreased to 231 mOsm/kg H2O, urinesodium had decreased to 90 mEq/L, and urine output hadincreased to 5300 mL, representing a 2000 mL negativefluid balance, and the patient's delirium had resolved. At 24hours after the second dose of tolvaptan, serum sodium was139 mEq/L, urine osmolality and urine sodium werenormal, and there was continued aquaresis, with the patientremaining in negative fluid balance. After a third dose oftolvaptan, the patient's serum sodium was 140 mEq/L andaquaresis persisted. Tolvaptan was discontinued. Thepatient underwent operative debridement of her woundand remained normonatremic for the remainder of herhospital stay.

This case of progressive fasciitis is representative ofsevere infections that can trigger hyponatremia; otherexamples common in intensive care practice includepneumonia, tuberculosis, encephalitis, meningitis, andHIV infection. Although the patient's initial sodium levelindicated mild hyponatremia, the hyponatremia wasunresponsive to fluid restriction. Even mild hyponatremia,it should be noted, should be corrected before surgicalprocedures such as the one performed on this patient. Inaddition, the patient's uncooperative state, which may havebeen related to her hyponatremia, made fluid restriction—which tends to worsen the patient's quality of life evenunder less onerous circumstances—even more difficult.Again, tolvaptan was selected over conivaptan due togreater cost-efficiency (direct and indirect costs of therapy)and its specificity for the vasopressin V2 receptor. Thedecision to use tolvaptan to correct hyponatremia in thispatient was an important step in the successful treatment ofher infection.

219.e11Hyponatremia in critical care patients

Acknowledgments

The authors wish to thank Eric Justice of BioScienceCommunications, New York, New York, for editorialassistance in the development of this manuscript (supportedby Otsuka America Pharmaceutical, Inc, Rockville, MD).

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