Horizonten Wie Pharmaforscher Medikamente entwickeln Eine Sonderpublikation in Zusammenarbeit mit der Boehringer Ingelheim GmbH Vom Elfenbeinturm zum Forschungsbiotop 02 _ Vom Elfenbeinturm zum Früher konnte es sehr lange dauern, bis neue wissenschaftliche Erkenntnisse in die Pharmaforschung einflossen. Der Grund dafür waren starke
Visit www.HyponatremiaCME.org for additional cases and activities Clinical Perspectives in As a physician scientist who has been studying and treating hyponatremic patients for the past 30 years, I am pleased to introduce this case-based continuing medical education publication and associated Web-based interactive learning program, Clinical Perspectives in Hyponatremia, to my colleagues in cardiology, endocrinology, critical care, nephrology, hepatology, and hospital-based internal medicine. This publication presents an overview on the pathophysiology and significance of hyponatremia and 4 case studies. Additional Joseph G. Verbalis, MD
cases are available at www.hyponatremiaCME.org. While hyponatremia is the most common disorder of fluid and electrolyte balance seen in clinical practice, it is not easily recognized and remains underdiagnosed. With a wide range of underlying diseases and causes including heart failure, cirrhosis, and the syndrome of inappropriate antidiuretic hormone secretion (SIADH), diagnosis and management can present challenging clinical issues and decisions. Informed decision making has never been more critical as new pharmacotherapeutics continue to widen treatment possibilities. Thus, we hope Clinical Perspectives in Hyponatremia will expand your understanding of the science behind hypoantremia and the therapeutic options available to you in your management of this challenging disorder.
Paul J. Hauptman, MD
Joseph G. Verbalis, MD
Professor of Medicine and Physiology Chief, Division of Endocrinology and Metabolism Georgetown University Stephan A. Mayer, MD, FCCM
Continuing Medical Education Information . 2The Pathophysiology and Significance of Hyponatremia . 3Case Study 1: Hyponatremia in SIADH . 8Case Study 2: Hyponatremia in Heart Failure . 10Case Study 3: Hyponatremia in Neurocritical Care . 12Case Study 4: Hyponatremia in Cirrhosis . 13Posttest . 15Evaluation Form . 16 Florence Wong, MBBS, MD,
This activity has been designed to meet the educational needs of cardiologists, Paradigm Medical Communications, LLC endocrinologists, critical care specialists, hospitalists, nephrologists, hepatologists, and hospital-based internists who manage patients with hyponatremia.
Orangeburg, NY 10962 After completing this activity, participants should be better able to: Senior Program Director
• Evaluate available therapeutic agents and approaches used in the management No financial relationships to disclose of hyponatremia, including clinical benefits and potential adverse events • Develop a treatment plan for patients with hyponatremia Instructions for Participation
No financial relationships to disclose To receive a CME certificate of participation, participants should: • Read the entire publication, including the Continuing Medical Education Information.
• Complete the posttest and evaluation form on page 16 and mail or fax the evaluation form No financial relationships to disclose with answer key to: Paradigm Medical Communications, LLC, 523 Route 303, Orangeburg, NY 10962; Fax: 845-398-5108.
A certificate of participation will be issued 4 to 6 weeks after receipt of a completed activity No financial relationships to disclose evaluation form and a completed posttest with a score of 70% or better.
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Paradigm Medical Communications, LLC designates this enduring material for a maximum of 1.5 AMA PRA Category 1 Credit(s) TM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
This activity is supported by an educational grant from Otsuka America Pharmaceutical, Inc.
This educational activity is sponsored by Paradigm Medical Communications, LLC, Orangeburg, NY.
Release Date: March 15, 2012
Last Review Date: March 8 , 2012
Expiration Date: March 14, 2013
Estimated Time to Complete Activity: 1.5 hours
Contributing Faculty and Disclosures
In accordance with ACCME requirements on disclosure, faculty and contributors are asked to disclose any relationships with commercial interests associated with the area of medicine featured in the activity.
Joseph G. Verbalis, MD
Professor of Medicine and Physiology Chief, Division of Endocrinology and Metabolism Georgetown University Consultant: Astellas Pharma US, Inc.; Cardiokine, Inc.; Otsuka America Pharmaceutical, Inc.
Paul J. Hauptman, MD
Professor of Medicine Division of Cardiology Department of Internal Medicine St. Louis University School of Medicine Consultant/Speaker: Otsuka America Pharmaceutical, Inc.
Stephan A. Mayer, MD, FCCM
This newsletter is published by Paradigm Medical Professor of Neurology and Neurosurgery Communications, LLC, Orangeburg, NY.
Columbia University College of Physicians and Surgeons 2012 Paradigm Medical Communications, LLC, Director, Neurocritical Care except where noted. This newsletter may not be New York Presbyterian Hospital reproduced in whole or in part without the express Columbia University Medical Center written permission of Paradigm Medical Communications, LLC. This CME program represents the views and opin- Speaker: Astellas Pharma US Inc.
ions of the individual faculty and does not constitute Florence Wong, MBBS, MD, FRACP, FRCPC
the opinion or endorsement of, or promotion by, Paradigm Medical Communications, LLC.
Division of Gastroenterology Reasonable efforts have been taken to present Department of Medicine educational subject matter in a balanced, unbiased University of Toronto fashion and in compliance with regulatory Toronto, Ontario, Canada requirements. However, each activity participant No financial relationships to disclose. must always use his or her own personal and Independent peer reviewer: No financial relationships to disclose.
professional judgment when considering further application of this information, particularly as it may No Paradigm Medical Communications staff member who was in a position to control or influence
relate to patient diagnostic or treatment decisions, the content of this educational activity has a conflict of interest.
including without limitation, FDA-approved uses and any off-label uses.
2 Clinical Perspectives in Hyponatremia n March 2012
Clinical Perspectives in Hyponatremia
The PaThoPhysiology and significance of hyPonaTremia JosePh g. Verbalis, mdHyponatremia is the most com- relatively impermeable to water. Any wa- to their serum osmolality. In normal indi- mon electrolyte abnormality en- ter in the nephron that makes it from the viduals, AVP levels should be suppressed countered in clinical practice. The glomerulus and proximal tubule into the to less than 0.5 pg/mL, which is the detec- disorder is defined as a serum sodium collecting duct is not reabsorbed, but is tion limit for AVP, when serum osmolality concentration ([Na+]) of <135 mEq/L. excreted via a process known as diuresis.
fal s below approximately 280 mOsm/kg Epidemiologic studies reveal that hypo- However, in response to AVP bind- H O. When it is not suppressed, an os- natremia is a common problem in hos- ing to the V receptor, a signal transduc- motical y inappropriate AVP secretion oc- pitalized patients, whether it is present at tion cascade is activated with generation curs, which in turn causes water retention admission or hospital-acquired. The dis- of cyclic AMP in the col ecting duct prin- and a dilutional hyponatremia. order increases the risk of admission to cipal cel s, which results in insertion of A study by Robertson demonstrated the intensive care unit (ICU) and is asso- aquaporin-2 water channels into the api- that 95% of dilutional hyponatremia is ciated with significantly increased mor- cal membrane of these cel s (Figure 1). caused by inappropriate, or nonosmotic, bidity and mortality and longer hospital This al ows a passive reabsorption of wa- secretion of AVP.1 Studies in both HF ter along osmotic gradients into the cel s, and cirrhosis showed a similar pattern of Hyponatremia also appears to be a and then out the basolateral side of cel s osmotical y inappropriate AVP secretion. marker for more severe underlying dis- through other water channels that are The role of AVP in water retention was ease with a poorer prognosis. Heart fail- constitutively expressed. The net result is explored in an early study of 37 hypona- ure (HF), cirrhosis, and neurologic disease reabsorption of water into the circulation, tremic HF patients; AVP was detected in are among the serious clinical conditions which is cal ed antidiuresis.
30 by immunoassay.2 Hyponatremia and Acute hospital care known to be associated with hyponatre- Stimuli to AVP secretion related to hypo-osmolality were more severe, as was Ambulatory hospital care mia. Chronic hyponatremia presents its fluid homeostasis include hyperosmolali- renal impairment, in the 30 patients with own set of challenges because even in ty, hypotension, angiotensin, and hypovo- detectable AVP than in the 7 patients with mild diseases that are often asymptom- lemia. In response to these stimuli, AVP undetectable AVP. Elevated AVP levels atic, hyponatremic patients are at height- is secreted to conserve water and prevent in HF did not appear to be consistently ened risk for gait disturbances, attention further dehydration and volume depletion related to the use of diuretics.2 Just as in deficits, falls, and fractures.
to maintain normal body water homeo- SIADH, plasma AVP levels are elevated stasis. Stimuli independent of fluid ho- despite normal low plasma osmolality.
The relationship between
meostasis include nausea, hypoxia, hyper- The kidney is exquisitely sensitive to hyponatremia and water homeostasis
carbia, hypoglycemia, stress (cytokines), very low levels of AVP. As plasma osmo- In the normal physiologic state, total body and physical activity. These nonosmotic lality increases there are linear increases water accounts for about 60% of body stimuli result in AVP secretion when it is in plasma AVP and urine osmolality, weight depending on sex, body mass in- not needed for body fluid homeostasis.
which can increase from 100 to more dex, and age. The level of water in the than 1000 mOsm/kg H O. However, body is control ed by a single hormone, Pathophysiology and role of AVP
urine volume decreases inversely as AVP arginine vasopressin (AVP), also cal ed Too little AVP secretion is associated with levels increase. With complete absence of antidiuretic hormone (ADH). To under- diabetes insipidus (DI)—there is exces- AVP, as in patients with DI, the kidney stand water homeostasis, it is important sive urination of water, because water has the capacity to excrete up to 1000 to understand AVP, how it is released, and cannot be reabsorbed by the kidney. Al- mL/h. But an AVP level of only 0.5 pg/ its pathophysiologic influence. ternately, nonosmotic AVP AVP is made in the hypothalamus Figure 1. Collecting Principal Duct Cell
secretion, which causes wa- and transported down the pituitary stalk ter retention when it is not to the posterior pituitary, where it is re- physiological y required, leased. A variety of excitatory and in- is associated with the syn- hibitory factors regulate AVP secretion. drome of inappropriate Once released into the bloodstream, antidiuretic hormone se- AVP affects various parts of the body by cretion (SIADH), HF, and interacting with receptors in different ar- eas. The major site of action of the AVP SIADH is the quint- V receptors, which affect water homeo- essential example of a stasis by regulating free water absorption, dilutional hyponatremia. is the renal col ecting duct.
Patients with SIADH have Under normal circumstances with- 2 receptor antagonist inappropriately elevated se- AP2, aquaporin-2; PKA, protein kinase A; cAMP, cyclic adenosine monophosphate; out AVP present, the collecting duct is ATP, adenosine triphosphate; AVP, arginine vasopressin.
rum AVP levels in relation Clinical Perspectives in Hyponatremia n March 2012 3
Serum [Na+] = Total body water Clinical Perspectives in Hyponatremia
mL—near the detection limit—halves the study showed that almost 50% of pa- than those who presented initially with a urinary excretion rate to 500 mL/h. With tients with liver cirrhosis and ascites had serum [Na+] >130 mEq/L.17 a further increase to 1 pg/mL, urinary ex- hyponatremia.7 Most were in the relatively Hyponatremia has also been found cretion decreases to 250 mL/h. Therefore, mild range of serum [Na+] from 131-135 to be an independent predictor of mor- AVP levels of 1 to 3 pg/mL often report- mEq/L, but approximately 20% had a se- tality in liver failure.18 For example, in ed in patients with SIADH are capable of rum [Na+] <130 mEq/L.
normonatremic patients awaiting liver substantial water retention by the kidney.
The elderly are particularly suscepti- transplantation with a MELD score of ble to hyponatremia. The overal incidence 25 to 29, mortality rates were 25% but Incidence and prevalence
has been estimated at 7% in the geriatric increased to 66% for patients with hy- Many studies support the statement population,8 but increases to 18% to 22% ponatremia. For patients with MELD that hyponatremia is the most com- in chronic care facilities.9 The incidence of scores above 30, mortality rates were mon electrolyte disorder seen in clinical hyponatremic episodes can reach levels as 50% in normonatremic patients, but practice. In a 2003 study in Singapore, high as 53% in nursing homes.10 Impor- 100% in hyponatremic patients.18 the prevalence of hyponatremia ([Na+] tantly, the mortality rate is doubled (16% <135 mEq/L) was 28% in hospitalized vs 8%) for hyponatremic patients over age Acute versus chronic hyponatremia
patients, 21% in hospital clinics, and 7% 65 compared with those without hypona- It is crucial to differentiate the symp- in outpatient community care clinics.3 tremia on admission to the hospital.11 toms of acute hyponatremia from those Many disorders can cause nonos- In several studies of elderly patients of chronic hyponatremia. Acute hypona- motic secretion of AVP and therefore with SIADH, hyponatremia was idiopath- tremia can cause seizures, coma, respira- potentially result in water retention and ic. A 1997 study demonstrated that about tory arrest and death. These symptoms hyponatremia, including pulmonary dis- 60% of patients over age Acute hospital car 6 reflect cerebral edema, which can poten- that sometimes synthe- 28.2 d no discoverable cause of hyponatre- tially lead to herniation of the brain into size AVP, central nervous system (CNS) mia—no offending drugs, n Ambulatory hospital car oe pneumo- the brain stem with consequent respira- can dysregulate pituitary nia, no carcinoma, and none of the usual tory arrest and death. The cerebral ede- function, drugs, and a range of diverse causes of SIADH.12 Without an underly- ma may be accompanied by neurogenic conditions from the postoperative state 21 ing cause, these patients wil be suscepti- pulmonary edema, and the resulting ercise to severe nausea. ble to hyponatremia for a prolonged time hypoxia can worsen the severity of the At a serum [Na+] <136 mEq/L, the because there is no possible treatment for brain swelling and therefore the rapidity of hyponatremia in HF was an underlying disease to eliminate the in- of death from respiratory arrest.
15 Acute and Chronic Thera- appropriate AVP secretion.
In chronic hyponatremia, symptoms peutic evalence Pr Impact of Vasopressin Antago- In hospitalized patients, hyponatre- are much less severe. In a study of 14 nist study of 319 hospitalized patients4 mia is a marker for higher mortality and patients with acute hyponatremia of less 10 254 HF patients enrolled in adverse outcomes compared with those than 12 hours' duration and 52 patients a related study.5 The Acute Decompen- are not hyponatremic whether the with chronic hyponatremia of more than sated Heart Failure National Registry of disease is HF,13 pulmonary tuberculo- 3 days' duration, stupor or coma occurred 5 patients showed a 5% inci- sis,14 childhood diarrhea,15 or myocardial in only 6% with chronic hyponatremia dence of hyponatremia on entry with a infarction16 1.43 (Figure 2). In one study, HF compared with 100% with acute hypona- ] of <130 mEq/L.6 patients who were hyponatremic (de- tremia; the mortality rate was 50% in the Hyponatremia also occu < 116 rs in cirrho-<135 fined as [Na+] <130 mEq/L) much acute state, 6% in the chronic condition.19 sis, another edema-forming disorder. One worse survival rates over a 3-year period Brain volume regulation
The reason for the profound difference Figure 2. Hyponatremia Is Associated with Higher Mortality13-16
between the symptoms of acute and chronic hyponatremia is the process of brain volume regulation. As extracel ular [Na+] decreases, whether because of a 2 receptor antagonist loss of sodium or a gain of water, there AP2, aquaporin-2; PKA, protein kinase A; cAMP, cyclic adenosine monophosphate;ATP, adenosine triphosphate; AVP, arginine vasopressin.
is an obligate movement of water into the brain along osmotic gradients, which causes cerebral edema. When this is great- er than approximately 8%, the capacity of the skul to accommodate brain expan- sion is exceeded, leading to herniation and death from respiratory arrest. Fortunately, not all hyponatremic patients die from cerebral edema be- cause the brain undergoes brain volume regulation, a process in which electro- 4 Clinical Perspectives in Hyponatremia n March 2012
Serum [Na+] = Total body water lytes and organic osmolytes are excreted and survived, but in a compensated state. than in normonatremic patients.23 from the brain as it swells.20 As the solute This is a classic example of "al ostasis," Kengne and col eagues explored the is lost, the brain eliminates excess water, and the al ostatic burden of the compen- potential consequences of fal s in 513 cerebral edema resolves, and osmolality sation is a solute-depleted brain.
patients who presented with a fal and a is balanced across the extracellular fluid One possible effect of the loss of resulting fracture and in age-matched con- spaces inside and outside the brain. brain amino acids including glutamate in trol patients who did not have a fal and Although these patients are no lon- patients with hyponatremia was demon- fracture.24 The incidence of hyponatremia ger at risk for life-threatening complica- strated by a seminal study from Belgium.23 was significantly higher in patients present- tions, they are still subject to lesser but A group of 16 patients judged to have ing with fal s and fractures than in controls still impairing neurologic symptoms of asymptomatic hyponatremia by normal (13.6% vs 4%). A similar study from Lenox more chronic hyponatremia including neurologic exam underwent a battery of Hil Hospital in New York showed analo- headache, nausea and vomiting, mental neurocognitive tests, which demonstrated gous results.25 In a study of 1408 female slowing, unstable gait and falls, confu- delayed reaction times to defined stimuli. patients with chronic kidney disease, a se- sion and delirium, and disorientation.
In addition, the patients walked a tandem rum [Na+] <135 mEq/L. was also clearly Often it is not evident when a pa- gait, heel-to-toe, eyes open, on a sensorized shown to be independently associated with tient presents to the hospital whether mat that measured the center of gravity on an increased risk of fractures.26 the hyponatremia is acute or chronic be- the bal of their feet. The researchers then In addition to falls and fractures, cause the duration of the patient's condi- were able to see deviations of their center osteoporosis has been associated with tion is unknown. Therefore, the degree of gravity off the tandem line by measur- chronic hyponatremia. In our laboratory, of symptomatology can serve as a sur- we found that hyponatremia induced rogate for the duration of the hyponatre- dramatic bone loss as a result of a 5-fold mia because it reflects whether the brain increase in osteoclasts in trabecular bone has undergone volume regulation or not. in rats who were hyponatremic for 3 Brain volume regulation is clearly months.27 Data analysis from the Third In hospitalized patients, hyponatremia is a marker important because it al ows hyponatremic for higher mortality and National Health and Nutrition Examina- patients to survive by eliminating brain tion Survey found a significant increased adverse outcomes.
edema. However, many remain symp- OR of 2.87 for the occurrence of osteo- tomatic despite brain volume regulation. porosis in patients with hyponatremia In a report of 223 patients with hypona- ing the total traveled way (TTW). Patients even though their mean serum [Na+] was tremia induced by thiazide, hyponatremia with chronic asymptomatic hyponatremia only 133 mEq/L.27 Thus, even very mild was accompanied by a high incidence of (mean [Na+] 128 mEq/L) had a TTW of levels of hyponatremia appear to be as- symptoms.21 While dizziness can poten- 1336 mm, which was significantly differ- sociated with worsened osteoporosis. tial y be attributed to diuretic-induced hy- ent from age-matched normal controls One of the potential complications povolemia, symptoms such as confusion, ([Na+] 140 mEq/L) whose TTW was 1035 of correcting hyponatremia is the os- obtundation, and seizures are more con- mm. When the investigators corrected the motic demyelination syndrome (ODS), sistent with hyponatremic symptomatol- hyponatremia in those 16 patients with a also known as pontine and extrapon- ogy. Because thiazide-induced hyponatre- variety of different treatments, including tine myelinolysis. Symptoms include mia can be readily corrected by stopping AVP receptor antagonists, their TTW was tremor, incontinence, and hyperreflexia the drug and/or administering sodium, equivalent to the normal controls. Thus, or pathologic reflexia, eventual y result- it represents an ideal condition in which some hyponatremic patients have abnor- ing in quadriparesis with dysarthria, dys- to assess improvement in symptomatol- mal gait instability that corrects with cor- phagia, cranial nerve palsies, and mutism ogy with normalization of [Na+]. In rection of their hyponatremia. or locked-in syndrome. Symptoms oc- this study, al symptoms resolved fol- The functional significance of cur because of demyelination of motor lowing correction of the hyponatremia, this gait instability is il ustrated in Ren- axons in the pons. Clinical y, the occur- indicating that hyponatremia was indeed neboog's accompanying study of 122 rence of central pontine myelinolysis in a responsible for them. patients with a variety of levels of hypo- setting of severe metabolic derangement, However, the "cost" of this adap- natremia, al judged to be asymptomatic particularly of serum sodium, has been tive process is a brain that is chronical y at the time of their emergency depart- noted.28 We know from animal stud- depleted of many organic solutes. In our ment (ED) visit.23 Researchers compared ies that hyponatremic animals are much lab, hyponatremic animals experienced a these patients with 244 normonatremic more susceptible to brain dehydration 30% depletion of glutamate, the major controls matched for age, sex, and under- with acute correction of the hyponatre- excitatory amino acid neurotransmitter in lying disease also presenting to the ED mia. The brains of hyponatremic rats the brain that is responsible for al motor during the same time period. The inci- shrink even more as the plasma [Na+] is movements.22 Thus, chronic hyponatre- dence of fal s was 21.3% in hyponatremic raised, because they have lost a substan- mia may be associated with neurocogni- patients and 5.3% in normonatremic tial part of their osmotic buffering capac- tive and motor defects because the chron- controls. The adjusted odds ratio (OR) ity during the process of brain volume ical y hyponatremic brain is not normal; it for presenting to the ED with a fal was regulation via solute losses.29 has accommodated to an external threat 67-fold higher in hyponatremic patients In animal studies, Adler and col- Clinical Perspectives in Hyponatremia n March 2012 5
Acute hospital care Ambulatory hospital care 2 receptor antagonist AP2, aquaporin-2; PKA, protein kinase A; cAMP, cyclic adenosine monophosphate;ATP, adenosine triphosphate; AVP, arginine vasopressin.
Clinical Perspectives in Hyponatremia
leagues investigated whether such shrink- ficiently and very slowly. A better ther- age might disrupt the blood-brain barrier Figure 3. Correcting Hyponatremia
apy would be blocking the process of (BBB).30 BBB intactness was evaluated urinary concentration, which originates using MRI fol owing IV gadolinium con- from AVP binding to the V receptor trast administration. The group noted in the kidney and would prevent all the that hypertonic saline infusion rapidly downstream intracellular consequences increased the plasma [Na+] and caused of V receptor activation including the BBB disruption more frequently in insertion of the aquaporin water chan- chronic than in acutely hyponatremic rats. nels into the apical membrane of the Similar increases in plasma [Na+] did not collecting duct cells. That is, in fact, disrupt the BBB in normonatremic rats. the mechanism of action of the vap- The disruption appeared to be due to tans, which stimulate increased water altered plasma osmolality, since infusion excretion from the kidney. Importantly, of hypertonic mannitol, which raised blocking the V receptor has no effect plasma osmolality without changing the on sodium or potassium excretion; it plasma [Na+], also disrupted the BBB in simply causes increased excretion of wa- hyponatremic but not normonatremic because it produces intolerable dehydra- ter without increased solute. Therefore, rats. Moreover, the osmotic threshold for tion and thirst.31 Secondly, fluid restric- vaptans are electrolyte-sparing, and it BBB disruption was lowest in chronic hy- tion works very slowly—generally 1 to is more appropriate to call their effect ponatremia, intermediate in acute hypo- 2 mEq/L per day even under a severe "aquaresis" or increased urinary water natremia, and highest in normonatremia. fluid restriction of <500 mL/d. Conse- excretion rather than diuresis, which The greater susceptibility to osmotic quently, this method can take many days classically has been defined as increased BBB disruption in chronic hyponatremia to correct a low serum [Na+].
urinary water and solute (particularly so- suggests that BBB disruption may play a While demeclocyline targets the patho- dium and potassium) excretion.
significant role in causing the demyelin- physiology of hyponatremia by causing a Patients with severe symptoms (eg, ation sometimes found fol owing too postreceptor defect in the col ecting duct vomiting, seizures, obtundation, respira- rapid correction of hyponatremia. cel , thereby impairing the concentration tory distress, coma) typically associated process, it is not FDA-approved for treat- with acute hyponatremia are at acute risk Current therapies of hyponatremia
ment of hyponatremia. of death and morbidity from other ad- and medical need for new therapies
The recently approved vaptans are verse neurologic outcomes, necessitating Until recently, the treatments available for cal ed aquaretic agents. Conivaptan is a prompt treatment.32 Although the vap- hyponatremia included isotonic and hyper- combined antagonist of the V and V tans are able to raise serum [Na+] fairly tonic saline for short-term use, and fluid receptors, and tolvaptan is a selective an- quickly—within 8 hours—hypertonic restriction, demeclocycline, furosemide, tagonist of the V receptor. Another V an- saline is even quicker and can increase salt tablets, and rarely mineralocorticoids tagonist, lixivaptan, is stil in clinical trials. serum [Na+] within minutes, and is there- and urea for long-term use. Al of these fore the treatment of choice. Once the therapies work in specific circumstances, The rationale for aquaretic therapies
serum [Na+] corrects to the desired level but none are ideal and al have limitations Aquaretic therapies can be best appreci- and patients are out of trouble, fluid re- for a variety of different reasons, including ated by an analysis of the determinants striction or, if necessary, a vaptan can variable efficacy, slow responses, intolerable of the serum [Na+], which is the ratio of then be used to further increase serum side effects such as thirst, and dangerous exchangeable sodium and potassium di- [Na+] to a normal level, or to maintain it. toxicities such as ODS. In the last several vided by total body water. Given this rela- More moderate symptoms (eg, nau- years a new class of agents, AVP receptor tionship, there are only two basic ways to sea, confusion, disorientation, altered antagonists, or vaptans, have become avail- raise the serum [Na+] (Figure 3). One is in- mental status)—that are not life-threat- able for treating hyponatremia: conivaptan creasing the numerator by infusing either ening but can impair a patient's ability to for short-term use, and tolvaptan for both sodium or potassium, which is efficacious function—can be treated with a vaptan, short- and long-term use. Of note, al treat- for patients who are solute-depleted, often followed if necessary by fluid restriction ments other than demeclocycline and the due to diuretic use. However, in numerous or sometimes by chronic vaptan use. vaptans fail to attack the mechanistic cause studies, up to two thirds of patients with Vaptans are suggested in these patients of dilutional hyponatremia, which is inap- hyponatremia are not solute-depleted but because it will generally take too long propriately elevated plasma AVP levels.
rather have water expansion as the cause for fluid restriction to correct the serum Fluid restriction, long the mainstay of their hyponatremia. For those patients, [Na+] to normal ranges. Safely improv- of treating chronic hyponatremia, is ar- the second strategy is the most appropri- ing serum [Na+] to increased or normal guably the least expensive and potentially ate: decreasing the denominator by re- ranges within 1 to 2 days is the most ap- the safest treatment. But its major draw- moving excess total body water. propriate therapy to relieve moderate back, reported as early as in the initial de- That is the objective of fluid re- scription of SIADH in 1957, is that fluid striction that decreases body water via Final y, patients with minimal symp- restriction usually cannot be sustained insensible losses of water, but very inef- toms (eg, headache, irritability, inability to 6 Clinical Perspectives in Hyponatremia n March 2012
concentrate, altered mood, depression) or with chronic heart failure: results from a double-blind, no symptoms at al , are most appropriately Table 1. Fluid Restriction
randomized trial. Circulation. 2003;107:2690-6.
treated initial y with fluid restriction. How- 6. ADHERE Registry. 3rd Quarter 2003 National Benchmark General guidelines
Report. Sunnyvale CA: Scios, Inc. 2004.
ever, one should consider use of a vaptan 7. Angeli P, Wong F, Watson H, Gines P, and the CAPPS In- even with mild or no symptoms under se- • Restrict all intake consumed by vestigators.Hyponatremia in cirrhosis: results of a patient drinking, not just water lect circumstances, including: population survey. Hepatology. 2006;44:1535-42.
8. Caird FI, Andrews GR, Kennedy RD. Effect of posture on • Aim for a fluid restriction 500 mL/d n Inability to tolerate fluid restriction blood pressure in the elderly. Br Heart J. 1973;35:527-30. or a failure of fluid restriction; below the 24-h urine output 9. Kleinfeld M, Casimir A, Borra S. Hyponatremia as ob- served in a chronic disease facility. J Am Geriatr Soc. n Patients with a high fracture risk, • Do not restrict sodium unless osteoporosis, and any degree of gait 10. Mil er M, Morley JE, Rubenstein LZ. Hyponatre- instability or history of falls with mia in a nursing home population. J Am Geriatr Soc. Predictors of fluid restriction failure
1995;43(12):1410-13. 11. Terzian C, Frye EB, Piotrowski ZH. Admission hypona- n Serum [Na+] <125 mEq/L, High urine osmolality tremia in the elderly: factors influencing prognosis. J Gen because these patients are at higher (>500 mOsm/kg H O) Intern Med. 1994;9(2):89-91.
risk for developing more 12. Hirshberg B, Ben-Yehuda A. The syndrome of inappro- • Sum of the urine [Na+] and [K+] symptomatic levels of hyponatremia; priate antidiuretic hormone secretion in the elderly. Am J is greater than the serum [Na+] n Correcting serum [Na+] to safer 13. Flear CT, Singh CM.The sick cel concept and hypo- • 24-hour urine output <1,500 mL/d levels for surgery, anesthesia, and natremia in congestive heart failure and liver disease. other procedures; Increase in serum [Na+] <2 mEq/L 14. Westwater JO, Stiven D, Garry RC. Serum sodium level n Prevention of worsening hypona- in patients suffering from tuberculosis. Clin Sci. 1939;4:73-7.
tremia with forced fluid administra- resolve within days; therefore the likeli- 15. Samadi AR, Wahed MA, Islam MR, Ahmed SM. Con- tion, typically for patients on par- hood of chronic hyponatremia is very low sequences of hyponatraemia and hypernatraemia in children with acute diarrhoea in Bangladesh. Br Med J. enteral nutrition (which increases and there should be no indication or need 1983;286(6366):671-3.
their volume load); for long-term treatment with vaptans.33 16. Flear CT, Hilton P. Hyponatraemia and sever- ity and outcome of myocardial infarction. Br Med J. n To put patients in a safer [Na+] Alternately, hyponatremia caused by tu- 1979;1(6173):1242-6. range for ICU or hospital discharge; mors, CNS disorders, HF, and cirrhosis 17. Lee WH, Packer Ml. Prognostic importance of serum is more typical y chronic, requiring some sodium concentration and its modification by converting- enzyme inhibition in patients with severe chronic heart n As a therapeutic trial in patients who form of long-term therapy.
have neurologic symptoms when The general guidelines for fluid re- 18. Ruf AE, Kremers WK, Chavez LL, Descalzi VI, et al. it is not clear whether the cause is striction are to restrict al intake consumed Addition of serum sodium into the MELD score predicts waiting list mortality better than MELD alone. Liver Trans- the hyponatremia or not.
by drinking (Table 1). Sodium restriction plantation. 2005;11(3):336-43. Patients should be in a hospital is not indicated for typical patients with 19. Arieff AI, Llach F, Massry SG. Neurological manifes- setting for initiation or re-initiation of SIADH, because they general y do not tations and morbidity of hyponatremia: correlation with brain water and electrolytes. Medicine. 1976;55(2):121-9. therapy both to evaluate the therapeutic have excess sodium or edema. In fact, so- 20. Gul ans SR, Verbalis JG. Control of brain volume dur- response and because too rapid correc- dium should be liberalized unless contra- ing hyperosmolar and hypoosmolar conditions. Annu Rev tion of hyponatremia can cause ODS (ie, indicated. Obviously, this does not apply Med. 1993;44:289-301.
21. Chow KM, Kwan BC, Szeto CC. Clinical studies +] increase >12 mEq/L in 24 to hyponatremic patients with HF or cir- of thiazide-induced hyponatremia. J Natl Med Assoc. h, or >8 mEq/L in patients with risk fac- rhosis. If a patient fails fluid restriction, it 2004;96(10):1305-8. tors for ODS). The serum [Na+] must be is appropriate to consider treatment with 22. Verbalis JG, Gul ans SR. Hyponatremia causes large sustained reductions in brain content of multiple organic monitored at regular intervals, at least ev- a vaptan. This can usual y be determined osmolytes in rats. Brain Res. 1991;567(2):274-82.
ery 8 hours but more frequently in higher by the initial response to fluid restriction in 23. Renneboog B, Musch W, Vandemergel X, Manto MU, risk patients, to make sure correction the first 1 to 2 days (Table 1), rather than Decaux G. Mild chronic hyponatremia is associated with fal s, unsteadiness, and attention deficits. Am J Med. stays within desired and safe limits. If it waiting 5 to 7 days before concluding that 2006;119(1):71.e1-71.e8.
is proceeding more rapidly than planned, fluid restriction is a failure, which wil un- 24. Kengne FG, Andres C, Sattar L, Melot C, et al. Mild hy- additional water should be administered, necessarily prolong hospitalization.
ponatremia and risk of fracture in the ambulatory elderly. either oral y or IV as 5% dextrose. For 25. Sandhu HS, Gil es E, DeVita MV, Panagopoulos G, Mi- the same reason, patients started on vap- chelis MF. Hyponatremia associated with large-bone frac- tans should not be fluid restricted initial y, 1. Robertson GL, Aycinena P, Zerbe RL. Neurogenic disor- ture in elderly patients. Int Urol Nephrol. 2009;41(3):733-7.
since the increased thirst that accompa- ders of osmoregulation. Am J Med. 1982;72(2):339-53.
26. Kinsel a S, Moran S, Sul ivan MO, Mol oy MG, Eustace 2. Szatalowicz VL, Arnold PE, Chaimovitz C, Bichet D, Berl JA. Hyponatremia independent of osteoporosis is as- nies increases in serum [Na+] wil blunt T, Schrier RW. Radioimmunoassay of plasma arginine va- sociated with fracture outcome. Clin J Am Soc Nephrol. further correction of the serum [Na 2010;5(2):275-80. sopressin in hyponatremic patients with congestive heart failure. N Engl J Med. 1981;305(5):263-6.
27. Verbalis JG, Barsony J, Sugimura Y, Tian Y, et al. The need to use tolvaptan, or other 3. Hawkins RC. Age and gender as risk factors for hypo- Hyponatremia-induced osteoporosis. J Bone Miner Res. therapies, for long-term therapy depends natremia and hypernatremia. Clin Chim Acta. 2003;337(1- 2010;25(3):554-63. on whether the cause of the hyponatre- 28. Wright DG, Laureno R, Victor M. Pontine and extrapon- tine myelinolysis. Brain. 1979;10(2):361-85.
mia is chronic. Some types of hypona- 4. Gheorghiade M, Gattis WA, O'Connor CM, Adams KF Jr, et al. Effects of tolvaptan, a vasopressin antagonist, 29. Berl T. Treating hyponatremia: Damned if we do and tremia (eg, postoperative hyponatremia, in patients hospitalized with worsening heart failure: a damned if we don't. Kidney Int. 1990;37(3):1006-18.
exercise-associated hyponatremia, pneu- randomized control ed trial. JAMA. 2004;291(16):1963-71.
30. Adler S, Verbalis JG, Wil iams D. Effect of rapid cor- 5. Gheorghiade M, Niazi I, Ouyang J, Czerwiec F, et al. Va- monia-associated hyponatremia) usual y rection of hyponatremia on the blood-brain barrier of rats. sopressin V2-receptor blockade with tolvaptan in patients Brain Res. 1995;679:(1):135-43. Clinical Perspectives in Hyponatremia n March 2012 7
Clinical Perspectives in Hyponatremia
31. Schwartz WB, Bennett W, Curelop S, Bartter FC. A 32. Verbalis JG, Goldsmith SR, Greenberg A, Schrier RW, 33. Verbalis JG. Managing hyponatremia in patients syndrome of rneal soium loss and hyponatremia probably Sterns RH. Hyponatremia treatment guidelines 2007: with syndrome of inappropriate antidiuretic hormone resulting from inappropriate secretion of antidiuretic syn- expert panel recommendations. Am J Med. 2007;120(11 secretion. Endocrinol Nutr. 2010;57(Suppl 2):30-40.
drome. Am J Med. 1957;23(4):529-42.
case sTudy 1: hyPonaTremia in siadh JosePh g. Verbalis, md Mrs. T, a 40-year-old woman hos- diuretic use, it would be very unusual for don't have a measured AVP level in this pitalized 8 times from 2007 to a patient on diuretics to present with a case, the patient's very high urine osmolal- 2009 for symptomatic hypona- urine osmolality >1000 mOsm/kg H O ity indicates the AVP level is also high. A tremia with serum [Na +] as low as 117 unless he or she was also very hypovo- urine osmolality >1000 mOsm/kg H O mEq/L and corresponding neurologic lemic; but by clinical examination, this requires plasma AVP levels >5 pg/mL. symptoms, presents again with severe patient is euvolemic.
Thus, the extremely high urine osmolal- hyponatremia. Despite treatment with Drug-induced-hyponatremia is a com- ity in this patient is most consistent with demeclocycline, 1200 mg/d, and fluid mon problem, with many different drugs SIADH from ectopic AVP production. restriction, the patient's serum [Na+] has capable of causing hyponatremia by a num- The most common cause of ectopic AVP remained at 129 mEq/L. She was not on ber of mechanisms, including volume de- production is tumors. any other medications.
pletion, stimulation of inappropriate AVP Consequently, in this relatively young secretion, potentiation of AVP effects at patient with a high urine osmolality indi- the kidney, and changes in plasma osmolal- cating a high plasma AVP level, the most Mrs. T had a serum [Na+] of 129 mEq/L ity.2 Methamphetamines are associated with likely cause of SIADH is a tumor. Idio- on demeclocycline and fluid restriction, hyponatremia, but drug abuse is not the pathic SIADH is far less likely because a plasma osmolality of 270 mOsm/kg likely cause of this patient's hyponatremia it is seen predominantly in much older H O, a urine osmolality of 1159 mOsm/ because its effect is relatively short-lived patients (>65 years) and because patients kg H O, and a urine [Na+] of 247 mEq/L. and hyponatremia is general y only present rarely have elevated urine osmolalities to Examination revealed that the patient during the period of acute administration.
was clinically euvolemic, without edema Body fluids are maintained within or ascites or orthostatic blood pressure a remarkably narrow range of osmolal- What further evaluation should be
changes. Thyroid function tests were ity (average basal level: 285-290 mOsm/ normal. Normal cortisol results after a kg H O), primarily through the action of The patient has had extensive imag- cosyntropin stimulation test indicated osmoreceptors in the hypothalamus that ing of the chest, abdomen, pelvis, and absence of adrenal insufficiency. Other can detect smal changes in plasma solute brain with no abnormal results reported. routine laboratory tests (CBC, metabolic concentrations, and then transform this Nonetheless, additional imaging and profile, liver functions) were all normal. information into neural signals that either testing might be considered, including A CT scan of the chest, abdomen, and stimulate or inhibit both thirst and AVP PET, lumbar puncture for cerebrospinal pelvis was similarly normal. MRI of the release. Hypo-osmolar states, such as oc- fluid cytology, MRI of the sinuses and brain was unrevealing, and all serologies cur in patients with SIADH, are primarily nasopharynx to look for nasopharyngeal for HIV and hepatitis were negative.
the result of dysregulated water excretion, lesions, and a serum plasma carcinoem- which is usual y caused by a defect in AVP bryonic antigen test to detect an occult What is the most likely etiology?
osmoregulation. According to Robert- gastrointestinal (GI) malignancy that Given this dilemma of a relatively young son's 1982 study in 100 patients with may not have been picked up by initial female with severe hyponatremia consis- SIADH, plasma AVP levels ranged wide- imaging. Or, perhaps further imaging is tent with SIADH, potential etiologies in- ly, but in most cases were stil measurable not necessary because the etiology of clude an activating mutation of the AVP when they should have been suppressed the patient's SIADH may not be a tumor. V receptor gene; surreptitious diuretic by the low plasma osmolality.3 Because brain tumors can cause use; ecstasy or other drug abuse; ectopic In cases of SIADH, AVP is inad- SIADH, the recommended course for AVP production by a tumor; or idiopathic equately suppressed despite low plasma this patient was to revisit her MRI of osmolality, which causes inappropriate the brain focusing on the nasopharynx. The nephrogenic syndrome of inap- circulating levels of AVP relative to the A second read of the imaging revealed propriate antidiuresis (NSIAD) is caused plasma osmolality. The antidiuretic effect a focal thickening of the superior nasal by an activating mutation of the AVP V of AVP at the kidney then leads to wa- mucosa that was not mentioned on the receptor at the same site that also can ter retention and subsequent dilution of initial read. An otolaryngology consul- cause DI via an inactivating mutation.1 body fluids (fal in plasma osmolality to tation advised resection of this lesion, However, this patient's initial presenta- <280 mOsm/kg H O and plasma [Na+] which led to the pathologic diagnosis of tion is not consistent with a genetic eti- to <135 mEq/L). Very high levels of esthesioneuroblastoma. After resection ology because of the late age of onset of AVP (>10 pg/mL) are general y indicative of the tumor, the patient's hyponatremia her hyponatremia. As for surreptitious of ectopic AVP production. Although we completely resolved. At 1-year follow up, 8 Clinical Perspectives in Hyponatremia n March 2012
the patient's serum [Na+] remained nor- turbances. It is one of the rarer types of antagonist (vaptan). mal and she no longer required treatment head and neck cancers with fewer than Traditional treatments for hypona- with demeclocycline or fluid restriction.
1000 cases reported. In all 9 previous tremia such as fluid restriction, demeclo- reports published in association with hy- cycline, urea, and hypertonic saline infu- Which tumors are associated
ponatremia secondary to SIADH, elec- sion have several significant limitations, with SIADH?
trolyte abnormalities, namely hyponatre- including limited efficacy data, potential SIADH is a leading cause of hyponatre- mia, led to the discovery of the tumor.7 toxicities, and compliance difficulties.13 mia in patients with cancer.4,5 SIADH oc- Many other factors also increase While each of these therapies can work curs with a wide range of cancers but the the risk for hyponatremia in cancer pa- in specific circumstances, none are ideal most common by far is small-cell lung tients. First, a variety of chemotherapies and al have significant limitations (Table cancer (11%–46%), followed by head stimulate AVP secretion.8 In particular, 2). Only the vaptans and demeclocycline and neck cancers (3%–5%). Cancers of immunomodulators such as interferon actual y target the underlying pathophysi- the brain (both primary and metastatic), and interleukin-2 are associated with hy- ology of dilutional hyponatremia, namely a variety of hematologic malignancies, ponatremia, as have been monoclonal inappropriately elevated AVP levels. Dem- intrathoracic but nonpulmonary tumors, antibodies.9 Second, the nausea and vom- eclocycline, however, exhibits significant and melanoma are rarely associated with iting that often occur with chemotherapy nephrotoxicity and is not FDA approved SIADH. GI and genitourinary cancers wil independently elevate AVP levels for the treatment of hyponatremia.
are even more rarely associated with and therefore can cause hyponatremia,10 In this patient, urea would be thera- SIADH. The incidence of breast and ad- particularly if hypotonic fluids are be- peutic, but it is inconvenient and has renal cancers with hyponatremia is very ing used to keep the patient hydrated.11 poor palatability. Hypertonic saline and low, but these have been reported. Over- Third, hypotonic dehydration, another conivaptan are short-term therapies and all, tumors account for about 30% of all cause of hyponatremia, can occur as a could not be employed in this case. So cases of hyponatremia, and in general, result of the nephrotoxicity produced by long-term treatment with tolvaptan would 3% to 5% of the entire patient popula- many chemotherapeutic agents. Fourth, be the only agent predicted to be success- tion with cancer has hyponatremia.6 analgesic agents can stimulate AVP se- ful in correcting this patient's serum [Na+] Given the high frequency of SIADH cretion, leading to water retention and and maintaining it within normal ranges in lung cancer, it was appropriate initial y SIADH,12 as can pain and physical stress, over a long period.14 to do a chest CT scan in this patient, which especial y when coupled with free water has the highest yield in terms of imaging administration.10 for tumors with hyponatremia. Next in 1. Feldman BJ, Rosenthal SM, Vargas GA, Fenwick RG, importance for imaging is an MRI of the Future management options
Huang GA, et al. Nephrogenic syndrome of inappropriate antidiuresis. N Engl J Med. 2005;352:1884-92.
head because of the high frequency of Therapeutic options for chronic hypo- 2. Liamis G, Milionis H, Elisaf M. A review of drug-induced head and neck cancers. The patient's tu- natremia with recurrence of the esthe- hyponatremia. Am J Kidney Dis. 2008;52:144-53.
mor, a cancer of the olfactory epithelium sioneuroblastoma would include fluid 3. Robertson GL, Aycinena P, Zerbe RL. Neurogenic disor- ders of osmoregulation. Am J Med. 1982;72(2):339-53.
also called olfactory neuroblastoma, can restriction, demeclocycline, urea, hyper- 4. Glover DJ, Glick JH. Metabolic oncologic emergencies. present with loss of smell and visual dis- tonic saline infusion, or an AVP receptor CA Cancer J Clin. 1987;37:302-20.
5. Silverman P, Distelhorst CW. Metabolic emergencies in clinical oncology. Semin Oncol. 1989;16:504-15.
Table 2. Treatments for Hyponatremia
6. Baylis PH. The syndrome of inappropriate antidiuretic hormone secretion. Int J Biochem Cel Biol. 2003;35:1495-9.
7. Plasencia YL, Cortes MB, Aencibia DM, et al. Ethesio- neuroblastoma recurrence presenting as a syndrome of Ineffective in dilutional hyponatremias; can't be used in inappropriate antidiuretic hormone secretion. Head Neck. edema-forming disorders; no controlled safety database 8. Vanhees SL, Paridaens R, Vansteenkiste JF. Syndrome of inappropriate antidiuretic hormone associated with Hypertonic saline No consensus re appropriate infusion rates; overcorrection can chemotherapy-induced tumor lysis in smal -cel lung cause osmotic demyelination; can't be used in edema-forming cancer: case report and literature review. Ann Oncol. disorders; no controlled safety database 9. Berghmans T, Paesmans M, Body JJ. A prospective Fluid restriction Slow to correct over many days; poorly tolerated due to thirst; study on hyponatremia in medical cancer patients: epide- miology, etiology and differential diagnosis. Support Care unsuccessful with high AVP levels and urine osmolalities Cancer. 1999;8:192-7.
10. Decaux G, Soupart A. Treatment of symptomatic hypo- Not FDA approved for hyponatremia; slow to correct; natremia. Am J Med. 2003;326:25-30.
nephrotoxic in cirrhosis and CHF 11. Bissett D, Cornford EJ, Sokal M. Hyponatremia fol ow- ing cisplatin chemotherapy. Acta Oncol. 1989;28:823.
Mineralocorticoid Only one report in elderly patients with SIADH; no safety 12. Langfeldt LA, Cooley ME. Syndrome of inappropriate database; can't be used in edema-forming disorders antidiuretic hormone secretuion in malignancy: review and implications for nursing management. Clin J Oncol No USP formulation; not FDA approved for hyponatremia; Nurs. 2003;7:425-30.
13. Goldsmith SR. Current treatments and novel pharma- poor palatability cologic treatments for hyponatremia in congestive heart failure. Am J Cardiol. 2005;95(suppl):14B-23B.
AVP receptor antagonist Conivaptan approved only for in-hospital use secondary 14. Berl T, Quittnat-Pel etier F, Verbalis JG, Schrier RW, to CYP3A4 inhibition; infusion-site reactions with IV use Bichet DG et al. Oral tolvaptan is safe and effective in chronic hyponatremia. J Am Soc Nephrol. 2010;21: 705-12.
Clinical Perspectives in Hyponatremia n March 2012 9
Clinical Perspectives in Hyponatremia
case sTudy 2: hyPnoTremia in hearT failure Paul J. hauPTman, md Mrs. M, a 66-year-old woman with a ly because the underlying QRS morphol- What is the significance of the
history of severe mitral and tricus- ogy demonstrated a right, not left bundle patient's hyponatremia?
pid regurgitation and right-sided branch block pattern. Addition of cardiac Hyponatremia is much more than an iso- HF, S/P implantation of an implantable resynchonization therapy requires a wide lated lab abnormality; it is a potent prog- cardioverter defibrillator (ICD) presents QRS, though greatest clinical response nostic marker.3 It may cause nonspecific with increased fatigue, decreased appe- appears to occur in the setting of a wide signs and symptoms including confusion tite, and the inability to put her shoes on (>150 ms) left bundle branch block pat- and gait disturbance. Multiple studies de- comfortably because of lower extrem- tern.1 Further, implantations during a rived from randomized clinical trials, reg- ity edema. She has recently taken extra hospitalization for HF have a greater istries, and observational databases have metolazone. Her husband reports that mortality rate than elective admissions.2 demonstrated that baseline serum [Na+] "She is not doing her crossword puzzles After due consideration, the patient con- predicts length of stay and resource uti- anymore." Her weight has increased sented to an ICD alone and she experi- lization and that persistent hyponatremia from 61 to 72 kg over the prior week. enced no periprocedural complications.
is an independent predictor of mortal- The patient is referred for inpatient man- ity and HF hospitalization.3-5 In multiple Recent clinical course
prognostic models, serum [Na+] predicts In the outpatient setting, the patient's se- outcome.6-8 For example, in the Seattle Past medical history
rum [Na+] values varied over time, from Heart Failure Model, each decrement in The patient had mitral and tricuspid valve 130 to 134 mEq/L. She was compliant serum [Na+] is associated with decreases repairs in 2005. Her course at that time with medications and reasonably com- in 1-, 2-, and 5-year survival.7 was complicated by respiratory failure pliant with diet, but had a predilection and intermittent heart block, for which for French fries and ketchup. Frequent What should be done to acutely
she received a dual chamber permanent modifications of diuretic dosing were mobilize fluid during inpatient care?
pacemaker; her left ventricular ejection attempted, including addition of meto- The options for diuretic therapy include fraction (LVEF) was 45% and the LV lazone, first on a once weekly basis and continuous IV loop diuretic, intermittent was mildly dilated. Her right ventricle was then every day 30 minutes prior to furo- IV loop diuretic, and IV loop diuretic dilated and her right ventricular systolic semide.
following pretreatment with a thiazide. pressure (RVSP) was 45 mm Hg. However, as shown by Rogers and col- Mrs. M has been chronical y main- Examination at presentation
leagues, diuretic therapy results in a sig- tained on an ACE inhibitor, a beta- The exam was notable for an elderly, frail nificant decline in the glomerular filtra- blocker, digoxin, and furosemide. In the female with a SBP of 92 mm Hg, heart tion rate (GFR).9 18 months prior to this presentation, she rate of 96, marked jugular venous disten- Recently, the DOSE study compared had a worsening functional status and sion and clear "v"-waves (from tricuspid continuous infusion of furosemide ver- dyspnea with 3 hospitalizations for HF. regurgitation), presence of a Kussmaul's sus q12-hour bolus strategies at both low Her serum creatinine varied from 1.1 to sign, decreased breath sounds at the bases and high doses in a 2x2 factorial design.10 1.5 mg/dL and was noted to be higher with egophony, a palpable liver, and 2+ Low dose was defined by the patient's oral when her diuretic dose was increased. bilateral lower extremity edema. She also dose converted to an IV dose. High dose Her SBP ranged from 85 to 90 mm Hg; had significant mitral and tricuspid regur- was defined by the oral dose multiplied by her electrocardiograms and pacemaker gitation murmurs and a right-sided third a factor of 2.5, both continued for a mini- interrogations consistently revealed 30% heart sound. She appeared to be slightly mum of 48 hours. Patients who received atrioventricular (AV) pacing, but she had distracted and her gait was unsteady. the high-dose formulation were more an underlying right bundle branch block likely to be congestion-free, had greater and occasional paroxysms of atrial fibril- Medications
loss of weight, and greater net loss of lation. An echocardiogram obtained dur- On admission the patient was on ramipril, volume. In addition, the reduction in B- ing the second of the 3 hospitalizations 5 mg daily; metoprolol succinate, 25 mg type natriuretic peptide levels was greater, revealed a LVEF of 20%, a dilated right once daily; digoxin, 0.125 mg every other though the significance of this finding is ventricle, RVSP of 65 mm Hg, a moder- day; isosorbide mononitrate, 30 mg daily; not clear. However, there was a clinical ate degree of mitral regurgitation without furosemide, 100 mg daily; and metola- consequence with high-dose furosemide a significant gradient across her repaired zone, 2.5 mg once a week. She also took therapy: a greater percentage of patients mitral valve, and severe tricuspid regurgi- lorazepam as needed.
(23% vs 14%) experienced an increase in creatinine of >0.3 mg/dL. Though a At that same time point, the patient Initial laboratory findings
crude reflection of GFR, this magnitude was under consideration for an ICD. Mrs. M had a serum [Na+] of 124 mEq/L, of change has often been used as a sign However, her cardiologist was uncertain a serum [K+] of 3.6 mEq/L, a BUN of of worsening renal function in clinical about the advisability of placing an LV 44 mg/dL, a bilirubin of 1.9 mg/dL, and studies of HF and is associated with a lead, partly for technical reasons and part- her alkaline phosplatase level was normal. worse prognosis. The primary end point 10 Clinical Perspectives in Hyponatremia n March 2012
in the DOSE study was patient global as- factors, relief of dyspnea, achievement of discharge is relevant in patients with HF. sessment at 72 hours, and there were no weight loss, improvement in serum sodium We do know that mortality after hospi- significant differences between the groups. if low and avoidance of worsening renal talization is related to the initial and final In addition, there were no differences in function, al of which may lessen the risk of serum [Na+] values. In a patient popula- death, rehospitalization, and ED visits at 60 readmission (though other nonphysiologic tion including patients with HF but also days, though this study is quite smal and factors may come into play).14 other conditions, the highest mortality may have been underpowered to show a Some of these variables are related; was among those who had persistent for example, there appears to be a linear hyponatremia; however, it is worthwhile Of particular note, elevated venous relationship between reductions in body to note that patients who acquired hypo- pressure is increasingly recognized as a ma- weight and dyspnea.15 The development of natremia during hospitalization also had jor contributor to worsening renal function. cardiorenal syndrome is a risk during acute increased in-hospital mortality as well as This is an important observation since right management though the cause may be mul- 1- and 5-year mortalities relative to pa- ventricular failure may develop in a signifi- tifactorial. One such pathway may be in- tients whose hyponatremia had resolved cant proportion of patients with HF and duced by aggressive diuretic therapy leading by the time of discharge.18 these patients may be at risk due to venous to neurohormonal activation, diminished congestion at the level of the kidney.
blood flow, decreased renal perfusion, and References
Ultrafiltration is an option as demon- impaired renal function. Clinical y, this can 1. Sipahi I, Carrigan TP, Rowland DY, Stambler BS, Fang strated in the UNLOAD study, JC. Impact of QRS duration on clinical event reduction 11 though manifest as diuretic resistance; when pres- with cardiac resynchronization therapy: meta-analysis of the exact timing of initiation and duration ent, clinical decision-making becomes more randomized control ed trials. Arch Intern Med. 2011 Sep of therapy has not been ful y evaluated. complicated and the patient is likely to ex- 12;171(16):1454-62.
2. Hauptman PJ, Mikolajczak P, Mohr CJ, George A, Fluid removal is general y isotonic, which perience a longer length of stay, increased Hoover R, Swindle J, Schnitzler M. Chronic continuous wil not correct hyponatremia. Rather, con- morbidity and lessened survival. home inotropic therapy in end-stage heart failure. Am Heart J. 2006;152:1096.e1-1096.e8.
sideration should be given to aggressive Additional y, lack of weight loss has 3. Jao GT, Chiong JR. Hyponatremia in acute decompen- fluid restriction and if that fails, the initia- been noted to occur in up to 16% of pa- sated heart failure: mechanisms, prognosis, and treat- tion of a vaptan. There are two commer- tients during hospitalization for HF.16 On ment options. Clin Cardiol. 2010;33:666-71.
cial y available drugs in this class: conivap- the basis of these studies, one can construct 4. Gheorghiade M, Rossi JS, Cotts W, Shin DD, et al. Char- acterization and prognostic value of persistent hypona- tan, a combined V /V receptor antagonist a scenario that places patients in various tremia in patients with severe heart failure in the ESCAPE available in IV formulation, and tolvaptan, risk groups for readmission. The presence trial. Arch Intern Med. 2007;167(18):1998-2005. 5. Gheorghiade M, Abraham WT, Albert NM, et al, on be- a V selective oral agent. The latter has been of worsening renal function, hyponatre- half of the OPTIMIZE-HF Investigators and Coordinators. shown to be effective in reducing body mia, poor quality of life at baseline, lack of Relationship between admission serum sodium concen- tration and clinical outcomes in patients hospitalized for weight and increasing urine output in the weight loss, multiple comorbidities, and lack heart failure: an analysis from the OPTIMIZE-HF registry. setting of HF exacerbation,12,13 but long- of engagement with the health care system Eur Heart J. 2007;28:980-8. term efficacy has not been prospectively are key components of this evaluation.
6. Aaronson KD, Schwartz JS, Chen T-Z, Wong K-L, Goin JE, Mancini DM. Development and prospective validation examined in the hyponatremic HF cohort.
For Mrs. M, inpatient management of a clinical index to predict survival in ambulatory pa- had achieved dyspnea relief, weight loss, ab- tients referred for cardiac transplant evaluation. Circula- sence of worsening of renal function, and 7. Levy WC, Mozaffarian D, Linker DT, Sutradhar SC, et al. Given the patient's symptoms, presence of improvement in serum [Na+]. Although Heart failure: The Seattle Heart Failure Model: prediction fluid overload, and clear worsening of se- these results offer no guarantee of an ex- of survival in heart failure. Circulation. 2006;113:1424-33.
8. Lee DS, Austin PC, Rouleau JL, Liu PP, Naimark D, Tu rum [Na+], IV furosemide, 5 mg by continu- tended period out of hospital, at the very JV. Predicting mortality among patients hospitalized for ous infusion and oral tolvaptan, 15 mg daily least they suggest that a degree of clinical heart failure. Derivation and validation of a clinical model. were administered. On day 1, urine output stability has been achieved. It might also 9. Rogers HL. Marshal J. Bock J. et al. A randomized, was 3.5 L and serum [Na+] increased to have been helpful to gauge the patient's control ed trial of the renal effects of ultrafiltration as 128 mEq/L. On day 2 the dose of tolvap- quality of life using a formal administration compared to furosemide in patients with acute decom- pensated heart failure. J Cardiac Fail. 2008;14:1-5.
tan was increased to 30 mg/d, and on day of a validated instrument; predictors of 10. Felker GM, Lee KL, Bul DA, Redfield MM, et al. Diuretic 3 the dose of furosemide was increased to persistently poor quality of life fol owing strategies in patients with acute decompensated heart 10 mg/h. On day 5, the patient's total urine an admission for HF have been published.17 failure. N Engl J Med. 2011;364:797-805.
11. Costanzo MR, Guglin ME, Saltzberg MT, Jessup ML, output for her first 5 days of hospitalization Readmission for HF is the number Bart BA, Teerlink JR, et al for the UNLOAD Trial Investi- was 13.5 L. Serum [Na+] had increased to one readmission DRG in the Medicare gators. Ultrafiltration versus intravenous diuretics for pa- tients hospitalized for acute decompensated heart failure. 134 mEq/L. The patient was noted to be population. However, patients are often re- J Am Col Cardiol. 2007;49:675-83.
eating wel and ambulating normal y. Her admitted for other causes and there are fre- 12. Gheorghiade M, Gattis WA, O'Connor CM, Adams Jr husband noted that she was fil ing out a quently competing risks for mortality due KF, Elkayam U et al for the Acute and Chronic Therapeutic Impact of a Vasopressin Antagonist in Congestive Heart crossword puzzle. Her weight was near her to the high prevalence of co-morbidities.
Failure (ACTIV in CHF) Investigators. Effects of tolvaptan, baseline, now at 63 kg.
a vasopressin antagonist, in patients hospitalized with worsening heart failure. JAMA. 2004;291:1963-71. What is the significance of
13. Gheorghiade M, Konstam MA, Burnett JC Jr, Grinfeld improvement in [Na+] at discharge
L, Maggioni AP, Swedberg K, Udelson JE, Zannad F, Cook In the management of acute decom- in patients with HF?
T, Ouyang J, Zimmer C, Orlandi C. Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvap- pensated HF, there are several impor- We do not know if the approach used tan (EVEREST) Investigators. Short-term clinical effects tant goals: identification of exacerbating to increase serum [Na+] by the time of of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure: the EVEREST Clinical Status Clinical Perspectives in Hyponatremia n March 2012 11
Clinical Perspectives in Hyponatremia
Trials. JAMA. 2007;297:1332-43.
Effects of tolvaptan on dyspnea relief from the EVEREST patients hospitalized with heart failure at risk for unfa- 14. Amarasingham R, Moore BJ, Tabak YP, et al. An au- trial. Eur Heart J. 2009;30(18):2233-40.
vorable future quality of life. Circ Cardiovasc Qual Out- tomated model to identify heart failure patients at risk for 16. Gheorghiade M, Filippatos G. Reassessing treatment 30-day readmission or death using electronic medical of acute heart failure syndromes: the ADHERE Registry. 18. Waikar SS, Mount DB, Curhan GC. Mortality after record data. Med Care. 2010;48:981-88.
Eur Heart J. 2005;7(supplB):B13-19. hospitalization with mild, moderate, and severe hypona- 15. Pang PS, Konstam MA, Krasa HB, Swedberg K, et al. 17. Allen LA, Gheorghiade M, Reid KJ, et al. Identifying tremia. Am J Med. 2009;122(9):857-65.
case sTudy 3: hyPonaTremia in neurocriTical care sTePhan a. mayer, md, fccm
Mrs. W is a 46-year-old woman of hyponatremia in hospitalized patients, Neurologic etiology of hyponatremia
who was admitted to the Neuro- Anderson and colleagues noted a 60- CNS conditions with a tendency to de- critical Care Unit with SAH. She fold higher death rate in hospitalized velop hyponatremia include subarach- was assessed as Hunt-Hess grade 3, con- patients who had a [Na+] <130 mEq/L noid hemorrhage (SAH), intracerebral fused and mildly lethargic, but following than in patients without documented hemorrhage (ICH), massive cerebral commands. She had a past medical his- hyponatremia.1 infarction, severe traumatic brain in- tory of hypertension and was an active To assess the outcome of severe jury, and infections such as meningitis tobacco smoker.
hyponatremia and characterize factors and encephalitis. Pain, stress, drugs, in- On admission, the patient's blood pres- influencing outcome in hospitalized pa- creased ICP, and hypovolemic states all sure was 170/78 mm Hg; heart rate, 71 bpm. tients, Nzerue conducted a retrospec- can stimulate the release of AVP. In ad- Initial lab findings were normal, including tive study of 168 hospitalized patients dition, intracranial hemorrhage and sur- chemistry-7 screen, CBC, and coagulation with severe hyponatremia ([Na+] <115 gical intervention can interrupt neuronal profile. EKG, however, showed widespread mEq/L).2 Neurologic symptoms were communication and hormonal feedback T-wave inversions, suggesting neurogenic documented in 53% of patients. Half of mechanisms. Therefore, in many neuro- cardiac injury. CT showed a thick clot in the the patients with symptomatic hypona- critical care units, serum [Na+] is taken as left sylvian fissure and more diffuse sub- tremia experienced changes in their level another vital sign.
arachnoid blood throughout. of consciousness or their sensorium; The important mechanisms by Initial treatment focused on the emer- they were confused, lethargic, and had which CNS disorders cause hyponatre- gency administration of antifibrinolytic slowed psychomotor function. Severe mia include SIADH and cerebral salt therapy, epsilon amino-caproic acid, at a hyponatremia was documented as lead- wasting (CSW). SIADH is defined by the dose of 1 g/h until 4 hours prior to cerebral ing to stupor or coma and reducing sei- presence of AVP when it is supposed to angiography. This treatment is increasingly zure threshold.
be fully suppressed, which normally oc- being used to minimize the risk of ultra- Physiological y, in hyponatremia ab- curs when plasma osmolality falls below early rebleeding prior to definitive aneurysm normal electrical discharges in the brain 280 mOsm/kg H O. This results in im- repair. She was given a phenytoin loading occur more often. In Nzerue's series, 20% paired renal water clearance, increased dose and maintenance therapy, which con- of patients with hyponatremic encepha- total body water, and the development tinued to reduce the risk of acute seizures lopathy developed seizures.2 Other less of hyponatremia. Triggers of SIADH that might precipitate an aneurysm rebleed. common symptoms including nausea and include drug exposures, pulmonary dis- Her hypertension was treated with IV ni- vomiting may be secondary to high intra- ease, and CNS disease (see Case 1).
cardipine as needed to maintain SBP <160 cranial pressure (ICP), which can result CSW is defined by the development mm Hg. She was also started on nimodip- from intracel ular edema and brain swel - of extracellular (ECF) volume depletion ine to reduce the risk of delayed treatment ing. Even in absence of increased ICP, because of an abnormality in renal sodi- ischemia from vasospasm. She also received mild hyponatremia has been associated um transport in patients with intracranial a nicotine patch to reduce the risk of the with an increased risk of gait disturbances disease. It can be difficult to differenti- stress related to nicotine withdrawal. ate CSW from SIADH because both can A STAT cerebral angiogram re- To explore the relationship of acute present with hyponatremia and concen- vealed a 7-mm anterior communicating hyponatremia with neurologic dysfunc- trated urine with natriuresis. The dis- artery aneurysm that was surgically re- tion, Arieff and col eagues plotted plasma tinction is important because treatment paired. Postoperatively, despite transcra- sodium levels against the level of con- options differ: isotonic volume repletion nial Doppler accelerations, no symptom- sciousness among patients with acute hy- is indicated in untreated CSW, while pro- atic vasospasm was detected.
ponatremia that had developed within 24 motion of free water clearance is recom- hours or less.3 The investigation showed mended in SIADH.
Hyponatremia and neurologic
that the more drastic the fal in plasma In SAH, inappropriate elevation of sodium, the larger the change in level of AVP despite normovolemia occurs in Hyponatremia is associated with sub- consciousness, with patients who were a majority of patients during the first stantial mortality. In a prospective analy- having seizures or were comatose having week. The AVP increase is consistent sis of the frequency, cause, and outcome the lowest sodium levels.3 with a central mechanism resulting from 12 Clinical Perspectives in Hyponatremia n March 2012
the hemorrhage. In these cases, osmotic cumulative positive 24-hour fluid balance in serum [Na+] levels can be expected 24 regulation of AVP escapes the normal over the same period.
hours later.5 Tolvaptan was discontinued. regulatory process. In addition, AVP The patient was monitored for another 24 increases occur as a result of ECF and Why is this patient hyponatremic?
hours and discharged to rehabilitation to plasma volume depletion due to natri- Because the patient is euvolemic, the cause make a ful neurologic recovery.
uresis. The increased AVP following the of the hyponatremia is SIADH. For CSW Patient cases such as this support a SAH leads to free water retention and to be associated with hyponatremia, the compel ing argument that correction of hyponatremia. In cases of euvolemic condition would have to have been uncor- hyponatremia leads to neurologic improve- hyponatremia following SAH, use of an rected or untreated and there would have ment. Even mild hyponatremia, in the ab- aquaretic agent minimizes electrolyte ex- been progressive negative sodium and fluid sence of frank symptoms, can cause neu- cretion associated with natriuresis there- balance from one day to the next leading rocognitive dysfunction and gait disorders by reducing the contribution of volume to a state of hypovolemia. Stated another as was demonstrated in Renneboog's study contraction to increased AVP.
way, untreated CSW leads to hypovolemic (see page 5).6 Hyponatremia also increases the risk of fal s. Kengne's study (see page 5) The patient's postoperative course
CSW causes hypo-osmolar hypona- showed the incidence of hyponatremia is Mrs. W had mild hydrocephalus, which tremia, but intravascular volume is reduced significantly higher among patients admit- was managed with serial lumbar punc- due to excessively high sodium losses that ted to the hospital with fal s and fractures tures. She was treated with a euvolemic are not rescued or reversed by fluid therapy. than in the control populations.7 This is a volume strategy with 0.9% saline given at Diringer's classic study of 19 patients con- very important safety issue for al intensiv- 100 mL/h, adjusted to maintain a central cluded that fol owing an acute aneurismal ists and al hospitalists but especial y for venous pressure of 6-8 mm Hg. Isotonic SAH, hypervolemic therapy prevents vol- neurointensivists, because we're trying to fluid resuscitation is a hallmark of SAH ume contraction but not hyponatremia.4 help people recover from brain injuries and management for the prevention of hypo- Diringer's group hypothesized that humor- get out of bed and on their feet to get on volemia. Limiting free water intake miti- al factors may favor both sodium loss and with their rehabilitation. That's why it is im- gates against brain edema and ICP exac- water retention, and that AVP regulation portant to diagnose and treat hyponatremia erbation. Treatment resulted in a mildly is disturbed and may contribute to hypo- when we encounter it. positive fluid balance. Throughout her natremia in this setting. A third of the early ICU stay, she remained confused SAH patients in the study developed hypo- References
and disoriented, but the lethargy gradu- natremia. 1. Anderson RJ, Chung H-M, Kluge R, Schrier RW. Hy- ally resolved. She remained confused and ponatremia: a prospective analysis of its epidemiology and the pathogenic role of vasopressin. Ann Intern Med. disoriented, but was less and less lethar- Treatment options for Mrs. W
gic from one day to the next.
The therapeutic choices for this patient 2. Nzerue CM, Baffoe-Bonnie H, You W, Falana B, Dai S. included fluid restriction to <1.5 L/d; salt Predictors of outcome in hospitalized patients with severe hyponatremia. J Natl Med Assoc. 2003;95(5):335-43.
tablets (NaCl), 2 g/d; fludrocortisone, 0.1 3. Arieff AI, Llach F, Massry S. Neurological manifestations After 1 week, on day 9, Mrs. W was trans- mg tid; IV furosemide; 20% mannitol (an and morbidity of hyponatremia: correlation with brain wa- ferred to the step-down care unit, the osmotic diuretic that wil remove free wa- ter and electrolytes. Medicine. 1976;55(2):121-9.
4. Diringer MN, Wu KC, Verbalis JG, Hanley DF. Hypervol- central line was discontinued, she was ter); 2% or 3% hypertonic saline; or tolvap- emic therapy prevents volume contraction but not hypona- continued on her normal saline at 100 tan, 15 mg once a day.
tremia fol owing subarachnoid hemorrhage. Ann Neurol. mL/h through peripheral IV, and then Mrs. W was treated with tolvaptan and 5. Berl T, Quittnat-Peletier F, Verbalis JG, Schrier RW, et al. the next day she seemed more confused. within 24 hours her serum [Na+] had in- Oral tolvaptan is safe and effective in chronic hyponatre- Lab findings showed a serum [Na+] level creased from 126 to 130 mEq/L. After 3 mia. J Am Soc Nephrol. 2010;21(4):705-12.
of 126 mEq/L. Though the central ve- days of therapy, the patient's serum [Na+] 6. Renneboog B, Musch W, Vandemergel X, Manto MU, Decaux G. Mild chronic hyponatremia is associated with nous pressures seemed to indicate eu- levels had corrected to 138 mEq/L. Her fal s, unsteadiness, and attention deficits. Am J Med. volemia, through 10 days of care the mental status at that time was less con- 2006;119(1):71.e1-71.e8.
patient's serum [Na+] had gradually fallen fused. Clinical trials indicate that for every 7. Kengne FG, Andres C, Sattar L, Melot C, et al. Mild hy- ponatremia and risk of fracture in the ambulatory elderly. to 126 mEq/L from 143 mEq/L despite 15 mg of tolvaptan, a 3- to 4-point increase QJM. 2008;101(7):583-8.
case sTudy 4: hyPonaTremia in cirrhosis florence Wong, mbbs, md, fracP, frcPc eat and because of multiple falls. He had very thin, weighing less than 50 kg, and also been coming to the hospital for re- very malnourished. He was lying in bed Mr. M, a 74-year-old male, first presented in June 2005 with cirrhosis from chronic hepati- peat large volume paracentesis as a treat- in a fetal position responding in a non- tis B infection, ascites, and confusion. ment of ascites associated with his cir- purposeful manner. His blood pressure His wife reported multiple prior hospi- rhotic condition.
was slightly low at 105/70 mm Hg; heart tal admissions because of his refusal to Exam revealed that the patient was rate, 64 bpm. Clinically he was not jaun- Clinical Perspectives in Hyponatremia n March 2012 13
Clinical Perspectives in Hyponatremia
diced. I was not able to elicit anything with a poor prognosis and an increased risk Following this regimen, the patient's but mild asterixis. Abdominal exam did of death in patients with decompensated serum [Na+] rose to 123 mEq/L. How- not reveal a palpable liver; however, there cirrhosis awaiting liver transplantation.2 ever, he continued to be weak and inter- was splenomegaly and gross ascites.
Therefore, there is a need to treat hypona- mittently confused. Hypertonic saline is Mr. M's daily medications included tremia in patients with cirrhosis and ascites. not recommended in cirrhosis, as this furosemide, 40 mg; spironolactone, 100 will significantly increase the sodium re- mg; nadolol (a nonselective beta-blocker), What are the symptoms
tention, and hence will significantly wors- 20 mg; lamivudine (an antiviral), 100 mg; of hyponatremia?
en the ascites. Demeclocycline is not in- and a multivitamin tablet.
In a study of 223 consecutive hospital- dicated in cirrhosis, as it can induce renal ized patients with symptomatic hypona- dysfunction related to its effects on the tremia ([Na+] 98–128 mEq/L), 49% were renal kallikrein-kinin system, involved in Mr. M's findings were as fol ows: he- found to have malaise or lethargy; 47% the maintenance of renal blood flow in moglobin, 99 g/L; WBC, 3.3 X 109/L; had dizzy spel s; 35% reported vomiting; cirrhosis and ascites. Although urea can platelets, 85 X 109/L; serum [Na+], 113 17% had confusion; 17% were fal ing; 6% give an osmotic diuresis and improve the mEq/L; serum [K+], 4.2 mEq/L; creati- had headaches, and 0.9% had seizures.3 serum [Na+], it can also induce hepatic nine, 1.01 mg/dL; apartate aminotrans- Al symptoms resolved when the serum encephalopathy in cirrhosis, and there- ferase, 54 IU/L; alanine aminotransferase, [Na+] was corrected by stopping thiazide fore is not recommended.
39 IU/L; alkaline phosphate, 74 IU/L; diuretics the patients had been taking. Therefore, Mr. M was started on an bilirubin, 0.54 mg/dL; albumin, 3.2 g/dL; In patients with cirrhosis, however, AVP receptor antagonist and gradual y and international normalized ratio (INR), symptoms of hyponatremia can be indistin- over the fol owing 2 weeks, serum [Na+] 1.35. His liver enzymes were mildly ab- guishable from those of advanced cirrhosis, levels improved, with associated improve- normal. His liver function (as indicated by such as a vague feeling of being unwel . In ment in mental alertness. Mr. M received his bilirubin, albumin, and INR) also was some patients, hyponatremia is asymptom- satavaptan, a V receptor antagonist avail- mildly abnormal.
atic, and therefore it is the responsibility able in a clinical trial at the time. of treating physicians to check electrolytes Pathophysiology of hyponatremia
regularly to detect hyponatremia.
Why is a vaptan effective?
Basical y, vaptans block the reabsorption In patients with cirrhosis, total body so- What is the best treatment for
of water in the renal col ecting duct sys- dium is increased as a result of increased significant hyponatremia?
tem. When AVP is attached to the V re- renal sodium retention. As a patient pro- Hyponatremia can be corrected in cases ceptor at the renal col ecting duct on the gresses through the cirrhotic process, such as Mr. M by changing either the nu- basolateral space, it sets off a series of going from the stage of compensated merator by adding more sodium or by sub- biochemical reactions, which ultimately cirrhosis to the development of ascites, tracting the denominator by changing total result in the insertion of aquaporin-2 on to the stage where ascites is no longer re- body water (Figure 3, page 6). However, the luminal side of the principal duct cell sponsive to diuretic therapy, to hepatore- patients with cirrhosis and therefore por- (Figure 1, page 3). This al ows water to nal syndrome there is a gradual reduction tal hypertension already have renal sodium be reabsorbed back into the basolateral in the serum [Na+] as a result of various and water retention. Adding sodium wil in- space, thereby concentrating the urine. In hemodynamic changes that occur in cir- crease total body sodium and also increase the presence of a vaptan that competi- rhosis. Hyponatremia occurs because wa- fluid retention, worsening ascites as the tively blocks off the V receptor, the se- ter retention far exceeds sodium retention. presence of portal hypertension wil push ries of biochemical reactions can no lon- In a survey conducted on patients the excess retained fluid into the peritoneal ger be initiated; therefore, no aquaporin-2 with liver cirrhosis and ascites, almost half cavity. Therefore, fluid restriction is pre- can be inserted onto the luminal side of had serum [Na+] ≤130 mEq/L, indica- ferred to correct excess water over excess the principal duct cel and water cannot tive of hyponatremia.1 In the same study, sodium. Sodium restriction wil help reduce be reabsorbed. This physiologic process the presence of hyponatremia was asso- the amount of fluid retained and therefore induces the production of very dilute ciated with complications such as the de- indirectly help to reduce the ascites. urine. Therefore, with less water being velopment of hepatic encephalopathy, the Mr. M was treated by withholding di- reabsorbed, total body water is reduced, presence of hepatorenal syndrome, and uretic therapy and restriction to 500 mL helping to normalize the ratio between the development of spontaneous bacte- of fluids a day. Oral sodium intake was total body sodium and total body water, rial peritonitis. In fact, the lower the serum restricted to 44 mEq per day, which can correcting serum sodium levels.
[Na+], the higher the prevalence of these be difficult to achieve. Electrolytes were complications. Patients with serum [Na+] checked daily. Mr. M and his wife were Clinical course
<130 mEq/L had the greatest frequency counseled to visit a dietitian for instruction During the ensuing 2 years, Mr. M was of these complications, but the frequency about special low-sodium food items. Basi- able to continue therapy with satvaptan was also increased in patients with serum cal y, he was advised not to consume any- and his serum [Na+] remained mostly [Na+] 131-135 mEq/L.
thing preserved or available in tins, jars, or within a normal range. He had no further The presence of hyponatremia (se- packets. Instructing patients to eat mostly hospital admissions after August 2005; rum [Na+] <130 mEq/L) is also associated fresh food items is helpful.
his wife reported no further episodes of 14 Clinical Perspectives in Hyponatremia n March 2012
confusion; in fact, vaptan therapy also ing weak and lethargic again and uninter- References
helped with ascites management, and Mr. ested in his surroundings. Final y, he died 1. Angeli P, Wong F, Gines P, and the CAPPS Investigators. M did not require paracentesis after Sep- in cardiac failure in August 2009. His fall Hepatology. 2006;44:1535-42.
tember 2005 when he was living at home in serum [Na+] fol owing stopping sat- 2. London MC, Cardenas A, Guevara M, Quinto L. et al. and self-caring. However, in August 2008, avaptan is consistent with what has been MELD score and serum sodium in the prediction of surviv- al of patients with cirrhosis awaiting liver transplantation. the satavaptan program was closed by the observed in large clinical trials which also Gut. 2007;56(9):1283-90.
sponsor. Over the next 2 weeks, Mr. M's show return of the serum [Na+] to the 3. Chow KM, Ching-Ha Kwan B, Szeto CC. Clinical stud- serum [Na+] fel from 134 to 125 mEq/L hyponatremic range with withdrawal of ies of thiazide-induced hyponatremia. J Natl Med Assoc. and his wife noticed that he was becom- vaptan therapy.
For each question below, please indicate your answer in the space provided
on the evaluation form on page 16.
1. Hyponatremia appears to be a marker for more severe
6. The goals of managing patients with hyponatremia in
underlying disease with a poorer prognosis for
acute decompensated heart failure include
A. Relief of dyspnea C. Neurologic disease C. Improvement in serum [Na+] (if low) and avoidance D. All of the above of worsening renal function D. All of the above 2. The level of water in the body is controlled by
A. The pituitary gland 7. The seminal article exploring the relationship between acute
B. Water consumption hyponatremia and neurologic dysfunction, published by Arieff
C. The hormone arginine vasopressin (AVP) in 1976, demonstrated that
D. Aquaporin-2 water channels A. Seizures developed in 20% of patients with hyponatremic 3. The syndrome of inappropriate antidiuretic hormone
B. Half the patients with symptomatic hyponatremia have secretion (SIADH) is an example of
changes in their level of consciousness or their sensorium A. Excessive urination of water because water cannot C. The more drastic the fall in serum [Na+], the greater the be reabsorbed by the kidney change in level of consciousness, with patients who were B. Dilutional hyponatremia having seizures or were comatose having the lowest C. Appropriately elevated serum AVP levels in relation serum sodium levels.
to serum osmolality D. Neurologic symptoms were documented in 53% of patients D. Serum osmolality > 280 mOsm/kg H O 8. In patients with cirrhosis, symptoms of hyponatremia are
4. A study in Singapore in 2003 showed that the
clearly distinct from those of advanced cirrhosis
prevalence of hyponatremia ([Na+] <135 mEq/L) was
A. 28% in hospitalized patients B. 21% in hospital clinics C. 7% in outpatient community care clinics 9. Which treatment to address hyponatremia is least likely to be
D. All of the above indicated in patients with cirrhosis and ascites?
A. Fluid restriction 5. In various studies, elderly patients have been shown to
B. Hypertonic saline have a higher incidence of hyponatremia than other
C. Arginine receptor antagonist groups. It has been estimated that
D. Albumin infusion A. The prevalence of hyponatremia in the elderly increases to 50% in chronic care facilities 10. Fluid restriction, long the mainstay of treating chronic
B. The incidence of hyponatremic episodes in the elderly can be as high as 75% in nursing homes A. Cannot be sustained because it produces intolerable C. The overall incidence of hyponatremia is 7% in the dehydration and thirst geriatric population B. Works very rapidly D. In patients over the age of 65, the mortality rate is C. Corrects serum [Na+] by 1 to 2 mEq/L per hour three-fold higher for hyponatremic patients than for D. Targets the mechanistic cause of dilutional hyponatremia those without hyponatremia on admission Clinical Perspectives in Hyponatremia n March 2012 15
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Evaluate available therapeutic agents and approaches used to manage hyponatremia, including clinical benefits and potential adverse events Develop a treatment plan for patients with hyponatremia 7. What barriers to applying what you have learned do you anticipate? _ 8. What challenges are you faced with when managing a patient that you have diagnosed with hyponatremia? _ 9. What other problem(s) or issue(s) in your practice would you like to see addressed in future CME activities? _10. What type of activity format do you prefer? (check all that apply) O Live meetings O DVD O Web-based O Print O Other (please specify) _ 11. Other comments or suggestions _12. Indicate your degree: O MD/DO O NP O PA O RN O Other (please specify) _13. Indicate your specialty: O Cardiology O Critical Care O Endocrinology O Hepatology O Hospital-BasedMedicine O Nephrology O Other _ O I have completed the activity and claim credit hours (maximum of 1.5).
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16 Clinical Perspectives in Hyponatremia n March 2012
Expression of Macrophage InflammatoryProtein-3␤/CCL19 in Pulmonary Sarcoidosis Agata Gibejova, Frantisek Mrazek, Daniela Subrtova, Veronika Sekerova, Jaroslava Szotkowska, Vitezslav Kolek,Roland M. du Bois, and Martin Petrek Departments of Immunology and Respiratory Medicine, Palacky University, Olomouc, Czech Republic; and Interstitial Lung Disease Unit,Royal Brompton Hospital, London, United Kingdom