2009 Hyponatremia in Neurosurgical Patients- Clinical Guidelines Development

8/13/2019 2009 Hyponatremia in Neurosurgical Patients- Clinical Guidelines Development

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NEUROSURGERY VOLUME 65 | NUMBER 5 | NOVEMBER 2009 | 925

REVIEW

Maryam Rahman, M.D.

Department of Neurosurgery,

University of Florida,Gainesville, Florida

William A. Friedman, M.D.

Department of Neurosurgery,

University of Florida,Gainesville, Florida

Reprint requests:

Maryam Rahman, M.D.,Department of Neurosurgery,University of Florida,

Box 100265,Gainesville, FL 32610-0265.

Email:[email protected]

Received, March 10, 2009.

Accepted,July 22, 2009.

Copyright 2009 by theCongress of Neurological Surgeons

Hyponatremia is the most common electrolyte disorderencountered in clinical medicine (25). Approximately 1million hospitalizations per year in the United States are

for a principal or secondary diagnosis of hyponatremia. Theannual cost of managing patients with hyponatremia has beenestimated at $3.6 billion (25). In addition to monetary costs,

hyponatremia is associated with negative outcomes for patients.Specifically, the mortality rates are significantly higher inhyponatremic patients across a broad range of primary disor-ders (4, 22, 56). In some disease states, such as congestive heartfailure, hyponatremia is an independent risk factor forincreased mortality (18, 96).

ABBREVIATIONS: ANP, atrial natriuretic peptide; CSW, cerebral salt wasting; CVP, central venous pressure; ECF, extracellular fluid; Na, sodium;ODS, osmotic demyelinating syndrome; PE, physical examination; Posm, plasma osmolality; SAH, subarachnoid hemorrhage; SIADH, syndromeof inappropriate antidiuretic hormone

HYPONATREMIA IN NEUROSURGICAL PATIENTS:CLINICAL GUIDELINES DEVELOPMENT

OBJECTIVE: Neurosurgical patients have a high risk of hyponatremia and associatedcomplications. We critically evaluated the existing literature to identify the determi-nants for the development of hyponatremia and which management strategies providedthe best outcomes.

METHODS: A multidisciplinary panel in the areas of neurosurgery, nephrology, criticalcare medicine, endocrinology, pharmacy, and nursing summarized and classifiedhyponatremia literature scientific studies published in English from 1950 through 2008.The panels recommendations were used to create an evaluation and treatment proto-col for hyponatremia in neurosurgical patients at the University of Florida.

RESULTS: Hyponatremia should be further investigated and treated when the serum

sodium level is less than 131 mmol/L (class II). Evaluation of hyponatremia should includea combination of physical examination findings, basic laboratory studies, and invasivemonitoring when available (class III). Obtaining levels of hormones such as antidiuretichormone and natriuretic peptides is not supported by the literature (class III). Treatmentof hyponatremia should be based on severity of symptoms (class III). The serum sodiumlevel should not be corrected by more than 10 mmol/L/d (class III). Cerebral salt wast-ing should be treated with replacement of serum sodium and intravenous fluids (class III).Fludrocortisone may be considered in the treatment of hyponatremia in subarachnoid hem-orrhage patients at risk of vasospasm (class I). Hydrocortisone may be used to prevent natri-uresis in subarachnoid hemorrhage patients (class I). Hyponatremia in subarachnoidhemorrhage patients at risk of vasospasm should not be treated with fluid restriction(class II). Syndrome of inappropriate antidiuretic hormone may be treated with urea,

diuretics, lithium, demeclocycline, and/or fluid restriction (class III).CONCLUSION: The summarized literature on the evaluation and treatment of hypona-tremia was used to develop practice management recommendations for hyponatremiain the neurosurgical population. However, the practice management recommendationsrelied heavily on expert opinion because of a paucity of class I evidence literature onhyponatremia.

KEY WORDS: Cerebral salt wasting, Evidence-based medicine, Hyponatremia, Syndrome of inappropriateantidiuretic hormone

Neurosurgery 65:925936, 2009 DOI: 10.1227/01.NEU.0000358954.62182.B3 www.neurosurgery-online.com


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The prevalence of hyponatremia in the neurosurgical popu-lation has been reported as high as 50% (26, 74, 107, 117, 120,140, 153). Because of the cerebral effects of hyponatremia, neu-rosurgical patients are at increased risk of complications. Suchcomplications include severe cerebral edema, mental statuschanges, seizures, vasospasm, and death. Unfortunately, these

complications may also arise from the inappropriate treatmentof hyponatremia. Correction of hyponatremia that is too slowor fast can lead to cerebral edema, seizures, osmotic demyeli-nating syndrome, or death (1, 42, 43, 138).

Despite the costs and complications associated with hypona-tremia in the neurosurgical population, few randomized stud-ies have been completed that describe when hyponatremiabecomes clinically significant and how it should be treated.The evaluation and treatment of hyponatemia are left to thediscretion of the individual health care provider or treatmentteam. This lack of a standardized treatment approach con-tributes to variable outcomes. Concern about the variability inthe approach to hyponatremia treatment in neurosurgery

patients prompted us to develop a standardized evaluationand treatment paradigm at the University of Florida.The algorithm that we developed specifically addresses the

most common causes of hyponatremia in neurosurgery patients:the syndrome of inappropriate antidiuretic hormone (SIADH)and cerebral salt wasting (CSW). Treatment of hyponatremia insubarachnoid hemorrhage (SAH) patients is also given specialconsideration. The evaluation and treatment algorithm for thetreatment of hyponatremia in neurosurgery patients was insti-tuted at the University of Florida in February 2008. The goal ofthe algorithm was to reduce the wide range of variation in treat-ment options.

PATIENTS AND METHODSThis paradigm was created by a multidisciplinary group represented

by neurosurgery (2 physicians, 4 nurse practitioners), nephrology (2physicians), critical care medicine (1 physician), endocrinology (1 physi-cian), pharmacy (1 pharmacist), and nursing (4 nurses). The collaboration

between these individuals ensured development of a comprehensive yetpractical approach to the treatment of hyponatremia in neurosurgicalpatients. The multidisciplinary group met every other month for 8months and agreed on the most pressing questions about hyponatremia.These questions were then examined by a detailed literature search. Thepanel developed 3 questions about the evaluation and treatment ofhyponatremia in the neurosurgical setting: 1) When should hyponatremia

be further evaluated and treated? 2) What is the optimal evaluation par-adigm for hyponatremia in the neurosurgical setting? 3) What is the opti-

mal treatment paradigm for hyponatremia in the neurosurgical setting?The literature search was performed by one of the physicians from the

Department of Neurosurgery. The search terms included hypona-tremia, hyponatremia and neurosurgery, osmotic demyelinatingsyndrome, cerebral salt wasting, syndrome of inappropriate antidi-uretic hormone, CSW and neurosurgery, and SIADH and neuro-surgery using PubMed and the Cochrane Database. The literature pub-lished between 1940 and 2008 was reviewed in both databases.Additional references were obtained from publications found by the lit-erature search. Relevant literature was graded on quality by the multidis-ciplinary group based on criteria developed by Walters (16) (Table 1).

RESULTS

For the first question about identifying the parameters forevaluation of hyponatremia, 16 of 38 studies were judged appro-priate for the analysis. Retrospective studies were excluded fromthe analysis in accordance to the evidence classification system

described by Walters (16) (Table 1). For the second question onoptimal evaluation, 88 studies were reviewed and all wereincluded in the analysis. For the third question regarding treat-ment, 71 studies were reviewed and all were included in theanalysis. The grading system was then applied according to themethodology of Lohr et al. (80) to construct clinical practiceguidelines for the evaluation and treatment of hyponatremia inneurosurgical patients at the University of Florida. The guide-lines were developed by the physician participants of the paneland approved by the entire panel.

DISCUSSION

Question 1: When Should Hyponatremia Be FurtherEvaluated and Treated (What Laboratory Values and/orClinical Symptoms Require Intervention)?

Review of the Literature

Although hyponatremia is classically defined as a serumsodium (Na) level less than 135 mmol/L, clinically significanthyponatremia has not been clearly defined (25, 69). Hypo-natremia is associated with increased mortality (22, 56). In aprospective study of patients hospitalized for medical illnessesother than dysnatremia, a serum Na level less than 130mmol/L was associated with a 60-fold increase in fatality(11.2% versus 0.19%). Patients with a serum Na level less than120 mmol/L had a mortality rate of 25% compared with 9.3%in patients with a serum Na level greater than 120 mmol/L (4).Another prospective study showed that hyponatremic patients(mean serum Na level of 125.3 mmol/L) were 7 times morelikely to die in the hospital and more than twice as likely to dieafter discharge compared with normonatremic patients, evenwhen controlling for underlying diagnoses (P 0.0001) (137).In another study, hyponatremic patients with an improvementin the serum Na level (2 mmol/L) had a mortality rate of11.1% at 60 days post-discharge compared with a 21.7% mortal-ity rate in those showing no improvement (115). A change inthe serum Na level was a significant predictor of 60-day mor-tality (hazard ratio, 0.736; 95% confidence interval, 0.5690.952for each 1 mmol/L increase from baseline).

Additional morbidity is associated with a serum Na levelless than 130 mmol/L (9, 25, 52, 69). A case-control study ofemergency department patients found 21% (26 of 122) ofhyponatremic patients (serum Na level 135 mmol/L) pre-sented with falls compared with 5% (13 of 244) of normona-tremic patients matched in multiple comorbidities. The meanserum Na level of hyponatremic patients was 126 mmol/L(range, 115132). The severity of the hyponatremia did not cor-relate with likelihood of presenting with falls (112). A fre-quently cited study by Arieff et al. (8) prospectively evaluated

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65 patients with a serum Na level less than 128 mmol/L. Thepatients in whom hyponatremia developed over 48 hours orless were all symptomatic and had a mean serum Na level of114 mmol/L. The mean serum Na level of chronic (48 hours)hyponatremic patients was 115 mmol/L in symptomaticpatients and 122 mmol/L in asymptomatic patients. Allpatients in whom seizures developed had a serum Na levelless than 121 mmol/L.

In SAH patients in particular, hyponatremia has a clear associ-ation with increased morbidity. Hyponatremia in SAH patients isassociated with increased rates of cerebral ischemia (61, 147). Inone study, in patients who were not fluid restricted, 24% whowere normonatremic and 12% who were hyponatremic (serumNa 135 mmol/L) demonstrated cerebral ischemia compared toonly 12% of normonatremic patients (61). Another prospectivestudy of SAH patients demonstrated that hyponatremia was sig-nificantly associated with poor outcomes at 3 months (odds ratio,

2.7; 95% confidence interval, 1.26.1). Poor outcomes were classi-fied according to the Glasgow Outcome Scale of death, vegetativestate, or severe disability (109).

The panel reviewed many other studies that also showedincreased morbidity and mortality associated with hypona-tremia (1, 6, 10, 11, 13, 19, 28, 31, 36, 47, 65, 100, 101, 107, 108,117, 119, 120, 135, 136, 140, 153). The serum Na value indicatingclinically significant hyponatremia varied in the literaturereviewed by the multidisciplinary panel. Therefore, the panelmade the following recommendation based on the best evi-

dence and expert opinion: hyponatremia should be furtherinvestigated and treated when the serum Na level is less than131 mmol/L (class II).

Question 2: What Is the Optimal Evaluation Paradigm,Clinical and Laboratory, for Hyponatremia in theNeurosurgical Setting?

Review of the Literature

Causes of hyponatremia have traditionally been categorizedby body fluid status. No standard reference test exists for theevaluation of hyponatremia. The lack of standard tests for theevaluation of hyponatremia often leads to inadequate evalua-tions of hyponatremic patients, such as failure to check plasmaosmolality (Posm), urine Na level, and urine osmolality. In aretrospective study of 104 patients with a serum Na level of lessthan 125 mmol/L, osmolality was measured in only 26% of

patients. Mortality was higher in the group with inadequateworkup and management (41% versus 20%; P 0.002) (61, 66).Therefore, most experts proposed a combination of physicalexamination (PE) findings and laboratory tests to distinguishbetween the causes of hyponatremia (21, 34, 43, 53, 59, 62, 69,73, 82, 92, 104, 110, 120, 138, 143). This approach is especiallyimportant to distinguish between SIADH and CSW.

Neurosurgery patients often develop hyponatremia in the set-ting of natriuresis. Hyponatremia with natriuresis is caused byeither SIADH or CSW after diuretic use has been excluded (50,


HYPONATREMIA IN NEUROSURGICAL PATIENTS

TABLE 1. Classification of evidence (16)

Class Prognosis Diagnostic tests Therapeutic effectiveness

I Evidence provided by 1 or more well-

designed clinical studies of a population

completely followed from a uniform point

in their disease, without bias, and with

adjustment for extraneous prognostic

variables (e.g., multivariate analysis)

Evidence provided by 1 or more well-

designed clinical studies of a diverse

population using a gold standard refer-

ence test in a blinded evaluation appropri-

ate for the diagnostic applications and

enabling the assessment of sensitivity,

specificity, positive and negative pre-

dictive values, and, where applicable,

likelihood ratios


designed, randomized, controlled trials,

including overviews of such trials

II Evidence provided by 1 or more clinical

studies of data on a restricted population,

collected prospectively, with complete

follow-up and adjustment for extraneous

prognostic variables (e.g., multivariate

analysis)

Evidence provided by 1 or more clinical

studies of a restricted population using a

reference test in a blinded evaluation of

diagnostic accuracy and enabling the

assessment of sensitivity, specificity,

positive and negative predictive values,and, where applicable, likelihood ratios


designed comparative clinical studies,

such as nonrandomized cohort studies

and case-control studies

III Evidence provided by expert opinion,

studies that include only 3 of the criteria

for practice standards, but data must be

collected prospectively

Evidence provided by expert opinion,

studies that do not meet the criteria for

the delineation of sensitivity, specificity,

positive and negative predictive values,

and, where applicable, likelihood ratios

Evidence provided by case series,

comparative studies with historical

controls, case reports, and expert opinion


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128). Criteria for SIADH proposed by Janicic and Verbalis (69)include Posm less than 275 mOsm/kg, inappropriate urinary con-centration (urine osmolality 100 mOsm/kg), clinical euvolemia(absence of orthostasis, tachycardia, decreased skin turgor, drymucous membranes, or edema and ascites), elevated urinary Naexcretion with normal salt and water intake, and absence of

other causes of euvolemic hypo-osmolality (hypothyroidism,hypocortisolism). However, these criteria have proven to beinadequate in distinguishing between SIADH and CSW. Ten of12 neurosurgery patients in a prospective study who met the lab-oratory criteria for SIADH (serum Na level 135 mmol/L, Posm280 mOsm/kg, urine Na 25 mmol/L, and urine osmolality Posm) had low blood cell mass, plasma volume, and total bloodvolume compared with controls (94). The authors suggestedtreating these patients with blood transfusions and replacementof volume. A retrospective study of 50 patients with a serum Nalevel less than 130 mmol/L and a diagnosis of SIADH showedan improvement in serum Na level with fluid restriction in only68% of cases (64).

Extracellular fluid (ECF) status is the key to distinguishingbetween SIADH and CWS (2, 21, 43, 49, 53, 59, 62, 82, 84, 92,104, 105, 110, 125, 138, 152). Determination of ECF status usingPE alone has been shown to be inaccurate (31, 66, 83, 116). Aprospective study of 35 patients with a serum Na level lessthan 130 mmol/L divided the patients into 4 groups (thosewho had received diuretics, polydypsic patients, saline respon-ders, and saline nonresponders). Saline responders werepatients who had a sustained increase in plasma Na of at least5 mmol/L. All patients were initially determined to be hypo- ornormovolemic based on PE findings (mucosal hydration, skinturgor, jugular vein distention), orthostatic changes in pulse(increase of 10% upright compared with supine), and systolicblood pressure (decrease of 10% upright compared withsupine). The saline responders and those who had receiveddiuretics were considered the true hypovolemic patients.Clinical determination of ECF status using PE finding param-eters had a sensitivity of 41.1% and a specificity of 80%. Thisand other studies found that a low fractional excretion of Naand urea are associated with saline responsiveness (30, 91).

Based on several studies of the evaluation of hyponatremia, aurinary Na level less than 30 mmol/L has a positive predictivevalue of 71% to 100% for an infusion of 0.9% saline to increasethe serum Na level (30, 91). Some authors propose an infusionof isotonic saline and measurement of urinary Na excretion todetermine the cause of the hyponatremia (90). However, theserecommendations targeted non-neurosurgical patients.

Uric acid has also been used to distinguish SIADH fromother causes of hyponatremia. In the study of saline responsive-ness in hyponatremic patients, the polydypsic and saline non-responsive patients tended to have lower plasma urea and uricacid compared with the other 2 groups (91). A serum uric acidlevel of less than 4 mg/dL (in the presence of hyponatremia)has been calculated to have a positive predictive value forSIADH of 73% to 100% (17, 48, 90, 106). However, the defini-tions for SIADH used in these studies were broad and mostlikely included patients with CSW.


RAHMAN AND FRIEDMAN

To distinguish between SIADH and CSW, central venouspressure (CVP) can be used to determine intravascular volumestatus. Damaraju et al. (38) treated hyponatremia based on CVPvalues (5 cm H2O, 610 cm H2O, 10 cm H2O). Hypovolemicpatients (CVP 5 cm H2O) were given normal saline (50mL/kg/d) and salt (12 g/d). Normovolemic patients (CVP 610

cm H2O) were given normal saline with 12 g of salt per day. Inaddition, patients with anemia (hematocrit 27%) were admin-istered whole blood. No patients were found to be hyper -volemic (CVP 10 cm H2O). The serum Na level was correctedwithin 72 hours in 73% of patients and 12% more within thenext 24 to 48 hours. The patients included 3 nonresponders, 2 ofwhom were found to have severe dehydration on blood volumemeasurements. Another prospective study used CVP to catego-rize 7 hyponatremic patients as SIADH (CVP 610 cm H2O)and 4 patients as CSW (CVP 6 cm H2O). The SIADH patientswere treated with less than 800 mL/d of fluid restriction, andthe CSW patients were treated with fluid replacement (50100mL/kg/d). Four patients achieved a normal serum Na level

within 36 hours and the other 7 patients within 72 hours (46).Treatment of hyponatremia in SAH has generated contro-versy given the association of fluid restriction or dehydrationwith symptomatic vasospasm (61, 147). Traditionally, hypona-tremia in SAH patients has been attributed to SIADH (120).However, more recent studies show that hyponatremic SAHpatients often demonstrate a negative Na balance (loss of Na inurine is greater than Na intake per day) and lower ECF (74,121). Peptides such as atrial natriuretic peptide (ANP), brainnatriuretic peptide, C-type natriuretic peptide, and digoxin-likesubstance have been found in SAH patients. Some have sug-gested a correlation between the presence of these peptides andCSW causing delayed hyponatremia (20, 33, 45, 67, 74, 139, 148).In a prospective study of 8 SAH patients who met the criteriafor SIADH proposed by Janicic and Verbalis (69), a linear rela-tionship was found between ANP levels and urinary Na excre-tion. However, ADH levels did not correlate with Na loss (145).

The ANP level was found to be elevated in 14 SAH patientscompared with controls in a study by Wijdicks et al. (146). Eightpatients had a twofold increase in ANP above baseline anddemonstrated natriuresis and a negative Na balance. Three ofthese patients had infarcts. Another study showed that cere-brospinal fluid adrenomedullin concentrations were signifi-cantly increased in hyponatremic patients (Na 135 mmol/L)and patients in whom delayed ischemic neurological deficitsdeveloped (72). Brain natriuretic peptide has also been shownto correlate with hyponatremia after SAH (20, 139).

Natriuretic peptides are associated with natriuresis but notalways with hyponatremia. In a study of 21 SAH patients,increased ANP was present in all SAH patients compared withcontrols, regardless of the serum Na level (44).

ADH has also been shown to have limited diagnostic value inhyponatremia (29). The appropriateness of an ADH level hasnot been defined. SIADH has been documented in patients withno detectable ADH (71). A prospective study of severe headinjury patients found that patients in whom hyponatremiadeveloped within 3 days of injury had higher ADH levels com-


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pared with patients whodeveloped hyponatremia aweek after the injury. How-ever, ADH was detectable inall patients (143). Neverthe-less, the available data on

ADH and natriuretic peptidesare conflicting (72, 77, 126).

The panel reviewed the fullrange of publications on theevaluation of hyponatremia(35, 14, 15, 19, 23, 24, 27,3437, 44, 51, 52, 58, 63, 81, 97,99, 102, 114, 117, 122124, 132,136, 141, 144). Having re-viewed the data, the panel rec-ommended a general approachto the evaluation of hypona-tremia (Fig. 1 and Table 2).

Using the evaluation para-digm, a serum Na value lessthan 131 mmol/L shouldprompt a workup that in-cludes measuring serum andurine osmolarity, urine elec-trolytes, uric acid, and an eval-uation of ECF volume status.A normal or high serum osmo-larity may result from laboratory error or pseudohyponatremiafrom hyperglycemia or hypertriglyceridemia. Hypotonichyponatremia is categorized by ECF volume status. Volume sta-tus can be determined based on the criteria listed in Table 2.Hypovolemia results from extrarenal loss or intrarenal loss suchas CSW, diuretics, or adrenal insufficiency. In normovolemicpatients, thyroid disease, hypocortisolism, and polydypsiashould be ruled out before a diagnosis of SIADH is given.Moreover, hypervolemic hyponatremia is less common in neuro-surgical patients, and the treatment team should rule out cir-rhosis, congestive heart failure, and renal failure.

Recommendation

Evaluation of hyponatremia should include a combinationof PE findings, basic laboratory study results, and invasivemonitoring when available (class III).

Obtaining levels of hormones such as ADH and natriureticpeptides is not supported by the literature (class III evi-

dence).

Question 3: What Is the Optimal Treatment Paradigmfor Hyponatremia in the Neurosurgical Setting?

Rate of Correction

Generally, the rate of correction of hyponatremia is deter-mined by the severity of symptoms and rapidity of onset.Studies have shown that the severity of hyponatremia symp-toms correlates with the magnitude of hyponatremia and the rate

of onset (4, 8, 153). Given the significant morbidity/mortality asso-ciated with severely symptomatic hyponatremia, evidence existsto correct symptomatic severe hyponatremia aggressively with



TABLE 2. Diagnostic criteria for cerebral salt wasting and syn-drome of inappropriate antidiuretic hormonea

CSW SIADH

Serum sodium, mmol/Lb 135 135

Serum osmolarity, mOsm/kgb 285 285

Urine osmolarity, mOsm/kgb 200 200

Urinary sodium, mmol/L 25 25

Weight

Fluid balance

Jugular venous distention

Hematocrit

Blood, urea, nitrogen

Creatinine

Uric acid

Bicarbonate

Central venous pressure, cm H2O 6 6

Pulmonary wedge pressure, mm Hg 8 8

aCSW, cerebral salt wasting; SIADH, syndrome of inappropriate antidiuretic hormone.b Must meet these criteria and at least 3 of the other criteria listed for a diagnosis.

FIGURE 1. Evaluation of hyponatremia. Hyponatremic patients should undergo a workup including laboratory (Lab)values and physical examination findings. Hypotonic hyponatremia can be categorized by volume status. S, serum;Osm, osmolarity; Ur, urine; ECF, extracellular fluid; vol, volume; Wt, weight; JVD, jugular venous distention; Hct,hematocrit; BUN, blood urea nitrogen; Cre, creatinine; bicarb, bicarbonate; CVP, central venous pressure; PCWP, pul-monary catheter wedge pressure; I/Os, in and out; N/V, nausea and vomiting; CSW, cerebral salt wasting; adrenal,adrenal insufficiency; TSH, thyroid-stimulating hormone; FT4, free thyroxine; LFTs, liver function tests; EKG, elec-trocardiogram; echo, echocardiogram; Abd US, abdominal ultrasound; CHF, congestive heart failure; RF, renal fail-ure; U Na, urinary sodium


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developed in those whoselevel was corrected moreslowly (134). Reinduction ofhyponatremia has been re-ported for the treatment ofODS (103, 131).

A prospective study of 33medical patients with sympto-matic hyponatremia (meanserum Na level 108 mmol/L)showed no episodes of ODSdespite an increase in meanserum Na level to 126 mmol/Lwithin 48 hours (12). Theauthors evaluated retrospec-tively a group of 12 patientswho all had evidence of cere-bral demyelinating lesions atautopsy. The rate of correction

of their hyponatremia wassimilar to the prospectivelyevaluated patients. However,they all had 1 of 4 characteris-tics: an increase in serum Nalevel to normal or hyperna-tremic levels within 48 hours,a change in serum Na level ofmore than 25 mmol/L within48 hours, a hypoxic episode,and/or hepatic encephalopa-thy (12). Based on case reportsand animal data, the develop-ment of ODS is associatedwith the rate and magnitudeof Na correction in chronichyponatremia (48 hours),with hypokalemia, and withmalnourished states (alco-

holism, cirrhosis, burns) (32, 40, 57, 75, 76, 79, 127, 129).Chronic hyponatremia should not be rapidly corrected.

Generally, rapid correction at a rate of more than 1 mmol/L/hshould be reserved for severely symptomatic and/or acutehyponatremia (48 hours) (47, 133, 134, 151). Severe symp-toms (e.g., seizures, coma) indicate cerebral edema and shouldtrigger prompt treatment. A retrospective study of inpatientswith a serum Na level less than 115 mmol/L demonstrated an

increase in mortality in those who had slower correction oftheir hyponatremia. The serum Na level after 48 hours of treat-ment was 127.1 mmol/L in survivors versus 118.8 mmol/L inpatients who died (P 0.0016) (96).

SIADH

The treatment of SIADH has been based on fluid restrictionunless patients are severely symptomatic, in which case hyper-tonic saline is used (51, 89, 142). In a study of 55 hyponatremicpatients after transsphenoidal pituitary tumor resection, all 44


RAHMAN AND FRIEDMAN

hypertonic saline (7, 21, 43, 53, 69, 73, 92, 104, 110, 138, 142).This approach is based loosely on the idea that acute hypona-tremia tends to be more symptomatic and that treatment com-plications happen in the setting of chronic hyponatremia (8).

Central pontine myelinolysis or osmotic demyelinating syn-drome (ODS) is the most frequently cited complication in thetreatment of hyponatremia. This entity was first described inthe 1970s (40). ODS is more likely to occur with correction of

a serum Na level greater than 12 mmol/L/d and in the settingof chronic hyponatremia (48 hours) (1, 2, 42, 113). In a retro-spective study of patients with ODS, all patients had chronichyponatremia (before admission) and a serum Na level lessthan 110 mmol/L. All the patients had their serum Na levelcorrected faster than 12 mmol/L/d (134). A review of the lit-erature found that in all the patients with severe hypona-tremia (Na 106 mEq/L) and in those with a serum Na levelcorrection greater than 12 mEq/L/d, some type of neurolog-ical complication developed. No neurological complications

FIGURE 2. Treatment of cerebral salt wasting (CSW). After a diagnosis of CSW is confirmed, treatment is based onsymptoms. Patients with severe symptoms should be treated in the intensive care unit (ICU) with hypertonic salineand fludrocortisone. Acute hyponatremia and/or severe symptoms should have 6 mmol/L corrected over 6 hours or untilsevere symptoms improve. The total correction of sodium (Na) should not exceed 8 mmol/L over 24 hours. Therefore,if 6 mmol/L is corrected in 6 hours, Na should not be increased more than 2 mmol/L in the following 18 hours. Thetotal correction of Na is based on the Na deficit (def), which is calculated conservatively with the formula depicted. Withimprovement of symptoms, the patients can be moved to the less aggressive treatments in the algorithm until Na reaches131 mmol/L. Subarachnoid hemorrhage (SAH) patients are an exception and receive treatment even for a serum Nalevel of 131 to 135 mmol/L. HHH, hypervolemia, hypertension, hemodilution; sx, symptoms; MS, mental status; sz,seizure; Tx, transfer; IMC, intermediate care unit; I/Os, in and out; vol, volume; wt, weight; N/V, nausea and vom-iting; U, urine; CVL, central venous line; inc, increase; NS, normal saline; IVF, intravenous fluids.


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asymptomatic patients (80%) were treated as outpatients withfluid restriction and a high-salt diet. Six of these patients hadfollow-up and showed an improvement in the serum Na level.The 11 symptomatic patients were hospitalized. Three of thesepatients responded to fluid restriction and salt tablets, and 8patients required hypertonic saline (153). The rationale for treat-ment with fluid restriction versus hypertonic saline was not given.

Other treatments for SIADH include diuretics and urea. Aprospective study described use of furosemide and ethacrynicacid in 11 of 12 SIADH patients and 2 volunteers. Na supple-

ments were necessary in 9 of 11 patients, and treatment ofhypokalemia was required in 7 patients. Two of the patientsrequired higher doses of diuretics (39). The use of urea inhyponatremia came from a study that showed that 20 hypona-tremic patients who met the criteria for SIADH had a low bloodurea level (41). In a retrospective study of hyponatremia in neu-rosurgical patients, 40 g of urea in 100 to 150 mL of normalsaline was given every 8 hours in addition to a continuous infu-sion of normal saline at 60 to 100 mL/h for 1 to 2 days. Patientswere not categorized as having SIADH or CSW because these

data were unavailable. Thepretreatment mean Na levelwas 130 mmol/L (range,119134 mmol/L) and theposttreatment mean was 138mmol/L (range, 129148

mmol/L) (P 0.001). In 85%of cases, only 1 day of treat-ment was necessary (111).

Traditionally, demeclocyclinehas been used in chronicSIADH (155). This approachmay be replaced by a new classof drugs that block ADH recep-tors (54, 55, 87). Conivaptan hasbeen approved for use in euv-olemic hyponatremia based onimprovement in hyponatremiain randomized, controlled tri-

als (54, 55). These drugs maycause volume depletion (88,130). ADH receptor blockershave been studied in patientswith heart failure, but furtherhuman studies are necessary todetermine their role in thetreatment of hyponatremia inthe neurosurgical population(53, 88, 98, 115, 118, 154).

CSW

Treatment of CSW has beenstudied mostly in the settingof SAH (59, 93). A retrospec-tive analysis of 134 SAH pa-tients demonstrated the risks

associated with fluid restriction in the treatment of hypona-tremia (147). Twenty-six of the 44 hyponatremic patients(serum Na level 135 mmol/L) were treated with fluid restric-tion (1 L/24 h in normothermic patients). Cerebral infarctiondeveloped in 21 of the 26 fluid-restricted patients and in 27 ofthe 44 patients with a serum Na level less than 135 mEq/Lcompared with 19 of the 90 normonatremic patients (147).Another study of SAH patients demonstrated a negative Nabalance in all patients regardless of the serum Na level betweendays 2 and 3 after SAH (74). Repletion of volume has become

the standard treatment. A case report of a patient with CSWdescribed a recurrence of hyponatremia when the intravenousfluids were stopped (44). A study of 21 hyponatremic (serumNa level 130 mmol/L) neurosurgical patients and 3 controlscategorized patients into groups based on hematocrit, CVP,and total blood volume. Group A (hypovolemic and anemic)and group B (hypovolemic without anemia) were treated withisotonic saline and oral salt. Group A patients also receivedblood transfusions. No patients demonstrated hypervolemichyponatremia. The endpoints were 72 hours after entry or 2



FIGURE 3. Treatment of the syndrome of inappropriate antidiuretic hormone (SIADH). Symptoms are used toguide the treatment of SIADH. Patients with severe symptoms or subarachnoid hemorrhage (SAH) at risk ofvasospasm receive hypertonic saline; otherwise the cornerstone of SIADH treatment is fluid restriction. Acutehyponatremia and/or severe symptoms should have 6 mmol/L corrected over 6 hours or until severe symptomsimprove. The total correction of sodium (Na) should not exceed 8 mmol/L over 24 hours. Therefore, if 6 mmol/L iscorrected in 6 hours, Na should not be increased more than 2 mmol/L in the following 18 hours. The total correctionof Na is based on the Na deficit (def), which is calculated conservatively with the formula depicted. With improve-ment of symptoms, the patients can be moved to the less aggressive treatments in the algorithm until Na reaches 131

mmol/L. MS, mental status; sx, symptoms; sz, seizure; tx, transfer; ICU, intensive care unit; I/Os, in and out; wt,weight; N/V, nausea and vomiting; IMC, intermediate care unit; CVL, central venous line; inc, increase.


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consecutive serum Na values more than 130 mEq/L. All thepatients had correction of their hyponatremia (serum Na level130 mmol/L) within 72 hours (124). This study demonstratesthat hyponatremia develops in many neurosurgical patients inthe setting of volume depletion, and it responds to fluid andNa replacement.

The loss of fluid and Na can also be treated with fludrocor-tisone. Fludrocortisone is a synthetic adrenocortical steroidwith mineralocorticoid properties. Mineralocorticoids act onthe distal tubules of the kidney to enhance Na reabsorption.In the neurosurgical literature, this medication has mostlybeen studied in SAH patients (149, 150). A randomized, con-trolled trial in SAH patients showed that fludrocortisonereduced the frequency of a negative Na balance (63% versus38%; P 0.041). The treatment group did tend to have ahigher plasma volume compared with controls, although thiswas not statistically significant. More patients in the controlgroup developed cerebral ischemia (31% versus 22%; P 0.349). Consequently, more control patients were treated with

volume expanders, which may have masked the volume-expanding benefits of fludrocortisone (60). Another random-ized, controlled trial in SAH patients showed that 0.1 mg flu-drocortisone 3 times daily reduced the mean Na and waterintake, urinary Na excretion, and urine volume (P 0.01).The patients demonstrated a decrease in serum potassiumthat was easily corrected (85).

Similar studies demonstrated a benefit of the use of hydro-cortisone in SAH patients. One study randomized 28 SAHpatients to receive no hydrocortisone or 1200 mg/d of hydro-cortisone for 10 days (86). All patients were treated withreplacement of water and Na to prevent vasospasm. The treat-ment group never experienced a serum Na level less than 135mmol/L compared with 43% of the control group in whomhyponatremia developed. The treatment group also had lowerurine volume and lower infusion volume to maintain a CVP of8 to 12 cm H2O. Both were statistically significant. Failure tomaintain an adequate CVP was observed in 12 control patients(86%) compared with 3 treatment patients (21%) (P 0.05). Arandomized, controlled trial of hydrocortisone in 71 SAHpatients failed to show a statistically significant difference inoutcome between patients randomized to placebo and thosereceiving 1200 mg/d hydrocortisone for 10 days after surgery.Nevertheless, hydrocortisone did prevent excess Na excretionand urine volume. It also maintained the targeted serum Nalevel throughout the 14 days (70).

Numerous other smaller series or review papers were dis-

cussed by the panel (3, 14, 24, 46, 58, 68, 78, 95, 125). Havingreviewed the data, the expert panel made recommendationsfor the treatment of SIADH and CSW. These recommendationswere then used to create a paradigm for the treatment ofhyponatremia in neurosurgical patients at the University ofFlorida (Figs. 2 and 3).

Treatment Paradigm at the University of Florida

The treatment paradigm includes patients with CSW andSIADH with special consideration for SAH patients.


RAHMAN AND FRIEDMAN

Recommendation

Treatment of hyponatremia should be based on severity ofsymptoms (class III).

Na should not be corrected by more than 10 mmol/d(class III).

CSW should be treated with replacement of Na and intra-

venous fluids (class III). Fludrocortisone may be considered in the treatment of

hyponatremia in SAH patients at risk of vasospasm (class I). Hydrocortisone may be used to prevent natriuresis in SAH

patients (class I). Hyponatremia in SAH patients at risk of vasospasm should

not be treated with fluid restriction (class II). SIADH may be treated with urea, diuretics, lithium, deme-

clocycline, and/or fluid restriction (class III).

CONCLUSION

Hyponatremia in neurosurgical patients is a complex issue

that requires a systematic approach for evaluation and treat-ment. Multiple measures are necessary to determine ECF statusand thus the appropriate underlying diagnosis for hypona-tremia. The appropriate diagnosis is critical for patient out-comes because the treatment varies widely depending on thediagnosis. A standardized approach by a multidisciplinaryteam will most likely result in improved management ofhyponatremia in neurosurgical patients.

Using the best available evidence, we developed a diagnosticand treatment algorithm in an attempt to reduce variabilityamong treating physicians and ensure the best possible outcomes.Further testing of the effectiveness of these recommendations isunder way. Given the significant morbidity and mortality associ-

ated with hyponatremia, well-designed studies addressing theevaluation and treatment of hyponatremia are necessary.

DisclosureThe authors have no personal financial or institutional interest in any of the

drugs, materials, or devices described in this article.

REFERENCES

1. Adrogu HJ: Consequences of inadequate management of hyponatremia.

Am J Nephrol 25:240249, 2005.

2. Adrogu HJ, Madias NE: Hyponatremia. N Engl J Med 342:15811589, 2000.

3. Albanese A, Hindmarsh P, Stanhope R: Management of hyponatraemia in

patients with acute cerebral insults. Arch Dis Child 85:246251, 2001.

4. Anderson RJ, Chung HM, Kluge R, Schrier RW: Hyponatremia: A prospec-

tive analysis of its epidemiology and the pathogenetic role of vasopressin.Ann Intern Med 102:164168, 1985.

5. Anpalahan M: Chronic idiopathic hyponatremia in older people due to syn-

drome of inappropriate antidiuretic hormone secretion (SIADH) possibly

related to aging.J Am Geriatr Soc 49:788792, 2001.

6. Arieff AI: Hyponatremia, convulsions, respiratory arrest, and permanent

brain damage after elective surgery in healthy women. N Engl J Med

314:15291535, 1986.

7. Arieff AI: Management of hyponatraemia. BMJ 307:305308, 1993.

8. Arieff AI, Llach F, Massry SG: Neurological manifestations and morbidity of

hyponatremia: Correlation with brain water and electrolytes. Medicine

(Baltimore) 55:121129, 1976.


9/12

9. Asadollahi K, Beeching N, Gill G: Hyponatraemia as a risk factor for hospi-

tal mortality. QJM 99:877880, 2006.

10. Ashraf N, Locksley R, Arieff AI: Thiazide-induced hyponatremia associated

with death or neurologic damage in outpatients. Am J Med 70:11631168, 1981.

11. Atchison JW, Wachendorf J, Haddock D, Mysiw WJ, Gribble M, Corrigan JD:

Hyponatremia-associated cognitive impairment in traumatic brain injury.

Brain Inj 7:347352, 1993.

12. Ayus JC, Krothapalli RK, Arieff AI: Treatment of symptomatic hyponatremiaand its relation to brain damage. A prospective study. N Engl J Med

317:11901195, 1987.

13. Ayus JC, Wheeler JM, Arieff AI: Postoperative hyponatremic encephalopa-

thy in menstruant women. Ann Intern Med 117:891897, 1992.

14. Barsoum NR, Levine BS: Current prescriptions for the correction of hypona-

traemia and hypernatraemia: Are they too simple? Nephrol Dial Transplant

17:11761180, 2002.

15. Baylis PH: The syndrome of inappropriate antidiuretic hormone secretion.

Int J Biochem Cell Biol 35:14951499, 2003.

16. Bean JR: Neurosurgery in Transition: The Socioeconomic Transformation of Neurological

Surgery (Concepts in Neurosurgery). Lexington, KY, Williams & Wilkins, 1998.

17. Beck LH: Hypouricemia in the syndrome of inappropriate secretion of antid-

iuretic hormone. N Engl J Med 301:528530, 1979.

18. Bennani SL, Abouqal R, Zeggwagh AA, Madani N, Abidi K, Zekraoui A,

Kerkeb O: Incidence, causes and prognostic factors of hyponatremia in inten-

sive care [in French]. Rev Med Interne 24:224229, 2003.

19. Benvenga S: What is the pathogenesis of hyponatremia after subarachnoid

hemorrhage? Nat Clin Pract Endocrinol Metab 2:608609, 2006.

20. Berendes E, Walter M, Cullen P, Prien T, Van Aken H, Horsthemke J, Schulte

M, von Wild K, Scherer R: Secretion of brain natriuretic peptide in patients

with aneurysmal subarachnoid haemorrhage. Lancet 349:245249, 1997.

21. Betjes MG: Hyponatremia in acute brain disease: The cerebral salt wasting

syndrome. Eur J Intern Med 13:914, 2002.

22. Beukhof CM, Hoorn EJ, Lindemans J, Zietse R: Novel risk factors for hospi-

tal-acquired hyponatraemia: A matched case-control study. Clin Endocrinol

(Oxf) 66:367372, 2007.

23. Bissram M, Scott FD, Liu L, Rosner MH: Risk factors for symptomatic

hyponatraemia: The role of pre-existing asymptomatic hyponatraemia.

Intern Med J 37:149155, 2007.

24. Biswas M, Davies JS: Hyponatraemia in clinical practice. Postgrad Med J

83:373378, 2007.

25. Boscoe A, Paramore C, Verbalis JG: Cost of illness of hyponatremia in the

United States. Cost Eff Resour Alloc 4:10, 2006.26. Callewart CC, Minchew JT, Kanim LE, Tsai YC, Salehmoghaddam S, Dawson

EG, Delamarter RB: Hyponatremia and syndrome of inappropriate antidi-

uretic hormone secretion in adult spinal surgery. Spine (Phila Pa 1976) 19:

16741679, 1994.

27. Carlotti AP, Bohn D, Rutka JT, Singh S, Berry WA, Sharman A, Cusimano M,

Halperin ML: A method to estimate urinary electrolyte excretion in patients

at risk for developing cerebral salt wasting. J Neurosurg 95:420424, 2001.

28. Chin MH, Goldman L: Correlates of major complications or death in patients

admitted to the hospital with congestive heart failure. Arch Intern Med

156:18141820, 1996.

29. Chung HM, Kluge R, Schrier RW, Anderson RJ: Postoperative hyponatremia.

A prospective study. Arch Intern Med 146:333336, 1986.

30. Chung HM, Kluge R, Schrier RW, Anderson RJ: Clinical assessment of extra-

cellular fluid volume in hyponatremia. Am J Med 83:905908, 1987.

31. Clayton JA, Le Jeune IR, Hall IP: Severe hyponatraemia in medical in-

patients: Aetiology, assessment and outcome. QJM 99:505511, 2006.32. Cluitmans FH, Meinders AE: Management of severe hyponatremia: Rapid or

slow correction? Am J Med 88:161166, 1990.

33. Coenraad MJ, Bolk JH, Frlich M, Meinders AE: Plasma arginine vasopressin

and atrial natriuretic peptide concentration in patients with hyponatremia at

diagnosis and following treatment. Eur J Intern Med 18:221229, 2007.

34. Coenraad MJ, Meinders AE, Taal JC, Bolk JH: Hyponatremia in intracranial

disorders. Neth J Med 58:123127, 2001.

35. Coenraad MJ, Meinders AE, Vandenbroucke JP, Frlich M, Taal JC, Bolk JH:

Causes of hyponatremia in the Departments of Internal Medicine and

Neurosurgery. Eur J Intern Med 14:302309, 2003.

36. Cort JH: Cerebral salt wasting. Lancet 266:752754, 1954.



37. Cusick JF, Hagen TC, Findling JW: Inappropriate secretion of antidiuretic

hormone after transsphenoidal surgery for pituitary tumors. N Engl J Med

311:3638, 1984.

38. Damaraju SC, Rajshekhar V, Chandy MJ: Validation study of a central

venous pressure-based protocol for the management of neurosurgical

patients with hyponatremia and natriuresis. Neurosurgery 40:312317, 1997.

39. Decaux G: Treatment of the syndrome of inappropriate secretion of antidi-

uretic hormone by long loop diuretics. Nephron 35:8288, 1983.40. Decaux G, Soupart A: Treatment of symptomatic hyponatremia. Am J Med

Sci 326:2530, 2003.

41. Decaux G, Brimioulle S, Genette F, Mockel J: Treatment of the syndrome of inap-

propriate secretion of antidiuretic hormone by urea. Am J Med 69:99106, 1980.

42. Dellabarca C, Servilla KS, Hart B, Murata GH, Tzamaloukas AH: Osmotic

myelinolysis following chronic hyponatremia corrected at an overall rate

consistent with current recommendations. Int Urol Nephrol 37:171173, 2005.

43.Diringer MN, Zazulia AR: Hyponatremia in neurologic patients: Conse-

quences and approaches to treatment. Neurologist 12:117126, 2006.

44. Diringer M, Ladenson PW, Borel C, Hart GK, Kirsch JR, Hanley DF: Sodium

and water regulation in a patient with cerebral salt wasting. Arch Neurol

46:928930, 1989.

45. Diringer M, Ladenson PW, Stern BJ, Schleimer J, Hanley DF: Plasma atrial

natriuretic factor and subarachnoid hemorrhage. Stroke 19:11191124, 1988.

46. Docci D, Cremonini AM, Nasi MT, Baldrati L, Capponcini C, Giudicissi A,

Neri L, Feletti C: Hyponatraemia with natriuresis in neurosurgical patients.

Nephrol Dial Transplant 15:17071708, 2000.

47. Ellis SJ: Severe hyponatraemia: Complications and treatment. QJM

88:905909, 1995.

48. Ellison DH, Berl T: Clinical practice. The syndrome of inappropriate antidi-

uresis. N Engl J Med 356:20642072, 2007.

49. Fall PJ: Hyponatremia and hypernatremia. A systematic approach to causes

and their correction. Postgrad Med 107:7582; quiz 179, 2000.

50. Fichman MP, Vorherr H, Kleeman CR, Telfer N: Diuretic-induced hypona-

tremia. Ann Intern Med 75:853863, 1971.

51. Fox JL, Falik JL, Shalhoub RJ: Neurosurgical hyponatremia: The role of inap-

propriate antidiuresis.J Neurosurg 34:506514, 1971.

52. Fraser CL, Arieff AI: Epidemiology, pathophysiology, and management of

hyponatremic encephalopathy. Am J Med 102:6777, 1997.

53. Fraser JF, Stieg PE: Hyponatremia in the neurosurgical patient: Epidemiology,

pathophysiology, diagnosis, and management. Neurosurgery 59:222229, 2006.

54. Ghali JK, Koren MJ, Taylor JR, Brooks-Asplund E, Fan K, Long WA, Smith

N: Efficacy and safety of oral conivaptan: A V1A/V2 vasopressin receptorantagonist, assessed in a randomized, placebo-controlled trial in patients

with euvolemic or hypervolemic hyponatremia. J Clin Endocrinol Metab

91:21452152, 2006.

55. Gheorghiade M, Gottlieb SS, Udelson JE, Konstam MA, Czerwiec F, Ouyang

J, Orlandi C; Tolvaptan Investigators: Vasopressin v(2) receptor blockade

with tolvaptan versus fluid restriction in the treatment of hyponatremia. Am

J Cardiol 97:10641067, 2006.

56. Gill G, Huda B, Boyd A, Skagen K, Wile D, Watson I, van Heyningen C:

Characteristics and mortality of severe hyponatraemiaa hospital-based

study. Clin Endocrinol (Oxf) 65:246249, 2006.

57. Gross P, Reimann D, Neidel J, Dke C, Prospert F, Decaux G, Verbalis J,

Schrier RW: The treatment of severe hyponatremia. Kidney Int Suppl

64:S6S11, 1998.

58. Halperin ML, Bohn D: Clinical approach to disorders of salt and water bal-

ance. Emphasis on integrative physiology. Crit Care Clin 18:249272, 2002.

59. Harrigan MR: Cerebral salt wasting syndrome. Crit Care Clin 17:125138,2001.

60. Hasan D, Lindsay KW, Wijdicks EF, Murray GD, Brouwers PJ, Bakker WH,

van Gijn J, Vermeulen M: Effect of fludrocortisone acetate in patients with

subarachnoid hemorrhage. Stroke 20:11561161, 1989.

61. Hasan D, Wijdicks EF, Vermeulen M: Hyponatremia is associated with cere-

bral ischemia in patients with aneurysmal subarachnoid hemorrhage. Ann

Neurol 27:106108, 1990.

62. Helmy A, Vizcaychipi M, Gupta AK: Traumatic brain injury: Intensive care

management. Br J Anaesth 99:3242, 2007.

63. Hensen J, Henig A, Fahlbusch R, Meyer M, Boehnert M, Buchfelder M:

Prevalence, predictors and patterns of postoperative polyuria and hypona-


10/12

traemia in the immediate course after transsphenoidal surgery for pituitary

adenomas. Clin Endocrinol (Oxf) 50:431439, 1999.

64. Hirshberg B, Ben-Yehuda A: The syndrome of inappropriate antidiuretic

hormone secretion in the elderly. Am J Med 103:270273, 1997.

65. Hoorn EJ, Lindemans J, Zietse R: Development of severe hyponatraemia in

hospitalized patients: Treatment-related risk factors and inadequate manage-

ment. Nephrol Dial Transplant 21:7076, 2006.

66. Huda MS, Boyd A, Skagen K, Wile D, van Heyningen C, Watson I, Wong S,Gill G: Investigation and management of severe hyponatraemia in a hospital

setting. Postgrad Med J 82:216219, 2006.

67. Isotani E, Suzuki R, Tomita K, Hokari M, Monma S, Marumo F, Hirakawa K:

Alterations in plasma concentrations of natriuretic peptides and antidiuretic

hormone after subarachnoid hemorrhage. Stroke 25:21982203, 1994.

68. Janardhan V, Ougorets I, Katz JM, Wells-Roth D, Segal A, Lahm D, Riina H,

Gobin YP, Stieg PE: Prospective protocol for management of hyponatremia

in nontraumatic subarachnoid hemorrhage patients by hypertonic saline

(3%) infusion: P71. Stroke 36:451, 2005. (Presented at the 8th Joint Annual

Meeting of the AANS/CNS section on Cerebrovascular Surgery and the

ASITN, Feb. 14, 2005; New Orleans, LA.)

69. Janicic N, Verbalis JG: Evaluation and management of hypo-osmolality in

hospitalized patients. Endocrinol Metab Clin N Am 32:459481, vii, 2003.

70. Katayama Y, Haraoka J, Hirabayashi H, Kawamata T, Kawamoto K, Kitahara

T, Kojima J, Kuroiwa T, Mori T, Moro N, Nagata I, Ogawa A, Ohno K, Seiki

Y, Shiokawa Y, Teramoto A, Tominaga T, Yoshimine T: A randomized con-

trolled trial of hydrocortisone against hyponatremia in patients with

aneurysmal subarachnoid hemorrhage. Stroke 38:23732375, 2007.

71. Kern PA, Robbins RJ, Bichet D, Berl T, Verbalis JG: Syndrome of inappropri-

ate antidiuresis in the absence of arginine vasopressin. J Clin Endocrinol

Metab 62:148152, 1986.

72. Kubo Y, Ogasawara K, Kakino S, Kashimura H, Yoshida K, Ogawa A:

Cerebrospinal fluid adrenomedullin concentration correlates with hypona-

tremia and delayed ischemic neurological deficits after subarachnoid hem-

orrhage. Cerebrovasc Dis 25:164169, 2008.

73. Kumar S, Berl T: Sodium. Lancet 352:220228, 1998.

74. Kurokawa Y, Uede T, Ishiguro M, Honda O, Honmou O, Kato T, Wanibuchi

M: Pathogenesis of hyponatremia following subarachnoid hemorrhage due

to ruptured cerebral aneurysm. Surg Neurol 46:500508, 1996.

75. Laureno R, Karp BI: Myelinolysis after correction of hyponatremia. Ann

Intern Med 126:5762, 1997.

76. Lauriat SM, Berl T: The hyponatremic patient: Practical focus on therapy.J

Am Soc Nephrol 8:15991607, 1997.77. Levin ER, Gardner DG, Samson WK: Natriuretic peptides. N Engl J Med

339:321328, 1998.

78. Liamis G, Kalogirou M, Saugos V, Elisaf M: Therapeutic approach in patients

with dysnatraemias. Nephrol Dial Transplant 21:15641569, 2006.

79. Lin SH, Chau T, Wu CC, Yang SS: Osmotic demyelination syndrome after

correction of chronic hyponatremia with normal saline. Am J Med Sci

323:259262, 2002.

80. Lohr KN, Eleazer K, Mauskopf J: Health policy issues and applications for

evidence-based medicine and clinical practice guidelines. Health Policy

46:119, 1998.

81. Lolin Y, Jackowski A: Hyponatraemia in neurosurgical patients: Diagnosis

using derived parameters of sodium and water homeostasis. Br J Neurosurg

6:457466, 1992.

82. Maesaka JK, Gupta S, Fishbane S: Cerebral salt-wasting syndrome: Does it

exist? Nephron 82:100109, 1999.

83. McGee S, Abernethy WB 3rd, Simel DL: The rational clinical examination. Isthis patient hypovolemic?JAMA 281:10221029, 1999.

84. Milionis HJ, Liamis GL, Elisaf MS: The hyponatremic patient: A systematic

approach to laboratory diagnosis. CMAJ 166:10561062, 2002.

85. Mori T, Katayama Y, Kawamata T, Hirayama T: Improved efficiency of hyper-

volemic therapy with inhibition of natriuresis by fludrocortisone in patients

with aneurysmal subarachnoid hemorrhage.J Neurosurg 91:947952, 1999.

86. Moro N, Katayama Y, Kojima J, Mori T, Kawamata T: Prophylactic manage-

ment of excessive natriuresis with hydrocortisone for efficient hypervolemic

therapy after subarachnoid hemorrhage. Stroke 34:28072811, 2003.

87. Multz AS: Vasopressin dysregulation and hyponatremia in hospitalized

patients.J Intensive Care Med 22:216223, 2007.

88. Munger MA: New agents for managing hyponatremia in hospitalized

patients. Am J Health Syst Pharm 64:253265, 2007.

89. Musch W, Decaux G: Treating the syndrome of inappropriate ADH secretion

with isotonic saline. QJM 91:749753, 1998.

90. Musch W, Decaux G: Utility and limitations of biochemical parameters in the

evaluation of hyponatremia in the elderly. Int Urol Nephrol 32:475493, 2001.

91. Musch W, Thimpont J, Vandervelde D, Verhaeverbeke I, Berghmans T,

Decaux G: Combined fractional excretion of sodium and urea better predictsresponse to saline in hyponatremia than do usual clinical and biochemical

parameters. Am J Med 99:348355, 1995.

92. Nathan BR: Cerebral correlates of hyponatremia. Neurocrit Care 6:7278,

2007.

93. Naval NS, Stevens RD, Mirski MA, Bhardwaj A: Controversies in the manage-

ment of aneurysmal subarachnoid hemorrhage. Crit Care Med 34:511524, 2006.

94. Nelson PB, Seif SM, Maroon JC, Robinson AG: Hyponatremia in intracranial

disease: Perhaps not the syndrome of inappropriate secretion of antidiuretic

hormone (SIADH).J Neurosurg 55:938941, 1981.

95. Nguyen MK, Kurtz I: New insights into the pathophysiology of the dysnatrem-

ias: A quantitative analysis. Am J Physiol Renal Physiol 287:F172F180, 2004.

96. Nzerue CM, Baffoe-Bonnie H, You W, Falana B, Dai S: Predictors of outcome

in hospitalized patients with severe hyponatremia. J Natl Med Assoc

95:335343, 2003.

97. Oh MS, Carroll HJ: Disorders of sodium metabolism: Hypernatremia and

hyponatremia. Crit Care Med 20:94103, 1992.

98. Oh MS: Management of hyponatremia and clinical use of vasopressin antag-

onists. Am J Med Sci 333:101105, 2007.

99. Olson BR, Gumowski J, Rubino D, Oldfield EH: Pathophysiology of hypona-

tremia after transsphenoidal pituitary surgery.J Neurosurg 87:499507, 1997.

100. Olson BR, Rubino D, Gumowski J, Oldfield EH: Isolated hyponatremia after

transsphenoidal pituitary surgery.J Clin Endocrinol Metab 80:8591, 1995.

101. Olson DR, Buchan GC, Porter GA: The syndrome of inappropriate antidiuretic

hormone secretion; an unusual case. Arch Intern Med 124:741747, 1969.

102. Oster JR, Singer I: Hyponatremia, hyposmolality, and hypotonicity: Tables

and fables. Arch Intern Med 159:333336, 1999.

103. Oya S, Tsutsumi K, Ueki K, Kirino T: Reinduction of hyponatremia to treat

central pontine myelinolysis. Neurology 57:19311932, 2001.

104. Palmer BF: Hyponatremia in patients with central nervous system disease:

SIADH versus CSW. Trends Endocrinol Metab 14:182187, 2003.

105. Palmer BF, Gates JR, Lader M: Causes and management of hyponatremia.

Ann Pharmacother 37:16941702, 2003.

106. Passamonte PM: Hypouricemia, inappropriate secretion of antidiuretic hormone,and small cell carcinoma of the lung. Arch Intern Med 144:15691570, 1984.

107. Peruzzi WT, Shapiro BA, Meyer PR Jr, Krumlovsky F, Seo BW: Hypo-

natremia in acute spinal cord injury. Crit Care Med 22:252258, 1994.

108. Peters JP, Welt LG, Sims EA, Orloff J, Needham J: A salt-wasting syndrome

associated with cerebral disease. Trans Assoc Am Physicians 63:5764, 1950.

109. Qureshi AI, Suri MF, Sung GY, Straw RN, Yahia AM, Saad M, Guterman LR,

Hopkins LN: Prognostic significance of hypernatremia and hyponatremia

among patients with aneurysmal subarachnoid hemorrhage. Neurosurgery

50:749756, 2002.

110. Rabinstein AA, Wijdicks EF: Hyponatremia in critically ill neurological

patients. Neurologist 9:290300, 2003.

111. Reeder RF, Harbaugh RE: Administration of intravenous urea and normal

saline for the treatment of hyponatremia in neurosurgical patients.

J Neurosurg 70:201206, 1989.

112. Renneboog B, Musch W, Vandemergel X, Manto MU, Decaux G: Mild

chronic hyponatremia is associated with falls, unsteadiness, and attentiondeficits. Am J Med 119:71.e1e8, 2006.

113. Riggs JE: Neurologic manifestations of electrolyte disturbances. Neurol Clin

20:227239, vii, 2002.

114. Robertson GL: Thirst and vasopressin function in normal and disordered

states of water balance.J Lab Clin Med 101:351371, 1983.

115. Rossi J, Bayram M, Udelson JE, Lloyd-Jones D, Adams KF, Oconnor CM,

Stough WG, Ouyang J, Shin DD, Orlandi C, Gheorghiade M: Improvement

in hyponatremia during hospitalization for worsening heart failure is asso-

ciated with improved outcomes: Insights from the Acute and Chronic

Therapeutic Impact of a Vasopressin Antagonist in Chronic Heart Failure

(ACTIV in CHF) trial. Acute Card Care 9:8286, 2007.


RAHMAN AND FRIEDMAN


11/12

116. Saeed BO, Beaumont D, Handley GH, Weaver JU: Severe hyponatraemia:

Investigation and management in a district general hospital. J Clin Pathol

55:893896, 2002.

117. Sata A, Hizuka N, Kawamata T, Hori T, Takano K: Hyponatremia after transsphe-

noidal surgery for hypothalamo-pituitary tumors. Neuroendocrinology

83:117122, 2006.

118. Schrier RW, Gross P, Gheorghiade M, Berl T, Verbalis JG, Czerwiec FS,

Orlandi C; SALT Investigators: Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia. N Engl J Med 355:20992112, 2006.

119. Schwartz WB, Bennett W, Curelop S, Bartter FC: A syndrome of renal

sodium loss and hyponatremia probably resulting from inappropriate secre-

tion of antidiuretic hormone. 1957.J Am Soc Nephrol 12:28602870, 2001.

120. Sherlock M, OSullivan E, Agha A, Behan LA, Rawluk D, Brennan P, Tormey

W, Thompson CJ: The incidence and pathophysiology of hyponatraemia

after subarachnoid haemorrhage. Clin Endocrinol (Oxf) 64:250254, 2006.

121. Shimoda M, Yamada S, Yamamoto I, Tsugane R, Sato O: Atrial natriuretic

polypeptide in patients with subarachnoid haemorrhage due to aneurysmal

rupture. Correlation to hyponatremia. Acta Neurochir (Wien) 97:5361, 1989.

122. Sica DA, Culpepper RM: Severe hyponatremia in spinal cord injury. Am J

Med Sci 298:331333, 1989.

123. Singh S, Bohn D, Carlotti AP, Cusimano M, Rutka JT, Halperin ML: Cerebral

salt wasting: Truths, fallacies, theories, and challenges. Crit Care Med

30:25752579, 2002.

124. Sivakumar V, Rajshekhar V, Chandy MJ: Management of neurosurgicalpatients with hyponatremia and natriuresis. Neurosurgery 34:269274, 1994.

125. Smith DM, McKenna K, Thompson CJ: Hyponatraemia. Clin Endocrinol

(Oxf) 52:667678, 2000.

126. Smith D, Moore K, Tormey W, Baylis PH, Thompson CJ: Downward reset-

ting of the osmotic threshold for thirst in patients with SIADH. Am J Physiol

Endocrinol Metab 287:E1019E1023, 2004.

127. Snell DM, Bartley C: Osmotic demyelination syndrome following rapid cor-

rection of hyponatraemia. Anaesthesia 63:9295, 2008.

128. Sonnenblick M, Friedlander Y, Rosin AJ: Diuretic-induced severe hypona-

tremia. Review and analysis of 129 reported patients. Chest 103:601606, 1993.

129. Soupart A, Decaux G: Therapeutic recommendations for management of

severe hyponatremia: Current concepts on pathogenesis and prevention of

neurologic complications. Clin Nephrol 46:149169, 1996.

130. Soupart A, Gross P, Legros JJ, Alfoldi S, Annane D, Heshmati HM, Decaux G:

Successful long-term treatment of hyponatremia in syndrome of inappropri-

ate antidiuretic hormone secretion with satavaptan (SR121463B), an orally

active nonpeptide vasopressin V2-receptor antagonist. Clin J Am Soc Nephrol

1:11541160, 2006.

131. Soupart A, Ngassa M, Decaux G: Therapeutic relowering of the serum sodium

in a patient after excessive correction of hyponatremia. Clin Nephrol

51:383386, 1999.

132. Steele A, Gowrishankar M, Abrahamson S, Mazer CD, Feldman RD, Halperin

ML: Postoperative hyponatremia despite near-isotonic saline infusion: A phe-

nomenon of desalination. Ann Intern Med 126:2025, 1997.

133. Sterns RH: Severe symptomatic hyponatremia: Treatment and outcome. A

study of 64 cases. Ann Intern Med 107:656664, 1987.

134. Sterns RH, Riggs JE, Schochet SS Jr: Osmotic demyelination syndrome fol-

lowing correction of hyponatremia. N Engl J Med 314:15351542, 1986.

135. Takaku A, Shindo K, Tanaka S, Mori T, Suzuki J: Fluid and electrolyte distur-

bances in patients with intracranial aneurysms. Surg Neurol 11:349356, 1979.

136. Taylor SL, Tyrrell JB, Wilson CB: Delayed onset of hyponatremia after transsphe-

noidal surgery for pituitary adenomas. Neurosurgery 37:649654, 1995.

137. Tierney WM, Martin DK, Greenlee MC, Zerbe RL, McDonald CJ: The progno-sis of hyponatremia at hospital admission.J Gen Intern Med 1:380385, 1986.

138. Tisdall M, Crocker M, Watkiss J, Smith M: Disturbances of sodium in critically

ill adult neurologic patients: A clinical review. J Neurosurg Anesthesiol

18:5763, 2006.

139. Tomida M, Muraki M, Uemura K, Yamasaki K: Plasma concentrations of brain

natriuretic peptide in patients with subarachnoid hemorrhage. Stroke 29:

15841587, 1998.

140. Upadhyay A, Jaber BL, Madias NE: Incidence and prevalence of hypona-

tremia. Am J Med 119 [Suppl 1]:S30S35, 2006.

141. Verbalis JG: Adaptation to acute and chronic hyponatremia: Implications

for symptomatology, diagnosis, and therapy. Semin Nephrol 18:319, 1998.

142. Verbalis JG: Disorders of body water homeostasis. Best Pract Res ClinEndocrinol Metab 17:471503, 2003.

143. Vingerhoets F, de Tribolet N: Hyponatremia hypo-osmolarity in neurosurgi-

cal patients. Appropriate secretion of ADH and cerebral salt wasting

syndrome. Acta Neurochir (Wien) 91:5054, 1988.144. Walker V: Fluid balance disturbances in neurosurgical patients: Physiological

basis and definitions. Acta Neurochir Suppl (Wien) 47:95101, 1990.

145. Weinand ME, OBoynick PL, Goetz KL: A study of serum antidiuretic hor-mone and atrial natriuretic peptide levels in a series of patients with intracra-

nial disease and hyponatremia. Neurosurgery 25:781785, 1989.146. Wijdicks EF, Ropper AH, Hunnicutt EJ, Richardson GS, Nathanson JA: A

trial natriuretic factor and salt wasting after aneurysmal subarachnoid hem-

orrhage. Stroke 22:15191524, 1991.147. Wijdicks EF, Vermeulen M, Hijdra A, van Gijn J: Hyponatremia and cerebral

infarction in patients with ruptured intracranial aneurysms: Is fluid restric-tion harmful? Ann Neurol 17:137140, 1985.

148. Wijdicks EF, Vermeulen M, van Brummelen P, den Boer NC, van Gijn J:

Digoxin-like immunoreactive substance in patients with aneurysmal sub-arachnoid haemorrhage. Br Med J (Clin Res Ed) 294:729732, 1987.

149. Wijdicks EF, Vermeulen M, van Brummelen P, van Gijn J: The effect of fludro-cortisone acetate on plasma volume and natriuresis in patients with aneurys-

mal subarachnoid hemorrhage. Clin Neurol Neurosurg 90:209214, 1988.

150. Woo MH, Kale-Pradhan PB: Fludrocortisone in the treatment of subarachnoidhemorrhage-induced hyponatremia. Ann Pharmacother 31:637639, 1997.

151. Worthley LI, Thomas PD: Treatment of hyponatraemic seizures with intra-venous 29.2% saline. Br Med J (Clin Res Ed) 292:168170, 1986.

152. Yeates KE, Singer M, Morton AR: Salt and water: A simple approach to

hyponatremia. CMAJ 170:365369, 2004.153. Zada G, Liu CY, Fishback D, Singer PA, Weiss MH: Recognition and manage-

ment of delayed hyponatremia following transsphenoidal pituitary surgery.J Neurosurg 106:6671, 2007.

154. Zeltser D, Rosansky S, van Rensburg H, Verbalis JG, Smith N; Conivaptan

Study Group: Assessment of the efficacy and safety of intravenous conivap-tan in euvolemic and hypervolemic hyponatremia. Am J Nephrol 27:447

457, 2007.

155. Zerbe R, Stropes L, Robertson G: Vasopressin function in the syndrome ofinappropriate antidiuresis. Annu Rev Med 31:315327, 1980.

AcknowledgmentsWe especially thank Dr. Marian Limacher and Dr. Jane Douglas for assistance

with manuscript revision and preparation.

COMMENTS

In this excellent review article, Rahman and Friedman summarize thecurrent cumulative knowledge, as reported in the literature since1950, on the nature, evaluation, and treatment of hyponatremia attrib-utable to the syndromes of inappropriate antidiuretic hormone secre-tion (SIADH) and cerebral salt wasting (CSW), with special emphasison hyponatremia occurring in patients with subarachnoid hemorrhage(SAH). On the basis of a review of the pertinent literature and experi-ence with hyponatremic neurosurgical patients, a multidisciplinarypanel at the University of Florida devised a set of guidelines for theevaluation and treatment of hyponatremia at that institution.

The reader of this thoroughly researched article is informed as tothe societal impact of managing patients with hyponatremia (esti-mated annual cost, $3.6 billion), the prevalence of hyponatremia inthe neurosurgical patient population (estimated, in some series, to be50%), the mortality and morbidity associated with hyponatremia,and, finally, the evaluation and treatment of hyponatremia in patientswith SIADH and CSW.

For example, the authors cite reports from the literature showing thatthe mortality in patients with a serum Na level of less than 120 mmol/Lwas 25%, versus 9% mortality in patients with a serum Na level ofgreater than 120 mmol/L. As for morbidity, a reference cited by the




12/12

authors indicates that a Na level of 120 mmol/L is probably the criticallevel for development of seizures. As for the evaluation of hyponatremia,the authors suggest that the previously reported criteria for diagnosis ofSIADH (plasma osmolality 275 mOsm/kg, urine osmolality 100mOsm/Kg, clinical euvolemia, and absence of other causes of euvolemichyponatremia, such as hypothyroidism and hypocortisolism) are inade-quate to distinguish between SIADH and CSW. Instead, the authors feelthat the key to distinguishing between these 2 syndromes is determina-tion of the extracellular fluid level. To that end, they suggest a numberof clinical and laboratory studies, including, as indicated, such invasivestudies as placement of a central line to determine central venous pres-sure. Finally, the authors discuss the optimal treatment paradigm, includ-ing treatment of SIADH in patients with SAH.

On the basis of this critical review of the pertinent literature andtheir own experience, a multidisciplinary panel at the University ofFlorida developed several recommendations regarding the evaluationand treatment of hyponatremia in general and in patients with SAH inparticular. Several of these recommendations struck this reviewer asimportant: 1) hyponatremia of 131 mmol/L merits evaluation andtreatment; 2) hyponatremia should not be corrected more than 10mmol/L/d, especially in patients with chronic hyponatremia. Failure

to do so can lead to severe neurological complications, such as centralpontine myelinosis and osmotic demyelinating syndrome; 3) CSWshould be treated with replacement of Na and intravenously adminis-tered fluids; 4) corticosteroids may be used in hyponatremic SAHpatients at risk for vasospasm (fludrocortisone) and to prevent natri-uresis (hydrocortisone); 5) SAH patients with hyponatremia who are atrisk for vasospasm should not be treated with fluid restriction. Thisarticle is recommended reading for neurosurgeons, critical care special-ists, and endocrinologists.

Ivan S. Ciric

Evanston, Illinois

ahman and Friedman have provided an excellent review of theevaluation and management of hyponatremia in neurosurgical

patients. In their review, they emphasize the importance of hypona-tremia as a cause of excessive morbidity and mortality in neurosurgi-cal patients. The fact that treatment of the electrolyte abnormalityseems to improve prognosis indicates that hyponatremia itself isimportant in the pathogenesis of neurological impairment and is not

just a related biomarker of severity of illness.The section of the article dealing with evaluation emphasizes the dif-

ferential diagnosis and the difficulty in making an easy diagnosis ofSIADH versus CSW in many neurosurgical patients. It is disappointingthat unambiguous laboratory studies, such as natriuretic peptide orvasopressin determinations, have not been helpful in this differentialprocess, undoubtedly because of the complex interaction betweenmechanisms responsible for volume and osmoregulation.

Finally, the recommendations for managing hyponatremia in neu-rosurgical patients will be useful to clinicians dealing with this com-mon problem. Some of the recommendations will be controversial tosome, especially with regard to the use of hydrocortisone and fludro-cortisone in management. Recommendations regarding the use ofhypertonic saline solutions may also be somewhat controversial.

Clearly, the use of hypertonic saline is an extremely effective therapyfor many patients, but determining exactly when to use it and howto balance it with the alternative of fluid restriction in patients withSIADH requires the exercise of a great deal of judgment. Hopefully,newer agents such as conivaptan will further facilitate the manage-ment of this common condition. The authors have provided a schol-arly review and systematically applied it to the care of patients at theUniversity of Florida on the basis of their assessment of the availableevidence.

Ralph G. Dacey, Jr.

St. Louis, Missouri


RAHMAN AND FRIEDMAN

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