Advertisement
American Journal of Kidney Diseases

Treatment of Hyponatremic Encephalopathy With a 3% Sodium Chloride Protocol: A Case Series

Published:November 25, 2014DOI:https://doi.org/10.1053/j.ajkd.2014.09.021

      Background

      3% sodium chloride solution is the accepted treatment for hyponatremic encephalopathy, but evidence-based guidelines for its use are lacking.

      Study Design

      A case series.

      Setting & Participants

      Adult patients presenting to the emergency department of a university hospital with hyponatremic encephalopathy, defined as serum sodium level < 130 mEq/L with neurologic symptoms of increased intracranial pressure without other apparent cause, and treated with a continuous infusion of 500 mL of 3% sodium chloride solution over 6 hours through a peripheral vein.

      Predictors

      Hyponatremic encephalopathy defined as serum sodium level < 130 mEq/L with neurologic symptoms of increased intracranial pressure without other apparent cause.

      Outcomes

      Change in serum sodium level within 48 hours, improvement in neurologic symptoms, and clinical evidence of cerebral demyelination, permanent neurologic injury, or death within 6 months’ posttreatment follow-up.

      Results

      There were 71 episodes of hyponatremic encephalopathy in 64 individuals. Comorbid conditions were present in 86% of individuals. Baseline mean serum sodium level was 114.1 ± 0.8 (SEM) mEq/L and increased to 117.9 ± 1.3, 121.2 ± 1.2, 123.9 ± 1.0, and 128.3 ± 0.8 mEq/L at 3, 12, 24, and 48 hours following the initiation of 3% sodium chloride solution treatment, respectively. There was a marked improvement in central nervous system symptoms within hours of therapy in 69 of 71 (97%) episodes. There were 12 deaths, all of which occurred following the resolution of hyponatremic encephalopathy and were related to comorbid conditions, with 75% of deaths related to sepsis. No patient developed neurologic symptoms consistent with cerebral demyelination at any point during the 6-month follow-up period.

      Limitations

      Lack of a comparison group and follow-up neuroimaging studies. Number of cases is too small to provide definitive assessment of the safety of this protocol.

      Conclusions

      3% sodium chloride solution was effective in reversing the symptoms of hyponatremic encephalopathy in the emergency department without producing neurologic injury related to cerebral demyelination on long-term follow-up in this case series.

      Index Words

      Hyponatremia is the most common electrolyte abnormality in the inpatient and outpatient setting.
      • Hawkins R.C.
      Age and gender as risk factors for hyponatremia and hypernatremia.
      • Mohan S.
      • Gu S.
      • Parikh A.
      • Radhakrishnan J.
      Prevalence of hyponatremia and association with mortality: results from NHANES.
      Hyponatremic encephalopathy is the most serious complication of hyponatremia.
      • Ayus J.C.
      • Wheeler J.M.
      • Arieff A.I.
      Postoperative hyponatremic encephalopathy in menstruant women.
      • Ayus J.C.
      • Varon J.
      • Arieff A.I.
      Hyponatremia, cerebral edema, and noncardiogenic pulmonary edema in marathon runners.
      • Ayus J.C.
      • Arieff A.I.
      Chronic hyponatremic encephalopathy in postmenopausal women: association of therapies with morbidity and mortality.
      Significant risk factors for developing hyponatremic encephalopathy include female sex, hypoxia, and underlying central nervous system disease.
      • Ayus J.C.
      • Achinger S.G.
      • Arieff A.
      Brain cell volume regulation in hyponatremia: role of sex, age, vasopressin, and hypoxia.
      • Ayus J.C.
      • Armstrong D.
      • Arieff A.I.
      Hyponatremia with hypoxia: effects on brain adaptation, perfusion, and histology in rodents.
      • Moritz M.L.
      • Ayus J.C.
      New aspects in the pathogenesis, prevention, and treatment of hyponatremic encephalopathy in children.
      • Kalantar-Zadeh K.
      • Nguyen M.K.
      • Chang R.
      • Kurtz I.
      Fatal hyponatremia in a young woman after ecstasy ingestion.
      The symptoms of hyponatremic encephalopathy are largely related to cerebral edema.
      • Ayus J.C.
      • Wheeler J.M.
      • Arieff A.I.
      Postoperative hyponatremic encephalopathy in menstruant women.
      Hyponatremic encephalopathy constitutes a medical emergency because it might lead to death or permanent neurologic deterioration due to transtentorial herniation or respiratory arrest if untreated.
      • Ayus J.C.
      • Wheeler J.M.
      • Arieff A.I.
      Postoperative hyponatremic encephalopathy in menstruant women.
      • Ayus J.C.
      • Arieff A.I.
      Chronic hyponatremic encephalopathy in postmenopausal women: association of therapies with morbidity and mortality.
      • Arieff A.I.
      Hyponatremia, convulsions, respiratory arrest, and permanent brain damage after elective surgery in healthy women.
      According to the recent European Clinical Practice Guidelines, hypertonic saline solution is recommended for the treatment of hyponatremic encephalopathy regardless of whether it is acute or chronic.
      • Spasovski G.
      • Vanholder R.
      • Allolio B.
      • et al.
      Clinical practice guideline on diagnosis and treatment of hyponatraemia.
      They acknowledge that “the body of evidence to base recommendations on this topic was limited.”
      • Spasovski G.
      • Vanholder R.
      • Allolio B.
      • et al.
      Clinical practice guideline on diagnosis and treatment of hyponatraemia.
      The guidelines’ recommendation for hypertonic saline solution were based on 9 case series that varied widely in regard to the setting, symptoms, severity, duration, and therapy used to treat hyponatremic encephalopathy.
      • Spasovski G.
      • Vanholder R.
      • Allolio B.
      • et al.
      Clinical practice guideline on diagnosis and treatment of hyponatraemia.
      According to the guidelines, most case reports used a total of 500 mL of 3% sodium chloride solution. The guidelines recommend using repeated 150-mL boluses of hypertonic saline solution, but they acknowledge that “there is no evidence in published research to support this assertion.”
      • Spasovski G.
      • Vanholder R.
      • Allolio B.
      • et al.
      Clinical practice guideline on diagnosis and treatment of hyponatraemia.
      In this article, we evaluated the efficacy and safety of a uniform treatment protocol of 500 mL of 3% sodium chloride solution infused over 6 hours for the management of hyponatremic encephalopathy in the emergency department.

      Methods

      Study Participants

      This study was conducted from January 1, 1996, through July 1, 2007, in patients older than 18 years presenting to the emergency department at Hospital Professor Alejandro Posadas in Buenos Aires, Argentina, with symptoms of hyponatremic encephalopathy. Patients with hyponatremic encephalopathy were treated with 3% sodium chloride solution according to a protocol recommended by the Argentinian Society of Critical Care Medicine.
      • Bazerque F.
      • Kairiyama O.
      Hyponatremia.
      The protocol consisted of intravenous infusion of 500 mL of 3% sodium chloride solution administered over 6 hours through a large-bore intravenous cannula in conjunction with fluid restriction.
      Patients were eligible for the hypertonic saline solution protocol if they had serum sodium levels < 130 mEq/L with advanced signs of hyponatremic encephalopathy, such as headache, nausea, vomiting, mental status changes, delirium, confusion, stupor, tremor, asterixis, seizures, respiratory arrest, noncardiogenic pulmonary edema, or other evidence of increased intracranial pressure without other apparent cause. Patients were not candidates for this hypertonic saline solution protocol if they had overt hypovolemic hyponatremia, hypervolemic hyponatremia, chronic kidney disease (CKD) stage 5, or pseudohyponatremia or were having a spontaneous free-water diuresis following the administration of saline solution.
      Therapy was initiated in the emergency department within the first few hours of presentation in all patients. All patients received a total of 500 mL of 3% sodium chloride solution over a 6-hour period. Fluid restriction was instituted following the hypertonic saline solution infusion, with further therapy directed in consultation with the nephrology service. Baseline blood chemistry values were obtained prior to the administration of 3% sodium chloride solution, and serum sodium samples were drawn according to protocol at 3, 12, 24, and 48 hours, or more often at the physician’s discretion. An arterial blood gas Pao2 was recorded when available. Patient demographics, baseline serum chemistry test results, clinical symptoms of hyponatremia, and their duration were recorded. The comorbid conditions assessed were diabetes mellitus, HIV (human immunodeficiency virus) infection, a history of compulsive or uncontrolled alcohol use (alcoholism), chronic obstructive pulmonary disease, CKD stage 3 or 4, hypertension, left ventricular dysfunction, a history of tobacco use (smoking), cerebrovascular accident, acute myocardial infarction, an active neoplasm (cancer), and hypokalemia (potassium < 3.5 mEq/L). Kidney function was assessed at the time of hospital admission with serum creatinine level. The CKD-EPI (CKD Epidemiology Collaboration) creatinine equation was used to calculate estimated glomerular filtration rate. Patients were monitored monthly for 6 months following the episode of hyponatremic encephalopathy in order to assess adverse outcomes, including mortality and neurologic impairment.
      All patients who received the hypertonic saline solution protocol were included in the study. Subsequent episodes of hyponatremic encephalopathy were included if the episode occurred more than 6 months after the previous episode following complete neurologic recovery.
      The study was approved by the Institutional Review Board of the Hospital Professor Alejandro Posadas.

      Statistical Analysis

      All data are expressed as mean ± standard error of the mean, median, or proportions as appropriate. The Kolmogorov-Smirnov test was used to verify the normality of the study variables. Patients with a poor outcome (death or major neurologic sequelae) were compared with those without.
      The Kruskal-Wallis or nonparametric Friedman 1-way analysis of variance (ANOVA) was used to compare groups, and repeated-measures ANOVA was used to evaluate changes in serum sodium concentrations within the first 48 hours postadmission. Fisher exact test was used for comparison of count variables.
      A univariate logistic regression analysis was carried out on the first episode of hyponatremic encephalopathy to determine whether death or neurologic sequelae was a dependent variable on the following potential covariates: sex, age, hypertension, diabetes, left ventricular dysfunction, CKD, hypokalemia, alcoholism, or cancer. Odds ratios with the appropriate 2-sided 95% confidence intervals were reported. All tests were 2 sided, and P < 0.05 was considered statistically significant. The analysis was conducted with SPSS, version 19.0, statistical software (IBM).

      Results

      Study Participants

      There were 71 episodes of hyponatremic encephalopathy in 64 individuals, with 58 individuals having 1 episode each, 5 individuals having 2 each, and 1 individual having 3 episodes of hyponatremic encephalopathy. Twenty-nine individuals presented with seizure activity, 10 were stuporous, 5 were comatose, and 2 had neurogenic pulmonary edema. Patient demographics are reported in Table 1. There was equal distribution of men and women, and most (72%) patients were 65 years or older. The main causes of hyponatremia were syndrome of inappropriate secretion of antidiuretic hormone (SIADH; n = 39 [61%]), thiazide diuretics (hydrochlorothiazide; n = 22 [34%]), and severe symptomatic hypothyroidism (n = 3 [5%]).
      Table 1Demographics and Comorbid Conditions of Participants Having Hyponatremic Encephalopathy at Initial Presentation by Baseline Serum Sodium Tertiles
      Overall (n = 64)Na = 102-110 mEq/L (n = 22)Na = 111-117 mEq/L (n = 21)Na = 118-126 mEq/L (n = 21)
      Demographics
       Age (y)68.0 ± 2.071.7 ± 3.365.1 ± 3.866.9 ± 3.3
       Sex (M/F)30/348/1410/1112/9
       Symptom duration preadmission (h)85.3 ± 9.272.7 ± 12.888.4 ± 18.584.2 ± 19.5
      Causes of hyponatremia
       SIADH39121215
       Thiazides22994
       Hypothyroidism3102
      Laboratory values
       Creatinine (mg/dL)0.93 ± 0.050.91 ± 0.070.92 ± 0.060.97 ± 0.11
       Sodium (mEq/L)113.8 ± 0.8106.3 ± 0.6114.5 ± 0.4121.4 ± 0.6
       Potassium (mEq/L)4.1 ± 0.14.2 ± 0.23.7 ± 0.34.3 ± 0.2
       Chloride (mEq/L)79.8 ± 1.373.4 ± 1.278.5 ± 2.287.4 ± 1.4
       eGFR (mL/min/1.73 m2)77.8 ± 3.474.7 ± 4.779.8 ± 5.679.2 ± 7.4
      Comorbid conditions
       Diabetes14644
       HIV3012
       Alcoholism5320
       COPD3102
       CKD stages 3 or 44112
       Hypertension44181214
       LVD221066
       Smoking13454
       CVA6015
       Acute MI3021
       Cancer10433
      Median Charlson score
      Charlson Comorbidity Index predicts 10-year mortality for a patient who may have a range of comorbid conditions: 0 points (none), 1-2 points (low), 3-4 points (moderate), and >5 points (high).
      2.02.02.02.0
      Note: Values for categorical variables are given as number; values for continuous variables, as mean ± standard error of the mean. Conversion factor for serum creatinine in mg/dL to μmol/L, ×88.4.
      Abbreviations: CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; CVA, cerebrovascular accident; eGFR, estimated glomerular filtration rate; HIV, human immunodeficiency virus; LVD, left ventricular dysfunction; MI, myocardial infarction; Na, sodium; SIADH, syndrome of inappropriate secretion of antidiuretic hormone.
      a Charlson Comorbidity Index predicts 10-year mortality for a patient who may have a range of comorbid conditions: 0 points (none), 1-2 points (low), 3-4 points (moderate), and >5 points (high).
      Comorbid conditions were present in 56 of 64 (88%) individuals. The most common comorbid conditions were hypertension (n = 45 [70%]), a history of left ventricular dysfunction (n = 23 [36%]), diabetes (n = 14 [22%]), smoking (n = 13 [20%]), and cancer (n = 10 [16%]). Four individuals had a history of alcoholism.

      Patient Outcome

      All individuals experienced symptoms attributable to hyponatremic encephalopathy, which ranged in duration from 4 hours to 15 days (median, 48 hours) prior to admission. Seventy-five percent presented to medical attention within 72 hours of the first symptom of hyponatremic encephalopathy. Baseline serum sodium level for the 71 episodes of hyponatremic encephalopathy was 114.1 ± 0.8 mEq/L and increased to 117.9 ± 1.3, 121.2 ± 1.2, 123.9 ± 1.0, and 128.3 ± 0.8 mEq/L at 3, 12, 24, and 48 hours following the initiation of 3% sodium chloride solution treatment, respectively. The increase in serum sodium level in response to 3% sodium chloride solution is shown in Fig 1. There was no significant difference in serum sodium concentrations during the first 48 hours of therapy between patients with and without adverse outcome or those with and without SIADH. Five individuals had significant overcorrection of hyponatremia, with change in serum sodium level ≥ 25 mEq/L 48 hours after admission (change in serum sodium level range, 25-32 mEq/L). The cause of hyponatremia was related to the use of thiazide diuretics in 3 and SIADH in 2 of these individuals, 2 of whom additionally had severe hypokalemia (potassium, 1.2 and 2.7 mEq/L). Desmopressin acetate was not used in any patient to prevent overcorrection of hyponatremia. No patient developed neurologic symptoms consistent with cerebral demyelination.
      Figure thumbnail gr1
      Figure 1Change in serum sodium levels over 48 hours in response to 500 mL of 3% sodium chloride solution administered over 6 hours in 64 patients with 71 episodes of hyponatremic encephalopathy. Results reported as mean and standard error of the mean.
      There was marked improvement in central nervous system symptoms within a few hours of initiation of treatment with 3% sodium chloride solution in 69 of 71 (97%) treated episodes, with complete neurologic recovery at 48 hours following the initiation of treatment. Two patients (Table 2; patients 2 and 7) did not respond to therapy and had permanent neurologic impairment with changes in serum sodium level of 2 and 3 mEq/L in the first 12 hours of therapy, respectively, and 7 mEq/L for both at 48 hours. Both patients presented with seizures, and one remained stuporous and the other was comatose following therapy.
      Table 2Main Characteristics of Patients With Hyponatremic Encephalopathy Having an Adverse Outcome
      Pt No.SexAge (y)CauseComorbid ConditionsSymptom Duration Preadmission (h)Charlson Score
      Charlson Comorbidity Index predicts 10-year mortality for a patient who may have a range of comorbid conditions: 0 points (none), 1-2 points (low), 3-4 points (moderate), and >5 points (high).
      Scr (mg/dL)eGFR (mL/min/1.73 m2)Serum Na (mEq/L)ΔNa
      Change in serum sodium level from baseline to the 48-hour time point.
      (mEq/L)
      Baseline Serum K (mEq/L)Pao2 at Admission (mm Hg)Symptoms Resolved
      Resolution of hyponatremic symptoms.
      Survival (d)Final EventOutcome
      Baseline12 h24 h48 h
      1F82HypoTCOPD, HTN, CVA7262.022.712412612913284.252Yes18ArrhythmiaDeath
      2M76SIADHCVA4821.164.912012312712775.357NoBrain damageNeurologic deficit
      3M55SIADHAlcololism, HTN7220.7106.2107110115125183.9NAYes11SepsisDeath
      4M55SIADHDM, COPD, HTN, CVA, cancer48120.8100.6121127131136154.6NAYes4SepsisDeath
      5M42SIADHHIV9660.6124.011812112112135.4NAYes11SepsisDeath
      6M79SIADHHTN, LVD4820.695.610411311712824NA43Yes130SepsisDeath
      7M85SIADHNone2400.691.71261281311337NA69NoBrain damageNeurologic deficit
      8M65SIADHAlcoholismNA30.6105.511412412813319NANAYes15SepsisDeath
      9M56SIADHNoneNA00.4132.811912012112124.691Yes5SepsisDeath
      10M29SIADHAlcoholismNA10.6135.9116131141134252.7NAYes135SepsisDeath
      11F75SIADHLVD, HTN1421.055.2103111115126235.9NA6ArrhythmiaDeath
      12F77HCTZCKD, HTN16832.319.9104109111122185.798Yes21SepsisDeath
      13M65SIADHAlcoholismNA10.6105.5111114116125143.499Yes136SepsisDeath
      14M77SIADHDM, cancer24101.352.611612012413014NA87Yes10ArrhythmiaDeath
      65.5 ± 4.4
      Mean ± standard error of the mean of all cases.
      3.57 ± 0.9
      Mean ± standard error of the mean of all cases.
      0.94 ± 0.15
      Mean ± standard error of the mean of all cases.
      86.7 ± 10.1
      Mean ± standard error of the mean of all cases.
      114.5 ± 2.0
      Mean ± standard error of the mean of all cases.
      119.7 ± 3.0
      Mean ± standard error of the mean of all cases.
      122.7 ± 2.5
      Mean ± standard error of the mean of all cases.
      127.6 ± 1.4
      Mean ± standard error of the mean of all cases.
      14.1 ± 2.0
      Mean ± standard error of the mean of all cases.
      4.4 ± 0.3
      Mean ± standard error of the mean of all cases.
      74 ± 7.3
      Mean ± standard error of the mean of all cases.
      38.6 ± 15.1
      Mean ± standard error of the mean of all cases.
      Note: Conversion factor for Scr in mg/dL to μmol/L, ×88.4.
      Abbreviations and definitions: Adverse outcome, death or permanent neurologic deficit; CKD, chronic kidney disease stage 3 or 4; COPD, chronic obstructive pulmonary disease; CVA, cerebrovascular accident; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; HCTZ, hydrochlorothiazide; HIV, human immunodeficiency virus; HTN, hypertension; HypoT, hypothyroidism; K, potassium; LVD, left ventricular dysfunction; Na, sodium; NA, not available; Pt, patient; Scr, serum creatinine; SIADH, syndrome of inappropriate secretion of antidiuretic hormone.
      a Charlson Comorbidity Index predicts 10-year mortality for a patient who may have a range of comorbid conditions: 0 points (none), 1-2 points (low), 3-4 points (moderate), and >5 points (high).
      b Change in serum sodium level from baseline to the 48-hour time point.
      c Resolution of hyponatremic symptoms.
      d Mean ± standard error of the mean of all cases.
      Fourteen (23%) individuals had adverse outcomes (Table 2), with 12 deaths and 2 patients having a permanent neurologic deficit. All adverse outcomes occurred following a single episode of hyponatremic encephalopathy. All 12 deaths occurred from causes unrelated to hyponatremia following the correction of serum sodium level and subsequent neurologic improvement. Mean survival for the 12 patients who died was 38.5 ± 15 days (Table 2). Male sex and alcoholism were associated with adverse outcome on univariate analysis, whereas hypokalemia and thiazide diuretic use were not (Table 3).
      Table 3Univariate Logistic Regression Analysis of Risk Factors for an Adverse Outcome in Individuals With Hyponatremic Encephalopathy
      VariableOR (95% CI)P
      Cancer1.13 (0.2-6.3)0.9
      Male sex4.49 (1.24-16.1)0.02
      LVD0.49 (0.12-1.96)0.3
      Diabetes0.81 (0.15-4.29)0.8
      Hyponatremia unrelated to thiazides4.71 (0.96-23.1)0.05
      HTN0.49 (0.15-1.58)0.2
      Age ≥ 65 y0.70 (0.20-2.44)0.6
      Alcoholism17.8 (1.81-175.4)0.01
      Hypokalemia2.19 (0.45-10.7)0.4
      Abbreviations and definitions: Adverse outcome, death or permanent neurological deficit; CI, confidence interval; HTN, hypertension; hypokalemia, serum potassium < 3.5 mEq/L; LVD, left ventricular dysfunction; OR, odds ratio.
      No patient developed neurologic symptoms consistent with cerebral demyelination at any point during the 6-month follow-up period. There also were no complications directly related to the infusion, such as a local infusion reaction, pulmonary edema, or hypertension.

      Discussion

      This article reports a uniform treatment protocol with 500 mL of intravenous 3% sodium chloride solution over 6 hours for the management of hyponatremic encephalopathy. To our knowledge, this is the largest study of its kind evaluating a uniform treatment protocol and the only study with long-term follow-up. This study demonstrated that 3% sodium chloride solution was effective in reversing the symptoms of hyponatremic encephalopathy. There was a favorable response to treatment with 3% sodium chloride solution, with prompt reversal of symptoms of hyponatremic encephalopathy, in 97% of episodes. There were no apparent cases of neurologic injury related to overcorrection of hyponatremia. The hypertonic saline solution was well tolerated through a peripheral vein without reports of phlebitis or tissue necrosis, and there were no episodes of acute hypertension or pulmonary congestion related to the 3% sodium chloride solution infusion.
      There were only 2 episodes in which response to therapy may have been inadequate (Table 2; patients 2 and 7). These 2 patients may have experienced long-term neurologic injury attributable to hyponatremic encephalopathy. In both cases, the patients had concomitant hypoxia, which is a known risk factor for brain damage.
      • Ayus J.C.
      • Wheeler J.M.
      • Arieff A.I.
      Postoperative hyponatremic encephalopathy in menstruant women.
      • Ayus J.C.
      • Armstrong D.
      • Arieff A.I.
      Hyponatremia with hypoxia: effects on brain adaptation, perfusion, and histology in rodents.
      • Kokko J.P.
      Symptomatic hyponatremia with hypoxia is a medical emergency.
      These 2 patients also had insufficient correction of hyponatremia because the absolute change in serum sodium level was only 2 to 3 mEq/L at 12 hours and 7 mEq/L at 48 hours. These 2 patients did not have the expected increase in serum sodium levels that would be predicted after receiving 3% sodium chloride solution. Both patients had SIADH, and it is known that the response to therapy can be less than expected due to concentrated and hypertonic urine.
      • Musch W.
      • Decaux G.
      Treating the syndrome of inappropriate ADH secretion with isotonic saline.
      • Elsaesser T.F.
      • Pang P.S.
      • Malik S.
      • Chiampas G.T.
      Large-volume hypertonic saline therapy in endurance athlete with exercise-associated hyponatremic encephalopathy.
      It also is possible that these individuals had larger than expected total-body water, which may have contributed to a less than predicted response to therapy. These 2 patients likely would have benefited from either a larger quantity of 3% sodium chloride solution or additional therapy to antagonize the renal concentration and promote urinary free-water loss, such as a loop diuretic or V2 antagonist.
      • Hantman D.
      • Rossier B.
      • Zohlman R.
      • Schrier R.
      Rapid correction of hyponatremia in the syndrome of inappropriate secretion of antidiuretic hormone. An alternative treatment to hypertonic saline.
      • Schrier R.W.
      • Gross P.
      • Gheorghiade M.
      • et al.
      Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia.
      The overall mortality rate for the study was 19%, which is similar to most other reports in the literature.
      • Ayus J.C.
      • Arieff A.I.
      Chronic hyponatremic encephalopathy in postmenopausal women: association of therapies with morbidity and mortality.
      • Huda M.S.
      • Boyd A.
      • Skagen K.
      • et al.
      Investigation and management of severe hyponatraemia in a hospital setting.
      • Hoorn E.J.
      • Lindemans J.
      • Zietse R.
      Development of severe hyponatraemia in hospitalized patients: treatment-related risk factors and inadequate management.
      • Nzerue C.M.
      • Baffoe-Bonnie H.
      • You W.
      • Falana B.
      • Dai S.
      Predictors of outcome in hospitalized patients with severe hyponatremia.
      • Vaishya R.
      • Kaur J.
      • Seema
      • Chopra S.
      • Jaswal S.
      Mortality predictors in severe hyponatraemia in emergency inpatients.
      • Clayton J.A.
      • Le Jeune I.R.
      • Hall I.P.
      Severe hyponatraemia in medical in-patients: aetiology, assessment and outcome.
      All deaths occurred after correction of hyponatremia and resolution of neurologic symptoms. None of the deaths could be attributed directly to hyponatremia. Only male sex and alcoholism were associated with death or poor neurologic outcome following univariate analysis. Alcoholism is a well-recognized risk factor for developing cerebral demyelination following the correction of hyponatremia, yet none of the patients appeared to develop symptoms consistent with this.
      • Ayus J.C.
      • Krothapalli R.K.
      • Arieff A.I.
      Treatment of symptomatic hyponatremia and its relation to brain damage. A prospective study.
      • Hagiwara K.
      • Okada Y.
      • Shida N.
      • Yamashita Y.
      Extensive central and extrapontine myelinolysis in a case of chronic alcoholism without hyponatremia: a case report with analysis of serial MR findings.
      All deaths were unrelated to hyponatremic encephalopathy (Table 2) and primarily were due to sepsis, as has been reported by others.
      • Hoorn E.J.
      • Lindemans J.
      • Zietse R.
      Development of severe hyponatraemia in hospitalized patients: treatment-related risk factors and inadequate management.
      • Nzerue C.M.
      • Baffoe-Bonnie H.
      • You W.
      • Falana B.
      • Dai S.
      Predictors of outcome in hospitalized patients with severe hyponatremia.
      • Rao M.Y.
      • Sudhir U.
      • Anil Kumar T.
      • Saravanan S.
      • Mahesh E.
      • Punith K.
      Hospital-based descriptive study of symptomatic hyponatremia in elderly patients.
      Numerous studies have demonstrated that hyponatremia is an independent risk factor for mortality.
      • Hoorn E.J.
      • Zietse R.
      Hyponatremia and mortality: moving beyond associations.
      • Corona G.
      • Giuliani C.
      • Parenti G.
      • et al.
      Moderate hyponatremia is associated with increased risk of mortality: evidence from a meta-analysis.
      The reasons for this are not entirely clear, but some insights into the potential mechanism are evolving. It now is recognized that even mild levels of chronic hyponatremia cause subtle cognitive impairment.
      • Renneboog B.
      • Musch W.
      • Vandemergel X.
      • Manto M.U.
      • Decaux G.
      Mild chronic hyponatremia is associated with falls, unsteadiness, and attention deficits.
      It also is known that hyponatremia affects bone metabolism and leads to bone demineralization.
      • Ayus J.C.
      • Negri A.L.
      • Kalantar-Zadeh K.
      • Moritz M.L.
      Is chronic hyponatremia a novel risk factor for hip fracture in the elderly?.
      Recent studies have shown that sodium balance plays an important role in immunity, with a hypertonic interstitial water content being necessary for lymphoid tissue to mount an immune response.
      • Kleinewietfeld M.
      • Manzel A.
      • Titze J.
      • et al.
      Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells.
      • Wu C.
      • Yosef N.
      • Thalhamer T.
      • et al.
      Induction of pathogenic TH17 cells by inducible salt-sensing kinase SGK1.
      • van der Meer J.W.
      • Netea M.G.
      A salty taste to autoimmunity.
      This may help explain why sepsis is a frequent cause of death in patients with hyponatremia.
      • Rao M.Y.
      • Sudhir U.
      • Anil Kumar T.
      • Saravanan S.
      • Mahesh E.
      • Punith K.
      Hospital-based descriptive study of symptomatic hyponatremia in elderly patients.
      • Mandai S.
      • Kuwahara M.
      • Kasagi Y.
      • et al.
      Lower serum sodium level predicts higher risk of infection-related hospitalization in maintenance hemodialysis patients: an observational cohort study.
      For these reasons, hyponatremia could adversely affect outcome independent of hyponatremic encephalopathy, and treatment in theory could improve outcome.
      Since embarking on this study, we proposed the use of the intermittent 100-mL 3% sodium chloride solution bolus to treat hyponatremic encephelopathy.
      • Ayus J.C.
      • Arieff A.
      • Moritz M.L.
      Hyponatremia in marathon runners.
      • Moritz M.L.
      • Ayus J.C.
      100 cc 3% sodium chloride bolus: a novel treatment for hyponatremic encephalopathy.
      However, this approach has yet to be validated in large-scale studies. A similar approach has since been adopted by 3 European societies, representing intensive care medicine, endocrinology, and nephrology, when they convened and published clinical practice guidelines in 2014 on the diagnosis and treatment of hyponatremia.
      • Spasovski G.
      • Vanholder R.
      • Allolio B.
      • et al.
      Clinical practice guideline on diagnosis and treatment of hyponatraemia.
      They recommend treating hyponatremic encephalopathy with moderate to severe symptoms, whether acute or chronic, by administering 3 consecutive 150-mL boluses of 3% sodium chloride solution over 20 minutes each or until a target of a 5-mEq/L increase in serum sodium concentration in 1 hour is achieved. Those recommendations are based largely on 9 case series reporting on the use of hypertonic saline solution as treatment for hyponatremic encephalopathy.
      • Spasovski G.
      • Vanholder R.
      • Allolio B.
      • et al.
      Clinical practice guideline on diagnosis and treatment of hyponatraemia.
      Those series varied widely in regard to the setting, symptoms, severity, duration, and therapy used. The total amount of 3% sodium chloride solution administered in this study is similar to the total volume recommended in the European guidelines, and the average change in serum sodium level at 12 hours of 7 mEq/L is in keeping with their recommendations.
      One of the main concerns with treating severe chronic hyponatremia is the potential for developing cerebral demyelination. Animal studies have demonstrated that large and abrupt increases in serum sodium levels in chronically hyponatremic animals results in astrocytic injury and subsequent demyelination.
      • Kleinschmidt-DeMasters B.K.
      • Norenberg M.D.
      Rapid correction of hyponatremia causes demyelination: relation to central pontine myelinolysis.
      • Ayus J.C.
      • Krothapalli R.K.
      • Armstrong D.L.
      Rapid correction of severe hyponatremia in the rat: histopathological changes in the brain.
      Humans rarely undergo the large changes in serum sodium levels that are generated in laboratory animals, but they frequently are subject to numerous other risk factors for demyelination that these animals are not, such as hypoxia, hypokalemia, hypophosphatemia, malnutrition, and liver disease.
      • Ayus J.C.
      • Wheeler J.M.
      • Arieff A.I.
      Postoperative hyponatremic encephalopathy in menstruant women.
      • Ayus J.C.
      • Krothapalli R.K.
      • Arieff A.I.
      Treatment of symptomatic hyponatremia and its relation to brain damage. A prospective study.
      • Lohr J.W.
      Osmotic demyelination syndrome following correction of hyponatremia: association with hypokalemia.
      • Turnbull J.
      • Lumsden D.
      • Siddiqui A.
      • Lin J.P.
      • Lim M.
      Osmotic demyelination syndrome associated with hypophosphataemia: 2 cases and a review of literature.
      This makes it difficult to determine the relationship between change in serum sodium level and demyelination in humans. We did not find clinical evidence of cerebral demyelination, but this case series may have been too small to detect this rare potential complication of chronic hyponatremia.
      One of the limitations of this study is that it neither was a randomized trial nor had different treatment arms or a comparison. This study was not randomized because it would be unethical to withhold therapy with 3% sodium chloride solution in patients with symptomatic hyponatremia and to treat them with fluid restriction alone. It previously has been demonstrated in a nonrandomized prospective study that fluid restriction alone is ineffective in treating hyponatremic encephalopathy and is associated with high morbidity and mortality.
      • Ayus J.C.
      • Arieff A.I.
      Chronic hyponatremic encephalopathy in postmenopausal women: association of therapies with morbidity and mortality.
      There was no comparison group because intravenous 3% sodium chloride solution is the only accepted treatment for hyponatremic encephalopathy. This study did not have different treatment arms of 3% sodium chloride solution because the primary aim of the study was to establish whether a uniform treatment protocol could be used effectively and safely for the management of hyponatremic encephalopathy, and not to establish the ideal treatment protocol. To our knowledge, there have been no randomized trials evaluating hypertonic saline solution for the management of hyponatremic encephalopathy, and an ideal protocol has not been validated. Other limitations of this study were that it was single center and restricted to patients with outpatient hyponatremia, and the patient population was not ethnically diverse. Therefore, these results may not be generalizable in a different patient population or hospital setting. We also do not have neuroimaging studies to absolutely exclude the development of demyelinating lesions, but the absence of adverse neurologic outcome on long-term follow-up is highly suggestive that there were no clinically significant demyelinating lesions. Given the rarity of cerebral demyelination, the number of cases in this study may have been too small to provide definitive assessment of the safety of this protocol.
      In conclusion, this study demonstrates that a uniform treatment protocol with 3% sodium chloride solution is effective in reversing the symptoms of hyponatremic encephalopathy in the emergency department. There were no local reactions or evidence of cerebral demyelination in this relatively small cohort.

      Acknowledgements

      We acknowledge the help and support of the emergency department and nephrology division physicians and nursing staff at Hospital Alejandro Posadas in conducting this study. We thank Karen Branstetter for editing the manuscript.
      Data in this manuscript were presented in part at the American Society of Nephrology’s Renal Week 2008, November 6-9, Philadelphia, PA.
      Support: None.
      Financial Disclosure: Drs Moritz and Ayus have received consulting fees from Otsuka Pharmaceuticals. The other authors declare that they have no relevant financial interests.
      Contributions: Research idea and study design: MLM, JCA, DC; data acquisition: DC, FB; data analysis/interpretation: MLM, JCA, DC, RH; statistical analysis: RH, CDG, MLM, JCA. Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved. JCA takes responsibility that this study has been reported honestly, accurately, and transparently; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned have been explained.

      References

        • Hawkins R.C.
        Age and gender as risk factors for hyponatremia and hypernatremia.
        Clin Chim Acta. 2003; 337: 169-172
        • Mohan S.
        • Gu S.
        • Parikh A.
        • Radhakrishnan J.
        Prevalence of hyponatremia and association with mortality: results from NHANES.
        Am J Med. 2013; 126: 1127-1137.e1121
        • Ayus J.C.
        • Wheeler J.M.
        • Arieff A.I.
        Postoperative hyponatremic encephalopathy in menstruant women.
        Ann Intern Med. 1992; 117: 891-897
        • Ayus J.C.
        • Varon J.
        • Arieff A.I.
        Hyponatremia, cerebral edema, and noncardiogenic pulmonary edema in marathon runners.
        Ann Intern Med. 2000; 132: 711-714
        • Ayus J.C.
        • Arieff A.I.
        Chronic hyponatremic encephalopathy in postmenopausal women: association of therapies with morbidity and mortality.
        JAMA. 1999; 281: 2299-2304
        • Ayus J.C.
        • Achinger S.G.
        • Arieff A.
        Brain cell volume regulation in hyponatremia: role of sex, age, vasopressin, and hypoxia.
        Am J Physiol Renal Physiol. 2008; 295: F619-F624
        • Ayus J.C.
        • Armstrong D.
        • Arieff A.I.
        Hyponatremia with hypoxia: effects on brain adaptation, perfusion, and histology in rodents.
        Kidney Int. 2006; 69: 1319-1325
        • Moritz M.L.
        • Ayus J.C.
        New aspects in the pathogenesis, prevention, and treatment of hyponatremic encephalopathy in children.
        Pediatr Nephrol. 2010; 25: 1225-1238
        • Kalantar-Zadeh K.
        • Nguyen M.K.
        • Chang R.
        • Kurtz I.
        Fatal hyponatremia in a young woman after ecstasy ingestion.
        Nat Clin Pract Nephrol. 2006; 2 (quiz 289): 283-288
        • Arieff A.I.
        Hyponatremia, convulsions, respiratory arrest, and permanent brain damage after elective surgery in healthy women.
        N Engl J Med. 1986; 314: 1529-1535
        • Spasovski G.
        • Vanholder R.
        • Allolio B.
        • et al.
        Clinical practice guideline on diagnosis and treatment of hyponatraemia.
        Nephrol Dial Transplant. 2014; 29 Suppl 2: i1-i39
        • Bazerque F.
        • Kairiyama O.
        Hyponatremia.
        in: Intensiva Sociedad Argentina de Critical Care Terapia Intensiva. 3rd ed. Editorial Médica Panamericana, Buenos Aires, Argentina2000: 630
        • Kokko J.P.
        Symptomatic hyponatremia with hypoxia is a medical emergency.
        Kidney Int. 2006; 69: 1291-1293
        • Musch W.
        • Decaux G.
        Treating the syndrome of inappropriate ADH secretion with isotonic saline.
        QJM. 1998; 91: 749-753
        • Elsaesser T.F.
        • Pang P.S.
        • Malik S.
        • Chiampas G.T.
        Large-volume hypertonic saline therapy in endurance athlete with exercise-associated hyponatremic encephalopathy.
        J Emerg Med. 2013; 44: 1132-1135
        • Hantman D.
        • Rossier B.
        • Zohlman R.
        • Schrier R.
        Rapid correction of hyponatremia in the syndrome of inappropriate secretion of antidiuretic hormone. An alternative treatment to hypertonic saline.
        Ann Intern Med. 1973; 78: 870-875
        • Schrier R.W.
        • Gross P.
        • Gheorghiade M.
        • et al.
        Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia.
        N Engl J Med. 2006; 355: 2099-2112
        • Huda M.S.
        • Boyd A.
        • Skagen K.
        • et al.
        Investigation and management of severe hyponatraemia in a hospital setting.
        Postgrad Med J. 2006; 82: 216-219
        • Hoorn E.J.
        • Lindemans J.
        • Zietse R.
        Development of severe hyponatraemia in hospitalized patients: treatment-related risk factors and inadequate management.
        Nephrol Dial Transplant. 2006; 21: 70-76
        • Nzerue C.M.
        • Baffoe-Bonnie H.
        • You W.
        • Falana B.
        • Dai S.
        Predictors of outcome in hospitalized patients with severe hyponatremia.
        J Natl Med Assoc. 2003; 95: 335-343
        • Vaishya R.
        • Kaur J.
        • Seema
        • Chopra S.
        • Jaswal S.
        Mortality predictors in severe hyponatraemia in emergency inpatients.
        J Indian Med Assoc. 2012; 110: 94-97
        • Clayton J.A.
        • Le Jeune I.R.
        • Hall I.P.
        Severe hyponatraemia in medical in-patients: aetiology, assessment and outcome.
        QJM. 2006; 99: 505-511
        • Ayus J.C.
        • Krothapalli R.K.
        • Arieff A.I.
        Treatment of symptomatic hyponatremia and its relation to brain damage. A prospective study.
        N Engl J Med. 1987; 317: 1190-1195
        • Hagiwara K.
        • Okada Y.
        • Shida N.
        • Yamashita Y.
        Extensive central and extrapontine myelinolysis in a case of chronic alcoholism without hyponatremia: a case report with analysis of serial MR findings.
        Intern Med. 2008; 47: 431-435
        • Rao M.Y.
        • Sudhir U.
        • Anil Kumar T.
        • Saravanan S.
        • Mahesh E.
        • Punith K.
        Hospital-based descriptive study of symptomatic hyponatremia in elderly patients.
        J Assoc Physicians India. 2010; 58: 667-669
        • Hoorn E.J.
        • Zietse R.
        Hyponatremia and mortality: moving beyond associations.
        Am J Kidney Dis. 2013; 62: 139-149
        • Corona G.
        • Giuliani C.
        • Parenti G.
        • et al.
        Moderate hyponatremia is associated with increased risk of mortality: evidence from a meta-analysis.
        PloS One. 2013; 8: e80451
        • Renneboog B.
        • Musch W.
        • Vandemergel X.
        • Manto M.U.
        • Decaux G.
        Mild chronic hyponatremia is associated with falls, unsteadiness, and attention deficits.
        Am J Med. 2006; 119: 71. e71-e78
        • Ayus J.C.
        • Negri A.L.
        • Kalantar-Zadeh K.
        • Moritz M.L.
        Is chronic hyponatremia a novel risk factor for hip fracture in the elderly?.
        Nephrol Dial Transplant. 2012; 27: 3725-3731
        • Kleinewietfeld M.
        • Manzel A.
        • Titze J.
        • et al.
        Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells.
        Nature. 2013; 496: 518-522
        • Wu C.
        • Yosef N.
        • Thalhamer T.
        • et al.
        Induction of pathogenic TH17 cells by inducible salt-sensing kinase SGK1.
        Nature. 2013; 496: 513-517
        • van der Meer J.W.
        • Netea M.G.
        A salty taste to autoimmunity.
        N Engl J Med. 2013; 368: 2520-2521
        • Mandai S.
        • Kuwahara M.
        • Kasagi Y.
        • et al.
        Lower serum sodium level predicts higher risk of infection-related hospitalization in maintenance hemodialysis patients: an observational cohort study.
        BMC Nephrol. 2013; 14: 276
        • Ayus J.C.
        • Arieff A.
        • Moritz M.L.
        Hyponatremia in marathon runners.
        N Engl J Med. 2005; 353: 427-428
        • Moritz M.L.
        • Ayus J.C.
        100 cc 3% sodium chloride bolus: a novel treatment for hyponatremic encephalopathy.
        Metab Brain Dis. 2010; 25: 91-96
        • Kleinschmidt-DeMasters B.K.
        • Norenberg M.D.
        Rapid correction of hyponatremia causes demyelination: relation to central pontine myelinolysis.
        Science. 1981; 211: 1068-1070
        • Ayus J.C.
        • Krothapalli R.K.
        • Armstrong D.L.
        Rapid correction of severe hyponatremia in the rat: histopathological changes in the brain.
        Am J Physiol. 1985; 248: F711-F719
        • Lohr J.W.
        Osmotic demyelination syndrome following correction of hyponatremia: association with hypokalemia.
        Am J Med. 1994; 96: 408-413
        • Turnbull J.
        • Lumsden D.
        • Siddiqui A.
        • Lin J.P.
        • Lim M.
        Osmotic demyelination syndrome associated with hypophosphataemia: 2 cases and a review of literature.
        Acta Paediatr. 2013; 102: e164-e168

      Linked Article

      • Treatment of Hyponatremic Encephalopathy
        American Journal of Kidney DiseasesVol. 66Issue 3
        • Preview
          In the March issue of AJKD, Ayus et al1 describe their experience treating hyponatremic encephalopathy with 500 mL of 3% sodium chloride solution over 6 hours. This provocative report raises at least 2 important questions.
        • Full-Text
        • PDF