Open access peer-reviewed chapter

Fluids and Sodium Imbalance: Clinical Implications

Written By

Gilda Diaz-Fuentes, Bharat Bajantri and Sindhaghatta Venkatram

Submitted: 02 May 2018 Reviewed: 25 May 2018 Published: 05 November 2018

DOI: 10.5772/intechopen.79121

From the Edited Volume

Fluid and Electrolyte Disorders

Edited by Usman Mahmood

Chapter metrics overview

2,315 Chapter Downloads

View Full Metrics


Fluids and electrolytes are basic components of the human body and essential for the survival of most species. Any imbalance can potentially lead to serious conditions and death. The replacement of fluids and electrolytes has been used since the ancient age. Modern medicine still requires certain degree of expertise in these areas, which ranges from simple replacement in patients with mild illness to a more complex management in critically ill or hospitalized patients. Training and education in the evaluation and management of patients with fluids and electrolyte abnormalities are fundamental for patient’s outcomes. Severe sodium abnormalities are associated with increased morbidity and mortality, and they are markers of poor outcomes. This review presents a concise discussion of frequently asked questions in the evaluation and management of patients with fluids and sodium abnormalities.


  • hypernatremia
  • hyponatremia
  • fluids
  • normal saline
  • ringer lactate
  • albumin

1. Introduction

The serum sodium (sNa) concentration and thus serum osmolality (sOsm) are closely controlled by water homeostasis, which is mediated by thirst, arginine vasopressin, and the kidneys. A disruption in this delicate balance is manifested as an abnormality in the sNa concentration—hyponatremia or hypernatremia and/or hemodynamic instability.

Fluid administration is an integral part of the clinician’s armamentarium to manage a wide variety of clinical conditions, which range from mild dehydration to more life-threatening conditions like shock or trauma.

The goal of this review is to provide a concise discussion regarding fluids and sodium imbalance with an attempt to answer practical clinical questions on those areas. We focus in discussing basics physiological principles, and addressing the most common clinical challenges encountered by the practicing clinician.

1.1. Basic physiologic principle of fluids and sodium

The human body is composed of approximately 60% of water of which two-third are in the intracellular space and one-third in the extracellular space. The extracellular space is composed by the intravascular compartment (~8%), the interstitial compartment (~25%) and the transcellular compartment like cerebrospinal, pericardial fluid, which is very small [1, 2]. In the healthy individual, the extracellular fluid (ECF) and intracellular fluid (ICF) are in osmotic equilibrium, water moves from areas of greater solute concentration to establish equilibrium. Additionally, osmotically active substance shifts water from lower osmolarity to higher osmolarity areas. This is an important concept to understand when we administer intravenous fluids (IVF), as the distribution of fluids is based on the type of fluid administered.

There is a delicate and complicated transport system of water through cell membranes to maintain fluids and electrolyte balance. Sodium is the predominant cation in the extracellular compartment, which is electro-neutralized by chloride (Cl) and bicarbonate (HCO3) as anions. In the intracellular space, potassium (K) is the major intracellular cation that is neutralized by many organic and nonorganic anions. The differential distribution of Na and K is tightly regulated by the sodium pump (Na-K ATPase) [1, 2]. Most osmotically active Na and K are dissolved and are sourced mostly from food intake. The body’s ability to store sodium in tissues (bone, cartilage, connective tissue, etc.) prevents large fluctuations in the sNa levels despite erratic sodium intake [3, 4]. Most of the components in the intracellular compartment are too large to be able to cross membranes exerting little osmotic pressure.

Estimating the ECF volume based on sNa is highly prone to errors in clinical judgment. The volume in both, intracellular and extracellular fluids is primarily determined by the concentration of effective solutes that attract water by osmosis. Sodium and its attendant monovalent anions are the most prevalent effective solutes in ECF volume. The concentration of Na is determined by content of Na as well as volume of water. The primary tonicity receptor is located in the hypothalamic osmoreceptor, which is in charge to regulate the antidiuretic hormone (ADH) or vasopressin. The absence of ADH prevents aquaporin insertion on the luminal surfaces of collecting ducts in the nephrons forming hypotonic urine. The osmoreceptor is linked to both the thirst center and the vasopressin release center via nerve connections. There is a genetic susceptibility to hyponatremia linked to the gene coding for TRPV4 [2, 5, 6, 7, 8]. Disease states releasing ectopic vasopressin or affecting vasopressin receptors will present with hyponatremia. Less prominent but important trigger for the regulation of vasopressin is large changes in effective arterial blood volume and blood pressure. Baroreceptors or stretch receptors in the carotid sinus and aortic arch are surrogates that detect changes in effective arterial blood volume. Nausea, pain, stress, and a number of other stimuli, including some drugs can also cause release of vasopressin [5].


2. Fluids

Intravenous fluids are one of the commonest used medications in hospitalized patients. They can be broadly categorized as crystalloids and colloids. Crystalloid solutions contain water, electrolytes with or without glucose. Colloids solutions contain albumin, starch, or other blood products. Fluids can be isotonic, hypotonic, or hypertonic.

Crystalloids: Common crystalloid solutions include 0.9%-normal saline (NS), 0.45%NS, lactated Ringers solutions (LR), Plasma-Lyte, and dextrose in water. Solutions with electrolyte compositions closer to that of plasma are called balanced fluids. Composition of commonly used crystalloids can be seen in Table 1.

SolutionNa+ (mEq/L)Cl− (mEq/L)K+ (mEq/L)Ca++ (mEq/L)Lactate (mEq/L)Glucose (g/l)pHOsmolarity (mOsm/L)
0.9%NS1541540000pH 5.6 (4.5–7.0)308
0.45 saline (1/2 saline)777700005.0 (4.5–7)154
3% saline51351300005.0 (4.5–7)1026
Ringers lactate130109432806.5272
Plasma-Lyte A*1409850807.4294
5% dextrose00000505.0260

Table 1.

Composition of crystalloids.

Also contains magnesium 3 mEq/L, acetate 27 mEq/L, gluconate 23 mEq/L.

Colloids: They can be divided into natural or synthetic. Natural colloidal solutions include red blood cells, fresh frozen plasma, and human albumin. Indications for the use of packed red cell and fresh frozen plasma are specific; they provide oxygen carrying capacity and clotting factors, respectively. Discussion regarding the use of red blood cells and plasma is beyond the scope of this review.

Synthetic colloidal solutions include hetastarch and dextran. They are used for volume expansion and include hetastarch and dextran.

Colloids can be categorized as hypo oncotic (e.g., gelatins, 4 or 5% albumin) and hyper oncotic (e.g., dextrans, hydroxyethyl starches (HES), and 20 or 25% albumin) solutions. Table 2 describes the composition of commonly used colloids.

FluidNa+ (mEq/L)Cl− (mEq/L)Colloidal oncotic pressure (mm Hg)Osmolarity (mOsm/L)
Albumin 5%130–160130–16020308
Albumin 25%154154100308
Hetastarch (6%)-NaCl15415430310
Gelatins (gelofusine 4%)15415433310
Dextran 70 + NaCl15415460310

Table 2.

Composition of colloids.

Indications for the use of either crystalloids or colloids depend of the clinical condition. Volume expansion by fluids is dependent on their osmolality and oncotic pressure. Isotonic fluids will distribute equally to all fluid compartments without a significant shift across cellular or vascular planes. However, hypertonic solutions will move fluids from intracellular and interstitial space into the intravascular compartment, while hypotonic fluids will result in shift of fluids from intravascular space to interstitial and intracellular compartments. Volume expansion of the intravascular compartment with colloids depends on the oncotic pressure.

The most common clinical indications for fluid administration are:

  • Replacement of volume losses

  • Maintenance of fluids and electrolyte balance

  • Correction of electrolyte or acid-base disorders

  • Persistent hypoglycemia or hyperglycemia

  • Provision of a source of fuel (glucose)

  • Intravenous administration of medication.

2.1. Question 1: which fluids are more effective—colloids or crystalloids?

Fluid resuscitation in critically ill patients in shock is the mainstay of therapy to maintain effective circulating blood volume. Timing of fluid resuscitation plays an important role in resuscitation and is based on the pathophysiology of shock [9, 10]. A long-standing controversy exists between proponents of colloids versus crystalloids for those patients. Supporters of crystalloids argue about risks of anaphylaxis, hemostasis impairment, and need for renal replacement therapy (RRT) with colloids as well as the potential to accumulate in tissues; whereas the colloid proponents argue with the risk of edema associated with crystalloids.

A recent Cochrane analysis concluded that there was no difference in mortality for hospitalized patients with trauma, burns, or following surgery when colloids were compared with crystalloids [11]. The use of HES may be associated with increased mortality; when they are compared to crystalloids, there was a higher incidence of adverse events and need for RRT [12, 13].

In the Crystalloid versus Hydroxyethyl Starch Trial (CHEST), involving 7000 adults in the ICU, the use of 6% HES (130/0.4), as compared with 0.9NS, was not associated with a significant difference in the rate of death at 90 days.

However, there was an increase in the rate of RRT and more adverse events in HES group [12]. The Colloids versus Crystalloids for the Resuscitation of the Critically Ill (CRISTAL) trial compared the effects of colloids versus crystalloids on mortality in patients presenting with hypovolemic shock [14]. There was no difference in mortality between the two groups at 28 days although 90-day mortality was lower in patients receiving colloids.

Low albumin levels are associated with all-cause mortality in both medical and surgical patients [15, 16]. Contrary to the belief that using albumin as a resuscitation fluid could improve mortality, a Cochrane review of 24 studies involving a total of 1419 patients, suggested that administration of albumin-containing fluids resulted in a 6% increase in the absolute risk of death when compared with use of crystalloid solutions [17]. This lead to the SAFE trial that showed similar outcomes between albumin and 0.9NS for resuscitation [18] No trial has consistently revealed superiority of albumin over crystalloids as resuscitative fluid.

In summary, there is no advantage of colloids versus crystalloids or vice versa. Considering the cost and adverse effect profile of colloids, crystalloids may be preferred over colloids. When colloids are used, care must be taken not to exceed recommended dose by regulatory agencies and avoid their use in patients with renal failure.

2.2. Question 2: are balanced fluids better than “0.9 normal saline?”

Normal saline is also referred as physiological or isotonic saline, neither of which is accurate. The sodium and chloride concentration of 154 mEq/L and the pH of 5.6 are certainly abnormal in “normal saline.” The strong ion difference (SID) is the difference between the positively- and negatively-charged strong ions in plasma. Disturbances that increase the SID increase the blood pH while disorders that decrease the SID lower the plasma pH. This may also occur with volume resuscitation with 0.9NS (>30 cc/kg/h) due to excessive chloride administration impairing bicarbonate resorption in the kidneys resulting in hyperchloremic metabolic acidosis [19]. Other potential effects of 0.9NS include renal vasoconstriction with worsening renal function [20], increased postoperative complications, coagulation abnormalities [21], and an increased risk of death [22, 23, 24].

Lactated ringer, Plasma-Lyte, and Normosol are often called ‘balanced fluids’ as their electrolyte contents are closer to human plasma. These balanced crystalloids are also nearly isotonic but have a chloride concentration less than 110 mEq/L and a SID close to plasma.

Several trials comparing 0.9NS to balanced fluids have reported multiple outcomes. Outcomes have ranged from renal failure to mortality. Among critically ill adults with sepsis, resuscitation with balanced fluids was associated with a lower risk of in-hospital mortality [25]. In a meta-analysis of 11 RCTs (8 trials in operation room and 3 in ICU) involving 2703 patients, the in-hospital mortality, occurrence of acute kidney injury (AKI), and need for RRT was not different between balanced solutions and 0.9NS, irrespective of the location of the patients [26]. In a before and after trial comparing 0.9NS with LR solution, use of saline was a safe, viable alternative to LR in the trauma population [27]. In ICU patients requiring crystalloid fluid therapy, the use of a buffered crystalloid compared with saline did not reduce the risk of AKI or mortality [28]. Data regarding best fluid for the perioperative period is still inconclusive [29]. In patients undergoing renal transplants, balanced electrolyte solutions were associated with less hyperchloremic metabolic acidosis compared to 0.9NS, but there were no difference in graft outcomes [30]. Among critically ill adults, the use of balanced crystalloids for IVF administration resulted in a lower rate of the composite outcome of death from any cause, new RRT or persistent renal dysfunction when compared to 0.9NS [31] Among noncritically ill adults treated with IVFs in the emergency department, there was no difference in hospital-free days between treatment with balanced crystalloids compared with saline [32].

Some myths about Ringers lactate:

  1. Ringers lactate in renal failure: In a study comparing acid-base status in kidney transplant patients, LR compared with 0.9NS may lead to a lower serum potassium level and a lower risk of acidosis [33]. In a randomized, double-blind comparison of LR’s solution and 0.9%NS during renal transplantation, LR was associated with less hyperkalemia and acidosis compared with 0.9NS [34].

  2. Ringers lactate in hepatic failure: LR is avoided in patients with hepatic failure with the fear of inducing or worsening lactic acidosis. However, lactate is given as sodium lactate, which is a base rather than an acid. There are no data describing LR causing worse outcomes compared to saline in patients with hepatic dysfunction.

In summary, 0.9%NS is not superior to balanced fluids in volume resuscitation in both critically ill and noncritically ill patients, perioperative patients and posttrauma. Studies suggest that use of balanced crystalloids for IVF administration results in a lower rate of the composite outcome of death from any cause, new RRT, or persistent renal dysfunction than the use of 0.9%NS in critically ill patients. Balanced fluids are not harmful compared to 0.9%NS and seem to be the fluid of choice. However, caution is advised when balanced solutions are used in patients with renal failure and hyperkalemia. Normal saline is an ideal choice in patients with metabolic alkalosis and chloride deficits who are vomiting or have nasogastric tube to suction.

2.3. Question 3: what are the common indications for hypertonic saline?

The classical indication for 3% saline is symptomatic severe hyponatremia. This is discussed in detail later in this chapter. Other indication for hypertonic saline is resuscitation in patients with traumatic brain injury (TBI). In patients with TBI, osmotic agents to reduce cerebral edema are recommended [35]. Common osmotic agents are mannitol and hypertonic saline. Hypertonic saline decreases intracranial pressure (ICP), improves microcirculation, and acts as anti-inflammatory [36]. A retrospective study comparing effectiveness of mannitol versus hypertonic saline revealed that hypertonic saline given in boluses may be more effective than mannitol in lowering ICP but no difference was found in short-term mortality [37]. A comparison of effects in coagulation function or increase in the risk of intracranial rebleeding in patients with moderate TBI when using 3% hypertonic saline versus 20% mannitol for the control of ICP showed no differences [38]. A comparison of pharmacologic therapeutic agents used for the reduction of intracranial pressure after traumatic brain injury concluded that hypertonic saline exhibits beneficial advantages compared with the other medications as a first-line treatment of intracranial hypertension in patients with severe TBI [39]. Complications of hypertonic saline use include hypernatremia, hyperchloremia, and renal failure. Mannitol and hypertonic saline in equiosmolar concentrations produced comparable effects on ICP reduction, brain relaxation, and systemic hemodynamic [40].

Hypertonic saline has been advocated in patients with volume loss after trauma, whereas TBI seems to be an indication to decrease cerebral edema, use of hypertonic saline in other situations is still unclear. In a meta-analysis, use of hypertonic saline showed no differences in clinical outcomes for hypotensive injured patients compared to isotonic fluid in the prehospital setting [41]. There is no evidence that hypertonic saline provides any additional benefit over isotonic crystalloid solutions for trauma resuscitation [42].

In summary, hypertonic saline can be used to decrease intra cranial pressure in patients with moderate to severe TBI. Care must be taken to avoid hypernatremia, hyperchloremia, and renal failure.

2.4. Question 4: how do we manage fluids in sepsis and septic shock?

In severe sepsis and septic shock, early volume resuscitation is indicated to save lives [43, 44, 45]; however, the best choice of fluids is unclear.

In a multicenter ICU trial of patients with severe sepsis randomly assigned to either 6% HES 130/0.42 or ringers acetate, patients receiving 6% HES 130/0.42 had a significant increase in the rate of death at 90 days and need for RRT. Several meta-analyses have shown that albumin does not provide a mortality benefit or decrease the need for RRT in critically ill patients, including those with hypoalbuminemia and sepsis [46, 47, 48]. A recent trial comparing albumin in addition to crystalloids versus crystalloids alone did not confer survival benefit in patients with severe sepsis or septic shock [49].

The early 2000s saw a resurgence in the use of hypertonic saline for sepsis resuscitation. Small volume resuscitation with hypertonic saline was postulated to achieve hemodynamic normalization by recruitment of fluid from the intracellular space, limiting interstitial edema [50]. Additional advantages included improved microcirculatory flow and favorable immunomodulatory effects. Two clinical trials have investigated the use of hypertonic saline in adult septic patients and there was no mortality difference [51, 52].

In the risk-adjusted inverse probability weighting analyses including 60,734 adults admitted to 360 ICUs across the United States between January 2006 and December 2010, the hospital mortality was 17.7% in the balanced fluid group, 19.2% in the 0.9%NS plus balanced fluids plus colloid group, 20.2% in the 0.9NS group ,and 24.2% in the saline plus colloid group. Balanced crystalloids were consistently associated with lower mortality. The authors concluded that when compared with exclusive use of 0.9%NS during resuscitation, coadministration of balanced crystalloids is associated with lower in-hospital mortality and no difference in LOS or costs per day. When colloids are coadministered, LOS and costs per day are increased without improved survival [53].

In summary, balanced fluids may be preferred over 0.9%NS in the resuscitation of patients with severe sepsis or septic shock without renal/liver or potassium issues. Hypertonic saline and other colloids including albumin are likely of no benefit over crystalloids. Use of starch is associated with adverse effects including increased need for RRT.

2.5. Question 5: fluid management in diabetic ketoacidosis

Patients with diabetic ketoacidosis (DKA) present with high anion gap metabolic acidosis, dehydration, and fluid deficits. Caution is advised in use of 0.9%NS due to two reasons. First, cerebral edema is a risk factor for death in patients with DKA. When a saline bolus is administered, it will distribute initially in the plasma that reaches the blood-brain barrier before equilibrating with the extracellular compartment. This has the potential to increase the interstitial volume of the brain ECF compartment and leads to cerebral edema. Second, chloride load in 0.9%NS can trigger nonanion gap metabolic acidosis.

A large bolus of 0.9%NS should be given only in emergent situations. It is advised to limit the amount of sodium ions infused in the first 120 min of therapy to about 3 mmol/kg body weight.

In a multicenter retrospective analysis of adults admitted for DKA to the ICU, which received almost exclusively Plasma-Lyte or 0.9%NS infusion up to 12 h, patients with PL had faster initial resolution of metabolic acidosis and less hyperchloremia, with a transiently improved blood pressure profile and urine output [54].

In summary: caution should be used using 0.9%NS in DKA and it is prudent to limit its use. If continued fluid resuscitation is needed, choice of fluids should be based on sNa levels. In patients with eunatremia or hypernatremia 0.45%NS is preferred and should be infused at 4–14 ml/kg/h, 0.9%NS is preferred in hyponatremia patients [55, 56].

2.6. Question 6: does my patient need maintenance fluids?

Maintenance fluid therapy is indicated in patients who are unable to eat for prolonged period of time in order to provide for fluids, electrolytes, and possibly some nutrition. The goal is to provide enough fluid and electrolytes to meet insensible losses and enable renal excretion of waste products. On an average, 2500 ml of water is ingested daily of which 60% is in form of fluids. Maintenance fluids should be a short-term measure since inappropriate therapy risks volume overload and electrolyte and acid-base disturbance. It is recommended to use 25–30 ml/kg/day water, 1 mmol/kg/day sodium, potassium, chloride, and 50–100 g/day glucose daily [57].

Higher insensible losses and hence higher maintenance of fluids needs to be considered in patients with ongoing losses, fever, burns, and third space losses especially in post-operative surgical patients. There is no evidence to use one kind of crystalloids over the other, hypotonic solutions should be avoided to avoid hyponatremia and avoidance of excessive sodium overload with 0.9%NS. Monitoring and avoidance of development of electrolyte imbalance is critical. Daily weights will prevent volume overload. Continuation of maintenance fluids should be critically reviewed in a daily bases.

2.7. Question 7: is there an ideal IV fluid?

An ideal resuscitative fluid should have an electrolyte composition close to plasma, should not accumulate in tissue, and must be completely metabolized. An ideal fluid does not exist and fluids should be treated as any other medication—indications, duration, effects, and adverse effects. Deciding which fluids are appropriate for each patient depends on the type of fluid lost and the body compartment(s) that require additional volume. It is advisable to consider patients comorbid conditions, acid-base and electrolyte status, and the indication for fluids before making a final selection. Timing of therapy is based on clinical context, delayed resuscitation is not only resuscitation denied but could have a detrimental effect.

Education of use of fluids to the health care providers, especially those who usually initiate care on hospital admission is paramount to improve outcomes and decrease morbidity and mortality.


  1. Treat IVF like medications and consider risks, benefits, alternatives, and risks of alternatives.

  2. In most instances, balanced solutions may be adequate.

  3. Normal saline is probably the fluid of choice in patients with metabolic alkalosis due to vomiting or gastrointestinal losses with volume and chloride deficits.

  4. In critically ill adults, the use of 0.9%NS for IVF administration results in a higher rate of the composite outcome of death from any cause, new RRT, or persistent renal dysfunction.

  5. In patients with DKA, use of 0.9%NS should be restricted to 1–1.5 L unless a compelling indication.

  6. Hypertonic saline or colloids are fluids of choice in TBI with cerebral edema.

  7. Role of hypertonic saline in trauma other than TBI, severe sepsis, septic shock, and hemorrhagic shock is uncertain.

  8. HES is a risk factor for renal injury and need for RRT.

  9. If a synthetic colloid is chosen, do not exceed the manufacturer recommended maximal dose.

  10. Use maintenance fluids only when indicated and review need daily.


3. Disorders of sodium imbalance

3.1. Hyponatremia

3.1.1. Question 8: what is the importance of hyponatremia?

Hyponatremia is a common laboratory abnormality; it is usually defined as a sNa of less than 136 mmol/L. The sNa cut offs to define hyponatremia varies from 125 to 135 mmol/L depending on different studies [58, 59].

Hyponatremia have been reported in 8% of the general population and in up to 60% of hospitalized patients [60]. Patients in ambulatory setting have a lower rate compared with hospital or skill nursing facility setting. Miller et al. reported an 11% incidence of hyponatremia in the ambulatory setting among elderly population with a median age of 78 years [61, 62].

The importance of hyponatremia is related not only to the absolute sNa value, but to the underlying conditions leading to it; it can be the tip of a serious condition. Severity of hyponatremia or its management can impact the patient’s outcomes. Hyponatremia is not a disease, but a manifestation of an underlying disorder. The main focus of the management of hyponatremia is to elucidate the etiology and correction of laboratory abnormalities when levels are life threatening [59, 63].

Two major international guidelines attempted to address best practices in the management of this condition. The United States guidelines were published in 2013, however, they did not include grade of evidence due to scarce clinical evidence and resorted to expert panel recommendations [64]. In 2014, the European guidelines were published and included quality of evidence grades [65, 66, 67]. Rather than the absolute value of the sNa levels, the acuity of development of hyponatremia and its correction are of prime importance because the rate of change in sNa levels is associated with mortality, morbidity, and LOS [68, 69]. Mortality associated with hyponatremia has been reported as high as 30% [69].

A summary of relevant publications addressing prevalence of hyponatremia can be seen in Table 3. The serum cut off values for sodium in all those studies was between 130 and 138 and most of the studies were randomized control studies [58, 59].

ReferenceFrequency (%)Sample sizeOutcome
Ambulatory setting
Hawkins et al.0.1424,027NA
Liamis et al.7.75179↑ Mortality
Gankam Kengne et al.63551↑ Mortality
Mohan et al.2.514,697NA
Hawkins et al.42.643,249NA
Hoorn et al.305437NA
Wald et al.3034,761↑ Mortality
Wakar et al.14.598,411↑ Mortality
Congestive heart failure
Gheorghiade2047,647↑ Mortality
Liver cirrhosis
Angeli et al.49997↑ Mortality
Dawas115152↑ Mortality
HIV infection
Tang38259↑ Mortality
Cusano et al.3196↑ Mortality
Non-dialysis kidney failure
Covesdy et al.13655,493↑ Mortality
Zilberberg et al.87965↑ Mortality

Table 3.

Prevalence and outcome of hyponatremia.

Modified from [58, 59].

3.2. Classification

Hyponatremia can be classified based in:

  • Severity: this is based only in the absolute level of sNa. Mild 130–135 mmol/L, moderate 125–130 mmol/L, and severe when sNA is lower than 125 mmol/L.

  • Time interval of development: acute-less than 48 h and chronic if more than 48 h. This information is occasionally difficult to obtain, but causes are usually different for acute and chronic hyponatremia.

  • Measured osmolarity: it is fundamental to differentiate between the true hypotonic state from the isotonic and hypertonic state. Isotonic hyponatremia is usually due to pseudohyponatremia secondary to high plasma concentrations of triglycerides or proteins [70]. Expected changes in sNa in hypertriglyceridemia (TG) can be calculated as TG × 0.0002 = decrease in sNa in mEq/L; for plasma proteins (PP), PP in gm/dl – 8 × 0.25 = decrease in sNa in mEq/L.

    Commonest causes of hypertonic hyponatremia are hyperglycemia, administration of mannitol or other agents; the osmotic shift of water from ICF to ECF increases the total plasma volume diluting the sNa levels. Each increase in serum glucose levels by every 100 mg/dl after 150 mg/dl, decreases the sNa by approximately 1.6 mmol/L [71].

  • Volume status: hypovolemia, euvolemia, and hypervolemia [72]. This is the most common classification used in the United States [64]. However, this classification is intrinsically flawed as there are no reliable, readily available and highly sensitive clinical tools to differentiate volume status, especially to differentiate hypovolemia from euvolemia [73, 74, 75]. Euvolemia itself is considered to be a misnomer as loss of sodium cannot happen without loss of water [2]. Clinical assessment is more reliable in cases of hypervolemia [2].

    Erroneous classification of patients into these categories can have detrimental outcomes [76].

3.3. Clinical features

Symptoms of hyponatremia are initially subtle, nonspecifics, and difficult to recognize. They mostly manifest as neurological changes, which ranges from altered personality, lethargy and confusion to seizures, coma and death in severe cases [2, 77]. Symptomatic differences between acute severe and chronic hyponatremia have been reported. Symptoms of acute severe hyponatremia include nausea, vomiting, headache, seizure, coma, respiratory failure, and death, which are manifestations of brain edema. In chronic hyponatremia, main symptoms are fatigue, gait and attention deficit, osteoporosis, and fractures. Nausea and vomiting are seen in both, acute severe and chronic hyponatremia [78, 79]. Older patients with comorbid conditions tend to develop symptoms of hyponatremia at an earlier onset than young healthier patients. Premenopausal women are prone for cerebral edema from acute hyponatremia, it is hypothesized that this could be secondary to the action of estrogen and progesterone inhibiting Na+K+-ATPase and decreasing solute expel from brain cells; if not recognized early, it will lead to neurological complications. The nonneurological manifestations are often due to the dysregulation in the volume status [5, 80].

3.3.1. Question 9: what are the causes of hyponatremia?

The best approach to evaluate causes of hyponatremia is to first decide if we are dealing with acute versus chronic hyponatremia.

Acute hyponatremia: the underlying etiological mechanism primarily causes large input of water. Normal individuals with intact thirst center and mental function develop aversion to large volume water intake. Table 4 shows most common causes of acute hyponatremia.

Ingestion of large volume of waterInfusion of large volume of 5% dextroseInfusion of large volume of hypotonic lavage fluidGeneration and retention of electrolyte-free water (“desalination”)
  • Mood-altering drugs which blocks aversion to large water intake

  • Increased water intake to avoid dehydration

  • Beer potomania

  • Psychotic state

  • Postoperative period (especially patients with a low muscle mass)

  • Input of water and organic solutes, with little or no Na+ ions (e.g. post transurethral resection of prostate)

  • Excretion of large volume of hypertonic urine caused by a large infusion of isotonic saline in a setting where vasopressin is present

Table 4.

Causes of acute hyponatremia.

Chronic hyponatremia: slow onset of hyponatremia, usually more than 48 h. The underlying etiology is lower rate of water excretion and involves release of vasopressin. In some case, decreased volume of filtered solute and residual water permeability play a role [5]. Table 5 shows most common causes of chronic hyponatremia and Table 6 shows the most common laboratory findings in the most common causes of hypotonic hyponatremia.

Lower rate of water excretion due to low volume of distal delivery of filtrateLower rate of water excretion due to vasopressin actions
  • Very low glomerular filtration rate states

  • States with enhanced reabsorption of filtrate in the proximal collecting tubules caused by low effective arterial blood volume

  • Loss of Na+ and Cl−

    Sweat: cystic fibrosis, marathon runner

    Gastrointestinal tract: diarrhea

    Renal: diuretics, aldosterone deficiency, renal or cerebral salt wasting

  • States with expanded extracellular fluid volume but low effective arterial blood volume (e.g., congestive heart failure, liver cirrhosis)

  • Non-osmotic stimuli: pain, anxiety, nausea

  • Baroreceptor-mediated release of vasopressin due to very low EABV

  • Central stimulation of vasopressin: drugs like 3,4-methylenedioxymethamphetamine (MDMA), nicotine, morphine, carbamazepine, tricyclic antidepressants, serotonin reuptake inhibitors, antineoplastic agents

  • Pulmonary disorders: bacterial or viral pneumonia, tuberculosis

  • Central nervous system disorders: encephalitis, meningitis, brain tumors, subdural hematoma, subarachnoid hemorrhage, stroke

  • Release of vasopressin from malignant cells: small-cell carcinoma of the lung, oropharyngeal carcinomas, olfactory neuroblastomas

  • Administration of desmopressin

  • Glucocorticoid deficiency

  • Severe hypothyroidism

  • Activating mutation of the vasopressin 2 receptor: nephrogenic syndrome of inappropriate antidiuresis

Table 5.

Causes of chronic hyponatremia.

Modified from [5].

Volume statusClinical conditionsUrine OsmUrine NaSerum uric acidFENA
Hypovolemic (appropriate ADH response)Extrarenal lossesElevated<10–20Elevated >4<1
Renal losses deficiency of mineralocorticoidsElevated>20Elevated>1
Hypervolemic (appropriate ADH response)Heart failure, liver cirrhosis, nephrotic syndromeElevated<20Low/normal<1
Renal failureDecreased>20Variable>1
EuvolemiaReset osmostatVariable
SIADHElevated >100–300>30–40Decreased <4>1
Primary polydipsiaDecreasedDecreasedLow/normal>1
Hypothyroidism, deficiency of mineralocorticoidsElevated>20Low/normal>1

Table 6.

Laboratory findings in most common causes of hypotonic hyponatremia.

3.3.2. Question 10: how we evaluate a patient with hyponatremia?

Evaluation of hyponatremia still remains to some extent controversial and occasionally cumbersome.

In an attempt to avoid the pitfalls of volume evaluation recommended in the 2012 guidelines, the European guidelines were released in 2014. They prioritized the use of urine sodium (uNa) levels and urine osmolality (uOsm) over assessment of volume status [67]. Conditions leading to a false low or high uNa levels like low sodium diet or recent diuretic use and chronic kidney disease respectively were addressed [66, 81, 82].

Role of vasopressin and copeptin levels: measurement of vasopressin levels seems logical for the investigation of hyponatremia, but its unstable nature when not bound to plasma, low accuracy, and not readily available makes it use unsuitable. Moreover, uOsm is a readily available, accurate, and inexpensive surrogate [83]. Vasopressin is degraded into neurophysin and copeptin by enzymatic cleavage. Copeptin has been considered also a reasonable surrogate for vasopressin. Copeptin levels were reported to be increased in hypo and hypervolemic hyponatremia but not in syndrome of inappropriate secretion of antidiuretic hormone (SIADH). A ratio of serum copeptin to uNa with a cut off value of 30 pmol/mmol had an AUC of 0.88 in identifying hypovolemia from euvolemia [84].

Other biomarkers like apelin and midregional proatrial natriuretic peptide (MR-ProANP) have been evaluated in hyponatremia. Apelin counteract vasopressin in homeostasis. MR-ProANP increases to a larger extent in hypo or hypervolemic hyponatremia rather than in SIADH. The true diagnostic potential of these biomarkers are yet to be validated [85, 86, 87, 88].

Based on existing guidelines and trying to overcome limitations of clinical evaluation of volume status, we suggest the following steps when evaluating a patient with hyponatremia:

  1. Measurement of serum osmolarity to differentiate between hypotonic hyponatremia from iso- and hypertonic.

  2. Hypotonic hyponatremia: clinical evaluation of volume status. In general, identification of hypervolemia is more accurate than differentiating between euvolemic and hypovolemic state.

  3. Measurement of urine osmolarity (uOsm) and urinary sodium (uNa). This is conjunction with sOsm and examination should narrow down the diagnosis. For example, a threshold of uOsm of >100 mOsm/kg predicts the action of ADH on the collecting tubules, which in case of hyponatremia is not the appropriate response. This together with elevated uNa >20–30 mmol/L strongly suggests the presence of SIADH [2].

  4. Needs to consider the presence of more than one disorder leading to hyponatremia [89].

  5. Management should ideally address correction of sNa levels as well as the underlying condition leading to it.

  6. Delayed or unavailability of sOsm is one of the major limiting factors during evaluation of hyponatremia as addressed by the United States guidelines, potentially leading to misclassification of patients based on clinical assessment of volume status.

  7. Some experts suggest that a limited work up including sOsm, uNa, uOsm, and infusion of isotonic saline 1–2 l over 24 h may be sufficient for an accurate diagnosis in most cases of hypotonic hyponatremia [2]. Increase in sNa after trial of volume expansion suggests hypovolemic hyponatremia. However, this can be also seen in SIADH [75, 90, 91, 92].

Volume expansion should be cautiously done in certain conditions like immediate post-operative period, where isotonic saline can worsen the hyponatremia by a process called desalination, as presence of vasopressin makes the urine hypertonic by water resorption [93]. In addition, patients with hypervolemic states like heart failure or liver cirrhosis could deteriorate with the additional fluid administration.

Figure 1 shows a flow diagram for initial evaluation of hyponatremia.

Figure 1.

Algorithm for initial evaluation of hyponatremia. Based in the USA and European guidelines [64, 65, 66, 67].

3.3.3. Question 11: how do we manage hyponatremia?

Goal should ideally focus in the prevention of hyponatremia knowing its association with significant morbidity and mortality. There is no data available regarding the effects of treating asymptomatic mild to moderate hyponatremia [2, 94, 95].

Patients presenting with severe, acute, or chronic hyponatremia should be treated in a monitor setting as those patients are at risk for adverse outcomes [2]. Acute respiratory failure from damage of the respiratory center or noncardiogenic pulmonary edema has been reported [9697]. Identification of patients at higher risk for osmotic demyelination remains a challenge during treatment; risks factors for development of osmotic demyelination include presence hypokalemia, alcoholism, malnutrition, and liver disease [64, 98]. Table 7 shows basic management of patients presenting with hyponatremia and comparison of the two major existing guidelines.

ConditionsGeneral agreement in guidelinesDisagreement between guidelines
Acute or symptomatic hyponatremia—less 48 hSevere symptoms: bolus 3% NaCl: 100–150 ml over 10–20 min × 2–3 as neededMinimal—just in amount of fluids
50 ml difference
Moderate symptoms: continuous infusion 3% NaCl 0.5–2 ml/kg/h or bolus 3% NaCl: 100–150 ml over 20 min × 1
Chronic hyponatremia—more 48 h
SIADHFirst line: fluid restrictionNone
Second line: demeclocycline, urea, or vaptanEuropean guidelines do not recommend vaptans when sNa > 130 and recommend against when sNa > 125.
Recommends against demeclocycline
Suggest oral NaCl or loop diuretics
Hypovolemic hyponatremiaIsotonic saline or balanced crystalloid solutionMinimal/none
Hypervolemic hyponatremiaFluid restriction—500—1 L/day
European guidelines recommend against vaptan
Correction ratesMinimum-only USA guidelines: 4–8 mmol/L/day, 4–6 mmol/L/day in high risk of neurological complicationsEuropean guidelines have no minimum
Limits: 10–12 mmol/L/day, 8 mmol/L/day in high risk patientsNone
Management of overcorrectionBaseline sNa ≥ 120 mmol/L: probably unnecessaryEuropean guidelines suggest to start once limit is exceeded
Baseline sNa < 120 mmol/L: relower with electrolyte-free water or desmopressin after correction exceeds 6–8 mmol/L/dayExpert consultations recommended by European guidelines

Table 7.

Management of hypotonic hyponatremia and comparison between existing guidelines.

Modified from [72].

Areas of concern with guidelines: caution must be excised when following guidelines. Areas of concern in the management of hyponatremia are:

  • There is no clear evidence regarding the 48 h cut off to differentiate between acute and chronic hyponatremia, neither to clearly differentiate risk for osmotic demyelination in those patients.

  • Clinically difficult to be certain regarding acuity of hyponatremia; in asymptomatic patients with hyponatremia, it could be assumed to be chronic.

  • Limited evidence regarding the best and safer correction rate. A lower correction rate of 6 mEq/L/24 h could be safer.

  • When to treat a patient with mild to moderate hyponatremia and none/minimal neurological symptoms remain a gray zone and depends on the clinical situation. Fluid restriction is the most common, cost effective, and safer modality of treatment [2, 72]. Fluid restriction of 500–1000 ml/day has been suggested and should be based in volume assessment. Urine Na to serum electrolyte ratio (uNa + urine K/sNa) >1 indicates antidiuretic phase and a ratio <1 suggests aquaretic phase. Fluid restrictions to less than 500 ml/day in antidiuretic phase and 1000 ml/day in aquaretic phase have been recommended; however, adherence is a problem [72].

  • Use of Vaptans. Vaptans are vasopressin type 2 receptor antagonist, present in the collecting duct and they induce excretion of hypotonic urine. Its use has been recommended in a subgroup of patients with hyponatremia secondary to excess vasopressin [99, 100]. There are many vaptans available including tolvaptan, satavaptan, lixivaptan, and conivaptan, which are been successful at increasing sNa and relieving symptoms in conditions like SIADH, congestive heart failure, and liver cirrhosis [101, 102, 103]. Sodium overcorrection is a concern and it was reported in 25% of 61 patients included in a study [103]. Side effects including liver injury, risk of overcorrection, and lack of long-term sodium improvement are some of limitations [101, 102, 104].

  • Demeclocycline and lithium have low quality evidence to support front line management of hyponatremia. Demeclocycline is thought to inhibit adenylate cyclase activity upon binding of vasopressin to its receptor in the collecting tubule. The adverse effects associated with the drugs make them less desirable for treatment [2, 105].

3.3.4. Question 12: what are the complications and outcomes of hyponatremia?

Complications of hyponatremia can be divided in those caused by hyponatremia per se and those caused by the treatment of hyponatremia. In general, worse outcomes are associated with sNa levels of less than 115 mEq/L and with faster rate of fall in sNa [2].

3.4. Complications and outcomes of untreated hyponatremia

Complications of hyponatremia range from chronic debilitating symptoms like gait deficit and neuromuscular symptoms to a more severe and life-threatening presentation of brain edema. Chronic and mild-moderate hyponatremia have been associated with attention or gait deficits, increased risk of falls, and bone fractures. Bone is a reservoir for Na. Observational retrospective cross sectional and epidemiological surveys have established an association between chronic hyponatremia and osteoporosis and major osteoporotic fracture [106, 107, 108, 109, 110, 111].

Unfortunately, there is a lack of evidence to suggest that osteoporosis is reversed with correction of hyponatremia [2].

The brain which is contained in the hard skull is not able to accommodate any swelling or increase in brain volume. This is evident especially in patients who develop acute hyponatremia. Cerebral edema occurs when cells within the brain swell, when there is an increase in extracellular fluid volume in the brain or both. Brain cells swell when there is a large osmotic force favoring an intracellular shift of water, owing to a higher effective osmolality in brain cells than the effective osmolality in plasma in capillaries near the blood–brain barrier [112, 113, 114, 115]. The elevated intracranial pressure with the resultant acute cerebral edema can potentially lead to serious symptoms that ranges from seizures, coma to brain herniation causing irreversible midbrain damage and death [116, 117]. Incidence of fatal brain damage secondary to severe hyponatremia is unknown, majority of the cases have been reported during the perioperative period secondary to infusion of hypotonic fluids or self-water intoxication like marathon runners and psychiatric patients [118].

Most cases of hyponatremia in the ambulatory setting are mild. An sNa of less than 125 mmol/L was seen in 0.14% in Hawkin et al. study [60]. The Dallas heart study, a large prospective multiethnic cohort study of 3551 ambulatory individuals with median age of 43 year/age and from diverse ethnicity, found that mild hyponatremia (median 133 mmol/L) was significantly associated with increased risk of death [119]. A large cross sectional observational study by the National Health and Nutrition Examination Survey in the United States with 15,000 individuals demonstrated that hyponatremia was an independent risk for increased mortality across age, gender, and comorbid conditions. Overall prevalence was around 2%. They also showed that prevalence of hyponatremia increased with age and was more frequent among women than men [120].

Others studies looking at the association of hyponatremia with specific comorbid conditions like heart failure, HIV, pneumonia, renal failure among others, concluded that hyponatremia is an independent risk factor for mortality regardless the levels of sNa [58, 121, 122, 123, 124, 125, 126, 127, 128, 129]. Among patients presenting with acute pulmonary emboli, hyponatremia is common and several studies has shown to be an independent risk factor for increased short-term mortality. This result could be encountered as a variable in determining of pulmonary emboli severity and mortality [130, 131].

Among the hospitalized population, many studies have estimated the prevalence of hyponatremia from 8 to 40% [60, 69, 89, 132]. In Wald et al. study evaluating more than 50,000 patients, he established that irrespective of onset of hyponatremia-community, hospital aggravated or hospital acquired, all were associated with increased mortality, length of stay, and discharge to a facility; and this was independent of the underlying comorbid conditions. Mortality was increased among older patients. The operational definition for normal sNa in this study was 138–142 mEq/L. In patients with hospital acquired hyponatremia, the risk of mortality was 15 times higher among patients with first serum sodium level of 127 mEq/L or less [69]. A larger prospective study by Waiker and colleagues with approximately 100,000 individuals followed up to 5 years showed that irrespective of the severity of hyponatremia, presence of hyponatremia independently increased risk of dead with an odd ratio of 1.47, 1.32, and 1.33 at the time of admission, 1 and 5 year follow-up, respectively. It was more pronounced among patients admitted with cardiovascular disease, metastatic cancer, and those admitted for procedures related to the musculoskeletal system. They also showed that resolution of hyponatremia attenuated the increased risk of mortality [132].

3.5. Complications and outcomes of treatment of hyponatremia

There are no many studies evaluating outcomes of treatment of hyponatremia. Two studies evaluated the impact of treatment on mortality among patients with congestive heart failure and concluded that treatment confers no mortality benefit, however, there was symptomatic improvement and decreased length of stay [94, 95]. Other studies suggested that correction of mild hyponatremia could reverse attention and gait deficits [133, 134].

When hyponatremia develops over a slower rate, 24–48 h, the brain cells are able to adapt to expel enough of anions and organic solutes along with water to maintain its size. Rapid correction of hyponatremia can lead to inability to regain the organic solutes causing osmotic demyelination, a process still poorly understood [5].

Osmotic demyelination syndrome (ODS) and central pontine myelinolysis (CPM) are terms usually used interchangeably, but they represent separate, not well understood and highly feared complications of the treatment of hyponatremia. The effect of rapid correction of hyponatremia is termed as ODS and it is specific to the central nervous system and not always localized to the pontine region. Extrapontine myelinolysis is as frequent as CPM [135, 136]. Risk factors making patients more susceptible to the development of ODS include severity and chronicity of hyponatremia, the increment of sNa, the treatment used for sodium correction, concomitant hypokalemia, presence of liver disease and the nutritional status [98]. A small study of 33 patients showed that an increase in sNa to normal or hypernatremic levels in the first 48 h, a change in the sNa concentration of >25 mmol/L in the first 48 h, a hypoxic-anoxic episode, and an elevation of sNa to hypernatremic levels in patients with hepatic encephalopathy were associated with CMP. However, rate of correction was not associated with demyelination [118].

The clinical manifestations of ODS are variable depending on the location of demyelination. They range from pontine and bulbar symptoms such as dysarthria, dysphagia, and dystonia to more severe forms like locked-in state and coma [137]. In the past, prognosis of ODS and CMP was considered to be very poor; however, several studies have reported near complete neurological recovery. In addition, ODS/CMP are associated with other complications like aspiration pneumonia, urinary tract infection, deep venous thrombosis, and pulmonary embolism [137, 138, 139].

3.6. How can ODS be avoided?

In the absence of an absolute threshold for the rate of correction, it is well accepted that the safest rate of correction of hyponatremia is 6–8 mEq/L/day. Brain demyelination has been reported over a range of rate of sNa correction of 8–12–18 mEq/L/day [2, 72]. Some investigators in small, nonrandomized studies suggest concomitant use of desmopressin and hypertonic saline for better control of the rate of sNa correction in hyponatremia [140, 141]. Experiments on rats have shown little success with the combination regimen of D5W and desmopressin for the treatment of overcorrection of hyponatremia [142, 143]. The role of urea for ODS have not been well studied.

3.7. Hypernatremia

A difference of the complexity of hyponatremia, the finding of hypernatremia invariably denotes hypertonic hyperosmolality and always causes cellular dehydration. It is usually defined as a sNa of more than 145 mmol/L. It can be a frequent finding in hospitalized patients or high risk patients with poor access to water like the elderly, infants, patients on mechanical ventilation, and patients with altered mental status. In the elderly, a physiologic decrease in the thirst mechanism have been reported; however, there can be a pathological decrease in free water intake as well [60].

In general, clinical manifestations of hypernatremia correlate with the severity of sodium abnormalities and are related to central nervous system dysfunction and ranges from weakness, confusion to seizure and coma. In addition, sign of hypovolemia and hemodynamic abnormalities can be found on examination.

The complications of hypernatremia vary from mild to life threatening [144]. Brain shrinkage induced by hypernatremia can cause vascular rupture, with cerebral bleeding, subarachnoid hemorrhage, and permanent neurologic damage or death.

Causes of hypernatremia can be loose classified in two: either net water losses due to gastrointestinal or renal etiologies or hypertonic solution administration [144, 145].

3.7.1. Management of hypernatremia

The focus of management is addressing the underlying cause leading to hypernatremia and the correction of serum sodium. Initial evaluation includes evaluation of vital signs. In hemodynamically unstable patients, administration of isotonic 0.9% normal saline or balance fluids is advised, irrespective of sNa. Goal in those patients is fluid resuscitation hemodynamic stabilization. Patient who are hemodynamically stable can be managed with oral or IVF replacement. The preferred route for fluid administration is the oral route or a feeding tube; otherwise IVF are required. Only hypotonic fluids are recommended, including pure water, 5% dextrose, and 0.2 or 0.45% sodium chloride. The more hypotonic the infusate, the lower the infusion rate required. An easy and efficient way to calculate this is by using Adrogue-Madias formula, which allows to calculate rate of infusate [144].

Correction rates: similar to management of hyponatremia, and to avoid sudden changes in tonicity, the target recommended fall in the sNa concentration is 8–10 mmol/L/day for patients with hypernatremia with a goal to reduce the sNa to 145 mmol/L [145, 146].


  1. Serum sodium abnormalities are common and carry significant morbidity and mortality.

  2. Evaluation of sodium abnormalities should focus in the underlying condition as well as management.

  3. Following recommended algorithms for evaluation of hyponatremia is advised.

  4. Evaluation of volume status in patients with sodium disorders can be a challenge.

  5. Needs to keep in consideration the presence of more than one disorder.

  6. Resuscitation of an unstable patient takes precedence over correction of sodium levels.

  7. There is no rush to correct sNa levels, risk of overcorrection, or rapid increase in sNa can lead to serious complications.


4. Conclusion

We reviewed issues related to fluids and sodium disturbance and the clinical implications of these issues. The dysregulation of fluid and sodium homeostasis leads to many direct and indirect effects and carries significant morbidity and mortality in a wide variety of patients and clinical settings. Those range from mild cases of dehydration to more severe cases of patients in shock or with severe hypo- or hypernatremia.

Since the high prevalence of these disorders, clinicians in virtually every medical specialty will interact with patients requiring fluid administration and need for electrolyte evaluation and correction. Appropriate and timely administration of fluids and electrolyte correction with focus in avoidance of complications and improvement of outcomes is fundamental.


Conflict of interest

The authors have no conflict of interest.



ECFextracellular fluid
ICFintracellular fluid
IVFintravenous fluids
RRTrenal replacement therapy
HEShydroxyethyl starches
SIDstrong ion difference
TBItraumatic brain injury


  1. 1. Watson PE, Watson ID, Batt RD. Total body water volumes for adult males and females estimated from simple anthropometric measurements. The American Journal of Clinical Nutrition. 1980;33(1):27-39
  2. 2. Gankam Kengne F. Physiopathology, clinical diagnosis, and treatment of hyponatremia. Acta Clinica Belgica. 2016;71(6):359-372
  3. 3. Farber SJ. Mucopolysaccharides and sodium metabolism. Circulation. 1960;21:941-947
  4. 4. Forbes GB, Tobin RB, Harrison A, McCoord A. Effect of acute hypernatremia, hyponatremia, and acidosis on bone sodium. The American Journal of Physiology. 1965;209(4):825-829
  5. 5. Kamel KS, Halperin ML. Chapter 10—Hyponatremia. In: Fluid, Electrolyte and Acid-Base Physiology. 5th ed. Philadelphia: Elsevier; 2017. pp. 265-308
  6. 6. Sharif-Naeini R, Ciura S, Zhang Z, Bourque CW. Contribution of TRPV channels to osmosensory transduction, thirst, and vasopressin release. Kidney International. 2008;73(7):811-815
  7. 7. Bichet DG, Arthus MF, Lonergan M, Hendy GN, Paradis AJ, Fujiwara TM, et al. X-linked nephrogenic diabetes insipidus mutations in North America and the Hopewell hypothesis. The Journal of Clinical Investigation. 1993;92(3):1262-1268
  8. 8. Decaux G, Vandergheynst F, Bouko Y, Parma J, Vassart G, Vilain C. Nephrogenic syndrome of inappropriate antidiuresis in adults: High phenotypic variability in men and women from a large pedigree. Journal of the American Society of Nephrology. 2007;18(2):606-612
  9. 9. Bickell WH, Wall MJ Jr, Pepe PE, Martin RR, Ginger VF, Allen MK, et al. Immediate versus delayed fluid resuscitation for hypotensive patients with penetrating torso injuries. The New England Journal of Medicine. 1994;331(17):1105-1109
  10. 10. Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. The New England Journal of Medicine. 2001;345(19):1368-1377
  11. 11. Perel P, Roberts I, Ker K. Colloids versus crystalloids for fluid resuscitation in critically ill patients. Cochrane Database of Systematic Reviews. 2013;(2). DOI: 10.1002/14651858.CD000567.pub6
  12. 12. Myburgh JA, Finfer S, Bellomo R, Billot L, Cass A, Gattas D, et al. Hydroxyethyl starch or saline for fluid resuscitation in intensive care. The New England Journal of Medicine. 2012;367(20):1901-1911
  13. 13. Perner A, Haase N, Guttormsen AB, Tenhunen J, Klemenzson G, Aneman A, et al. Hydroxyethyl starch 130/0.42 versus Ringer's acetate in severe sepsis. The New England Journal of Medicine. 2012;367(2):124-134
  14. 14. Annane D, Siami S, Jaber S, Martin C, Elatrous S, Declere AD, et al. Effects of fluid resuscitation with colloids vs crystalloids on mortality in critically ill patients presenting with hypovolemic shock: The CRISTAL randomized trial. Journal of the American Medical Association. 2013;310(17):1809-1817
  15. 15. Gibbs J, Cull W, Henderson W, Daley J, Hur K, Khuri SF. Preoperative serum albumin level as a predictor of operative mortality and morbidity: Results from the National VA Surgical Risk Study. Archives of Surgery. 1999;134(1):36-42
  16. 16. Jellinge ME, Henriksen DP, Hallas P, Brabrand M. Hypoalbuminemia is a strong predictor of 30day all-cause mortality in acutely admitted medical patients: A prospective, observational, cohort study. PLoS One. 2014;9(8):e105983
  17. 17. Cochrane Injuries Group Albumin R. Human albumin administration in critically ill patients: Systematic review of randomised controlled trials. BMJ. 1998;317(7153):235-240
  18. 18. Finfer S, Bellomo R, Boyce N, French J, Myburgh J, Norton R, et al. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. The New England Journal of Medicine. 2004;350(22):2247-2256
  19. 19. Park M, Calabrich A, Maciel AT, Zampieri FG, Taniguchi LU, Souza CE, et al. Physicochemical characterization of metabolic acidosis induced by normal saline resuscitation of patients with severe sepsis and septic shock. Revista Brasileira de Terapia Intensiva. 2011;23(2):176-182
  20. 20. Yunos NM, Bellomo R, Hegarty C, Story D, Ho L, Bailey M. Association between a chloride-liberal vs chloride-restrictive intravenous fluid administration strategy and kidney injury in critically ill adults. Journal of the American Medical Association. 2012;308(15):1566-1572
  21. 21. Waters JH, Gottlieb A, Schoenwald P, Popovich MJ, Sprung J, Nelson DR. Normal saline versus lactated Ringer's solution for intraoperative fluid management in patients undergoing abdominal aortic aneurysm repair: An outcome study. Anesthesia and Analgesia. 2001;93(4):817-822
  22. 22. Shaw AD, Bagshaw SM, Goldstein SL, Scherer LA, Duan M, Schermer CR, et al. Major complications, mortality, and resource utilization after open abdominal surgery: 0.9% saline compared to Plasma-Lyte. Annals of Surgery. 2012;255(5):821-829
  23. 23. Shaw AD, Raghunathan K, Peyerl FW, Munson SH, Paluszkiewicz SM, Schermer CR. Association between intravenous chloride load during resuscitation and in-hospital mortality among patients with SIRS. Intensive Care Medicine. 2014;40(12):1897-1905
  24. 24. Magder S. Balanced versus unbalanced salt solutions: What difference does it make? Best Practice & Research. Clinical Anaesthesiology. 2014;28(3):235-247
  25. 25. Raghunathan K, Shaw A, Nathanson B, Sturmer T, Brookhart A, Stefan MS, et al. Association between the choice of IV crystalloid and in-hospital mortality among critically ill adults with sepsis. Critical Care Medicine. 2014;42(7):1585-1591
  26. 26. Serpa Neto A, Martin Loeches I, Klanderman RB, Freitas Silva R, Gama de Abreu M, Pelosi P, et al. Balanced versus isotonic saline resuscitation—A systematic review and meta-analysis of randomized controlled trials in operation rooms and intensive care units. Annals of Translational Medicine. 2017;5(16):323
  27. 27. Davis JS, Alsafran S, Richie CD, Moore JW, Namias N, Schulman CI. Time to resuscitate a sacred cow…with normal saline. The American Surgeon. 2014;80(3):301-306
  28. 28. Young P, Bailey M, Beasley R, Henderson S, Mackle D, McArthur C, et al. Effect of a buffered crystalloid solution vs saline on acute kidney injury among patients in the intensive care unit: The SPLIT randomized clinical trial. Journal of the American Medical Association. 2015;314(16):1701-1710
  29. 29. Bampoe S, Odor PM, Dushianthan A, Bennett-Guerrero E, Cro S, Gan TJ, et al. Perioperative administration of buffered versus non-buffered crystalloid intravenous fluid to improve outcomes following adult surgical procedures. Cochrane Database of Systematic Reviews. 2017;9:CD004089
  30. 30. Wan S, Roberts MA, Mount P. Normal saline versus lower-chloride solutions for kidney transplantation. Cochrane Database of Systematic Reviews. 2016;8:CD010741
  31. 31. Semler MW, Self WH, Wanderer JP, Ehrenfeld JM, Wang L, Byrne DW, et al. Balanced crystalloids versus saline in critically ill adults. The New England Journal of Medicine. 2018;378(9):829-839
  32. 32. Self WH, Semler MW, Wanderer JP, Wang L, Byrne DW, Collins SP, et al. Balanced crystalloids versus saline in noncritically ill adults. The New England Journal of Medicine. 2018;378(9):819-828
  33. 33. Khajavi MR, Etezadi F, Moharari RS, Imani F, Meysamie AP, Khashayar P, et al. Effects of normal saline vs. lactated ringer's during renal transplantation. Renal Failure. 2008;30(5):535-539
  34. 34. O'Malley CM, Frumento RJ, Hardy MA, Benvenisty AI, Brentjens TE, Mercer JS, et al. A randomized, double-blind comparison of lactated Ringer's solution and 0.9% NaCl during renal transplantation. Anesthesia and Analgesia. 2005;100(5):1518-1524 table of contents
  35. 35. Carney N, Totten AM, O'Reilly C, Ullman JS, Hawryluk GW, Bell MJ, et al. Guidelines for the management of severe traumatic brain injury, fourth edition. Neurosurgery. 2017;80(1):6-15
  36. 36. de Oliveira MF, Pinto FC. Hypertonic saline: A brief overview of hemodynamic response and antiinflammatory properties in head injury. Neural Regeneration Research. 2015;10(12):1938-1939
  37. 37. Mangat HS, Chiu YL, Gerber LM, Alimi M, Ghajar J, Hartl R. Hypertonic saline reduces cumulative and daily intracranial pressure burdens after severe traumatic brain injury. Journal of Neurosurgery. 2015;122(1):202-210
  38. 38. Wang H, Cao H, Zhang X, Ge L, Bie L. The effect of hypertonic saline and mannitol on coagulation in moderate traumatic brain injury patients. The American Journal of Emergency Medicine. 2017;35(10):1404-1407
  39. 39. Alnemari AM, Krafcik BM, Mansour TR, Gaudin D. A comparison of pharmacologic therapeutic agents used for the reduction of intracranial pressure after traumatic brain injury. World Neurosurgery. 2017;106:509-528
  40. 40. Sokhal N, Rath GP, Chaturvedi A, Singh M, Dash HH. Comparison of 20% mannitol and 3% hypertonic saline on intracranial pressure and systemic hemodynamics. Journal of Clinical Neuroscience. 2017;42:148-154
  41. 41. Blanchard IE, Ahmad A, Tang KL, Ronksley PE, Lorenzetti D, Lazarenko G, et al. The effectiveness of prehospital hypertonic saline for hypotensive trauma patients: A systematic review and meta-analysis. BMC Emergency Medicine. 2017;17(1):35
  42. 42. Patanwala AE, Amini A, Erstad BL. Use of hypertonic saline injection in trauma. American Journal of Health-System Pharmacy. 2010;67(22):1920-1928
  43. 43. Mouncey PR, Osborn TM, Power GS, Harrison DA, Sadique MZ, Grieve RD, et al. Trial of early, goal-directed resuscitation for septic shock. The New England Journal of Medicine. 2015;372(14):1301-1311
  44. 44. Pro CI, Yealy DM, Kellum JA, Huang DT, Barnato AE, Weissfeld LA, et al. A randomized trial of protocol-based care for early septic shock. The New England Journal of Medicine. 2014;370(18):1683-1693
  45. 45. Investigators A, Group ACT, Peake SL, Delaney A, Bailey M, Bellomo R, et al. Goal-directed resuscitation for patients with early septic shock. The New England Journal of Medicine. 2014;371(16):1496-1506
  46. 46. Patel A, Laffan MA, Waheed U, Brett SJ. Randomised trials of human albumin for adults with sepsis: Systematic review and meta-analysis with trial sequential analysis of all-cause mortality. BMJ. 2014;349:g4561
  47. 47. Xu JY, Chen QH, Xie JF, Pan C, Liu SQ, Huang LW, et al. Comparison of the effects of albumin and crystalloid on mortality in adult patients with severe sepsis and septic shock: A meta-analysis of randomized clinical trials. Critical Care. 2014;18(6):702
  48. 48. Rochwerg B, Alhazzani W, Gibson A, Ribic CM, Sindi A, Heels-Ansdell D, et al. Fluid type and the use of renal replacement therapy in sepsis: A systematic review and network meta-analysis. Intensive Care Medicine. 2015;41(9):1561-1571
  49. 49. Caironi P, Tognoni G, Masson S, Fumagalli R, Pesenti A, Romero M, et al. Albumin replacement in patients with severe sepsis or septic shock. The New England Journal of Medicine. 2014;370(15):1412-1421
  50. 50. Oliveira RP, Velasco I, Soriano FG, Friedman G. Clinical review: Hypertonic saline resuscitation in sepsis. Critical Care. 2002;6(5):418-423
  51. 51. Li F, Sun H, Han XD. The effect of different fluids on early fluid resuscitation in septic shock. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue. 2008;20(8):472-475
  52. 52. Zhu GC, Quan ZY, Shao YS, Zhao JG, Zhang YT. The study of hypertonic saline and hydroxyethyl starch treating severe sepsis. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue. 2011;23(3):150-153
  53. 53. Raghunathan K, Bonavia A, Nathanson BH, Beadles CA, Shaw AD, Brookhart MA, et al. Association between initial fluid choice and subsequent in-hospital mortality during the resuscitation of adults with septic shock. Anesthesiology. 2015;123(6):1385-1393
  54. 54. Chua HR, Venkatesh B, Stachowski E, Schneider AG, Perkins K, Ladanyi S, et al. Plasma-Lyte 148 vs 0.9% saline for fluid resuscitation in diabetic ketoacidosis. Journal of Critical Care. 2012;27(2):138-145
  55. 55. Gosmanov AR, Gosmanova EO, Kitabchi AE. Hyperglycemic crises: Diabetic ketoacidosis (DKA), and hyperglycemic hyperosmolar state (HHS). In: De Groot LJ, Chrousos G, Dungan K, Feingold KR, Grossman A, Hershman JM, et al., editors. Endotext. South Dartmouth, MA:, Inc.; 2000
  56. 56. Kitabchi AE, Umpierrez GE, Miles JM, Fisher JN. Hyperglycemic crises in adult patients with diabetes. Diabetes Care. 2009;32(7):1335-1343
  57. 57. Padhi S, Bullock I, Li L, Stroud M. National Institute for H, Care Excellence Guideline Development G. Intravenous fluid therapy for adults in hospital: Summary of NICE guidance. BMJ. 2013;347:f7073
  58. 58. Corona G, Giuliani C, Parenti G, Norello D, Verbalis JG, Forti G, et al. Moderate hyponatremia is associated with increased risk of mortality: Evidence from a meta-analysis. PLoS One. 2013;8(12):e80451
  59. 59. Upadhyay A, Jaber BL, Madias NE. Epidemiology of hyponatremia. Seminars in Nephrology. 2009;29(3):227-238
  60. 60. Hawkins RC. Age and gender as risk factors for hyponatremia and hypernatremia. Clinica Chimica Acta. 2003;337(1-2):169-172
  61. 61. Miller M, Hecker MS, Friedlander DA, Carter JM. Apparent idiopathic hyponatremia in an ambulatory geriatric population. Journal of the American Geriatrics Society. 1996;44(4):404-408
  62. 62. Miller M, Morley JE, Rubenstein LZ. Hyponatremia in a nursing home population. Journal of the American Geriatrics Society. 1995;43(12):1410-1413
  63. 63. Liamis G, Rodenburg EM, Hofman A, Zietse R, Stricker BH, Hoorn EJ. Electrolyte disorders in community subjects: Prevalence and risk factors. The American Journal of Medicine. 2013;126(3):256-263
  64. 64. Verbalis JG, Goldsmith SR, Greenberg A, Korzelius C, Schrier RW, Sterns RH, et al. Diagnosis, evaluation, and treatment of hyponatremia: Expert panel recommendations. The American Journal of Medicine. 2013;126(10, Suppl 1):S1-S42
  65. 65. Spasovski G, Vanholder R, Allolio B, Annane D, Ball S, Bichet D, et al. Clinical practice guideline on diagnosis and treatment of hyponatraemia. European Journal of Endocrinology. 2014;170(3):G1-G47
  66. 66. Spasovski G, Vanholder R, Allolio B, Annane D, Ball S, Bichet D, et al. Clinical practice guideline on diagnosis and treatment of hyponatraemia. Nephrology, Dialysis, Transplantation. 2014;29(Suppl 2):i1-i39
  67. 67. Spasovski G, Vanholder R, Allolio B, Annane D, Ball S, Bichet D, et al. Clinical practice guideline on diagnosis and treatment of hyponatraemia. Intensive Care Medicine. 2014;40(3):320-331
  68. 68. Halperin ML, Kamel KS. Fluid, Electrolyte, and Acid-base Physiology: A Problem-based Approach. Philadelphia, PA: Elsevier; 2017. Available from: EBSCOhost; ScienceDirect R2 Digital Library;;
  69. 69. Wald R, Jaber BL, Price LL, Upadhyay A, Madias NE. Impact of hospital-associated hyponatremia on selected outcomes. Archives of Internal Medicine. 2010;170(3):294-302
  70. 70. Kim GH. Pseudohyponatremia: Does it matter in current clinical practice? Electrolyte & Blood Pressure: E & BP. 2006;4(2):77-82
  71. 71. Fisher PG. 50 years ago in the Journal of Pediatrics: Cerebrospinal fluid and blood electrolytes in 62 mentally defective infants and children. The Journal of Pediatrics. 2014;165(3):515
  72. 72. Hoorn EJ, Zietse R. Diagnosis and treatment of hyponatremia: Compilation of the guidelines. Journal of the American Society of Nephrology. 2017;28(5):1340-1349
  73. 73. Chung HM, Kluge R, Schrier RW, Anderson RJ. Clinical assessment of extracellular fluid volume in hyponatremia. The American Journal of Medicine. 1987;83(5):905-908
  74. 74. McGee S, Abernethy WB 3rd, Simel DL. The rational clinical examination. Is this patient hypovolemic? Journal of the American Medical Association. 1999;281(11):1022-1029
  75. 75. Musch W, Thimpont J, Vandervelde D, Verhaeverbeke I, Berghmans T, Decaux G. Combined fractional excretion of sodium and urea better predicts response to saline in hyponatremia than do usual clinical and biochemical parameters. The American Journal of Medicine. 1995;99(4):348-355
  76. 76. Hoorn EJ, Halperin ML, Zietse R. Diagnostic approach to a patient with hyponatraemia: Traditional versus physiology-based options. QJM. 2005;98(7):529-540
  77. 77. Tasdemir V, Oguz AK, Sayin I, Ergun I. Hyponatremia in the outpatient setting: Clinical characteristics, risk factors, and outcome. International Urology and Nephrology. 2015;47(12):1977-1983
  78. 78. Kengne FG, Decaux G. CNS manifestations of hyponatremia and its treatment. In: Simon EE, editor. Hyponatremia: Evaluation and Treatment. New York, NY: Springer New York; 2013. pp. 87-110
  79. 79. Babaliche P, Madnani S, Kamat S. Clinical profile of patients admitted with hyponatremia in the medical intensive care unit. Indian Journal of Critical Care Medicine. 2017;21(12):819-824
  80. 80. Nagler EV, Vanmassenhove J, van der Veer SN, Nistor I, Van Biesen W, Webster AC, et al. Diagnosis and treatment of hyponatremia: A systematic review of clinical practice guidelines and consensus statements. BMC Medicine. 2014;12:1
  81. 81. Hoorn EJ, Hotho D, Hassing RJ, Zietse R. Unexplained hyponatremia: Seek and you will find. Nephron. Physiology. 2011;118(3):p66-p71
  82. 82. Roussel R, Fezeu L, Marre M, Velho G, Fumeron F, Jungers P, et al. Comparison between copeptin and vasopressin in a population from the community and in people with chronic kidney disease. The Journal of Clinical Endocrinology and Metabolism. 2014;99(12):4656-4663
  83. 83. Moses AM, Clayton B. Impairment of osmotically stimulated AVP release in patients with primary polydipsia. The American Journal of Physiology. 1993;265(6 Pt 2):R1247-R1252
  84. 84. Fenske W, Stork S, Blechschmidt A, Maier SG, Morgenthaler NG, Allolio B. Copeptin in the differential diagnosis of hyponatremia. The Journal of Clinical Endocrinology and Metabolism. 2009;94(1):123-129
  85. 85. Blanchard A, Steichen O, De Mota N, Curis E, Gauci C, Frank M, et al. An abnormal apelin/vasopressin balance may contribute to water retention in patients with the syndrome of inappropriate antidiuretic hormone (SIADH) and heart failure. The Journal of Clinical Endocrinology and Metabolism. 2013;98(5):2084-2089
  86. 86. Nigro N, Winzeler B, Suter-Widmer I, Schuetz P, Arici B, Bally M, et al. Mid-regional pro-atrial natriuretic peptide and the assessment of volaemic status and differential diagnosis of profound hyponatraemia. Journal of Internal Medicine. 2015;278(1):29-37
  87. 87. Hus-Citharel A, Bodineau L, Frugiere A, Joubert F, Bouby N, Llorens-Cortes C. Apelin counteracts vasopressin-induced water reabsorption via cross talk between apelin and vasopressin receptor signaling pathways in the rat collecting duct. Endocrinology. 2014;155(11):4483-4493
  88. 88. Tzikas S, Keller T, Wild PS, Schulz A, Zwiener I, Zeller T, et al. Midregional pro-atrial natriuretic peptide in the general population/Insights from the Gutenberg Health Study. Clinical Chemistry and Laboratory Medicine. 2013;51(5):1125-1133
  89. 89. Hoorn EJ, Lindemans J, Zietse R. Development of severe hyponatraemia in hospitalized patients: Treatment-related risk factors and inadequate management. Nephrology, Dialysis, Transplantation. 2006;21(1):70-76
  90. 90. Cohen DM, Ellison DH. Evaluating hyponatremia. Journal of the American Medical Association. 2015;313(12):1260-1261
  91. 91. Moritz ML, Ayus JC. The syndrome of inappropriate antidiuresis. The New England Journal of Medicine. 2007;357(9):942 author reply
  92. 92. Musch W, Decaux G. Treating the syndrome of inappropriate ADH secretion with isotonic saline. QJM. 1998;91(11):749-753
  93. 93. Steele A, Gowrishankar M, Abrahamson S, Mazer CD, Feldman RD, Halperin ML. Postoperative hyponatremia despite near-isotonic saline infusion: A phenomenon of desalination. Annals of Internal Medicine. 1997;126(1):20-25
  94. 94. Hauptman PJ, Burnett J, Gheorghiade M, Grinfeld L, Konstam MA, Kostic D, et al. Clinical course of patients with hyponatremia and decompensated systolic heart failure and the effect of vasopressin receptor antagonism with tolvaptan. Journal of Cardiac Failure. 2013;19(6):390-397
  95. 95. Konstam MA, Gheorghiade M, Burnett JC Jr, Grinfeld L, Maggioni AP, Swedberg K, et al. Effects of oral tolvaptan in patients hospitalized for worsening heart failure: The EVEREST Outcome Trial. Journal of the American Medical Association. 2007;297(12):1319-1331
  96. 96. Ayus JC, Armstrong D, Arieff AI. Hyponatremia with hypoxia: Effects on brain adaptation, perfusion, and histology in rodents. Kidney International. 2006;69(8):1319-1325
  97. 97. Ayus JC, Arieff AI. Pulmonary complications of hyponatremic encephalopathy. Noncardiogenic pulmonary edema and hypercapnic respiratory failure. Chest. 1995;107(2):517-521
  98. 98. Huq S, Wong M, Chan H, Crimmins D. Osmotic demyelination syndromes: Central and extrapontine myelinolysis. Journal of Clinical Neuroscience. 2007;14(7):684-688
  99. 99. Berl T. Vasopressin antagonists. The New England Journal of Medicine. 2015;372(23):2207-2216
  100. 100. Lehrich RW, Ortiz-Melo DI, Patel MB, Greenberg A. Role of vaptans in the management of hyponatremia. American Journal of Kidney Diseases. 2013;62(2):364-376
  101. 101. Berl T, Quittnat-Pelletier F, Verbalis JG, Schrier RW, Bichet DG, Ouyang J, et al. Oral tolvaptan is safe and effective in chronic hyponatremia. Journal of the American Society of Nephrology. 2010;21(4):705-712
  102. 102. Schrier RW, Gross P, Gheorghiade M, Berl T, Verbalis JG, Czerwiec FS, et al. Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia. The New England Journal of Medicine. 2006;355(20):2099112
  103. 103. Tzoulis P, Waung JA, Bagkeris E, Carr H, Khoo B, Cohen M, et al. Real-life experience of tolvaptan use in the treatment of severe hyponatraemia due to syndrome of inappropriate antidiuretic hormone secretion. Clinical Endocrinology. 2016;84(4):620-626
  104. 104. Sarges P, Steinberg JM, Lewis JH. Drug-induced liver injury: Highlights from a review of the 2015 literature. Drug Safety. 2016;39(9):801-821
  105. 105. Dousa TP, Wilson DM. Effects of demethylchlortetracycline on cellular action of antidiuretic hormone in vitro. Kidney International. 1974;5(4):279-284
  106. 106. Kruse C, Eiken P, Verbalis J, Vestergaard P. The effect of chronic mild hyponatremia on bone mineral loss evaluated by retrospective national Danish patient data. Bone. 2016;84:9-14
  107. 107. Usala RL, Fernandez SJ, Mete M, Cowen L, Shara NM, Barsony J, et al. Hyponatremia is associated with increased osteoporosis and bone fractures in a large US health system population. The Journal of Clinical Endocrinology and Metabolism. 2015;100(8):3021-3031
  108. 108. Holm JP, Amar AOS, Hyldstrup L, Jensen JEB. Hyponatremia, a risk factor for osteoporosis and fractures in women. Osteoporosis International. 2016;27(3):989-1001
  109. 109. Kwak MK, Choi D, Lee JH, Kim HJ, Park HK, Suh KI, et al. Relationship between decrease in serum sodium level and bone mineral density in osteoporotic fracture patients. Journal of Bone Metabolism. 2015;22(1):915
  110. 110. Kruse C, Eiken P, Vestergaard P. Hyponatremia and osteoporosis: Insights from the Danish National Patient Registry. Osteoporosis International. 2015;26(3):1005-1016
  111. 111. Kinsella S, Moran S, Sullivan MO, Molloy MG, Eustace JA. Hyponatremia independent of osteoporosis is associated with fracture occurrence. Clinical Journal of the American Society of Nephrology. 2010;5(2):275-280
  112. 112. Melton JE, Nattie EE. Brain and CSF water and ions during dilutional and isosmotic hyponatremia in the rat. The American Journal of Physiology. 1983;244(5):R724-R732
  113. 113. Verbalis JG, Drutarosky MD. Adaptation to chronic hypoosmolality in rats. Kidney International. 1988;34(3):351-360
  114. 114. Verbalis JG, Gullans SR. Hyponatremia causes large sustained reductions in brain content of multiple organic osmolytes in rats. Brain Research. 1991;567(2):274-282
  115. 115. Videen JS, Michaelis T, Pinto P, Ross BD. Human cerebral osmolytes during chronic hyponatremia. A proton magnetic resonance spectroscopy study. The Journal of Clinical Investigation. 1995;95(2):788-793
  116. 116. Arieff AI. Hyponatremia, convulsions, respiratory arrest, and permanent brain damage after elective surgery in healthy women. The New England Journal of Medicine. 1986;314(24):1529-1535
  117. 117. Arieff AI, Llach F, Massry SG. Neurological manifestations and morbidity of hyponatremia: Correlation with brain water and electrolytes. Medicine (Baltimore). 1976;55(2):121-129
  118. 118. Ayus JC, Krothapalli RK, Arieff AI. Treatment of symptomatic hyponatremia and its relation to brain damage. A prospective study. The New England Journal of Medicine. 1987;317(19):1190-1195
  119. 119. Gankam-Kengne F, Ayers C, Khera A, de Lemos J, Maalouf NM. Mild hyponatremia is associated with an increased risk of death in an ambulatory setting. Kidney International. 2013;83(4):700-706
  120. 120. Mohan S, Gu S, Parikh A, Radhakrishnan J. Prevalence of hyponatremia and association with mortality: Results from NHANES. The American Journal of Medicine. 2013;126(12):1127-1137 e1
  121. 121. Rusinaru D, Tribouilloy C, Berry C, Richards AM, Whalley GA, Earle N, et al. Relationship of serum sodium concentration to mortality in a wide spectrum of heart failure patients with preserved and with reduced ejection fraction: An individual patient data meta-analysis(dagger): Meta-Analysis Global Group in Chronic heart failure (MAGGIC). European Journal of Heart Failure. 2012;14(10):1139-1146
  122. 122. Gheorghiade M, Abraham WT, Albert NM, Gattis Stough W, Greenberg BH, O'Connor CM, et al. Relationship between admission serum sodium concentration and clinical outcomes in patients hospitalized for heart failure: An analysis from the OPTIMIZE-HF registry. European Heart Journal. 2007;28(8):980-988
  123. 123. Shorr AF, Tabak YP, Johannes RS, Gupta V, Saltzberg MT, Costanzo MR. Burden of sodium abnormalities in patients hospitalized for heart failure. Congestive Heart Failure. 2011;17(1):1-7
  124. 124. Kim WR, Biggins SW, Kremers WK, Wiesner RH, Kamath PS, Benson JT, et al. Hyponatremia and mortality among patients on the liver-transplant waiting list. The New England Journal of Medicine. 2008;359(10):1018-1026
  125. 125. Kovesdy CP, Lott EH, Lu JL, Malakauskas SM, Ma JZ, Molnar MZ, et al. Hyponatremia, hypernatremia, and mortality in patients with chronic kidney disease with and without congestive heart failure. Circulation. 2012;125(5):677-684
  126. 126. Nigwekar SU, Wenger J, Thadhani R, Bhan I. Hyponatremia, mineral metabolism, and mortality in incident maintenance hemodialysis patients: A cohort study. American Journal of Kidney Diseases. 2013;62(4):755-762
  127. 127. Chang TI, Kim YL, Kim H, Ryu GW, Kang EW, Park JT, et al. Hyponatremia as a predictor of mortality in peritoneal dialysis patients. PLoS One. 2014;9(10):e111373
  128. 128. Zilberberg MD, Exuzides A, Spalding J, Foreman A, Jones AG, Colby C, et al. Hyponatremia and hospital outcomes among patients with pneumonia: A retrospective cohort study. BMC Pulmonary Medicine. 2008;8:16
  129. 129. Tang WW, Kaptein EM, Feinstein EI, Massry SG. Hyponatremia in hospitalized patients with the acquired immunodeficiency syndrome (AIDS) and the AIDS-related complex. The American Journal of Medicine. 1993;94(2):16974
  130. 130. Tamizifar B, Kheiry S, Fereidoony F. Hyponatremia and 30 days mortality of patients with acute pulmonary embolism. Journal of Research in Medical Sciences. 2015;20(8):777-781
  131. 131. Scherz N, Labarere J, Mean M, Ibrahim SA, Fine MJ, Aujesky D. Prognostic importance of hyponatremia in patients with acute pulmonary embolism. American Journal of Respiratory and Critical Care Medicine. 2010;182(9):1178-1183
  132. 132. Waikar SS, Mount DB, Curhan GC. Mortality after hospitalization with mild, moderate, and severe hyponatremia. The American Journal of Medicine. 2009;122(9):857-865
  133. 133. Vandergheynst F, Gombeir Y, Bellante F, Perrotta G, Remiche G, Melot C, et al. Impact of hyponatremia on nerve conduction and muscle strength. European Journal of Clinical Investigation. 2016;46(4):328-333
  134. 134. Renneboog B, Musch W, Vandemergel X, Manto MU, Decaux G. Mild chronic hyponatremia is associated with falls, unsteadiness, and attention deficits. The American Journal of Medicine. 2006;119(1):71 e1-71 e8
  135. 135. de Souza A, Desai PK. More often striatal myelinolysis than pontine? A consecutive series of patients with osmotic demyelination syndrome. Neurological Research. 2012;34(3):262-271
  136. 136. Sterns RH, Riggs JE, Schochet SS Jr. Osmotic demyelination syndrome following correction of hyponatremia. The New England Journal of Medicine. 1986;314(24):1535-1542
  137. 137. Menger H, Jorg J. Outcome of central pontine and extrapontine myelinolysis (n = 44). Journal of Neurology. 1999;246(8):700-705
  138. 138. Louis G, Megarbane B, Lavoue S, Lassalle V, Argaud L, Poussel JF, et al. Long-term outcome of patients hospitalized in intensive care units with central or extrapontine myelinolysis. Critical Care Medicine. 2012;40(3):970-972
  139. 139. Kallakatta RN, Radhakrishnan A, Fayaz RK, Unnikrishnan JP, Kesavadas C, Sarma SP. Clinical and functional outcome and factors predicting prognosis in osmotic demyelination syndrome (central pontine and/or extrapontine myelinolysis) in 25 patients. Journal of Neurology, Neurosurgery, and Psychiatry. 2011;82(3):326-331
  140. 140. Sood L, Sterns RH, Hix JK, Silver SM, Chen L. Hypertonic saline and desmopressin: A simple strategy for safe correction of severe hyponatremia. American Journal of Kidney Diseases. 2013;61(4):571-578
  141. 141. Perianayagam A, Sterns RH, Silver SM, Grieff M, Mayo R, Hix J, et al. DDAVP is effective in preventing and reversing inadvertent overcorrection of hyponatremia. Clinical Journal of the American Society of Nephrology. 2008;3(2):331-336
  142. 142. Soupart A, Penninckx R, Crenier L, Stenuit A, Perier O, Decaux G. Prevention of brain demyelination in rats after excessive correction of chronic hyponatremia by serum sodium lowering. Kidney International. 1994;45(1):193-200
  143. 143. Gankam Kengne F, Soupart A, Pochet R, Brion JP, Decaux G. Re-induction of hyponatremia after rapid overcorrection of hyponatremia reduces mortality in rats. Kidney International. 2009;76(6):614-621
  144. 144. Adrogue HJ, Madias NE. Hypernatremia. The New England Journal of Medicine. 2000;342(20):1493-1499
  145. 145. Liamis G, Filippatos TD, Elisaf MS. Evaluation and treatment of hypernatremia: A practical guide for physicians. Postgraduate Medicine. 2016;128(3):299-306
  146. 146. Sterns RH. Disorders of plasma sodium—Causes, consequences, and correction. The New England Journal of Medicine. 2015;372(1):55-65

Written By

Gilda Diaz-Fuentes, Bharat Bajantri and Sindhaghatta Venkatram

Submitted: 02 May 2018 Reviewed: 25 May 2018 Published: 05 November 2018