**Fluids and Sodium Imbalance: Clinical Implications**

Gilda Diaz-Fuentes, Bharat Bajantri and Sindhaghatta Venkatram

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.79121

### **Abstract**

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.-

**Keywords:** 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 (HCO<sup>3</sup> ) 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 surfacesof 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, 5–8]. 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**.

*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.

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


**Table 1.** Composition of crystalloids.-


**Table 2.** Composition of colloids.-

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:-


#### **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 90days.-

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 28days 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 154mEq/L and the pH of 5.6 are certainly abnormal in "normal saline." The strong ion difference (SID) is the difference between the positivelyand 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 (>30cc/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 [22–24].

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 110mEq/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 3in 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*:


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 [43–45]; 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 90days 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 [46–48]. 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 120min of therapy to about 3mmol/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 12h, 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 4–14ml/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, 2500ml 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 25–30ml/kg/day- water, 1mmol/kg/day sodium, potassium, chloride, and 50–100g/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.

Pearls:-


### **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 136mmol/L.-The sNa cut offs to define hyponatremia varies from 125 to 135mmol/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 etal. reported an 11% incidence of hyponatremia in the ambulatory setting among elderly population with a median age of 78years [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 [65–67]. 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].

#### **3.2. Classification-**

Hyponatremia can be classified based in:-


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- 100mg/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 [73–75]. Euvolemia itself is considered to be a misnomer as loss of sodiumcannot 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].


**Table 3.** Prevalence and outcome of hyponatremia.-

### **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.-

*Chronic hyponatremia:* slow onset of hyponatremia, usually more than 48h. 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.-

### *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


**Table 4.** Causes of acute hyponatremia.-

#### **Lower rate of water excretion due to low Lower rate of water excretion due to vasopressin actionsvolume of distal delivery of filtrate-**


Modified from [5].

**Table 5.** Causes of chronic hyponatremia.-


**Table 6.** Laboratory findings in most common causes of hypotonic hyponatremia.-

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 30pmol/mmol had an AUC of 0.88in 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 [85–88].

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:-


Volume expansion should be cautiously done in certain conditions like immediate postoperative 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.-

### *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].

**Figure 1.** Algorithm for initial evaluation of hyponatremia. Based in the USA and European guidelines [64–67].

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 [96,-97]. 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.-

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


 electrolyte ratio (uNa-+urine K/sNa) >1 indicates antidiuretic phase and a ratio-<1 suggests- aquaretic phase. Fluid restrictions to less than 500ml/day in antidiuretic phase and 1000ml/day- in aquaretic phase have been recommended; however, adherence is a problem [72].


### *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 115mEq/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 [106–111].

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 [112–115]. 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].


**Table 7.** Management of hypotonic hyponatremia and comparison between existing guidelines.-

Most cases of hyponatremia in the ambulatory setting are mild. An sNa of less than 125mmol/L- was seen in 0.14% in Hawkin etal. study [60]. The Dallas heart study, a large prospective multiethnic cohort study of 3551 ambulatory individuals with median age of 43year/age and from- diverse ethnicity, found that mild hyponatremia (median 133mmol/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, 121–129]. 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 etal. 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- 138–142mEq/L.-In patients with hospital acquired hyponatremia, the risk of mortality was 15- times higher among patients with first serum sodium level of 127mEq/L or less [69]. A larger- prospective study by Waiker and colleagues with approximately 100,000 individuals followed- up to 5years 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 5year 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, 24–48h, 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 48h, a change in the sNa concentration of >25mmol/L in the first 48h, a hypoxicanoxic episode, and an elevation of sNa to hypernatremic levels in patients with hepatic encephalopathy were associatedwith 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 [137–139].

#### **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 6–8mEq/L/day. Brain demyelination has been reported over a range of rate of sNa correction of 8–12–18mEq/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 145mmol/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 8–10mmol/L/day for patients with hypernatremia with a goal to reduce the sNa to 145mmol/L [145, 146].

Pearls:-


### **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.-

### **Abbreviations**


### **Author details**

Gilda Diaz-Fuentes1,2\*, Bharat-Bajantri1,2 and Sindhaghatta-Venkatram1,2-

\*Address all correspondence to: gfuentes@bronxleb.org-

1-Division of Pulmonary Critical Care, Department of Medicine, BronxCare Health System, Bronx, New York, USA-

2-Icahn School of Medicine at Mount Sinai, USA-

### **References**


## **Hyponatremia and Psychotropic Drugs**

Mireia Martínez Cortés and Pedro Gurillo Muñoz

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.79029

### **Abstract**

Given the widespread use of psychotropic drugs in the population, it's important to consider hyponatremia as an avoidable and reversible adverse effect and include the detection of high-risk subjects to establish safer medications, as well as early detection measures in routine clinical practice. Although hyponatremia has been especially associated with serotonergic antidepressants (SSRIs), there is also an elevated risk with tricyclics, duals and heterocyclic antidepressants, due to the different mechanisms of action at the renal tubular level and the release of ADH. Hyponatremia secondary to tricyclics with slow CYP2D6 metabolizers have higher plasma concentrations of antidepressants metabolized by CYP2D6. Hyponatremia secondary to SSRIs appears in the first week of treatment, it is "not dose-dependent" and normalization of natremia occurs between 2 and 20 days after stopping the medication. Bupropion, trazodone, mianserin, reboxetine and agomelatine are a safe alternative. Also antiepileptics have been related to hyponatremia. Both typical and atypical antipsychotics have been exposed to an increased risk of hyponatremia, even after adjusted factors such as age, sex and comorbidity. Other factors that favor the onset of hyponatremia act synergistically with psychotropic drugs, such as: advanced age, female sex, concomitant diuretic intake, low body weight and low sodium levels; NSAID, ACEIs, and warm.

**Keywords:** hyponatremia, antipsychotic, antidepressant, antiepileptic, psychotropic drugs

### **1. Introduction**

 Hyponatremia is the most frequent hydroelectrolytic disorder in clinical practice, both in hospital and outpatient settings-[1]. Defined as a serum sodium concentration or sodium level < 135 mmol/L, its frequency varies according to its intensity, with severe and more severe hyponatremia in hospitalized patients. Hyponatremia is present in 15–20% of urgent hospital

> © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

admissions and in up to 20% of critical patients. Although it estimates a daily incidence of 1% in hospitalized patients and a prevalence of 2.5%, its frequency is probably higher, since it is frequently underdiagnosed [2]. Some epidemiological studies report that only 30% of patients with hyponatremia are diagnosed, including the most serious ones [3]. Clinical manifestations of hyponatremia have a broad spectrum, from mild to severe or even potentially lethal. Hyponatremia is related to an increase in mortality, morbidity, duration of hospital stay and socio-health costs in patients with multiple pathologies. Some studies show that the presence of hyponatremia is an independent predictor of mortality rate, implying a relative risk of death between 1 and 2 times higher [4]; risk that is maintained per year and even 5 years after a hospital admission. Hyponatremia is related to a higher rate of hospitalization in Intensive Care Units and mechanical ventilation units.

Etiology of hyponatremia is multifactorial, highlighting the pharmacological origin. Some of the mechanisms involved in the development of pharmacological hyponatremia are the alteration of sodium and water homeostasis (diuretics), the increase in the production of the antidiuretic hormone (antidepressants, antipsychotics, antiepileptics, anticancer drugs, methrotrexate, interferon alfa, opiates) and the potentiation of the effects of antidiuretic- hormone (antiepileptic, hypoglycemic, nonsteroidal anti-inflammatory drugs [NSAIDs],- angiotensin-converting enzyme inhibitors [ACEIs] and anticancer drugs). Factors such as- female sex, weight, advanced age, the presence of associated pathologies (cardiological, hepatic, neurological and endocrine), the concomitant use of drugs (especially thiazide diuretics, inhibitors of the reuptake of serotonin and carbamazepine) and basal sodium levels in the low threshold of normality have been related to the development of hyponatremia [5].

Prescription and use of psychotropic drugs is currently growing, both due to the increase in the incidence of mental illnesses and depression, which according to the WHO will be the second cause of disability in the world in 2020 [6]. Elderly patients have higher prevalences of mood disorders, which together with the greater frequency of polypathology and polypharmacy, makes them a risk group for presenting hyponatremia.

### **2. Hyponatremia**

### **2.1. Definition of hyponatremia-**

#### *2.1.1. Definition of hyponatremia based on biochemical severity-*

Mild (sodium between 130 and 135 mmol/L); moderate (sodium between 125 and 129 mmol/L); severe (sodium <125 mmol/L).

### *2.1.2. Definition of hyponatremia based on development time-*

Acute (<48 h) or chronic (greater or equal to 48 h). Current literature establishes the limit of 48 h to distinguish between acute and chronic hyponatremia, since cerebral edema appears more frequently when hyponatremia is established in less than 48 h. Experimental studies suggest that the brain needs approximately 48 h to adapt to a hypotonic environment; there is a risk of cerebral edema before such adaptation. However, once the adaptation is completed, a rapid rise in the serum sodium level can cause lesions of the myelin sheath, which is known as osmotic demyelination syndrome. Hence, the importance in clinical practice to distinguish between acute and chronic hyponatremia, evaluating whether a subject is at greater risk of cerebral edema or osmotic demyelination. If there are doubts about the development time of hyponatremia [7], it should be considered chronic, unless there are reasons to think otherwise.

#### *2.1.3. Definition of hyponatremia based on symptoms-*

Moderate: any degree of hyponatremia associated with moderately severe symptoms of hyponatremia: nausea without vomiting, confusion, and headache.

Severe: any biochemical degree of hyponatremia associated with severe symptoms of hyponatremia: vomiting, cardiorespiratory distress, abnormal and deep drowsiness, seizures, and coma.

#### *2.1.4. Definition of hyponatremia based on plasma osmolality-*

	- **a.** *hypotonic hyponatremia with hypovolemia*: occurs when there are losses of sodium and water, with partial supplementation of fluid losses without electrolytes. Losses can occur- through the skin, digestive tract, renal pathway or leakage of fluids into a third space.-
	- **b.** *hypotonic hyponatremia with isovolemia*: SIADH is the most common cause of hyponatremia.
	- **c.** *hypotonic hyponatremia with hypervolemia*: it occurs both in situations of increased vasopressin secretion in states of a relative decrease in effective intravascular volume (chronic heart failure, liver cirrhosis with ascites, nephrotic edema); excessive fluid intake without electrolytes and an altered excretion of free water (acute kidney injury, advanced chronic kidney disease).

### **2.2. Etiology**

#### *2.2.1. Acute hyponatremia-*

Primary polydipsia, intensive physical exercise, thiazide diuretics, postoperative state, vasopressin analogs, colonoscopy preparations, 3,4-methylenedioxymethamphetamine intake.

### *2.2.2. Nonhypotonic hyponatremia-*


### *2.2.3. Hypotonic hyponatremia-*


#### *2.2.4. Hyponatremia and psychotropic drugs-*

As we have previously described, in case of psychotropic drugs, hyponatremia is mediated by the inappropriate release of ADH. ADH or vasopressin is a hypothalamic hormone that is stored and released through the neurohypophysis in response to osmotic and nonosmotic stimuli:


Vasopressin has three receptors coupled to G proteins: V1 (presents vasopressor effect), V2 (responsible for the reabsorption of water in the collecting tubule of the nephron) and V3 (responsible for the release of ACTH). Vasopressin or ADH has several functions:


### **2.3. Symptomatology**

The symptomatology of hyponatremia varies depending on the biochemical severity and the speed of the establishment. It can be classified as mild, moderate and severe.-

#### *2.3.1. Mild symptoms-*

(Na 130–135mEq/L): headache, attention deficit, memory alterations, irritability, depression.-

#### *2.3.2. Moderate symptoms-*

(Na 120–130 mEq/L): nausea, vomiting, bradypsychia, confusion, disorientation.

#### *2.3.3. Severe symptoms-*

(Na < 120 mEq/L): stupor, seizures, coma, respiratory depression.

#### *2.3.4. Hyponatremic encephalopathy-*

In hyponatremia, low serum osmolarity causes an osmotic gradient between the extracellular space and the intracellular space, with the consequent passage of free water into the interior of the cell. This accumulation of water in the brain cells causes cerebral edema. The cellular edema produces an increase in the size of the various organs, however in the case of brain, expansion is not possible due to the limitation of the cranial cavity. Thus, increases in brain volume of 8–10% can cause coma and compromise the condition of the individual due to intracranial hypertension and transtentorial herniation. However, hyponatremia activates a series of compensatory mechanisms to decrease the volume of intracellular fluid, to reduce the risk of cerebral edema and the risks derived from it [9]. Adequate regulation of brain volume is an essential factor in the prognosis of hyponatremic encephalopathy. Some of these compensatory mechanisms are:


Brain adaptation to hyponatremia is related to the speed of its establishment. In chronic hyponatremia (that lasts more than 48 h) the slow and progressive decrease of sodium allows a compensatory regulation of the whole volume, limiting the degree of cerebral edema and being asymptomatic or slightly symptomatic. However, in cases of acute hyponatremia, adaptive mechanisms are exceeded and symptoms are more likely to occur even with mild hyponatremia.

There are some risk factors for the development of hyponatremic cerebral edema:


#### *2.3.5. Age-*

Elderly patients are a vulnerable population and at risk of developing hyponatremia due to various causes. In the first place, the physiological changes characteristic of aging, such as the decrease in volume and body weight, pose a risk to develop hyponatremia. On the other hand, they are a population often with multi co-morbidities, exposed to diets without salt, to forced hydration (oral or intravenous) and with the use of polytherapy, which makes them candidates for risk.

#### *2.3.6. Institutionalization-*

Some studies have shown a higher incidence of hyponatremia in subjects older than 60 years institutionalized in residences than in patients of the same age living at home (18 versus 8%) [10].

#### *2.3.7. Female sex-*

Female sex has been associated with an increased risk of hyponatremia and the development of hyponatremic encephalopathy [11]. Some hypothesis proposed for this difference are based on hormonal factors and cellular transport of sodium and volume of distribution of body water different from men.-

#### *2.3.8. Comorbidity-*

Hyponatremia has been associated with multiple pathologies (infectious, oncological, neurological, renal, metabolic, etc.).

### *2.3.9. Polytherapy-*

Multiple drugs have been associated with an increased risk of hyponatremia, especially antipsychotics, antidepressants and antiepileptic [12], diuretics (mainly thiazides), ACEIs and NSAIDs. Other drugs have been related to hyponatremia, such as vasopressin analogs, interferon, antidiabetics, anticancer drugs, proton pump inhibitors and monoclonal antibodies, among others.


### **2.4. Treatment**

It is important to remember that despite of the severity of the neurological signs and symptoms of acute hyponatremia, the correction of hyponatremia in a rapid and uncontrolled way can generate chronic neurological lesions due to osmotic demyelination. When there is a decrease in sodium, cells excrete organic solutes and other molecules to maintain homeostasis, in a process that can last between 48 and 72h, so hyponatremia can be classified as acute or chronic if the duration is shorter or greater than 48 h, respectively.

It is recommended that sodium correction rate does not exceed 8 mmol/L in any 24-h period, being even lower in those patients susceptible to osmotic demyelination (as in the case of advanced cirrhosis, alcoholism or severe malnutrition). Even in patients with severe hyponatremia that are accompanied by severe neurological symptoms, 4 – 6 mEq/L rise in serum sodium is sufficient in the first 24-h (this target can be achieved in first few hours in severely symptomatic patients and then maintained at that level for the first 24-h). Three percent sodium chloride solution can be used to achieve this. It is important to remember that the recommended correction rates of 24 h should not be exceeded.

There is a series of formulas that allow to calculate in a quantitative way the effect of the prescribed fluid therapy on patient's serum sodium.-

The **Adrogue-Madias Formula (AMF)** [13] helps to estimate the effect of a given fluid on serum sodium. It takes into account the sodium concentration and the total body weight (TBW) adjusted by a correction factor that varies according to age and sex. However, the AMF does not take into account the losses and the pathophysiology that underlies them and requires that sodium levels be monitored frequently during the infusion of the fluid.-

*Infusate formula: Adrogue-Madias formula.-*

$$\Delta[\text{Na}^+]\_\text{s} = \frac{[\text{Na}^+ + \text{K}^+]\_{\text{mf}} - [\text{Na}^+]\_\text{s}}{\text{TBW} + \text{T}} \tag{1}$$

However, this formula has the limitation of being approximate as rise in sodium level is often greater than that predicted by the formula.

Fluid restriction should be the first therapeutic measure in cases of euvolemic or hypervolemic hyponatremia. Depending on the severity of the hyponatremia and symptomatic severity, the fluid should be restricted to provide a negative fluid balance of approximately 500ml per day.

There are several therapeutic options for the treatment of hyponatremia secondary to SIADH:

**Demeclocycline.** It is a tetracyclic antibiotic whose mechanism of action is the inhibition of ADH receptors in the renal distal tubule, inducing nephrogenic diabetes insipidus. It is administered in doses of (300 – 600mg twice a day). Side effects include photosensitivity, nephrotoxicity and nausea.

**Antagonists of the vasopressin receptor ("vaptans").-**ADH or vasopressin acts at the level of various receptors: V1a (causes vasoconstriction), V1b (secretion of ACTH) and V2 (water reabsorption and release of von Willebrand factor and factor VIII). Drugs that act on V2 receptors at the tubular level increase the excretion of water (aquaresis).


#### **3. Hyponatremia and antipsychotics-**

Antipsychotics are a family of drugs used primarily in the treatment of schizophrenia, bipolar disorder and other affective psychoses, but also in other neuropsychiatric disorders (such as dementia and autism), symptomatic treatment of acute confusional symptoms and other conditions not psychiatric (nausea, hiccups, migraine). Some studies show stability in the prevalence (2.05%) and incidence (0.66%) in the use of antipsychotics in the last decade, although showing an increase in its use in the infant-juvenile population and higher employment of second generation antipsychotics (SGAPs) [14]. Its mechanism of action is dopaminergic blocking. They are classified into two main groups: the classic or typical antipsychotics, which present a blockade of the D2 dopaminergic receptor and are effective in the positive symptoms of schizophrenia (hallucinations and delusions) but show extrapyramidal symptoms as the most notable side effects; and the atypical or second generation antipsychotics, in addition to blocking the D2 receptor, exhibit muscarinic, adrenergic, serotonergic and histamergic receptor activity, showing a broader spectrum of action (including positive and negative symptoms) and a different side effect profile of the typical ones (minor extrapyramidal symptoms, but weight gain, dry mouth, orthostatic hypotension, constipation, urinary retention, narrow-angle glaucoma, sedation).

Hyponatremia is an adverse effect described both in the case of classical and atypical antipsychotics. It is postulated that the etiopathogenesis of hyponatremia in atypical antipsychotics is mediated by the action of serotonin, both by the release of ADH induced by the stimulation of central receptors 5-HT2 and 5-HT1c and by the increase in the effects of ADH at the renal medullary level [15]. In the case of typical antipsychotics, prolonged blockade of dopamine D2 receptors stimulates the release of ADH and increases its peripheral response [16]. The occurrence of hyponatremia occurs in the first 3 weeks of treatment in up to 50% of cases, although cases have also been reported in patients undergoing long-term chronic treatments. On the other hand, in the case of antipsychotics, neither age nor female sex are risk factors. The chemical structure and receptor affinity profiles of the dopamine D2 receptor and serotonin 5-HT2A have not shown a variation with respect to the risk of hyponatremia [17]. Several studies describe that hyponatremia at admission is associated with greater medical deterioration in hospitalized psychiatric patients [18], therefore adequate clinical monitoring should be performed to identify and treat somatic pathologies and concomitant use of drugs. Also, it is recommended to measure serum sodium in those patients on antipsychotic treatment who present with seizures.

In a follow-up study over 15 years with a sample of 2051 patients diagnosed with schizophrenia [19] from 1998 to 2013, an incidence of hyponatremia of 6.7% was observed. The study showed that the use of antipsychotics, both typical and atypical, was associated with an elevated risk of hyponatremia with respect to the nonuse of antipsychotics, even after adjusting for age, sex and physical comorbidity. Age of diagnosis of the disease, low income, physical comorbidity, psychiatric admissions and concomitant treatment with carbamazepine were also associated with an increased risk of hyponatremia. Another retrospective study showed that treatment with atypical antipsychotics in the elderly was associated with a modest but statistically significant increase in the risk of hospitalization for hyponatremia in 30days, an association that- was smaller than other psychotropic drugs [20]. A systematic review on hyponatremia and the use of antipsychotics, published in 2010 [16], which includes 4 studies and 91 cases and series of cases, showed that the diagnosis of schizophrenia and male sex were more frequently associated with hyponatremia. Using the Naranjo Scale of Adverse Drug Reaction Probability Scale, in 80% of the cases possible causality was determined, in 19% probable causality and in 1% impossible causality. No significant association was found between daily doses of drugs- and serum sodium or time to onset of hyponatremia. Currently, tolvaptan is positioned as a drug approved by the FDA in the treatment of euvolemic and hypervolemic hyponatremia,- and useful in the management of hyponatremia associated with the use of antipsychotics [21].

### **3.1. First generation antipsychotics (FGAS)-**

In recent decades the use of typical antipsychotics has been progressively replaced by atypical ones, by the receptor profile and side effects. Nonetheless, haloperidol continues to be thedrug of choice in the management of agitation and acute confusional syndrome. Haloperidolrelated hyponatremia has been reported for decades [22, 27], but also with other first-generation antipsychotics such as chlorpromazine, perphenazine, and fluphenazine [23–25]. In the majority of cases there were other intercurrent factors involved in the development of hyponatremia (concomitant treatment with ACE inhibitors, diuretics and other psychotropic drugs).

### **3.2. Second generation antipsychotics (SGAS)-**

#### *3.2.1. Aripiprazole-*

Aripiprazole is a partial agonist of dopamine, frequently used for its efficacy in cognitive and affective symptoms in psychosis. There are currently presentations for oral, parenteral and prolonged release treatment. Literature collects cases of aripiprazole-induced hyponatremia both in patients who developed the symptoms at the start of treatment [15] and in increasing the dose [26], improving in all of them the clinical symptoms with interruption of treatment and water restriction.

#### *3.2.2. Olanzapine-*

It is an atypical antipsychotic, antagonist of D2 and 5HT2A receptor. It is commonly used in clinical practice to control agitation and positive symptoms. Cases of olanzapine-induced hyponatremia have been reported together with the concomitant use of other psychoactive drugs [5, 27]. In 2014, a case of death was described in a young schizophrenic male who presented with hyponatremia secondary to excessive water intake and which was related to the increase in the dose of olanzapine, which could have acted aggravating the intoxication itself [28].

#### *3.2.3. Quetiapine-*

Synthesized in 1985, it is used in the treatment of schizophrenia, bipolar disorder, Alzheimer's disorder and major depression. There are few cases of SIADH induced by quetiapine, something that could be related to underdiagnosis and underreporting of this situation. Nonetheless, some cases are collected where quetiapine, together with other factors such as advanced age and polytherapy, is involved in the development of hyponatremia [29–31].

#### *3.2.4. Risperidone-*

Approved by the FDA in 1993 for the use of schizophrenia, exists in oral presentation and depot. Like the other antipsychotics, risperidone has also been associated with the risk of developing hyponatremia, although some cases have been described in which the use of risperidone improved polydipsia in the schizophrenic patient [32, 33]. However, the results in the literature are inconclusive and controversial regarding the improvement of certain atypical antipsychotics (olanzapine and risperidone) on primary polidipsia.

### *3.2.5. Paliperidone-*

Paliperidone is an active metabolite of risperidone, indicated in the management of schizophrenia and schizoaffective disorder. In 2016, a case of rhabdomyolysis, malignant neuroleptic syndrome and SIADH associated with paliperidone prolonged release in a 35-year-old man hospitalized for psychotic decompensation was described. Two days after the administration of the treatment, the patient presented with a tonic-clonic seizure that was attributed to hypoosmolar hyponatremia [34]. It is important to remember that in all patients receiving antipsychotic treatment, serum sodium should be measured in the presence of epileptic seizures.

#### *3.2.6. Ziprasidone-*

Ziprasidone is an atypical antipsychotic indicated in psychotic agitation, schizophrenia and manic and mixed episodes in bipolar disorder. The literature includes a series of cases in which hyponatremia is observed in the context of the use of ziprasidone, concomitantly with other psychopharmaceuticals such as duloxetine [35] and with comitial symptoms in the debut of the hyponatremia [36], as a neurological symptom present in cases of hyponatremia.

#### *3.2.7. Clozapine-*

Synthesized in the late 1950s, clozapine is considered the first atypical antipsychotic. It emphasizes its low rate of extrapyramidal effects and its antipsychotic potency, being currently indicated in the management of resistant psychosis and psychotic symptoms in Parkinson's disease. Literature collects controversial data on its relationship with hyponatremia, although some authors defend its use in Syndrome of Psychosis, Intermittent Hyponatremia and Polydipsia (PIP syndrome) [37].

#### **3.3. Syndrome of psychosis, intermittent hyponatremia and polydipsia (PIP syndrome)-**

Hyponatremia in psychotic patients is a relatively frequent complication, both due to the osmotic dysregulation of the disease and the secondary effect of antipsychotics. The PIP syndrome is characterized clinically by the presence of acute confusional symptoms derived from symptomatic hyponatremia and water intoxication. Between 6 and 20% of psychotic patients presents with polydipsia. In psychotic patients, in addition to xerostomia and consequent compulsive water intake, the role of supra-optic and paraventricular hypothalamic nuclei, responsible for the regulation of thirst and secretion of antidiuretic hormone (ADH) in the pathophysiology of hyponatremia, is postulated, as well as dopamine and endogenous opioids as neurotransmitters involved in the ingestion of water. Neuroimaging studies in schizophrenic patients show a ventricular dilation in basal conditions, however under conditions of hyponatremia cerebral edema and ventricular contraction are observed. Some studies show that the MDR1 C3435T polymorphism may increase the susceptibility to polydipsia in schizophrenia [38].

Despite its prevalence, morbidity and mortality, it is an underestimated entity in its prevention and early diagnosis. One of the diagnostic challenges is the differentiation between hyponatremia induced by antipsychotics and PIP, since often the treatment of one of the entities worsens the other. Some studies show that urine concentration measurements are useful to differentiate both situations, detecting more frequently concentrated urine in pharmacological hyponatremia and dilute urine secondary to psychotic decompensation [39]. While some studies show that clozapine can generate polydipsia and hyponatremia, others show that it improves the symptoms of polydipsia, so clozapine is postulated as a therapeutic option [37], especially as an alternative to electroconvulsive therapy in cases of catatonia [40].

### **4. Antidepressants**

The consumption of antidepressants has increased significantly in most Organization for Economic Co-operation and Development (OECD) countries since the year 2000. There is significant variation in consumption of antidepressants between countries. For example, in Germany, antidepressant use had risen 46% in just 4 years, in case of Spain and Portugal, it rose about 20% during the same period and Iceland led the pack in overall use with about one in 10 people taking a daily antidepressant [41]. The new generation of antidepressant drugs are widely used as the first line of treatment for major depressive disorders and are considered to be safer than tricyclic agents due to a profile of better tolerability and lower rate of side effects [42]. Several side effects are transient and may disappear after a few weeks following treatment initiation, but potentially serious adverse events may persist or ensue later.

Hyponatramia is the most common electrolyte disorder in ambulatory outpatients, especially in the elderly, and is one of the many well-known side effects of antidepressants [43]. Most of the evidence pointing toward an increased risk of hyponatremia with the use of antidepressant medications is based on multiple case reports and a few observational studies. It is important to remember that mild hyponatremia is associated with instability and falls, reduced cognitive function, osteoporosis and increased morbidity and mortality [44]. Most studies are small and observational and only few have had the power to examine whether specific antidepressants carry a higher or lower risk of hyponatremia.-

Hyponatremia, usually, is not dose dependent and the patient recovers when treatment with antidepressant is interrupted. For this reason, early detection as well as the evaluation of concomitant risk factors in all patients starting antidepressant are important. Besides, it seems necessary to supervise sodium plasma levels periodically when patients are in treatment with antidepressants and to choose safe drugs between all possibilities [45].

The selective serotonin reuptake inhibitors (SSRIs) and venlafaxine appear to be the antidepressants most commonly associated with hyponatremia. Between the SSRIs, the incidenceof hyponatremia varies based on the definition of hyponatremia used. On the one- hand, studies which defined hyponatremia as serum sodium levels <135mmol/l, the incidence ranged from 9 to 40%. On the other hand, the incidence decreased to 0.06–2.6% when

hyponatremia was defined as serum sodium levels <130mmol/l. The number of case reports- and small observational studies with hyponatremia concerning SSRI is substantially higher than the number of case reports and observational studies with other antidepressants, but it is not clear whether this is due to a true difference in incidence of hyponatremia. A review- concluded that current evidence suggests a relatively higher risk of hyponatremia with SSRIs and venlafaxine compared to tricyclic antidepressants (TCA) and mirtazapine, but for several antidepressants, data were insufficient to determine the risk of hyponatremia [46]. We found that there were no consistent difference in the incidence of hyponatremia among different- SSRI members, but available data indicate that the incidence could be slightly higher for citalopram, fluoxetine and escitalopram, whereas incidence rates may be lower for sertraline- and paroxetine [47–49].

Nevertheless, according to national and international pharmacovigilance committees, 1/3 of the reports of drug induced hyponatremia are severe, with the greatest frequency involving paroxetine, fluoxetine, fluvoxamine, citalopram, venlafaxine, escitalopram and sertraline [50].

The data looking at the risk of hyponatremia associated with the use of serotonin–norepinephrine reuptake inhibitors (SNRIs) are even more limited. Most studies have found incidence rates of hyponatremia comparable to the ones reported for SSRIs. Incidence figures for mirtazapine and tricyclic antidepressants (TCAs) appear to be lower [46, 51].

The mechanisms of antidepressants induced hyponatremia remain incompletely elucidated, but these agents can act by either increasing the release of antidiuretic hormone (ADH) or increasing the sensitivity to ADH resulting in a clinical picture similar to the syndrome of inappropriate secretion of ADH [12]. It must be clarified that the precise mechanism is not known but today it is known that antidepressants are thought to cause the syndrome of inappropriate antidiuretic hormone release (SIADH) by direct or indirect stimulation of vasopressin release from the posterior pituitary gland. SIADH can be produced by multiple causes (hyponatremia with plasma hyposmolality and increased urinary excretion of sodium, increase in urinary osmolality, hypotension, heart failure, nephropathy, liver disease…) and lead to retention of water and to hyponatremia [52]. The prevalence of SIADH in patients using antidepressants has been described in several case reports and a case series and is estimated to occur in five of every 1000 patients treated per year [44, 46, 53–54]. If we take into account the genetic factor, it is known that most antidepressants are metabolized by the hepatic enzyme cytochrome P450 2D6 (CYP2D6), which is highly polymorphic with >60 variant alleles (http://- www.cypalleles.ki.se). In case of individuals carrying two functional CYP2D6 alleles (\**1*, \**2)*  have "normal" enzyme activity and are classified as extensive metabolizers. However, 5–10% of the population lack enzyme activity due to inheritance of two nonfunctional alleles (\**3*, \**4*, \**5*, \**6*) and form the so-called poor metabolizers. *CYP2D6*\**4* is the most common variant allele in Caucasians (allele frequency of 20%) [55]. Poor metabolizers have higher plasma concentrations of antidepressants metabolized by CYP2D6 and are therefore more likely to suffer from adverse drug events [56]. It has been hypothesized that hyponatraemia or low serum sodium concentration may be one of these adverse events [57]. This review evaluated the literature on association of hyponatremia and the different families of antidepressants.-

### **4.1. SSRI: selective serotonin reuptake inhibitors-**

The phenomenon of recurrent hyponatremia induced by the use of SSRI has been described in the literature by some authors in subjects who were exposed to it.

*Sertraline:* In 2013 there were over 41 million prescriptions, making it the most prescribed antidepressant and second most prescribed psychiatric medication in the United States [58] and is used for a number of conditions. There are many publications with patient cases that take this treatment and suffer from hyponatremia [59, 60].

*Paroxetine:* Paroxetine is primarily used for many mental disorders, has a well-known discontinuation syndrome and shares many of the common adverse effects of SSRIs such as hyponatremia [61–63].

*Fluoxetine:* It is a widely used antidepressant, with a multitude of indications and has been assessed as the most effective and safe medicine needed in a health system [64]. There are many cases of patients with hyponatremia taking this treatment [65].

*Citalopram:* This antidepressant has a good anxiolytic profile but some cases of hyponatremia were recorded [66, 67].

*Escitalopram:* Is the (*S*)-stereoisomer of the earlier medication citalopram, used in clinical practice and is related with cases of hyponatremia [68, 69].

*Fluvoxamine:* Antidepressant with some uses and some analgesic properties. Many cases of hyponatremia were related [70, 71].

#### **4.2. SNRI: serotonin-norepinephrine reuptake inhibitors-**

Data looking at the risk of hyponatremia associated with the use of SNRIs are even more limited but some cases were described.

*Venlafaxine:* Drug widely used in daily clinical practice, with indications for mental disorders and painful pathology. Cases of hyponatremia were registered [72–74].

*Duloxetine:* Recommended as a first line agent for the treatment of chemotherapy-induced neuropathy and for fibromyalgia in the presence of mood disorders, in addition to other disorders. There are patient cases that take this treatment and suffer from hyponatremia [75, 76].

*Desvenlafaxine:* Desvenlafaxine is a synthetic form of the major active metabolite of venlafaxine and some cases of hyponatremia were registered [77].

### **4.3. Mirtazapine**

It has noradrenergical and specific serotonergical antidepressant effect and it is more likely to cause weight gain and sleepiness than other treatments. Some cases of hyponatremia were described [14, 53–55], however, this antidepressant has not been associated with hyponatremia in all cases or with less power of association to this side effect [46, 49, 53, 60, 76, 78].

### **4.4. Bupropion**

Is a norepinephrine-dopamine reuptake inhibitor (NDRI) primarily used as an antidepressant and smoking cessation aid and related with cases of hyponatremia [79, 80], but less than other antidepressants and that does not happen in all cases [51, 61].

### **4.5. Tricyclic antidepressants**

Discovered in the early 1950s, they have number of uses, many of their side effects may be related to the antimuscarinic properties and cases of hyponatremia were registered [81], but with fewer registered cases than with other antidepressants [47, 49, 82].

### **4.6. Vortioxetine**

New antidepressant so-called serotonin modulator and stimulator and two cases of patients with hyponatremia were registered [83].

### **4.7. Trazodone**

Is a serotonin antagonist and reuptake inhibitor that is widely used for the treatment of depression and insomnia. We found controversial results for relationship between trazodone and hyponatremia: case reports in patients on treatment [84], some cases were reported in overdose [85] or articles which describe less power of association to this side effect [51].

### **4.8. Agomelatine**

Agomelatine is a potent agonist at melatonin receptors and an antagonist at serotonin-2C (5-HT2C) receptors. Given the limited references of hyponatremia associated with agomelatine, it has been postulated as a therapeutic alternative in those patients with risk or a history of hyponatremia that require antidepressant treatment [5].

### **4.9. Mianserine**

Mianserin is a tetracyclic antidepressant with serotonergic (5HT2, 5HT1c), histaminergic and adrenergic (α1,α2) inhibitory activity. Some studies report that the association of hyponatremia and mianserin is low [86].

### **5. Antiepileptics**

Epilepsy is a group of neurological disorders characterized by epileptic seizures. It is estimated that nearly 40 million people have epilepsy [86], with differences between countries and age- groups. The median incidence of epilepsy is around 50.4/100,000/year: 45.0 for high-income countries and 81.7 for low- and middle-income countries [87]. Incidence is highest in old age (>60 years of age), with an estimated 60–135 new cases per 100,000 older adults each year [87]. Antiepileptics are, usually, initiated as monotherapy for the treatment of epilepsy [88].

However, these drugs are also often used in treatment of nonepileptic conditions such as pain and psychiatric disorders, for this reason it is very common in clinical practice that we find- antiepileptics associated with other drugs [89].

As with antidepressants, many cases of hyponatremia are associated with the use of antiepileptic drugs and have been reported and published. However, there are great differences between them [90]. Besides all this, it is important to differentiate cases of antiepileptic that induce asymptomatic hyponatremia and can be easily corrected [91] from cases of severe or symptomatic hyponatremia. Last ones are associated with various types of neurological damage: seizures, altered mentality, brain stem herniation, death, etc., [92]. Because hyponatremia frequently goes undiagnosed and untreated with associated risks, next we will talk about the effect of different antiepileptics in this electrolyte abnormality.-

#### **5.1. Phenytoin-**

This drug was approved by the FDA in 1953. It works by blocking voltage-sensitive sodium channels. It is one of the most used and affordable antiepileptics, with several presentations. Some cases of hyponatremia related to the use of this drug have been described [93], but with less intensity than with other antiepileptic drugs [94].

### **5.2. Carbamazepine**

Is used primarily in the treatment of epilepsy, neuropathic pain, schizophrenia along with other medications and as a second line agent in bipolar disorder. Carbamazepine is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system World Health Organization [70]. It has sodium channel blocking effect. There are many publications with patient cases that take this treatment and suffer from hyponatremia, so it is one of the antiepileptics most frequently associated with this side effect [90, 93, 95–97].

### **5.3. Oxcarbazepine**

Is a structural derivative of carbamazepine and acts by blocking voltage-sensitive sodium channels. Its use can reduce the occurrence of epileptic episodes, and in psychiatry, has been shown to improve mood (option for add-on therapy in the treatment of bipolar disorder) and reduce anxiety. There is approximately a 25–30% chance of cross-reactivity between carbamazepine and oxcarbazepine. Number of cases of hyponatremia have been recorded with this treatment and with greater strength of association [49, 84, 90, 92, 98, 99].

### **5.4. Eslicarbazepine acetate**

The active component, eslicarbazepine, stabilizes the inactive state of voltage-gated sodium channels (same mechanism of action as oxcarbazepine). This new antiepileptic has potential uses for the treatment of trigeminal neuralgia and bipolar disorder. Cases of hyponatremia were recorded [91, 100, 101].

### **5.5. Topiramate**

Its therapeutic activity and medical indications are very extensive, probably related to multireceptorial effects: voltage-gated sodium channels, GABA-A, AMPA/kainate, high-voltageactivated calcium channels and carbonic anhydrase isoenzymes. Some cases of hyponatremia are related [85], but with less frequency than with other antiepileptic drugs [102].

### **5.6. Lamotrigine**

Is a sodium channel blocking drug (inhibits voltage-sensitive sodium channels), suppress the release of glutamate and aspartate (two dominant excitatory neurotransmitters) and blocks L-, N-, and P- type calcium channels, among other receptor effects. It is used in several neurological and psychiatric disorders and patients with hyponatremia has been notified [90, 103].

### **5.7. Valproate**

Acts through blockade of voltage-gated sodium channels and increased brain levels of gamma-aminobutyric acid (GABA). It is used as primary option to treat epilepsy, bipolar disorder and to prevent migraine headaches, and is included in the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system [64]. Many casesof hyponatremia with Valproate's treatment were identified [90, 93, 104–106].

#### **5.8. Gabapentin-**

Is used primarily to treat seizures and neuropathic pain, and is commonly used to treat anxiety and other disorders. Gabapentin bind to the α2δ-1 subunit of voltage-gated calcium channels, interacts with NMDA receptors, protein kinase C and inflammatory cytokines. There is little relationship between hyponatremia and the use of this drug [90].

#### **5.9. Levetiracetam-**

This antiepileptic is used to treat epilepsy and different types of seizures. It also associates a multitude of indications for its use: Tourette syndrome, anxiety disorder, neuropathic pain… It acts as a neuromodulator binding to a synaptic vesicle glycoprotein (SV2A) and by inhibiting presynaptic calcium channels. Association of some cases of hyponatremia and use of levetiracetam has been documented [90, 107].

#### **5.10. Pregabalin-**

It is useful when added to other treatments for many indications. It is an analog of GABA and increases the density of GABA transporter proteins, the rate of functional GABA transport and the extracellular GABA concentrations. Few cases of hyponatremia with use of pregabalin were reported [108].

### **6. Conclusions**

Hyponatremia is a frequent clinical situation in clinical practice, both in outpatient and inpatient settings. Clinical manifestations have a broad spectrum with effect on different indicators such as morbidity and mortality. Nevertheless, this side effect is avoidable and reversible. Given the wide use of psychotropic drugs (antidepressants, antipsychotics and antiepileptics) and its current growing use, it is important to know those pharmacological options with lower risk of hyponatremia such as bupropion, trazodone, mianserin, pregabalin or gabapentin.

We have seen that etiology of hyponatremia is multifactorial and involves pharmacological origin (increase in the production or potentiation of the effects of antidiuretic hormone, alteration of the homeostasis of sodium and water), but many other factors such as advanced age, associated pathologies, female sex, weight or use of concomitant drugs also contribute to the development of hyponatremia. It is important to identify vulnerable patients and to measure sodium levels frequently, especially in the first few days after initiating treatment to help prevent or correct hyponatremia and its undesirable effects.-

### **Conflict of interest-**

The authors declare no conflict of interests.-

### **Author details-**

Mireia Martínez Cortés\* and Pedro Gurillo Muñoz

\*Address all correspondence to: mireia.martinez.cortes@gmail.com

Service of Psychiatry, Hospital Marina Baixa, Alicante, Spain

### **References-**


**Chapter 3**

. Normally

**Provisional chapter**

**Metabolic Alkalosis**

**Metabolic Alkalosis**

Holly Mabillard and John A. Sayer

http://dx.doi.org/10.5772/intechopen.78724

**Abstract**

**1. Introduction**

Additional information is available at the end of the chapter

Holly Mabillard and John A. SayerAdditional information is available at the end of the chapter

DOI: 10.5772/intechopen.78724

Metabolic alkalosis is a disorder where the primary defect, an increase in plasma bicarbonate concentration, leads to an increase in systemic pH. Here we review the causes of metabolic alkalosis with an emphasis on the inherited causes, namely Gitelman syndrome and Bartter syndrome and syndromes which mimic them. We detail the importance of understanding the kidney pathophysiology and molecular genetics in order to distinguish these syndromes from acquired causes. In particular we discuss the tubular transport of salt in the thick ascending limb of the loop of Henle, the distal convoluted tubule and the collecting duct. The effects of salt wasting, namely an increase in the reninangiotensin-aldosterone axis are discussed in order to explain the biochemical pheno-

**Keywords:** salt-wasting, inherited tubulopathy, renin-angiotensin-aldosterone axis

Metabolic alkalosis is a disorder where the primary defect, an increase in plasma bicarbonate concentration, leads to an increase in systemic pH. Various mechanisms underpin the pathophysiology of metabolic alkalosis, which is defined by an arterial bicarbonate concentration of over 28 mmol/L or a venous total carbon dioxide concentration of greater than 30 mmol/L. The body compensates for alkali retention and subsequent elevated arterial pH by

the kidney, which has a protective mechanism against the development of significant increases in bicarbonate, will excrete excess alkali to restore the body to its homeostatic pH, but certain factors can impair this ability resulting in a sustained alkalotic state. Here we will review the pathophysiological mechanisms and clinical settings in which metabolic alkalosis

inducing respiratory hypoventilation resulting in an accompanying rise in PaCO2

types and targeted treatment approaches to these conditions.

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

distribution, and reproduction in any medium, provided the original work is properly cited.

## **Metabolic Alkalosis**

Holly Mabillard and John A. Sayer

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.78724

### **Abstract**

Metabolic alkalosis is a disorder where the primary defect, an increase in plasma bicarbonate concentration, leads to an increase in systemic pH. Here we review the causes of metabolic alkalosis with an emphasis on the inherited causes, namely Gitelman syndrome and Barttersyndrome and syndromes which mimic them. We detail the importance of understanding the kidney pathophysiology and molecular genetics in order to distinguish these syndromes from acquired causes. In particular we discuss the tubular transport of salt in the thick ascending limb of the loop of Henle, the distal convoluted tubule and the collecting duct. The effects of salt wasting, namely an increase in the reninangiotensin-aldosterone axis are discussed in order to explain the biochemical phenotypes and targeted treatment approaches to these conditions.

**Keywords:** salt-wasting, inherited tubulopathy, renin-angiotensin-aldosterone axis

### **1. Introduction**

 Metabolic alkalosis is a disorder where the primary defect, an increase in plasma bicarbonate concentration, leads to an increase in systemic pH. Various mechanisms underpin the pathophysiology of metabolic alkalosis, which is defined by an arterial bicarbonate concentration of over 28 mmol/L or a venous total carbon dioxide concentration of greater than 30 mmol/L. The body compensates for alkali retention and subsequent elevated arterial pH by inducing respiratory hypoventilation resulting in an accompanying rise in PaCO2 . Normally the kidney, which has a protective mechanism against the development of significant increases in bicarbonate, will excrete excess alkali to restore the body to its homeostatic pH, but certain factors can impair this ability resulting in a sustained alkalotic state. Here we will review the pathophysiological mechanisms and clinical settings in which metabolic alkalosis

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

may occur [1–4] and give an overview of the causes of the inherited forms of metabolic alkalosis. The importance of defining a molecular genetic cause of metabolic alkalosis is reviewed alongside the common mimics of some of the inherited metabolic alkalosis syndromes.

### **2. Pathophysiology of metabolic alkalosis**

The following mechanisms result in the elevation of serum bicarbonate; excessive loss of hydrogen ions by the kidney or via the GI tract, intracellular shift of hydrogen ions, retention of exogenous bicarbonate ions or volume contraction around a constant supply of extracellular bicarbonate (contraction alkalosis) [5].

As water dissociates in the body to hydrogen and hydroxyl ions, the hydroxyl ions combine with carbon dioxide, resulting in bicarbonate, as hydrogen ions are removed from extracellular fluid. Hydrogen ion removal in the kidney and GI tract is accompanied by loss of potassium- and chloride so hypokalaemia and hypochloraemia often coexist with metabolic alkalosis.

Ability to excrete excess bicarbonate depends on the normal function of nephrons within the kidneys. The kidney therefore is implicated in the pathophysiology of most forms of metabolic alkalosis. The following scenarios result in a degree of impairment of this important mechanism: hypovolaemia, reduced glomerular filtration rate (GFR), reduced effective arterial volume, hypokalaemia, hypochloraemia or hyperaldosteronism.

### **2.1. Volume depletion**

Both reduced extracellular volume and arterial pressure will reduce GFR and thus activate the renin-angiotensin-aldosterone and sympathetic nervous system. Decreased GFR reduces bicarbonate filtration by the kidney and angiotensin and sympathetic activation increases bicarbonate reabsorption and generation in addition to sodium reabsorption in the tubule. This is done in the following ways:


### **2.2. Sodium intake**

A low sodium chloride diet will increase the bicarbonate reabsorption in the kidney enough to elevate serum pH although the reverse is not true with a high salt diet even though this will encourage the kidney to excrete sodium bicarbonate.

### **2.3. Chloride depletion**

Chloride depletion secondary to vomiting or nasogastric suction leads to a metabolic alkalosis. Chloride depletion metabolic alkalosis causes concomitant potassium depletion through renal loss of potassium. A less severe chloride depletion metabolic alkalosis is seen with the use of thiazide and loop diuretics.

### **2.4. Hypokalaemia**

Hypokalaemia causes alkalosis by moving hydrogen ions into the intracellular space in exchange for extracellular movement of potassium and hypokalaemia maintains an alkalosis by increasing renal bicarbonate reabsorption. Hypokalaemia (and aldosterone) stimulates the distal Na+ -K+ -ATPase and H+ -ATPase pumps in the apical membrane of alpha-intercalated cells to reabsorb potassium and secrete hydrogen and subsequently maintain alkalosis. Hypokalaemia also causes extracellular movement of potassium in exchange for intracellular movement of sodium and hydrogen which generates extracellular bicarbonate although coexistent intracellular acidosis. This intracellular acidosis stimulates renal bicarbonate reabsorption, hydrogen secretion and ammonium synthesis and excretion.

### **2.5. Increased aldosterone**

Hyperaldosteronism in addition to increased distal tubule sodium delivery results in sodium reabsorption and hydrogen and potassium ion secretion. Any hyper-reninaemic state which will result in an increase in aldosterone production will have the same effects.-

### **2.6. Volume contraction and beta-intercalated cells**

Distal tubule chloride delivery is essential for the beta-intercalated cell to secrete bicarbonate as this occurs by an apical anion exchange protein called Pendrin (**Figure 3**). As volume contraction reduces distal chloride delivery, bicarbonate secretion will reduce as will chloride reabsorption. Urine pH becomes acidic with little chloride, sodium and potassium, so beta-intercalated cells- are blunted from excreting bicarbonate and correcting the metabolic alkalosis [1–4].

### **3. Causes of metabolic alkalosis**

### **3.1. Diuretics**

Loop diuretics (Furosemide, Bumetanide, Torsemide) inhibit the apical Na<sup>+</sup> –K+ –2Cl<sup>−</sup> cotransporter in the thick ascending limb of the loop of Henle where 20–25% of sodium is typically reabsorbed. Metabolic alkalosis occurs in several ways [6, 7]:


The same principle also applies to other diuretics such as thiazides.

### **3.2. Post-hypercapnia**

Patients who are chronic CO2 retainers typically develop a compensatory metabolic alkalosis due to renal bicarbonate retention. Once the hypercapnia is reversed with ventilatory support, the renal bicarbonate retention takes longer to correct and these patients usually have a chronically elevated bicarbonate [8].

### **3.3. Non-reabsorbable anion delivery**

Antibiotics particularly Beta-lactams act as non-reabsorbable anions in the renal tubule which therefore promotes potassium and hydrogen excretion which results in metabolic alkalosis [9].

### **3.4. Inherited salt wasting alkaloses**

Bartter and Gitelman syndromes are both autosomal recessive inherited disorders which result in characteristic features due to a hereditary dysfunction in a tubular salt handling [10]. Both result in hypokalaemia, metabolic alkalosis, hyper-reninaemia and hyperaldosteronism with low blood pressure. The prevalence of Gitelman syndrome is about 1 in 40,000 compared with Bartter syndrome, which has a prevalence of 1in 1,000,000. Bartter syndrome is more severe and may cause perinatal death due to salt wasting crises. The clinical phenotype that is seen with Gitelman syndrome mimics the chronic ingestion of a thiazide diuretic and that of Bartter syndrome mimics a chronic loop diuretic effect (**Table 1**). Bartter and Gitelman- syndrome carriers (heterozygous for a mutation in causative gene) typically have lower blood pressure than that of the general population and may have mild biochemical phenotypes and some clinical symptoms.

Bartter syndrome results from a primary defect in sodium chloride reabsorption in the thick ascending limb of the loop of Henle (**Figure 1**). Salt (sodium) wasting results in volume depletion which activates juxtaglomerular secretion of renin and subsequent juxtaglomerular hyperplasia and hyperaldosteronism. Volume depletion and increased distal tubular sodium delivery result in tubular potassium and hydrogen secretion in the urine [11, 12]. Paracellular reabsorption of calcium and magnesium in the thick ascending limb of the loop of Henle is driven by sodium chloride reabsorption in this nephron segment. Reduced sodium absorption here results in hypercalciuria and hypomagnesaemia [13].

To date, there are five types of Bartter syndrome based on different genetic defects (**Figure 1**) with slightly variable phenotypic presentations [14].

Type 1: mutations *SLC12A1* which encodes the apically located Na-K-2Cl (NKCC2) result in a severe phenotype which can cause maternal polyhydramnios and prematurity. Subsequently, few survive infancy due to extreme salt wasting resulting in significant hypokalaemia, metabolic alkalosis, polyuria and hypercalciuria.

Type 2: mutations in *KCNJ1*, which encodes the apical potassium channel ROMK essential for potassium recirculation in the thick ascending limb of the loop of Henle results in salt-wasting alkalosis. Nephrocalcinosis is common which often results in later renal dysfunction and, in some cases, end stage renal failure [15].


**Table 1.** Differences between Bartter and Gitelman syndrome.-

Type 3: mutations in *CLCNKB* result in loss of function of the basolateral chloride channel ClC-Kb which is historically described as the 'classical' form of Bartter syndrome. This form is less severe and may present later in childhood. Co-expression of ClC-Ka results in a less severe phenotype. Some patients with *CLCNKB* mutations have a Gitelman syndrome phenotype with hypocalciuria and thiazide non-responsiveness because ClC-Kb is also involved with chloride reabsorption along the distal convoluted tubule in addition to the thick ascending limb of the loop of Henle. Late renal impairment can feature in this form of Bartter syndrome mainly due to nephrocalcinosis and the adverse effects of NSAIDS (used as treatment for the condition) [16].

**Figure 1.** The thick ascending loop of Henle and the transporters and channels associated with tubulopathies.

Type 4: two mechanisms underlie type 4 Bartter syndrome. Both defects cause severe disease in the antenatal period and present with co-existent congenital deafness. Progressive renal failure is more common but nephrocalcinosis is less commonly seen. Type 4A is a consequence of a defect in the Barttin subunit that is essential to the function of both the chloride channels ClC-Ka and ClC-Kb which are present in both the renal tubule and the stria vascularis of the cochlear (inner ear). Bartter type 4b involves a second mechanism whereby digenic mutations affect both chloride channels (*CLCNKA* and *CLCNKB*) [17].

Type 5: this form of Bartter syndrome is due to a gain of function mutation in *CASR* encoding the calcium sensing receptor (CaSR). This is also termed autosomal dominant hypocalcaemia. This condition results in a low serum calcium as a result of downward 'resetting' of the parathyroid gland and hypocalcaemia subsequently inhibits parathyroid hormone release. The gain of function mutation in CaSR additionally regulates paracellular calcium transport in the thick ascending limb of the loop of Henle. CaSR over-activation reduces ROMK expression in addition to blunting Na+ –K+ –2Cl<sup>−</sup> co-transporter expression resulting in renal sodium chloride wasting. Calcium and magnesium reabsorption via paracellular channels is inhibited due to lack of electrochemical gradient to drive paracellular reabsorption. This Bartter syndrome subtype is unique due to the presence of hypocalcaemia and an autosomal dominant inheritance pattern and has a milder phenotype (with much less alkalosis) and with later onset [18].

A transient form of Bartter syndrome exists as an X-linked pattern of inheritance which manifests in the antenatal period. This form presents with severe polyhydramnios and prematurity if the foetus survives to this stage. Severe salt wasting results in foetal polyuria and those that survive to birth have spontaneous resolution in symptoms over the first few months/years of life. Mutations in *MAGED2*, which encodes melanoma-associated antigen D2, underlie this condition. The gene is thought to affect the antenatal expression and function of NKCC2 and NCC via adenylate cyclase, a cytoplasmic heat-shock protein and cyclic AMP [19].

The apically expressed furosemide sensitive co-transporter/sodium potassium chloride cotransporter (NKCC2) is shown. Mutations in Type 1 Bartter syndrome are associated with dysfunction in this channel, leading to salt wasting. Mutations in the apical potassium channel *ROMK* cause Type 2 Bartter syndrome. ROMK is essential for potassium recycling back to the lumen of the tubule in this nephron segment. Mutations in *CLCNKB* encoding the basolateral chloride channel ClC-Kb cause type 3 Bartter syndrome (as well as causing phenotypes similar to Gitelman syndrome). Type 4 Bartter syndrome is due to mutations in *BSND* which acts as a subunit for both ClC-Kb and ClC-Ka (not shown). *BSND* mutations also cause sensorineural deafness. The basolateral calcium-sensing receptor (CaSR) regulates ROMK and its overstimulation/gain of function causes an inhibition of ROMK, producing a Bartter-like phenotype. Calcium and magnesium are resorbed via paracellular channels, and any loss of the electrochemical driving force will lead to hypercalciuria and magnesium wasting. Dysfunction at this nephron segment leads to severe renal salt wasting, which activates the renin-angiotensin-aldosterone system. The increased delivery of salt to the cortical collecting duct promotes aldosterone dependant Na+ reabsorption via ENaC, which is coupled to K+ and H+ secretion, thus accounting for the hypokalaemic alkalosis seen.

Gitelman syndrome differs from Bartter syndrome due to the presence of hypocalciuria and does not typically manifest until adolescence or adulthood. Differentiating Gitelman syndrome from Type 3 Bartter syndrome can be difficult [20] due to expression of CLCKNB in distal nephron segments as well as the thick ascending limb of the loop of Henle.

Gitelman syndrome results from inactivating mutations in *SLC12A3* which encodes the sodium chloride co-symporter (NCCT) (**Figure 2**) in the distal convoluted tubule [21]. The clinical phenotype can be variable and no phenotype-genotype correlation is yet understood. It is theorised that lack of correlation could be due to differences in function and/or expression of other basolateral chloride channels such as the voltage-gated chloride channel, KCl co-transporter or the cystic fibrosis transmembrane conductance regulator [22].

EAST syndrome (alias SeSAME, OMIM #612780) is causes by mutations in *KCNJ10*, a basolateral potassium channel (**Figure 2**) expressed in the distal convoluted tubule [23, 24]. Biochemically, the phenotype exactly mimics Gitelman syndrome. Extra-renal manifestations of epilepsy, ataxia and speech dyspraxia make the syndrome recognisable.

The apically expressed thiazide sensitive co-transporter/sodium chloride co-transporter (NCCT) is shown. Mutations in Gitelman syndrome are associated with dysfunction in this channel, leading to salt wasting. Mutations in the basolateral potassium channel *KCNJ10*  cause EAST syndrome and the serum biochemistry phenotypically mimics Gitelman syndrome. This channel is required for potassium recycling from the Na+ –K+ –ATPAse. Mutations in *CLCNKB* encoding the basolateral chloride channel ClC-Kb can also mimic Gitelman syndrome (as well as causing Bartter syndrome). Dysfunction of the apical magnesium channel in the distal convoluted tubule encoded by *TRPM6* is seen in Gitelman syndrome, explaining

**Figure 2.** The distal convoluted tubule and the transporters and channels associated with tubulopathies.

the hypomagnesaemia. Renal salt loss activates the renin-angiotensin-aldosterone system and increased delivery of salt to the cortical collecting duct promotes aldosterone dependant Na+ reabsorption via ENaC, which is coupled to K+ and H+ secretion, thus accounting for the hypokalaemic alkalosis seen.

Treatment for these in inherited salt wasting alkaloses conditions, in addition to electrolyte replacement, can comprise of NSAIDs, typically indomethacin. Renal production of PGE2 is typically elevated in response to reduced entry of chloride into the macula densa in the end of the thick ascending limb in these conditions [25]. Cyclooxygenase 2 expression is subsequently increased. PGE2 stimulates renin release by the juxtaglomerular apparatus contributing to the phenotype. PGE2 synthesis inhibition by NSAIDS will therefore reverse many of the clinical and biochemical abnormalities found in Bartter syndrome or phenotypically severe Gitelman syndrome (and EAST syndrome) [26].

### **4. Pendred Syndrome**

Pendred syndrome is an autosomal recessive disorder resulting from biallelic mutations in *SLC26A4* which encodes Pendrin, a multi-functional anion transporter. Pendrin acts a chloride/ bicarbonate exchanger in the cochlear, mediates iodide transport in the apical membrane of thyrocytes and as a chloride/bicarbonate exchanger in the apical membrane of beta-intercalated cells in the collecting duct (**Figure 3**). The resulting clinical picture is of sensorineural deafness, hypothyroidism, goitre and impaired bicarbonate secretion in states of metabolic alkalosis.

**Figure 3.** Pendrin expression in the intercalated cells of the kidney.

Failure of the compensatory mechanisms in alkalotic states such as those triggered by diuretics,- including thiazides, can result in a life threatening metabolic alkalosis [27].

Pendrin is expressed on the apical membranes of type B intercalated cells (shown) as well as and non-A, non-B intercalated cells (not shown). Mutations in *SLC26A4*, which encodes Pendrin, lead to a failure of the kidney to secrete a bicarbonate load, which is generated from intracellular carbonic anhydrase type 2, leading towards a metabolic alkalosis.

### **4.1. Glucocorticoid remedial Aldosteronism**

Glucocorticoid remediable aldosteronism (GRA) is an autosomal dominant inherited cause- of hypertension and is one of three known forms of familial hyperaldosteronism. Normally, aldosterone synthesis occurs in the zona glomerulosa of the adrenal gland which intentionally lacks the 17-hydroxylase enzyme to synthesise cortisol. In GRA, aldosterone is synthesised- in the ACTH-sensitive zona fasciculata. In the zona glomerulosa, the gene *CYP11B2* encodes aldosterone synthase which catalyses the conversion of deoxycorticosterone to corticosterone and 18-hydroxycorticosterone to aldosterone. In the zona fasciculata, *CYP11B1*, which encodes 11β-hydroxylase, catalyses the conversion of 11-deoxycortisol to cortisol. In GRA, there is a- chimeric gene duplication that results from unequal crossing over of CYP11B1 and CYP11B2 resulting in ACTH-dependent activation of aldosterone synthase (rather than by the reninangiotensin-aldosterone system) which causes a significant increase in 18-oxocortisol and18-hydroxycortisol. As this reaction occurs in the zona fasciculate, the aldosterone secretion is not sensitive to potassium loading as it would be in a normal subject due to the consistent prolonged release of ACTH. Consequentially, you do not always get hypokalaemia with this condition in contrast to subjects with other forms of hyperaldosteronism. Hypertension typically develops before the age of 21 and significant hypokalaemia develops following thiazide- diuretic administration due to its effect on increased distal tubular sodium delivery to aldosterone-sensitive potassium secretion site in the collecting duct. Although there is intra-family phenotypic variability with GRA, there is a strong prevalence of haemorrhagic stroke related to- cerebral aneurysm which is even more prevalent than seen in autosomal dominant polycystic kidney disease [28, 29]. Subjects with GRA should subsequently have a cerebral MRA every- 5 years from puberty. Genetic testing is now preferred to a dexamethasone suppression test and demonstration of elevated 18-oxocortisol and 18-hydroxycortisol [30]. Treatment comprises of ACTH suppression with glucocorticoids with careful attention to the growth retardation effects- of over-treatment in paediatric subjects. This will restore normotension and normokalaemia. Alternatively, mineralocorticoid receptor antagonists such as spironolactone may be used [31].

### **4.2. Congenital adrenal hyperplasia**

Over 95% of patients with congenital adrenal hyperplasia have defective conversion of 17-hydroxyprogesterone (17OHP) to 11-deoxycortisol. This is because of a mutation in the *CYP21A2* gene which encodes the enzyme 21-hydroxylase which is responsible for this conversion. CAH is an autosomal recessive disorder comprising two distinct types based on whether the condition is accompanied by salt wasting. Girls typically present with atypical genitalia (clitoral enlargement, urogenital sinus, labial fold fusion and genital orifice migration) but can present simply with severe salt wasting alone in the neonatal period. Boys typically present with severe salt wasting and do not manifest genital abnormalities until they reach an early onset puberty when they are toddlers. Phallic enlargement and hyperpigmentation can occur. CAH is diagnosed when the serum 17-hydroxyprogesterone concentration is elevated. Adrenal ultrasound has additional diagnostic value in the neonatal period revealing a lobulated surface, adrenal limb length greater than 4 mm and abnormal echogenicity. A prenatal diagnosis can be made by molecular analysis of *CYP21A2*. Treatment involves a glucocorticoid such as hydrocortisone to replace cortisol deficiency and hyperandrogenaemia and subsequent fertility difficulties. Mineralocorticoid replacement such as fludrocortisone is necessary to reverse salt wasting and volume depletion and testicular US surveillance from adolescence due to an increased risk of testicular adrenal rest tumours [32, 33].

### **4.3. Apparent mineralocorticoid excess**

Mineralocorticoid receptors in the collecting duct bind aldosterone and cortisol with similar affinity. Cortisol is normally converted into its inactive form cortisone by the enzyme 11-betahydroxysteroid type 2 at sites of aldosterone activity to prevent competitive inhibition with aldosterone. In AME, a mutation in 11-beta-hydroxysteroid type 2 results in a reduction of cortisol conversion to cortisone and subsequently the mineralocorticoid receptor is activated by excess cortisol. AME is autosomal recessive and causes severe hypertension in children in addition to hypercalciuria, nephrocalcinosis and renal failure due to an unknown mechanism. Nephrogenic diabetes insipidus can also occur due to chronic hypokalaemia. Defects in *HSD11B2* are responsible for this condition, some mutations result only in partial inhibition of 11-beta hydroxysteroid 2 resulting in a less severe phenotype. There is rough genotypicphenotypic correlation which includes the ratio of cortisol to cortisol metabolites which can be measured. Treatment for this condition aims at reducing endogenous cortisol production by dexamethasone or by blocking the mineralocorticoid receptor with spironolactone/eplerenone. ENaC blockade has similar success with less side effects, so it is reasonable to instead use amiloride or triamterene especially in men. If hypercalciuria is present then it is reasonable to use a thiazide to prevent nephrocalcinosis and subsequent renal impairment [34–36].

### **4.4. Liquorice ingestion and carbenoxolone**

Liquorice (root of *Glycyrrhiza glabra*) is found in tobacco, snuff, foods, soft drinks, herbal medicine and teas in addition to its popular consumption as a confectionary item. Not all sweets contain the compound glycyrrhiza but instead are flavoured with alternative compounds to mimic liquorice so chronic ingestion should not cause the clinical picture of apparent mineralocorticoid excess. Glycyrrhiza inhibits 11-beta hydroxysteroid dehydrogenase which converts cortisol to cortisone. Carbenoxolone, a liquorice-like compound has the same effect [37].

### **4.5. Liddle syndrome**

Liddle syndrome is a rare autosomal dominant disorder associated with a gain of function mutation in the epithelial sodium channel (ENaC) situated on the luminal membrane of principal cells in the collecting duct. In Liddle syndrome, ENaC function is increased which results in hypokalaemia and metabolic alkalosis. Increased activity of ENaC results in increased sodium reabsorption and potassium secretion and subsequent hypertension, hypokalaemia and metabolic alkalosis. Most patients present at a young age and not all have hypokalaemia but their potassium does run at lower range of normal.

Net sodium reabsorption occurs down a concentration gradient in principle cells via both ENaC on the luminal membrane and the Na–K–ATPase on the basolateral membrane. The greater net sodium reabsorption enhances potassium secretion through basolateral Na–K– ATPase and subsequent open luminal potassium channels.

Mutations in *SCNN1B* and *SCNN1G* which encode the beta and gamma subunits of ENaC cause Liddle syndrome. When volume expansion occurs there is failure to remove ENaC channels from the luminal membrane under the influence of low renin and aldosterone and the phenotype mimics a hyperaldosteronism state yet plasma and urine aldosterone levels are in fact reduced. Treatment involves potassium paring diuretics which directly block ENaC such as Amiloride or Triamterene. Spironolactone, which competes with aldosterone to bind to the mineralocorticoid receptor, would not be effective as increased ENaC activity in not mediated by aldosterone [38, 39].

**Figure 4.** Salt transport in the principal cell.

### **4.6. Cortisol excess**

Excess cortisol may allow stimulation of the mineralocorticoid receptor to leading to hypertension and a hypokalemic metabolic alkalosis. Causes include excess exogenous administration of glucocorticoids such as hydrocortisone or secondary to endogenous cortisol hypersecretion either by Cushing's syndrome or disease, ectopic ACTH production most commonly by small cell lung cancers or by a deoxycorticosterone-secreting tumour on the adrenal gland [2] (**Figure 4**).

Principal cells respond to a variety of stimuli to control Na+ and K+ transport. Aldosterone has the most pronounced effect. It acts through the mineralocorticoid receptor (MR) to increase surface expression of the epithelial sodium channel ENaC. Electrogenic Na+ reabsorption via ENaC is balanced by K+ secretion through ROMK and Cl−reabsorption through multiple pathways (not shown). The driving force that sets the electrochemical gradient for principal cell Na+ and K+ transport is the basolateral Na+ –K+ –ATPase.

### **5. Reasons to suspect and inherited cause of alkalosis**

Clinical features of a metabolic alkalosis include muscle cramps, weakness, arrhythmias and seizures. Some of these signs and symptoms may be related to alterations in ionised calcium (increased pH causes plasma proteins to bind calcium more avidly, thus lowering ionised calcium concentration). The associated hypokalaemia may also give rise to many of these symptoms. Inherited forms of alkalosis are secondary to a heterogeneous group of renal tubulopathies. Typical manifestations range from asymptomatic biochemical disturbances to severe salt wasting leading in early life and may be complicated by renal failure. The important clues to diagnosing an inherited cause of metabolic alkalosis include consistent electrolyte abnormalities (versus acquired changes in serum biochemistry), nephrocalcinosis, renal stone formation and renal impairment. Historical blood values are invaluable in this regard. A detailed family history is required to look for autosomal dominant and recessive patterns of disease. In children, failure to thrive, short stature, learning difficulties and rickets may also be evident. A history of early onset hypertension and a family history of stroke at a young age provides clues to look for inherited forms of hypertension including Liddle syndrome and GRA.-

Individual syndromes may be distinguished by distinct biochemical profiles but modern day molecular genetics allows a more robust means to come to a firm diagnosis. A very similar biochemical picture to Bartter and Gitelman syndromes can be induced by diuretic use or abuse, laxative abuse and chronic liquorice ingestion. However, urinary chloride will be raised in Bartter and Gitelman syndromes (>20mmol/L) whereas vomiting, gastric drainage, diuretics and post-hypercapnia will all have a low urinary chloride concentration (<10 mmol/L). Therefore, obtaining a careful drug and food history is important together with urine electrolyte analysis and diuretic screening to make certain that the cause is not an acquired one. The optimal treatment of a metabolic alkalosis clearly depends on identifying the underlying cause. Treatment of life-threatening alkalosis may involve control of ventilation (sedation, intubation and controlled hypoventilation). Historically, administration of HCl or ammonium chloride/arginine chloride has been advocated. These are not advocated. Control of ventilation and correction of volume status and improvement of renal haemodynamics is effective in cases of chloride loss. Haemodialysis may be used in extreme cases. Hypokalaemia should be corrected alongside the alkalosis. Treatment of Bartter and Gitelman syndrome, as detailed above, relies upon electrolyte replacement, attempts at disrupting the renal production of renin with NSAIDs and blocking the effects of excess mineralocorticoids with spironolactone, eplerenone and amiloride. Treatment of Liddle syndrome relies on sodium restriction and potassium-sparing diuretics which block ENaC and allow the correction of blood pressure, hypokalaemia and metabolic alkalosis.

### **6. Conclusions**

A systemic metabolic alkalosis is an important electrolyte disturbance which can have significant sequelae including neuromuscular irritability, tetany and cardiac rhythm disturbances. Hypokalaemia is a frequent accompanying electrolyte abnormality. Numerous inherited tubulopathies can cause this clinical and biochemical picture and acquired causes may mimic these. Molecular genetic testing allows a precise diagnosis and appropriate management to be given to patients with inherited salt wasting alkaloses.

### **Author details**

Holly Mabillard and John A. Sayer\*

\*Address all correspondence to: john.sayer@ncl.ac.uk

Institute of Genetic Medicine, Newcastle University, Newcastle Upon Tyne, United Kingdom

### **References**

