Total Body Water and Osmolality Regulation

In adults, water accounts for 45 to 60% of body weight [1]. It is distributed between intracellular fluid (ICF) and extracellular fluid (ECF) compartments. About 2/3 of total body water (TBW) is in the ICF and 1/3 in the ECF compartment [2]. The volume of each compartment is determined by its osmolality (osmolality is the number of dissolved particles in a kilogram of water). The cell membrane is freely permeable to water, but not most other intracellular and extracellular constituents. As a result, water moves through the cell membrane until the osmotic gradient dissipates and the osmolality across the cell membrane equalizes. A rapid decrease in extracellular osmolality will lead to a shift of water to the intracellular compartment, cell swelling, and a reduction in ECF volume [3].

Plasma sodium is the major extracellular cation and is the primary determinant of plasma osmolality. Therefore, maintaining a steady sodium concentration is an essential physiological process. Thirst, arginine vasopressin (AVP) and the kidneys are responsible for maintaining plasma osmolality. The hypothalamus senses changes in osmolality and regulates synthesis and secretion of AVP [4-6]. It also regulates hypoosmolality-mediated thirst [7]. AVP acts on V2 receptors in the kidney collection ducts and increases water absorption. This is achieved by inserting aquaporin-2 (AQP2) water channels into the luminal surface of the principal cells [8].

Brain cells adapt within hours to hypoosmolality by loss of electrolytes (rapid adaptation) and to chronic hypoosmolar ECF by loss of organic osmolytes (slow adaptation) [9]. Overly aggressive correction of chronic hyponatremia leads to shrinkage of brain cells and irreversible damage (osmotic demyelination syndrome (ODS) [10].

Clinical Manifestations of Hyponatremia

Manifestations of hypotonic hyponatremia are primarily related to dysfunction of the central nervous system and are more evident when the drop in sodium concentration is significant or rapid (i.e. within hours). Headache, nausea, vomiting, muscle cramps, lethargy, restlessness, disorientation, and depressed reflexes can be observed. Severe and rapidly evolving hyponatremia can cause seizure, coma, brain- stem herniation, respiratory arrest, and death.

Causes of Hyponatremia

Hyponatremia is the most common electrolytes disturbance in hospitalized patients and the general population [11-13]. It is caused by excessive water gain in relation to sodium, excessive sodium loss in relation to water, or a trans-cellular water shift. Hyponatremia does not always represent a hypoosmolar state but can be associated with normal or even high osmolality. It is useful to clinically divide the causes of hyponatremia into hypovolemic, euvolemic and hypervolemic hyponatremia, table1.

 

The most common causes of severe hyponatremia are thiazide diuretics and the syndrome of inappropriate anti-diuretic hormone secretion (SIAD). Excessive water intake can lead to hyponatremia if the excretory capacity for the free water of the kidney is overwhelmed (primary polydipsia). Hyperglycemia is the most common cause of translocational hyponatremia. An increase of 100 mg per deciliter (5.6 mmol) in serum glucose concentration reduces serum sodium by 2.4 mmol/L and leads to an increase in serum osmolality of 2.0 mOsm / kg of water.14 Common causes of hyponatremia are listed in table 1.

Decreased volume of ECF	Increased volume of ECF	Normal volume of ECF
Renal sodium loss -         Diuretics -         Osmotic diuresis (glucose, urea, mannitol) -         Adrenal insufficiency -         Salt-wasting nephropathy -         Renal tubular acidosis Extrarenal sodium loss -         Diarrhea -         Vomiting -         Blood loss Fluid sequestration -         Bowel obstruction -         Peritonitis -         Pancreatitis -         Muscle trauma -         Burns	Congestive heart failure Liver cirrhosis Nephrotic syndrome Kidney failure (acute or chronic) Pregnancy	Thiazide Hypothyroidism Adrenal insufficiency Syndrome of inappropriate antidiuretic hormone secretion Exercise induced hyponatremia

Table 1: Common Causes of Hyponatremia.

Evaluation of Hyponatremia

It is essential to first exclude pseudo-hyponatremia and hyperosmolar state in evaluating hyponatremic patients. Pseudohyponatremia is a laboratory error that results from using an indirect method to measure serum sodium (which involves sample dilution) in patients with hyperlipidemia or hyperproteinemia [15]. Indirect methods (e.g. indirect ion-selective electrode potentiometry) do not take into account  that large volume of plasma is occupied by proteins or lipids in these patients. Measuring plasma osmolality or sodium using an ion-specific electrode (i.e., a blood gas analyzer) confirms hypotonic hyponatremia.

When plasma contains an excess of osmotically active molecules (such as glucose and mannitol), free water moves from intracellular to extracellular compartments down the osmotic gradient and dilutes serum sodium. This can be confirmed by correcting sodium levels for hyperglycemia or by measuring plasma osmolality.

The other essential aspect of hyponatremia assessment is its duration. Hyponatremia of unknown duration should be considered chronic.

Typical laboratory workup for hyponatremia includes:

• Serum osmolality, plasma glucose
• Urine osmolality (surrogate of vasopressin activity), and urine sodium
• Total protein and triglycerides
• Assessing hypothyroidism, hypoadrenalism
• Confirming SIAD
• Imagine looking for the cause of SIAD.
• During correction, serum sodium every 2-4 hours, urine electrolytes and osmolality (especially if the urine output exceeds 100ml/h).

Investigations should not be exhaustive if the cause is evident from clinical assessments (such as acute gastroenteritis, congestive heart failure, and a recent start of thiazide diuretics).

Management of Hyponatremia

Treatment of hyponatremia requires balancing the risk of hypotonicity (brain edema) and rapid sodium correction (ODS). The severity of symptoms and the duration of hyponatremia determine the correction rate.

Adrogué and Madia’s equation can be used to estimate the effect of giving 1 liter of IVF on a patient’s serum sodium by assuming a closed system, i.e. no net water or electrolytes gain or loss other than  the IVF given [16].

The effect of one liter of any IVF on serum sodium can be calculated as follows:

 

The equation can be used to guide both hyponatremia and hypernatremia management. The sodium concentration of common IVF is as follows: D5water: 0, 0.45sodium chloride: 77 mmol/L, Ringer’s lactate: 130 mmol/L, 0.9 sodium chloride: 154 mmol/L, 3% sodium chloride: 513 mmol/L.

For example, an 80 kg elderly patient presented with hyponatremia, [Na⁺] = 115 mmol/L and seizure. The management plan was to administer 3% sodium chloride to raise serum sodium by  5 mmol and to give lorazepam. To calculate how much fluid is needed to raise serum sodium  5 mmol/L: 

Effect of one liter 3% sodium chloride ==9.7mmol

Using simple calculation: the volume of 3% sodium chloride needed = 5/9.7=0.515 liter=  515 ml. As mentioned earlier, this calculation does not consider the electrolytes-free water diuresis, insensible, and ongoing GI water losses.

Symptomatic Hypotonic Hyponatremia

For patients with severe symptoms or serum sodium below 115-120 mmol/L, treatment with hypertonic sodium chloride is recommended. This can be administered as boluses or continuous infusion. A bolus of 100-150 ml of 3% sodium chloride, repeated 2-3 times as needed, should be given. A continuous 3% sodium chloride infusion at 0.5 to 2 ml/kg/h is an alternative for those with moderate symptoms [17]. Compared to the 3% sodium chloride infusion, boluses are easier to administer and do not lead to more sodium over-correction [18]. Raising serum sodium by a few mmol (5 mmol) is adequate to reverse the CNS manifestations and permit further and slower correction [19]. Patients with seizures also require immediate anticonvulsant drug therapy.

In managing patients with chronic (>48 hours) hyponatremia, it is crucial to monitor serum sodium frequently (20 minutes after the hypertonic fluid boluses and every 2 to 4 hours) and strictly monitor urine output. The 24-serum sodium correction should not exceed 8 mmol in the first 24 hours. Clinically significant ODS has been mainly reported upon correcting hyponatremia by more than 12mmol/24h [20]. Other risk factors for ODS include initial serum sodium <110 mmol/L, alcoholism, malnutrition, chronic liver disease, hypokalemia, and female gender [21,22]. By contrast, rapid correction of acute hyponatremia (< 24 hours duration) carries no risk of ODS [23]. Also, hyponatremia that accompanies edematous states carries minimal risk of ODS, as the prevailing defect is impaired water excretion (unless AVP blocker has been used) [16].

A 50-100 ml of 8.4% sodium bicarbonate (contains 1 mmol/ ml sodium) can be used if the 3% sodium chloride is not readily available. 8.4% sodium bicarbonate is not commonly used to treat severe hyponatremia. However, it is easily and timely accessible, raise the serum sodium [24,25] and decrease intracranial pressure similar to the 3% sodium chloride [26].

The rate of hyponatremia correction depends not only on the IVF rate and sodium concentration, but also on the kidney response. As most hyponatremic conditions are associated with elevated AVP, rapid correction could occur when hypovolemia is corrected, AVP stimulation abates, and the urine becomes hypotonic relative to the plasma (free water diuresis). In case of overcorrection, a hypotonic fluid (relative to the urine) should be given. Overcorrection can be prevented by giving desmopressin 2 to 4 micrograms subcutaneously or IV to prevent hypotonic diuresis [27-29]. The rapid correction of hyponatremia should be stopped when life-threatening manifestations seize, and other symptoms improve, or achieving a serum sodium 125 to 130 mmol/L (or even lower if the initial serum sodium is below 100 mmol/L).

Mildly Symptomatic/Asymptomatic Hyponatremia

There is no consensus about the optimal treatment of hyponatremia with mild symptoms. Nevertheless, correction should be sufficient to reverse the manifestations of hypotonicity, but not so rapid to pose a risk of developing ODS. The correction rate should not exceed 8-10 mmol/L on any day of treatment.

Water restriction is the mainstay of long-term management for edematous patients with hyponatremia. Optimization of hemodynamics in severe heart failure by several measures can increase the excretion of electrolyte-free water. Also, loop diuretics reduce urine concentration and increase excretion of electrolytefree water. In heart failure, treatment with AVP V2 receptor antagonists improves the serum sodium, and augments diuresis [30]. However, this was not translated into improved survival or decreased heart failure morbidities [31].

Syndrome of Inappropriate Antidiuresis (SIAD)

The syndrome of inappropriate antidiuresis (SIAD) is a common cause of hyponatremia [32]. SIAD is caused by inappropriate secretion of AVP, which is not suppressed by plasma hypoosmolality, secretion of AVP at lower osmotic setpoint (reset osmostat), or abnormal water retention by the kidney. The causes of SIAD can be categorized as related to malignant diseases, pulmonary diseases, central nervous system disorders, and druginduced, table 2.

Malignant Diseases	Pulmonary Disorders	Disorders of the CNS	Drugs	Other Causes
Carcinomas (lung, GI, Genitourinary) Thymoma Ewing’s sarcoma Lymphoma	Infections Asthma Cystic fibrosis Respiratory failure w ith positive pressure ventilation	Infection Bleeding and masses Multiple sclerosis Guillain Barre syndrome Delirium tremens	Drugs that stimulate AVP release -         Chlorpropamide -         SSRIs -         Tricyclic antidepressants -         Clofibrate -         Carbamazepine -         Nicotine -         Narcotics -         Antipsychotics AVP analogues -         Desmopressin -         Oxytocin	Heriditary (gain of function mutation of V2 receptor) Acute intermittent porphyria Endurance exercise General anesthesia Nausea Pain Stress

Table 2: Common causes of SIAD.

The hallmark of SIAD is plasma hypoosmolality and inappropriately concentrated urine. Criteria for the diagnosis of SIAD are summarized in table 3 [33].

Management of SIAD should be directed to prevent hyponatremia (post-operative), treatment of the underlying cause, and amelioration of hypotonicity. Administration of isotonic instead of hypotonic maintenance fluid can prevent post-operative hyponatremia [34]. Water restriction is the mainstay of management hyponatremia in SIAD. If this is unsuccessful, sodium chloride with/without loop diuretics can be tried. If these measures fail, an AVP V2-receptor antagonist (such as Tolvaptan) can be used [35]. Initially, a low dose should be started, and the patient’s sodium level should be monitored. Also, treatment with urea is associated with improvement of hyponatremia and is well-tolerated [36].

	Essential features
-	Decreased effective osmolality (<275 mOsm/kg of water)
-	Urinary osmolality >100 mOsm/kg of water during hypotonicity
-	Clinical euvolemia
-	Urinary sodium >40 mmol/liter with normal dietary salt intake
-	Normal thyroid and adrenal function
-	No recent use of diuretic age
	Supplemental features
-	Plasma uric acid <4 mg/dl
-	Blood urea nitrogen <10 mg/dl
-	Fractional sodium excretion >1%; fractional urea excretion >55%
-	Failure to correct hyponatremia after 0.9% saline infusion
-	Correction of hyponatremia through fluid restriction
-	An abnormal result on the test of water load (<80% excretion of 20 ml of water per kilogram of body weight over a period of 4 hours), or inadequate urinary dilution (<100 mOsm/kg of water)
-	Elevated plasma ADH levels despite the presence of hypotonicity and clinical euvolemia

Table 3: Criteria for SIAD diagnosis [26].