Sodium and Chloride Balance in Critically Ill Patients

Abstract

This chapter discusses the importance of sodium and chloride balance in critically ill patients. Infusion of high amounts of chloride is associated with hyperchloremia and metabolic acidosis, while hypernatremia and hyperchloremia are associated with adverse outcomes. The use of 0.9% sodium chloride is not ideal as it results in a rise in serum chloride, and in brain-injured patients, large volumes of hypotonic solutions must be avoided to prevent cerebral swelling and intracranial hypertension. The use of ‘balanced’ solutions is suggested to reduce the development of hyperchloremic acidosis in brain-injured patients. Chloride is a key contributor to the strong ion difference (SID), and alterations in the chloride balance can have negative implications on acid-base status, renal function, and haemostasis. Further research is needed to understand the clinical consequences of disorders of chloride balance and concentration.

FormalPara IFA Commentary (MLNGM)

The administration of excessive amounts of sodium during intravenous fluid therapy in the hospital can lead to iatrogenic fluid overload, which is a potential side effect that has received little attention [1]. While excessive fluid volume has traditionally been considered the primary cause of this condition, a recent review suggests that the sodium that is administered is also a significant factor in causing harm to hospitalized patients [2]. Intravenous fluid therapy is associated with a range of detrimental effects, including clinical problems related to specific colloid solutions (e.g. hydroxyethyl starches) and NaCl 0.9%. The most serious side effect of fluid therapy is fluid overload, which is an independent risk factor for morbidity and mortality in critically ill and surgical patients. While the root cause of iatrogenic fluid overload has been attributed to excessive fluid volume, the amount of sodium administered has been largely neglected. The largest source of sodium in the ICU comes from maintenance fluid therapy, which is prescribed to meet patients’ daily needs for fluids and electrolytes. Additionally, a significant amount of sodium is obtained through fluid creep, where large amounts of fluids are administered as a vehicle for intravenous medication or to keep intravenous lines open, often using NaCl 0.9%. Attention should be drawn to the significant amounts of sodium administered to hospitalized patients and how it contributes to fluid retention. The amount of sodium administered during typical hospital stays exceeds regular dietary sodium intake and the kidneys only have limited capacity handling of an acute sodium load. Moreover, the retention of water associated with sodium overload is energy-demanding and catabolic. The review quantifies the effect size of sodium-induced fluid retention and discusss its potential clinical impact, proposing various preventive and therapeutic options, including low-sodium maintenance fluid therapy and avoiding NaCl 0.9% as the diluent for medication. While caution should be exercised to avoid hyponatremia and hypovolemia, we believe that addressing sodium-induced fluid overload is the next logical step after addressing iatrogenic volume overload. In summary, unphysiological amounts of sodium administered to hospitalized patients through maintenance fluid therapy and fluid creep can lead to harmful fluid retention.

Suggested Reading

• 1. Van Regenmortel N, Langer T, De Weerdt T, Roelant E, Malbrain M, Van den Wyngaert T, Jorens P: Effect of sodium administration on fluid balance and sodium balance in health and the perioperative setting. Extended summary with additional insights from the MIHMoSA and TOPMAST studies. J Crit Care; 2022, 67:157–165.

• 2. Van Regenmortel N, Moers L, Langer T, Roelant E, De Weerdt T, Caironi P, Malbrain M, Elbers P, Van den Wyngaert T, Jorens PG: Fluid-induced harm in the hospital: look beyond volume and start considering sodium. From physiology towards recommendations for daily practice in hospitalized adults. Ann Intensive Care; 2021, 11(1):79.

FormalPara Learning Objectives

After reading this chapter, you will:

• 1. ICU patients receive large amounts of sodium and chloride during treatment, which can lead to hypernatremia and hyperchloremia.

• 2. Infusion of high amounts of chloride can cause hyperchloremic metabolic acidosis.

• 3. The proportions of sodium and chloride in 0.9% sodium chloride are equal, resulting in a SID of zero, so administration of large volumes can result in a rise in serum sodium and chloride.

• 4. In brain-injured patients, large volumes of hypotonic solutions must be avoided to prevent cerebral swelling and intracranial hypertension.

• 5. The use of ‘balanced’ solutions for maintenance and resuscitation can reduce the development of hyperchloremic acidosis in sepsis patients.

• 6. Chloride is the major strong anion in blood and plays an important role in the pathogenesis of metabolic acidosis.

• 7. Alterations in the chloride balance and chloraemia can alter the acid-base status, cell biology, renal function, and haemostasis, and may have negative implications.

FormalPara Case Vignette

An 18-year-old male was brought to ER in an unconscious state. He had an alcoholic smell on his breath and his blood pressure (BP) was 110/60 mmHg. Physical examination was unremarkable except for him being drowsy. Preliminary laboratory results were as follows: Serum sodium 139 meq/L, potassium 5 meq/L, bicarbonate 22 meq/L, chloride 87 meq/L and glucose of 90 mg/ dL. Blood alcohol level was undetectable and urine microscopy was significant for oxalate crystals. A diagnosis of poisoning with antifreeze (ethylene glycol) was made.

Questions

• Q1: Analyse the acid-base status?

Introduction

Patients admitted to the intensive care unit (ICU) typically receive large amounts of sodium and chloride during their ICU treatment [1]. Both hypernatremia and hyperchloremia are frequent complications in critically ill patients and are associated with adverse outcomes [2, 3]. The infusion of high amounts of chloride is also recognized as a cause of hyperchloremic acidosis [4, 5]. The problem with 0.9% sodium chloride is that the proportions of sodium and chloride are equal in solution, and administration of large volumes will result in a rise in serum chloride. Hyperchloremia (relative to serum sodium) results in a metabolic acidosis because of the decrease in strong-ion difference (SID), first described by Stewart in 1983.

The lactate, acetate, and gluconate anions that replace chloride in balanced solutions are removed rapidly from the plasma by the liver (which is faster than renal chloride elimination); this widens the plasma SID and are alkalinizing.

The choice of fluid for resuscitation has been ongoing debate for long, and the ‘ideal’ resuscitation fluid has yet to be identified. In patients with brain injury, large volumes of hypotonic solutions must be avoided because of the risk of cerebral swelling and intracranial hypertension. Traditionally, 0.9% sodium chloride has been used in patients at risk of intracranial hypertension, but there is increasing recognition that 0.9% sodium chloride is not without its problems.

Roquilly et al. [6] showed a reduction in the development of hyperchloremic acidosis in brain-injured patients when given ‘balanced’ solutions for maintenance and resuscitation compared with 0.9% sodium chloride. Balanced solutions will be discussed in Chap. 24.

Water and Sodium Balance

Disorders of water and sodium balance are common, but the pathophysiology is frequently misunderstood. As an example, the plasma sodium concentration is regulated by changes in water intake and excretion, not by changes in sodium balance. Hyponatremia primarily reflects water excess, while hypernatremia is a free water deficit state. Hypovolemia represents the loss of sodium and water, and edema is primarily due to sodium and water retention.

It has to be understood that both hyponatremia and hypernatremia are frequently iatrogenic and associated with adverse patient outcomes, especially in the elderly. Hyponatremia occurs more commonly than hypernatremia and is usually in acute hospital care rather than community care; both conditions are more common in the elderly.

Disorders of Sodium Balance

The two disorders of sodium balance are hyponatremia and hypernatremia.

Determinants of Plasma Sodium Concentration

Sodium and accompanying anions (mostly chloride and bicarbonate) are the main determinants of the plasma and extracellular fluid (ECF) osmolality. By contrast, intracellular potassium and accompanying anions are the main determinant of the intracellular osmolality.

Since water freely crosses most cells, the osmolality is the same in the extracellular and intracellular fluids. Thus, the plasma sodium concentration reflects the osmolality in both compartments even though potassium is the major intracellular cation.

Theoretically, hypernatremia is caused by a disturbance in water homeostasis and sodium content [7]. These mechanisms are derived from the Edelman equation, which in simplified form is as follows [8]:

$$ \mathrm{Plasma}\ \mathrm{sodium}=\frac{\left(\mathrm{Total}\kern0.5em \mathrm{exchangeable}\kern0.5em {\mathrm{Na}}^{+}+\mathrm{total}\kern0.5em \mathrm{exchangeable}\kern0.5em {\mathrm{K}}^{+}\right)}{\mathrm{Total}\ \mathrm{body}\ \mathrm{water}} $$

It should be noted that approximately 30% of total body sodium and a smaller fraction of total body potassium are bound in areas such as bone where they are nonexchangeable and osmotically inactive.

Hyponatremia

Hyponatremia is almost always due to the oral or intravenous intake of water that cannot be completely excreted. Normal individuals can excrete more than 10 L of urine per day (and more than 400 mL per hour) and therefore will not develop hyponatremia unless water intake exceeds this value, which occurs most often in psychotic patients with primary polydipsia. Hyponatremia caused by massive water intake rapidly resolves as soon as water intake stops, provided that the ability to dilute the urine is intact.

Persistent hyponatremia is associated with impaired water excretion, which is most often due to an inability to suppress the release of antidiuretic hormone (ADH) or to advanced renal failure. The two major causes of persistent ADH secretion are the syndrome of inappropriate ADH secretion (SIADH) and reduced effective arterial blood volume. The latter can occur due to true volume depletion (e.g., diuretics, vomiting, or diarrhea) or decreased tissue perfusion in heart failure or cirrhosis. In the last two disorders, severity of the hyponatremia parallels that of the underlying disease.

Although water is retained in patients with hyponatremia, the degree of ECF volume expansion is not clinically important. The cell membranes are permeable to water, and approximately two-thirds of the excess fluid moves into the cells.

Hyponatremia due to water retention, is typically associated with a reduction in plasma osmolality and tonicity. This creates an osmotic gradient that favours water movement from the ECF into cells and the brain. Water movement into the brain can lead to cerebral edema and potentially severe neurologic symptoms, particularly if hyponatremia is acute. In addition, overly rapid correction of severe chronic hyponatremia can lead to potentially irreversible neurologic injury (central pontine myelinolysis).

True hyponatremia is always a hypoosmolar condition. The aberration to this rule is illustrated by the following examples:

Hyponatremia can be caused by osmotic water movement out of the cells, which increases the extracellular volume and, by dilution, lowers the plasma sodium concentration. This phenomenon can occur when hyperosmolality is induced by hyperglycemia or the administration of hypertonic mannitol. Because plasma tonicity is increased, these patients do not experience an increase in intracellular and brain volume caused by water movement into the cells. On the contrary, hypertonicity results in water movement out of the cells and the brain. The movement of water out of the brain with hypertonic mannitol provides the rationale for its use in the treatment of cerebral edema and increased intracranial pressure. The plasma sodium rises towards its baseline value as the hyperglycemia is treated or mannitol is excreted in the urine. This condition, where hyponatremia is associated with an increase in plasma osmolality, is called redistributive or translocational hyponatremia.

Hyponatremia may occur in the presence of normal plasma osmolality. Extreme elevations in plasma lipids or proteins will increase the volume of the non-aqueous phase of plasma. In this situation, the measured plasma sodium concentration can be significantly lower than the actual (aqueous phase) sodium concentration. This condition is called pseudohyponatremia.

Hyponatremia may be associated with a normal or high plasma osmolality in patients with renal failure in whom the osmotic effect of urea retention counterbalances the reduction in plasma osmolality induced by hyponatremia. However, urea readily diffuses into cells and is considered an ineffective osmole. The plasma tonicity (i.e., effective plasma osmolality) is equal to the plasma osmolality minus the contribution of urea and is reduced in proportion to the reduction in plasma sodium. Thus, these patients can develop the manifestations of hyponatremia.

Hypernatremia

Hypernatremia is most often the result of failure to replace water losses due to impaired thirst or lack of access to water. It can also be induced by the intake of salt in excess of water or the administration of a hypertonic salt solution.

In contrast to hyponatremia in which water moves into the cells, the increase in plasma tonicity in hypernatremia usually pulls water out of the cells, resulting in a decrease in intracellular volume.

Disorders of Water Balance

The two disorders of water balance are hypovolemia and edema.

Hypovolemia

Hypovolemia refers to any condition in which the ECF volume is reduced and, when severe, can lead to hypotension or shock. Hypovolemia is usually induced by salt and water losses that are not replaced (e.g., vomiting, diarrhea, diuretic therapy, bleeding, or third-space sequestration). By contrast, unreplaced primary water loss, due to insensible loss by evaporation from the skin and respiratory tract or to increased urinary water loss due to diabetes insipidus, does not usually lead to hypovolemia, because water is lost disproportionately from the intracellular fluid compartment which contains approximately two-thirds of the total body water.

True hypovolemia due to fluid losses should be distinguished from decreased tissue perfusion in heart failure and cirrhosis in which cardiac dysfunction and systemic vasodilation, respectively, are the major hemodynamic abnormalities.

Concurrent Changes in Plasma Sodium Concentration

The plasma sodium concentration in hypovolemic patients may be normal, low (most often due to hypovolemia-induced release of ADH, which limits urinary water excretion), or high (if water intake is impaired). The effect on the plasma sodium concentration depends upon both the composition of the fluid that is lost and fluid intake.

In true hypovolemia due to vomiting, diarrhea, or diuretic therapy, the direct effect of fluid loss on the plasma sodium concentration depends upon the concentration of sodium plus potassium in the fluid that is lost. The rationale for including the potassium concentration is discussed above.

If, as occurs in most cases of vomiting and diarrhea, the sodium plus potassium concentration in the fluid that is lost is less than the plasma sodium concentration, water is lost in excess of sodium plus potassium which will tend to increase the plasma sodium concentration. As an example, suppose that 1 L of diarrheal fluid has a sodium plus potassium concentration of 75 mEq/L. This represents the electrolytes contained in 500 mL of isotonic saline (sodium concentration 154 mEq/L). The loss of 500 mL of isotonic electrolytes will have no effect on the plasma sodium concentration. In addition, 500 mL of electrolyte-free water is excreted, which will raise the plasma sodium concentration.

If the sodium plus potassium concentration is the same as the plasma sodium concentration (as with bleeding), there will be no change in plasma sodium concentration induced by the fluid loss.

If the sodium plus potassium concentration lost is greater than the plasma sodium concentration, as can occur with thiazide diuretics, the plasma sodium concentration will fall. The high urine sodium plus potassium concentration (which exceeds the sodium concentration of the plasma) is produced because thiazide diuretics act in the distal tubule and therefore do not interfere with urinary concentrating ability, which depends upon sodium chloride reabsorption in the loop of Henle. The high ADH levels induced by hypovolemia result in water reabsorption, high urine osmolality, and high urine electrolyte concentrations.

The changes in plasma sodium concentration directly induced by fluid loss do not necessarily represent the final outcome. Hypovolemia stimulates nonosmotic release of ADH, which will promote retention of ingested water or infused electrolyte-free water, which will lower the plasma sodium concentration, independent of the composition of the fluid lost.

Edema

Edema (including ascites) is a manifestation of sodium excess and an expanded ECF volume. Movement of fluid out of the vascular space into the interstitium is most often mediated by an increase in capillary hydraulic pressure. Tissue perfusion is variable in these disorders, depending upon the cause of edema.

When due to renal failure or glomerulonephritis, tissue perfusion may be increased if cardiac function is intact.

When due to heart failure or cirrhosis, tissue perfusion is often reduced due to decreased cardiac function and vasodilation, respectively.

When due to nephrotic syndrome, tissue perfusion may be reduced due to hypoalbuminemia or edema due to primary renal sodium retention.

Effect on Plasma Sodium Concentration

Sodium retention in edematous patients is not associated with hypernatremia, since a proportionate amount of water is retained. However, hyponatremia can occur if there is a concurrent reduction in the ability to excrete water. As an example, hyponatremia is common in patients with heart failure and cirrhosis because the reduction in tissue perfusion increases the secretion of ADH, thereby limiting the excretion of ingested water. In these disorders, the severity of hyponatremia is directly related to the severity of the underlying disease and is therefore a predictor of an adverse prognosis.

Management of Hyponatremia

The spectrum of hyponatremia ranges from hypovolemic, normovolemic to hypervolemic state. Therefore the estimation of volume status is of paramount importance since the treatment protocol in these three situations differ vastly. See Figure 23.1

Fig. 23.1

Flowchart on diagnosis and management of hyponatremia

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The diagnosis of hyponatremia should be carried out systematically. It consists of five components- osmolality(hypo/normo/hyper), serum sodium, acute/chronic, symptomatic/asymptomatic and hypo/normo/hypervolemia status. So a patient with acute diarrhoea may have an acute, symptomatic, hypovolemic, hypoosmolar hyponatremia, whereas a patient with pneumonitis and SIADH may have a chronic, asymptomatic, normovolemic, hypoosmolar hyponatremia.

Hypovolemic hyponatremia may be due to non-renal sodium losses e.g. GI losses (diarrhoea, vomiting), skin losses (burns) or dietary sodium restriction. Typically, the UNa < 20 mEq/L, UOsm >400 mOsm/kg H₂O, FE UA < 8% (indicating hypovolaemia), FE Na < 1% or FE Urea<35%. The latter is used in preference to FENa if prior diuretics have been used.

Hypovolaemic hyponatremia may also occur due to predominantly renal losses, the culprits being diuretic excess, renal failure (tubular disease), mineralo-corticoid deficiency and cerebral salt wasting syndrome. Typically, the UNa > 20 mEq/L, UOsm < 300–400 mOsm/kg H₂O, FE UA < 8%.

Euvolaemic hyponatremia is the most common form seen in hospitalized patients, who may have a slight increase or decrease in volume, but it is not clinically evident, and they do not have oedema. Examples include:

• SIADH (syndrome of inappropriate ADH).

• Glucocorticoid deficiency.

• Hypothyroidism.

• Impaired water excretion.

• Hypotonic fluid replacement post surgery.

The essential features of diagnosis of SIADH are as follows:

• Decreased serum osmolality.

• High urine osmolality (>300 mOsm/L).

• Clinical euvolumia.

• Urinary sodium >40 mEq/L.

• Serum uric acid <4 mg/ dl.

• FE UA >12%.

• Normal thyroid and adrenal function.

• No recent diuretic use.

The common causes of SIADH are malignancy, pulmonary disorders, CNS disorders and various drugs.

Hypervolaemic hyponatremia is characterized by both sodium and water retention, with proportionately more water. Therefore, these patients have an increased amount of total body sodium but as water retention is more significant, there is relative hyponatremia. Examples include:

• CCF.

• Nephrotic syndrome.

• Cirrhosis.

• Acute or chronic renal failure.

Clinical manifestations depend on the severity and acuity.

Chronic hyponatremia can be severe (sodium concentration less than 110 mEq/L), yet remarkably asymptomatic because the brain has adapted by decreasing its tonicity over weeks to months.

Acute hyponatremia that has developed over hours to days can be severely symptomatic with relatively moderate hyponatremia.

Mild hyponatremia (sodium concentrations of 130–135 mEq/L) is usually asymptomatic.

Clinical presentations include nausea, malaise, headache, lethargy, disorientation, respiratory arrest, seizure, coma, permanent brain damage, brainstem herniation and death. Patients may exhibit signs of hypovolemia or hypervolemia.

Treatment: Four aspects must be considered:

• 1. Asymptomatic vs. symptomatic.

• 2. Acute (within 48 h).

• 3. Chronic (>48 h).

• 4. Volume status.

Correction of serum sodium:

Acute symptomatic hyponatremia

• more rapid correction may be possible,

• 1–2 mEq/L to a total 4–6 mEq.

Chronic hyponatremia

• slower rate of correction advised,

• 12 mEq in 24 h

• < 18 mEq in first 48 h.

Hemodynamic monitoring distinguishes hypovolemic from euvolaemic and hypervolaemic hyponatremia in cases where formulae may give deceptive results.

There are different formulae to calculate the sodium deficit in critically ill patients; these are popular amongst intensive care unit residents.

Hypovolaemic hyponatremia not only needs sodium correction, but also replacement of lost water. Euvolaemic and hypervolaemic hyponatremia needs water restriction.

Treatment of symptomatic hyponatremia

• Initial bolus 2 ml/kg 3% saline.

• Repeat at 5 min interval > max 3 boluses.

• Thereafter 100-200 ml 3% saline over 1–2 hours (rule of thumb: 1 ml/kg increases serum sodium by 1 mEq/L).

• Cerebral symptoms subside with increase in serum sodium by 4–6 mEq/L.

Management of euvolaemic hyponatremia

• Cornerstone of sodium correction in SIADH is correction of the cause (e.g. tumor, pain, nausea, stress).

• Free water restriction.

• Replacement of water loss with normal saline or 3% saline.

• Loop diuretics like furosemide to decrease the concentrating ability of kidneys.

• Drugs.

  • Democlocycline.

  • ADH antagonists e.g. tolvaptan, conivaptan.

Expect a rapid increase in serum sodium with increasing urine output when non-osmotic ADH release subsides after volume repletion. This is the time when desmopressin has to be added to avoid over rapid correction.

Vaptans

These are nonpeptide competitive ADH antagonists, which act by inhibiting the action of vasopressin on its receptors V1a/V2 and enhancing free water excretion without increasing renal sodium and potassium excretion (Aquaretics).

• Indication.

  • Refractory case of euvolemic and hypervolemic moderate-to-severe hyponatremia.

• Contraindication.

  • Hypovolemic hyponatremia.

  • Anuria.

• Dosage.

  • Loading dose: 20 mg IV over 30 minutes.

  • Continuous infusion 20 mg/day over 24 hr., maximum duration 4 days.

• Adverse reaction.

  • Pyrexia.

  • Hypokalemia.

  • Headache.

  • Orthostatic hypotension.

• Specific consideration.

  • Hepatic impairment.

    • decrease the dose,

  • Renal impairment.

    • decrease the dose,

  • Pregnancy.

    • can cause harm to fetus,

  • Pediatric use.

    • no studies.

Osmotic demyelination syndrome

• Rapid correction of sodium in hyponatremia would cause the extracellular fluid to be relatively hypertonic.

• Free water would then move out of the cells to decrease this relative hypertonicity, leading to a central pontine myelinolysis.

• Central pontine myelinolysis is a concentrated, frequently symmetric, noninflammatory demyelination within the central basis ponts.

• In at least 10% of patients with central pontine myelinolysis, demyelination also occurs in extrapontine regions, including the midbrain, thalamus, basal nuclei and cerebellum.

Clinical presentation of osmotic demyelination syndrome (ODS) is heterogeneous and depend on the regions of the brain involved:

• Seizures.

• Disturbed consciousness.

• Gait changes.

• Respiratory depression or arrest.

• Spastic quadriparesis.

• Dysphagia.

• Dysarthria.

• Diplopia.

  Risk factors of ODM includes alcoholism, malnutrition, hypokalemia, liver failure and malignancy.

Management of Hypernatremia

The incidence of hypernatremia is much less common than hyponatremia. Hypernatremia can be divided again into three subtypes in the same fashion as hyponatremia -hypovolaemic, euvolaemic and hypervolaemic. The attached flowchart describes the different types and treatment of this disorder. See Figure 23.2

Fig. 23.2

Flowchart on diagnosis and management of hypernatremia

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Chloride Balance

Introduction

Chloride is the major strong anion in blood, accounting for approximately one-third of plasma tonicity, for 97 to 98% of all strong anionic charges and for two-thirds of all negative charges in plasma [9]. Sodium and chloride ions were once termed the ‘king and queen of electrolytes’ respectively [10]; over the years, chloride has become the forgotten ion. With progress in our understanding of acid–base and chloride channel physiology, the chloride ion is regaining its prominence.

In the 1990s, hyperchloraemic acidosis became more intently studied [11] as the physicochemical approach (Stewart approach) to acid–base analysis [12] received wider acceptance.

Within the Stewart approach, chloride is the dominant negative strong ion in plasma and a key contributor to the strong ion difference (SID), one of three independent variables that determine the hydrogen ion concentration. Hyperchloraemia is quite commonly encountered in intensive care unit (ICU) patients [13] and plays an important role in the pathogenesis of metabolic acidosis.

Chloride Distribution and Measurement

Chloride distribution in the three major body fluid compartments – plasma, interstitial fluid (ISF) and intracellular fluid. It is the most abundant anion in plasma and ISF (extracellular fluid); its concentration in these two compartments differ slightly as a result of capillary impermeability to proteins, especially albumin.

Chloride is the predominant extracellular ion with a normal concentration ranging from 94–111 meq/L [14]. The main source of chloride is dietary sodium chloride (table salt), the intake of which is 7.8 to 11.8 g/day (133 to 202 mmol) for adult men and 5.8 to 7.8 g/day (99 to 133 mmol) for adult women in the United States [15]. This intake approximates to administration of 0.5 to 1.3 litres per day of 0.9% saline (chloride, 154 mmol/l).

Chloride significantly contributes to plasma tonicity and is used in formulae to estimate serum anion gap, urine anion gap, and strong ion difference (Stewart method) which is less popular for use in clinical practice due to its complex interpretations.

$$ \mathrm{Serum}\ \mathrm{An} ion\ \mathrm{Gap}=\mathrm{serum}\kern0.5em \Big[{\mathrm{Na}}^{+}-\left[{\mathrm{Cl}}^{-}+{\mathrm{HCO3}}^{-}\right] $$

(23.1)

$$ \mathrm{Delta}\ \mathrm{gap}=\left(\mathrm{change}\ \mathrm{in}\ \mathrm{anion}\ \mathrm{gap}\right)-\left(\mathrm{change}\ \mathrm{in}\ \mathrm{bicarbonate}\right) $$

(23.2)

(The normal anion gap is assumed to be 12, and the normal HCO₃ is assumed to be 24.)

Interpretation of the generated ratio:

• −6 = Mixed high and normal anion gap acidosis

• −6 to 6 = Only a high anion gap acidosis exists

• over 6 = Mixed high anion gap acidosis and metabolic alkalosis

$$ \mathrm{Delta}\ \mathrm{ratio}=\left(\mathrm{change}\ \mathrm{in}\ \mathrm{anion}\ \mathrm{gap}\right)/\left(\mathrm{change}\ \mathrm{in}\ \mathrm{bicarbonate}\right) $$

(23.3)

(The normal anion gap is assumed to be 12, and the normal HCO₃ is assumed to be 24.)

Interpretation of the generated ratio:

• 0.4 = normal anion gap metabolic acidosis

• 0.4–0.8 = mixed high and normal anion gap acidosis exists.

• 0.8–2.0 = purely due to a high anion gap metabolic acidosis

• Over 2.0 = high anion gap acidosis with pre-existing metabolic alkalosis.

$$ \mathrm{Urine}\ \mathrm{Anion}\kern0.5em \mathrm{Gap}=\mathrm{urine}\ \left[{\mathrm{Na}}^{+}+{\mathrm{K}}^{+}\right]-{\mathrm{Cl}}^{-} $$

(23.4)

$$ {\displaystyle \begin{array}{c}\mathrm{Strong}\ \mathrm{ion}\kern0.5em \mathrm{difference}\kern0.5em \left(\mathrm{SID}\right)=\left({\mathrm{Na}}^{+}+{\mathrm{K}}^{+}+{\mathrm{Mg}}^{++}+{\mathrm{Ca}}^{++}\right)\\ {}\kern1em -\left({\mathrm{Cl}}^{-}+\mathrm{lactate}+\mathrm{other}\ \mathrm{strong}\ \mathrm{anions}\right)\end{array}} $$

(23.5)

$$ \mathrm{Na}+,\mathrm{K}+,\mathrm{Cl}-,\mathrm{HCO}3-\mathrm{in}\ \mathrm{meq}/\mathrm{L} $$

The role of chloride in urine anion gap measurements is unique and indirect as chloride here serves as a surrogate marker of NH4 + excretion in urine. A positive urine anion gap in the presence of metabolic acidosis is often abnormal and points towards low urinary NH4 + excretion, thus impaired urinary acid excretion.

Chloride Physiology

Approximately 21,000 mEq of chloride is filtered everyday, of which >99% is absorbed (55% in the proximal tubule, 25–35% in the thick ascending loop (TAL) of Henle and the remainder in the distal tubule) and only 100–250 meq is excreted every day [16].

Once in the proximal tubular lumen, chloride is reabsorbed actively via anion exchangers [SLC26A6] (chloride-formate, chloride-hydroxyl, chloride-oxalate exchanger) on luminal side and leaves the cell via a K + Cl- co-transporter and chloride selective channels.

In the TAL, chloride is reabsorbed via luminal Na-K-2Cl co-transporter and leaves the cell via ClC-Ka channel co-localized with Barttin protein. Reabsorption of sodium chloride in the TAL is essential for generation of medullary osmotic gradient, a pre-requisite for excreting concentrated urine. Once tubular fluid reaches the macula densa, its activity is modulated by chloride concentration such that low chloride concentration activates macula densa cells, thereby stimulating renin release.

In the distal convoluted tubule, chloride is actively reabsorbed via luminal Na-Cl co-transporters and leaves the cell via basolateral chloride channels.

Chloride and the Stewart Approach

An understanding of Stewart’s approach may help to understand how chloride might affect the hydrogen ion concentration [H+] [12].

In the traditional approach, bicarbonate independently determines pH as reflected by the Henderson–Hasselbalch equation:

$$ \mathrm{pH}=\mathrm{pK}+\log\ \left(\left[\mathrm{HCO}3-\right]/\left[\mathrm{CO}2\right]\right) $$

With the Stewart approach however, bicarbonate is just one of the various dependent ions. Together with other completely dissociated strong ions, chloride determines the SID:

$$ \mathrm{SID}=\left(\mathrm{Na}+\mathrm{K}+\mathrm{Mg}+\mathrm{Ca}\right)-\left(\mathrm{Cl}+\mathrm{lactate}\right) $$

Determination of [H+] depends on three independent variables:

• the SID.

• the partial pressure of carbon dioxide.

• total weak acid concentration.

A change in any of these three variables, and not in bicarbonate, will change the acid–base balance. Bicarbonate becomes a marker and not a mechanism, a major difference between the Stewart approach and the traditional Henderson–Hasselbalch approach.

Quantitatively, a change in the strong ion composition leading to lower SID will increase [H+] while an increase in SID will decrease [H+].

Hyperchloremic acidosis therefore causes acidosis by decreasing SID and not through hyperchloremia alone. This notion is supported by data demonstrating a stronger association between SID and bicarbonate than that between chloride and bicarbonate [31]. Hyperchloraemic acidosis is now increasingly described in terms of its SID nature, including the contribution of the strong ion gap or unmeasured anions [19, 20].

At the other end of the spectrum, alkalosis may thus occur with both hypochloraemia and hyperchloraemia, with the latter occurring in the presence of greater hypernatraemia (greater SID) [21]. This again highlights the importance of relative rather than absolute chloraemia.

In a study of patients with chronic obstructive pulmonary disease, subjects were found to have hypochloraemia without significant changes in plasma sodium, resulting in a higher SID and subsequent alkalosis [22]. This interestingly concurs with an animal study showing increased renal chloride excretion during hypochloraemia of respiratory acidosis.

Disorders of Chloraemia and Manipulation of Chloride in the ICU

Hyperchloraemia or hypochloraemia, resulting from disease processes or clinical manipulations, is common in the ICU and should always be considered in relation to sodium.

Hyperchloraemia with hypernatraemia, or hypochloraemia with hyponatraemia, will not change the SID and thus will not affect the acid–base balance. Intravenous administration of chloride-rich fluids is probably the most common and modifiable cause of hyperchloraemia in the ICU.

Chloride is also an essential component of intravenous fluids used in daily clinical practice and its concentration in different replacement fluids (mmol/L) is as follows [14]:

4% Albumin = 128; Normal saline (0.9%) = 154; Half normal saline (0.45%) = 77; Ringers lactate = 111,; PlasmaLyte = 98; Hydroxyethyl starch = range 110–154.

The chloride content of these fluids, from 0.9% saline to the various colloids suspended in saline is supraphysiologic [23], with significant hyperchloraemia following the administration of such fluids in volunteers, intraoperatively or as cardiopulmonary bypass priming fluid.

Whilst saline was a life-saving measure when first introduced during the cholera pandemic of Europe in the 1830s [24], it should be noted that the saline used then was of a different composition. A reconstitution of the Thomas Latta solution revealed a sodium concentration of 134 mmol/l, chloride 118 mmol/l and bicarbonate 16 mmol/l. The historical or scientific basis of the present-day 0.9% composition of saline remains a mystery, even when traced to those cholera pandemic days that marked the beginning of the intravenous fluid therapy and its various solutions [25].

Finally, the role of chloride-rich fluids and resulting acidosis in causing inferior outcomes in sepsis [17], renal vasoconstriction [17] and acute kidney injury [18] has been debated. Chloride-rich fluids result in acidosis, and evidence from animal studies particularly in sepsis point to a possible association with negative outcomes.

Clinical Approach to Dyschloremia

Symptoms related to derangement in chloride levels usually depend upon underlying cause and hence treatment also widely varies.

Hypochloremia

Hypochloremia can occur due to various reasons (Table 23.1), most commonly due to gastrointestinal or renal loss of chloride ions and also following administration of hypotonic fluids or water gain in excess of chloride (dilutional hypochloremia).

Table 23.1 Causes of hypochloremia

Chloride levels are inversely proportional to bicarbonate levels so to maintain electroneutrality, hence hypochloremia is usually associated with alkalosis due to increased bicarbonate reabsorption.

Patient with hypochloremia may present with following clinical features which may be due to concomitant metabolic alkalosis, rather than hypochloremia per se.

• Confusion/stupor/coma.

• Dizziness.

• Neuromuscular irritability - muscle twitching, numbness or tingling in the face and extremities.

• Arrhythmias.

• Nausea, vomiting.

• Tetany.

The initial diagnostic step in patients with hypochloremia and metabolic alkalosis is to assess urinary chloride which if >40 meq/L (chloride resistant metabolic alkalosis) suggests either salt wasting nephropathy such as Bartter or Gitelman syndrome (distinguished by urinary calcium excretion) or volume overload states such as congestive heart failure, hyperaldosteronism or apparent mineralocorticoid excess (differentiated through clinical history, physical exam, echocardiogram and measurement of serum aldosterone level along with plasma renin activity or concentration).

If hypochloremia exists with metabolic acidosis, the prevalent acid-base abnormality is usually normal AG metabolic acidosis. The urine AG can be used to differentiate between GI or renal loss.

In a patient with hypochloremia with normonatremia and normal or low serum bicarbonate, serum anion gap (Eq. 23.1) and delta gap (Eq. (23.2)) or delta ratio (Eq. 23.3) should be routinely measured which will uncover the mixed acid–base disorders as seen in case 1.

If poisoning with alcohol is suspected, serum osmolar gap (Eqs. 23.6 and 23.7) should be calculated. However, in patients with hypochloremia and hyponatremia, the primary focus should be shifted towards hyponatremia management.

$$ {\displaystyle \begin{array}{c}\mathrm{Serum}\ \mathrm{Osmolar}\ \mathrm{Gap}=\mathrm{Calculated}\ \mathrm{Serum}\ \mathrm{Osmolar}\mathrm{ity}\\ {}-\mathrm{measured}\ \mathrm{serum}\ \mathrm{osmolarity}\end{array}} $$

(23.6)

$$ {\displaystyle \begin{array}{c}\mathrm{Calculated}\kern0.5em \mathrm{S}.\mathrm{Osmolarity}\left(\mathrm{mosm}/\mathrm{kg}\right)=2\ \left[\mathrm{Na}+\right]+\mathrm{BUN}/2.8\\ {}+\mathrm{Glucose}/18+\mathrm{Ethanol}/4.6\end{array}} $$

(23.7)

$$ \mathrm{Na}+\left(\mathrm{meq}/\mathrm{L}\right),\mathrm{BUN},\mathrm{glucose}\ \mathrm{and}\ \mathrm{ethanol}\ \left(\mathrm{mg}/\mathrm{dL}\right) $$

Hyperchloremia

The most common modifiable etiology of hyperchloremia is excessive infusion of chloride-rich solutions e.g. saline especially during fluid resuscitation or total parenteral nutrition. It may also be secondary to water loss relative to chloride loss which may be related to renal or extra renal causes, the most common in ICU being diarrhoea. Another mechanism is an increase in tubular chloride reabsorption as seen in renal tubular acidosis (RTA) (Table 23.2).

Table 23.2 Causes of hyperchloremia

In patients with hyperchloremia, metabolic acidosis and high anion gap metabolic acidosis, poisoning with toluene and isopropyl alcohol should be suspected. Urine osmolar gap (Eqs. 23.8 and 23.9) should be calculated.

In those with hyperchloremia, metabolic acidosis and negative serum anion gap, pseudohyperchloremia should be suspected. Hypertriglyceridemia, multiple myeloma and toxicity with salicylate or bromide must be considered and their levels checked [16, 17].

$$ \mathrm{Urine}\ \mathrm{Osmolar}\ \mathrm{Gap}=\mathrm{Calculated}\ \mathrm{Urine}\ \mathrm{osmolarity}-\mathrm{measured}\ \mathrm{urine}\ \mathrm{osmolarity} $$

(23.8)

$$ {\displaystyle \begin{array}{c}\mathrm{Calculated}\ \mathrm{Urine}\ \mathrm{Osmolarity}\ \left(\mathrm{mosm}/\mathrm{kg}\right)=2\ \left[{\mathrm{Na}}^{+}+{\mathrm{K}}^{+}\right]\ \\ {}+\mathrm{BUN}/2.8+\mathrm{Glucose}/18\end{array}} $$

(23.9)

With the following units used in the formula

$$ {\mathrm{Na}}^{+},{\mathrm{K}}^{+}\left(\mathrm{meq}/\mathrm{L}\right),\mathrm{BUN}\&\mathrm{glucose}\ \left(\mathrm{mg}/\mathrm{dL}\right) $$

In patients with hyperchloremia and metabolic acidosis, patients usually have normal-anion gap metabolic acidosis (NAGMA) that could be either due to gastrointestinal losses or renal loss of HCO3 or renal inability to acidify urine. This can be differentiated using urine anion gap (Eq. 23.4) and urine osmolar gap (Eqs. 23.8 and 23.9).

Critical Analysis of Crystalloids on the Basis of above Discussion

Numerous crystalloids are commercially available; clinicians are often perturbed as to the appropriate use of these fluids. A wrong choice can lead to deterioration in critically ill patients.

The commonest fluid used in clinical practice is normal saline. Unfortunately, the terminology itself is a misnomer as it is not normal because it has a higher sodium and chloride content relative to plasma and it is also slightly hyperosmolar. As already explained, hyperchloremia is harmful. There is a significant increase in mortality if the plasma chloride level exceeds 110 meq/L. Moreover, the high sodium load is detrimental to a failing kidney. The SID of normal saline is 0, and as we know the lower the SID, the higher the possibility of metabolic acidosis. Thus normal saline has the propensity to cause metabolic acidosis. However, being slightly hyperosmolar, it is an ideal solution for head trauma patients.

Ringer’s lactate on the other hand has less sodium and chloride content. However, the lactate that is present is converted into bicarbonate, and glucose is produced by the gluconeogenetic pathway. In patients with impaired hepatic function, lactic acidosis might occur and in diabetic patients, hyperglycemia is a possibility. However, the SID of Ringer’s lactate is close to that of plasma, which adds to its advantage.

Balanced salt solutions replace lactate with acetate and gluconate, which has an extrahepatic mechanism of conversion to bicarbonate. The level of acetate is too low to cause cardiovascular instability. The SID of most of the balanced salt solutions exceeds 40; their alkaline state makes them a near ideal solution in metabolic acidosis.

Chloride in the ICU: The Research Agenda

Clinically, there is a need to re-evaluate our intravenous fluid practice - the patient’s main source of external chloride. The evidence that the choice of fluids affects acid–base balance and could cause the undesirable physiological alterations described above cannot be ignored.

More importantly, all of this preliminary evidence leads to a number of research questions that are pertinent to chloride and the care of ICU patients:

How common is hyperchloraemia in the ICU?

Is hyperchloraemia an independent predictor of death or other adverse outcomes?

Does hyperchloraemia only matter when associated with SID changes or acidaemia?

Can the elimination of chloride-rich fluids lead to clinical benefits?

These questions need urgent attention because millions of litres of saline and millions of millimoles of excess chloride are being administered to patients worldwide every day.

Case Vignette

In this patient, most of the laboratory values appear normal, and it is possible to easily overlook the serious acid-base disorder if attention is not given towards the remarkably low chloride value which suggests a complex acid–base disorder with high anion gap metabolic acidosis (serum anion gap of 30) and superimposed metabolic alkalosis (delta gap of 18 and delta ratio of 10). The high anion gap points towards unmeasured anions, later found to be oxalic acid, the metabolite of ethylene glycol.

Conclusions

Chloride has been neglected for too long. Alterations in the chloride balance and chloraemia, both absolute and relative to natraemia, can alter the acid–base status, cell biology, renal function, and haemostasis but the clinical consequences of these biological and physiological alterations remain unclear. Most of these alterations appear to have negative implications so there is an urgent need to conduct trials & research into the epidemiology and outcome implications of disorders of chloride balance and chloride concentration.

Take Home Messages

• Avoid using large volumes of 0.9% sodium chloride in ICU patients, except those at risk of intracranial hypertension.

• Consider using ‘balanced’ solutions for maintenance and resuscitation in sepsis patients.

• Hyperchloremic acidosis can be caused by the infusion of high amounts of chloride.

• Chloride is an important ion in blood and should not be neglected in acid-base analysis.

• Further research is needed to fully understand the clinical implications of alterations in sodium and chloride balance and concentration.