• Chloride ions (Cl^-) are formed when elemental chlorine accumulates one electron. Chloride can also be found in compound form by covalent bonds.
• Cl^- is an abundant anion found in the intracellular and extracellular compartments. It functions primarily in the roles of metabolism, acid–base balance, and maintenance of electroneutrality. Normal blood reference range of chloride for most adults is 95–105 mEq/L.
• Medications and anesthetics (diuretics, gastrointestinal drugs, propofol, etomidate, and benzodiazepines) that influence Cl^- levels are of perioperative concern and relevance.

• Cerebrospinal fluid (CSF). Secretion of fluid into the ventricles by the choroid plexus depends on active transport of sodium ions (Na⁺) through the epithelial cells that line the outside of the plexus. Sodium ions "carry" large amounts of Cl^- to maintain electroneutrality. The two ions, when combined, increase the quantity of osmotically active ions in the CSF, which in turn causes osmosis of water through the membrane. Less important transport processes move small amounts of glucose into the CSF while moving both potassium and bicarbonate ions out, and into the capillaries, thus concentrating Cl^- (the [Cl^-] is ~15% greater in the CSF as compared to the plasma).
• Neuronal resting membrane potential. Cl^- is maintained in high concentration in the extracellular fluid compared to the intracellular environment of the neuron (via the semipermeable bilayer lipid membrane in combination with active transport processes). The Cl^- gradient (107 mEq/L extracellularly and 8 mEq/L intracellularly) yields a Nernst potential of –70 mV inside the neuron that is only slightly more negative than the actual measured value of –65 mV (major contributor).
• GABA (gamma-aminobutyric acid). Functions as a chief inhibitory neurotransmitter in the CNS to regulate neuronal excitability. GABA receptors are ligand-activated, chloride channels and bind GABA neurotransmitter and several other drugs (hypnotics, benzodiazepines, etc.). When an agonist binds, Cl^- channels open and ions flow down their concentration gradient and enter the cell; this results in hyperpolarization (cell becomes more negative). By further decreasing the membrane resting potential, the ability for an action potential to be reached is also decreased.
• Stomach. The tubular, oxyntic glands are composed of parietal cells and are located on the inside surfaces of the body and fundus of the stomach. When stimulated, parietal cells secrete an acidic solution (at their villus-like projections) that contains 160 mmol/L of HCl, which is nearly isotonic to body fluid but has a pH of ~0.8. The rate of formation and secretion of HCl by the parietal cells is directly related to the amount of histamine secreted by the enterochromaffin-like cells (ECL cells) that lie in the deep recesses of the oxyntic glands.
• Kidneys
  • Following glomerular filtration, the filtrate enters the proximal convoluted tubule (PCT) of the nephron. The epithelial cells in the first half of the PCT are highly permeable to most ions and are responsible for ~70% of Na⁺ (via a Na⁺/K⁺ ATPase antiporter), as well as significant water, urea, organic acid, H⁺, HCO₃^-, Cl^-, and phosphate reabsorption. When Na⁺ is reabsorbed, negative ions "follow" to maintain electroneutrality; they passively diffuse through paracellular pathways and are also reabsorbed via secondary active transport with Na⁺ across the luminal membrane.
  • The lumen of the nephron in the second half of the PCT has a relatively high concentration of chloride (~140 mEq/L) as compared to the early proximal tubule (~105 mEq/L). This higher concentration favors diffusion of ions through intercellular junctions and into the renal interstitial fluid.
  • As the PCT enters the hyperosmotic medulla, it becomes narrower and eventually forms the Loop of Henle. Electrolytes are actively transported out of the lumen to create a concentration gradient in the renal medulla; consequently, the epithelial cells have a high metabolic rate. Approximately 25% of the filtered load of Cl^- is reabsorbed here
• Blood/plasma. Carbonic acid (H₂CO₃), formed in red blood cells (RBCs), dissociates with hydrogen (H⁺) and bicarbonate ions (HCO₃^-).
  • The H⁺ remains within the RBC and reversibly binds to hemoglobin (Hg) thus, the Hg molecule functions as an acid–base buffer.
  • The HCO₃^- diffuses out of the RBC and into the plasma, while Cl^- diffuses into the cells to maintain electroneutrality; this occurs via the bicarbonate–chloride carrier protein that is embedded in the membrane.
  • As a consequence, the chloride content of venous RBCs is greater than that of arterial red cells. This is referred to as "chloride shifting."
• Sweat secretions. The secretory portion of the sweat gland secretes a fluid called the primary secretion or precursor secretion; the concentration of the ion constituents is then modified as the fluid flows through the duct.
  • The precursor secretion composition is similar to that of plasma (minus the plasma proteins), with a Cl^- concentration of ~104 mEq/L.
  • As this precursor solution flows through the duct portion of the gland, it is modified by reabsorption of most of the sodium and Cl^-
  • The autonomic nervous system, and hence, the rate of sweating, determines the tonicity of the sweat. A slight stimulation can result in a near complete reabsorption of sodium and chloride with a resultant concentration as low as 5 mEq/L (hypotonic sweat). Alternatively, a strong sympathetic stimulation aims to preserve water, and results in a hypertonic sweat (~50–60 mEq/L).

• Hyperchloremia is defined as an elevated Cl^- plasma concentration (>107–110 mEq/L) and can result from diarrhea, renal disease, hyperchloremic fluid administration, and as a side effect of medications. It can result in impaired blood sugar control in diabetics, muscle weakness, deep and rapid breathing, a nongap metabolic acidosis, and possibly coma.
• Hypochloremia is defined as a low Cl^- plasma concentration (<95 mEq/L). It is commonly seen with hypokalemia from gastrointestinal losses (vomiting, diarrhea, nasogastric suctioning); potassium binds with chloride (KCl). Hypochloremia may result in muscle hypertonicity/tetany, shallow and depressed breathing, and metabolic alkalosis.
• Cystic fibrosis (CF) is an autosomal-recessive disease caused by a mutation in the CFTR gene that impairs Cl^- transport and has multiple organ system involvement.
  • The primary source of morbidity and mortality is due to the progressive nature of obstructive pulmonary disease characterized by chronic inflammation, infection, and destruction of airways.
• Bartter's syndrome is characterized by the defective transport of Cl^- in the thick ascending Loop of Henle, resulting in salt wasting, metabolic alkalosis, and hypokalemia. It is a rare genetic condition.

• Iatrogenic fluid administration. The infusion of large amounts of saline-based solutions can result in hyperchloremia. Normal saline has a [Cl^-] of 154 mEq/L; additionally, albumin and hydroxyethyl starch solutions (Hetastarch) are prepared in a normal saline solution. A hyperchloremic, nongap, metabolic acidosis can result, initially from dilution of HCO₃^-. Ultimately, however, HCO₃^- anion is eliminated by the kidneys in order to maintain electroneutrality (increased chloride anion load). Clinical consequences of the metabolic acidosis are unclear. However, attempts at correcting the abnormality may actually cause more issues (iatrogenic causes such as administering additional hyperchloremic crystalloids).
• Mannitol has been shown to reduce the viscosity of mucus in patients with CF and is currently being examined for the treatment of CF and bronchiectasis. When inhaled as a dry powder orally, it osmotically draws water into the lungs and thins the mucus. This may also facilitate coughing as an expectorant during physiotherapy.
• Loop diuretics (furosemide, bumetanide, torsemide) are competitive antagonists at the Cl^- binding site on the luminal surface of the PCT. This results in impaired Na⁺ reabsorption and increased urine output (natriuresis). Additionally, the hyperosmotic medulla created by the countercurrent exchange is hindered.
• Thiazide diuretics (hydrochlorothiazide) are secreted into the PCT from the bloodstream and selectively inhibit Na⁺–K⁺-Cl^- transporters in the distal convoluted tubule. This results in impaired Na⁺ and Cl^- reabsorption and increased urine output (natriuresis).
• Antacids are orally ingested, inorganic salts that release anions on dissolving in acidic gastric secretions. The anions combine and neutralize hydrochloric acid immediately; they do not affect gastric pH.
• H₂ antagonists are competitive, as well as inverse, antagonists at H₂ receptors of gastric parietal cells. Consequently, they decrease baseline parietal cell acid and volume secretion as well as blunt the response to normal stimuli, which subsequently inactivates pepsin and stimulates gastrin release.
• Propofol, etomidate, and benzodiazepines potentiate GABA receptor binding by attaching to the beta subunit of the GABA_A receptor; thus it facilitates an inhibitory response by hyperpolarizing the cell membrane.

Plasma anion gap (mEq/L) = [Na⁺] – ([HCO₃^-] + [Cl^-])

• Cystic Fibrosis
• Aspiration
• Hyperchloremic Nongap Metabolic Acidosis
• Propofol Infusion Syndrome

Amy Barulic , BS, MHS