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Electrolyte composition of body fluid compartments. The extracellular fluid compartment (ECF) is composed of the blood/plasma compartment and the interstitial fluid compartment. Chloride is confined to the ECF compartment.
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Electrolyte composition of body fluid compartments. The extracellular fluid compartment (ECF) is composed of the blood/plasma compartment and the interstitial fluid compartment. Chloride is confined to the ECF compartment.
). Normal serum chloride concentrations range from 96 to 106 mEq/L.Several techniques for the determination of chloride are available including (1) the autoanalyzer (a colorimetric technique—SMA and ACA methods); (2) a coulometric method; (3) a mercurimetric method; and (4) chloride-specific ion electrodes.
In the autoanalyzer method, chloride ions displace thiocyanate from mercuric thiocyanate. The free thiocyanate reacts with ferric ions to form a colored complex, ferric thiocyanate, which is measured photometrically.
This technique is not specific for the chloride anion. Other halogens, including bromide and sulfhydryl ions, react with mercuric thiocyanate. Bromide has a greater affinity for the mercuric ion than chloride, so equimolar quantities of bromide yield more Fe(SCN)3 than equimolar quantities of chloride. Therefore a small amount of bromide will result in a reaction that will be read as a marked elevation in the serum chloride determination.
The Cotlove coulometric chloride titrator is another technique that measures the total chloride concentration. With this method, the passage of a constant direct current between silver electrodes produces silver ions. The free silver ions react with the chloride forming silver chloride.
After all the chloride combines with Ag+, free silver ions accumulate, causing an increase in current across the electrodes and indicating the end point to the reaction. Although various halogens have differing affinities for Ag+, this method is insensitive to these differences, so 1 mEq of any halogen will result in the reaction being read as a 1 mEq rise in the serum chloride concentration. When the serum chloride determination by the autoanalyzer is out of proportion to the determination by the chloride titrator technique, the presence of bromide is highly probable, and a serum bromide analysis should be performed.
In the mercurimetric method, chloride is titrated with a standard solution of mercuric ions and forms the soluble complex HgCl2. The end point for the reaction is detected colorimetrically when excess Hg++ combines with an indicator dye, diphenylcarbazone, to form a blue color. Bromide will cause the same elevation of serum chloride as that which occurs during the coulometric titrator technique.
Chloride-specific electrodes are solid-state electrodes composed of membranes of AgCl. These electrodes can measure chloride potentiometrically in serum and in small quantities of sweat. Specific ion electrodes are presumably not susceptible to bromide or other halogen interference.
A typical nephron, the functional unit of the kidney. Each nephron is composed of a capillary bed for filtration, called the glomerulus, and tubule segments located in the cortex and medulla of the kidney. Chloride is both actively and passively transported in various segments of the tubules.
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). In the straight portion of the proximal tubule, the pars recta, chloride reabsorption continues as a result of passive diffusion down a favorable electrochemical gradient.
The descending limb of the loop of Henle, the next portion of the nephron, is relatively impermeable to NaCl, and no Na or Cl transport occurs. In the next segment, the thick ascending limb (loop of Henle), chloride is actively transported by a specific carrier-mediated process and Na+ (or K+) follows passively to maintain electroneutrality. The most recent data suggest a model in which two Cl− ions are transported for each Na+ and K+. Evidence also suggests that chloride transport is further increased in this segment through the generation of cyclic adenosine monophosphate by antidiuretic hormone.
In the distal convoluted tubule, as in the proximal tubule, chloride transport may be passive or active. It has been postulated, but not proven, that chloride transport is coupled to energy provided by the passive influx of sodium into the cell. Other data suggest that the measured trans-epithelial potential difference is sufficiently negative to explain chloride movement down a favorable electrochemical gradient.
The last segment of the nephron, the collecting duct, is composed of three segments: the cortical collecting tubule, the medullary collecting tubule, and the papillary collecting tubule. Chloride transport occurs as a result of both active and passive processes in the cortical collecting duct, but by only active transport processes in the papillary collecting duct. No data are currently available for the medullary collecting duct.
In summary, both active and passive transport processes are important in the reabsorption of chloride by the nephrons of the kidney. The proximal tubule appears responsible for reabsorbing the majority of the filtered chloride, and the ascending loop of Henle reabsorbs another significant amount. The distal tubule and collecting duct, although reabsorbing a smaller quantity of chloride, may also play an important role in this balance. The quantity of chloride excreted into the urine (i.e., not reabsorbed by the tubules of the nephron) is not constant, but varies from day to day depending on whether the kidneys are trying to conserve or eliminate chloride. This ability of the kidneys to vary daily chloride excretion keeps total body chloride values relatively constant and maintains serum chloride concentrations within a narrow range despite marked daily variations in chloride intake.
The presence of specific clinical disorders can affect the ability of the kidneys to maintain chloride balance. The result is hyperchloremia (elevated serum chloride concentrations) or hypochloremia (reduced serum chloride concentrations.
The serum chloride value, like the serum sodium value, is a concentration measurement (e.g., the amount of chloride/liter of plasma water). Therefore, the serum chloride concentration can be elevated above the normal range—hyperchloremia—either by the addition of excess chloride to the ECF compartment or by the loss of water from this compartment, and vice versa. The serum chloride concentration can be reduced below the normal range—hypochloremia—by the loss of chloride from the ECF or the addition of water to this compartment. This means that one cannot evaluate total body chloride stores from the serum chloride concentration. Clinical parameters must be used in conjunction with serum chloride values to assess the significance of hypochloremia or hyperchloremia.
| Total body chloride depletion |
| Extrarenal |
 Inadequate NaCl intake |
| Losses of gastrointestinal fluids |
| Vomiting |
| Nasogastric suction |
| Small bowel fistulas |
| Burns |
| Renal |
| Diuretic abusers |
| Salt-losing nephropathy |
| Interstitial nephritis |
| Adrenal insufficiency |
| Dilutional (decreased chloride concentration) |
| Increased effective circulatory blood volume |
| Hypertonic infusions |
| Hyperglycemia (early stages) |
| Normal effective circulatory blood volume |
| Pathologic water drinkers |
| Intrinsic renal diseases |
| Hypothyroidism |
| Syndrome of inappropriate antidiuretic hormone (SIADH) |
| Drugs |
| Barbiturates |
| Chlorpropramide |
| Clofibrate |
| Morphine |
| Nicotine |
| Tricyclics |
| Decreased effective circulatory blood volume |
| Edema states |
| Congestive heart failure |
| Cirrhosis of the liver |
| Nephrotic syndrome |
| Acid–base abnormalities |
| Compensated respiratory acidosis |
| Metabolic alkalosis |
Another finding often associated with total chloride depletion is metabolic alkalosis (blood pH greater than 7.45). The reabsorption of sodium bicarbonate (NaHCO3) in the proximal and distal tubule is augmented because total body chloride depletion results in both ECF volume contraction (which stimulates HCO3 reabsorption) and decreased quantities of filtered chloride available to the tubules for reabsorption with sodium. The virtual absence of chloride in the urine in the presence of a metabolic alkalosis is a strong indication that total body chloride depletion is present. Augmented reabsorption of NaHCO3 will persist until adequate quantities of chloride are administered and/or the volume of the ECF compartment is normalized. Metabolic alkalosis also increases potassium excretion by the kidneys which can lead to hypokalemia.
A number of chloride-containing solutions can be used to correct total body chloride depletion including isotonic sodium chloride (normal saline, physiologic saline) for replacement of just sodium and chloride; potassium chloride for replacement of potassium and chloride; and lysine monochloride, arginine monochloride, ammonium chloride, or HCl when acid replacement is necessary in conditions associated with chloride depletion and severe metabolic alkalosis.
Specific acid–base abnormalities may also be associated with hypochloremia. Conditions associated with a respiratory acidosis (e.g., retention of CO2 as with chronic obstructive lung disease) cause the proximal tubule to increase its secretion of hydrogen ion. This results in sodium being retained prefentially as sodium bicarbonate and not sodium chloride. Although this is a compensatory mechanism to help ameliorate the acidemia, the end result is increased concentrations of serum bicarbonate (greater than 30 mEq/L) and decreased serum chloride concentrations. Conditions causing dilutional hyponatremia and hypochloremia do not require chloride-containing fluids, since they do not have total body chloride depletion. However, respiratory acidosis associated with hypochloremia may need chloride-containing fluids if a metabolic alkalosis and/or hypokalemia is also present.
| Loss of electrolyte free fluids (pure water loss) |
| Skin losses |
| Fever |
| Hypermetabolic states |
| Increased ambient room temperature |
| Inadequate water intake |
| Loss of thirst perception |
| Renal losses |
| Central diabetes insipidus |
| Nephrogenic diabetes insiuidos |
| Loss of hypotonic fluids (water deficit in excess of sodium and chloride deficits) |
| Extrarenal |
| Diarrhea |
| Burns |
| Renal losses |
| Osmotic diuresis |
| Diuretics |
| Postobstructive diuresis |
| Intrinsic renal disease |
| Sodium gain |
| Administration of 3 to 5% NaCl |
| Saltwater drowning |
| Saline abortion |
| Hyperchloremic metabolic acidosis |
| Renal tubular acidosis |
| Interstitial renal disease |
| Multiple myeloma |
| Idiopathic |
| Drugs |
| Carbonic anhydrase inhibitors—acetazolamide |
| Topical sulfamylon acetate and metabolites |
| Small bowel diarrhea |
| Ureteral diversion procedures |
| Ureterosigmoidostomy |
| Ileal bladder |
| Ileal ureter |
| Administration of acidic salts |
| NH4Cl |
| Arginine HCl |
| Lysine HCl |
| Hyperalimentation |
| Early renal failure |
| Primary hyperparathyroidism |
| Recovery from diabetic ketoacidosis |
| Respiratory alkalosis |
Individuals with hyperchloremia secondary to electrolyte-free fluid losses will have physical findings of dehydration: dry mucous membranes, coated tongue, and no axillary sweat. Urine chloride and sodium concentrations may or may not be helpful. However, the finding of a dilute urine (Uosm less than 100 mOsm with low chloride and sodium concentrations) in the presence of hyperchloremia and hypernatremia most likely confirms the diagnosis of diabetes insipidus. With the loss of hypotonic fluids, individuals will have findings of both dehydration (a result of electrolyte-free fluid losses) and sodium depletion. As a consequence of the latter, such individuals will have evidence of ECF contraction (hypotension, tachycardia, orthostatic hypotension) in addition. In contrast, individuals with hyperchloremia secondary to administration of NaCl-containing solutions will have physical findings indicative of an expanded ECF volume: hypertension, edema, congestive heart failure, and pulmonary edema.
Elevated levels of serum chloride without increased levels of serum sodium occur as a result of clinical conditions that predispose to a hyperchloremic metabolic acidosis. Individuals with this acid–base disturbance have a serum chloride concentration above 110 mEq/L (and a low bicarbonate concentration) in association with an acidemic blood pH (pH lower than 7.35). Hyperchloremic metabolic acidosis can occur when the kidney tubules (either proximal or distal) do not reabsorb adequate quantities of the bicarbonate filtered by the glomerulus. Disorders causing intrinsic damage to the tubules (e.g., interstitial nephritis); drugs that block bicarbonate reabsorption (e.g., carbonic anhydrase inhibitors—acetazolamide; and topically applied sulfur drugs and their metabolites used as a topical antibiotic in burn patients) result in the condition called renal tubular acidosis (RTA). A diagnosis of RTA can frequently be made if one finds a blood pH that is acidemic in association with a nonacidic urine (a urine pH above 5.5). Other causes of hyperchloremic metabolic acidosis include conditions associated with severe diarrhea having losses of bicarbonate equivalents (e.g., lactate and acetate); ureteral diversion procedures, which often have hyperreabsorption of chloride by the interposed bowel segment; and ingestion of acidic chloride-containing salts (NH4Cl, arginine chloride, and lysine chloride); or acidic salts of amino acids found in some hyperalimentation solutions. Hyperchloremic metabolic acidosis can also be seen in the early stages of chronic renal failure, especially secondary to conditions resulting from interstitial renal damage; in the recovery phase of diabetic ketoacidosis (loss of ketone bodies in the urine prevents them from being converted to bicarbonate in the liver and results in bicarbonate deficits); and in primary hyperparathyroidism (which is associated with renal bicarbonate losses). In addition, respiratory alkalosis, a condition seen in individuals with hyperventilation (e.g., sepsis, pregnancy, pulmonary infections, anxiety) is associated with an elevated serum chloride concentration and a low bicarbonate concentration. An arterial blood pH will help distinguish between hyperchloremic metabolic acidosis and respiratory alkalosis.
Hyperchloremia is also seen with bromide intoxication because bromide is measured as a chloride equivalent by certain chloride measurement techniques. This results in the finding of an anion gap (as measured by the difference of sodium plus potassium minus chloride plus the total CO2 content being less than 8 mEq/L). Although the use of medications with bromide has decreased, cases of bromide intoxications still occur. It is unusual to see acute bromide intoxication, since bromide causes significant gastrointestinal irritation, resulting in nausea and vomiting, making toxic levels difficult to achieve. Slow chronic ingestion of bromide, however, can lead to toxic levels, since bromide is excreted by the kidneys, and accumulation can occur if intake exceeds output. The clinical features of bromide intoxication include fever, neurologic disturbances, skin rash, and history of ingesting proprietary bromide-containing drugs. Toxic manifestations include irritability, delirium, sedation, psychic disturbances, tremors, motor incoordination, and increases in CSF pressure and protein. Spuriously increased levels of serum chloride concentration appear in bromism, but the degree of elevation is dependent on the chloride methodology employed. There may be a poor correlation between the severity of bromide intoxication and serum bromide levels. However, bromide intoxication will cause mental and neurologic symptoms when the serum levels of bromide exceed 9 mEq/L. Most patients show signs of bromide poisoning when the serum bromide concentrations are in the range of 19 to 25 mEq/L.
