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Chloride metabolism, arterial blood gas, and pathophysiology.

Chloride is the major extracellular anion, with a plasma and interstitial fluid concentration of approximately 103 mmol/L. Sodium and chloride represent the majority of the osmotically active constituents of plasma. For this reason, chloride is involved significantly in the maintenance of water distribution, osmotic pressure, and anion-cation balance in the extracellular fluid compartment. In contrast to its high extracellular concentrations, the concentration of chloride in the intracellular fluid of erythrocytes is 45-54 mmol/L, and in intracellular fluid of most other tissue cells, is only about 1 mmol/L.

Chloride ions are very abundant in our diets because of the overuse of salt in the commercial food chain as well as personal dietary habits. Chloride ions in food are absorbed almost completely from the gastrointestinal tract. In the kidney, chloride is filtered from plasma at the glomeruli and passively reabsorbed, along with sodium ions, in the proximal tubules. In the thick ascending limb of the loop of Henle, the chloride pump promotes passive reabsorption of sodium ion and actively reabsorbs chlorine ion.

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We are familiar with patients who are on blood pressure medications called diuretics, which cause increased urine output and thus lower blood volume and therefore blood pressure. A number of these diuretics are known as loop diuretics because they function at the level of the loop of Henle mentioned above. Drugs included in this category are furosemide, bumetanide, ethacrynic acid and tosemide. These drugs have their effect on the sodium-potassium-chloride symporter (Cotransporter) in the thick ascending limb of the loop of Henle. By disrupting the reabsorption of these ions, loop diuretics prevent the urine from becoming concentrated and disrupt the generation of a hypertonic renal medulla. Without the concentrating effect of the medulla, water has less of an osmotic driving force to leave the collecting duct system, ultimately resulting in increased urine production.

Another vital role of chloride is in the exchange of bicarbonate and chloride ions across the red blood cell membrane. This process is commonly called the chloride shift, or Hamburger shift. In this process, carbon dioxide that is produced as a biproduct of oxygen metabolism in the cells, enters the blood stream and dissolves in the plasma of the red blood cells, it forms carbonic acid. Carbonic acid dissociates to form bicarbonate and a hydrogen ion. When carbon dioxide levels fall as the blood passes through the lungs, bicarbonate levels fall in the serum because the equilibrium shifts to replace CO2, and consequently bicarbonate in the red blood cells will move out into the serum. Because this upsets the balance of charges, chloride ion from the plasma enters the red blood cell. Reverse changes occur in the lungs when carbon dioxide is eliminated from the blood. Here, the exchange of bicarbonate for chloride in RBCs flushes the bicarbonate from the blood and increases the rate of gas exchange. Some feel that chloride shift may also control the affinity of hemoglobin for oxygen through the chloride ion acting as an allosteric effector (reacts with a nonbinding site of an enzyme molecule or protein molecule and causes a change in the function of the molecule).

The amount of chloride in the body is a reflection of the balance between chloride intake and output. The chloride content of most foods parallels that of sodium. Generally, the average adult takes in about 50 to 200 mmol of chloride/day. Chloride loss occurs by three main routes; the GI tract, skin, and urinary tract. We have already discussed the urinary tract loss so lets turn our attention to the GI tract and skin.

Generally, chloride loss through the gastrointestinal system is very small. Adults normally only loose 1-2 mmol/day. With severe diarrhea or in the presence of gastric or intestinal drainage tubes, chloride loss through the GI tract can be in excess of 100 mmol/day. Most causes for chloride loss is the same as those for sodium loss. There is one condition, however, there this is not true; hypochloremic metabolic alkalosis. In this condition chloride depletion may occur without sodium depletion. Hypochloremic metabolic alkalosis may result from loss of chloride in excess of sodium loss, usually from abnormal loss of gastric fluid. Bicarbonate must be retained to maintain electrical neutrality, leading to a base-excess alkalosis. Other conditions that involved bicarbonate retention with hypochloremia include renal compensation for chronic respiratory acidosis.

The chloride composition of sweat in the average adult is about 40 mmol/L but quite variable. Chloride in sweat is decreased by aldosterone and increased in cystic fibrosis. The mechanism for increased sweat chloride in cystic fibrosis remained an unsolved mystery until the gene responsible had been identified, cloned and sequenced. This allowed the amino acid sequence and hence the three-dimensional structure of the gene to be predicted. The protein, known as the "cystic fibrosis transmembrane conductance regulator", is involved in the control of transmembrane chloride transport. Sweat chloride is increased in cystic fibrosis and it's measurement is a useful test for diagnosis. A sweat chloride of 60 mmol/L or greater is generally indicative of a positive test. A sweat chloride of 80 mmol/L is considered confirmatory, especially on repeated testing. When the test is positive, molecular genetic analysis for the common mutations in the cystic fibrosis gene can be used for additional confirmation. Presence of the DF 508 gene will identify about 70% of the abnormal genes or about 50% affected patients.

Before concluding this topic, a small discussion of urine chloride would be helpful. The concentration of chloride in the urine is important in the differential diagnosis of metabolic alkalosis. Metabolic alkalosis that results from loss of extracellular water compartment is associated with a urine chloride concentration of less than 15 mmol/L. This type of metabolic alkalosis can be corrected with the addition of saline to the patient. Metabolic alkalosis with a normal extra cellular water volume is associated with a urine chloride concentration of greater than 15 mmol/L and may be resistant to saline administration.

A urine chloride can be used to distinguish between diuretic abuse and vomiting from Bartter's syndrome. All of these patient conditions produce hypokalemia, metabolic alkalosis, hyhperreninemia, and hyperaldosteronism. Patients with Bartter's syndrome always have elevated urinary chloride concentrations even in the face of urine total volume loss.

I hope this short discussion will give you new incites into chlorine pathophysiology and it's effect on blood gases, to say nothing about new information on plain old table salt!

Don Steinert is an Associate Professor in the Department of Nursing and a faculty member in the RT Program at the Univ. of the District of Columbia.

Don Steinert MA, RRT, MT, CLS
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Title Annotation:CLINICAL LABORATORY MEDICINE
Author:Steinert, Don
Publication:FOCUS: Journal for Respiratory Care & Sleep Medicine
Date:May 1, 2010
Words:1108
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