Physiology 5th Ed.

ACID-BASE DISORDERS

Disturbances of acid-base balance are among the most common conditions in all of clinical medicine. Acid-base disorders are characterized by an abnormal concentration of H+ in blood, reflected as abnormal pH. Acidemia is an increase in H+ concentration in blood (decrease in pH) and is caused by a pathophysiologic process called acidosis. Alkalemia, on the other hand, is a decrease in H+ concentration in blood (increase in pH) and is caused by a pathophysiologic process called alkalosis.

Disturbances of blood pH can be caused by a primary disturbance of HCO3 concentration or a primary disturbance of PCO2. Such disturbances are best understood by considering the Henderson-Hasselbalch equation for the HCO3/CO2 buffer. Recall that the equation states that blood pH is determined by the ratio of the HCO3 concentration to the CO2 concentration. Thus, changes in either HCO3 concentration or PCO2 will produce a change in pH.

Disturbances of acid-base balance are described as either metabolic or respiratory, depending on whether the primary disturbance is in HCO3 or CO2. There are four simple acid-base disorders, wheresimple means that only one acid-base disorder is present. When there is more than one acid-base disorder present, the condition is called a mixed acid-base disorder.

Metabolic acid-base disturbances are primary disorders involving HCO3Metabolic acidosis is caused by a decrease in HCO3 concentration that, according to the Henderson-Hasselbalch equation, leads to a decrease in pH. This disorder is caused by gain of fixed H+ in the body (through overproduction of fixed H+, ingestion of fixed H+, or decreased excretion of fixed H+) or loss of HCO3Metabolic alkalosisis caused by an increase in HCO3concentration that, according to the Henderson-Hasselbalch equation, leads to an increase in pH. This disorder is caused by loss of fixed H+ from the body or gain of HCO3.

Respiratory acid-base disturbances are primary disorders of CO2 (i.e., disorders of respiration). Respiratory acidosis is caused by hypoventilation, which results in CO2 retention, increased PCO2, and decreased pH. Respiratory alkalosis is caused by hyperventilation, which results in CO2 loss, decreased PCO2, and increased pH.

When there is an acid-base disturbance, several mechanisms are utilized in an attempt to keep the blood pH in the normal range. The first line of defense is buffering in ECF and ICF. In addition to buffering, two types of compensatory responses attempt to normalize the pH: respiratory compensation and renal compensation. A helpful rule of thumb to learn is this: If the acid-base disturbance is metabolic (i.e., disturbance of HCO3), then the compensatory response is respiratory to adjust the PCO2; if the acid-base disturbance is respiratory (i.e., disturbance of CO2), then the compensatory response is renal (or metabolic) to adjust the HCO3 concentration. Another helpful rule is this: The compensatory response is always in the same direction as the original disturbance. For example, in metabolic acidosis, the primary disturbance is a decrease in the blood HCO3 concentration. The respiratory compensation is hyperventilation, which decreases the PCO2. In respiratory acidosis, the primary disturbance is increasedPCO2. The renal compensation increases the HCO3 concentration.

As each acid-base disorder is presented, the buffering and compensatory responses are discussed in detail. Table 7-2 presents a summary of the four simple acid-base disorders and the expected compensatory responses that occur in each.

Table 7–2 Summary of Acid-Base Disorders

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Bold arrows indicate initial disturbance.

Anion Gap of Plasma

A measurement that is useful in the diagnosis of acid-base disorders is the anion gap of plasma (or simply anion gap). The anion gap is based on the principle of electroneutrality: For any body fluid compartment such as plasma, the concentration of cations and anions must be equal. In routine analysis of plasma, some cations and anions are measured and others are not. The cation that usually is measured is Na+; the anions that usually are measured are HCO3 and Cl. When the Na+ concentration (in mEq/L) is compared with the sum of the HCO3 and Cl concentrations (in mEq/L), there is an anion gap; that is, the Na+ concentration is greater than the sum of the HCO3concentration and the Cl concentration (Fig. 7-9). Because electroneutrality is never violated, plasma must contain unmeasured anions that make up this difference, or “gap.” The unmeasured anions of plasma include plasma proteins, phosphate, citrate, and sulfate.

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Figure 7–9 Anion gap of plasma.

The anion gap of plasma is calculated as follows:

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where

Plasma anion gap

= Unmeasured anions (mEq/L)

[Na+]

= Measured cation (mEq/L)

[HCO3] and [Cl]

= Measured anions (mEq/L)

The range of normal values for the plasma anion gap is 8 to 16 mEq/L. The normal value for anion gap can be obtained by substituting normal values for plasma Na+ concentration, HCO3 concentration, and Cl concentration into the equation. Thus, if the Na+ concentration is 140 mEq/L, the HCO3 concentration is 24 mEq/L, and the Cl concentration is 105 mEq/L, then the plasma anion gap is 11 mEq/L.

The plasma anion gap is useful primarily in the differential diagnosis of metabolic acidosis. Metabolic acidosis is, by definition, associated with a decrease in plasma HCO3 concentration. Assuming that the Na+ concentration is unchanged, to preserve electroneutrality of the plasma compartment, the concentration of an anion must increase to replace the “lost” HCO3. That anion can be one of the unmeasured anions, or it can be Cl. If HCO3 is replaced by unmeasured anions, the calculated anion gap is increased. If HCO3 is replaced by Cl, the calculated anion gap is normal.

Increased Anion Gap

In several forms of metabolic acidosis, an organic anion (e.g., ketoacid, lactate, formate, salicylate) is accumulated. In these cases, the decrease in HCO3 concentration is offset by an increase in the concentration of an unmeasured organic anion. Thus, there is an increased anion gap, and this type of metabolic acidosis is called metabolic acidosis with an increased anion gap. Examples of increased anion gap metabolic acidosis are diabetic ketoacidosis, lactic acidosis, salicylate poisoning, methanol poisoning, ethylene glycol poisoning, and chronic renal failure.

In certain causes of metabolic acidosis with increased anion gap (i.e., methanol and ethylene glycol poisoning), there is also an osmolar gap. Osmolar gap is the difference between the measured plasma osmolarity and the estimated plasma osmolarity. (Recall from Chapter 6 that plasma osmolarity is estimated by summing the major solutes in plasma; that is, Na+ [and its accompanying anions Cl and HCO3], glucose, and urea. As explained in Chapter 6, estimated plasma osmolarity = 2 × Na+ + glucose/18 + BUN/2.8.) Normally, there is little difference between measured and estimated plasma osmolarity because the estimation method accounts for almost all solutes normally present. However, in the case of methanol poisoning or ethylene glycol poisoning, because these substances have low molecular weight, there is significant addition of moles of solute to plasma, thus increasing the measured plasma osmolarity. Because the estimated plasma osmolarity does not count these unusual solutes, an osmolar gap is present. Theoretically, other substances that cause metabolic acidosis with increased anion gap (e.g., ketoacids, lactic acid, salicylic acid) could produce an osmolar gap. However, because of their relatively high molecular weights, toxic concentrations contribute little to the total osmolarity of plasma.

Normal Anion Gap

In a few causes of metabolic acidosis (e.g., diarrhea, renal tubular acidosis), no organic anion is accumulated. In these cases, the decrease in HCO3 concentration is offset by an increase in the concentration of Cl, which is a measured anion. Because one measured anion (HCO3) is replaced by another measured anion (Cl), there is no change in the anion gap. This type of metabolic acidosis is calledhyperchloremic metabolic acidosis with a normal anion gap. (Some may use the term “nonanion gap,” but this is a misnomer. In such cases, an anion gap is still present, but it is normal, rather than increased.)

Acid-Base Map

Each of the four simple acid-base disorders is associated with a range of values for pH, PCO2, and HCO3 concentration. These values can be superimposed as shaded areas on the acid-base map, as shown inFigure 7-10. This map provides a convenient method for assessing a patient’s acid-base status.

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Figure 7–10 Values for simple acid-base disorders superimposed on acid-base map. Shaded areas show the range of values usually seen for each of the simple acid-base disorders. There are two shaded areas for each respiratory disorder: one for the acute phase and one for the chronic phase.

image Metabolic disorders. Each of the simple metabolic disorders has one range of expected values, since respiratory compensation for metabolic acidosis or metabolic alkalosis occurs immediately.

image Respiratory disorders. Each of the simple respiratory disorders has two ranges of expected values, one for the acute disorder and one for the chronic disorder. The acute disorder is present before renal compensation has occurred, and, therefore, values for blood pH tend to be more abnormal. The chronic disorder is present once renal compensation has occurred, which takes several days. Because of the compensatory process, values for blood pH tend to be more normal in the chronic phase.

The acid-base map is used as follows: If a patient’s values fall within a shaded area, it can be concluded that only one acid-base disorder is present. If a patient’s values fall outside the shaded areas (e.g., between two areas), then it can be concluded that more than one disorder is present (i.e., mixed disorder). As each simple acid-base disorder is described subsequently, refer to Table 7-2 and the acid-base map shown in Figure 7-10.

Rules for Compensatory Responses

The acid-base map is useful pictorially, but it may be inconvenient to use at the patient’s bedside. Therefore, “rules of thumb,” or “renal rules,” have been developed to determine if the patient’s pH, PCO2, and HCO3 concentrations are consistent with a simple acid-base disorder. These rules are summarized in Table 7-3. For each metabolic disorder, the rules predict the expected compensatory change in PCO2 (i.e., respiratory compensation) for a given change in HCO3 concentration. For each respiratory disorder, the rules predict the expected compensatory change in HCO3 concentration (i.e., renal compensation) for a given change in PCO2. As with the acid-base map, for each respiratory disorder there are two sets of predictions: one for the acute phase and one for the chronic phase.

Table 7–3 Renal Rules for Predicting Compensatory Responses in Simple Acid-Base Disorders

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If a patient’s blood values are the same as the predicted values, a single acid-base disorder is present. If a patient’s values are different from the predicted values, a mixed acid-base disorder is present.

SAMPLE PROBLEM. A woman who had been vomiting for 3 days was taken to the emergency department, where the following blood values were measured: pH, 7.5; PCO2, 48 mm Hg; and HCO3, 37 mEq/L. What acid-base disorder does she have? Does she have a simple or mixed acid-base disorder?

SOLUTION. The woman has an increased (alkaline) blood pH and increased PCO2 and HCO3 concentration. These values all are consistent with a metabolic alkalosis. Metabolic alkalosis is initiated by an increase in HCO3concentration, which leads to an increase in pH. The increase in pH, acting through chemoreceptors, causes hypoventilation. Hypoventilation leads to CO2 retention and increased PCO2, which is the respiratory compensation for metabolic alkalosis.

The question of whether the woman has simple metabolic alkalosis or a mixed acid-base disorder can be answered by applying the renal rules (see Table 7-3). For metabolic alkalosis, the renal rules predict the expected increase in PCO2 for a given increase in HCO3 concentration. If the actual PCO2 is the same as the predicted PCO2, the person has simple metabolic alkalosis. If the actual PCO2 differs from the predicted PCO2, the person has metabolic alkalosis combined with another acid-base disorder (i.e., mixed disorder). In this example, the renal rules are applied as follows:

Increase in HCO3

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To interpret this calculation, in simple metabolic alkalosis with an HCO3 concentration of 37 mEq/L, compensatory hypoventilation is expected to raise the PCO2 to 49.1 mm Hg. The woman’s actual PCO2 of 48 mm Hg is virtually identical. Thus, she has the expected degree of respiratory compensation for simple metabolic alkalosis, and no other acid-base disorder is present.

Metabolic Acidosis

Metabolic acidosis is caused by a decreased HCO3concentration in the blood. Metabolic acidosis can result from increased production of fixed acids such as ketoacids or lactic acid; from ingestion of fixed acids such as salicylic acid; from the inability of the kidneys to excrete the fixed acids produced from normal metabolism; or from loss of HCO3 via the kidneys or the gastrointestinal tract (Table 7-4 and Box 7-1). The arterial blood profile seen in metabolic acidosis is

Table 7–4 Causes of Metabolic Acidosis

Cause

Examples

Comments

Excessive production or ingestion of fixed H+

Diabetic ketoacidosis

Accumulation of β-OH butyric acid and acetoacetic acid

↑ Anion gap

 

Lactic acidosis

Accumulation of lactic acid during hypoxia

↑ Anion gap

 

Salicylate poisoning

Also causes respiratory alkalosis

↑ Anion gap

 

Methanol/formaldehyde poisoning

Converted to formic acid

↑ Anion gap

↑ Osmolar gap

 

Ethylene glycol poisoning

Converted to glycolic and oxalic acids

↑ Anion gap

↑ Osmolar gap

Loss of HCO3

Diarrhea

Gastrointestinal loss of HCO3

Normal anion gap

Hyperchloremia

 

Type 2 renal tubular acidosis (type 2 RTA)

Renal loss of HCO3 (failure to reabsorb filtered HCO3)

Normal anion gap

Hyperchloremia

Inability to excrete fixed H+

Chronic renal failure

↓ Excretion of H+ as NH4+

↑ Anion gap

 

Type 1 renal tubular acidosis (type 1 RTA)

↓ Excretion of H+ as titratable acid and NH4+

↓ Ability to acidify urine

Normal anion gap

 

Type 4 renal tubular acidosis (type 4 RTA)

Hypoaldosteronism

↓ Excretion of NH4+

Hyperkalemia inhibits NH3 synthesis

Normal anion gap

BOX 7–1 Clinical Physiology: Diabetic Ketoacidosis

DESCRIPTION OF CASE. A 56-year-old woman has a 15-year history of type I diabetes mellitus, which has been controlled by careful dietary monitoring and treatment with subcutaneous injections of insulin twice a day. A recent viral illness results in loss of appetite, fever, and vomiting. She becomes short of breath and is admitted to the intensive care unit of the hospital.

Physical examination reveals that the woman is acutely ill. Her mucous membranes are dry, and she has decreased skin turgor. She is breathing deeply and rapidly. A urine sample contains glucose and ketones.

Laboratory tests on her blood yield the following information:

Arterial blood

Venous plasma

pH, 7.07

[Na+], 132 mEq/L

PCO2, 18 mm Hg

[Cl], 94 mEq/L

[HCO3], 5 mEq/L

[K+], 5.9 mEq/L

 

[Glucose], 650 mg/dL

The woman is given an insulin injection and an intravenous infusion of isotonic saline solution. Her blood values and her breathing return to normal within 12 hours after beginning treatment.

EXPLANATION OF CASE. The woman’s diabetes mellitus was well controlled until an acute viral illness precipitated an episode of diabetic ketoacidosis. Her elevated blood glucose level of 650 mg/dL (normal, 80 mg/dL) and the presence of glucose in her urine are evidence that her diabetes mellitus is not being controlled. She is excreting glucose in her urine because the blood glucose concentration is so high that the filtered load has exceeded the reabsorptive capacity of the renal tubule.

On admission, the woman has arterial blood values consistent with metabolic acidosis: decreased pH, decreased [HCO3], and decreased PCO2. Metabolic acidosis in uncontrolled type I diabetes mellitus is caused by excessive production of the fixed acids β-OH butyric acid and acetoacetic acid. The absence of insulin causes increased lipolysis (increased fat breakdown); fatty acids, the products of lipolysis, then are converted to the ketoacids β-OH butyric acid and acetoacetic acid. (The presence of ketones in her urine supports the diagnosis of ketoacidosis.) These excess fixed acids are buffered by extracellular HCO3, which decreases the blood [HCO3] and decreases blood pH. The decreased PCO2 is a result of hyperventilation (rapid, deep breathing), a respiratory compensation for metabolic acidosis known as Kussmaul’s respiration.

Does the woman have simple metabolic acidosis (one acid-base disorder), or does she have a mixed acid-base disorder? To answer this question, the rules of thumb are used to calculate the predicted change in PCO2(respiratory compensation) for the measured change in [HCO3] (refer to Table 7-3 for this calculation). For simple metabolic acidosis, the rules state that a decrease in [HCO3] of 1 mEq/L will produce a decrease in PCO2 of 1.3 mm Hg. The woman’s [HCO3] is 5 mEq/L, which is a decrease of 19 mEq/L from the normal value of 24 mEq/L; thus, the predicted change in PCO2 for this change in [HCO3] is 25 mm Hg (19 × 1.3). The predicted change in PCO2 now is compared with the actual change in PCO2. The woman’s PCO2 is 18 mm Hg, which is 22 mm Hg lower than the normal value of 40 mm Hg. The predicted change in PCO2 (25 mm Hg) and the actual change in PCO2 (22 mm Hg) are close and suggest that only one acid-base disorder is present, metabolic acidosis.

The plasma anion gap provides useful information in the differential diagnosis of metabolic acidosis. The woman’s anion gap is calculated as follows:

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The normal range for plasma anion gap is 8 to 16 mEq/L. At 33 mEq/L, the woman’s anion gap is severely elevated due to the presence of unmeasured anions. In other words, HCO3, a measured anion, is decreased and is replaced by unmeasured anions to maintain electroneutrality of the plasma compartment. Considering the woman’s history of diabetes mellitus and the presence of ketones in her urine, these unmeasured anions most likely are β-OH butyrate and acetoacetate.

The decreased skin turgor and dry mucous membranes suggest ECF volume contraction. The cause of her ECF volume contraction is loss of solute and water in urine due to an osmotic diuresis of glucose. Because the woman’s blood glucose is so high, a portion of the filtered glucose cannot be reabsorbed. The unreabsorbed glucose then acts as an osmotic diuretic, and NaCl and water are excreted along with it to cause ECF volume contraction.

Hyponatremia, or decreased blood [Na+], is often seen in diabetic ketoacidosis and can be explained as follows: Because the woman’s ECF [glucose] is markedly elevated, her ECF osmolarity also is elevated (glucose is an osmotically active solute). As a result of this hyperosmolarity of ECF, water shifts out of the cells to achieve osmotic equilibration between ECF and ICF, diluting the solutes in the ECF and decreasing the blood [Na+].

The woman has hyperkalemia (increased blood [K+]). The relationship between acid-base balance and K+ balance is often complicated, but particularly so in cases of diabetic ketoacidosis. The most likely cause of her hyperkalemia is the lack of insulin. Recall from Chapter 6 that insulin is a major factor causing a shift of K+ into cells. In the absence of insulin, K+ shifts out of cells and produces hyperkalemia. The other factor contributing to her hyperkalemia is hyperosmolarity, which is presumed to be a result of the elevated blood glucose. As water shifts out of the cells to achieve osmotic equilibration, it carries K+ along with it, causing further hyperkalemia. The metabolic acidosis is most likely not a factor in causing her hyperkalemia, because when H+ enters the cells to be buffered, it enters with the ketoanions; it need not exchange for K+.

TREATMENT. Treatment consists of an injection of insulin, which decreases the woman’s blood glucose level, corrects her ketoacidosis, and corrects her hyperkalemia. She also is given an intravenous saline solution to replace the losses of Na+ and water resulting from the osmotic diuresis.

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The following sequence of events occurs in the generation of metabolic acidosis to produce this blood profile. Although metabolic acidosis can be caused by a frank loss of HCO3, as in diarrhea and type 2 renal tubular acidosis (leading directly to a decrease in HCO3 concentration), most often it is caused by an excess of fixed acid in the body.

1.          Gain of fixed H+. Excess fixed H+ is accumulated in the body either through increased production or ingestion of fixed acid or from decreased excretion of fixed acid.

2.          Buffering. The excess fixed H+ is buffered in both ECF and ICF. In ECF, the H+ is buffered primarily by HCO3, which produces a decrease in HCO3concentration. The decrease in HCO3concentration causes a decrease in pH, as predicted by the Henderson-Hasselbalch equation (pH = pK + log HCO3/CO2).

  In ICF, the excess fixed H+ is buffered by organic phosphates and proteins. To utilize these intracellular buffers, H+ first must enter the cells. H+ can enter the cells with an organic anion such as ketoanion, lactate, or formate, or it can enter the cells in exchange for K+. When the H+ is exchanged for K+hyperkalemia occurs.

3.          Respiratory compensation. Decreased arterial pH stimulates peripheral chemoreceptors in the carotid bodies, which respond by causing hyperventilation. In turn, hyperventilation produces adecreased PCO2, which is the respiratory compensation for metabolic acidosis. To appreciate why this is a compensatory response, examine the Henderson-Hasselbalch equation:

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The primary disturbance is decreased HCO3 concentration, which, by itself, would lead to a profound decrease in pH. The respiratory compensation, hyperventilation, decreases the PCO2, which tends to normalize the ratio of HCO3/CO2 and to normalize the pH.

4.          Renal correction. Buffering and respiratory compensation occur quickly. However, the ultimate correction of metabolic acidosis (that will return the person’s acid-base status to normal) occurs in the kidneys and takes several days. The excess fixed H+ will be excreted as titratable acid and NH4+. Simultaneously, new HCO3 will be synthesized and reabsorbed by the kidneys to replace the HCO3 that was consumed earlier in buffering. In this way, the blood HCO3 concentration will be returned to normal.

Metabolic Alkalosis

Metabolic alkalosis is caused by an increased HCO3 concentration in the blood. Metabolic alkalosis is the result of loss of fixed H+ from the gastrointestinal tract; loss of fixed H+ from the kidney (e.g., hyperaldosteronism); administration of solutions containing HCO3; or ECF volume contraction (e.g., administration of diuretics) (Table 7-5 and Box 7-2). The arterial blood profile seen in metabolic alkalosis is

Table 7–5 Causes of Metabolic Alkalosis

Cause

Examples

Comments

Loss of H+

Vomiting

Loss of gastric H+

HCO3 remains in the blood

Maintained by volume contraction

Hypokalemia

 

Hyperaldosteronism

Increased H+ secretion by intercalated cells

Hypokalemia

Gain of HCO3

Ingestion of NaHCO3

Milk-alkali syndrome

Ingestion of large amounts of HCO3 in conjunction with renal failure

Volume contraction alkalosis

Loop or thiazide diuretics

↑ HCO3 reabsorption due to ↑ angiotensin II and aldosterone

BOX 7–2 Clinical Physiology: Metabolic Alkalosis due to Vomiting

DESCRIPTION OF CASE. A 35-year-old man is admitted to the hospital for evaluation of severe epigastric pain. For several days prior to admission, he has had persistent nausea and vomiting. On physical examination, he has midepigastric tenderness. His blood pressure is 120/80 mm Hg when supine and 100/60 mm Hg when standing. Upper gastrointestinal endoscopy reveals a pyloric ulcer with partial gastric outlet obstruction. The following blood values are obtained on admission:

Arterial blood

Venous blood

pH, 7.53

[Na+], 137 mEq/L

PCO2, 45 mm Hg

[Cl], 82 mEq/L

[HCO3], 37 mEq/L

[K+], 2.8 mEq/L

The man is treated with intravenous isotonic saline solution and K+, and surgery is recommended.

EXPLANATION OF CASE. In this patient, the pyloric ulcer has created a gastric outlet obstruction. Because the gastric contents could not pass easily to the small intestine, the man started vomiting. Arterial blood values are consistent with metabolic alkalosis: increased pH, increased [HCO3], and increased PCO2. The man has vomited and lost H+ from his stomach, leaving HCO3 behind in the blood. Note that his blood [Cl] is decreased (normal, 100 mEq/L), because H+ is lost from the stomach as HCl. His PCO2 is elevated as a result of hypoventilation, which is the expected respiratory compensation for metabolic alkalosis.

The anion gap is calculated with any acid-base disorder. The man’s plasma anion gap is elevated, at 18 mEq/L:

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This case shows that an increased anion gap does not necessarily mean that there is metabolic acidosis. In this man, the acid-base disorder is metabolic alkalosis. His anion gap is elevated because he has not eaten for several days. Fat is being catabolized, and the resulting fatty acids are generating ketoacids, which are unmeasured anions.

The man has orthostatic hypotension (his blood pressure falls when he stands), which is consistent with ECF volume contraction. His ECF volume contraction activates the renin–angiotensin II–aldosterone system, which worsens his metabolic alkalosis. The increased angiotensin II increases HCO3 reabsorption by stimulating Na+-H+ exchange, and the increased aldosterone increases H+ secretion. Together, these two effects on the renal tubule exacerbate the metabolic alkalosis. To summarize this point, the loss of gastric H+ generated the metabolic alkalosis and volume contraction maintained it by not allowing the excess HCO3 to be excreted in the urine.

The hypokalemia has several explanations. First, some K+ is lost in gastric fluids. Second, in metabolic alkalosis, H+ shifts out of cells and K+ shifts into cells, causing hypokalemia. Finally, the most important factor is that ECF volume contraction has caused increased secretion of aldosterone. This secondary hyperaldosteronism causes increased K+ secretion by the renal principal cells (see Chapter 6), which leads to further hypokalemia.

TREATMENT. Immediate treatment consists of intravenous saline and K+. To correct the metabolic alkalosis, ECF volume must be restored even if the vomiting stops.

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The following sequence of events occurs in the generation of metabolic alkalosis to produce this blood profile. Although metabolic alkalosis can be caused by administration of HCO3, most often it is caused by loss of fixed acid from the body.

1.          Loss of fixed acid. The classic example of metabolic alkalosis is vomiting, in which HCl is lost from the stomach. The gastric parietal cells produce H+ and HCO3 from CO2 and H2O. The H+ is secreted with Cl into the lumen of the stomach to aid in digestion, and the HCO3 enters the blood. In normal persons, the secreted H+ moves from the stomach to the small intestine, where a low pH triggers the secretion of HCO3 by the pancreas. Thus, normally, the HCO3 added to blood by the parietal cells is later removed from blood in the pancreatic secretions. However, when vomiting occurs, H+ is lost from the stomach and never reaches the small intestine. HCO3 secretion from the pancreas, therefore, is not stimulated, and the HCO3 remains in the blood, resulting in an increase in HCO3concentration.The increase in HCO3 concentration causes an increase in pH, as predicted by the Henderson-Hasselbalch equation (pH = pK + log HCO3/CO2).

2.          Buffering. As with metabolic acidosis, buffering occurs in both ECF and ICF. To utilize ICF buffers, H+ leaves the cells in exchange for K+, and hypokalemia occurs.

3.          Respiratory compensation. Increased arterial pH inhibits the peripheral chemoreceptors, which respond by causing hypoventilation. In turn, hypoventilation produces an increased PCO2, which is the respiratory compensation for metabolic alkalosis. As before, examine the Henderson-Hasselbalch equation to understand the compensation:

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The primary disturbance in metabolic alkalosis is an increased HCO3 concentration that, by itself, would lead to a profound increase in pH. The respiratory compensation, hypoventilation, increases PCO2, which tends to normalize the ratio of HCO3/CO2 and to normalize the pH.

4.          Renal correction. The correction of metabolic alkalosis should be the most straightforward of all the acid-base disorders. Because the primary disturbance is increased HCO3 concentration, restoration of acid-base balance will take place when the excess HCO3 is excreted by the kidneys. This can be accomplished because the renal tubule has a finite reabsorptive capacity for filtered HCO3. When the filtered load of HCO3 exceeds the reabsorptive capacity, HCO3 is excreted in the urine, eventually reducing the HCO3 concentration to normal. However, the correction of metabolic alkalosis is often not so straightforward. It is complicated when there is associated ECF volume contraction (e.g., due to vomiting). ECF volume contraction produces three secondary effects on the kidney, all of which conspire tomaintain the metabolic alkalosis (contraction alkalosis) by not allowing the excess HCO3 to be excreted in urine (Fig. 7-11): (1) ECF volume contraction, via the Starling forces, causes increased HCO3reabsorption in the proximal tubule; (2) ECF volume contraction, via the renin–angiotensin II–aldosterone system, produces increased levels of angiotensin II; angiotensin II stimulates Na+-H+ exchange and promotes reabsorption of filtered HCO3; (3) Increased levels of aldosterone stimulate secretion of H+ and reabsorption of “new” HCO3. When combined, these effects, all of which are secondary to ECF volume contraction, increase the HCO3 concentration and maintain the metabolic alkalosis, even when vomiting has stopped.

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Figure 7–11 Generation and maintenance of metabolic alkalosis with vomiting. ECF, Extracellular fluid.

Respiratory Acidosis

Respiratory acidosis is caused by hypoventilation, which results in retention of CO2. The retention of CO2 can be caused by inhibition of the medullary respiratory center, paralysis of respiratory muscles, airway obstruction, or failure to exchange CO2 between pulmonary capillary blood and alveolar gas (Table 7-6 and Box 7-3). The arterial blood profile seen in respiratory acidosis is

Table 7–6 Causes of Respiratory Acidosis

Cause

Examples

Comments

Inhibition of the medullary respiratory center

Opiates, barbiturates, anesthetics

Lesions of the central nervous system

Central sleep apnea

Oxygen therapy

Inhibition of peripheral chemoreceptors

Disorders of respiratory muscles

Guillain-Barré syndrome, polio, amyotrophic lateral sclerosis (ALS), multiple sclerosis

 

Airway obstruction

Aspiration

Obstructive sleep apnea

Laryngospasm

 

Disorders of gas exchange

Acute respiratory distress syndrome (ARDS)

Chronic obstructive pulmonary disease (COPD)

Pneumonia

Pulmonary edema

↓ Exchange of CO2 between pulmonary capillary blood and alveolar gas

BOX 7–3 Clinical Physiology: Chronic Obstructive Pulmonary Disease

DESCRIPTION OF CASE.  A 68-year-old man has smoked three packs of cigarettes per day for 40 years. He has a history of producing morning sputum, cough, and dyspnea (shortness of breath), and he has had frequent episodes of asthmatic bronchitis. He is admitted to the hospital with a low-grade fever, dyspnea, and wheezing. His physical examination indicates that he is cyanotic and that he has a barrel-shaped chest. The following blood values are obtained on admission:

Arterial blood

Venous blood

pH, 7.29

[Na+], 139 mEq/L

PCO2, 70 mm Hg

[Cl], 95 mEq/L

PO2, 54 mm Hg

 

[HCO3], 33 mEq/L

 

EXPLANATION OF CASE. The man’s history of smoking combined with asthma and bronchitis suggests chronic obstructive pulmonary disease (COPD). The arterial blood values are consistent with respiratory acidosis: decreased pH, increased PCO2, and increased [HCO3]. When obstructive lung disease is present, alveolar ventilation is inadequate. Thus, his PO2 is markedly depressed, at 54 mm Hg (normal PO2, 100 mm Hg) because there is insufficient O2 transfer from alveolar gas into pulmonary capillary blood. Likewise, his PCO2 is markedly elevated because there is insufficient transfer of CO2 from pulmonary capillary blood into alveolar gas (i.e., respiratory acidosis). The [HCO3] is elevated because of mass action and possibly, in addition, because of renal compensation.

The rules of thumb can be used to determine whether renal compensation has taken place; that is, whether this man has acute or chronic respiratory acidosis. Recall that in respiratory acidosis, the change in [HCO3] is predicted for a given change in PCO2. In this man, the PCO2 is 70 mm Hg, which is 30 mm Hg higher than the normal value of 40 mm Hg. His [HCO3] is 33 mEq/L, which is 9 mEq/L higher than the normal value of 24 mEq/L. Is this increase in HCO3consistent with acute or chronic respiratory acidosis? For a 30 mm Hg increase in PCO2, the rules for acute respiratory acidosis predict an increase in [HCO3] of 3 mEq/L; for chronic respiratory acidosis, the rules predict an increase of 12 mEq/L. Thus, the change in the man’s [HCO3] is closer to that predicted for compensated chronic respiratory acidosis (he has a history of chronic lung disease). Because the change in [HCO3] is not exactly the value predicted by the rules, a second acid-base disorder may be present, which may be lactic acidosis due to poor tissue oxygenation.

The anion gap is 11 mEq/L anion gap = Na+ − (Cl + HCO3) = 139 − 95 − 33 = 11 mEq/L, which is within the normal range, suggesting that if any lactic acidosis is present, it is not yet significant. The anion gap should be carefully monitored for the development of lactic acidosis superimposed on his chronic respiratory acidosis.

TREATMENT. The man is treated with antibiotics and his lungs are mechanically ventilated.

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The following sequence of events occurs in the generation of respiratory acidosis to produce this blood profile:

1.          Retention of CO2. Hypoventilation causes retention of CO2 and an increase in PCO2. The increased PCO2 is the primary disturbance in respiratory acidosis and, as predicted by the Henderson-Hasselbalch equation, causes a decrease in pH (pH = 6.1 + log HCO3/CO2). The increased PCO2, by mass action, also causes an increased concentration of HCO3.

2.          Buffering. Buffering of the excess CO2 occurs exclusively in ICF, especially in red blood cells. To utilize these intracellular buffers, CO2 diffuses across the cell membranes. Within the cells, CO2 is converted to H+ and HCO3and the H+ is buffered by intracellular proteins (e.g., hemoglobin) and by organic phosphates.

3.          Respiratory compensation. There is no respiratory compensation for respiratory acidosis, since respiration is the cause of this disorder.

4.          Renal compensation. Renal compensation for respiratory acidosis consists of increased H+ excretion as titratable acid and NH4+ and increased synthesis and reabsorption of new HCO3. Reabsorption of new HCO3 increases the HCO3 concentration even further than the effect of mass action alone. The Henderson-Hasselbalch equation can be used to understand why the increased HCO3 concentration is a compensatory response. Thus,

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In acute respiratory acidosis, renal compensation has not yet occurred, and the pH tends to be quite low (there is an increase in the denominator in the Henderson-Hasselbalch equation but little increase in the numerator). On the other hand, in chronic respiratory acidosis, renal compensation is occurring, which increases the HCO3 concentration and tends to normalize both the ratio of HCO3/CO2 and the pH. The difference between acute and chronic respiratory acidosis lies in the renal compensation. Accordingly, based on the absence or presence of renal compensation, the renal rules give different calculations for the expected change in HCO3 concentration that occurs in acute and chronic respiratory acidosis (see Table 7-3).

Respiratory Alkalosis

Respiratory alkalosis is caused by hyperventilation, which results in excessive loss of CO2. Hyperventilation can be caused by direct stimulation of the medullary respiratory center, by hypoxemia (which stimulates peripheral chemoreceptors), or by mechanical ventilation (Table 7-7). The arterial blood profile seen in respiratory alkalosis is

Table 7–7 Causes of Respiratory Alkalosis

Cause

Examples

Comments

Stimulation of the medullary respiratory center

Hysterical hyperventilation

Gram-negative septicemia

Salicylate poisoning

Neurologic disorders (tumor; stroke)

Also causes metabolic acidosis

Hypoxemia

High altitude

Pneumonia; pulmonary embolism

Hypoxemia stimulates peripheral chemoreceptors

Mechanical ventilation

   

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The following sequence of events occurs in the generation of respiratory alkalosis to produce this blood profile:

1.          Loss of CO2. Hyperventilation causes an excessive loss of CO2 and a decrease in PCO2. The decreased PCO2 is the primary disturbance in respiratory alkalosis and, as predicted by the Henderson-Hasselbalch equation, causes an increase in pH (pH = 6.1 + log HCO3/CO2). The decreased PCO2, by mass action, also causes a decreased concentration of HCO3.

2.          Buffering. Buffering occurs exclusively in ICF, particularly in red blood cells. In this case, CO2 leaves the cells and intracellular pH increases.

3.          Respiratory compensation. As with respiratory acidosis, there is no respiratory compensation for respiratory alkalosis because respiration is the cause of the disorder.

4.          Renal compensation. Renal compensation for respiratory alkalosis consists of decreased excretion of H+ as titratable acid and NH4+ and decreased synthesis and reabsorption of new HCO3. Decreased reabsorption of HCO3decreases the HCO3 concentration even further than did the effect of mass action alone. The Henderson-Hasselbalch equation can be used to understand why the decreased HCO3concentration is a compensatory response:

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In acute respiratory alkalosis, renal compensation has not yet occurred and pH is quite high (there is a decrease in the denominator of the Henderson-Hasselbalch equation but little decrease in the numerator). In chronic respiratory alkalosis, renal compensation is occurring, which further decreases the blood HCO3 concentration and tends to normalize both the ratio of HCO3/CO2 and the pH. The difference between acute and chronic respiratory alkalosis lies in renal compensation. Again, on the basis of the absence or presence of renal compensation, the renal rules give different calculations for the expected change in HCO3 concentration in acute and chronic respiratory alkalosis (see Table 7-3).

SAMPLE PROBLEM. A patient has the following arterial blood values: pH, 7.33; [HCO3], 36 mEq/L; PCO2, 70 mm Hg. What is the patient’s acid-base disorder? Is it acute or chronic? Are the blood values consistent with a simple or mixed acid-base disorder?

SOLUTION. With a pH of 7.33, the patient is acidemic. The [HCO3] and PCO2 are consistent with respiratory acidosis rather than metabolic acidosis. The PCO2 is elevated due to primary hypoventilation. (If it was metabolic acidosis, the PCO2 would be decreased due to compensatory hyperventilation.)

Whether the respiratory acidosis is acute or chronic can be determined by comparing the patient’s values with the ranges on the acid-base map. Using the acid-base map, it can be concluded that the patient haschronic respiratory acidosis.

The rules of thumb also can be used to distinguish between acute and chronic respiratory acidosis by calculating the predicted change in [HCO3] for the change in PCO2. The patient’s PCO2 is 70 mm Hg, which is 30 mm Hg above normal (normal PCO2, 40 mm Hg). The compensatory response is an increased [HCO3]. The patient’s [HCO3] is 36 mEq/L, which is 12 mEq/L above normal (normal [HCO3], 24 mEq/L). The change in [HCO3] relative to the change in PCO2 is therefore 12/30, or 0.4 mEq/L/mm Hg. The compensation is exactly as predicted by the rules of thumb for chronic respiratory acidosis. It can be concluded that the patient has simple chronic respiratory acidosiswith the expected level of renal compensation.