1 How is extracellular hydrogen ion concentration regulated?

The hydrogen ion concentration [H⁺] in the extracellular fluid is very tightly controlled and is regulated by the respiratory system, the kidneys, and various buffers. The very close relationship between the [H⁺], PCO₂, and [] can be expressed as follows:

A process that raises [H⁺] is called an acidosis whereas a process that lowers [H⁺] is called an alkalosis. If these processes lead to an alteration in blood pH to <7.36 or >7.44, there is metabolic derangement that can be described as an acidemia or an alkalemia, respectively. However, in everyday language these terms are used rather loosely, and-osis is often used when-emia is really what is meant.

2 How does a change in or in PCO₂ affect pH?

A change in of 10 mEq/L up or down causes pH to increase or decrease by 0.15 unit, respectively. Acutely, a change in PCO₂ of 10 mm Hg up or down causes pH to decrease or increase by 0.08 unit, respectively. A chronic change in PCO₂ levels alters blood pH by 0.03 unit per 10 mm Hg of PCO₂ (due to renal compensation; see Case 5-2 for details).

The first step in interpretation is to determine the primary disorder. Figure 5-1 can be used for this purpose. Normal values for [] and PCO₂ are 22 to 28 mEq/L and 35 to 45 mm Hg, respectively.

Figure 5-1 Determining the primary acid-base abnormality.

(From Piccini JP, Nilsson KR: The Osler Medical Handbook, 2nd ed. Baltimore, Johns Hopkins University, 2006.)

1 What is the primary acid-base disorder?

The laboratory results reveal acidemia (more specifically, metabolic acidosis with normal anion gap), which is consistent with the history of diarrhea for 2 days.

Note: If you had trouble arriving at this diagnosis, we will attempt to walk you through it here. The first thing you must do is look at the pH and realize that it is abnormally low. This number tells us our patient has an acidemia. Next, determine whether the acidemia is the result of respiratory or metabolic causes. Bicarbonate and PCO₂ are both low. Bicarbonate is a base, and decreased levels of bicarbonate will result in metabolic acidosis. CO₂, on the other hand, is an acid. Low levels of CO₂ thus result in an alkalosis. In this situation, the body tries to correct for the decreased pH of metabolic acidosis through hyperventilation and loss of CO₂. Therefore, this patient has a metabolic acidosis with respiratory compensation. In contrast with metabolic compensation by the kidneys, respiratory compensation occurs immediately.

Anion gap (AG) can be assessed using the formula:

Because potassium concentration is generally small in comparison to the other electrolytes in the formula, it is normally discounted from the formula. Note that the anion gap is normally positive because unmeasured anions (primarily serum proteins) far outnumber unmeasured cations.

Therefore, . In this patient, AG is 13 mEq/L (normal range  = 8-16 mEq/L). In the normal state, these unmeasured anions consist primarily of albumin and phosphate.

2 What are the mechanisms involved in metabolic acidosis due to diarrhea?

Diarrhea essentially represents the loss of bicarbonate-rich fluid. Intestinal fluid is fairly rich in bicarbonate, but normally much of this bicarbonate is reabsorbed via a exchange process in the colon. Diarrhea shortens intestinal transit time, limiting the opportunity for colonic exchange and thereby increasing the concentration of bicarbonate in the stool. This loss of bicarbonate is thus electrically balanced by an increase in serum Cl⁻ concentration. As mentioned in the preceding note, the AG remains unchanged. A similar process of Cl⁻ retention occurs in all non-AG acidoses. This is why a non-AG metabolic acidosis can alternatively be described as a hyperchloremic metabolic acidosis.

3 What else is considered in the differential diagnosis for non–anion gap metabolic acidosis?

Non-AG metabolic acidoses can be roughly divided into renal and nonrenal causes. In the setting of an acidemia, the appropriate response of the kidney is to excrete excess acid as . This is generally paired with Cl⁻ to maintain electrical neutrality. As such, the urine excretion of Cl⁻ can be measured to determine renal excretion. This calculation is specifically done using the equation for the urine anion gap (UAG):

Note that urine is excluded from this equation because, due to the acidity of urine, its concentration is typically negligible. A negative UAG signifies an appropriate renal response since makes up a large portion of the unmeasured cations in the equation, and, likewise, urine Cl⁻ concentration will be increased due to pairing with . A failure to excrete ammonium during an acidemia will give a positive UAG.

An acidosis resulting from such a failure by the kidney to excrete is called a renal tubular acidosis (RTA). See Table 5-1 for a description of the three types of renal tubular acidoses.

Table 5-1 Classification of Renal Tubular Acidosis (RTA)

A negative UAG in the setting of a non-AG acidosis most often indicates diarrhea as the nonrenal cause. However, other causes include ureteral-colonic fistulas, exogenous acid ingestion or administration (consider parenteral nutrition in a hospitalized patient), posthypocapnic acidosis, early renal failure, and “dilutional acidosis.” In the case of ureteral-colonic fistulas, urine rich in Cl⁻ enters the colon, where the Cl⁻ is reabsorbed in exchange for , resulting in loss in a mechanism similar to diarrhea. Posthypocapnic acidosis is a result of persisting renal compensation to a chronic respiratory alkalosis (see Case 5-2, question 2). Acidosis in early renal failure can result from loss of the ability to generate ammonia; late renal failure, in contrast, generally results in a mixed AG/non-AG acidosis (see next question). Dilutional acidosis, which is commonly seen in hospitalized patients, is a result of excess normal saline administration; normal saline represents a large Cl⁻ load (specifically, 154 mEq/L of Cl⁻), which results in increased bicarbonate excretion to maintain electrical neutrality.

4 Is there appropriate compensation or is there a mixed disorder in this patient?

An appropriate compensation for metabolic acidosis is to decrease PCO₂, that is, excrete volatile acid, through hyperventilation. Such respiratory compensation is virtually immediate. Using the equation in Table 5-2, the expected change in PCO₂ = 1.2 × (25 – 7) = 21.6. The actual change in this case is (40 – 19) = 21, reflecting appropriate compensation.

Table 5-2 Respiratory Compensation for Metabolic Acid-Base Disturbances

Condition	Primary Change	Expected Compensation
Metabolic acidosis	Decreased	Decreased
Metabolic alkalosis	Increased	Increased

In looking at Table 5-2, it is apparent that the lungs, in responding to metabolic acid-base disturbances, can more readily excrete CO₂ than retain it. This response is both rather intuitive (severe hypercapnia can be quite dangerous, rapidly leading to mental status changes and coma) and useful in remembering that the degree of respiratory compensation for metabolic acidosis is greater than the compensation. Note: Compensation during any acid-base disturbance is never complete.

5 What would it mean if, in the same patient, appropriate compensation was not present and PCO₂ was instead 30 mm Hg?

This value would mean that there is a mixed disorder, that is, more than one primary disorder occurring at the same time. A PCO₂ of 30 mm Hg in this case would represent inappropriate retention of CO₂, indicating a respiratory acidosis in addition to the metabolic acidosis.

1 What is the primary acid-base disorder?

Following Figure 5-1, we see that the primary disorder is a respiratory alkalosis.

2 What is the differential diagnosis in this patient?

Intensive care unit (ICU) patients are at increased risk for pulmonary embolism (PE) because they are immobile and more often have serious diseases such as congestive heart failure (stasis), recent surgery (injury to endothelium), or cancer (hypercoagulable state). Therefore, a PE is the most likely cause of his condition (particularly given the sudden onset of his vital signs changes). Pleuritic chest pain, mild fever, or hemoptysis would also support a diagnosis of PE, but signs and symptoms of PE in an ICU patient are often much more subtle.

Hypoxia from a PE leads to hyperventilation and respiratory alkalosis. However, hypoxia and hyperventilation can occur in virtually any form of lung disease, including pneumonia, pulmonary edema (as caused by congestive heart failure [CHF] or acute respiratory distress syndrome [ARDS]), or restrictive lung disease. Pain, anxiety, and various central nervous system (CNS) disorders are common causes of respiratory alkalosis in the ICU that occur in the absence of hypoxia. Asthma patients are interesting because although they can develop hypoxia, these patients very dramatically hyperventilate during asthma attacks such that a degree of respiratory alkalosis develops that is out of proportion to the hypoxia.

It is important to note that if hyperventilation persists, respiratory muscle fatigue can arise, leading to CO₂ accumulation and respiratory acidosis (a process referred to as hypercapnic respiratory failure).

3 Is there appropriate compensation or is this a mixed disorder?

Because the full effect of renal compensation for respiratory disturbances is not immediate, for acid-base disturbances with a respiratory cause, one must first determine if the disturbance is acute or chronic. In this patient, the respiratory alkalosis is acute. The appropriate compensation for any respiratory alkalosis is to decrease serum through increased renal excretion. Using the equation in Table 5-3, the appropriate acute change in . The actual change in this case is 25 – 20 = 5; therefore, there is appropriate acute compensation.

Table 5-3 Renal Compensation for Respiratory Acid-Base Disturbances

Condition	Primary Change	Expected Compensation
Acute respiratory acidosis	Increased PCO2	Increased PCO2
Chronic respiratory acidosis	Increased PCO2	Increased PCO2
Acute respiratory alkalosis	Decreased PCO2	Decreased PCO2
Chronic respiratory alkalosis	Decreased PCO2	Decreased PCO2

4 Does the degree of compensation allow you to draw any conclusions as to the duration of the condition?

Yes. Even if the history of an acute process was not available in this patient, we could conclude from his laboratory values that his respiratory alkalosis is acute. If this were a more chronic presentation, as occurs at high altitude or in pregnant women (progesterone-induced increase in tidal volume), the kidneys would have responded by excreting more bicarbonate. The decrease in would have been 0.5 × ΔPCO₂ = 10. Because it takes a couple of days for the kidneys to fully adjust to an alkalosis, we know that the duration of this condition is much shorter.

If you are attempting to remember the preceding numbers, it is useful to realize that the kidneys more easily and more rapidly excrete than retain when responding to respiratory acid-base disturbances. Thus, renal compensation for respiratory alkaloses is both more complete and more rapid than the compensation for respiratory acidoses (see Table 5-3 and Fig. 5-2).

Figure 5-2 Time course of acid-base compensatory mechanisms. In response to a metabolic acid or alkaline load, individual approaches to completion of distribution and extracellular buffering mechanisms, cellular buffering events, and respiratory and renal regulatory processes are presented as a function of time. ECF, extracellular fluid.

(From Brenner BM: Brenner and Rector’s The Kidney, 7th ed. Philadelphia, WB Saunders, 2004.)

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