I. Introduction
II. Basic concepts
III. Stepwise approach to diagnosing acid-base disorders.

• Step 1: Acidemic or Alkalemic?
• Step 2: Is the primary disturbance respiratory or metabolic?
• Step 3. For a respiratory disturbance, determine whether it is acute or chronic.
• Step 4. For a metabolic acidosis, determine whether an anion gap is present.
• Step 5. Determine whether other metabolic disturbances co-exist with an anion gap acidosis.
• Step 6. Assess the normal compensation by the respiratory system for a metabolic disturbance.

IV. Specific Acid-Base Disorders and Diagnoses

I. Introduction

This document is designed to provide a practical approach to arterial blood gas analysis and will provide basic principles for understanding acid-base disturbances commonly encountered in medical practice. Although physiologic equations will appear throughout, the derivation and physiologic basis will not be discussed. Prior background in the physiology of respiratory system and acid-base disturbances is strongly recommended, but not required to complete this section.

II. Basic concepts

The anatomy of an arterial blood gas (ABG) as seen most often in the medical record:

7.40/40/98/24 or

pH/P_aCO₂/P_aO₂/HCO₃^-

pH: arterial blood pH
P_aCO₂: arterial CO₂ pressure, mm Hg (often written more simply as PCO₂)
P_aO₂: arterial O₂ pressure, mm Hg (often written more simply as PO₂)
HCO₃^-: serum bicarbonate concentration, mEq/liter

Hypoxia refers to reduced oxygen pressure in the alveolus. Hypoxemia refers to low arterial P_aO₂. At or near sea level, the following equation will estimate the average value for arterial P_aO₂:

P_aO₂ = 104.2 - (0.27 x age)

_{PAO2 = FiO2(700) - (PACO2 x 1.25), or}

_{PAO2 = 147 - (PACO2 x 1.25)}

The P_ACO₂ is equivalent to P_aCO₂ because there is no gradient. The P_AO₂ to P_aO₂ gradient is normally close to 10 (up to 21 in older individuals) and is written as follows:

P(A-a)O₂ = 10 mmHg

These relationships are most pertinent in cases of hypercarbia or elevated P_aCO₂, due to impaired ventilation. Impaired ventilation results in respiratory acidosis which is discussed in greater detail in the next section. The following table illustrates the effect of increased PACO2 in a patient with a normal P(A-a)O2 gradient of 10.

Table 1. Effect of P_ACO₂ on P_aO₂

Acidemia and alkalemia refer to the alterations in the blood pH. Both respiratory and metabolic disorders can contribute to alterations in pH and are referred to as a respiratory acidosis or respiratory alkalosis, and a metabolic acidosis or metabolic alkalosis. A single disorder may account for the observed acidemia or alkalemia, but often more than one disorder occurs concurrently. These are referred to as mixed or complex acid-base disorders. For example an alkalemic ABG may exhibit a mixed respiratory acidosis and a metabolic alkalosis. Identifying the simple as well as the complex acid-base disorders will be possible by applying the stepwise approach outlined in the next section.

III. Stepwise approach to diagnosing acid-base disorders

The following is a six-step logical approach to analyzing acid-base disorders utilizing the ABG and serum electrolyte data. It was originally proposed by Narins and Emmett (3) and further refined by Morganroth (1,2). These steps are based on sound physiologic principles, yet require an elementary understanding of those principles on the part of the student.

• Step 1: Acidemic or Alkalemic?

The pH of the arterial blood gas measurement identifies the disorder as alkalemic or acidemic.

Normal arterial blood pH = 7.40 ± 0.02

Acidemic: pH < 7.38
Alkalemic: pH > 7.42

• Step 2: Is the primary disturbance respiratory or metabolic?

This step requires one to determine whether the disturbance effects primarily the arterial P_aCO₂ or the serum HCO₃^-

A respiratory disturbance alters the arterial P_aCO₂ (normal value 40, range 38-42). Go to step 3.

A metabolic disturbance alters the serum HCO₃^- (normal value 24, range 22-26).

• If HCO₃^- < 22, metabolic acidosis is present. Go to step 4.
• If HCO₃^- > 26, metabolic alkalosis is present, is respiratory compensation adequate? Go to step 6.

The Henderson-Hasselbalch equation provides the basis for the relationship between the blood pH and PaCO₂, HCO₃^-, and it is shown below. The calculation, however, has no practical value.

pH = pK + log [HCO₃^-/P_aCO₂] x K, or

[H+] = 24 x P_aCO₂/HCO₃^-

• Step 3. For a respiratory disturbance, determine whether it is acute or chronic.

A respiratory acidosis results from accumulation of PaCO₂ and a respiratory alkalosis results from hyperventilation or a low PaCO₂ (specific causes of respiratory acidosis and alkalosis are listed in section IV). For acute disturbances a P_aCO₂ variation from normal by 10 mm Hg is accompanied by a pH shift of approx. 0.08 units. A chronic disturbance reflects renal mediated HCO₃^- shifts. Renal compensation requires several hours to develop and is maximal after 4 days. Therefore during chronic disturbances, a P_aCO₂ variation from normal of 10 is accompanied by a smaller pH shift of only 0.03 units. Also, the renal correction brings the pH back towards normal, but not completely. These relationships are spelled out in the following equations:

Acute respiratory acidosis: pH decrease = 0.08 x (P_aCO₂ - 40)/10
Chronic respiratory acidosis: pH decrease = 0.03 x (P_aCO₂ - 40)/10

Acute respiratory alkalosis: pH increase = 0.08 x (40 - P_aCO₂)/10
Chronic respiratory alkalosis pH increase = 0.03 x (40 - P_aCO₂)/10

• Step 4. For a metabolic acidosis, determine whether an anion gap is present.

The anion gap calculation simplifies the diagnosis of the cause for a metabolic acidosis.

What is the anion gap? The normal anion gap is 12 mEq/L. The anion gap is the calculated difference between negatively charged (anion) and positively charged (cation) electrolytes, which are measured in routine serum assays. The total of measured cations represented by sodium (Na⁺), is greater than the total measured anions, HCO₃^- and chloride (Cl^-). Turned around, that difference or gap also can be viewed as the unmeasured anion concentration. The unmeasured anion concentration dominates the balance between the unmeasured serum anions and cations as illustrated in Table 2.

Table2. Anion Gap reflects the unmeasured anion and cations.

Thus the balance favors the unmeasured anions by 12 mEq/L, which is the normal anion gap. The unmeasured anions rarely change enough to effect anion gap interpretation. Knowledge of the unmeasured anions is not essential to the calculation of the anion gap. However, one needs to understand the concept in order to recognize the rare instances when the anion gap is not 12 for reasons other than a metabolic acidosis. These exceptions are listed at the end of this section.

The causes of an anion gap acidosis differ from those of a normal or non-anion gap acidosis (see causes of metabolic acidosis in section IV). The anion gap determination is an excellent tool for narrowing the list of potential causes of a metabolic acidosis. The simple calculation is shown below. The anion gap calculation requires values for the serum Na⁺, Cl^-, and HCO₃^-:

Anion gap = Na⁺ - (Cl^- + HCO₃^-),
Anion gap metabolic acidosis, anion gap > 12
Normal or non-anion gap acidosis, anion gap £ 12

The calculation of the anion gap provides reliable data with the following rare exceptions (One should come back to these later after one has a solid grasp of the six-step system for acid-base analysis):

Patients with a low serum albumin (e.g. cirrhosis, nephrotic syndrome, malnutrition) have an anion gap acidosis, but the measured anion gap is normal or < 12. The reason is that albumin has many negative charges on its surface and accounts for a significant proportion of the unmeasured anions. Severe hypoalbuminemia may exhibit a normal anion gap as low as 4. Therefore in severe hypoalbuminemia if the anion gap increases and approaches 12, one must suspect an additional metabolic cause for the increased anion gap (see causes of anion gap acidosis in section IV)

Alkalemic patients with pH > 7.5, the anion gap may be elevated due to metabolic alkalosis and not because of additional metabolic acidosis. This is probably due to unmeasured anion accumulation. Specifically, the negative charges on the surface of albumin become more negative in alkalemic conditions which would increase the unmeasured anions (Table 2) and the anion gap. The distinction between whether an anion gap is due to alkalemia or an underlying acidosis in an alkalemic patient needs to be considered in some clinical situations.

• Step 5. Determine whether other metabolic disturbances co-exist with an anion gap acidosis.

A non-anion gap acidosis or a metabolic alkalosis (section IV for specific causes) may exist concurrently with an anion gap acidosis. This determination requires one to account for the increase in the anion gap and determine whether additional variation in HCO₃^- exists. If no other metabolic disturbance exists, then the following calculation would result in 24:

Corrected HCO₃^- = measured HCO₃^- + (anion gap - 12)

If the corrected HCO₃^- varies significantly above or below 24, then a mixed or more complex metabolic disturbance exists. To be more specific, if the corrected HCO₃^- is greater than 24, a metabolic alkalosis co-exists. If the corrected HCO₃^- is less than 24 then a non-gap acidosis co-exists.

The following examples help one understand how this step works. A patient with a anion gap metabolic acidosis has a HCO₃^- of 10 mEq/L and an anion gap of 26. By calculating the corrected HCO₃^- one finds the result to be 24 and can conclude that no other metabolic disturbance co-exists. If this patient had a HCO₃^- of 15 and an anion gap of 26, then the corrected HCO₃^- would calculated to 29, a value significantly greater than 24. One would then conclude that metabolic alkalosis co-exists with the gap acidosis.

• Step 6. Assess the normal compensation by the respiratory system for a metabolic disturbance.

The respiratory system responds quickly to a metabolic disturbance and most predictably to a metabolic acidosis. The change in P_aCO₂ exhibits a linear correlation with the change in HCO₃^-. The equation that predicts the respiratory response to a metabolic acidosis is called Winter’s formula:

Expected P_aCO₂ = (1.5 x HCO₃^-) + (8 ± 2)

In the setting of a simple metabolic acidosis, the measured P_aCO₂ will fall within the range predicted by Winter’s formula. If a respiratory disturbance is occurring concurrently with the metabolic acidosis, it would be defined by the direction the P_aCO₂ varies outside the range predicted by Winter’s formula, not by the P_aCO₂ variation from the normal value of 40.

Working through the following example illustrates how to utilize Winter’s formula to assess the respiratory response to metabolic acidosis. If the serum HCO₃^- is 10 mEq/L, the P_aCO₂ should be between 21 and 25 according to Winter’s formula. If the measured P_aCO₂ falls outside of this range, then an additional respiratory disturbance must be occurring concurrently. If the measured P_aCO₂ is less than 21, then the additional disturbance is a respiratory alkalosis. If the measured P_aCO₂ is greater than 25, then the additional disturbance is a respiratory acidosis.

Winter’s formula does not predict the respiratory response to a metabolic alkalosis. The magnitude of respiratory response to metabolic alkalosis is not easily predictable. When present, the respiratory response to metabolic alkalosis is hypoventilation, but the degree of P_aCO₂ increase does not exhibit a linear relationship with the HCO₃^-. Two general rules hold up for the respiratory response to a metabolic alkalosis:

• a patient will increase P_aCO₂ above 40 but not greater than 50-55 to compensate for a metabolic alkalosis.
• a patient will be alkalemic (pH > 7.42) if the P_aCO₂ is elevated to compensate for a metabolic alkalosis (If the patient is acidemic, pH < 7.38, then an additional respiratory acidosis is present).

IV. Specific Acid-Base Disorders and Diagnoses

1. Respiratory Acidosis:

Respiratory acidosis results from hypoventilation which is manifested by the accumulation of CO₂ in the blood and a drop in blood pH. Examples of specific causes can be categorized as follows:

• Central Nervous System Depression (Sedatives, CNS disease, Obesity Hypoventilation syndrome)
• Pleural Disease (Pneumothorax)
• Lung Disease (COPD, pneumonia)
• Musculoskelatal disorders (Kyphoscoliosis, Guillain-Barre, Myasthenia Gravis, Polio)

2. Respiratory Alkalosis:

Respiratory alkalosis results from hyperventilation which is manifested by excess elimination of CO₂ from the blood and a rise in the blood pH. Examples of specific causes are listed below:

• Catastrophic CNS event (CNS hemorrhage)
• Drugs (salicylates, progesterone)
• Pregnancy (especially the 3^rd trimester)
• Decreased lung compliance (interstitial lung disease)
• Liver cirrhosis
• Anxiety

3. Anion Gap Acidosis

Anion gap acidosis results from accumulation of acidic metabolites and is manifested by a low HCO₃^- and an anion gap > 12 (anion gap calculation discussed in step 3). Examples of specific causes:

• Uremia
• Ketoacidosis (diabetic hyperglycemia, EtOH withdrawal)
• Alcohol poisons or drug intoxication (methanol, ethylene glycol, paraldehyde, salicylates)
• Lactic acidosis (sepsis, left ventricular failure)

One may use a mnemonic device to remember these items. MULEPAK is a mnemonic commonly used (Methanol, Uremia, Lactic acidosis, Ethylene glycol intoxication, Paraldehyde intoxication, Aspirin, Ketoacidosis).

4. Non-Anion Gap Acidosis

Non-anion gap acidosis results from loss of bicarbonate or external acid infusion and is manifested by a low HCO₃^-, but the anion gap is <12 (anion gap calculation is discussed in step 3). Examples of specific causes:

• GI loss of HCO₃^- (diarrhea)
• Renal loss of HCO₃^-
• Compensation for respiratory alkalosis
• Carbonic anhydrase inhibitor (Diamox)
• Renal tubular acidosis
• Ureteral diversion
• Other causes: HCl or NH₄Cl infusion, Cl gas inhalation, Hyperalimentation

A mnemonic device may be used to remember this list of causes. The commonly used mnemonic is ACCRUED (Acid infusion, Compensation for respiratory alkalosis, Carbonic anhydrase inhibitor, Renal tubular acidosis, Ureteral diversion, Extra alimentation or hyperalimentation, Diarrhea).

5. Metabolic Alkalosis

Metabolic alkalosis results from elevation of serum bicarbonate. Examples of specific causes:

• Volume contraction (vomiting, overdiuresis, ascites)
• Hypokalemia
• Alkali ingestion (bicarbonate)
• Excess gluco- or mineralocorticoids
• Bartter’s syndrome

References:

1. Morganroth, ML. An analytic approach to diagnosing acid-base disorders. J Crit Ill 5(2):138-150, 1990
2. Morganroth, ML. Six steps to acid-base analysis: clinical applications. J Crit Ill 5(5) 460-469, 1990.
3. Narins, RG. Simple and mixed acid-base disorders: a practical approach. Medicine 59:161-187, 1980.