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Definition, Diagnosis, and Clinical Features

Acidosis means net acid accumulation with a decrease of pH 7.35. In contrast, alkalosis occurs with net accumulation of base (or net loss of acid) with an increase of pH 7.40. Based on pathogenesis, acid−base disorders can be classified as follows:

• simple disorders:
  • respiratory disorders with primary change in PCO2: respiratory acidosis/alkalosis
  • metabolic disorders with primary change in [HCO3 -]: metabolic acidosis/alkalosis
• complex disorders:
  • combination of a metabolic and a respiratory disorder
  • combination of two metabolic disorders
  • triple acid−base disorders (two metabolic and one respiratory or three metabolic disorders).

Arterial Blood Gas Analysis

Diagnosis of acid−base disorders is performed with arterial blood gas analysis. It is important to recall that with this method pH is measured in the extracellular space. Intracellular pH values are normally lower (7.1 instead of 7.4) and probably physiologically more important. However, since there is a largely linear correlation between intracellular and extracellular pH, arterial blood gas analysis is sufficient for clinical purposes.

Simple Acid−Base Disorders

These can be diagnosed when:

• PCO2 and [HCO3 -] change in the same direction
• the compensation is in the expected range

The table below shows the pattern for the four principle acid− base disorders. Double arrows indicate the primary change. As mentioned above, respiratory compensation of metabolic disorders occurs within a few hours, whereas the renal compensation of respiratory disorders requires a few days. Therefore, the analysis of compensation in the case of respiratory disorders has to distinguish between acute and chronic conditions. The analysis of compensation can be performed by various means:

• by using empiric formulas, which are summarized in the table below
• by using acid−base nomograms
• in the case of metabolic disorders with [HCO3 −] between 10−40 mmol/L, a simple general rule can be applied as follows: [HCO3 -] + 15 = PCO2 = pH (digits after decimal point) Example: A metabolic acidosis with [HCO3 −] = 15 mmol/ L has adequate respiratory compensation, when PCO2 is around 30mmHg and the pH is 7.30.

Complex Acid−Base Disorders

If the compensation of a primary acid−base disorder is not in the expected range, we have to search for a complex disorder. The table below shows typical examples with the respective findings in arterial blood gas analysis.

For closer analysis of acid−base disorders and their etiology, secondary laboratory parameters are often necessary. These include electrolyte measurements in serum and urine and based on these the calculation of anion gaps in serum and urine (SAG, UAG).

An overview is given in the table below. The use of these parameters for differential diagnosis is explained in the following paragraphs.

Clinical Features

The clinical symptoms and signs of acid−base disorders depend on the cause and the associated electrolyte disorders. The table below gives symptoms and signs of the four basic disorders, which are independent of the etiology.

Metabolic Acidosis

Pathogenesis and Use of the Serum Anion Gap (SAG)

A metabolic acidosis is defined as a decrease of pH 7.35 with low serum bicarbonate and subsequent decrease of PCO2 due to respiratory compensation (Kussmaul breathing). Two main pathophysiologic situations lead to metabolic acidosis:

• net intake (extrarenal: endogenous/exogenous) and/ or retention of acid (renal)
• net loss of bicarbonate (extrarenal or renal).

The table below shows the differential diagnosis of metabolic acidosis classified according to the underlying pathogenetic mechanism.

Serum Anion Gap. For the differential diagnosis of metabolic acidosis the serum anion gap (SAG) is a very helpful tool. In the figure below the definition of the SAG is shown schematically with the use of ionograms: the SAG is defined as the difference between nonmeasured anions and cations in serum. Its normal value is 12 ± 2 mmol/L (ionogram A).

In the case of a metabolic acidosis with bicarbonate loss, the SAG does not change. However, for electroneutrality reasons the kidney retains chloride, which leads to a hyperchloremic metabolic acidosis with normal SAG (ionogram B).

In contrast, intake or retention of fixed acids leads in most cases (except HCl) to an increase of nonmeasured anions, e. g., lactate, citrate, ketones, etc. Serum bicarbonate decreases in an equimolar range, which leads to a normochloremic metabolic acidosis with increased SAG (ionogram C).

If the increase of SAG is smaller than the decrease in serum bicarbonate, the diagnosis of a combined normochloremic and hyperchloremic acidosis (ionogram D) can be made.

When analyzing the SAG, it is important to notice that the SAG changes with the serum protein concentration, since part of the nonmeasured anions are represented by proteins.

As a general rule, a decrease of the serum albumin concentration by 10 g/L leads to a decrease of SAG by 2.5 mmol/L.

Normochloremic Metabolic Acidosis (with Increased SAG)

All acidoses of this group occur by endogenous acid accumulation or by exogenous acid intake. We have to search for the nonmeasured anion leading to an enhanced SAG. The most common clinical causes are the following:

• Diabetic ketoacidosis: the hallmark of this disorder is the accumulation of ketoacids that are generated from free fatty acids under the influence of glucagon in the absence of insulin. The most important ketones are acetoacetic acid and -hydroxybutyric acid. They can be measured in the urine using standard test stripes. However, the following two problems may arise:
  • Standard test stripes only measure acetoacetic acid. Since in severe forms of ketoacidosis mainly -hydroxybutyric acid is generated, the test results can be paradoxically negative.
  • Ketonuria leads to volume depletion. As a consequence, the test results will be positive in the early phase of ketoacidosis, when the kidney function is still maintained, and later under therapy with fluid resuscitation. However, in the severe forms of ketoacidosis with concomitant prerenal failure, the ketonuria decreases and may wrongly suggest an amelioration of the metabolic situation.

• Fasting ketoacidosis: milder forms of ketoacidosis due to increased fat metabolism occur with chronic malnutrition due to starving or alcoholism. Acetoacetic acid is the main ketone generated in these situations.

• Lactic acidosis: in the situation of tissue hypoxia, glucose and alanine are metabolized via anaerobic glycolysis. The end product of this pathway is L-lactate, which leads to an increased anion gap.We can distinguish the following variants of lactic acidosis:
  • All situations with tissue hypoxia (respiratory failure, shock, carbon monoxide intoxication, etc.) may lead to lactic acidosis type A.
  • Lactic acidosis type B occurs without tissue hypoxia. Common causes are cyanide intoxication, biguanide medication, liver failure, etc.
  • A particular variant is a lactic acidosis caused by the stereoisomer D-lactate, which can be produced in the gut by an altered gut flora. This isomer is not measured with standard techniques to determine lactate concentration, but can be determined upon special request.

• Exogenous acid intake: metabolic acidosis due to exogenous acid intake occurs in the context of hyperalimentation with amino acid solutions, but also with various intoxications. The most common intoxications are salicylates and alcohol/glycol. In the latter case formic acid, as the end product of alcohol/glycol metabolism, represents the unmeasured anion leading to the increased SAG. These intoxications are also associated with an increased serum osmolal gap. In addition, typical calcium oxalate crystals can be found in the urine with ethylene glycol intoxication.

• Reduced acid excretion: The kidney is the only organ to excrete fixed acids. Therefore, chronic renal failure usually leads to metabolic acidosis due to retention of sulphuric, phosphoric, and organic acids, which increases the SAG.

Hyperchloremic Metabolic Acidosis (with Normal SAG)

• Renal causes: if a hyperchloremic metabolic acidosis occurs due to a problem in the kidney, it is called renal tubular acidosis (RTA). We can distinguish three major forms:
  • Bicarbonate loss in the proximal tubule leads to type 2 or proximal renal tubular acidosis. Urinary bicarbonate loss leads to increased natriuresis with increased distal sodium delivery. This leads to concomitant volume depletion and hypokalemia (see above).
  • In contrast, acid secretion in the distal nephron is impaired in the case of type 1 or distal renal tubular acidosis. This variant is often associated with polyuria (renal diabetes insipidus) and nephrolithiasis/nephrocalcinosis due to concomitant calcium loss.
  • Patients with hyporeninemic hypoaldosteronism in the context of a diabetic or interstitial nephropathy often present with hyperkalemic hyperchloremic metabolic acidosis, known as type 4 or hyperkalemic renal tubular acidosis. The pathology seems to lie in the juxtaglomerular apparatus.

• Extrarenal causes: mineralocorticoids stimulate renal acid secretion. Therefore, all situations with mineralocorticoid deficit can lead to a hyperchloremic metabolic acidosis, which is typically associated with hyperkalemia. In contrast, bicarbonate loss is the main pathogenetic mechanism leading to hyperchloremic metabolic acidosis with gastrointestinal causes, e. g., diarrhea, fistulas, ureterosigmoidostomy.

For the differential diagnosis between renal tubular acidosis and extrarenal causes of hyperchloremic metabolic acidosis the urinary anion gap (UAG) is a helpful tool. The UAG measures the capacity of the distal nephron to excrete acid. Its normal value is around +30−50 mmol/L.

In the case of metabolic acidosis with a functioning renal compensation, the UAG should become negative (due to enhanced ammonium secretion). However, if the UAG stays positive, it indicates tubular dysfunction and suggests renal tubular acidosis.

Metabolic Alkalosis

Pathogenesis and Importance of the Urine Chloride Concentration

A metabolic alkalosis is defined as an increase of pH 7.40 in arterial blood gas analysis with a primary increase in serum bicarbonate and secondary increase in PCO2 due to respiratory compensation (hypoventilation). Two main pathophysiologic situations lead to metabolic alkalosis:

• net intake of bicarbonate
• net loss of acid (extrarenal or renal).

Bicarbonate excretion in the kidney is very efficient. Therefore, a metabolic alkalosis can only persist when at least one of the following maintenance factors is present: volume depletion, hypokalemia, or hyperaldosteronism.

Urine Chloride Concentration, UCl. For the differential diagnosis of metabolic alkaloses the urinary chloride concentration is a very helpful tool. Chloride depletion is a major pathogenetic mechanism for metabolic alkalosis, since the excretion of bicarbonate requires the reabsorption of another anion, namely chloride. If the UCl is 20 mmol/L, chloride depletion, often combined with volume depletion, is a very likely diagnosis, and therefore correction of alkalosis requires volume and NaCl repletion. We call this situation a chloride-sensitive metabolic alkalosis as opposed to the chloride-resistant form, when UCl is 20 mmol/L.

Chloride-Sensitive Metabolic Alkaloses

A source of chloride loss, renal or extrarenal, has to be searched for.

• Extrarenal loss of chloride and acid: this occurs with the loss of gastric fluid (repetitive vomiting, especially in the context of anorexia/bulimia; gastric alkalosis = very frequent!) or with the loss of chloride-rich fluid from the small intestine (chloride diarrhea occurs in the context of villous adenomas or as a congenital disease; rare).
• Renal chloride loss: the main cause is the use of diuretics. Under persistent therapy UCl is 20 mmol/L, however it drops quickly after stopping the treatment.

Use or abuse of diuretics is the absolute most frequent cause of metabolic alkalosis, which persists due to concomitant volume and potassium depletion.

Chronic hypercapnia leads to chloride loss, since the renal compensation of respiratory acidosis saves bicarbonate and excretes chloride. Therefore, the therapy of chronic hypercapnia unmasks a so-called posthypercapnic alkalosis, which can be corrected with chloride repletion.

Chloride-Resistant Metabolic Alkaloses

• Increased renal acid excretion: all disorders with primary mineralocorticoid excess lead to the stimulation of distal acid excretion and therefore metabolic alkalosis. They are usually associated with volume expansion, hypertension, and hypokalemia. Based on the pathogenesis they do not respond to chloride substitution.

• Renal chloride loss: it occurs if tubular chloride reabsorption is impaired. This is the case with persistent abuse of diuretics, but also with congenital disorders of chloride transporters, e. g., Bartter and Gitelman syndromes. In all these cases, the concomitant volume depletion and loss of potassium and magnesium lead to persistence of metabolic alkalosis.

Metabolic Alkalosis via Exogenous Alkali Intake

Exogenous alkali intake occurs either via bicarbonate infusion or alkali tablets (sodium bicarbonate, sodium or potassium citrate). A particular disorder is milk-alkali syndrome, which is discussed below. It is important to notice that even in the case of exogenous alkali intake a metabolic alkalosis only occurs with the presence of an additional maintenance factor, which may be either chronic renal insufficiency (with reduced capacity for bicarbonate excretion) or a volume, chloride, and/or potassium deficit (as discussed above).

Respiratory Acidosis

Acute and Chronic Disorders

A respiratory acidosis is defined as a decrease of the arterial pH to 7.35 with primary increase of PCO2 and secondary increase of serum bicarbonate as a result of renal compensation. The following main pathophysiologic situations can lead to respiratory acidosis:

• central disorders of respiratory regulation with hypoventilation
• mechanical diseases of the chest wall (skeletal, neuromuscular)
• gas exchange disorders (ventilation and/or diffusion)
• lung perfusion disorders
• mechanic hypoventilation (“permissive hypercapnia”).

Since renal compensation requires several days,we have to distinguish between acute and chronic forms of respiratory acidosis. Severe forms of acidosis occur in the context of severe acute diseases or with decompensation of a preexistent chronic disease (“acute or chronic respiratory failure”).

Patients with chronic respiratory insufficiency suffer from chronic hypercapnia, and their main stimulus for respiration remains hypoxemia. Uncontrolled therapy with oxygen or sedative drugs (e. g., central analgesics, sleeping pills) leads to severe CO2 retention, acidosis and eventually CO2 coma.

Differential Diagnosis of Respiratory Acidosis

As mentioned earlier, many diseases leading to respiratory acidosis also cause hypoxemia and lead to a metabolic acidosis through lactate generation. The combination can lead to life-threatening forms of acidosis. With controlled alveolar hypoventilation in the context of therapy for “acute respiratory distress syndrome” (ARDS), hypercapnia and respiratory acidosis are intentionally tolerated (“permissive hypercapnia”), since it allows lung-protective modes of mechanical ventilation with lower airway pressures and fewer barotraumas.

Respiratory Alkalosis

Acute and Chronic Disorders

Respiratory alkalosis is defined as an increase of the arterial pH 7.40 with primary decrease of PCO2 and secondary decrease of serum bicarbonate due to renal compensation. The following main pathophysiologic situations can lead to respiratory alkalosis:

• central disorders of respiratory regulation with hyperventilation
• extrapulmonary causes of hypoxemia
• pulmonary causes of hypoxemia
• mechanical hyperventilation.

The main stimulators of respiration are first hypercapnia and second hypoxemia. Hypoxemia with PaO2 60mmHg leads to alveolar hyperventilation and subsequent decrease of PCO2 with respiratory alkalosis. However, hypocapnia limits the degree of hyperventilation. Since renal compensation, i. e., the adaptation to increase bicarbonate excretion, requires several days, we have to distinguish acute and chronic forms of respiratory alkalosis.

A particular form of this disorder is called pseudorespiratory alkalosis and occurs in the context of severe circulatory failure. A severe decrease in cardiac output leads to tissue hypoxemia and severe venous hypercapnia. However, the arterial pH is normal or even slightly increased due to hyperventilation. Therefore, in patients with shock the measurement of central venous oxygen pressure is crucial to get an idea of tissue oxygenation.

Differential Diagnosis of Respiratory Alkalosis

The most common cause of respiratory alkalosis is acute psychogenic hyperventilation. This disorder is benign and usually responds to a nonpharmaceutic calming intervention. Acute hyperventilation can, however, lead to an impressive clinical picture with tetany, paresthesia, muscle shivering, and carpopedal spasms. These symptoms occur due to cerebral hypoperfusion in the context of an acute rise of pH and due to concomitant electrolyte disorders e. g., hypocalcemia.

It is clinically important to distinguish primary hyperventilation with respiratory alkalosis from secondary hyperventilation due to metabolic acidosis (Kussmaul respiratory pattern), which is easily done with an arterial blood gas analysis.

Controlled alveolar hyperventilation can occur with mechanical ventilation in the attempt to correct metabolic acidosis or arterial hypoxemia. In addition, it is a therapeutic approach to diseases with increased intracranial pressure.

References

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