A simple acid-base disorder is one in which there is either acidosis or alkalosis (Table 28–1), but not both simultaneously, and this primary pathologic process is either of metabolic or respiratory origin, but not both. If sufficiently severe, a simple acid-base disturbance will always result in an abnormality in blood pH, that is, either alkalemia or acidemia. Thus, there are four cardinal acid-base disorders: metabolic acidosis, metabolic alkalosis, respiratory acidosis, and respiratory alkalosis. The patterns of pH, Paco2, and bicarbonate concentration representing these cardinal disturbances, uncomplicated by any superimposed acid-base disorder, have been observed in animal models in which the cardinal disturbance is imposed by an experimental procedure (eg, infusing an acid, such as HCl or lactic acid intravascularly, or manipulating minute ventilation in mechanically ventilated animals). These patterns have also been observed clinically in patients by independently surmising the particular acid-base process present and then examining the associated arterial blood gas assay results. Limited studies have also been performed in healthy human volunteers. The next four sections explain the patterns observed in these simple cardinal disorders, delineate the associated quantitative relationship between blood gas variables, list the differential diagnosis (ie, the underlying causes) of each cardinal disorder, and provide some simple methods for narrowing the differential diagnosis.
Table 28–1Basic nomenclature for describing primary acid-base disorders. ||Download (.pdf) Table 28–1 Basic nomenclature for describing primary acid-base disorders.
|Acidemia ||A state of abnormally low blood pH (< 7.36) |
|Alkalemia ||A state of abnormally high blood pH (> 7.44) |
|Acidosis ||A pathological process tending to acidify body fluids |
|Alkalosis ||A pathological process tending to alkalinize body fluids |
|Metabolic ||In describing an acid-base disorder, a disturbance caused by pathological gain or loss of acid (other than carbonic acid) or bicarbonate from the body |
|Respiratory ||In describing an acid-base disorder, a disturbance caused by pathological gain or loss of carbonic acid (or CO2) from the body |
|Acute ||In describing a primary respiratory acid-base disorder, a disturbance present from minutes to hours |
|Chronic ||In describing a primary respiratory acid-base disorder, a disturbance present for more than about 2 days |
From equation (28-7), it can be seen that loss of bicarbonate from the body, for example, from diarrhea, will result in formation of excessive hydrogen ion concentration by the principle of chemical mass action. On the other hand, addition of acid, either exogenous or generated by pathophysiologic metabolic processes, can directly increase hydrogen ion concentration and therefore lower pH. Also, equation (28-7) shows that addition of acid (H+) to body fluids generates carbon dioxide above and beyond the amount would be produced by normal physiologic mechanisms. Blood pH is expected to decrease from the added hydrogen ions that have not reacted with bicarbonate, and bicarbonate concentration will decrease from the hydrogen ions that combine with bicarbonate to form carbon dioxide. To prevent hypercapnia, the body has a built-in reflexive mechanism for dealing with this increased CO2 generation, namely, hyperventilation mediated through the brainstem at the level of the medulla. The afferent limb of this physiologic reflex reacts to the fall in pH to neurogenically effect hyperventilation. The increase in ventilation does not simply suffice to maintain baseline Paco2, but rather it lowers Paco2 below the normal range to a degree that is proportional to the extent of the metabolic acidosis. Empiric analysis of this proportionality in humans has been found to be linear, and can be represented by5
where HCO3– is the patient's observed bicarbonate concentration (in millimoles per liter), and expected Paco2 is the arterial carbon dioxide gas tension (in torr) that occurs statistically (ie, on average) in uncomplicated metabolic acidosis of a severity level corresponding to the observed bicarbonate concentration in the patient at hand.
Equation (28-16) follows the general form of a linear equation: y = mx + b, where m represents the slope of the linear equation when graphed on Cartesian coordinates with the X-axis representing HCO3– concentration and the Y-axis representing Paco2, and b represents the point of interception of the line along the Y-axis. The slope, given above by the factor 1.5 in equation (28-16), has been shown in some studies to be closer to 1.2.6 The term ±2 is appended to represent the 95% confidence interval derived from empiric data. If simple (ie, uncomplicated by another primary acid-base disorder) metabolic acidosis is present, substituting the patient's bicarbonate concentration into equation (28-16) and finding the patient's Paco2 to be within the expected range derived from solving the equation, would signify that the patient's arterial blood gas findings are consistent with metabolic acidosis. A Paco2 value lying outside this range implies that metabolic acidosis either is not present, is incompletely developed, or is present in combination with some other cardinal acid-base disturbance. The latter situation would constitute a mixed acid-base disturbance.
Table 28–2 provides a differential diagnosis for metabolic acidosis. A classic method for narrowing this differential diagnosis is to use the results of a basic multiphasic serum (or plasma) electrolyte panel to arrive at the anion gap by7,8,9
Table 28–2Etiologies of metabolic acidosis classified by typical serum anion gap association. ||Download (.pdf) Table 28–2 Etiologies of metabolic acidosis classified by typical serum anion gap association.
Elevated Serum Anion Gap
Normal Serum Anion Gap
Chronic Renal Failure
Type A: due to tissue hypoxia or shock
Type B1: due to certain disease states, but ostensibly not due to tissue hypoxia or hypoperfusion (eg, thiamine deficiency and some neoplasms)
Type B2: due to certain drugs of toxins (eg, cyanide, metformin, propylene glycol, and nucleoside reverse transcriptase inhibitors)
Type B3: congenital forms* (eg, glycogen storage disease type I and hereditary fructose intolerance)
Infantile forms* (eg, succinyl CoA:3-ke-toacid CoA transferase deficiency)
Methanol or ethylene glycol poisoning
Drug-induced pyroglutamic acidosis (eg, secondary to acetaminophen)
Other Congenital Organic Acidoses*
including those which do not necessarily manifest as ketoacidosis or lactic acidosis (eg, 3-hydroxy-3-methylglutaryl-CoA lyase deficiency and maple syrup urine disease)
Diarrhea (some forms, especially small bowel secretory causes)
Pancreatic or biliary drainage
Some rectal villous adenomas
Acute kidney injury
Renal tubular acidosis (types I, II, and IV)
Other tubulointerstitial renal disorders
Ileal loop bladder
Diabetic ketoacidosis (mainly in recovery phase)
Pseudohypoaldosteronism (types I and II)
Toluene-containing glue inhalation
Excessive volumes of normal saline (ie, dilutional acidosis)
Carbonic anhydrase inhibitors (eg, acetazolamide)
Cationic amino acids (total parenteral nutrition infusions with insufficient organic anion additive)
Hydrochloric acid administration
Arginine HCl administration
where each analyte concentration is expressed in units of millimoles (or milliequivalents) per liter. The normal range for the serum anion gap varies among clinical chemistry laboratories, and has declined somewhat following the adoption of contemporary assay methods, but for some laboratories, it is 12 ± 4 mEq/L. Values exceeding the upper normal limit imply that an anion, other than chloride or bicarbonate, is present at pathological concentrations. The cause of abnormally high anion gap values, particularly if the degree of elevation is not subtle, often can be confirmed, in whole or in part, by measurement of the culpable anion; for example, lactate if the cause is lactic acidosis, or β-hydroxybutyrate if the cause is ketoacidosis. Assays for some organic anions that can increase the anion gap, for example, glycolate in ethylene glycol poisoning as well as some inorganic anions, for example, sulfate accumulation in chronic renal failure, are not commonly available; however, information from the patient's medical history, physical examination, and ancillary laboratory assays can often corroborate the specific diagnosis in these cases.
If the anion gap is normal, the cause of the metabolic acidosis is basically either loss of bicarbonate from the body or an etiology that does not involve excessive production of an organic acid. In cases of metabolic acidosis where the serum anion gap is not elevated, clinical information coupled with other simple laboratory tests can often facilitate delineation of the cause.10,11 In cases of mild metabolic acidosis due to organic anion accumulation, the corresponding mild perturbation in the anion gap may not be sufficient to increase the gap above the upper normal limit. Similarly, a low baseline serum anion gap, as can occur in marked hypoalbuminemia, can have the same effect.8 The latter phenomenon can be taken into account by measuring serum albumin and recognizing that for every 1 g/dL decrease in serum albumin concentration, the serum anion gap decreases by about 2.4 mEq/L, on average.12
The serum osmole gap, often used as a screening test when methanol or ethylene glycol intoxication is suspected, is another simple derived laboratory-based expression that can be helpful in the differential diagnosis of metabolic acidosis when either of these poisonings is suspected.13 The osmole gap can be elevated after methanol or ethylene glycol ingestion even before the metabolic acidosis develops. As methanol is metabolized to formate, or ethylene glycol is metabolized to glycolate, both of which are acid anions, the serum osmole gap declines, the serum anion gap rises, and metabolic acidosis evolves.14 The osmole gap is the difference between serum osmolality determined by freezing point depression osmometry (Osmfp) and serum osmolality estimated from routinely available clinical chemistry testing (Osmest), expressed as
Osmest is calculated from simultaneous measurements of the main osmotically active constituents of normal plasma: sodium, urea nitrogen (BUN), and glucose, along with ethanol, if applicable, by:
where Na+ is expressed in millimoles per liter and the other serum assay results are expressed in milligrams per deciliter. The sodium concentration is doubled to account for osmotically active attendant anions that balance the positive charges of the sodium ions. The divisors in the other terms are derived from their respective molecular weights and convert their concentration units to millimoles (equivalent to milliosmoles) per liter. An elevated osmole gap (>15 mOsm/kg H2O or so) suggests the presence of occult osmoles, such as methanol or ethylene glycol molecules present in the sample and contributing to total osmolality.13 Other potential causes of an elevated serum osmole gap include ethanol intoxication (if the ethanol term is deleted from equation [28-19]), ketoacidosis, and severe degrees of circulatory shock.9,13
Addition of bicarbonate or loss of hydrogen ions from the body elevates extracellular bicarbonate concentration, decreases hydrogen ion concentration, and correspondingly increases pH. As in metabolic acidosis, there is normally an associated reflexive change in pulmonary minute ventilation, but in this case manifesting as hypoventilation and resulting in CO2 retention. The resulting hypercapnia does not represent respiratory dysfunction, but is an expected physiologic response to the metabolic alkalosis. The proportional change in ventilation, as manifested by Paco2, is related to the degree of metabolic alkalosis as expressed by the plasma bicarbonate concentration. One empirically derived equation describing this relationship is
The slope, given above as 0.9, has been shown in some studies to be closer to 0.7.6 Greater variability in this relationship has been observed compared to that seen in metabolic acidosis. Nevertheless, arterial blood gas values that approximate this relationship are consistent with simple metabolic alkalosis.
Once the diagnosis of metabolic alkalosis is established, the range of possible mechanisms or etiologies is considered (Table 28–3). As with metabolic acidosis, the applicable etiology is often apparent from information available through the medical history and physical examination.11,15 Gastric fluid loss, diuretic use, and extracellular volume contraction are among the most common causes. Excess alkali intake (< 10 mEq/kg) is excreted rapidly in most patients with normal renal function. However, exogenous alkali administration can lead to alkalosis in patients with compromised renal function, low chloride intake, or mineralocorticoid excess.16 Sources of exogenous alkali include oral or parenteral bicarbonate (including oral baking soda or overtreatment with intravenous NaHCO3), acetate (eg, in parenteral nutrition formulas or dialysate solutions), citrate (including secondary to multiple blood transfusions), lactate (including Ringer's lactate solutions), and gluconate salts (found, eg, in certain proprietary intravenous balanced salt solutions), or CaCO3 (eg, in oral calcium supplements).
Table 28–3Etiologies of metabolic alkalosis classified by expected urine chloride concentration or excretion. ||Download (.pdf) Table 28–3 Etiologies of metabolic alkalosis classified by expected urine chloride concentration or excretion.
High (or normal) Urine Chloride (> 20 m Eq/L)
Active diuretic use or abuse
Severe potassium depletion
Severe magnesium depletion
Chronic diarrhea (colonic origin, chiefly)
Chronic laxative abuse
Apparent mineralocorticoid excess syndrome
Renal artery stenosis
Therapeutic corticosteroid use
Refeeding alkalosis (normal NaCl intake)
Alkali ingestion or treatment (normal Cl- intake and normal circulating volume, or nonoliguric renal failure)
Nonabsorbable antacids plus sodium polystyrene sulfonate
Low Urine Chloride (< 20 mEq/L)
Vomiting or nasogastric suction
Some colonic villous adenomas
Recently discontinued diuretic treatment
Extracellular volume depletion in general (ie, contraction alkalosis)
Chloride-deficient diet (eg, soybean and protein-based infant formula diet)
Alkali ingestion or treatment (low Cl- intake and low circulating volume)
Acute correction of chronic hypercapnia
Refeeding alkalosis (in the face of low NaCl intake)
Nonreabsorbable anion (eg, high-dose penicillin or carbenicillin) in the face of extracellular volume contraction
In cases when the etiology is not straightforward, a simple laboratory test, urine chloride measurement, can sometimes be helpful. Low urine chloride concentration (< 20 mmol/L), commonly points to gastric fluid losses (by vomiting or gastric suction), recently discontinued diuretic therapy, or a posthypercapnic state. The latter occurs commonly in patients with chronic carbon dioxide retention due to chronic obstructive pulmonary disease who are placed on mechanical ventilation with resultant rapid lowering of Paco2. High urine chloride concentration (> 20 mmol/L), on the other hand, points to a renal mechanism that involves chloride wasting with retention of the alternative anion bicarbonate. Common causes of chloride wasting in the intensive care unit setting are active diuretic administration and corticosteroid therapy. The urine chloride concentration also has therapeutic implications. Low urine chloride concentrations in the face of metabolic alkalosis are often readily corrected by simply supplying chloride in the form of ample sodium chloride-containing intravenous fluids. Patients with high urine chloride levels, for example, mediated by excessive mineralocorticoid activity, are resistant to therapy with chloride-containing parenteral fluid administration because the administrated chloride load is excreted without correction of the alkalosis. Note that some patients with chloride-resistant forms of metabolic alkalosis may not manifest high urine chloride levels if they have been deprived of dietary or parenteral chloride.
Acute hypoventilation in an otherwise normal subject results in decreased elimination of carbon dioxide, with a resultant rise in Paco2. Accompanying this rise is an immediate concomitant rise in the plasma bicarbonate level. This rapid rise in bicarbonate concentration is not mediated by renal mechanisms, but rather by the principle of chemical mass action affecting equation (28-7), shifting accumulated CO2 leftward to form bicarbonate. Controlled and observational studies have demonstrated that the average rise in bicarbonate concentration (here measured in millimoles per liter) is approximately one-tenth the increase in arterial CO2 tension (measured in torr), that is,2,6,17
When a hypercapnic patient's arterial blood gas values (Paco2 tension and bicarbonate concentration) conform to equation (28-21) by comparison to known or assumed baseline (prehypercapnic) values, the results are consistent with simple acute respiratory acidosis.
The kidney normally reclaims bicarbonate filtered at the glomerulus by secreting hydrogen ions into the renal tubular lumen. The reaction between bicarbonate and hydrogen ions forms CO2 by equation (28-7), and the CO2 is readily absorbed from the tubules into the bloodstream where equation (28-7) then can operate in reverse, thus effectively resulting in bicarbonate reabsorption.2 In sustained hypercapnia, the kidney normally responds by gradually increasing tubular hydrogen ion secretion, thereby enhancing bicarbonate reabsorption, adding to the bicarbonate-elevation effect given by equation (28-21). This renal effect on plasma bicarbonate concentration takes several days to fully evolve and is proportional to the degree of prevailing hypercapnia. Although the relationship is not precisely linear, the combined mass action and renal effects of chronic hypercapnia on bicarbonate concentration can be approximated by2,6:
When the patient's arterial blood gas values yield a plasma bicarbonate concentration that approximately conforms to that given by equation (28-22), the results are consistent with simple chronic respiratory acidosis. Patients having a bicarbonate concentration intermediate between the values obtained using equations (28-21) and (28-22) either have an intermediate degree of chronicity with respect to their hypercapnia, or have a mixed acid-base disturbance (see the final section).
Etiologies of hypercapnia can be divided into primary pulmonary derangements, primary neurological abnormalities, and metabolically mediated causes, with the latter potentially including drug or toxin-mediated causes (Table 28–4). The patient's medical history, physical examination, chest imaging studies and, where necessary, other investigations will assist in narrowing the differential diagnosis and arriving at the reason for respiratory acidosis.
Table 28–4Etiologies of respiratory acidosis. ||Download (.pdf) Table 28–4 Etiologies of respiratory acidosis.
Chronic obstructive lung disease
Acute respiratory distress syndrome
Cardiogenic pulmonary edema (severe)
Pneumothorax or hemothorax
Thoracic skeletal disorders (eg, kyphoscoliosis, rib fractures, and flail chest)
Extrathoracic restrictive processes (eg, obesity, ascites, and abdominal compartment syndrome)
Mechanical ventilation with excessive deadspace
Incorrect mechanical ventilation settings or ventilator malfunction
Upper airway obstruction (eg, laryngospasm, airway tumor or foreign body, and obstructive sleep apnea)
Neurologic Illness or Injury
Traumatic brain injury
Spinal cord injury
Central nervous system infection
Amyotrophic lateral sclerosis
Obesity hypoventilation syndrome
Muscle and Neuromuscular Disorders
Thyrotoxic hypokalemic periodic paralysis
Familial hypokalemic periodic paralysis
Severe hyperkalemia (rare)
Drug and Toxin Related
Sedative hypnotic drugs (eg, benzodiazepines, barbiturates, and propofol)
General anesthetic (eg, halothane and other volatile anesthetics; nitrous oxide)
Opioids (eg, morphine, heroin, hydromorphone, oxycodone, and fentanyl)
Nondepolarizing neuromuscular blocking drugs (eg, pancuronium, vecuronium, and atracurium)
Reversible carbamate cholinesterase inhibitor overdose (eg, physostigmine and pyridostigmine)
Organophosphate insecticide poisoning (eg, malathion and diazinon)
Military nerve agents (eg, sarin, soman, and VX)
Sodium bicarbonate administration in the face of ventilatory limitation
Tetrodotoxin poisoning (eg, from puffer fish ingestion)
Acute hyperventilation in an otherwise normal subject results in increased elimination of carbon dioxide and therefore a fall in Paco2. Accompanying this fall is an immediate concomitant decrease in plasma bicarbonate concentration. This rapid fall in bicarbonate is not mediated by renal mechanisms, but rather by the principle of chemical mass action affecting equation (28-7), causing a rightward shift in the reaction sequence to partially fill the void left by the expired CO2. Human observational studies have shown that the fall in bicarbonate concentration (measured in millimoles per liter) is approximately two-tenths the decrease in arterial CO2 tension (measured in torr), that is,6
Arterial blood gas values showing hypocapnia and decreased plasma bicarbonate concentrations that approximate those given by equation (28-23) are consistent with simple acute respiratory alkalosis.
As described earlier, the kidney normally regulates bicarbonate reabsorption by adjusting hydrogen ion secretion into the renal tubular lumen. Sustained hypocapnia downregulates this hydrogen ion secretion, resulting in less reclaimed bicarbonate and thus enhancing bicarbonate excretion, adding to the bicarbonate lowering effect accounted for by equation (28-23). This added renal effect on bicarbonate concentration takes several days to fully evolve and is proportional to the degree of prevailing hypocapnia, as given by6,18
However, this proportionality, representing the combined mass action and renal bicarbonate wasting effects of hypocapnia on plasma bicarbonate concentration, eventually reaches a limit such that further degrees of hypocapnia have little additional effect on the plasma bicarbonate level. Thus, plasma HCO3– concentrations much less than 17 mmol/L are not commonly observed in simple chronic respiratory alkalosis. Within this limit, arterial blood gas results that show hypocapnia and plasma bicarbonate concentrations that conform to that given by equation (28-24) are consistent with simple chronic respiratory alkalosis. Patients having a bicarbonate concentration intermediate between the values obtained by equations (28-23) and (28-24) either have an intermediate degree of chronicity to their hypocapnia, or have a mixed acid-base disturbance (see the following section).
Etiologies of hypocapnia can be classified according to whether the primary disorder is pulmonary, neurological, metabolic, or a drug or toxin-mediated cause (Table 28–5). The patient's medical history, physical examination, chest imaging studies and, where necessary, other investigations will assist in narrowing the differential diagnosis and arriving at the reason for respiratory acidosis.
Table 28–5Etiologies of respiratory alkalosis. ||Download (.pdf) Table 28–5 Etiologies of respiratory alkalosis.
Pulmonary edema (mild to moderate)
Interstitial lung disease
Other causes of hypoxemia
Traumatic brain injury
Central nervous system infection
Burn injury or trauma
Recovery phase of metabolic acidosis
Stimulant drug overdose (eg, cocaine, amphetamine)