The different types of acid-base disturbances are differentiated based on:
- Origin: Respiratory or metabolic
- Primary or secondary (compensatory)
- Uncomplicated or mixed: A simple or uncomplicated disturbance is a single or primary acid-base disturbance with or without compensation. A mixed disturbance is more than one primary disturbance (not a primary with an expected compensatory response).
Acid-base disturbances have profound effects on the body. Acidemia results in arrythmias, decreased cardiac output, depression, and bone demineralization. Alkalemia results in tetany and convulsions, weakness, polydipsia and polyuria. Thus, the body will immediately respond to changes in pH or H+
, which must be kept within strict defined limits. As soon as there is a metabolic or respiratory acid-base disturbance, body buffers immediately soak up the proton (in acidosis) or release protons (alkalosis) to offset the changes in H+
(i.e. the body compensates
for the changes in H+
). This is very effective so minimal changes in pH occur if the body is keeping up or the acid-base abnormality is mild. However, once buffers are overwhelmed, the pH will change and kick in stronger responses. Remember that the goal of the body is to keep hydrogen (which dictates pH) within strict defined limits. The kidney and lungs are the main organs responsible for maintaining normal acid-base balance.
- The lungs compensate for a primary metabolic condition and will correct for a primary respiratory disturbance if the disease or condition causing the disturbance is resolved.
- The kidney is responsible for compensating for a primary respiratory disturbance or correcting for a primary metabolic disturbance. Thus, normal renal function is essential for the body to be able to adequately neutralize acid-base abnormalities and return pH (or H+) to normal. Note that mild renal disease or dysfunction or mild to moderate prerenal azotemia from dehydration or hypovolemia may not have any effect on the ability of the kidney to respond to an acid-base disturbance. Also, since the kidney is so crucial for normal acid-base balance, renal disease (particularly acute kidney injury, but also chronic renal disease leading to failure) can and does result in acid-base abnormalities (usually acidosis, due to failure to excrete the normal acid load generated by protein metabolism).
Renal excretion of hydrogen
There are four primary types of acid-base disorders, which the body responds to (compensates for or corrects).
- Metabolic acidosis: This is due to increases in non-volatile (non-carbonic) acids, which can contain chloride as their anion (e.g. ammonium chloride) or another anion (e.g. lactate).
- Body buffers in plasma (bicarbonate particularly, but also proteins) and intracellularly (hemoglobin in RBCs in particular) or in bone immediately start to offset any increase in H+ from a non-volatile acidosis. The lungs also blow off carbon dioxide, which is respiratory compensation. If needed, the kidney will kick in and increase ammoniagenesis (regenerating new bicarbonate and excreting ammonium chloride or NH4Cl in the proximal tubules and ascending limb of the loop of Henle) and excreting H+ directly via H-ATPases (in all tubules, but primarily collecting tubules; chloride follows) as correction for the acidosis (as long as the kidney is not dysfunctional and causing the acidosis in the first place) (see image to the right).
- Respiratory acidosis: This is due to increases in the volatile (it can be blown off) or so-called "respiratory" acid, carbonic acid, which comes from increases in carbon dioxide due to inadequate ventilation.
- Carbon dioxide is freely diffusible and moves rapidly into cells (hemoglobin in RBCs in particular) which starts to offset any increase in H+ from a volatile acidosis. The kidney will kick in and increase ammoniagenesis (regenerating new bicarbonate and excreting ammonium chloride or NH4Cl) and excreting H+ directly via H-ATPases (chloride follows) as compensation for the volatile acidosis (this is very effective and, in some species, can correct pH given time). Carbonic acid, which generates bicarbonate, cannot obviously, be buffered by bicarbonate.
- Metabolic alkalosis: This is due to accumulation of a base or loss of a non-volatile acid (which usually but does not always contains chloride as its anion).
- Body buffers in serum (proteins) and intracellularly (hemoglobin in RBCs in particular) immediately start to offset any decrease in H+ from a metabolic alkalosis. The lungs also retain carbon dioxide, which is respiratory compensation. If needed, the kidney will kick in and decrease ammoniagenesis (thus reducing ammonium chloride or NH4Cl excretion and bicarbonate generation, thus retaining H+ and chloride) and decreasing activity of the H-ATPases (retaining H+ and chloride) as correction for the alkalosis (as long as the kidney is not dysfunctional and causing the acidosis in the first place). The kidney also filters excess bicarbonate in plasma and can actively excrete bicarbonate in collecting tubules.
- Respiratory alkalosis: This is due to decreases in carbon dioxide or carbonic acid secondary to hyperventilation (increased tidal volume).
- Hydrogen is liberated off intracellular buffers (hemoglobin in RBCs in particular), which moves extracellularly offsetting the decrease in H+ in plasma. The kidney will kick in and decrease ammoniagenesis and H+ excretion (chloride is retained). This is very effective and, in some species, can correct pH given time.
Combinations of these primary disturbances (more than one primary at the same time) results in a mixed disturbance
. Note, that you cannot have a primary respiratory acidosis and a primary respiratory alkalosis at the same time; the lungs can create only one primary disturbance. But you can have a primary metabolic acidosis (e.g. accumulation of lactic acid) and a primary metabolic alkalosis (vomiting gastric HCl) at the same time.
In general, primary disturbances can be distinguished from secondary or compensatory responses by the pH and degree and direction of change of the acid-base results. For example, an acidemia indicates that there is an acidosis and it is the dominant disturbance. If the bicarbonate and base excess are low, it indicates a primary metabolic acidosis. If the pCO2
is high, it indicates a primary respiratory acidosis. If the bicarbonate and base excess are low and the pCO2
is high, it indicates a mixed primary metabolic acidosis (low bicarbonate or base excess) and primary respiratory acidosis (high pCO2
). In the latter scenario, the pH would be expected to be quite low (very acidemic), because of the combination of two primary types of acidosis.
A metabolic acidosis is the most common acid-base disturbance encountered in sick small animals, horses and camelids. A metabolic acidosis is identified by a decreased bicarbonate (HCO3-) and base excess (BE) on a blood gas analysis, and a decreased HCO3- on the chemistry panel.
Metabolic acidosis can be caused by:
Metabolic acidosis gamblegram
- Consumption of bicarbonate by a non-volatile (non-carbonic) and non-chloride containing acid: This is called a high anion gap- or titration acidosis, because the noncarbonic acid increases the anion gap (it is an unmeasured anion) and the bicarbonate is titrating or buffering the accumulated acid (or the acid is consuming bicarbonate). An alternative term that has been used by some is a "buffer ion" acidosis (Constable 2014). Electroneutrality is maintained because the unmeasured anion (UA-) that is liberating its proton is making up for the decrease in bicarbonate (HCO3-) (see gamblegram to the right). An example of a non-volatile non-chloride containing acid is lactic acid, which has the formula CH3CH(OH)CO2H with the H+ on the end being the acid and the remaining lactate being the "unmeasured" anion accompanying the acid (CH3CH(OH)CO2-). Lactic acid is a strong acid, which means it dissociates readily releasing the free proton (H+), which must be buffered by body buffers, including bicarbonate.
- Loss of bicarbonate or gain of chloride-containing acid: This is called a normal anion gap or hyperchloremic acidosis. An alternative term used with strong ion principles is a "strong ion" acidosis (Constable 2014). When considering bicarbonate loss, think about loss of bicarbonate being accompanied by gain or retention of chloride (with hydrogen, the actual acid part) to maintain electroneutrality (which rules! - see gamblegram), because this is what actually happens. In contrast, direct gain of a chloride-containing non-volatile acid (such as decreased ammoniagenesis in the kidney, leading to retention of NH4Cl) is far more intuitive to understand. In these scenarios (loss of bicarbonate or gain of a chloride-containing non-volatile acid), the anion gap does not change, because there is no accumulation of a non-volatile acid which has something other than chloride as its anion (see lactate example above). So think of chloride as the anion of the accumulating acid or in strong ion terms, chloride is a "weak acid".
These causes/types of acidosis can be differentiated on clinical history (processes responsible for the acidosis), corrected chloride
) and anion gap
Titration metabolic acidosis
Titration acidosis equations
Bicarbonate can be consumed or titrated by a non-volatile non-chloride containing acid that is produced in the body or is an exogenous toxin, i.e. it is always pathologic. Examples of acids produced in the body are lactic acid (from anaerobic metabolism), ketones (diabetes mellitus, ketosis), and acids (phosphates [H2
), sulfates [H2
]) normally excreted by the kidneys (that are produced from amino acid metabolism). Examples of exogenous toxins are salicylate, methanol, ethylene glycol and their metabolites. The acids (H+
part which is released with dissociation of strong acids) are buffered by or consume HCO3-
in plasma, which maintains electroneutrality, therefore the Cl-corr
is normal. The anion portion of the non-volatile acids are "unmeasured anions" and their accumulation will increase the AG. Thus, titration or consumption of bicarbonate by a non-volatile non-chloride containing acid results in a high anion gap metabolic acidosis. With an uncomplicated high anion gap metabolic acidosis, the decrease in HCO3-
is roughly equivalent to the increase in AG or unmeasured anions (UA-
A titration or high anion gap acidosis is a primary acid-base disorder (i.e. it does not
occur in compensation to a primary respiratory acid-base disorder). It is the most common acid-base disturbance in most species (except ruminants, such as cattle and sheep).
Causes of a titration metabolic acidosis include:
- All species: Common acid-base disturbance in most species, except for ruminants (camelids are an exception).
- L-lactate: From hypovolemia from fluid losses causing decreased tissue perfusion, or hypoxia from severe anemia. Both lead to anaerobic metabolism in tissues.
- Decreased excretion of normally filtered acids due to kidney dysfunction: This usually occurs with renal azotemia or post-renal azotemia, particularly in acute renal injury but you can see an acidosis with chronic kidney disease (may also see with a very severe prerenal azotemia).
- Small animals:
- Ketoacidosis: Ketones are acids.
- Toxic metabolites (e.g. ethylene glycol, salicylates).
- D-lactate acidosis (calves, particularly due to fermentation of carbohydrates by bacteria in the colon with intestinal-associated diarrhea or ruminal acidosis from excessive milk intake). Note that D-lactate will not be measured with point of care analyzers that provide lactate measurements (these only detect L-lactate).
- Camelids: Ketoacidosis and L-lactate.
Bicarbonate loss or gain of a chloride-containing non-volatile acid metabolic acidosis
- Bicarbonate loss: Bicarbonate is usually lost through the gastrointestinal tract or kidneys. Causes include vomiting of intestinal contents (pancreatic/intestinal secretions are rich in bicarbonate), secretory diarrhea, inability to swallow saliva (ruminants, in particular, have lots of bicarbonate in salivary secretions), and proximal renal tubular acidosis (filtered bicarbonate is not being retained or new bicarbonate is not being regenerated). Intestinal loss from secretory diarrhea is the most common cause of this type of primary acid-base disturbance and is the most frequent cause of a bicarbonate loss acidosis in ruminants, particularly calves. Since HCO3- is an anion, the body maintains electroneutrality by increasing or retaining Cl-, another anion, with hydrogen (in the kidney, loss of bicarbonate is accompanied by retention of hydrogen with chloride in excess of sodium). Thus, an acidosis due to HCO3- loss is usually accompanied by a corrected hyperchloremia. The AG will be normal because unmeasured anions are not increased. Therefore, loss of HCO3- usually causes a hyperchloremic normal anion gap metabolic acidosis. With an uncomplicated hyperchloremic metabolic acidosis, the decrease in HCO3- is roughly equivalent to the increase in corrected Cl-.However, it should be noted that some authors attribute the hyperchloremic metabolic acidosis in calves due to loss of sodium in excess of chloride (Constable 2014).
- Gain of a chloride-containing non-volatile acid: Think of chloride as an acid - this is certainly the case when it has hydrogen as its proton (e.g. ammonium chloride or NH4Cl or hydrogen chloride or HCl). The kidney is the main site of retention of chloride with hydrogen. For instance, a primary hyperchloremic metabolic acidosis occurs with distal renal tubular acidosis, when the proton pump (H-ATPase) in the distal nephron cannot pump out hydrogen (with chloride passively following). Thus, hydrogen with chloride (in excess of sodium) is retained resulting in a primary hyperchloremic normal anion gap metabolic acidosis. In humans, this occurs with inherited defects in the H-ATPase in the distal nephron that causes excretion of hydrogen into the urine. Administration of ammonium chloride, as a research tool, also causes a primary hyperchloremic normal anion gap metabolic acidosis.
The kidney also can create a hyperchloremic normal anion gap metabolic acidosis as compensation for a primary respiratory alkalosis or as correction for a primary metabolic alkalosis. This is accomplished through:
- Decreased ammoniagenesis in the proximal renal tubules (primarily) so hydrogen is no longer excreted as NH4Cl. This will result in concomitant loss of bicarbonate, and
- Decreased H-ATPase activity in the collecting tubule (primarily), so hydrogen (and chloride) are retained.
- Both of these processes will result in retention of hydrogen and chloride (in excess of sodium) leading to a compensatory or corrective hyperchloremic normal anion gap metabolic acidosis.
- Gain of chloride without hydrogen as the proton: Not that administration of 0.9% saline can cause a mild acidifying effect (Constable 2014) . It is surprising to think about an isotonic solution such as 0.9% NaCl being potentially acidifying, however this is explained by Constable (2014) by the strong ion difference of the infused solution. An alternative way to consider the acidifying effect of 0.9% saline is that normally in plasma, sodium exceeds chloride (roughly 138-147 mEq/L versus 92-102 mEq/L in cattle). However, by giving equal amounts of sodium and chloride, you may be giving more chloride than is normally present in plasma, creating acidifying situation, using strong ion principles. Note in this scenario, sodium and chloride will still change proportionally in plasma (as you are giving equal amounts). When animals, particularly cattle, are given calcium chloride or diets with negative cation to anion balance (i.e. more anions than cations), this also causes an acidifying effect and cause urinary acidification as a corrective response, via strong ion principles. In these scenarios, chloride will be disproportionally increased compared to sodium.
The presence of a hyperchloremic normal anion gap metabolic acidosis (low bicarbonate, high Cl-corr
) does not mean the acidosis is a primary disorder. A hyperchloremic metabolic acidosis can be secondary (or in compensation for) a primary respiratory alkalosis (or the correction for a primary metabolic alkalosis as indicated above). Whether a hyperchloremic metabolic acidosis is primary or secondary to a respiratory acidosis requires clinical assessment of the patient and knowledge of the underlying disease (e.g. a dog that has small intestinal diarrhea likely has a primary hyperchloremic metabolic acidosis from bicarbonate losses into the intestinal tract). If there is a primary respiratory alkalosis with a compensatory hyperchloremic metabolic acidosis, there will be a clinical disease or condition causing hyperventilation, the blood pH will be more alkaline than acidic (because alkalosis is the primary disturbance) and the pCO2
will be quite low (remember, compensation usually does not return the pH to normal). Kidney function must also be normal for an animal to be able to compensate for a primary respiratory alkalosis.
Causes of a hyperchloremic metabolic acidosis include:
- All species:
- Primary: Secretory diarrhea. Most common metabolic acid-base disturbance in calves (Constable 2014), uncommon in other species. Administration of fluids or diets that have chloride concentrations equal to (0.9% NaCl) or higher than sodium (e.g. diets with negative dietary cation anion balance, administration of calcium chloride to cattle) (Constable 2014) - the latter have a mild acidifying effect.
- Secondary: Compensation for a primary respiratory alkalosis. Uncommon. Requires normal renal function.
- Correction: For a primary metabolic acidosis.
- Small animals:
- Primary: Proximal or distal renal tubular acidosis, vomiting of intestinal contents because pancreatic secretions are rich in bicarbonate (uncommon).
- Primary: Loss of bicarbonate in saliva (choke, rabies).
A metabolic alkalosis is identified by an increased HCO3-
and base excess (BE) on a blood gas analysis, and an increased HCO3-
and/or decreased Cl-corr
on the chemistry panel. Metabolic alkalosis is caused by:
Metabolic alkalosis gamblegram
- Loss of a chloride-containing non-volatile acid: Loss of these types of acid (e.g. HCl, NH4Cl) causes loss of Cl- without concomitant loss of Na+. Similarly, loss of Cl- in excess of Na+ (chloride acts an “acid” and sodium acts as a “base”) will be alkalinizing. Both will cause (and are recognized by) a decreased Cl-corr. Importantly, these types of metabolic alkalosis are chloride-responsive, i.e. they will be corrected by administration of fluids high in chloride. In rare cases, renal losses of hydrogen (e.g. stimulation of the H-ATPase in the collecting tubules) can cause acid loss without much chloride loss, e.g. primary hyperaldosteronism. The latter type of metabolic alkalosis will not respond to chloride administration.
- Gain of a base or bicarbonate: Gain of bicarbonate (e.g. administration of bicarbonate in fluids) can cause a metabolic alkalosis, but this is a far less common cause than loss of a chloride-containing non-volatile acid.
Once metabolic alkalosis is established, other conditions associated with the primary process causing the alkalosis will perpetuate or maintain the alkalosis, specifically hypovolemia, hypochloremia, and hypokalemia.
Metabolic alkalosis due to acid loss
Gastric HCl production
is usually lost through the gastrointestinal tract (primarily vomiting of gastric contents or HCl, see image to the right) or urinary tract (e.g. hyperaldosteronism; aldosterone promotes activity of the hydrogen ATPase pump in the luminal membrane of collecting tubules, resulting in hydrogen excretion in the urine). For each milliequivalent of H+
secreted, an equivalent amount of HCO3-
will be generated (see image to right). Since H+
is concurrently lost with Cl-
in disorders causing hydrogen loss (except for hyperaldosteronism), these patients typically have a low Cl-corr
. Excessive loss of Cl-
(with respect to Na+
) will also result in a metabolic alkalosis as HCO3-
increases to maintain electroneutrality. This can occur with loop and thiazide diuretics (for more information, see renal physiology
page relating to sodium absorption) or excess sweating in horses (lose potassium chloride). In an uncomplicated metabolic alkalosis, the increase in HCO3-
is usually proportional to the decrease in Cl-corr
and the AG is normal. A metabolic alkalosis is a common acid-base abnormality in ruminants with abomasal outflow obstruction (e.g. displaced abomasum) and in small animals with vomiting of gastric contents. This type of alkalosis usually responds to chloride supplementation, except for hyperaldosteronism (which is very rare).
Causes of metabolic alkalosis include:
- All animals
- Compensation for a primary respiratory acidosis or correction for a primary metabolic acidosis: Renal excretion of hydrogen by H by H-ATPases in the collecting tubules (chloride passively follows) or ammonium chloride (proximal tubule ammoniagenesis) occurs in compensation for a primary respiratory acidosis or correction of a primary metabolic acidosis (see above).
- Small animals:
- Primary: Vomiting of gastric contents (HCl loss; most common cause), renal losses (e.g. loop [these block the NaK2Cl carrier, so you are losing 2 Cl for the price of 1 Na] or thiazide diuretics). Other causes are rare.
- Primary: Excessive sweating (loss of KCl), ileus, gastric ulcers.
- Primary: Sequestration of abomasal contents (displaced abomasa, abomasal atony, proximal duodenal obstruction). Most common acid-base disturbance in adult cattle but not calves.
Metabolic alkalosis due to base gain
Administration of NaHCO3
(e.g. treatment of metabolic acidosis) or organic anions (which are metabolized to HCO3-
, e.g. citrate in massive blood transfusions), may cause a metabolic alkalosis, particularly under conditions of volume depletion or renal dysfunction.
The presence of a metabolic alkalosis (high bicarbonate, low Cl-corr
) does not mean the metabolic alkalosis is a primary disorder. A metabolic alkalosis can be secondary to (or in compensation for) a primary respiratory acidosis. Whether a metabolic alkalosis is primary or secondary to a respiratory acidosis requires clinical assessment of the patient and knowledge of the underlying disease. For instance, if there is a clinical disease causing hypoventilation in a dog and the dog is acidemic (or pH is trending low towards acidemia), with a high pCO2
, then there is a primary respiratory acidosis with a secondary or compensating metabolic alkalosis. In contrast, a dog that is vomiting gastric contents likely has a primary metabolic alkalosis (in this case, the pH will be alkaline or trending towards alkaline, unless there is a concurrent primary metabolic acidosis dominating the acid-base picture). Remember compensation does not usually correct pH to normal and over-compensation does not occur. Normal renal function is also required for an animal to be able to compensate for a primary respiratory acidosis.
A metabolic alkalosis due to gain of base is uncommon (and usually iatrogenic).
The following table provides a summary of the changes in the blood gas (pH, HCO3-
, BE) and biochemical panel (HCO3-
, AG, Cl-corr
) with primary metabolic acid-base disturbances, based on the type of disturbance.
||Effect on pH
|Titration metabolic acidosis
|Bicarbonate loss metabolic acidosis
A respiratory acidosis is identified by an increased pCO2
and low pH (or tendency towards a low pH) on a blood gas analysis. As mentioned previously, the chemistry panel will not provide any information on the respiratory component of acid-base status. A respiratory acidosis is caused by decreased ventilation or gas exchange in the alveoli, which can be secondary to neurologic (affecting the medullary respiratory center), musculoskeletal (affecting the diaphragm and thoracic wall), pulmonary, and cardiac disorders. The most common causes are primary pulmonary disease, ranging from upper airway obstruction to pneumonia, in animals. Note that pneumonia alone unlikely to cause a respiratory acidosis (since pCO2
diffuses so readily across alveolar walls) unless the lung involvement is extensive or there is concurrent respiratory muscle fatigue from a prior hypoxic or pain-induced hyperventilation. Diseases or drugs that inhibit the medullary respiratory center also produce a profound respiratory acidosis, e.g. general anesthesia.
Causes of a respiratory acidosis include:
- All species:
- Primary: Respiratory obstruction (uncommon), severe pulmonary disease (usually accompanied by muscle fatigue), inadequate ventilation during anesthesia (iatrogenic).
- Secondary: Compensation for a primary metabolic alkalosis.
A respiratory alkalosis is identified by a decreased pCO2
and high pH (or tendency towards one) on a blood gas analysis. A respiratory alkalosis is caused by hyperventilation. Ventilation is stimulated by central and peripheral (carotid or aortic bodies) chemoreceptors.
Causes of respiratory alkalosis include:
- Central chemoreceptors: Respond to pH changes in cerebrospinal fluid (CSF) and hypercapneic hypoxia (characterized by decreased oxygen and increased carbon dioxide ). Changes in CSF parallel changes in blood when there are respiratory disturbances, due to the ready diffusibility of carbon dioxide; pH does not change as readily in CSF with a primary metabolic acidosis, since hydrogen cannot diffuse into the CSF.
- Peripheral chemoreceptors: Respond to hypoxemia (low pO2, i.e. primary respiratory alkalosis), increased partial pressure of carbon dioxide (pCO2, i.e. correction for a primary respiratory acidosis), and acidemia (low pH or high H+, i.e. the respiratory alkalosis is occurring in compensation for a primary metabolic acidosis). Hypoxemia can be due to respiratory, cardiac or hematological (e.g. anemia, carbon monoxide poisoning) disorders and must be quite low (<50 mmHg) to stimulate hyperventilation, unless there is concurrent acidosis, whereby the body responds to a pO2 < 70-80 mmHg. Hyperventilation can also be stimulated by pain (nociceptors), stretch (e.g. lung disease), marked stress, or anxiety and will then result in a primary respiratory alkalosis.
- All species:
- Primary: Any cause of hyperventilation (e.g. hypoxemia, pneumonia causing pain, anxiety).
- Secondary: Compensation for a primary metabolic acidosis (common).
The following table provides a summary of the changes in the blood gas (pH, pCO2) with primary respiratory acid-base disturbances, based on the type of disturbance. Note, that a respiratory disturbance cannot be detected from a biochemical panel and a respiratory disturbance does not alter BE.
||Effect on pH
A mixed acid-base disturbance is defined as the presence of more than one primary disturbance. There could be two (not respiratory) or even three primary acid-base disturbances (one respiratory and two different metabolic). Note that it is incorrect to use this term for a single primary disturbance with the appropriate compensatory response. A mixed acid-base disturbance is quite common in animals and should be suspected in these situations:
- The pH is normal but there is an abnormal pCO2 and/or bicarbonate. (Remember that compensation rarely results in a normal pH).
- The change in pH is greater than can be attributed to one disorder alone.
- The pCO2 and HCO3- change in opposite directions (compensatory responses should parallel the primary change).
- The expected compensatory response is:
- Not present and sufficient time has elapsed for it to have occurred.
- Opposite to that which is expected (parallel changes are expected).
- Exceeds that which is expected. For example, in a primary metabolic acidosis, the expected response is a compensatory respiratory alkalosis. If the pCO2 is normal or increased, there is a concurrent primary respiratory acidosis (remember, mild changes may not shift the pH). The pH would be lower than expected for a primary metabolic acidosis alone, because the combined primary respiratory and primary metabolic acidosis would have an additive effect on lowering the pH.
- The degree of change in acid-base results is not proportional.
- There are easy formulas used to assess for these proportional changes. These formulas depend on whether there is an increased anion gap or not. For all these formulas, the change in test result is compared to the midpoint of the reference interval for the test.
- Change in AG = Measured AG - Normal AG (midpoint of interval)
- Change in bicarbonate = Measured bicarbonate - Normal bicarbonate (midpoint of interval)
- Change in chloride = Corrected chloride - Normal chloride (midpoint of interval)
- Assessment of proportional changes
- In an uncomplicated titration high anion gap metabolic acidosis, the increase in the AG is roughly proportional to the decrease in HCO3- and Cl-corr should be normal.
- In an uncomplicated hyperchloremic metabolic acidosis, the decrease in HCO3- is roughly proportional to the increase in Cl-corr and the AG should be normal.
- In an uncomplicated metabolic alkalosis, the increase in HCO3- is roughly proportional to the decrease in Cl-corr and the AG is usually normal.
Any deviations from that listed above suggest the likelihood of a mixed-acid disturbance. Remember that changes in serum proteins (mostly albumin) may impact the AG (and should be considered when using these guidelines). Also, do not over-interpret mild changes in electrolytes or other test results; no analyzer or test is perfect!
- High anion gap metabolic acidosis: In an uncomplicated high anion gap acidosis, the change in AG is equivalent to the change in bicarbonate.
- If the decrease in bicarbonate is greater than the increase in anion gap, this indicates that there is a mixed disturbance, with something lowering the bicarbonate greater than expected. In this instance, this is compatible with a mixed primary high anion gap and primary hyperchloremic (normal anion gap) acidosis, e.g. chronic renal failure, resolving diabetic ketoacidosis, secretory diarrhea with anaerobic metabolism causing a lactic acidosis. Other potential explanations for these changes are:
- Primary titration acidosis with false decrease in anion gap due to decreased unmeasured anions (very low albumin) or increased unmeasured cations (very high monoclonal immunoglobulins).
- Mixed primary titration acidosis AND primary chronic respiratory alkalosis. The body will compensate for the primary respiratory alkalosis by retaining hydrogen and chloride in the kidneys (hyperchloremic acidosis). This will only occur if the alkalosis is the dominating disturbance (pH trending alkaline or alkaline).
- If the decrease in bicarbonate is less than the increase in anion gap, this can indicate that there is a mixed disturbance, with something preventing the bicarbonate from being as low as it should be. This is compatible with a mixed primary high anion gap acidosis and primary metabolic alkalosis, e.g. gastric dilatation volvulus syndrome in dogs (lactic acidosis with sequestration of HCl-rich fluid), renal failure with vomiting/diuretics, vomiting gastric contents and diabetic ketoacidosis or lactic acidosis. In this case, the corrected chloride will be low and the anion gap will be high. The bicarbonate will be dictated by the balance between the two opposing disorders and may be normal. Other potential explanation for these changes are:
- Non acidotic high anion gap (bicarbonate is normal or high): Animal has a high anion gap for other reasons, such as increased negative charge on proteins (e.g. severe alkalemia, carbenicillin therapy and dehydration causing increased albumin - the latter is an uncommon cause of a high anion gap in our experience)
- Mixed primary titration metabolic acidosis AND primary respiratory acidosis, e.g. cardiopulmonary arrest. The primary respiratory acidosis will cause a compensatory metabolic alkalosis, as long as the kidneys are functionally normally and can excrete acid (with chloride).
- Normal anion gap hyperchloremic metabolic acidosis or metabolic alkalosis: In an uncomplicated normal anion gap or hyperchloremic primary acidosis or a primary metabolic alkalosis, the change in chloride is equivalent to the change in bicarbonate
- If the decrease in chloride (after correction) is greater than the increase in bicarbonate, this indicates that there is a mixed disturbance, with something decreasing the bicarbonate. In this instance, this is compatible with a mixed primary normal anion gap hyperchloremic acidosis and a primary metabolic alkalosis. This can occur renal failure with vomiting/diuretics, vomiting and diarrhea, and liver disease.
- If the increase in chloride (after correction) is less than the decrease in bicarbonate, this indicates that there is a mixed disturbance, with something enhancing the decrease in bicarbonate. This is compatible with a mixed primary high anion gap and normal anion gap hyperchloremic acidosis. One would expect the anion gap to be high in this situation.
Some examples of mixed acid-base disturbances and the changes that ensue are shown in the table below. Note that not all possible combinations are shown in this table.
||Primary titration metabolic acidosis (low HCO3- high AG) AND respiratory acidosis (high pCO2) AND primary or compensatory metabolic alkalosis (low Cl-corr)
||N to ↓
(depending on if the alkalosis is primary or secondary)
||Primary titration metabolic acidosis (high AG) AND metabolic alkalosis (low Cl-corr). The pH will likely be normal so a compensatory respiratory response will not be triggered.
(if the dominating disturbance shifts the pH, there should be respiratory compensatory changes and changes in pCO2)
||Primary metabolic alkalosis (high HCO3-, low Cl-corr) AND respiratory alkalosis (low pCO2)
||Primary titration AND bicarbonate loss metabolic acidosis (very low HCO3-, high AG, high Cl-corr), compensatory respiratory alkalosis (low pCO2)
The most common mixed acid-base disturbances are:
- Small animals: Titration metabolic acidosis (ketoacidosis, uremic acidosis, lactic acidosis) and metabolic alkalosis (vomiting of gastric contents frequently accompanies these disorders).
- Ruminants: Titration metabolic acidosis (lactic acidosis) and metabolic alkalosis (sequestration of hydrochloric acid due to abomasal atony or displaced abomasa in adult cattle; titration metabolic acidosis (lactic acidosis) and hyperchloremic (bicarbonate loss) metabolic acidosis (secretory diarrhea) in calves.
- Horses: Uncommon.
- Camelids: Uncommon.
- Laboratory detection: Use of laboratory tests to diagnose acid-base disturbances, including more information on bicarbonate measurement and the anion gap calculation.
- Quick test interpretation: A guide to interpreting blood gas results.
- Chloride: Measurement of chloride and interpretation of changes in chloride.
- Clinical Physiology of Acid-Base and Electrolyte Disorders by Rose BD and Post DW, 5th edition, 2001. McGraw-Hill, New York, NY.
- Fluid, Electrolyte and Acid-Base Disorders in Small Animal Practice by DiBartola SP, 3rd edition, 2006. Elsevier-Saunders, St Louis, MO.