Types of disturbances


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 crucial for allowing the body to respond to an acid-base disturbance and for maintaining normal acid-base balance. Of course, an acid-base disturbance can be the consequence if things go wrong with these organs (but is not an inevitable consequence of lung or renal disease – it all depends on the disease).

  • Lungs: 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 lungs:

    • Blow off carbon dioxide (it is an acid): CO2 is more diffusible across membranes than O2 (so it is easier to blow off).
    • Retain and are the source of oxygen.
  • Kidney: 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 a 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 result in acid-base abnormalities (usually acidosis, due to failure to excrete the normal acid load generated by protein metabolism). 
    The kidney:

    • Maintains normal acid-base balance: Excretes the daily acid load (called titratable acidity) from protein metabolism.
    • Compensates for a primary respiratory disorder and corrects for a primary metabolic disorder (acidemia or alkalemia).
      • With acidemia, the kidneys gets rid of acids as follows:
        • Simple excretion via glomerular filtration (non-chloride non-volatile acids, e.g. ketoacids).
        • Active excretion of protons (pH of urine expected to go down):
          • NH4Cl via increased ammoniagenesis in the proximal convoluted tubules. The hydrogen is excreted with ammonium chloride.
          • H+ via an ATP-dependent antiporter (H+-ATPase) in type A intercalated cells in the late distal and collecting tubules (Cl goes along for the ride). In the cortical collecting tubule, this transporter is dependent on sodium resorption by principal cells (which creates a lumen negative potential, facilitating proton secretion) and aldosterone, whereas in the medullary collecting tubule, this transporter is sodium independent (but also influenced by aldosterone).
          • Active excretion is linked to bicarbonate absorption so…..the net effect of the kidney’s active excretion of protons is: acid (H+) loss with chloride (in excess of sodium) = bicarbonate (base) gain (metabolic alkalosis).
      • With alkalemia, the kidney gets rid of base (HCO3) as follows:
        • Simple excretion via glomerular filtration.
        • Active excretion of bicarbonate into the lumen by type B intercalated cells in collecting tubules (pH of urine expected to go up). This is linked to chloride resorption via a chloride/bicarbonate transporter (pendrin), which moves from the basolateral to the apical (luminal) surface. 
        • Decreased acid excretion
          • Reduced ammoniagenesis (NH4Cl is retained) in proximal convoluted tubules.
          • Reduced H+-ATPase activity in the late distal and collecting tubules (chloride is passively retained).
          • Net effect: Gain of chloride-containing acid (hyperchloremic metabolic acidosis) = loss of bicarbonate.
Renal excretion of hydrogen

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 when combined with water, 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 via type B intercalated cells 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.

Metabolic 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

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 (Clcorr) and anion gap (AG).

Titration metabolic acidosis

Titration 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 [H2PO4), sulfates [H2SO4]) 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 Clcorr 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 a high anion gap acidosis with chronic kidney disease (particularly in more advanced stages). In rare cases, may also see with a very severe prerenal azotemia.
  • Small animals:
    • Ketoacidosis: Ketones are acids.
    • Toxic metabolites (e.g. ethylene glycol, salicylates).
  • Cattle:
    • Ketoacidosis
    • 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). Proximal renal tubular acidosis occurs as an acquired and inherited condition in animals and humans(e.g. as part of Fanconi syndrome, which can be inherited or acquired, such as due to copper or lead toxicity). 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.
    • Primary hyperchloremic metabolic acidosis: This occurs with distal renal tubular acidosis (DRTA), 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 or anion exchanger (AE1) in the distal nephron that causes excretion of hydrogen into the urine. Acquired causes include early chronic kidney disease, immune-mediated disease and certain drugs, e.g. amphotericin (Dhondup and Qian 2017). Proximal renal tubular acidosis, or Fanconi syndrome, can also result in a hyperchloremic metabolic acidosis due to excess bicarbonate loss with retention of chloride by hte proximal renal tubules. However, the metabolic acidosis is usually milder than that with DRTA, because the distal tubules can usually excrete the excess acid and the urine pH can be neutral or even acidic. In contrast, with DRTA, the urine cannot be acidified. Causes of a proximal renal tubular acidosis (also called Fanconi syndrome) are inherited conditions, e.g. Basenji dogs (Bovee et al 1978), or acquired conditions secondary to toxicity (e.g. jerky toxicosis, lead toxicity, copper toxicity [Langlois et al 2103]) or other causes of proximal renal tubular injury. Proximal renal tubular acidosis is also frequently accompanied by other tubular defects, such as proteinuria in excess for the USG, glucosuria without hyperglycemia and ketonuria. Administration of ammonium chloride, as a research tool, also causes a primary hyperchloremic normal anion gap metabolic acidosis. In animals, we rarely see DRTA and a hyperchloremic metabolic acidosis is less common than a titration acidosis in chronic kidney disease.
    • Secondary (compensation or correction) hyperchloremic 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. 
      • 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 Clcorr) 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).
  • Cattle:
    • Primary: Loss of bicarbonate in saliva (choke, rabies).

Metabolic alkalosis

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 Clcorr on the chemistry panel. Metabolic alkalosis is caused by:

Metabolic alkalosis

Metabolic alkalosis gamblegram

  • Loss of a chloride-containing non-volatile acid (chloride-depleted metabolic alkalosis): 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 Clcorr. Importantly, these types of metabolic alkalosis are chloride-responsive, i.e. they will be corrected by administration of fluids high in chloride, and are usually associated with volume depletion. This is the most common type of metabolic alkalosis in animals.
  • Renal losses of hydrogen: In rare cases, renal losses of hydrogen (e.g. stimulation of the H+-ATPase in the collecting tubules) can cause acid loss without chloride loss, e.g. primary hyperaldosteronism. The latter type of metabolic alkalosis will not respond to chloride administration and animals usually have normal or increased volume status.
  • 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.
Kidney and met alkalosis

The kidney and perpetuation of metabolic alkalosis

Once metabolic alkalosis begins, other conditions associated with the primary process causing the alkalosis will perpetuate or maintain the alkalosis, specifically hypovolemia, hypochloremia (this is the principal driver of this problem) and hypokalemia. These, particularly the hypochloremia, worsen the alkalosis and help it manifest clinically or in laboratory tests by causing (in various ways) increased sodium delivery to the distal nephron and increasing aldosterone. Thus, the kidney, instead of helping correct the metabolic alkalosis actually hurts, by excreting acid (H+) in the collecting tubules (when you really want to retain it to offset the alkalosis) in exchange for sodium resorption. In a nutshell, this is because the kidney becomes sodium avid (wants to retain all filtered sodium as this is the primary determinant of blood volume and sodium retention will help water retention and offset hypovolemia). Both hypochloremia and hypovolemia induce aldosterone secretion to retain sodium but the retention of sodium comes at the cost of potassium and hydrogen excretion (aldosterone not only stimulates sodium absorption by principal cells in the collecting tubules, it also directly stimulates the H+-ATPase in type A intercalated cells in the collecting tubules). In addition, chloride and potassium depletion decrease sodium resorption in the loop of Henle and early distal tubules, thus increasing distal sodium delivery so more sodium is absorbed in the cortical collecting tubules in exchange for hydrogen, particularly when potassium is depleted. So the kidney (primarily the collecting tubules) is largely responsible for persistence of metabolic alkalosis, regardless of cause. We can help the kidney by giving it what it needs to do its job: Volume (replacement fluids), chloride and potassium. Once it has these tools, it will be able to excrete the excess bicarbonate and correct the alkalosis.

Metabolic alkalosis due to acid loss

Gastric HCl

Gastric HCl production

Metabolic alkalosis can be secondary to losses of chloride (with or without hydrogen) in a so-called chloride-depleted or chloride-responsive metabolic alkalosis or when there is stimulated excretion of hydrogen with losses in the urine, e.g. primary hyperaldosteronism. In the latter rare disorder, the excess aldosterone directly stimulates the H+-ATPase in the collecting tubules causing hydrogen (acid) loss without chloride depletion and is thus non-responsive to chloride supplementation.

In an uncomplicated metabolic alkalosis, the increase in HCO3 is usually proportional to the decrease in Clcorr 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. The different types of metabolic alkalosis are elaborated on below:

  • Chloride-responsive (chloride-depleted) metabolic alkalosis: Since H+ is concurrently lost with Cl in these disorders, patients typically have a low Clcorr.  Excessive loss of Cl (with respect to Na+) will result in a metabolic alkalosis as HCO3 increases (if you think about maintaining electroneutrality – loss of a negative ion like chloride means a negative ion needs to be retained, which is bicarbonate). It is important to recognize a chloride-responsive metabolic alkalosis (i.e. low corrected chloride = metabolic alkalosis) because the most effective treatment is to provide the chloride back, with sodium- and potassium-containing fluids, in these patients. H+ is usually lost through the gastrointestinal (primarily vomiting of gastric contents or HCl, see image to the right) or urinary (e.g. diuretics) tracts together with chloride. Thus, these conditions are associated with volume depletion and sodium avidity, with aldosterone release.
    • Gastric contents are richer in chloride than sodium (e.g. 150 mEq/L chloride versus 110 mEq/L or 120 mEq/L sodium in dogs and cats, respectively). In the gastrointestinal tract, for each milliequivalent of H+ lost in gastric fluid, an equivalent amount of HCO3 will be generated in the intestine and absorbed (see image to right). This should be rapidly excreted by the kidneys (filtration and active secretion), however the latter is often impaired in a metabolic alkalosis because of chloride-, volume- and potassium depletion, whereby the collecting tubules act to resorb excess delivered sodium in the distal tubular lumen, resulting in acid excretion (which increases bicarbonate in blood, i.e. excess bicarbonate in blood is linked to increased hydrogen excretion and sodium absorption in the cortical collecting tubule).
    • With diuretics, a chloride-depleted metabolic alkalosis ensues due to increased delivery of sodium to the distal nephron. This occurs with loop (block the Na-K-2Cl carrier) and thiazide (block the early distal tubule NaCl carrier) diuretics (for more information, see renal physiology page relating to sodium absorption). The increased distal sodium delivery causes increased sodium resorption in the collecting tubules, which is directly linked to hydrogen (and potassium) excretion, thus causing bicarbonate retention (equivalent to acid excretion) by the kidneys. Diuretics also cause water loss and hypovolemia (particularly if the animal cannot compensate by drinking) and hypochloremia, both of which may result in aldosterone secretion. Genetic defects in the Na-K-2Cl carrier (Bartter syndrome) or early distal tubule NaCl carrier (Gitelman syndrome) can cause similar changes as loop or thiazide diuretics, respectively.
    • Excess sweating in horses results in loss of KCl. This results in increased distal delivery of sodium (less Na is absorbed in the loop of Henle) with subsequent sodium resorption and hydrogen excretion (particularly since potassium is also depleted) in collecting tubules.
      The bottom line is that: With all causes of chloride-depleted metabolic acidosis, instead of the kidney correcting the problem, the distal nephron is in fact responsible for sustaining or worsening the metabolic alkalosis because of increased sodium delivery and aldosterone with subsequent increased sodium absorption linked to hydrogen excretion in the distal tubules. To treat these patients, give chloride (as hypertonic saline), supplemented with potassium.
  • Metabolic alkalosis that is non-responsive to chloride supplementation: The main example is primary aldosteronism, although genetic defects in the early distal tubule sodium transporter (resulting in increased delivery of sodium to the collecting tubule) will also result in a metabolic alkalosis. All of these disorders are quite rare in animals.

In summary, causes of metabolic alkalosis are:

  • Compensation for a primary respiratory acidosis or correction for a primary metabolic acidosis
    • All species:
      • In the proximal tubule, increased renal ammoniagenesis with excretion of ammonium chloride (HCl loss with ammonia) promote hydrogen excretion and bicarbonate retention.
      • In the collecting tubules of the distal nephron, renal excretion of hydrogen by H+-ATPases and H+/K+ ATPases in type A intercalated cells (chloride passively follows) will promote bicarbonate retention and acid excretion. 
      • In cases of chronic respiratory acidosis (>30 days) that has been corrected by intervention of some kind, there is a posthypercapnic metabolic alkalosis. What starts off as a compensatory response, becomes a primary metabolic alkalosis with resolution of the primary respiratory acidosis. This is because the kidney has not yet had time to eliminate the excess bicarbonate that has been retained. What the kidney needs to do this job is chloride, i.e. a posthypercapnic metabolic alkalosis is chloride-responsive.
  • Primary metabolic alkalosis
    • Small animals:
      • Gastrointestinal loss of HCl: Vomiting of gastric contents; this is most common cause.
      • Renal losses of chloride, e.g. loop or thiazide diuretics. Loop diuretics block the Na-K-2Cl carrier in the loop of Henle, so you are losing 2 Cl for the price of 1 Na. Thiazide diuretics block the NaCl cotransporter in the early distal tubule. With both diuretics, there is increased sodium delivery to the collecting tubules, which then resorbs sodium (sodium transporter in principal cells) in exchange for hydrogen or potassium (type A intercalated cells with H+-ATPases in the cortical collecting tubule or H+/K+-ATPases) resulting in acid excretion and retention of bicarbonate (metabolic alkalosis) with concurrent potassium depletion, which helps sustain the alkalosis; for more on the latter see response to a metabolic alkalosis.
      • Other causes are rare, such as Liddle syndrome in humans which is due to increased aldosterone-independent expression of the sodium transporter in the collecting tubules (ENaC), or posthypercapnic metabolic alkalosis.
    • Horses: This is an uncommon acid-base disturbance due to:
      • Gastrointestinal HCl loss: Gastrointestinal issues causing sequestration or reflux of gastric contents (e.g. proximal enteritis, ileus, strangulating small intestinal obstruction, gastric rupture, gastric ulcers). We have seen severe metabolic alkalosis with gastric rupture or reflux in horses. Losses of chloride with specific types of diarrhea (e.g. Potomic horse fever or Neorickettsia risticii) can cause a metabolic alkalosis (the organism interferes with the chloride carrier in the colon).
      • Excessive sweating: Loss of KCl.
      • Renal loss: Rare (we don’t give them diuretics usually)
    • Cattle: This is the most common acid-base disturbance in adult cattle but not calves and is usually due to sequestration of abomasal contents (displaced abomasa, abomasal atony, proximal duodenal obstruction). This occurs in cattle with primary gastrointestinal disease but also other diseases that are associated with or cause secondary abomasal atony, e.g. renal failure. Other causes of chloride loss or metabolic alkalosis are rare or not reported in cattle.

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, where the kidney acts to retain acid as indicated above. In situations with normal kidney function and chloride concentration, the kidney should rapidly excrete the excess base.

The presence of a metabolic alkalosis (high bicarbonate, low Clcorr) 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).

Metabolic summary

The following table provides a summary of the changes in the blood gas (pH, HCO3, BE) and biochemical panel (HCO3, AG, Clcorr) with primary metabolic acid-base disturbances, based on the type of disturbance.

Disturbance HCO3
AG Clcorr Effect on pH
Titration metabolic acidosis normal
Bicarbonate loss metabolic acidosis normal
Metabolic alkalosis normal


Respiratory 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.

Respiratory 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.

  • 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.

Causes of respiratory alkalosis include:

  • All species:
    • Primary: Any cause of hyperventilation (e.g. hypoxemia, pneumonia causing pain, anxiety).
    • Secondary: Compensation for a primary metabolic acidosis (common).

Respiratory summary

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.

Disturbance pCO2 Effect on pH
Respiratory acidosis
Respiratory alkalosis

Mixed disorders

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 HCO3change 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 Clcorr should be normal.
      • In an uncomplicated hyperchloremic metabolic acidosis, the decrease in HCO3 is roughly proportional to the increase in Clcorr and the AG should be normal.
      • In an uncomplicated metabolic alkalosis, the increase in HCO3 is roughly proportional to the decrease in Clcorr 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!

For example,

  • 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.

HCO3 pCO2 AG Clcorr Disorders Expected pH
Primary titration metabolic acidosis (low HCO3  high AG) AND respiratory acidosis (high pCO2) AND primary or compensatory metabolic alkalosis (low Clcorr) N to
(depending on if the alkalosis is primary or secondary)
N N Primary titration metabolic acidosis (high AG) AND metabolic alkalosis (low Clcorr). The pH will likely be normal so a compensatory respiratory response will not be triggered. N
(if the dominating disturbance shifts the pH, there should be respiratory compensatory changes and changes in pCO2)
N Primary metabolic alkalosis (high HCO3, low Clcorr) AND respiratory alkalosis (low pCO2) ↑↑
↓↓ Primary titration AND bicarbonate loss metabolic acidosis (very low HCO3, high AG, high Clcorr), 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.

Related links

  • 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.
  • Gennari 2011. Pathophysiology of Metabolic Alkalosis: A New Classification Based on the Centrality of Stimulated Collecting Duct Ion Transport. Am J Kidney Dis 58:626.