This electrolyte imbalance is caused by an abnormal decrease in the plasma sodium ion concentration.

5 Select the FALSE statement below:

a.

Although the ventilatory response to metabolic acidosis is ameliorative, it is insufficient to completely normalize the arterial pH.

The normal kidneys are incapable of excreting as much acid as the lungs.

In diabetic ketoacidosis, very little, if any, HCO3− should appear in urine.

The degree of acidemia produced by a reduction in the plasma HCO3− concentration during metabolic acidosis will be increased by a simultaneous decrease in the Pco2.

HC03− reabsorption by proximal renal tubular epithelial cells, normally requires H+ secretion in exchange for Na+.

Metabolic Acidosis

Metabolic acidosis is an important contributor to PEW in CKD. Metabolic acidosis exacerbates muscle wasting through various mechanisms. In classic experimental studies, May et al. demonstrated that rats with renal failure and metabolic acidosis had preferential degradation of muscle protein.69 This protein breakdown occurs even at moderate levels of acidosis (20 mmol/L bicarbonate).70,71 Protein breakdown is mediated by activation of the adenosine triphosphate-dependent pathway involving ubiquitin and proteasomes.72,73 Metabolic acidosis also causes a decrease in serum levels of essential branched-chain amino acid levels in muscle, contributing to muscle wasting.68 Abnormal muscle signaling, inflammation, and dysregulation of IGF-1 signaling may also contribute to muscle wasting seen in patients with metabolic acidosis.74 Metabolic acidosis induces insulin resistance.75 Bailey et al. showed that acidosis in CKD leads to accelerated proteolysis through the IRS/PI3K/Akt pathway.47 Correction of metabolic acidosis in rats decreased muscle catabolism through increasing IRS-associated PI3K activity, illustrating the importance of insulin and IGF-1 signaling in modulating muscle protein catabolism.47

Metabolic acidosis

Metabolic acidosis may occur with increased anion gap (high) or normal anion gap. Anion gap is defined as the difference between measured cations (sodium and potassium) and anions (chloride and bicarbonate) in serum. However, sometimes concentration of potassium is omitted because it is low compared to sodium ion concentration in serum.

Aniongap=sodium−chloride+bicarbonate

Normal value: 8–12 mmol/L (mEq/L)

In metabolic acidosis, bicarbonate should decrease resulting in increased anion gap metabolic acidosis. If the chloride level increases, then even with decline in bicarbonate the anion gap may remain normal. This is normal anion gap metabolic acidosis. Thus, normal anion gap metabolic acidosis is also referred to as hyperchloremic metabolic acidosis. Causes of normal anion gap metabolic acidosis include loss of bicarbonate buffer from the gastrointestinal tract (chronic diarrhea, pancreatic fistula, and sigmoidostomy) or renal loss of bicarbonate due to kidney disorder such as renal tubular acidosis and renal failure. Causes of increased anion gap metabolic acidosis is remembered by the mnemonic MUDPILES (M for methanol, U for uremia, D for diabetic ketoacidosis, P for paraldehyde, I for isopropanol, L for lactic acidosis, E for ethylene glycol, and S for salicylate). In addition, alcohol abuse and other toxins such as formaldehyde toluene and certain drug overdose may also cause metabolic acidosis with increased anion gap. In general, if any other metabolic disturbance coexists with increased anion gap metabolic acidosis, this can be diagnosed from corrected bicarbonate level.

Corrected bicarbonate = measured value of bicarbonate + (anion gap-12).

If corrected bicarbonate is < 24 mmol/L, then there exists additional metabolic acidosis and if corrected bicarbonate is > 24 mmol/L, then there exists additional metabolic alkalosis.

Winter’s formula is used to assess whether there exits adequate respiratory compensation with metabolic disturbance:

Winter’sformula:expectedpCO2=1.5×Bicarbonate+8±2

If pCO2 is as expected by Winter’s formula, then there is adequate respiratory compensation, but if pCO2 is less than expected, then additional respiratory alkalosis may be present. However, if pCO2 is more than expected, then there is additional respiratory acidosis

Acid–base balance

Metabolic acidosis has been reported in patients taking zonisamide [47]. Zonisamide inhibits carbonic anhydrase [48], which might have contributed, as has been suggested by another case of metabolic acidosis in a 7-year-old boy, in which the mechanism was renal tubular acidosis.

Ammonium chloride, bicarbonate, and furosemide loading tests in an epileptic man with metabolic acidosis and episodic hypokalemia taking zonisamide showed evidence of distal renal tubular acidosis [49]. On re-examination 7 weeks after zonisamide had been replaced with phenytoin, the renal tubular acidosis had resolved.

In 70 patients taking topiramate (n = 55) or zonisamide (n = 14) or both (n = 1), 18 had a metabolic acidosis, which was significantly more severe in those taking topiramate. There was no association between serum bicarbonate and the dose of drug or the duration of treatment. Serum bicarbonate concentrations were not associated with the CA type XII polymorphisms rs2306719 and rs4984241 after correction for multiple testing [50].

Metabolic Acidosis

Metabolic acidosis results from a loss of HCO3− or a gain of non-CO2 acid. The acidosis may be acutely attenuated by increased respiratory loss of CO2 because of the much more rapid response time of the respiratory system. If the kidneys are also functioning, the renal compensation for acidosis is to excrete acidic urine. Chronically, the renal excretion of H+ is enhanced as the renal ability to produce ammonium from glutamine is induced. Common causes of metabolic acidosis include renal failure, uncontrolled diabetes (ketoacidosis), and diarrhea.

Metabolic Acidosis

Metabolic acidosis occurs relatively commonly in small animal patients, identified in 43% of dogs and cats that had blood gas analysis at a university teaching hospital.32 As described previously, metabolic acidosis can result from the loss of bicarbonate or the gain of acid, and the calculation of the AG may aid in determining which of these processes is present. Metabolic acidosis caused by bicarbonate loss, typified by hyperchloremia and a normal anion gap, can occur through the intestinal tract via diarrhea or can be due to renal losses. Hyperchloremic metabolic acidosis in association with small bowel diarrhea has been well reported in human patients and large animal species but is an infrequent occurrence in dogs and cats. Renal loss of bicarbonate can be an appropriate response to a persistent respiratory alkalosis (metabolic compensation). When it occurs as a primary disease process, it is known as renal tubular acidosis (RTA). It can be broadly categorized as proximal or distal tubular dysfunction. In animals with proximal RTA there is inadequate reabsorption of bicarbonate in the proximal nephron. Reported causes in dogs and cats include congenital abnormalities (e.g., Fanconi syndrome), as well as acquired abnormalities secondary to toxins, drugs, and various diseases (e.g., hypoparathyroidism and multiple myeloma). Distal RTA is a disorder involving inadequate hydrogen ion secretion in the distal tubule that prevents maximal acidification of the urine; it is often accompanied by hypokalemia and is more rarely reported in the veterinary literature than proximal RTA. Potential causes include pyelonephritis and immune mediated hemolytic anemia. The interested reader is directed to reference 33 for further reading on RTA. Hypoadrenocorticism not only leads to hypovolemia and a lactic acidosis but also impairs urine acidification, leading to metabolic acidosis.

Treatment of metabolic acidoses caused by bicarbonate loss is primarily based on therapy of underlying diseases. In addition, intravenous (IV) fluid therapy may speed the resolution of this disorder. Fluids containing a “buffer” such as lactated Ringer's solution will aid in the metabolism of hydrogen ions. When treating patients with a hyperchloremic metabolic acidosis, use of lower chloride containing fluids (i.e., avoiding 0.9% NaCl) will also be of benefit. When the acidosis is severe or the compensatory respiratory alkalosis is considered detrimental to the patient, bicarbonate administration is indicated (see Bicarbonate Therapy later in the chapter).

Metabolic acidosis caused by a gain in acid is typified by normochloremia and an elevated AG. The common causes in dogs and cats were mentioned previously—diabetic ketoacidosis (DKA), uremia, lactic acidosis, and ethylene glycol intoxication. Less common causes include D-lactic acidosis and various additional intoxications, including salicylates and methanol.20

Treatment of metabolic acidosis caused by an acid gain is primarily focused on resolution of the underlying cause and appropriate selection of IV fluid therapy, as described earlier. Bicarbonate administration may be beneficial in some uremic patients, but is not typically indicated for treatment of other acidoses (see Bicarbonate Therapy later in this chapter).

It is interesting to note that in a retrospective study of metabolic acidosis in dogs and cats, 25% of dogs and 34% of cats had neither an elevated AG nor hyperchloremia, suggesting there are limitations to this categorization of metabolic acidosis.32

Serum Electrolytes (Sodium, Chloride, Potassium, Magnesium, Phosphorus, Bicarbonate)

Metabolic acidosis results either from the increased production or decreased excretion of nonvolatile acids or from the loss of body alkali. The serum anion gap helps to distinguish between these two types of metabolic acidosis. Most toxins produce an increased anion gap by the accumulation of organic acids. The anion gap is measured by subtracting the measured anions (Cl– and HCO3−) from the measured cations (Na and K). The normal anion gap is 12 to 25 mEq/L. Accumulation of unmeasured anions (e.g., sulfates, phosphates, protein, and organic acids) results in an increased or abnormal anion gap. Most often a high anion gap is associated with metabolic acidosis and is caused by accumulation of organic acids, such as lactate or formate. Toxins that can cause an elevated anion gap and metabolic acidosis include alcohol, methanol, toluene, ethylene glycol, propylene glycol, paraldehyde, iron, salicylates, and any toxin that causes lactic acid build-up. Ethylene glycol should be placed high on the differential diagnostic list whenever an animal presents with a high anion gap of unknown cause. Another electrolyte abnormality that has been seen in dogs is hypokalemia related to albuterol intoxication.

Diagnosis of metabolic acidosis

Metabolic acidosis is associated with several different diseases and should be considered in any severely ill patient. Often, the diagnosis is first suspected by review of the electrolyte and total CO2 results on the patient's biochemical profile. It is confirmed by blood gas analysis. The causes of metabolic acidosis may be divided into those associated with a normal anion gap (hyperchloremic metabolic acidosis) and those associated with an increased anion gap (normochloremic metabolic acidosis) (Box 10-1).

The anion gap represents the difference between the commonly measured plasma cations and the commonly measured anions. This concept is discussed in detail in Chapters 9 and 12. The normal electrolyte composition of canine plasma is compared with that in normal (hyperchloremic) and increased (normochloremic) anion gap metabolic acidosis in Figure 10-2. The anion gap concept is useful in the diagnostic approach to the patient with metabolic acidosis, but it must not be taken literally. In reality, electroneutrality is maintained, and there is no actual anion gap. Normally, the anion gap is made up of the net negative charge on sulfates, phosphates, plasma proteins, and organic anions (e.g., lactate, citrate). Recent studies have shown that in normal dogs and cats, a substantial portion of the anion gap arises from the negative charge on plasma proteins. The net protein charge of plasma at p. 7.40 was calculated to be 16.0 mEq/L in dogs,60 and this value was determined to be 13.7 mEq/L in cats.155 Factors other than metabolic acidosis also may affect the value of the anion gap, and these are discussed in Chapter 12.

When the anion gap is calculated as [(Na+ + K+) − (Cl− + HCO3−)], normal values in dogs are in the range of 12 to 25 mEq/L.4,60,191,217 Values for the anion gap may be somewhat higher in cats (17 to 31 mEq/L) than in dogs (13 to 25 mEq/L) because of some unaccounted protein and phosphate charge.60,155 In other studies, the mean anion gap for normal cats (calculated as described above) was approximately 20 mEq/L.42,45,46 If the observed metabolic acidosis is characterized by a high anion gap, it is assumed to have arisen from an acid that does not contain chloride as its anion. Examples include some inorganic acids (e.g., phosphates, sulfates) or organic acids (e.g., lactate, ketoacids, salicylate, metabolites of ethylene glycol). In this setting, titration of body buffers by the acid results in accumulation of an anion other than chloride. If the observed metabolic acidosis is characterized by a normal anion gap, there is a reciprocal increase in the plasma chloride concentration to balance the decrease in plasma HCO3− concentration. In the following discussion, the causes of metabolic acidosis have been divided into those associated with a normal anion gap and those associated with an increased anion gap.

Metabolism

Metabolic acidosis and hyperlactatemia have been attributed to lorazepam [22].

A 34-year-old woman with a history of renal insufficiency induced by long-term use of cocaine developed respiratory failure and was intubated and sedated with intravenous lorazepam (65 mg, 313 mg, and 305 mg on 3 consecutive days). After 2 days she had a metabolic acidosis, with hyperlactatemia and hyperosmolality. Propylene glycol, a component of the lorazepam intravenous formulation, was considered as a potential source of the acidosis, as she had received more than 40 times the recommended amount over 72 hours. Withdrawal of lorazepam produced major improvements in lactic acid and serum osmolality.

Metabolic acidosis

Metabolic acidosis is more common in children with salicylate intoxication than in adults. In adults with salicylate intoxication, respiratory alkalosis is the most prominent acid–base disorder with only a modest degree of metabolic acidosis. Because toxicity is caused by the monovalent salicylate anion and occurs when the concentration is 3 to 5 mmol/L, the contribution of salicylic acid itself to the metabolic acidosis is small. Metabolic acidosis in these patients is usually caused by the accumulation of ketoacids and L-lactic acid. Increased glucose consumption in the brain may lead to cerebral glycopenia with increased release of catecholamines. Hypoglycemia is common in patients with salicylate intoxication, which likely reflects increased utilization of glucose by the brain (uncoupling of oxidative phosphorylation) and/or impaired hepatic gluconeogenesis (perhaps by a direct effect of salicylate anion). The relative lack of insulin action (low insulin blood level caused by hypoglycemia, and high blood level of catecholamines) may lead to increased release of fatty acids from adipose tissues. In this setting, a modest degree of uncoupling of oxidative phosphorylation can increase the production of ketoacids in the liver (see Chapter 5). In severe intoxications, the degree of uncoupling of oxidative phosphorylation may be excessive. If this compromises the rate of conversion of ADP to ATP, glycolysis is stimulated and a severe degree of L-lactic acidosis develops.