High Anion Gap Metabolic Acidosis

From the above reaction, excess lactate production can be expected by the following pathophysiologic processes:

Increased pyruvate production caused by intravenous (i.v.) glucose or epinephrine infusion, and metabolic or respiratory alkalosis

An increase in NADH/NAD⁺ ratio due to hypoxic conditions

Combination of above two processes

Causes

Excess lactic acid production occurs in certain situations, as shown in Tables 28.1 and 28.2

Table 28.1

Causes of type A lactic acidosis

Cause	Mechanism(s)
Shock
Septic shock	Hypotension
Hypovolemic shock	↓ O₂ delivery, ↑ glycolysis, ↓ ATP, ↑ pyruvate production→ ↑ lactic acid production
Cardiogenic shock	↓ O₂ delivery, ↑ glycolysis, ↓ ATP, ↑ pyruvate production→ ↑ lactic acid production
Hemorrhagic	↓ O₂ delivery, ↑ glycolysis, ↓ ATP, ↑ pyruvate production→ ↑ lactic acid production
Severe tissue hypoxia	↓ O₂ delivery, ↑ glycolysis, ↓ ATP, ↑ pyruvate production→ ↑ lactic acid production
Severe regional hypoperfusion due to hypotension	↓ O₂ delivery, ↑ glycolysis, ↓ ATP, ↑ pyruvate production→ ↑ lactic acid production
Severe anemia (< 4.0 g/dL)	Tissue hypoxia
Severe asthma	Respiratory alkalosis stimulation of glycolysis and lactate production, tissue hypoxia, β-adrenergic stimulation, and lactate production
Carbon monoxide poisoning	Carbon monoxide binds more avidly to Hb than O₂, leading to less delivery to tissues and hypoxia, inhibition of electron transport system, ↓ ATP, ↑ anaerobic glycolysis

Table 28.2

Causes of type B lactic acidosis

Causes	Mechanism(s)
Liver disease	↓ Lactate metabolism, ↓ pyruvate dehydrogenase complex (PDC)^a activity, respiratory alkalosis, and hypoglycemia may precipitate lactate production
Diabetes mellitus	Presence of microvascular disease and atherosclerosis compromising circulation, drug use such as metformin, ↓ PDC activity
Renal failure and renal replacement therapies	Stimulation of lactate production by alkalinization due to HCO₃ ⁻, dialysate baths containing lactate
Malignancy	Lymphomas, leukemias, and carcinomas (breast, lung, colon, pancreas), production of lactate by tumor cells via ↑ anaerobic glycolysis, ↑ cytokine production, hypoxia-inducible factor
ATP depletion	↑ Anaerobic glycolysis
Thiamine deficiency	Inhibits PDC activity, thereby limiting glucose metabolism to glycolysis only
Seizures	Increased muscle activity, compromised blood flow, and tissue hypoxia
Hypoglycemia	Inhibits lactate uptake by liver, ↑ epinephrine release causing increased production of pyruvate
Drugs/toxins
Metformin	Promotes lactate production from glucose in small intestine, ↑ NADH/NAD⁺ ratio, inhibits gluconeogenesis from lactate, inhibition of mitochondrial respiration, patients with renal, hepatic, and cardiac failure are at risk
Ethanol	Impairs gluconeogenesis from lactate to glucose, depletes NAD⁺ favoring lactate accumulation
Methanol	Toxic products of methanol (formaldehyde, formic acid) inhibits oxidative phosphorylation and ATP synthesis
Ethylene glycol	↑ NADH/NAD⁺ ratio during metabolism of ethylene glycol via alcohol dehydrogenase
Propylene glycol	Used as solvent (during infusion of lorazepam, nitroglycerine, or topical application of silver sulfadiazine), produces lactate during its metabolism via alcohol dehydrogenase. This reaction produces high NADH/NAD⁺ ratio
Salicylates	Respiratory alkalosis-stimulated lactate production, inhibition of oxidative phosphorylation
Cyanide poisoning	Inhibition of oxidative phosphorylation, ↓ ATP production, ↑ glycolysis, ↑ NADH/NAD⁺ ratio, leading to pyruvate conversion to lactate production
Catecholamines	Epinephrine increases glycolysis and inhibits pyruvate formation from lactate. Increased vasoconstriction of skin, skeletal muscle, and splanchnic circulation with high concentrations of epinephrine and norepinephrine. Lactic acidosis may be the initial finding in pheochromocytoma
Cocaine	Increased vasoconstriction
Antiretrovirals (didanosine, zidovudine, stavudine, zalcitabine, tenofovir)	Inhibition of mitochondrial DNA synthesis, ↓ ATP production, ↑ glycolysis
Linezolid	Mitochondrial toxicity
Propofol	Sedative, increased production of lactate on high doses due to uncoupling of oxidative phosphorylation

^aPyruvate dehydrogenase complex is an enzymatic system that converts pyruvate to acetyl CoA in mitochondria, and hence to CO₂ and H₂O via citric acid cycle

Lactic acidosis is divided into two types: type A and type B acidosis
Type A acidosis results from generalized or regional tissue hypoxia
Type B acidosis results from biochemical abnormalities due to systemic diseases or toxins
Note that both type A and type B conditions can be superimposed on one another rather commonly in any patient (metformin use in CHF patient)

Lactic Acidosis due to Hereditary or Acquired Enzymatic Defects

Lactic acidosis can occur due to a variety of inherited defects in enzymes involved in glycogen storage diseases, gluconeogenesis, citric acid cycle (pyruvate oxidation), and electron transport (complex I deficiency, complex I, III, and IV deficiency, and complex I and IV deficiency). These are inborn errors associated with “primary” lactic acidosis
Disorders associated with “secondary” lactic acidosis include organic acidurias (propionic acidemia, methylmalonic acidemia, etc.), defects in fatty acid oxidation, and urea cycle enzymes
Acquired enzyme defects are related to thiamine deficiency (↓ pyruvate dehydrogenase complex activity) and biotin deficiency (↓ pyruvate decarboxylase activity)
Infants and children are affected the most from inherited defects of enzymes
Clinical assessment of skeletal muscle, heart, hepatic, and neurologic functions help in assessing the enzyme defect
Lactate measurement in plasma and CSF, and enzyme determinations in cultured fibroblasts, lymphocytes, and muscle biopsies will help in making the final diagnosis
Treatment is generally unsatisfactory. Therapies that enhance lactate metabolism are of some help

Diagnosis

No unique clinical symptoms and signs attributable to lactic acidosis
Instead conditions such as shock and other tissue hypoxic conditions with high AG metabolic acidosis should suggest the presence of lactic acidosis
ΔAG/ΔHCO₃ ⁻ of 1.6 is suggestive of lactic acidosis, because lactate anions are buffered by non-HCO₃ ⁻ buffers (mostly bone) sparing HCO₃ ⁻/CO₂ buffer system
The following laboratory results are unique to lactic acidosis:

1.

Hyperuricemia: lactate competes with urate secretion in the proximal tubule

2.

Hyperphosphatemia: cellular phosphate efflux due to hypoxia and unreplenished ATP hydrolysis

3.

Leukocytosis: demargination of white blood cells due to epinephrine release

4.

Normokalemia: lack of electrical gradient establishment due to lactate permeation into the cell. Therefore, K⁺ exit from ICF to ECF does not occur

Treatment

Removing or treating the underlying cause improves lactic acidosis. However, it is not that simple to eliminate the cause, particularly in critically ill patients
Circulatory support is essential
Broad-spectrum antibiotic administration for sepsis is extremely important for SIRS/sepsis syndrome with circulatory support

Alkali treatment of metabolic acidosis is important; however, there are several disadvantages with this treatment (Table 28.3)

Table 28.3

Intravenous alkali treatment for metabolic (lactic) acidosis

Alkali	Advantages	Disadvantages
NaHCO₃	Rapid effect, inexpensive, easy to administer	Hypertonicity, hypernatremia, ↑ CO₂ production, ↑ intracellular acidosis, volume overload, no survival benefit
THAM	No increase in CO₂, penetrates cells to buffer intracellular pH, useful in the treatment of mixed metabolic and respiratory acidosis	Respiratory depression, hypoglycemia, hyperkalemia, liver necrosis in children. Avoid in renal failure
Carbicarb	A mixture of 0.33 M NaCO₃ and 0.33 M NaHCO₃, less CO₂ production	Same as NaHCO_3, no clinical benefit and nonavailability

NaHCO₃ Requirements

Decide how much serum [HCO₃ ⁻] you need to raise, i.e., ΔHCO₃ ⁻
Estimate HCO₃ ⁻ space as 50 % of body weight (kg) in metabolic acidosis. Some authors calculate as 40 % (note that HCO₃ ⁻ space or deficit increases with an increase in [H⁺] or a decrease in pH)
Calculate the amount of NaHCO₃ that is needed to raise serum [HCO₃ ⁻] to the desired level

Example:

$\begin{aligned}& \text{Serum}\ \text{ }\!\![\!\!\text{ HC}{{\text{O}}_{\text{3}}}^{-}\text{ }\!\!]\!\!\text{ }=\text{1}0\ \text{mEq}/\text{L} \\& \text{Desired}\ \text{serum}\ [\text{HC}{{\text{O}}_{\text{3}}}^{-}]=\text{15}\ \text{mEq}/\text{L} \\& \Delta \text{HC}{{\text{O}}_{\text{3}}}^{-}=\text{5}\ \text{mEq}/\text{L} \\& \text{HC}{{\text{O}}_{\text{3}}}^{-}\ \text{space}\ \text{in}\ \text{a}\ \text{7}0\ \text{kg}\ \text{patient}=\text{7}0\times 0.\text{5}=\text{35}\ \text{L} \\& \text{Amount}\ \text{of}\ \text{NaHC}{{\text{O}}_{\text{3}}}\ \text{required}=\text{35}\times \text{5}=\text{175}\ \text{mEq} \\ \end{aligned}$

These calculations should be based on an ongoing pathologic process that is causing metabolic acidosis
Administer slowly as an isotonic solution at a rate of ~ 0.1 mEq/kg/min
Consider administration of calcium gluconate separately to prevent fall in ionized Ca²⁺ after alkali administration to improve cardiac function

THAM (Tris-Hydroxymethyl Aminomethane) Requirements

THAM is an amino alcohol
It buffers H⁺ by virtue of its NH₃ moiety in the urine. Therefore, its use is limited only to those with GFR > 30 ml/min
It does not increase CO₂
Improves cardiac contractility
THAM is given as a 0.3 M solution (300 mEq/L), and its requirements for initial dose are calculated for the above example as:

$\begin{aligned}& \text{ml}\ \text{of}\ 0.\text{3}\ \text{M}\ \text{solution}\ \text{required}=\text{Body}\ \text{weight}\times \text{Base}\ \text{deficit}\ (\Delta \text{HC}{{\text{O}}_{\text{3}}}^{-}) \\& \text{7}0\times \text{5}=\text{35}0\ \text{ml} \\ \end{aligned}$

Continue THAM until blood pH > 7.20

Tribonat

A buffering agent available in Europe
It is a mixture of THAM, NaHCO₃, acetate, and phosphate
Seems to generate less CO₂ and without much effect on intracellular pH
Not used in the USA

Renal Replacement Therapies

Dialysis is another mode of alkali administration
It has been used to avoid NaHCO₃-induced hyperosmolality and volume overload
Continuous hemofiltration with NaHCO₃ replacement fluid was found to be efficacious in improving lactic acidosis (type A) in hemodynamically unstable patients and in type B acidosis due to metformin and other agents

Thiamine and Riboflavin

Thiamine is a cofactor for PDC, and activation of PDC may improve lactate levels
Riboflavin may provide FAD (flavin adenine dinucleotide), which is required in electron transport system
Both of these do not cause any adverse effects, and their use is optional

Insulin

Insulin increases the activity of PDC, and its use is beneficial in some patients with mild to moderate hyperglycemia

Dichloroacetate

Stimulates PDC and enhances pyruvate oxidation
Reduces lactate levels, improves pH, and raises serum [HCO₃ ⁻]
Despite its beneficial effects on lactic acidemia, there was no survival benefit, therefore not used routinely
However, it is effective in some patients with lactic acidosis due to inherited enzyme defects

d-Lactic Acidosis

d-lactate is the d-stereoisomer of lactate and not a product of human metabolism
Produced by bacteria and ruminants (cows, etc.)
In humans, d-lactate is produced by subjects with intestinal bypass surgery for obesity or intestinal resection, or patients with chronic pancreatic insufficiency
Some patients on prolonged antibiotics may also develop d-lactic acidosis due to overgrowth of gram-positive anaerobes such as d-lactate-producing bacteria (lactobacilli)
d-lactate is not detected by the standard method of l-lactate determination
Characterized by episodes of neurologic manifestations (confusion, slurred speech, ataxia, memory loss, irritability, or abusiveness), including encephalopathy, and high AG metabolic acidosis with normal l-lactate levels. The neurologic manifestations can last from hours to days
High carbohydrate ingestion in subjects with intestinal surgery can precipitate d-lactic acidosis because of large delivery to the colon
d-lactate can be determined by a special technique using d-lactate dehydrogenase

Treatment

Low carbohydrate or starch diet, oral vancomycin, neomycin, or metronidazole

Diabetic Ketoacidosis (DKA)

DKA is caused by insulin deficiency and relative glucagon excess
DKA presents with a triad of hyperglycemia (glucose > 300 mg/dL), ketones in blood and urine, and high AG metabolic acidosis
The accumulated ketoacids are acetoacetate and β-hydroxybutyrate (BHB)
Insulin deficiency promotes lipolysis and fatty acid release, whereas glucagon stimulates the hepatic production of ketoacids from fatty acids

Diagnosis

Diagnosis of DKA is made by high AG metabolic acidosis with documentation of ketones in blood and urine. Volume depletion and many electrolyte abnormalities are commonly associated with DKA

The dipstick that is used to detect ketones contains nitroprusside, which reacts strongly (2–4+) with acetoacetate and poorly with BHB (1+). If initial dipstick reaction is 1+ and then 4+ during treatment of DKA, it suggests that severe acidosis initially is due to BHB, and patient’s acidosis is improving
Use NaHCO_3, as previously discussed
Follow changes in AG, and adjust the requirement for NaHCO₃ administration
Changes in AG also indicate the potential HCO₃ ⁻ regeneration from ketoacids
As AG improves, the HCO₃ ⁻ space or deficit decreases

Treatment

Insulin administration and correction of fluids and electrolytes improve high AG acidosis

Note that hyperchloremic metabolic acidosis does develop during treatment of DKA in some patients because the regeneration of HCO₃ ⁻ from ketones is decreased due to loss of excess ketones in the urine prior to hospitalization

Alcoholic Ketoacidosis

Develops following alcohol abstinence as a result of nausea, vomiting, abdominal pain, and possibly starvation
Most common in women and diabetics following binge
Alcohol withdrawal also precipitates ketoacidosis due to catecholamine release
Pathogenesis includes ethanol itself, starvation, insulin deficiency, excess glucagon and catecholamines, and vomiting
Ethanol inhibits gluconeogenesis and stimulates lipolysis. It is metabolized to acetaldehyde (catalyzed by alcohol dehydrogenase) and then to acetic acid (catalyzed by aldehyde dehydrogenase). These reactions involve conversion of NAD⁺ to NADH, which enhances the production of lactate from pyruvate and BHB from acetoacetate
Starvation depletes hepatic glycogen store. Excess glucagon stimulates lipolysis and production of ketoacids from fatty acids
Ketoacids are also formed from acetic acid
Hypoglycemia is present in some patients

Treatment

Includes fluid replacement with D5W and normal saline, thiamine, and correction of electrolytes

Note that hyperchloremic metabolic acidosis develops during the recovery phase of alcoholic ketoacidosis

Starvation Ketoacidosis

Starvation ketoacidosis is mild and self-limited
Relative decrease in insulin secretion and an increase in glucagon secretion cause ketoacid formation
Unlike DKA, the presence of insulin prevents progression of full-blown ketoacidosis
Also, insulin secretion is stimulated by ketones and fatty acids during prolonged fasting, thereby minimizing even further the formation of ketoacids
Intense ketonuria with a weak serum reaction to nitroprusside test is usually observed in starvation ketosis

Treatment

Resumption of food intake corrects ketoacidosis

Acidosis Due to Toxins

General Considerations

Ingestion of alcohols, such as ethanol, methanol, ethylene glycol, or administration of propylene glycol generates not only hyperosmolality but also metabolic acidosis with high AG. Whenever ingestion of these alcohols is suspected, it is important to measure and calculate serum osmolality to identify osmolal gap
Osmolal gap is defined as the difference between the measured and calculated serum osmolality. Generally, the measured osmolality is 10 mOsm higher than the calculated osmolality. Values > 10 mOsm represent the presence of an osmolal gap
Elevated osmolal gap suggests the presence of osmotically active substances that are measured, but not included in the calculation of osmolality
Lactate and ketoacids also cause high osmolal gap

Traditionally, the presence of an osmolal gap and an elevated anion gap is considered to represent the ingestion of toxic alcohols such as methanol, ethylene glycol, and others (Table 28.4)

Table 28.4

Contribution of some toxic substances to serum osmolality

Substance (100 mg/dL)	Molecular weight	mOsm/L
Ethanol	46	22
Methanol	32	31
Ethylene glycol	62	16
Propylene glycol	76	13
Isopropanol	60	17
Salicylate	180	6
Acetone	58	17
Paraldehyde	132	8

Metabolism: The first step in the metabolism of all toxic alcohols is catalyzed by the enzyme alcohol dehydrogenase (ADH), which is the most critical step in metabolism

Administration of an antidote to inhibit the enzyme ADH prevents the toxic metabolites of the parent alcohol. Table 28.5 shows metabolic end products that cause toxicity

Table 28.5

Toxic metabolites of alcohols and acetylsalicylate (aspirin)

Substance	Toxic metabolite(s)	Comment
Ethanol	Acetoacetic acid, β-hydroxybutyric acid	Commonly seen in alcoholic intoxication, low mortality
Methanol	Formic acid	Blindness and mortality high, if not recognized and treated early
Ethylene glycol	Glycolic acid, oxalic acid	Acute kidney injury, ↓ cardiac contractility, mortality high, if not treated early
Propylene glycol Only gold members can continue reading. Log In or Register to continue Share this: Click to share on Twitter (Opens in new window) Click to share on Facebook (Opens in new window) Related posts: Disorders of ECF Volume: Congestive Heart Failure Disorders of Phosphate: Hyperphosphatemia Disorders of Phosphate: Physiology Disorders of Magnesium: Physiology Disorders of Water Balance: Hypernatremia Disorders of Water Balance: Physiology Stay updated, free articles. Join our Telegram channel Tags: Fluid Electrolyte and Acid-Base Disorders Clinical Evaluation and Management Jun 20, 2017 \| Posted by admin in NEPHROLOGY \| Comments Off on High Anion Gap Metabolic Acidosis Full access? Get Clinical Tree Get Clinical Tree app for offline access Get Clinical Tree app for offline access