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13 Anion Gap Metabolic Acidosis
13 Anion Gap Metabolic Acidosis
13
Metabolic Acidosis:
13 Anion Gap
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The Fluid, Electrolyte and Acid-Base Companion
–
HCO3 H+ HCO3 HCO3 H+ C
The addition of hydro-
gen ions lowers pH. Bi-
carbonate is consumed
buffering the added hy-
drogen. H+ HCO3 HCO3 H+ C
The difference between anion and non-anion gap metabolic acidosis is discussed in Chap-
ter 11, MetabolicAcidosis: The Overview
.
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S. Faubel and J. Topf 13 Metabolic Acidosis: Anion Gap
+ CH2 CH2 O C
Oxygen Na
Cl–
HO C CH3 C CH3
H O CH3
HCO3
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The Fluid, Electrolyte and Acid-Base Companion
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S. Faubel and J. Topf 13 Metabolic Acidosis: Anion Gap
glycolysis
lactate metabolism
ruvate •
py lactic acid + NAD+
py
glucose
ruvate •
ruvate •
all cells
py
py
ruvate •
gluconeogenesis oxygen
mitochondria
acetyl
glucose
CO2
CoA
mitochondria
ATP
NAD+
TCA cycle oxidative
phosphorylation
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The Fluid, Electrolyte and Acid-Base Companion
py
glucose
ruvate •
ruvate •
+ NAD+
all cells
py
py
ruvate •
oxygen
gluconeogenesis
mitochondria
acetyl
CO2
glucose CoA
mitochondria
ATP
NAD+
TCA cycle oxidative
phosphorylation
330
S. Faubel and J. Topf 13 Metabolic Acidosis: Anion Gap
R.I.P.
C
C
C
C
C
C
C
C
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S. Faubel and J. Topf 13 Metabolic Acidosis: Anion Gap
insulin
Metformin increases the sensitivity of
fat cells (adipocytes) to insulin so that
they absorb more glucose and de-
crease the release of free fatty acids.
protein
lactate
Metformin decreases hepatic conversion
of lactate to glucose. Since lactate is not
converted to glucose, gluconeogenesis glucose
and fasting hyperglycemia are prevented.
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The Fluid, Electrolyte and Acid-Base Companion
O O O O
C C
HO C H H C OH
CH3 CH3
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S. Faubel and J. Topf 13 Metabolic Acidosis: Anion Gap
xxx
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The Fluid, Electrolyte and Acid-Base Companion
A BIOCHEMICAL FEAST
Muscle. Protein synthesis. protein
insulin synthesis
glucagon glucose
pyruvate
After eating, blood sugar rises. In response, the pancreas secretes insulin
and shuts off the secretion of glucagon. This is known as the fed state during
which the primary fuel for the body is glucose.
Insulin promotes the building of muscle, storage of fat and hepatic glyco-
gen synthesis. The effects of increased insulin and decreased glucagon are
summarized below.
INCREASED INSULIN PROMOTES : DECREASED GLUCAGON PROMOTES :
Insulin acts on muscle and fat cells to increase _________ ab- glucose
sorption.
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S. Faubel and J. Topf 13 Metabolic Acidosis: Anion Gap
amino acids
pyruvate
fatty acids
glucose
fatty acids
Adipocytes. Lack of in- ketones
glycogen
sulin induces lipolysis. TCA
During fasting, as blood sugar falls, the pancreas releases glucagon and
H
suppresses insulin. Initially, the liver converts glycogen stores into glucose
to prevent hypoglycemia. If the fasting state is prolonged, the primary fuel
is switched from glucose to ketones.
Glucagon stimulates the liver to convert glycogen to glucose, fatty acids
to ketones and alanine to glucose. The effects of decreased insulin and in-
creased glucagon are summarized below.
DECREASED INSULIN CAUSES : INCREASED GLUCAGON CAUSES :
Hypoglycemia can also stimulate the release of growth hormone, norepinephrine and corti-
sol. These hormones (the counter-regulatory hormones) promote lipolysis, protein catabo-
lism and gluconeogenesis. Norepinephrine is responsible for the symptoms of hypoglyce-
mia: sweating, tremors and agitation.
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The Fluid, Electrolyte and Acid-Base Companion
glycolysis
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S. Faubel and J. Topf 13 Metabolic Acidosis: Anion Gap
glucagon lipolysis
insulin
hypoglycemia adipocytes
triglycerides
CO2 to fatty acids
ATP
NAD+
ß-oxidation
TCA cycle oxidative phosphorylation
acetyl CoA
O O O O
CH3
C C
O CH2
CH2 CH2 acetyl CoA
CH3
HO C CH3 C ketogenesis
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The Fluid, Electrolyte and Acid-Base Companion
ALCOHOL
Alcohol stimulates lipolysis, supplying METABOLISM
substrate for ketogenesis xxx nontoxic
metabolite
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S. Faubel and J. Topf 13 Metabolic Acidosis: Anion Gap
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The Fluid, Electrolyte and Acid-Base Companion
protein glycogen
insulin
O O O O
C C
CH2 CH2
HO C CH3 C
H O CH3
To remember the different triggers of diabetic ketoacidosis think“ iof”: initial (new diagno-
sis of type 1 diabetes mellitus),infection, illicit drug use, insulin (lack of), infarction
(myocardial),infant (pregnancy).
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S. Faubel and J. Topf 13 Metabolic Acidosis: Anion Gap
mental
hypovolemic status abdominal pain,
shock changes nausea and vomiting
C
C
C
Patients with diabetic ketoacidosis are very ill. In severe cases, patients can
present with hypovolemic shock, altered mental status or coma. Symptoms of
DKA include abdominal pain, vomiting, polydipsia, polyuria and weight loss.
Signs of DKA include Kussmaul respirations (deep rhythmic respiration), ta-
chycardia, hypotension and a fruity odor on the breath due to acetone. Some
patients present with abdominal pain which can mimic a surgical abdomen.
While the classic description of DKA limits the disease to patients with type 1 diabetes, the
condition is well described in young (third decade), obese, black patients with new onset
type 2 diabetes. Older patients with long-standing type 2 diabetes can also become ketotic
with stress.
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The Fluid, Electrolyte and Acid-Base Companion
Na Cl
BUN HPO4
2–
pH PCO2 PO2
+ –
glucose
K+ HCO3 amylase
–
Creatinine
The lab abnormalities in diabetic ketoacidosis are found across the entire
chemistry and ABG panel. Successful management of these problems re-
quires frequent monitoring of electrolytes and early electrolyte repletion.
Sodium is typically decreased due to pseudohyponatremia. (See
Chapter 6, page 113.) Hypertonic plasma draws water from the
cells into the vascular space, diluting the plasma sodium. To esti-
mate the corrected sodium for the elevated glucose, add 1.6 mEq/L
to the measured sodium for every 100 mg/dL the glucose is above
100 mg/dL.
Potassium is usually increased due to a shift of potassium out of
cells. Despite high plasma levels, total body potassium is markedly
decreased due to increased renal loss of potassium. (See Chapter
18, page 519.)
Bicarbonate is decreased because it is consumed buffering acid.
BUN and creatinine are typically elevated due to hypovolemia
causing pre-renal azotemia.
Glucose is elevated, usually above 300 mg/dL.
Anion gap is increased due to the presence of ketone anions. It is
usually greater than 20 mEq/L.
Phosphorous is decreased.
Amylase is increased because ketones interfere with the labora-
tory assay for amylase. Lipase is usually normal.
pH is decreased.
P CO2 is decreased due to compensatory hyperventilation (Kus-
smaul’s respiration).
White blood cell count is increased due to demargination.
In DKA, K+ , BUN, glucose and creatinine are typically _________. increased
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S. Faubel and J. Topf 13 Metabolic Acidosis: Anion Gap
maximum
resorption
osmolality osmolality
glucosuria
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The Fluid, Electrolyte and Acid-Base Companion
.9%
ouch!
NaCl
.9%
NaCl
.9%
NaCl
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S. Faubel and J. Topf 13 Metabolic Acidosis: Anion Gap
.9%
NaCl
O O O O
BUN
Na+ Cl–
C C CH3
glucose
CH2 CH2 O CH2
K HCO3
HO C C
+
CH3 CH3
–
Creatinine
H O CH3
IV insulin can be discontinued when the ______ _____ is normal. anion gap
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The Fluid, Electrolyte and Acid-Base Companion
.9%
NaCl
ouch!
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H+ HCO3– R.I.P.
+
H
–
SO4 H +
+
H
SO4 H +
–
–
SO4
Protein in the diet is metabolized The kidney resorbs all filtered bi- With advanced kidney failure, the
into acid. Plasma bicarbonate is carbonate and creates “new” bi- daily hydrogen load and accom-
consumed buffering the daily carbonate to replace any lost buff- panying anions are not fully excret-
acid load. ering the daily acid load. Anions ed. Bicarbonate is not replaced,
are filtered and excreted. causing metabolic acidosis.
With a normal diet, 50-100 mmol of acid is generated every day (the daily
acid load). The acid produced is mostly H2SO4 from the metabolism of sulfur-
containing amino acids. Plasma bicarbonate is consumed buffering this acid
load. Normally, the kidney creates new bicarbonate to replace the 50-100 mil-
liequivalents of bicarbonate lost daily buffering hydrogen. The anions of the
daily acid load (e.g., SO4–2, PO4–3, urate, and hippurate) are filtered and ex-
creted.
In chronic renal failure, glomerular filtration rate falls due to a loss of
functioning nephrons. Because of decreased filtration, the kidneys are un-
able to clear the daily acid load. As a result, increased hydrogen lowers
plasma bicarbonate and the associated anions increase the anion gap.
For more information on the daily acid load and how it is handled by the kidney
, see Chapter
12, MetabolicAcidosis: Non-anion Gap,page 296.
The kidney is responsible for replacing the ________ lost buffering the bicarbonate
daily acid load and secreting filtered ________. anions
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The Fluid, Electrolyte and Acid-Base Companion
Both renal failure and RTA cause metabolic acidosis, but only
renal failure causes an increased anion gap.
– –
HCO3 HCO3
– –
HCO3 HCO3
SO–4 SO4
–
– –
HCO3 HCO3 HCO3
–
– –
HCO3 HCO3 –
HCO3
Since renal failure and renal tubular acidosis both cause metabolic
acidosis due to kidney disease, it is important to understand how they
differ. In renal tubular acidosis, every nephron has a specific defect which
prevents it from effectively producing new bicarbonate (secreting hy-
drogen); however, the excretion of anions occurs normally. Because the
excretion of anions is normal, RTA is associated with a normal anion
gap.
In renal failure, the number of functional nephrons is greatly reduced.
Each functional nephron produces more bicarbonate than normal, but
total bicarbonate production is still below normal because there are
simply not enough functional nephrons. As the number of functional
nephrons decreases, the glomerular filtration rate (GFR) falls, and the
filtration of all substances decreases including the anions associated
with the daily acid load. These anions increase the anion gap. Acidosis
generally does not occur until the GFR falls below 40 mL/min.
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S. Faubel and J. Topf 13 Metabolic Acidosis: Anion Gap
Ca H+ PO4 H+
H+
Ca H+ CO3 H+
K HCO3 H+
Na HCO3 H+
The acidosis of chronic renal failure progresses gradually, giving the body
plenty of time to compensate. In chronic renal failure, plasma bicarbonate
drifts down until it plateaus between 12 and 20 mEq/L. At this point, the
daily acid load continues to accumulate, but bones release bicarbonate and
phosphate to buffer the additional acid. This process prevents worsening of
the acidemia at the expense of bone integrity. Therefore, a long-term com-
plication of chronic renal failure is osteopenia (decreased bone density).
Despite the fact that the acidosis of chronic renal failure is well-compen-
sated, the eventual development of osteopenia illustrates why treatment
with bicarbonate may be beneficial. Because it can decrease the rate of bone
demineralization, oral bicarbonate therapy should be considered in patients
with chronic renal failure.
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The Fluid, Electrolyte and Acid-Base Companion
The ingestion of various chemicals can cause an anion gap metabolic aci-
dosis. Typically, the ingested chemical is not itself an acid, but induces an
acidosis (aspirin) or is metabolized into an acid (methanol, ethylene glycol).
The ingestions which can cause anion gap metabolic acidosis are listed above
and are described in detail on the following pages.
Paraldehyde is a potent hypnotic and sedative which is no longer in use, in part because of
its offensive odor.
There are _____ classes of anion gap metabolic acidosis: lactic four
acidosis, ketoacidosis, renal failure and ___________. ingestions
The acidosis from __________ is not typically due to the intake ingestions
of an acid, but rather from the body’s reaction to the ingestion.
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S. Faubel and J. Topf 13 Metabolic Acidosis: Anion Gap
At therapeutic doses, 90% of salicylic acid At therapeutic doses, 10% of salicylic acid is
is protein-bound and hence inactive (i.e., free and therapeutically active. Above thera-
nontoxic). peutic doses, a greater percentage of the as-
pirin is not protein-bound.
Aspirin is the trade name of the drug acetylsalicylic acid. After ingestion,
aspirin is rapidly converted to the active form, salicylic acid, which at thera-
peutic doses is 90% protein-bound. Protein-bound salicylic acid is inactive,
nontoxic and trapped in the vascular compartment.
Salicylic acid is converted in the liver to salicyluric acid which is less
toxic and easily cleared by the kidney.
Aspirin was perfected by the German researchers Felix fman Hof and Hermann Dreser .
Hoffman and Dreser developed the powdered analgesic and antipyretic from coal . This
tar
new medication was less irritating to the GI tract than salicylic acid.The addition of the
neutral salt, calcium glutamate, made it less irritating still. It was marketed under the trade
name Bayer Aspirinin 1905 and quickly became the world’ s best-selling drug.
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The Fluid, Electrolyte and Acid-Base Companion
s
tic
strates increase. At this point, detoxification
e
in
rk
Zero order kinetics: the rate of enzymes are saturated.
de
or
At toxic levels, the free portion of salicylic acid is _________ (de- increased
creased/increased).
The enzymes which convert salicylic acid to ________ acid are salicyluric
saturated at ______ concentrations. low
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S. Faubel and J. Topf 13 Metabolic Acidosis: Anion Gap
O O O O glucose
C C C lactate–
CO2
C CO2
C CO CH2 CH2
CO2 2
C
HO C CH3 C
H O CH3
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The Fluid, Electrolyte and Acid-Base Companion
H+
Salicylic acid is H+ 1 Alkalinization shifts
in equilibrium the equilibrium to-
between the in- wards salicylate for-
tracellular and mation in the plasma,
extracellular lowering the salicylic
compartments. acid concentration.
The initial goal in the treatment of aspirin toxicity is to get the drug out of
cells. This is done by a process called ion trapping. Salicylic acid, like all acids
in solution, is in equilibrium with its anion, salicylate. The anion is polar and
unable to cross lipid membranes, but salicylic acid is less polar and diffuses
across the cell membranes so that there are equal concentrations of salicylic
acid in both the intracellular and extracellular compartments.
Increasing the plasma pH shifts the equilibrium toward the formation of the
anion, salicylate, and decreases the extracellular concentration of salicylic acid.
The decreased plasma concentration of salicylic acid causes intracellular sali-
cylic acid to leave cells, trapping the acid in the plasma. By administering bi-
carbonate and increasing the arterial pH from 7.2 to 7.5, the tissue level of
salicylic acid is halved.
Ion trapping is a three step process:
1. Alkalinizing the plasma ________ the plasma concentra- decreases
tion of diffusible _________ ______. salicylic acid
2. The plasma salicylic acid then diffuses from ______ cells
down its concentration gradient into the ________. plasma
3. Once salicylic acid arrives in the ______, it is converted plasma
to the nondiffusible salicylate and is trapped in the plasma.
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S. Faubel and J. Topf 13 Metabolic Acidosis: Anion Gap
Alkalinization of the
1 tubular fluid shifts
the equilibrium to-
wards salicylate.
3 Once in the tubular fluid, salicylic
acid is converted to salicylate and
is trapped in the tubule.
H+
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The Fluid, Electrolyte and Acid-Base Companion
H OH
H3C OH H C H C
alcohol
dehydrogenase O O
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S. Faubel and J. Topf 13 Metabolic Acidosis: Anion Gap
MINUS
BUN glucose
2 × Na + +
2.8 18
C ALCUL ATED PLASMA OSMOLALITY
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The Fluid, Electrolyte and Acid-Base Companion
activated charcoal
Alcoholics have up-regulated alcohol dehydrogenase activity and often require higher doses
of ethanol to saturate alcohol dehydrogenase and prevent methanol metabolism.
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S. Faubel and J. Topf 13 Metabolic Acidosis: Anion Gap
R.I.P.
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The Fluid, Electrolyte and Acid-Base Companion
78 C
C
C
C
32 C
C
CARDIOVASCULAR METABOLIC
decreased cardiac contractility insulin resistance
arterial dilation, venoconstriction inhibition of glycolysis
increased pulmonary vascular resistance reduced ATP synthesis
predisposition to arrhythmias hyperkalemia
decreased response to catecholamine
CEREBRAL
(endogenous and pharmacologic)
mental status
RESPIRATORY coma
hyperventilation
Regardless of the etiology, severe acidosis can have important clinical con-
sequences. Severe metabolic acidemia, pH less than 7.2, is dangerous be-
cause of its wide ranging effects on both the cardiovascular system and ba-
sic metabolic processes.
As the pH falls below 7.2, the cardiovascular system becomes especially
compromised. Acidemia decreases cardiac contractility and cardiac output.
Arteries dilate, dropping blood pressure. Furthermore, the cardiovascular
system is less responsive to the effects of catecholamines which normally
boost cardiac output and vascular tone. The commonly used vasopressors
(e.g., dopamine, norepinephrine) are less effective in the presence of severe
acidemia.
Low pH is also arrhythmogenic and the heart is less responsive to antiar-
rhythmic measures, both electrical and pharmacologic.
As cardiac output drops, cells become more dependent on anaerobic me-
tabolism to replenish ATP. It is interesting to note, however, that anaerobic
metabolism (glycolysis) is also compromised by severe acidemia.
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S. Faubel and J. Topf 13 Metabolic Acidosis: Anion Gap
sodium bicarbonate
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The Fluid, Electrolyte and Acid-Base Companion
+
Lactate + H
CO2
Oxidative phosphorylation pro- Increased carbon dioxide is not re-
duces carbon dioxide. moved because of impaired circulation,
causing intracellular acidosis.
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S. Faubel and J. Topf 13 Metabolic Acidosis: Anion Gap
Na+ Na+
Cl– A-
Cl–
H+
HCO3
HCO3 H+ A-
K+ A-
other
anions A-
other
anions
K+
There are four basic processes which can cause anion gap metabolic aci-
cations = anions cations = anions
O O O O
C C CH3
CH2 CH2 O CH2
Oxygen
HO C CH3 C CH3
H O CH3
Lactic acidosis occurs when mitochondria stop producing ATP and NAD+.
Type A lactic acidosis is due to tissue ischemia, usually from shock. Type B
lactic acidosis is due to mitochondrial dysfunction in the presence of ad-
equate perfusion.
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The Fluid, Electrolyte and Acid-Base Companion
HO C CH3 C CH3
H O CH3
ß-hydroxybutyrate acetoacetate acetone
Renal failure causes an anion gap metabolic acidosis when the kidneys
are unable to excrete the daily acid load. It differs from RTAs in that the
problem is not a specific tubular defect impairing the excretion of acid; rather,
it is a generalized decrease in glomerular function.
RENAL TUBULAR ACIDOSIS RENAL FAILURE
– – –
HCO3 HCO3 HCO3
– – –
HCO3 HCO3 HCO3
- -
SO4 SO
SO4 4
-
Methanol and ethylene glycol are toxic because of the metabolites pro-
duced from their metabolism. Alcohol dehydrogenase produces toxic me-
tabolites which can cause severe symptoms. To prevent the metabolism of
methanol or ethylene glycol, alcohol is administered to competitively in-
hibit alcohol dehydrogenase. Hemodialysis may be needed for large inges-
tions.
366