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University of the Witwatersrand, Johannesburg

SCHOOL OF PHYSIOLOGY

PHYSIOLOGY III – PHSL 3002 & 3006

2012

COURSE NOTES: ACID-BASE

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INTRODUCTION
Many structural components of the human body are sensitive to changes in hydrogen
ion concentration, as are many enzymes. pH homeostasis is thus vital for survival.
Intracellular pH normally is slightly below that of the surrounding extracellular fluid,
but may be much lower, e.g. in the cells of exercising muscle. Normal arterial pH is
7.36-7.44, and deviations from this value are assumed to reflect whole body acid-base
status. Acid-base disturbances therefore are interpreted clinically primarily on the
basis of analysis of arterial blood samples.

BODY BUFFERS
Challenges to acid-base homeostasis are initially countered in situ by intracellular
(tissue) and by blood buffer systems. Most of the buffer capacity resides not in the
blood, but in the cells of other tissues, particularly skeletal muscle. The major tissue
intracellular buffer systems are shown below:
 Protein/proteinate-
 CO2/HCO3-
 H2PO4-/HPO42-

Whole blood concentration (‘buffer base’) is approximately 48 mmol/l made up as

follows:
Concentration % total buffer base
(mmol/l)
Bicarbonate 24 50
Haemoglobin 14 29
Protein (e.g. albumen) 7.5 16
Inorganic and organic phosphate 2.5 5
48 100

Deviation of buffer base from normal is denoted by the term ‘base excess’. A
negative base excess signifies a net loss of buffer base (metabolic acidosis) and a
positive base excess denotes a net gain of buffer base (metabolic alkalosis).
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Though bicarbonate is the most abundance blood buffer, its concentration is not
measured directly, in assessment of acid-base status. Blood-gas analyzers measure
arterial blood pH and PaCO2 directly. Bicarbonate concentration is computed from the
Henderson-Hasselbalch equation:
pH = 6.10 + log [HCO3-]
0.03.PaCO2
[HCO3-] is in mmol/l and PaCO2 is in mm Hg

PCO2 cannot be accurately measured in a venous blood sample, but laboratories given
venous blood can provide a measurement of total CO2. Total CO2 is the sum of
bicarbonate and dissolved CO2. Since the amount of dissolved CO2 is very little, total
CO2 provides a measure of HCO3- concentration, giving an indication of whether an
acid-base disturbance has a metabolic origin. Complete interpretation of a patient
acid-base status, however, requires analysis of an arterial blood sample.

TCO2 = [HCO3-] + PCO2.0.03

The bicarbonate buffer system is in prompt equilibrium with the other blood buffer
systems, and indeed with the tissue intracellular buffer systems. It is thus a direct
reflection of acid-base status, and is therefore very important in identifying the
previously acid-base status.

ELIMINATION OF ACIDS AND BASES FROM THE BODY

Body buffers are the first line of defense against threats to acid-base homeostasis.
Buffers limit the impact acid or alkali loads have on pH, but they do not eliminate the
acid or alkali. Ultimately, CO2 eliminated via or retained in the lung, and acids
(phosphate, sulphate, lactate, ketoacids) or alkalic (bicarbonate) excreted in urine
eliminate the excesses.

The normal acid burden

Most disturbances of acid-base homeostasis tend to lower the pH, and result from
accumulation of H+ derived from metabolism. Table 1 shows the magnitude of the
various sources of endogenous acid. The extracellular and intracellular buffers play a
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transient role in counteracting pH changes, but acid burdens must thereafter be

eliminated. The table shows three classes of acids, according to their mode of
elimination. CO2 from cellular respiration is much the largest potential generator of
H+. The burden from lactic acid, other organic acids and urea synthesis is about ten
times smaller.

H+ derived from metabolism of compounds containing sulphur and phosphorus is

about 100 times less. Metabolism of sulphur-containing amino acids in the diet results
in sulphuric acid production. Phosphoric acid may be derived from many sources (e.g.
nucleic acid and phosphoproteins such as milk casein). Both these acids are non-
volatile. Excretion of H+ from these sources occurs in the urine, in combination with
urinary buffer.
Table 1: Production of elimination of H+ ions over 24h
Daily Source Excretion in Metabolic Normal
production breath removal elimination
(mol)
Class I
CO2 15 Tissue Yes Lungs
respiration
Class II
Organic acids
and urea
synthesis

(1) Lactic acid 1.2 Muscle, brain, Yes Liver (50%),

rbc, skin kidneys, heart

(2) Hydroxy- 0.6 Liver Yes Many tissues

Butyric and (not liver)
acetoacetic acid

(3) Free fatty 0.7 Adipose tissue Yes Most tissues

acids

(4) H+ generated 1.1 Liver Yes Most tissues

during urea Small fraction
synthesis in urine
Class III
‘Fixed’ acid

Sulphuric acid 0.1 Dietary sulphur- Partly excreted

containing in urine
amino acids

Phosphoric acid Organic

phosphate
metabolism
Note: Values apply to a resting 70kg man after an overnight fast. The value for H + from urea is that
obtained on a 100g protein diet. Ingestion of food during daytime and consequent suppression of FFA
and ketone body production may mean that the values given for these acids are considerable
overestimates.
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HA  H+ + A- Ka = [H+] [A-]
HA
Ka (acid dissociation constant) is a measure of the strength of an acid.
pKa is the pH at which the acid and its conjugate base (A- and HA) are present in
equal concentrations. The stronger the acid, the smaller the pKa.
The pKa for H2CO3/HCO3- is 6.1

The organic acids have pK values much less than blood pH, and are therefore present
mainly as the organic acid anions rather than the undissociated acid. The organic acid
anions (lactate, -hydroxybutyrate, acetoacetate and fatty acids) are non-volatile, but
may be eliminated by metabolism. This consumes H+, regenerates bicarbonate and
results in electroneural products (e.g. glucose or CO2 and H2O). H+ from organic acids
also can be eliminated via the kidneys, but this route normally would be much slower.
However, substantial amounts of ketones can be lost in the urine when their plasma
concentration is elevated. Lactate has a high renal threshold (8 mmol/l; normal blood
lactate is 0.6-2.5 mmol/l) and a low pK value. It is thus not lost in the urine until
blood lactate is grossly elevated, and any lactate so lost represents loss of potential
alkali. Urea appears, somewhat unconventionally, in Table 1. The synthesis of each
mole of urea also results in the production of 2 moles of H+. A person consuming
100g of protein daily produces approximately 1.1 moles of H+ during the conversion
of most of the protein nitrogen into urea. This H+ is almost exactly neutralized by the
bicarbonate produced from metabolism of the carbon skeletons of the amino acid
residues. The excess can be excreted, buffered, as dihydrogen phosphate, or as the
ammonium ion (NH4+). The more nitrogen excreted as NH4+ the less is available for
urea synthesis and concomitant H+ production. There is correspondingly less
neutralization of the bicarbonate produced from the carbon skeletons of the amino
acids, and the tendency for acidosis as a result of protein metabolism is thus
countered.

Ammonium ion is generated in the renal proximal tubular cells from glutamine. Each
glutamine metabolised effectively results in 2 HCO3- (new bicarbonate) and 2 NH4+.
The NH4+ is secreted into the tubular lumen in exchange for sodium. Non-ionic
diffusion of NH3 also contributes to ammonium excretion. NH4+ is reabsorbed in the
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thick ascending limb of the loop of Henle and accumulates in the medulla. NH3 then
diffuses from the medullary interstitum into the tubular fluid, combines with H+, and
is ‘trapped’ in the lumen.

No class of acid in Table 1 has substantial access to a disposal route normally

associated with another class. Total failure of elimination of CO2 would result in
critically severe acidosis in 30 minutes, whereas elimination of lactate removal would
take several hours to produce a lethal acidosis; in acute renal failure several days may
elapse before acidosis becomes a major problem.

Elimination of carbon dioxide

CO2 + H2O  H2CO3  H+ + HCO3-

A normal adult at rest consumes about 400l (18 moles) of O2 and generates about 350l
(15 moles) of CO2 per day. This vast amount of CO2 produced daily poses a serious
potential threat to H+ homeostasis. However, normal respiratory function ensures that
CO2 does not accumulate. The central chemoreceptors (in the brainstem) are
extremely sensitive to changes in [H+]. Increase in [H+] (i.e. lowered pH) promptly
results in an increased respiratory rate (hyperventilation), leading to a diminished
PaCO2. Conversely, a decrease in [H+] causes a retardation of respiration
(hypoventilation) and an elevation of PaCO2. Such changes in PaCO2 in response to
changes in pH causes by metabolic derangements are termed ‘respiratory
compensation’. Respiratory compensation can result in a PaCO2 as low as 10 mm Hg,
or as high as 60 mm Hg.

Predicted PaCO2 = 1.2 [HCO3-] + 10 mm Hg

Adjustment in PaCO2 in response to a metabolic acidosis should correlate with the

equation which should hold true with a 10% margin of deviation. An actual PaCO2
significantly greater than the predicted value indicates a superimposed respiratory
acidosis. A superimposed respiratory alkalosis is present if the actual PaCO2 is much
lower than predicted.
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There is a corresponding equation for PaCO2 adjustment consequent to a metabolic

alkalosis, but it is seldom used, because compensatory hypoventilation is self-
limiting. As PaCO2 rises, PaO2 will drop, resulting in the stimulation of peripheral
chemoreceptor and the reactivation of respiratory effort.

Elimination of fixed acids

On a typical Western diet, the kidney must dispose of some 50-80 moles of H+
equivalent per day. These hydrogen ions arise as metabolic end-products of ingested
phosphates (phosphoric acid) and sulphur-containing proteins (sulphuric acid). These
strong acids are excreted in buffered form: 30-40% of the total strong acid load is
eliminated as NaH2 PO4 (‘tritratable acidity’) and the balance as the NH4+ salts of
phosphate and sulphate. Net acidification occurs in the distal nephron, with
reabsorption of HCO3-.

The organic strong acids (lactic acid and -hydroxybutyric/acetoacetic acid), when
present in excess, are excreted in the urine largely as their NH4+ salts. Excess HCO3
will be eliminated as KHCO3 and NaHO3.

Unlike respiratory responses, the renal response to pH disturbances is sluggish,

requiring 1-3 days to gather momentum. HCO3- concentration may be adjusted to
between 18 and 45 mmol/l.

Other tissues in pH homeostasis

The major vehicle for the net removal of excess H+ from the body is NH4+, derived
from the hydrolysis of glutamine by renal glutaminase. Most of the circulating
glutamine derives from muscle protein catabolism, and glutamine synthesis in muscle
is enhanced in acidaemia. Hepatic nitrogen disposal may also be adjusted. Carbamoyl
phosphate synthetase (the rate-limiting enzyme of urea synthesis) is inhibited by an
increased [H+], while hepatic glutamine synthetase is stimulated. Consequently, there
may be a rerouting of nitrogen in the liver from urea synthesis to glutamine synthesis
and export. The kidney is then largely a ‘dumping ground’ for H+ (as NH4) which has
already been neutralized elsewhere through synthesis of glutamine.
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IDENTIFYING ACID-BASE DISTURBANCES

The pathophysiological manifestations of acid-base disturbances are non-specific, and
may not be evident in the early stages. Accurate characterisation, both qualitative and
quantitative, requires laboratory investigation. In addition to that derived from
analysis of arterial blood, useful information may be obtained from measurement of
plasma sodium, potassium, chloride and bicarbonate, and subsequent calculation of
the anion gap.

Acidaemia or alkalaemia indicate that the arterial pH is lower or higher than normal.
Acidosis refers to a situation of relative excess of acid production in the body, so that
the pH is low, or the pH is normal but would be low had compensatory mechanisms
not operated. An equivalent definition applies to alkalosis. Most acid-base
disturbances result from an imbalance of production and removal of H+ derived from
the endogenous sources classified in Table 1. However, some result from ingestion or
infusion of excessive amounts of acids or bases (particularly bicarbonate). When the
primary disturbance is related to abnormal CO2 elimination, the acid-base disturbance
is termed ‘respiratory’. All other primary disturbances (disturbances of production or
removal of Class I and II acids, or of ureagenesis) are termed ‘metabolic’. The term
‘primary’ is used to contrast with ‘secondary’ disturbances, which are compensatory
in nature. Thus metabolic acidosis is compensated for by hyperventilation, and PaCO2
is lowered; respiratory acidosis is compensated for by elevation of plasma
bicarbonate.

Interpretation of arterial blood gas data

Most acid-base disturbances can be interpreted from the values of pH, PaCO2, and
HCO3-. Of paramount importance is the pH, abnormalities of which reveal a
acidaemia or alkalaemia. Next, the immediate cause of a decreased or increased pH
must be established. Thirdly, any compensatory changes must be identified.

Example 1
 pH
 PaCO2
 HCO3-
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The immediate cause of the acidaemia is the decreased HCO3- i.e. metabolic acidosis.
The decreased PaCO2 cannot be the cause of an acidaemia; a decreased PaCO2 alone
would give rise to an alkalaemia. The decreased PaCO2 is thus compensatory for the
metabolic acidosis. Whether such respiratory compensation is adequate must be tested
using the equation for ‘predicted PaCO2’.

Example 2
 Ph
 PaCO2
 HCO3-

The acidaemia in this case has two causes, namely increased PaCO2 (respiratory
acidosis) and decreases [HCO3-] (metabolic acidosis). There is no point in calculating
‘predicted PaCO2’. It is imperative in metabolic acidosis to calculate the anion gap
(AG), so as to distinguish between ‘increased AG metabolic acidosis’ and ‘normal
AG/hyperchloraemic metabolic acidosis’. Additional information would be necessary
to diagnose the underlying cause of each of the acid-base disturbance identified.

Standard bicarbonate and base excess

The arterial blood gas printout often provides two further variables, the ‘standard
bicarbonate’ and the ‘base excess’ or ‘base deficit’. Standard bicarbonate represents
what the plasma [HCO3-] would be if the blood had a normal PaCO2 (40 mm Hg).
This value provides a measurement independent of concurrent respiratory disturbance,
and thus is an estimate of underlying pure metabolic disturbance. ‘Base deficit’ (or
negative base excess) represents the amount of alkali (e.g. NaOH) in mmol required
to restore the pH of 1l of the blood in vitro to normal at PaCO2 = 40 mm Hg, and
might be considered a quantitative measure of metabolic acidosis. Unfortunately the
titration curve of blood in vitro is different to that in vivo; circulating blood is in
equilibrium with interstitial and intracellular fluids, from which it may gain or lose
HCO3- . In addition, interstitial fluid and intracellular fluid buffering capacity differs
from blood. These considerations detract somewhat from the usefulness of base
excess/deficit as a guide to diagnosis or therapy.
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EFFECTS OF ACID-BASE DISTURBANCES

Respiratory
Metabolic acidosis and acute respiratory acidosis induced by breathing high PCO2
result in hyperventilation. Deep sighing respiration (Kussmaul breathing) is a
common sign of metabolic acidosis. Control of ventilation in response to pH is
determined largely via chemoreceptors in the medulla which monitor pH of brain
extracellular fluid (similar to that of CSF). The carotid and aortic body
chemoreceptors are much less sensitive to changes in pH. However, sudden onset of
metabolic acidosis (low pH and low HCO3-) will induce a mild hyperventilation via
the carotid and aortic body chemoreceptors, lowering PaCO2. CO2 is rapidly
equilibrated across the blood-brain barrier, and thus PCO2 of brain extracellular fluid
(ECF) also falls. It will take many hours for brain ECF [HCO3-] to fall in response to
the lowering of plasma HCO3- as movement of HCO3- across the blood brain barrier is
very much slower than that of CO2. The temporary alkalinization of brain ECF in the
presence of a systemic metabolic acidosis somewhat offsets the ventilatory drive
provided by the peripheral chemoreceptors. After some delay, pH of brain ECF and
plasma pH will coincide, and hyperventilation increases. This sequence of events is
rarely seen, but persistence of hyperventilation after restoration of normal arterial pH
during therapy of metabolic acidosis is seen commonly. Systemic alkalinization
suppresses peripheral chemoreceptors, raising PaCO2. This rise causes paradoxical
acidification of brain ECF, and hyperventilation which may persist for over 24 hours.

The ventilatory drive in response to acute respiratory acidosis lessens with time, as the
initial rapid fall in brain ECF pH is gradually eliminated. In chronic hypercapnia a
further effect is noted: direct depression of the respiratory centre. The respiratory
response to increments of PaCO2 is progressively lost, and ventilation becomes
increasingly dependent on hypoxic drive. Patients exposed to chronic hypercapnia
must not be given excessive supplemental O2, as the increase in PO2 may abolish the
hypoxic drive.

Cardiac
Acidaemia impairs cardiac contractility (negative inotropism). Alkalaemia has
opposite but smaller effects. The negative inotropism is greater in acute respiratory
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acidosis than in acute metabolic acidosis, for the same extracellular pH. Excitation-
contraction coupling and energy supply are impaired. Acidaemia inhibits both the
inward slow calcium current during the action potential and the release of calcium
from the sacroplasmic reticulum, and depresses glycolysis. This sequence of events
may explain circulatory collapse occurring after some hours of severe metabolic
acidosis.

Mild-moderate acidaemia usually is not associated with impaired contractility,

because catecholamine release overcomes the effects of the deranged pH. In more
severe acidaemia this protection breaks down. Patients on beta blockers are thus
potentially more susceptible to the negative inotropic effects of acidaemia.

Peripheral vasculature
Effects are best observed in the cerebral circulation, where they are little obscured by
circulating catecholamines. Cerebral arterioles are very sensitive to the pH of brain
ECF, dilating when pH falls and constricting when it increases. Most systemic
arterioles dilate in response to acidaemias, a response which may be offset by
circulating catecholamines. The peripheral veins constrict in acidaemia, shifting blood
from the peripheral capacitance vessels to the central circulation. Acidaemia
potentiates hypoxic vasoconstriction in the lung, and thus pulmonary hypertension.

Carbohydrate metabolism
Glycolysis is inhibited by acidaemia and stimulated by alkalaemia, via the effects of
intracellular pH or phosphofructokinase, a rate-limiting enzyme. Respiratory alkalosis
might therefore be expected to raise blood lactate, but the effect is normally very
small, presumably due to removal of lactate by the liver. In severe liver disease a
grossly raised lactate may be seen in association with respiratory alkalosis, and the
increased production of lactic acid may partially compensate for the alkalaemia.

Oxygen uptake and delivery

One of the factors determining uptake of O2 in the lungs and delivery to the tissues is
the position of the oxygen-haemoglobin dissociation curve, with respect to the x-axis
(partial pressure of O2) and y-axis (percentage of Hb saturation). Right shifts of the
curve improve O2 unloading in the tissues, but will impair O2 uptake in the lungs. The
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position of the curve is determined by three ligands which can interact with the Hb
molecule: H+, CO2 and 2,3-bisphosphoglycerate (2,3-BPG). Increases in the
concentration of any of these ligands will cause a right shift. Shifts due to changes in
extracellular H+ and CO2 (Bohr effect) are immediate, and operate via changes in
intra-erythrocytic H+ and CO2. A fall in intra-erythrocytic pH (increased H+) inhibits
the synthesis of 2,3-BPG, and encourages its breakdown. 2,3-BPG is a by-product of
the unique RBC glycolytic pathway, which is inhibited by acidaemia at the level of
phosphofructokinase (see above), together with inhibition of BPG-mutase and
stimulation of 2,3-BPG phosphotase. Opposite effects occur in alkalaemia. These
reactions are very slow compared to the immediate Bohr effect.

An acute metabolic acidosis will cause a right shift and hence improved O2 delivery.
After several hours the 2,3-BPG level falls, restoring the position of the curve
approximately to normal. If the patient now is rapidly treated with an alkalainizing
solution the Bohr effect will cause an immediate left shift, and a sudden deterioration
in O2 delivery. It may be many hours, even up to 2-3 days, before 2,3-BPG
concentrations are restored.

Nervous system
Effects on the CNS from changes in cerebral blood flow and O2 dissociation (see
above), as well as other mechanism less well characterised. Severe acidosis often is
associated with some degree of impairment of consciousness, from mild drowsiness to
coma. The degree of disturbance is not closely related to systemic pH.

Neuromuscular excitability in general is increased by alkalaemia and decreased by

acidaemia. Tetany is common in respiratory alkalosis, and may also occur when a
chronic metabolic acidosis is corrected in a patient with low plasma calcium (as may
happen in renal failure). Though the effects on neurones of changes in pH often are
attributed to changes in protein binding of calcium, and therefore of ionized calcium
concentration, they can, and usually do, occur in the absence of chances of ionized
calcium. Convulsions (fits, seizures) in epileptics may be precipitated by alkalaemia
and suppressed by acidaemia.
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Potassium
Acidaemia results in a shift of K+ out of the cells into the ECF in exchange for the H+
ion. As a result hyperkalaemia often is seen in acidosis due to renal failure, diabetic
ketoacidosis or acute respiratory failure. Alkaline therapy in such cases will cause a
shift of K+ back into the cells. Substantial amounts of K+ may be lost through the
kidneys during the period of hyperkalaemia, and so the body may be potassium
depleted despite a high serum [K+]. Alkali therapy may thus result in serious
hypokalaemia. Treatment of diabetic ketoacidosis includes intravenous insulin, which
will cause uptake of glucose and potassium into the cells, and may also result in the
fall in [K+]. Treating the acidosis without addressing the potassium problem could
result in cardiac arrest due to further fall of plasma [K+].

Chronic metabolic alkalosis often is accompanied by K+ depletion, because distal

tubule K+ secretion then is not inhibited by competition for secretion with H+ ions.
The increased tubular secretion often is further enhanced by chloride depletion
(increased HCO3- associated with decreased Cl-).

Kidney
Acidaemia causes a marked increase in renal gluconeogenesis, by affecting the rate-
limiting enzyme phosphoenolpyruvate carboxykinase. This process is believed to be
linked to the increase in renal ammoniagenesis which is a crucial part of the renal
response to acidosis. The main precursor of renal ammonium is glutamine, and
substantial changes in glutamine metabolism take place in acidaemia. Glutamine
release from liver and skeletal muscle is increased and disposal of glutamine nitrogen
is shifted away from urea production in the liver to ammonium excretion in the
kidney. Acidaemia not only stimulates renal ammoniagenesis, but inhibits urea
production directly. Chronic acidaemia increases the activity of renal glutaminase, the
critical enzyme of ammoniagenesis.

Ammonium production normally accounts for about 50% of the acid excreted and
50% of the new HCO3- generated by the kidneys. However, in chronic acidosis NH4+
excretion becomes the dominant mechanism for elimination of cid.
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In acidaemia the kidneys are capable of increasing effective renal acid secretion from
a typical normal value of 100 mmol/day to about 500 mmol/day. The normal
minimum pH of urine is 4,5, the maximum pH is about 8.

Nett acid excretion = NH4+ + Tritratable acid - HCO3-

Titrable acid refers to H+ excreted in combination with phosphate and other organic
buffers (calculated by titrating urine with a strong base such as NaOH to a pH of 7.4,
typically in millimolar terms about 25-30% of the NH4+ excretion). HCO3- excretion
is small, except in alkaline urine. During acidaemia NH4+ excretion may increase five-
fold or more.

Bone
Bone acts as a buffer in chronic metabolic acidosis. Leaching out of calcium
carbonate and exchange of extracellular phosphate for carbonate within the
hydroxyapaptite crystal result in neutralization of H+. A negative calcium balance
results. Although experimental chronic metabolic acidosis in rats leads to
osteoporosis, renal tubular acidosis in humans leads to osteomalacia, which can be
corrected by alkali therapy. Osteomalacia is usually related to vitamin D deficiency or
inappropriate metabolism, or phosphate deficiency; its mechanism in the content of
acidosis is uncertain.

Leukocytes
Severe acidaemia often is associated with marked leukocytosis (increased leukocytes),
unrelated to the presence of infection. Blood leukocyte counts up to 60 x 109/l
(normal 4-11) have been recorded in lactic acidosis and high values also are common
in diabetic ketoacidosis.
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MAJOR SYNDROMES OF METABOLIC ACIDOSIS

Table 2 provides an overview of common causes of acid-base disorders. Some of the
important syndromes are discussed below.

Table 2: Causes of acid-base disturbances

Metabolic acidosis
1. AG 
 Lactic acidosis (e.g. shock, hypoxia, liver failure)
 Ingestion of acid (e.g. aspirin, ethylene glycol, methanol, ethanol)
 Ketoacidosis (e.g. diabetes mellitus, ethanol)
2. Normal AG
 Retention of acid (e.g. renal tubule disease, Addison’s disease)
 Loss of bone (e.g. diarrhoea)
Metabolic alkalosis
 Vomiting
 Mineralocorticoid excess
 K+ depletion
 Ingestion of base (e.g. bicarbonate, milk-alkali syndrome)
Respiratory acidosis
 Hypoventilation (CNS, neuromuscular, pulmonary, drugs)
Respiratory alkalosis
 Hyperventilation
o CNS causes (e.g. stroke, meningitis)
o Anxiety
o Fever
o Hyperthyroidism
o Pregnancy
o Mechanical ventilation

Uraemic acidosis
Metabolic acidosis is a feature of both acute and chronic renal failure. The remaining
nephrons are usually able to lower the urinary pH to the normal minimum value.
Ammonium excretion is low, presumably because of loss of glutaminase-containing
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proximal tubules and because the supply of glutamine is curtailed by impaired renal
blood flow. The classical explanation of the acidosis of renal failure has been that the
decreased supply of ammonia lowers the ability of the tubular fluid to buffer secreted
H+. However, this explanation is inadequate, as ammonium secreted into the tubular
fluid cannot act as a urinary buffer. It seems instead that the nitrogen, which fails to
be excreted as ammonium, is diverted to the liver where it is converted into urea, with
concomitant H+ production. The acidosis of renal failure is therefore due to over-
production of urea, and not due to failure of excretion of H+ buffered in the urine with
NH3.

Diabetic ketoacidosis
Diabetic ketoacidosis (DKA) often is regarded as a classical high anion gap metabolic
acidosis, in which bicarbonate is simply titrated by the ketoacids. If this were the case,
the fall in plasma HCO3- should equal the rise in AG and the plasma concentration of
ketoacids. The situation is frequently more complex. Patients presenting in DKA with
relatively well-preserved renal function tend to have an elevation of AG which is
much less than the fall in HCO3-. Large quantities of ketoacid anions are lost in the
urine, and chloride is retained to maintain electroneutrality. The resulting
hyperchloraemia, together with the urinary loss of ketones, leads to a relatively low
elevation of AG compared with the HCO3- deficit. In contrast, patients with relatively
poor renal function lose much smaller amounts of ketoacid anions and present with a
more classical high AG metabolic acidosis.

The reference value for ketone bodies in blood is <0.3 mmol/l. The concentration in
DKA often is above 10 mmol/l, and can rise as high as 30 mmol/l. The resultant
acidaemia produces respiratory and renal responses. Rate and depth of breathing
increase (Kussmaul breathing – deep, sighing breathing seen in KDA and uraemia).
In spite of the hyperventilation the arterial pH may drop to less than 7.0. Urinary
phosphate buffer is fully titrated by secreted H+, and the minimum possible urinary
pH is attained (~4.5).

After therapy with insulin and fluid the tissue oxidation of ketones generates alkali,
and pH returns to normal over several hours. Those patients who presented with a
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high AG tend to recover their plasma bicarbonate concentration more rapidly on

treatment than those with a relatively normal AG.

Lactic acidosis
Lactic acid is generated by reduction of pyruvate in muscle, red blood cells and other
tissues; the enzyme involved is lactate dehydrogenase. Lactate levels rise when
cellular respiration is impaired and anaerobic glycolysis occurs. Common causes of
lactic acidosis are shock, septicaemia, severe hypoxia, and toxins such as drugs.

Normal venous lactate concentration is 0.6-2.5 mmol/l. It is relatively low when

fasting and rises somewhat after meals. In exercise the concentration may rise to 20
mmol/l or higher, rapidly returning to normal afterwards. Lactic acid has a pK of 3.86
and is thus virtually completely dissociated over the physiological range of pH, so that
generation of the lactate ion produces a similar amount of hydrogen ion. The term
lactic acidosis implies a rise in lactate concentration and an accompanying H+
accumulation sufficient to lower blood pH; generally this occurs when blood lactate is
5 mmol/l or above.

Type A lactic acidosis: Patients have poor tissue perfusion, with or without
hypoxia (e.g. haemorrhagic shock, or a severe myocardial
infarct and left ventricular failure).

Type B lactic acidosis: No signs of tissue hypoxia or underperfusion, except as a

secondary and late event (e.g. drugs, chemicals, inherited
metabolic defect). Less common than type A.

Lactic acidosis occurs in association with many disorders, but most frequently with
diabetes mellitus (especially with biguanide therapy), liver disease, renal failure, acute
pancreatitis, bacterial infections, leukaemia and lymphoma. Lactic acidosis can make
a substantial contribution to the metabolic acidosis in DKA. Patients may occasionally
develop lactic acidosis during treatment, despite having a relatively low lactate
concentration at presentation.
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Increased blood lactate results from increased production, impaired utilisation, or

both. 30-50 percent of totally daily lactate production is taken up by the liver, and
some 30-40 percent of patients with lactic acidosis have evidence of liver disease. The
use of the biguanide drug phenformin, an oral antidiabetic agent, resulted in a high
incidence of type B lactic acidosis. Phenformin increases lactate production in the
splanchnic bed and decreases hepatic lactate uptake. Increased peripheral production
of lactic acid may also be involved. Phenformin has been withdrawn from use in most
countries, but another biguanide, now is the medication used most commonly in Type
2 diabetes, called metformin. Lactic acidosis during metformin therapy is rare.

Alcohol (ethanol) ingestion

In normal subjects, relatively modest ethanol ingestion after 12-24h without adequate
food intake may result in a quite severe hypoglycaemia. Liver glycogen levels have
fallen due to low energy intake and maintenance of blood glucose depends solely on
gluconeogenesis from lactate and other substrates. Ethanol inhibits gluconeogenesis
by diversion of NAD+ for its own metabolism. Lactate therefore accumulates and a
significant though usually mild lactic acidosis may be seen. Treatment is by
administering glucose, and re-feeding.

In chronic alcoholics, many of whom have marked liver damage, a range of acid-base
disorders may occur. In alcoholic ketosis, a long period of heavy alcohol ingestion
culminates in a few days of severe vomiting. A few of these patients have significant
acidosis due to ketoacid accumulation, but in others a metabolic alkalosis is present,
due to ketoacidosis being outweighed by the effects of vomiting. Whatever the acid-
base disturbance, administration of glucose and rehydration is usually adequate
therapy.

PHYSIOLOGICAL BASIS OF TREATMENT OF ACID-BASE

DISTURBANCES
Generally the underlying cause should be treated, rather than correcting the pH. In
extreme cases pH correction may be essential as a life-saving interim measure.
 A-B-19

Respiratory acidosis
Improve ventilation. Bronchodilators may help, but mechanical ventilation may be
necessary in severe cases.

Respiratory alkalosis
Decrease the rate of pulmonary gas exchange – re-breathing from a paper bag
increases PaCO2. Give O2 if hypoxia is causing the hyperventilation.

Metabolic acidosis
Intravenous NaHCO3 should not be given unless the pH is less than 7.1. Rapid
reversal of acidosis generally is not desirable, unless the acidosis is life-threatening.
Additional CO2 from NaHCO3 can diffuse into cells, and worsen intracellular
acidosis. Increased pH will shift the O2-Hb dissociation curve to the left, decreasing
O2 delivery to the tissues. The drive of the respiratory centre to hyperventilate may be
impaired, and blood vessels may constrict, reducing tissue perfusion.

Metabolic alkalosis
The most common type is associated with hypokalaemia, volume and salt depletion.
Intravenous saline is often sufficient, treatment while more severe cases may also
require KCl.

HOW TO HANDLE ACID-BASE PROBLEMS – SUMMARY

1. What is the pH? Acidaemia or alkalaemia?
2. If PCO2 and [HCO3-] are not both given, calculate the unknown using the H-H
equation.
3. Establish the primary cause of the pH change. Is it the PaCO2 (respiratory) or
the [HCO3-] (metabolic) or both?
4. Has compensation occurred? In the case of a simple primary metabolic
acidosis, calculate whether respiratory compensation is adequate.
5. Calculate the anion gap, so as not to miss a ‘hidden’ metabolic acidosis.
6. Consider possible pathophysiological causes of the disturbance.

School of Physiology, University of the Witwatersrand, 2012