CHAPTER I

INTRODUCTION
1.1
Background
Acidbase homeostasis exerts a major influence on protein function, thereby critically
affecting tissue and organ performance. Deviations of systemic acidity in either
direction can have adverse consequences and, when severe, can be life-threatening.
Yet it is the nature of the condition responsible for severe acidemia or alkalemia that
largely determines the patient's status and prognosis. Whereas a blood pH of 7.10 can
be of little consequence when caused by a transient or easily reversible condition,
such as an isolated seizure, it forecasts an ominous outcome if it is the result of
methanol intoxication. Similarly, a blood pH of 7.60 seldom has serious consequences
when caused by the anxietyhyperventilation syndrome, but it imparts a major risk to
a patient with cardiomyopathy treated with digitalis and diuretics. Consequently, the
management of serious acidbase disorders always demands precise diagnosis and
treatment of the underlying disease, and in certain circumstances, it requires steps to
combat the deviation in systemic acidity itself. In this article, we address general
concepts and some specific aspects of the management of life-threatening acidbase
disorders.
1.2

Purpose of writing
Understanding more about Management of Life-Threatening Acid Base
Balance Disorder

1.3

Problems
1.3.1

Definition and physiology of Acid Base Balance

1.3.2

Etiology, pathogenesis, and clinical manifestations of Life-Threatening

Acid Base Balance Disorder

1.3.3

Diagnosis, differential diagnosis, treatment, and prevention of LifeThreatening Acid Base Balance Disorder

1.4

Benefits of writing

1.4.1 Provide an understanding of Life-Threatening Acid Base Balance

Disorder and management so that the right can be granted
1.4.2

As a source of knowledge for other academics to be the development

of subsequent papers

CHAPTER II
2

LITERATURE REVIEW

2.1. Definition
The term pH means potentials of Hydrogen. Acidity and alkalinity are
expressed on the pH scale, which ranges from 0 (strongly acidic) to 14 (strongly
basic, or alkaline). A pH of 7.0, in the middle of this scale, is neutral. Blood is
normally slightly basic, alkaline, with a pH range of 7.35 to 7.45. To function
properly, the body maintains the pH of blood close to 7.40.
An important property of blood is its degree of acidity and alkalinity, and this
is referred to as acid-base balance. The acidity or alkalinity of the blood is indicated
on the pH scale. The acidity level increases when the level of acidic compounds in the
blood rises or when the level of alkaline compounds in the blood falls. Alkalinity
levels increases with the reverse process. The level of acidic or alkaline compounds in
the body rises through increased intake, production, or decreased elimination and falls
through decreased intake, production, or increased elimination.
2.2. Proton concentration and pH
Maintaining of stable anion and cation concentrations in blood plasma is
denoted as isoionia. Maintaining of constant proton (H+) concentration is isohydria.
pH is used for express concentration of the protons:
pH = log c(H+)
Plasma and extracellular space concentrations of the protons are held in very
narrow physiologic range. There is 40 nmol/l of protons in the arterial blood
physiologically (note that concentrations of other plasma ions, e.g. [Na+] = 140
mmol/l or [HCO3-] = 25 mmol/l, are three orders of magnitude higher). pH could be
easily calculated as follows:
pH = -log 40 x 10-9 mol/l
pH = 7,4

Physiologic range of the pH is 7,36-7,44.

Value of pH higher than 7,44 in arteries is denoted as alkalemia, pH lower than
7,36 is acidemia. Extensive deviations of pH value can cause serious consequences.
For example change of protein structure (i.e. enzymes), membranes permeability, and
electrolyte distribution. Value of pH in arterial blood higher than 7,8, resp. lower than
6,8 are incompatible with life.
Values mentioned above apply for arterial blood. Values differ in different
body compartments hence there are different H+ concentrations. There is quite
variable and lower pH value intracellular, it is about 7,0 ([H+] = 100 nmol/l).
Intracellular pH compared to arterial pH gives difference 0,4. This corresponds to fact
that there is 2,5 fold difference between intracellular and arterial H+ concentration.
This concentration gradient drives the movement of H+ from cells to blood. Therefore
it is not surprising that venous pH and pH of interstitial fluid is lower (i.e. more
acidic) than arterial pH. Approximate value is 7,35.
2.3. Acids & Bases in the Body
Acid is defined as molecule that can cleave off H+ (Arrhenius) or donor of H+
(Brnsted). Base is au contraire molecule that can cleave off OH- (Arrhenius) or
acceptor of H+ (Brnsted). Source of acids in the body is chiefly metabolism, source
of bases is predominantly nutrient.
Acids and bases undergo either (1) metabolic conversion (e.g. lactate to
glucose in gluconeogenesis, lactate to pyruvate and oxidation in cardiomyocytes), or
(2) excretion from body. Three types of reactions can be distinguished from point of
view of the acid-base balance. (1) proton-productive, (2) proton-consumptive, (3)
proton-neutral. Examples follow:
1) Proton-productive reactions
a) Anaerobic glycolysis in muscles and erythrocytes
Glucose 2 CH3CHOHCOO- + 2 H+

b) Ketogenesis production of ketone bodies

Fatty acids ketone bodies + n H+
c) Lipolysis
TAG 3 FA + glycerol + 3 H+
d) Ureagenesis
CO2 + 2 NH+4 urea + H2O + 2 H+
2) Proton-consumptive reactions
a) Gluconeogenesis
2 lactate + 2 H+ Glc
b) Neutral and dicarboxylic amino acids oxidation
3) Proton-neutral reactions
a) Complete glucose oxidation
b) Lipogenesis from glucose
Human organism (healthy or not) every day produces great quantities of acids
source of protons. Organism is acidified by these processes:
1) Complete oxidation
Carbon skeleton CO2 + H2O HCO3- + H+
2) Incomplete oxidation
Carbohydrates glucose pyruvate, lactate + H+

Triacylglycerol fatty acids, ketone bodies + H+

Phospholipids phosphate + H+
Proteins amino acids sulphate, urea + H+
Acids can be divided into two groups: (1) volatile acids (respiratory acids), (2) nonvolatile acids (metabolic acids).
The most important volatile acid is carbonic acid (H2CO3). H2CO3 is
produced by reaction of carbon dioxide (CO2 is acid-forming oxide) with water. 15
000 20 000 mmol CO2 (therefore same amount of carbonic acid) is produced every
day. Respiratory system however very efficiently eliminates it. This justifies the term
volatile acid.

Two groups are distinguished among non-volatile acid: (1) organic, and (2)
inorganic. 1 mmol/kg of body weight is produced every day. Non-volatile acid could
be either (1) metabolised, or (2) excreted (using mainly kidneys).

Organic non-volatile acids are for example: (1) lactic acid, (2) fatty acids, (3)
ketone bodies (acetoacetic acid, -hydroxybutyric acid). They are continually
produced by metabolism (incomplete oxidation of TAG, carbohydrates, proteins). As
organic non-volatile acids are products of metabolism in normal conditions they are
oxidized completely to CO2 and H2O. Therefore they have no influence on proton
overall balance.
Inorganic non-volatile acids are: (1) H2SO4 (sulphuric acid is produced by
oxidation of sulfhydryl groups e.g. in amino acids that contain sulphur, i.e. cysteine,
methionine), (2) H3PO4 (phosphoric acid is produced by hydrolysis of
phosphoproteins, phospholipids, nucleic acids). Inorganic non-volatile acids are
predominantly excreted in urine. You should notice now that ATP production is
coupled with H+ production. Human body is evolutionary capable to handle acid
load.
2.4. System responsible for maintenance of the acid-base system
Several systems maintain constant pH. The list below is made according to
order when they act:
1) Chemical buffering systems
Buffers react immediately acute regulation. Capacity of buffers is not
indefinite that is why chemical buffers act only in the short-term. Chemical buffering
systems deal with pH deviations in common metabolism.
2) Respiratory system
Respiration reacts in 1-3 minutes. Respiratory system regulates carbon
dioxide. Respiration is able to change pCO2 by its elimination or retention.
Respiratory centre is in brainstem.
3) Kidneys
Kidneys react in hours-days. Their role in acid-base balance is very complex.

4) Liver
Liver is pivotal organ of the energetic metabolism it also have important
influence on the acid-base balance. Liver is the most important tissue where
ammonium is detoxified in both (1) urea cycle, and (2) glutamine synthesis. Which
one of these fates of ammonium is favoured closely depends on status of the acid-base
balance:
a) NH4+ urea + 2 H+ acidification of the body
CO2 + 2 NH4+ CO(NH2)2 + 2 H+ + H2O
H+ + HCO3- H2O + CO2 (consumption of bicarbonate-)
b) NH4+ glutamine synthesis H+ is not produced, glutamine is taken up by the
kidneys. In the kidney is H+ excreted as NH4+

5) Myocardium
Myocardium influences acid-base balance through lactate and ketone bodies
oxidation.
2.5. Buffering Systems
Buffers are substances capable of releasing and binding H+. Short-term and
acute changes in acid-base balance can be balanced by buffers. Each buffer keeps its
particular pH. This pH could be calculated by means of the Henderson-Hasselbalch
equation:
pH = pK + log [conjugated base]/[acid]
Henderson-Hasselbalch equation for bicarbonate buffer (HCO3-/CO2):
pH = pKH2CO3 + log ([HCO3-] / [H2CO3])
pH = pKH2CO3 + log ([HCO3-] / x pCO2)
is conversion factor, that is used for calculation of molar concentration
(mmol/l) from partial pressure of CO2 (pCO2). = 0,226 for pCO2 in kPA, = 0,03
for pCO2 in mmHg).
pH = pK 1 is range where buffers work optimally.
In Henderson-Hasselbalch equation above you should notice that for pH that
buffers keep depends primarily on ratio of conjugated base and acid (Of course
concentration of each component is important but not that much). Therefore it is
really important to know the ratio. Ratio of conjugated base and acid could be
calculated from relation between pH and pK. For example bicarbonate buffer (pH =
7,4; pK = 6,1):
pH = pKH2CO3 + log ([HCO3-] / [H2CO3])
7,4 = 6,1 + log ([HCO3-] / [H2CO3])
9

1,3 = log ([HCO3-] / [H2CO3])

[HCO3-] / CO2 20 / 1
The ratio in bicarbonate buffer is 20:1 (HCO3- : CO2)
There are several buffer systems in the body. The most important include: (1)
bicarbonate buffer (HCO3-/CO2), (2) hemoglobin buffer (in erythrocytes), (3)
phosphate buffer, (4) proteins, and (5) ammonium buffer. Their importance differs as
it depends on localization.
Main buffer systems according to body compartments.
Localization
ISF

Buffer

Commentary

Bicarbonate

Buffers metabolic acids

Phosphate

Low

concentration

limited

limited

significance
Proteins

Low

concentration

significance
Blood

Bicarbonate

Buffers metabolic acids

Hemoglobin

Buffers

CO2

(carbonic

acid

production)
Plasma proteins

Minor

Phosphate

Low

concentration

limited

significance
ICF

Proteins

Significant buffer

Phosphate

Significant buffer

10

Urine

Phosphate

Responsible for majority of the

titratable urine acidity

Ammonium

Significant:

elimination

of

ammonium nitrogen and protons;

cation
_
Following table shows buffering capacity of blood buffers.

2.5.1. Blood Buffers and their buffer capacity

Buffer
HCO3- / CO2
Hb / Hb-H+
Plasma proteins
Inorganic
phosphate
Organic phosphate

Plasma

Erythrocytes

Together

35%
7%
1%

18%
35%
1%

53%
35%
7%
2%

43%

3%
57%

3%
100%

Because of fact that all buffer systems are in equilibrium any kind of drift in
pH causes response in all buffer systems. Any concentration change of any component
of any buffer influences both pH, and all buffer systems.
2.5.2. Bicarbonate buffer (HCO3-/CO2)
Bicarbonate buffer is the most important buffer system in blood plasma
(generally in the extracellular fluid). This buffer consists of weak acid H2CO3 (pK1 =
6,1) and conjugated base HCO3- (bicarbonate).
Bicarbonate concentration is given in mmol/l (average value is 24 mmol/l).
Since carbonic acid is very unstable molecule measurement of its concentration is
very difficult. H2CO3 is produced from CO2 hence it is possible to express carbonic
11

acid concentration as partial pressure of CO2 (pCO2) because pCO2 is directly

proportional to CO2 concentration. pCO2 is easily measured (kPa, mmHg). Average
value in arterial blood is 5,3 kPa = 40 mmHg. pCO2 multiplied by gives us molar
concentration of dissolved CO2 ( = 0,226 for pCO2 in kPa, = 0,03 if pCO2 for
mmHg). Conversion relationship between mmHg and kPa is: 1 Pa = 0,0075 mmHg
(i.e. 760 mmHg 100 kPa). In normal plasma pH is HCO3-/CO2 ratio 20 / 1.
Henderson-Hasselbalch equation for bicarbonate buffer:
pH = pK + log [conjugated base] / [acid]
pH = pK + log ([HCO3-] / [H2CO3])
pH = 6,1 + log ([HCO3-] / pCO2 x )
pH = 6,1 + log (24 / 40 x 0,03)
pH = 6,1 + 1,3
pH = 7,4
HCO3-/CO2 is so called open buffer system. This means body is capable to
actively alter both bicarbonate, and carbon dioxide. pCO2 is regulated by respiratory
tract (by means of ventilation respiratory rate and depth of breathing). HCO3- levels
are altered by the kidneys and the liver. HCO3- could be both synthesized, and
eliminated.
Now you should recall what is stated above: pH = pK 1 is range where
buffers work optimally. This should mean that bicarbonate buffer would work best in
range 5,1-7,1, but in pH 7,4 it is very effective because it is open That is: organism is
able to actively change both components.
We use status of bicarbonate buffer for clinical evaluation of patients acidbase balance. (pH measurement, [HCO3-] a pCO2)

12

2.5.3. Protein buffers

Body proteins (plasma proteins and intracellular) are the most abundant and
the most powerful buffer system in whole organism. Some amino acids have acid or
basic side chains (His, Lys, Arg, Glu, Asp). Among blood proteins haemoglobin is the
most important. It provides 35 % of buffering capacity of blood, remaining proteins
provide only 7 %.
Role of erythrocytes and haemoglobin in the acid-base balance
Intensive change of blood gases occurs in working tissue. CO2 diffuses to
erythrocytes. In the red blood cell CO2 either (1) binds to haemoglobin (and
carbaminohemoglobin is formed), or (2) reacts with water. This reaction is catalysed
by carbonic anhydrase (CA, carbonate dehydratase):
CO2 + H2O H2CO3
Produced carbonic acid dissociates:
H2CO3 HCO3- + H+
More than 70% of produced HCO3- leave erythrocyte using special
HCO3-/Cl- antiport. That is bicarbonate is exchanged for Cl-. This process is called
Hamburgers effect (chloride shift). In carbonic acid dissociation H+ is produced.
Generated protons are buffered by haemoglobin. Deoxygenated haemoglobin is
stronger base than oxygenated thus deoxygenated is more capable of taking up
protons.
In lungs HCO3- is changed to CO2, using enzyme CA. CO2 is exhaled. Reaction
HCO3- CO2 + H2O demands H+. Protons for this process are taken from
haemoglobin which affinity to H+ has lowered just when it arrived to lungs where is
high

pO2

and

haemoglobin

become

oxygenated.

Reaction

catalysed

by

carboanhydrase has reverse course in lungs in comparison to other tissues:

13

HCO3- + H+ CO2 + H2O

2.5.4. Phosphate buffer

Phosphate buffer consists of inorganic and organic bound phosphate (i.e. esters
of organic substances, e.g. AMP, ADP, and ATP). Phosphate buffer is important
intracellular and urine buffer. In blood it accounts for only 5 % of buffering capacity.
2.5.5. Urine buffers
There are two important urine buffers: (1) ammonium buffer (NH3/NH4+) and
(2) phosphate buffer. Every day is excreted 30-50 mmol of NH4+. This is important
because excretion of NH4+ is significantly regulated when the acid-base balance is
disturbed. That is excretion of ammonium could be much decreased or much
increased. In acidosis is glutaminase activated in the kidneys. Glutaminase splits
glutamine to glutamate and NH3. NH3 is then eliminated to the urine. This process
includes also the liver, where less urea and more glutamine is produced in acidosis.
Every day is excreted 20 mmol of phosphates (i.e. titratable urine acidity).
Physiologic urine pH is 4,4-8,0.
2.6. Role of the respiratory tract in maintaining the acid-base balance
Every day is exhaled approximately 15-20 moles of CO2 by the respiratory
system. CO2 is well soluble in water therefore its concentration in both alveoli and
arterial blood is the same (i.e. pCO2 = 5,33 kPa = 40 mmHg). In venous blood is
pCO2 6,13 kPa = 46 mmHg.
pCO2 depends besides other things on the pulmonary ventilation (= respiratory
minute volume). Pulmonary ventilation is defined as respiratory rate (RR) multiplied
by tidal volume (VT). For understanding following concept you should recall that pH
of buffer depends on ratio of its components (e.g. HCO3- : pCO2) and so when ratio
changes, pH changes consequently. You can now easily deduce that:
1) increased ventilation leads to drop in pCO2 and that leads to alkalisation (increased
pH)

14

2) decreased ventilation leads to accumulation of CO2 increased pCO2 and that

leads to acidification (decreased pH)
There are many ways for controlling breathing. One of them is chemical
control. Chemoreceptors check both pCO2, and pO2. Increased pCO2 activates
breathing centre. Sensitivity of chemoreceptors is decreasing when pCO2 is 8 kPa or
higher. Only remaining stimulus for breathing centre is decreased pO2.

2.7. Role of the kidneys in maintaining the acid-base balance

Chemical buffers are capable of stopping increase in acids or bases. Buffers
however are not capable of eliminating those acids and bases from body. Respiratory
tract can eliminate (or cumulate) volatile carbonic acid by means of eliminating CO2
(or cumulate it). Only the kidneys are able to clean the body from non-volatile
(metabolic) acids (i.e. phosphoric acid, sulphuric acid, uric acid, ). Thus preventing
acidosis. In addition the kidneys are only organ that is efficiently capable of solving
alkalosis (respiratory system btw offers another option, i.e. stop breathing).
The kidneys take part in maintaining the acid-base balance by means of:
1) Reabsorbing, excreting and producing bicarbonate
2) Excreting or producing H+
You should notice that loss of bicarbonate is the same as acquire of H+ and
production of bicarbonate is the same as loss of H+. It is shown below that these
processes are connected (e.g. excretion of H+ in proximal tubule is connected with
reabsorption of HCO3- in the same place or excretion of H+ in distal tubule is
connected with production of HCO3- in the same place). Next important concept is
that higher bicarbonate concentration increases pH, lower bicarbonate concentration
decreases pH.
In this section are in detail described basic processes as reabsorption of bicarbonate,
new bicarbonate production, ammonium ion production, proton excretion in kidneys,
15

bicarbonate secretion.
2.7.1. Bicarbonate reabsorption
Bicarbonate reabsorption takes place in proximal tubule cells. In glomerular
ultrafiltrate there is filtered bicarbonate. To the lumen of the proximal tubule is
transported H+. H+ is transported by Na+/H+ antiport H+ reacts with HCO3- and
H2CO3 is thus produced. H2CO3 split up into H2O and CO2. Water and carbon
dioxide get through apical membrane of tubular cells. Inside these cells H2CO3 is
again produced. H2CO3 dissociates into HCO3- and H+. Now their fates get
different: (1) H+ becomes again substrate for Na+/H+ antiport and it is transported
again to the lumen of the proximal tubule where it can catch another bicarbonate
molecule. (2) Bicarbonate however traverse basolateral membrane into interstitial
fluid (and then to the blood of the peritubular capillaries). Bicarbonate gets through
basolateral membrane using either Na+/3 HCO3- cotransport, or anion exchanger
(Cl-/HCO3- exchange).
Together it can be stated: for one secreted H+, one Na+ and one HCO3- are
resorbed. Na+ is transported to the blood among other things by active transport i.e.
Na+/K+ ATPase.

16

2.7.2. New bicarbonate production (connected with H+ excretion)

New bicarbonate production takes place in intercalated cells type A of distal
tubule and collecting duct. These cells absorb CO2 from the blood and inside the cells
carbon dioxide reacts with water and carbonic acid is thus produced, catalysed by the
enzyme carboanhydrase. Carbonic acid dissociates to H+ and HCO3-. H+ has totally
different fate than bicarbonate: (1) H+ is excreted by the H-ATPase to the urine. This
process is active, hence it consumes ATP. In order to eliminate as much H+ as
possible it is necessary to buffer H+ in the urine. The most important buffers in the
urine are ammonium and phosphate buffer. (2) Produced bicarbonate is transported to
the blood in peritubular capillaries exchanged for Cl- (Cl-/HCO3- exchanger in
basolateral membrane). Aldosterone stimulates H+ secretion (and therefore H+
excretion).

2.7.3. Ammonium ion excretion

This process uses ammonium generated in glutamine metabolism in tubular
cells. For every metabolised glutamine two ammonium ions and two bicarbonates are
produced. Bicarbonates are transported to the blood, whilst ammonium ions are
excreted to the blood.

17

2.7.4. Proton excretion in the kidneys

Both bicarbonate resorption, and new bicarbonate production (both mentioned
above) need transport of H+ (protons) to the tubules (protons are derived from
carbonic acid dissociation). Precise mechanism is however quite different. In the cells
of the proximal tubule the transport of proton to the lumen is based on its exchange
for Na+. On the basolateral membrane act Na+/K+-ATPase and HCO3-/Clexchanger.
In the intercalated cells type A (in the distal tubule and the collecting duct) the
transport of proton to the lumen is based on active transport (H+-ATPase).
Aldosterone promotes (1) excretion of H+ and K+ in the distal tubule and the
collecting duct and (2) reabsorption of the sodium (and water). The result of both
described processes is generation of high concentration gradient for H+, i.e. in the
urine there is thousand times higher concentration of protons than in the cells/blood.
This thousand fold gradient is however maximal, thus the lowest achievable pH of the
urine is 4,4 (40 mol/l H+) compare this value with value of the pH in blood: 7,4
(40 nmol/l H+).

18

2.7.5. Bicarbonate secretion

In conditions of rising pH (alkalosis) type B of the intercalated cells start to
act. They secrete bicarbonate and gain H+. These mechanisms are absolutely inverse
than processes described in the type A of the intercalated cells (see above). Even in
alkalosis nephrons however excrete less bicarbonate than they retain. We can
summarize that extracellular pH is kept by the buffer systems and involved organs.
These systems maintain pH value 7,36-7,44. The respiratory system modulates pCO2
and the kidneys modulate concentration of bicarbonate.

2.8. Laboratory assessment of the acid-base balance status

Laboratory assessment of the acid-base balance status consists of: (1) acidbase balance parameters (pH, [HCO3-], pCO2, pO2 a BE) and (2) examination of
other substances that can alter acid-base balance. These substances are for example:
1) Cations: [Na+], [K+], [Ca2+], [Mg2+]
2) Anions: [Cl-], [lactate], albumin
3) Metabolites: [urea], [creatinine], [ketone bodies]
Acid-base balance status is assessed according to the status of the bicarbonate
buffer. It is so called examination of the ABR parameters by Astrup (ASTRUP).
This examination is used for assessment of the actual status of the acid-base
balance in particular patient. The specimens are measured in analysers and these
particular specimens are called Astrup after one of the first acid-base balance theory
authors. Some parameters are not measured directly but calculated by software using
Henderson-Hasselbalch equation. The specimens are obtained from arterial blood (a.
radialis or a. femoralis), sometimes it is necessary to collect capillary blood too. We
can analyse only non-clotting blood (for this purpose heparin is added). Arterial blood
must not contain air bubbles (because presence of air could alter pO2 (increase),
pCO2 (decrease) and pH (increase)) and analysis should take place as soon as
possible.
19

Normal arterial Astrup results:

Directly measured values:
1) pH = 7,36 7,44
2) pCO2 = 4,8 5,9 kPa (35-45 mmHg), average is 5,3 kPa (40 mmHg)
pCO2 < 4,8 kPa is denoted as hypocapnia
pCO2 > 5,9 kPa is denoted as hypercapnia
3) pO2 = 9,9 13,3 kPa (80-100 mmHg)
Calculated values:
4) [HCO3-] = 22-26 mmol/l
5) BE = 0 2,5 mmol/l

2.8.1. BE (base excess)

Base excess is defined as number of moles of strong acid that is needed to add
to one litre of fully oxygenated blood to achieve pH 7,4 when pCO2 is 5,3 kPa and
temperature is 37C. BE is optimal quantity for assessing metabolic component of
acid-base balance. Normal values are 0 2,5 mmol/l. Negative value indicates excess
of acids (so the value is negative). Excess of acids is metabolic acidosis. Positive
value indicates excess of bases (base excess), hence metabolic alkalosis. There is
however one very similar quantity base deficit (BD). It indicates deficit of bases in
mmol/l.

2.8.2. Ions and pH

20

Ion composition of extracellular fluid is closely related to the acid-base

parameters. Kalemia is influenced most by acid-base balance disturbances.
Acidosis leads to efflux of K+ from the cells. That leads to the hyperkalemia.
K+ is lost in the urine. When acidosis is treated quickly alkalization of the body leads
to the influx of K+ back to the cells. That leads to hypokalemia. Hypokalemia is
mostly dangerous for the heart membrane signal transmission.
Alkalosis leads to efflux of H+ from the cells. To maintain electrical charges
the same, K+ enter the cells in order to replace H+. Thus alkalosis leads to the
hypokalemia. K+ is excreted in the urine instead of H+.

2.8.3. Anion Gap (AG)

Anion gap is a quantity which is almost equal to the sum of concentrations of
unmeasurable anions (albumin plasma proteins, phosphates, sulphates, organic
anions). Unmeasurable is not accurate term, more precise is commonly non-measured.
AG is calculated as follows:
AG = ([Na+] + [K+]) ([Cl-] + [HCO3-])
Na+ (140) + K+ (5) = Cl- (105) + HCO3- (25) + AG (15)
Normal AG: 14 2 mmol/l
Anion gap is used for assessing causes of the metabolic acidosis. One of the
causes is the accumulation of the acids. Concentrations of some of them are not
commonly measured. When there is accumulation of commonly non-measured acids
unexpected rise in difference of measured cations and anions. This increase in
difference could be revealed by AG. Therefore when there is increased AG it indicates
that commonly non-measured acids accumulated. They become part of AG. Thus
greater AG indicates acidosis.

21

Increased AG is caused by:

1) Increase in concentration of ions that physiologically make the AG
2) Presence of new anions
This method is unfortunately dependent on accuracy of the measurements.
Little mistake in big numbers lead to greater mistake in the result. There are particular
situations when we need to measure commonly non-measured acids (anions)
concentrations. Then we measure:

1) Lactate in tissue hypoxia

2) 3-hydroxybutyrate in diabetic ketoacidosis
3) Phosphates and sulphates in renal failure

2.9. Basic disturbances in the acid-base balance and compensation

Acidosis is process that leads to the drop in pH value. Alkalosis is au contraire
process that leads to the increase in pH value. Acid-base balance parameters are
calculated for plasma which pH is alkalic, i.e. pH = 7,4 (H+ concentration is 40
nmol/l). Thus you should notice that even alkalic pH (e.g. 7,2) is acidosis!
Respiratory disturbances are indicated by shifts in pCO2 (respiratory disorder
hyper- or hypocapnia). Metabolic disturbances are indicated by shifts in BE (or
[HCO3-])
Four basic acid-base balance disturbances are distinguished:
1) Respiratory acidosis (RAC): decreased blood pH; its primary cause is increased
22

pCO2
2) Respiratory alkalosis (RAL): increased blood pH; its primary cause is decreased
pCO2
3) Metabolic acidosis (MAC): decreased blood pH; its primary cause is decreased
BE ([HCO3-])
4) Metabolic alkalosis (MAL): increased blood pH; its primary cause is increased
BE ([HCO3-])

2.10. Compensation and correction of acid-base disturbances

Compensation is process when organism tries to maintain almost normal pH.
Compensation is performed by system that works normally, i.e. the acid-base
disturbance is caused by the other system. Compensation thus means metabolic
disturbances are compensated by respiratory system and respiratory disturbances are
compensated by metabolic components of acid-base balance.
Correction is solving the acid-base problem in the spot where it started. I.e.
metabolic disturbances are solved by metabolic component of acid-base balance. In
the body correction takes place only in metabolic disorders, i.e. metabolic disorder is
corrected by another component of the metabolic component of acid-base balance.
Doctors however are capable of correction of both respiratory, and metabolic
disturbances. Respiratory disturbances can be solved by artificial ventilation,
metabolic disturbances by for example dialysis.

2.11. Respiratory acid-base balance disturbance

All the people (healthy or not) produce every day large quantities of acids. The

23

most important acid is CO2. Carbon dioxide is normally eliminated from the body by
the respiratory system. When respiratory system is not capable of normal CO2
elimination (carbon dioxide could be eliminated too much or too few) respiratory
acid-base balance disturbances come into existence.
Normal pCO2 is 4,8-5,9 kPa (35-45 mmHg). pCO2 lower than 4,8 indicates
respiratory alkalosis, pCO2 higher than 5,9 indicates respiratory acidosis. Respiratory
disturbances are compensated by the kidneys. The kidneys retain or excrete HCO3- in
order to (1) keep ratio HCO3- : pCO2 and (2) draw pH nearer to the normal values.
Renal compensation needs hours to days for full development.

2.12. Respiratory acidosis (RAC)

Respiratory acidosis emerges when the lungs eliminate too few CO2 (it
usually occurs in hypoventilation). Low CO2 elimination leads to increased pCO2 in
the blood (hypercapnia). Increased pCO2 causes decreased pH.
Causes of RAC are for example:
1) Loss of functional lung parenchyma (pneumonia, cystic fibrosis, emphysema)
2) Airway obstruction (loss of tonus of tongue muscles)
3) Insufficient ventilation (e.g. neuromuscular disorders, CNS disorders, intoxications
(opiates), asthmatic paroxysm)
4) Thorax movement restriction (e.g. spine deformities)
Organism compensates RAC by increased HCO3- concentration in the blood
by means of increased resorption and increased production in tubular cells of the

24

kidneys (acidic urine is produced). Thus pH of the blood is drawn nearer to the
normal values. Causes of RAC mentioned above can sometimes cause decreased pO2
too. Tissue hypoxia leads to the metabolic acidosis caused by accumulation of lactate,
thus it is called lactate acidosis (see below).

2.13. Respiratory alkalosis (RAL)

Respiratory alkalosis is caused by hyperventilation. Hyperventilation causes
increased elimination of carbon dioxide and that leads to hypocapnia (decreased
pCO2). There is one important aspect concerning calcium. One of the important
buffers in blood is albumin. You should recall that albumin binds approximately 50 %
of plasma calcium. When pH changes, albumin binds or releases H+ and therefore
calcemia is changed. This is very important in RAL. In this condition ratio between
ionised and bound calcium is changed. In RAL is decreased ionised calcium hence
hypocalcemia develops. Hypocalcemia could cause muscle spasms.
Causes of RAL are for example:
1) Hyperventilation due to psychic reasons (exhalation of the carbon dioxide =
exhalation of the emotions) or hyperventilation due to the high altitude (i.e. breathing
in lack of oxygen). In both principles pCO2 is lowered and you know that low pCO2
is alkalosis. Interestingly HCO3- is slightly lowered as well. This is because pCO2 is
lowered and thus to keep equilibrium part of bicarbonate is converted to CO2.
(HCO3- + H+ CO2 + H2O). Ions H+ needed for this reaction are provided from
non-bicarbonate buffers.
2) CNS trauma
3) Salicylates poisoning (Aspirin) fever, etc
Compensation is decreased HCO3-. This is provided by larger excretion of HCO3- by
the kidneys.

25

2.14. Metabolic acidosis (MAC)

Metabolic acidosis is the most common acid-base balance disorder. It is
indicated by decreased pH (increased H+) and negative BE ([HCO3-]). BE is the best
marker for assessing metabolic component of the acid-base balance. It can be stated
that metabolic acidosis is pH that is too acidic compared with given pCO2 (i.e.
metabolic component must be always assessed with knowledge of pCO2 in particular
patient).
General causes of MAC:
1) Accumulation of metabolic acid. Anion of this acid eliminates bicarbonate.
2) Loss of bicarbonates (this loss of anion is accompanied by loss of cation, it is not
surprising that most abundant cation (Na+) is lost mostly)
3) Loss of cations, predominantly Na+. This is compensated by decrease of
bicarbonate
Every acid in the body apart from carbonic acid is so called metabolic acid. Metabolic
acids are non-volatile, therefore they have to be neutralized and either metabolised, or
eliminated by kidneys.
Bicarbonate are lost most commonly from the GIT. Duodenal and pancreatic juice
have abundant bicarbonates. Normally high concentrations of bicarbonate in these
juices neutralize low pH of chyme from stomach. Normally bicarbonates are resorbed
in small intestine. There are however some diseases of the GIT (diarrhoea, short
intestine

syndrome,

etc)

when

bicarbonates

are

resorbed

insufficiently.

Bicarbonates can be lost in the kidneys too (renal tubular acidosis, adverse effect of
diuretics carbonic anhydrase inhibitors (acetazolamide)). AG calculation is useful in
differential diagnosis of MAC. Excessive production of acids leads to high AG.
Elevated loss of bicarbonates has normal AG.

26

Now we mention some particular states that lead to MAC:

1) Hypoxia lack of oxygen in tissues. This condition makes tissues to process
glucose in anaerobic glycolysis. By-product of anaerobic glycolysis is lactate. Thus
hypoxia leads to the lactate acidosis. Lactate acidosis is typical companion of RAC,
shock or overdose of biguanides (metformin).
2) Excessive production of ketone bodies (acetoacetic acid and -hydroxybutyric
acid). This condition is caused by situations when glucose cannot be used as source of
energy. This leads to excessive use of fatty acids as the main energy source. Thus
excessive production of ketone bodies accompanies diabetes mellitus or starving. This
condition is called ketoacidosis.
3) Alcohol intoxication (e.g. methanol, ethylene glycol). These alcohols are
metabolised to strong organic acids (formic acid, oxalic acid). These acids release lots
of H+. Oxalates can lead to renal failure. Overdose of salicylates (Aspirin) can cause
MAC as well.
4) Renal insufficiency leads to condition when normally excreted acids are cumulated
(sulphates, phosphates, some other anions). This is called renal acidosis.
5) Heavy diarrhoea
6) Loss of bicarbonates in the kidneys
In all these conditions at first buffering of excessive H+ takes place (it is
carried out by bicarbonate and non-bicarbonate bases). Bicarbonate forms with H+
carbonic acid that forms CO2 and water, carbon dioxide is eliminated by the lungs.
Second step is compensation using hyperventilation. You should recall that
hyperventilation leads to decreased pCO2 and decreased pCO2 means higher pH. This
is often called Kussmaul acidotic breathing (breathing centre is stimulated by high H+
concentration). Third step is correction by kidneys. Correction is launched in case that
acidosis despite the compensation is still present. Kidneys perform (1) increased
excretion of H+ and (2) new bicarbonate production (intercalated cells type A). This
27

results in acidic urine.

2.15. Metabolic alkalosis (MAL)

Metabolic alkalosis is characterized by increased pH and risen BE. General
causes are:
1) Loss of some anions (usually chlorides or proteins). This loss of anions is
compensated by replenishing of other anions, predominantly bicarbonates (and
increased bicarbonates mean alkalosis)
2) Increased cation concentration (most commonly Na+)
3) Increased alkali intake (e.g. alkalising medication bicarbonate infusion)
Now we mention some particular states that lead to MAL:
1) Vomiting loss of HCl (thus loss of H+). So called hypochloremic alkalosis
develops (it is caused by diuretics as well (e.g. furosemide causes loss of K+ and Cl-)
2) Hypoproteinemia proteins are anions thus decreased protein concentration is
compensated by increased bicarbonate concentration (i.e. bicarbonates replenish
missing anions). Hypoproteinemia is caused by liver failure, nephrotic syndrome or
malnutrition.
3) Hyperaldosteronism. High aldosterone causes increased retention of Na+. This
increased cation concentration must be accompanied by replenishing of anions
because electroneutrality must be maintained (i.e. bicarbonate concentration is
increased).
4) Iatrogenic bases delivery (e.g. HCO3- infusions)

28

At first buffering takes place. Compensation is second and body uses hypoventilation,
thus less CO2 is exhaled and pCO2 rises, that leads to lowering pH. In case that
alkalosis is not caused by kidneys, renal correction can take place. It is performed by
higher excretion of bicarbonate (intercalated cells type B). One of serious
consequences of alkalosis is hypokalemia that can lead to heart rhythm disturbances.

2.16. Mixed disturbances of acid-base balance

Mixed disturbances of acid-base balance are quite common. It is defined as
either (1) combination of two or more basic disturbances of acid-base balance, or (2)
combination of more causes that cause the same acid-base balance disturbance, (3) or
both.
As an example we can use hypoventilation that leads not only to the respiratory
acidosis because less CO2 is exhaled but also to the metabolic acidosis because less
O2 is delivered to the tissues.

2.17. Adverse consequences of severe acidemia

The effects on the cardiovascular system are particularly pernicious and can
include decreased cardiac output, decreased arterial blood pressure, decreased hepatic
and renal blood flow, and centralization of blood volume. Reentrant arrhythmias and a
reduction in the threshold for ventricular fibrillation can occur, while the defibrillation
threshold remains unaltered. Acidemia triggers a sympathetic discharge but also
progressively attenuates the effects of catecholamines on the heart and the
vasculature; thus, at pH values below 7.20, the direct effects of acidemia become
dominant.
Although metabolic demands may be augmented by the associated
sympathetic surge, acidemia decreases the uptake of glucose in the tissues by inducing
insulin

resistance

and

inhibits

anaerobic

glycolysis

by

depressing

629

phosphofructokinase activity. This effect can have grave consequences during

hypoxia, since glycolysis becomes the main source of energy for the organism. The
uptake of lactate by the liver is curtailed, and the liver can be converted from the
premier consumer of lactate to a net producer. Acidemia causes potassium to leave the
cells, resulting in hyperkalemia, an effect that is more prominent in nonorganic
acidoses than in organic and respiratory acidoses. Increased net protein breakdown
and development of a catabolic state also occur in patients with acidosis. Brain
metabolism and the regulation of its volume are impaired by severe acidemia,
resulting in progressive obtundation and coma.

2.18. Management of life-threatening acidosis

2.18.1. Metabolic acidosis
In the presence of an appropriate ventilatory response, severe metabolic
acidemia implies a plasma bicarbonate concentration of 8 mmol per liter or lower.
What options are available for replenishing the depleted bicarbonate stores? In certain
organic acidoses (e.g., ketoacidosis and lactic acidosis), effective treatment of the
underlying disease can foster conversion of the accumulated organic anions to
bicarbonate within hours. By contrast, in hyperchloremic acidosis (e.g., that produced
by diarrhea), such an endogenous regeneration of bicarbonate cannot occur. Although
the kidneys can, of course, contribute to bicarbonate neogenesis in both types of
acidoses, several days are required to obtain a meaningful effect. Therefore, even if
the cause of the acidosis can be reversed, exogenous alkali is often required for the
prompt attenuation of severe acidemia.

30

2.18.1.1. Alkali therapy

The goal of alkali therapy is to prevent or reverse the detrimental
consequences of severe acidemia, especially those affecting the cardiovascular
system. In moderating acidemia, the physician buys time, thus allowing general and
cause-specific measures as well as endogenous reparatory processes to take effect.
Alkali therapy also provides a measure of safety against additional acidifying stresses
caused by a further decrease in plasma bicarbonate or an increase in the partial
pressure of arterial carbon dioxide.
Currently, intravenous sodium bicarbonate is the mainstay of alkali therapy.
Other alkalinizing salts, such as sodium lactate, citrate, or acetate, are not reliable
substitutes, since their alkalinizing effect depends on oxidation to bicarbonate, a
process that can be seriously impaired in several clinical conditions (e.g., liver disease
and circulatory failure).
How much bicarbonate need be dispensed? Because the administration of
sodium bicarbonate entails certain risks, it should be given judiciously in amounts that
will return blood pH to a safer level of about 7.20. To accomplish this goal, plasma
bicarbonate must be increased to 8 to 10 mmol per liter. There is no simple
prescription for reaching this target, since several ongoing, and at times competing,
processes can affect the acidbase status (e.g., increased net lactic acid production,
vomiting, or renal failure), and the apparent space of distribution of infused
bicarbonate is variable. (The apparent space of distribution is calculated by dividing
the administered alkali load, in millimoles per kilogram of body weight, by the
observed change in the plasma bicarbonate concentration, in millimoles per liter, and
multiplying the ratio by 100.) Whereas patients with very low plasma bicarbonate
concentrations can have a bicarbonate space of 100 percent of body weight or greater,
others with less severe metabolic acidosis have a space closer to 50 percent of body
weight, the normal value.
Being mindful of overtreatment, we recommend that, as the starting point,
bicarbonate space be taken to be 50 percent of body weight. Thus, to raise the plasma
bicarbonate concentration from 4 to 8 mmol per liter in a 70-kg patient, one should
administer 4 70 0.5, or 140, mmol of sodium bicarbonate. Except in cases of
extreme acidemia, sodium bicarbonate should be dispensed as an infusion (over a
period of several minutes to a few hours) rather than a bolus. Follow-up monitoring of
31

the patient's acidbase status will determine additional alkali requirements. About 30
minutes must elapse after the infusion of bicarbonate is completed before its clinical
effect can be judged.

2.18.1.2. Risk of sodium bicarbonate therapy

The administration of sizable amounts of sodium bicarbonate is associated
with certain risks. Infusion of the usual undiluted 1N preparation (containing 1000
mmol of sodium bicarbonate per liter) can give rise to hypernatremia and
hyperosmolality. This complication can be avoided by adding two 50-ml ampules of
sodium bicarbonate (each containing 50 mmol of sodium bicarbonate) to 1 liter of
0.25 N sodium chloride or three ampules to 1 liter of 5 percent dextrose in water,
thereby rendering these solutions nearly isotonic. Alkali therapy can lead to
extracellular-fluid volume overload, especially in patients with congestive heart
failure or renal failure. Administration of loop diuretics may prevent or treat this
complication. If adequate diuresis cannot be established, hemofiltration or dialysis
may be required. Overshoot alkalosis, in which an abrupt and poorly tolerated
transition from severe acidemia to alkalemia develops, can result from overly
aggressive alkali loading (especially when compounded by endogenous regeneration
of bicarbonate from accumulated organic anions) and persistent hyperventilation.
Alkali stimulates 6-phosphofructokinase activity and organic acid production,
effects that must be considered in the management of lactic acidosis and ketoacidosis.
Such effects are usually viewed as nonsalutary, since they limit the alkalinizing action
of bicarbonate. However, alkali-induced stimulation of 6-phosphofructokinase activity
may allow the partial regeneration of depleted ATP stores in vital organs (e.g., in cases
of tissue hypoperfusion and hypoxemia), thereby fostering survival.
Buffering of protons by bicarbonate releases carbon dioxide (HCO3- + H+
H2CO3 H2O + CO2) and can raise the prevailing partial pressure of carbon
dioxide in body fluids. This effect can be consequential in patients with limited
ventilatory reserve, those in advanced circulatory failure, or those undergoing
cardiopulmonary resuscitation. Under these circumstances, paradoxical worsening of
intracellular (and even extracellular) acidosis can occur if the fractional increase in
32

partial pressure of carbon dioxide exceeds the fractional increase in the bicarbonate
concentration. This counterproductive effect may be evident only in mixed venous
blood, which better reflects the acidbase status of the tissues.

2.18.1.3. Alternative alkalinizing agents

Concern about the carbon dioxideproducing effect of bicarbonate led to the
development of Carbicarb, which consists of equimolar concentrations of sodium
bicarbonate and sodium carbonate. Because carbonate is a stronger base, it is used in
preference to bicarbonate for buffering hydrogen ions, generating bicarbonate rather
than carbon dioxide in the process (CO3 2- + H+ HCO3-). In addition, the
carbonate ion can react with carbonic acid, thereby consuming carbon dioxide (CO3
2- + H2CO3 2HCO3-). Thus, Carbicarb limits but does not eliminate the
generation of carbon dioxide. In experimental lactic acidosis, Carbicarb increased
blood and intracellular pH with little or no rise in the arterial or venous partial
pressure of carbon dioxide. However, the risks of hypervolemia and hypertonicity are
similar with the two alkalinizing agents, and neither agent prevented the progressive
reduction in myocardial-cell pH in animals with ventricular fibrillation. Clinical
experience with Carbicarb is limited, and this product is not yet commercially
available for clinical use.
Another carbon dioxideconsuming alkalinizing agent is THAM, a
commercially available solution of 0.3 N tromethamine. This sodium-free solution
buffers both metabolic acids (THAM + H+ THAM+) and respiratory acids
(THAM + H2CO3 THAM+ + HCO3-). Like Carbicarb, THAM limits carbon
dioxide generation and increases both extracellular and intracellular pH. Nevertheless,
THAM has not been documented to be clinically more efficacious than bicarbonate.
In fact, serious side effects, including hyperkalemia, hypoglycemia, ventilatory
depression, local injury in cases of extravasation, and hepatic necrosis in neonates,
markedly limit its usefulness.

33

2.18.1.4. Specific disorders

Lactic Acidosis
Conventionally, two broad types of lactic acidosis are recognized: type A, in
which there is evidence of impaired tissue oxygenation, and type B, in which no such
evidence is apparent. However, inadequate tissue oxygenation may at times defy
clinical detection, and tissue hypoxia can be a part of the pathogenesis of certain
conditions that cause type B lactic acidosis. Thus, the distinction between the two
types is occasionally blurred. Most cases of lactic acidosis are caused by tissue
hypoxia arising from circulatory failure. Both overproduction and underuse of lactic
acid contribute to its accumulation. In turn, the resultant acidemia, when severe,
compounds the hemodynamic disarray and further suppresses lactate consumption by
the liver and the kidneys, thereby establishing an ominous vicious circle.
Experimental data have implicated the lactate ion itself, in addition to the acidemia
associated with lactic acid, as a contributor to circulatory malfunction. Therapy should
focus primarily on securing adequate tissue oxygenation and on identifying and
treating the underlying cause. Improvement of tissue oxygenation may require a
number of measures, including maintenance of a high inspired oxygen fraction,
ventilator support, repletion of the volume of extracellular fluid, afterload-reducing
agents, and inotropic compounds such as dopamine and dobutamine. Drugs causing
vasoconstriction (such as norepinephrine) should be avoided, since they can worsen
tissue hypoxia.
Cause-specific measures should be instituted promptly, including antibiotics
for sepsis; operative intervention for trauma or tissue ischemia; dialytic removal of
certain toxins, such as methanol and ethylene glycol; discontinuation of metformin
and nitroprusside; administration of insulin in patients with diabetes mellitus; glucose
infusion in those with alcoholism and certain forms of congenital lactic acidosis;
correction of thiamine deficiency in cases of ethanol intoxication, short-bowel
syndrome, fulminant beriberi, and pyruvate dehydrogenase deficiency; a lowcarbohydrate diet and antibiotics in cases of d-lactic acidosis (for example, with shortbowel syndrome); and treatment of an underlying cancer or pheochromocytoma.
In the presence of severe metabolic acidemia, these measures should be
supplemented by the cautious administration of sodium bicarbonate, initially at a dose

34

of no more than 1 to 2 mmol per kilogram of body weight, given as an infusion rather
than as a bolus. Infusion of additional sodium bicarbonate should be guided by careful
monitoring of the patient's acidbase status. Amelioration of extreme acidemia with
alkali should be regarded as a temporizing measure adjunctive to cause-specific
measures. Particular restraint should be exercised in using alkali during
cardiopulmonary resuscitation; the markedly reduced pulmonary blood flow can lead
to retention of some of the carbon dioxide generated in the process of buffering,
potentially exacerbating the prevailing acidosis.
There is considerable excitement about the therapeutic potential of
dichloroacetate in lactic acidosis. This investigational agent stimulates pyruvate
kinase, thereby accelerating the oxidation of pyruvate to acetylcoenzyme A.
Although the effects of dichloroacetate in experimental lactic acidosis were
impressive, and the initial clinical observations were promising, a controlled clinical
study failed to demonstrate a substantial advantage of dichloroacetate over
conventional management of lactic acidosis.
The prognosis of patients with lactic acidosis remains ominous, because the
underlying disease frequently cannot be managed effectively. Its development should
therefore be prevented by maintaining adequate fluid balance, optimizing
cardiorespiratory function, managing infection, and being cautious when prescribing
drugs that promote lactic acidosis. Particular attention should be paid to patients at
special risk for lactic acidosis, such as those with diabetes mellitus or advanced
cardiac, respiratory, renal, or hepatic disease.
Diabetic Ketoacidosis
Insulin administration is the cornerstone of the treatment of diabetic
ketoacidosis. Water, sodium, and potassium deficits should also be replaced. Alkali
should not be administered routinely, since the metabolism of the retained ketoacid
anions in response to insulin therapy results in swift regeneration of bicarbonate with
partial or complete resolution of the acidemia. Indeed, the administration of alkali
may even delay recovery by augmenting hepatic ketogenesis. Nonetheless, small
amounts of bicarbonate may benefit patients with marked acidemia (blood pH, <7.10),
in whom decreased myocardial performance can worsen tissue perfusion. Patients
with a substantial component of hyperchloremic acidosis (i.e., those with a relatively

35

normal anion gap) due to urinary loss of ketoacid anions with sodium or potassium
can benefit from alkali therapy, even when acidemia is moderately severe. In these
patients, endogenous correction of the hypobicarbonatemia depends largely on
increased renal acid excretion, a process requiring several days for completion.
Alcoholic Ketoacidosis
Alcoholic ketoacidosis can induce severe hypobicarbonatemia that largely
corrects itself spontaneously with the provision of nutrients and interruption of
ethanol intake. The infusion of dextrose stimulates insulin secretion but inhibits
glucagon secretion, thereby promoting the regeneration of bicarbonate stores from the
metabolism of retained ketoacid anions. The administration of saline will repair the
existing extracellular-fluid volume deficit and thus suppress counterregulatory
hormones that enhance ketoacidosis; the often coexisting element of lactic acidosis
will also be reversed.
Methanol and Ethylene Glycol Intoxications
Methanol and ethylene glycol intoxications can produce severe, high-aniongap metabolic acidoses caused by the accumulation of toxic metabolites. Large
amounts of alkali are often required to combat the severe acidemia. Additional
therapeutic measures include gastric lavage, oral charcoal, intravenous or oral ethanol
(which inhibits the generation of toxic metabolites from ingested alcohols because of
its higher affinity for alcohol dehydrogenase), and in severe cases, single-pass
hemodialysis. Forced diuresis can prevent acute renal failure in patients with ethylene
glycol intoxication. Although it is not available in the United States, 4-methylpyrazole
is a potent inhibitor of alcohol dehydrogenase that effectively reduces the generation
of toxic metabolites.
Aspirin Intoxication
Aspirin intoxication can result in respiratory alkalosis, mixed respiratory
alkalosis and metabolic acidosis, or (less commonly) simple metabolic acidosis.
Respiratory alkalosis is caused by direct stimulation of the respiratory center by
salicylate, whereas the accumulation of lactic acid and ketoacids largely accounts for
metabolic acidosis. Because the risk of death and the severity of neurologic

36

manifestations depend on the concentration of salicylate in the central nervous

system, therapy is directed at limiting further drug absorption by administering
activated charcoal and promoting the exit of the toxin from the cerebral tissues by
increasing the alkalinity of the blood. Thus, unless the blood is already alkalinized by
respiratory alkalosis, sodium bicarbonate must be administered to raise the blood pH
to about 7.45 to 7.50. In turn, the resultant alkalinization of the urine promotes the
excretion of salicylate by minimizing the back-diffusion of salicylic acid from the
lumen of the kidney tubules. Establishing a high urinary flow rate by means of the
infusion of fluid also enhances salicylate excretion. Hemodialysis is reserved for
severe cases, especially those involving renal dysfunction.
Toluene Exposure
Exposure to toluene by sniffing glue can cause severe metabolic acidosis
resulting from the stepwise metabolism of toluene to benzoic acid and hippuric acid.
If renal function is reasonably well maintained, swift excretion of the hippurate anion
with sodium and potassium can convert a high-anion-gap acidosis to hyperchloremic
acidosis simulating distal renal tubular acidosis.
Bicarbonate Loss
Loss of bicarbonate from the digestive tract can lead to marked metabolic
acidosis that requires exogenous replenishment of body alkali stores, in addition to
replenishment of water, sodium, and potassium. Patients with severe diarrhea (for
example, from acute salmonella enteritis or cholera) and those with pancreatic
allografts, in whom the exocrine pancreas drains into the urinary bladder, have this
type of acidosis. Although hyperchloremic metabolic acidosis is usually seen, a high
anion gap can develop when fluid losses are profuse; hyperproteinemia,
hyperphosphatemia, renal failure, and lactic acidosis all contribute to raising the
plasma anion gap.
Renal Failure
Renal failure, especially acute renal failure in a patient in a catabolic state, can cause
severe metabolic acidosis reflecting retention of the endogenous acid load. Patients
with classic (type 1) renal tubular acidosis can present with profound
hypobicarbonatemia and hypokalemia that require prompt administration of

37

potassium and alkali. The resulting acidemia can be compounded by an inadequate

ventilatory response caused by paresis of the respiratory muscles induced by
potassium depletion.
Dilutional Acidosis
Sizable expansion of the extracellular-fluid volume with solutions that do not
contain bicarbonate can give rise to dilutional acidosis. Severe examples of this entity
have recently been identified as a complication of aggressive volume resuscitation in
patients with right ventricular myocardial infarction. Provision of the requisite
amounts of sodium bicarbonate in the infusate should prevent this complication.

2.18.2. Respiratory acidosis

Respiratory acidosis is observed whenever carbon dioxide excretion by the
lungs lags behind carbon dioxide production, resulting in positive carbon dioxide
balance. The rise in the partial pressure of arterial carbon dioxide elicits an acute
increase in plasma bicarbonate that originates from buffering mechanisms, but the
overall magnitude of this adaptation is quite small.
When hypercapnia is sustained, the plasma bicarbonate concentration is
amplified markedly as a result of up-regulation of renal acidification. Three to five
days are required for this adaptation, with increased acid excretion and chloruresis
generating the hypochloremic hyperbicarbonatemia characteristic of chronic
hypercapnia. Consequently, life-threatening acidemia of respiratory origin occurs
during severe, acute respiratory acidosis or during respiratory decompensation in
patients with chronic hypercapnia.
Acute respiratory acidosis develops as a consequence of upper- or lowerairway obstruction, status asthmaticus, severe alveolar defects such as those occurring
in

pneumonia

or

pulmonary

edema,

central

nervous

system

depression,

neuromuscular impairment, and ventilatory restriction (as in patients with rib fractures
with flail chest). The alveolar-gas equation predicts that the rise in the partial pressure
of arterial carbon dioxide will cause obligatory hypoxemia in patients breathing room
air. The resultant fall in the partial pressure of arterial oxygen limits hypercapnia to
38

approximately 80 to 90 mm Hg; a higher partial pressure of arterial carbon dioxide

imposes a partial pressure of arterial oxygen that is incompatible with life. Under
these circumstances, it is hypoxemia, not hypercapnia or acidemia, that poses the
principal threat to life. Consequently, oxygen administration represents a critical
element in the management of respiratory acidosis. Whenever possible, treatment
must be directed at removing or ameliorating the underlying cause. Immediate
therapeutic efforts should focus on securing a patent airway and restoring adequate
oxygenation by delivering an oxygen-rich inspired mixture. Mechanical ventilation
must be initiated in the presence of apnea, severe hypoxemia unresponsive to
conservative measures, or progressive respiratory acidosis (partial pressure of arterial
carbon dioxide, >80 mm Hg).
Chronic hypercapnia results from many conditions, including chronic
obstructive or restrictive pulmonary diseases, upper-airway obstruction, central
nervous system depression, neuromuscular impairment, and abnormal chest-wall
mechanics. Respiratory decompensation in patients with these conditions, commonly
resulting from infection, use of narcotics, or uncontrolled oxygen therapy,
superimposes an acute element of carbon dioxide retention and acidemia on the
chronic base-line disorder. Progressive narcosis and coma, known as hypercapnic
encephalopathy, can ensue. Management of respiratory decompensation depends on
the cause, severity, and rate of progression of carbon dioxide retention. Vigorous
treatment of pulmonary infections, bronchodilator therapy, and removal of secretions
can offer considerable benefit. Naloxone will reverse the suppressive effect of
narcotic agents on ventilation. Avoidance of tranquilizers and sedatives, gradual
reduction of supplemental oxygen (aiming at a partial pressure of arterial oxygen of
about 60 mm Hg), and treatment of a superimposed element of metabolic alkalosis
will optimize the ventilatory drive.
Whereas an aggressive approach that favors the early use of ventilator
assistance is most appropriate for patients with acute respiratory acidosis, a more
conservative approach is advisable in those with chronic diseases that limit pulmonary
reserve, because of the great difficulty often encountered in weaning such patients
from ventilators. However, if the patient is obtunded or unable to cough, and if
hypercapnia and acidemia are worsening, mechanical ventilation should be instituted.
Minute ventilation should be raised so that the partial pressure of arterial carbon
dioxide gradually returns to near its long-term base line and excretion of excess
39

bicarbonate by the kidneys is accomplished (assuming that chloride is provided). By

contrast, overly rapid reduction in the partial pressure of arterial carbon dioxide risks
the development of posthypercapnic alkalosis, with potentially serious consequences.
Should posthypercapnic alkalosis develop, it can be ameliorated by providing
chloride, usually as the potassium salt, and administering the bicarbonate-wasting
diuretic acetazolamide at doses of 250 to 375 mg once or twice daily. Noninvasive
mechanical ventilation with a nasal or facial mask is being used with increasing
frequency to avert the possible complications of endotracheal intubation.
Permissive Hypercapnia
It has long been standard practice to prescribe tidal volumes two to three times
normal (i.e., 10 to 15 ml per kilogram) when instituting mechanical ventilation for
patients with acute respiratory distress syndrome, severe airway obstruction, or other
types of respiratory failure. This approach is being challenged by data indicating that
alveolar overdistention can cause tissue injury, culminating in increased
microvascular permeability and lung rupture. Although the evidence is incomplete,
there is a growing tendency to prescribe tidal volumes of 5 to 7 ml per kilogram (or
less) to achieve a plateau airway pressure no higher than 35 cm of water. Because an
increase in the partial pressure of arterial carbon dioxide might ensue, the strategy is
referred to as permissive hypercapnia or controlled hypoventilation. The severity of
carbon dioxide retention varies widely in different reports, but the partial pressure of
arterial carbon dioxide rarely exceeds 80 mm Hg.
Uncontrolled clinical trials and a preliminary report of a randomized study
suggest that permissive hypercapnia results in lower morbidity and mortality than
conventional mechanical ventilation. However, the available results remain
inconclusive. The increased respiratory drive associated with permissive hypercapnia
causes extreme discomfort, making sedation necessary. Because the patients
commonly require neuromuscular blockade as well, accidental disconnection from the
ventilator can cause sudden death. Furthermore, after the neuromuscular-blocking
agent is discontinued, there may be weakness or paralysis for several days or weeks.
There are several contraindications to the use of permissive hypercapnia, including
cerebrovascular disease, brain edema, increased intracranial pressure, and
convulsions; depressed cardiac function and arrhythmias; and severe pulmonary

40

hypertension. It is important to note that most of these entities can develop as adverse
effects of permissive hypercapnia itself, especially when hypercapnia is associated
with substantial acidemia. In fact, some experimental evidence indicates that
correction of acidemia attenuates the adverse hemodynamic effects of permissive
hypercapnia. It appears prudent, although still controversial, to keep the blood pH at
approximately

7.30

by

administering

intravenous

alkali

when

controlled

hypoventilation is prescribed.
Alkali Therapy
The presence of an element of metabolic acidosis is the primary indication for
alkali therapy in patients with respiratory acidosis. However, this practice entails
some risks, including pH-mediated depression of ventilation, enhanced carbon
dioxide production from bicarbonate decomposition, and volume expansion. Yet alkali
therapy may have a special role in patients who have acidemia and severe
bronchospasm from any cause by restoring the responsiveness of the bronchial
musculature to beta-adrenergic agonists, as well as in patients treated with controlled
hypoventilation. The use of THAM has been suggested in patients with chronic
hypercapnia, because of its theoretical potential to decrease the partial pressure of
arterial carbon dioxide. However, this expectation has not been borne out. The
resultant decrease in alveolar ventilation worsens hypoxemia and offsets the disposal
of carbonic acid that is due to the buffering effect of THAM.

2.18.3. Mixed acidosis

Coexistent respiratory acidosis and metabolic acidosis can be observed in
several clinical conditions, including cardiorespiratory arrest, chronic obstructive
pulmonary disease complicated by circulatory failure or sepsis, severe pulmonary
edema, combined respiratory and renal failure, diarrhea or renal tubular acidosis
complicated by hypokalemic paresis of the respiratory muscles, and poisoning with
various toxic agents and drugs. The additive effects on blood acidity of primary
hypercapnia, on the one hand, and the bicarbonate deficit, on the other, can produce
profound acidemia requiring prompt therapy. Whenever possible, treatment must be
41

targeted at both components of the mixed acidosis.

2.19. Adverse consequences of severe alkalemia

Severe alkalemia (blood pH greater than 7.60) can compromise cerebral and
myocardial perfusion by causing arteriolar constriction, an effect that is more
pronounced in respiratory than in metabolic alkalosis.
Neurologic abnormalities may ensue, including headache, tetany, seizures,
lethargy, delirium, and stupor. The associated reduction in the plasma concentration of
ionized calcium probably contributes to these manifestations. Although it exerts a
moderate positive inotropic effect on the isolated heart, alkalemia reduces the anginal
threshold and predisposes the patient to refractory supraventricular and ventricular
arrhythmias. This arrhythmogenic action is more pronounced in patients with
underlying heart disease. Alkalemia depresses respiration, causing hypercapnia and
hypoxemia. Such effects are of little consequence in patients with adequate
ventilatory reserve, but they can be consequential in patients with compromised
ventilation. Even mild alkalemia can frustrate efforts to wean patients from
mechanical ventilation.
Hypokalemia is an almost constant feature of alkalemic disorders, but it is
more prominent in those of metabolic origin. Translocation of potassium into cells
and renal and extrarenal losses contribute in varying degrees to its generation. In turn,
hypokalemia can have several adverse effects, including neuromuscular weakness;
sensitization to digitalis-induced arrhythmias; polyuria; and increased ammonia
production, which can heighten the risk of hepatic encephalopathy. Alkalemia
stimulates anaerobic glycolysis and increases the production of lactic acid and
ketoacids. Along with the alkalemic titration of plasma proteins and the
hyperproteinemia accompanying chloride-responsive metabolic alkalosis, this effect
contributes to the characteristic moderate elevation in the plasma anion gap. Although
acute alkalemia can reduce the release of oxygen to the tissues by tightening the
binding of oxygen to hemoglobin, chronic alkalemia negates this effect by increasing
the concentration of 2,3-diphosphoglyceric acid in red cells.

42

2.20. Management of life-threatening alkalosis

2.20.1. Metabolic alkalosis
In the presence of an appropriate ventilatory response, severe alkalemia of
metabolic origin requires that the plasma bicarbonate concentration exceed 45 mmol
per liter. Just as in severe metabolic acidemia, the immediate goal of therapy is
moderation but not full correction of the alkalemia. Reducing plasma bicarbonate to
less than 40 mmol per liter is an appropriate short-term goal, since the corresponding
pH is on the order of 7.55 or lower. Most severe metabolic alkalosis is of the chlorideresponsive form, the most common causes being loss of gastric acid and the
administration of loop or thiazide diuretics. The characteristic hypochloremic
hyperbicarbonatemia results from the loss of hydrochloric acid in gastric secretions or
from urinary excretion of excess ammonium chloride caused by these chloruretic
diuretics.
Substantial contraction of the volume of extracellular fluid as a result of
diuretic-induced losses of sodium chloride can further amplify the resulting
hyperbicarbonatemia by limiting the space of distribution of bicarbonate. Such a
contraction alkalosis is particularly likely in patients with massive edema treated
with combination regimens of diuretics (such as furosemide and metolazone).
Maintenance of chloride-responsive metabolic alkalosis is then effected by heightened
renal bicarbonate reabsorption, frequently coupled with a reduced glomerular
filtration rate, changes that are mediated by chloride depletion itself, contraction of
extracellular-fluid volume, and the associated potassium deficit.
If the processes that generate metabolic alkalosis are still ongoing, every effort
should be made to moderate or stop them, even if only temporarily. Vomiting should
be countered with antiemetics. If continuation of gastric drainage is required, the loss
of gastric acid can be reduced by administering H2-receptor blockers or inhibitors of
the gastric H+/K+ATPase. Notably, these treatments substitute loss of sodium
chloride for loss of hydrochloric acid. Decreasing the dose of loop and thiazide
diuretics can be coupled with the addition of potassium-sparing diuretics
(spironolactone, amiloride, or triamterene), drugs that decrease distal acidification and
43

curtail potassium excretion.

Prompt attention should be given to additional factors that might compound
the alkalosis. Administration of bicarbonate or its precursors, such as lactate, citrate,
and acetate (the latter being a common ingredient of parenteral-nutrition solutions),
should be discontinued. At times, absorbable alkali is not a complicating factor but the
very cause of the metabolic alkalosis, as in patients ingesting inordinate amounts of
calcium carbonate or large quantities of absorbable alkali and milk; severe metabolic
alkalosis coupled with variable degrees of hypercalcemia and renal impairment can
occur. Coadministration of cation-exchange resins with aluminum hydroxide in effect
renders the nonabsorbable alkali absorbable. If drugs with mineralocorticoid activity,
such as fludrocortisone and various glucocorticoid compounds, are being
administered, their indication and dose should be reassessed.
Having addressed the factors that cause or aggravate the alkalosis, the
clinician must then focus on ameliorating the existing hyperbicarbonatemia. Patients
with volume depletion require provision of both sodium chloride and potassium
chloride. Repair of the prevailing sodium, potassium, and chloride deficits and of the
often-present functional azotemia will promote bicarbonaturia heralded by
alkalinization of the urine. Administration of acetazolamide (250 to 375 mg once or
twice daily) fosters bicarbonaturia but requires consideration of the associated
kaliuresis and phosphaturia.
If the pace of correction of the alkalemia must be accelerated, alkali stores can
be titrated by infusing hydrochloric acid. Hydrochloric acid administered
intravenously as a 0.1 to 0.2 N solution (that is, one containing 100 to 200 mmol of
hydrogen per liter) is safe and effective for the management of severe metabolic
alkalosis. The acid can be infused as such or can be added to amino acid and dextrose
solutions containing electrolytes and vitamins without causing adverse chemical
reactions. Because of its sclerosing properties, hydrochloric acid must be administered
through a central venous line at an infusion rate of no more than 0.2 mmol per
kilogram of body weight per hour. However, it can also be administered through a
peripheral vein if it is added to an amino acid solution and mixed with a fat emulsion.
Calculation of the amount of hydrochloric acid solution to be infused is based
on a bicarbonate space of 50 percent of body weight.15 Thus, to reduce plasma
bicarbonate from 50 to 40 mmol per liter in a 70-kg patient, the estimated amount of
hydrochloric acid required is 10 70 0.5, or 350 mmol. Precursors of hydrochloric
44

acid, such as ammonium chloride (20 g per liter, with 374 mmol of hydrogen per liter)
and arginine monohydrochloride (100 g per liter, with 475 mmol of hydrogen per
liter), can substitute for hydrochloric acid, but they entail substantial risks and are
used less commonly. Both of these preparations are hyperosmotic solutions; to avoid
local tissue injury, they must be infused through a central catheter. In addition,
ammonium chloride can raise serum ammonia concentrations in patients with liver
failure, and arginine monohydrochloride can induce serious hyperkalemia in patients
with renal failure, especially when there is coexisting liver disease.
Treatment of severe chloride-responsive metabolic alkalosis is considerably
more challenging in patients with cardiac or renal dysfunction. Expansion of the
extracellular-fluid volume may either accompany alkalemia or develop as a result of
treatment. Potassium chloride can induce hyperkalemia in patients with renal failure.
In certain cases, downgrading the diuretic regimen, adding acetazolamide, and
cautiously administering sodium chloride and potassium chloride may suffice. In
many other cases, however, cardiac and renal failure pose such limitations that the
physician must resort to more aggressive measures. Infusion of hydrochloric acid can
be efficacious, but the associated fluid load is often problematic. Under these
circumstances, use of an extracorporeal device is advisable. Hemodialysis and
ultrafiltration can rapidly correct severe alkalemia and volume overload, especially if
the bicarbonate concentration of the standard dialysate is reduced. In patients with
unstable hemodynamics, the same goals can be achieved by continuous arteriovenous
or venovenous hemofiltration with sodium chloride as the replacement solution.
Life-threatening alkalemia is a very rare occurrence in chloride-resistant
metabolic alkalosis. Disorders of mineralocorticoid excess, severe potassium
depletion, and Bartter's or Gitelman's syndrome are the causes of this form of
alkalosis. Aggressive potassium repletion will correct or ameliorate chloride-resistant
alkalosis, but the thrust of the therapy should be directed at reversing the underlying
disorder, if possible. When the cause of the mineralocorticoid excess cannot be
reversed, potassium-sparing diuretics coupled with moderate restriction of sodium
chloride can provide symptomatic relief. Identifying laxative abuse as the culprit may
prevent recurrence of the problem. Potassium-sparing diuretics, nonsteroidal
antiinflammatory drugs, or angiotensin-convertingenzyme inhibitors can ameliorate
Bartter's or Gitelman's syndrome.

45

2.20.2. Respiratory alkalosis

Respiratory alkalosis is the most frequently encountered acidbase disorder,
since it occurs in normal pregnancy and with high-altitude residence. The pathologic
causes of respiratory alkalosis include various hypoxemic conditions, pulmonary
disorders, central nervous system diseases, salicylate intoxication, hepatic failure,
sepsis, and the anxietyhyperventilation syndrome. Respiratory alkalosis is
particularly prevalent among the critically ill; in these patients, its presence is a bad
prognostic sign, because mortality increases in direct proportion to the severity of the
hypocapnia.
Hypocapnia elicits a secondary change in plasma bicarbonate that, as in
hypercapnia, has two components. A moderate acute decrease in plasma bicarbonate
originates from tissue buffering. A larger decrease accompanies chronic hypocapnia as
a result of down-regulation of renal acidification and requires two to three days to
reach completion. Because blood pH does not exceed 7.55 in most cases of
respiratory alkalosis, severe manifestations of alkalemia are usually absent. Marked
alkalemia can be observed, however, in certain circumstances, such as with
inappropriately set ventilators, some psychiatric conditions, and lesions of the central
nervous system. Obviously, clinical manifestations of severe alkalemia are more
likely to occur in the acute, rather than the chronic, phase of respiratory alkalosis.
Management of respiratory alkalosis must be directed toward correcting the
underlying cause, whenever possible. Because most cases of respiratory alkalosis,
especially chronic cases, pose little risk to health and produce few or no symptoms,
measures to treat the deranged acidbase composition are not required. The anxiety
hyperventilation syndrome is an exception. An active therapeutic approach that
provides reassurance, sedation, and ultimately psychotherapy is most helpful in these
cases. Rebreathing into a paper bag or any other closed system provides prompt, but
unfortunately short-lived, symptomatic relief. If hypocapnia-induced alkalemia is
severe and persistent, sedation may be required.
2.20.3. Pseudorespiratory alkalosis
Arterial hypocapnia does not necessarily imply respiratory alkalosis or the
46

secondary response to metabolic acidosis but can be observed in an idiotypic form of

respiratory acidosis. This entity, which we have termed pseudorespiratory alkalosis,
occurs in patients with profound depression of cardiac function and pulmonary
perfusion but with relative preservation of alveolar ventilation, including patients
undergoing cardiopulmonary resuscitation. The severely reduced pulmonary blood
flow limits the carbon dioxide delivered to the lungs for excretion, thereby increasing
the mixed venous partial pressure of carbon dioxide. By contrast, the increased
ventilation:perfusion ratio causes the removal of a larger-than-normal amount of
carbon dioxide per unit of blood traversing the pulmonary circulation, thereby
creating arterial eucapnia or frank hypocapnia.
Nonetheless, the absolute excretion of carbon dioxide is decreased and the
carbon dioxide balance of the body is positive the hallmark of respiratory acidosis.
Such patients may have severe venous acidemia (often due to mixed respiratory and
metabolic acidosis) accompanied by an arterial pH that ranges from the mildly acidic
to the frankly alkaline. Furthermore, the extreme oxygen deprivation prevailing in the
tissues may be completely disguised by the reasonably preserved values of arterial
oxygen. To rule out pseudorespiratory alkalosis in a patient with circulatory failure,
blood gas monitoring must include sampling of mixed (or central) venous blood. The
management of pseudorespiratory alkalosis must be directed toward optimizing
systemic hemodynamics.

2.20.4. Mixed alkalosis

Extreme alkalemia can occur in patients with metabolic and respiratory
alkalosis, even in the presence of only moderate changes in plasma bicarbonate and
the partial pressure of arterial carbon dioxide. This disorder can occur in various
settings, including among patients with primary hypocapnia associated with chronic
liver disease, in whom metabolic alkalosis develops because of vomiting, nasogastric
drainage, diuretics, profound hypokalemia, or alkali administration, especially in the
context of renal insufficiency. Mixed alkalosis is also observed in patients with endstage renal disease in whom primary hypocapnia develops; the inappropriately high
plasma bicarbonate level reflects the absence of the renal response to the prevailing
47

hypocapnia and the dialysis-induced alkali load. Patients undergoing peritoneal

dialysis are more vulnerable than those undergoing hemodialysis, because peritoneal
dialysis maintains plasma bicarbonate at a higher level (25 to 26 mmol per liter, as
compared with a value of 20 to 21 mmol per liter before hemodialysis). Reducing the
base concentration of the dialysate or switching the patient from peritoneal dialysis to
hemodialysis will ameliorate the situation.

BIBLIOGRAPHY

1. Adrogue HJ, Chap Z, Okuda Y, et al. Acidosis-induced glucose intolerance is

not prevented by adrenergic blockade. Am J Physiol 1988;255:E812-E823
2. Adrogu HJ, Madias NE. Mixed acidbase disorders. In: Jacobson HR, Striker
GE, Klahr S, eds. The principles and practice of nephrology. 2nd ed. St. Louis:
Mosby-Year Book, 1995:953-62.
3. Brooks Geo F, et all. .Jawetz,

Melnick

&

Adelbergs Medical

Microbiology.25th ed: McGraw Hill 2010

4. Cardenas VJ Jr, Zwischenberger JB, Tao W, et al. Correction of blood pH
attenuates changes in hemodynamics and organ blood flow during permissive
hypercapnia. Crit Care Med 1996;24:827-834
5. Functions of Cells and Human Body, multimedia textbook
6. Hood VL, Tannen RL. Maintenance of acid base homeostasis during
ketoacidosis and lactic acidosis: implications for therapy. Diabetes Rev
1994;2:177-194
7. Horacio J. Adrogue M.D., and Nicolaos E. Madias, M.D., Management of
Life-threatening Acid Base Disorders; The New England Journal of Medicine,
1998

48

8. Katzung Bertram G, et all. Basic And Clinical Pharmacology. 11th ed: Mcgraw
Hill 2009
9. Lebovitz HE. Diabetic ketoacidosis. Lancet 1995;345:767-772
10. Longo, et all. Harrisons Principles of Internal Medicine. 18th ed: Mcgraw Hill
2012
11. Madias NE. Lactic acidosis. Kidney Int 1986;29:752-774
12. Madias NE, Goorno WE, Herson S. Severe lactic acidosis as a presenting
feature of pheochromocytoma. Am J Kidney Dis 1987;10:250-253
13. Mccance Kathryn L, et all. Pathophysiology The Biologic for Disease in
Adults and Children. 6th ed: Saunders Elesevier 2010
14. Sudoyo, Aru.W, dkk. Buku Ajar Ilmu Penyakit Dalam. 5 th ed. Jilid III. Interna
Publishing: Jakarta; 2009.

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