Acid Base Abnormalities

This teaching module will provide an overview of acid base abnormalities. Below is a list of topics that will be covered:
Introduction to Acid Base Disturbances and Definitions
Compensatory Responses
Calculations: Anion Gap, Delta Ratio, Urine Anion Gap, Osmolar Gap
Step by Step Approach to interpretin an arterial blood as
!hysioloic "ffects of Acid Base Disorders
"tioloy of Acid Base Disorders
Introduction to Acid Base Disorders
In order to approach acid base disorders, consider the following equations:
1) #enderson #asselbalch e$uation: p# % &'( ) lo *#CO+,-. /'/+ !CO0
where 6.1 is the pa !negative logarithm of the acid dissociation constant) for carbonic acid !"#$%&) and '.'&, the factor which
relates ($%# to the amount of $%# dissolved in plasma.
#) 1assirer,Bleich e$uation: *#)- % 02 3 !CO0 . *#CO+,-
p# *#)-, nanomol.4
5'6/ (&
5'5/ 0/
5'&/ 0&
5'7/ +0
5'2/ 2/
5'+/ 7/
5'0/ &+
5'(/ 6/
5'// (//
&'8/ (07
&'6/ (&/
)lthough cumbersome and somewhat difficult to use at the bedside, both equations represent a ver* important relationship. The*
predict that the ratio of dissol9ed CO0 to #CO+, , rather than their actual concentrations, determines h*drogen ion concentration
and thus p".
) drop or rise in ($%# will result in a drop or rise in +",- respectivel*.
+"$%&.- on the other hand is inversel* related to ", concentration whereb* a drop in bicarbonate levels result in an increase in ",
concentration while a rise in bicarbonate levels result in a reduction in ", concentration.
This buffer s*stem is of ph*siologic importance because both the pulmonar* and renal mechanisms for regulating p" wor/ b*
ad0usting this ratio.
The ($%# can be modified b* changes in alveolar ventilation, while plasma +"$%&.- can be altered b* regulating its generation
and e1cretion b* the /idne*s.
Definitions
An acid base disorder is a change in the normal value of extracellular pH that may result when renal or respiratory function is
abnormal or when an acid or base load overwhelms excretory capacity.
1
:ormal acid base 9alues
p# !CO0 #CO+,
2ange: 3.&4. 3.54 &6.55 ##.#6
%ptimal value 3.5' 5' #5
Acid base status is defined in terms of the plasma pH.
Acidemia . decrease in the blood p" below normal range of 3.&4 .3.54
Al;alemia . 6levation in blood p" above the normal range of 3.&4 7 3.54
Clinical disturbances of acid base metabolism classically are defined in terms of the
HCO3- /CO2 buffer system.
Acidosis < process that increases +",- b* increasing ($%# or b* reducing +"$%&.-
Al;alosis < process that reduces +",- b* reducing ($%# or b* increasing +"$%&.-
It is important to note that thouh acidosis and al;alosis usually leads to acidemia and al;alemia respecti9ely, the
e=ception occurs >hen there is a mi=ed acid base disorder' In that situation, multiple acid base processes coe=istin may
lead to a normal p# or a mi=ed picture' ?his >ill be discussed in more detail later'
8ince ($%# is regulated b* respiration, abnormalities that primaril* alter the ($%# are referred to as respiratory acidosis !high
($%#) and respiratory al;alosis !low ($%#).
In contrast, +"$%&.- is regulated primaril* b* renal processes. )bnormalities that primaril* alter the +"$%&.- are referred to as
metabolic acidosis !low +"$%&.-) and metabolic al;alosis !high +"$%&.-).
Simple acid base disorders : 9isorders that are either metabolic or respirator*.
@i=ed acid base disoders: :ore than one acid base disturbance present. p" ma* be normal or abnormal.
Compensatory Responses
)cid Base disoders are associated with defense mechanisms referred to as compensator* responses that function to reduce the
effects of the particular disorder on the p". They do not restore the pH back to a normal value. This can onl* be done with correction
of the underl*ing cause. In each of these disorders, compensator* renal or respirator* responses act to minimi;e the change in ",
concentration b* minimi;ing the alteration in the ($%# <+"$%&.- ratio.
This teaching module will e1amine the compensator* responses associated with each acid base disorder.
Compensatory Responses: @etabolic Acidosis
:etabolic )cidosis is an acid base disturbance characteri;ed b* a reduction in bicarbonate ions leading to an elevation in the
($%#<"$%&. ratio and thus an elevation in h*drogen ion concentration according to the following equation:
*#)- % 02 3A!CO0 . *#CO+,-B
In metabolic acidosis, this reduction in bicarbonate ions ma* result from increased e1tracellular buffering of an increased acid load
or less commonl*= loss of bicarbonate ions in the urine.
2emember that, "$%&. is the main buffer of nonvolatile or noncarbonic acids in the bod* and therefore in the presence of e1cess
acid, its concentration will decrease.
The bod* responds to metabolic acidosis b* tr*ing to restore the ($%# < +"$%&.- ratio. This is done b* reducing the ($%#.
The reduction in ($%# is accomplished b* increasing alveolar ventilation. The drop in arterial p" stimulates both the central and
peripheral chemoreceptors controlling respiration, resulting in an increase in alveolar ventilation. The inccrease in ventilation is
characteri;ed more b* an increase in tidal 9olume than b* an increase in respirator* rate, and ma* if the acidemia is severe, reach
a ma1imum of &'><min !nl ? 4.6 ><min).
In its most pronounced clinical manifiestation, the increase in ventilation is referred to as 1ussmaul Respiration.
2
In general, respiratory compensation results in a .2 mmHg reduction in !CO2 for e"ery .# me$/% reduction in the plasma HCO3-
concentration do&n to a minimum !CO2 of # to 'mmHg'
@or e1ample, if an acid load lowers the plasma "$%&. concentration to A meq<>, then:
9egree of "$%&. reduction is #5 !optimal value) 7 A ? 14.
Therefore, ($%# reduction should be 14 B 1.# ? 1C.
Then ($%# measured should be 5' !optimal value) 7 1C ? ##mm"g.
CinterDs Eormula
To estimate the e1pected ($%# range based on respirator* compensation, one can also use the DinterEs @ormula which predicts:
!CO0 % A('7 3 *#CO+,-B ) 6 F 0
Therefore in the above e1ample, the ($%# according to DinterEs should be
!1.4 B A) , C F # ? #'.#5
)nother useful tool in estimating the ($%# in metabolic acidosis is the recognition that the pCO0 is al>ays appro=imately e$ual
to the last 0 diits of the p#'
Compensatory Responses: Respiratory Acidosis
2espirator* )cidosis is an acid base disturbance characteri;ed b* an elevation in the partial pressure of dissolved $%# leading to
an elevation in the ($%#<+"$%&.- ratio which subsequentl* increases the h*drogen ion concentration according to the following
equation:
*#)- % 02 3 !CO0 . *#CO+,-
In 2espirator* )cidosis, the elevation in ($%# result from a reduction in alveolar ventilation. 6levation in ($%# is never due to an
increase in $%# production.
In response to the increase in +",- and reduction of the p", the bod* responds b* tr*ing to increase the plasma +"$%&.- to match
the increase in ($%# and thus maintain the ($%#<"$%&. ratio. This is accomplished via two mechanisms= a) rapid cell bufferin
and b) an increase in net acid e=cretion'
Because these mechanisms occur at different moments in time, acute respirator* acidosis can be distinguished from chronic
respirator* acidosis.
Acute Respiratory Acidosis
$ell buffering occur within minutes after the onset of respirator* acidosis.
The elevation in $%# levels lead to an increase in carbonic or volatile acid in the plasma. Gnli/e nonvolatile acids, carbonic acid
!"#$%& ) cannot be buffered b* "$%&. in the e1tracellular fluid. ?herefore, in contrast to metabolic acidosis, bicarbonate le9els
do not fall in respiratory acidosis''
In this setting, carbonic acid !"#$%& ) can onl* be buffered b* the limited intracellular buffers Aprimarily hemolobin and
proteinsB'
"#$%& , "b. H ""b , "$%&.
)s shown above, each buffering reaction produces "$%&., which leads to an increase in plasma +"$%&.-.
(ue to this process, acutely, there is an increase in the plasma )HCO3-*, a"eraging me$/% for e"ery # mmHg rise in the
!CO2'
Chronic Respiratory Acidosis
In chronic respirator* acidosis, the persistent elevation in ($%# stimulates increased e1cretion of titratable acid and ammonium,
resulting in the addition of new "$%&. to the e1tracellular fluid.
This process is complete after &.4 da*s resulting in a new stead* state in which there is appro1imatel* a 3.' me$/% increase in
the plasma HCO3- concentration for e"ery # mmHg increase in the !CO2.
To put into perspective the impact of cell buffering vs renal adaptation on protecting the p" in respirator* acidosis, consider the
following e1amples:
3
If the ($%# is acutel* increased to C' mm"g, there will be appro1imatel* a 5meq<> elevation in the plasma +"$%&.- to #C meq<>
and a potentiall* serious reduction in e1tracellular p" to 3.13.
$hange in ($%# ? C'. 5' ? 5'.
Therefore elevation in +"$%&.- ? 5'<1' B1 ? 5
)ccording to the "enderson."asselbach equation, p" ? 6.1 , log+"$%&.-<'.'& ($%#
"ence p" ? 6.1 , log !#C< '.'&BC') ? 3.13.
In another e1ample: If the ($%# were chronicall* increased to C' mm"g, the plasma +"$%&.- should rise b* 15 !+!C'.5')<1'- B &.4)
to a new concentration of &C meq<> !#5,15)
The p" in this situation would be:
p" ? 6.1 , log !&C< '.'&BC') ? 3.&'
?hus renal compensation offers more sinificant p# protection in the settin of chronic respiratory acidosis in
contrast to intracellular bufferin in the acute situation'
$hronic respirator* acidosis is commonl* caused b* $%(9. These patients can tolerate a ($%# of up to A'.11' mm"g and not
have a severe reduction in p" due to renal compensation.
Compensatory Responses: @etabolic Al;alosis
:etabolic al/alosis is an acid base disorder characteri;ed b* an elevation in +"$%&.- above the normal range, which leads to a
reduction in the ($%#<+"$%&.- ratio and subsequentl* a reduction in h*drogen ion concentration according to the following
equation:
*#)- % 02 3A!CO0 . *#CO+,-B
This elevation in bicarbonate ions is due to an addition in al/ali to the bod* which then cannot be e1creted b* the /idne*. :etabolic
al/alosis is alwa*s associated with renal impairment of some /ind because the /idne* has a vast capacit* in e1creting e1cess
al/ali.
(lease note, loss of acid from the bod* as occurs in vomiting induced metabolic al/alosis is equivalent to adding al/ali to the bod*.
In response to the reduction in +",- and elevation in p", the bod* responds b* tr*ing to increase the ($%# to match the increase in
+"$%&.- and thus maintain the ($%#<+"$%&- ratio. 6levation in ($%# is accomplished b* lowering alveolar ventilation.
The development of al/alemia is sensed b* central and peripheral chemoreceptors, resulting in a reduction in the rate of ventilation
and a reduction in tidal volume and thus an elevation in the p$%#. This happens fairl* quic/l* following the onset of metabolic
al/alosis.
On a"erage the pCO2 rises #.+ mmHg for e"ery .# me$/% increment in the plasma )HCO3-*.
@or e1ample, if an al/ali load raises the the plasma "$%&. concentration to &5 meq<>, then:
9egree of "$%&. elevation is &5 7 #5 !optimal value)? 1'.
Therefore, ($%# elevation should be '.3 B 1' ? 3.
Then ($%# measured should be 5' !optimal value) ,3 ? 53mm"g.
Compensatory Responses: Respiratory Al;alosis
2espirator* al/alosis is caused b* an elevation in the frequenc* of alveolar ventilation and more importantl* tidal volume that result
in an increase in minute ventilation. The increase in ventilation leads to the e1cretion of $%# at a rate greater than that of cellular
$%# production.
This leads to a net reduction in ($%# and subsequentl* to a reduction in the ($%# < +"$%&.- ratio which reduces the h*drogen ion
concentration !and increases the p") according to the following equation: *#)- % 02 3 !CO0 . *#CO+,-
In response to the decrease in +",- and elevation in p", the bod* responds b* tr*ing to reduce the plasma +"$%&.- to match the
reduction in ($%# and thus maintain the ratio. There are two mechanisms responsible for this compensation to respirator*
al/alosis= (B rapid cell bufferin and 0B a decrease in net renal acid e=cretion'
)s in respirator* acidosis, these responses occur in different moments of time, distinguishing acute respirator* al/alosis from
chronic respirator* al/alosis.
4
Acute Respiratory Al;alosis
)bout 1' minutes after the onset of respirator* al/alosis, h*drogen ions move from the cells into the e1tracellular fluid, where the*
combine with +"$%&. to form carbonic acid in the following reaction:
", , "$%&. H "#$%& !$))
The h*drogen ions are primaril* derived from intracellular buffers such as hemoglobin, protein and phosphates. The reaction with
bicarbonate ions in this reaction leads to a mild reduction in plasma +"$%&.-.
In acute respiratory al,alosis, as a result of cell buffering, for e"ery # mmHg decrease in the !CO2, there is a 2me$/%
decrease in the plasma HCO3- concentration.
(lease note that the cellular buffering does not offer adequate protection against respirator* al/alosis. @or e1ample:
If the ($%#, were reduced to #' mm"g, the change in ($%# would be #' !5'.#') and therefore the fall in plasma +"$%&.- would
be 5 meq<> !#'<1' B #). The new plasma +"$%&.- would be #' meq<> !#5.5).
The p" in this circumstance would be:
p" ? 6.1 , log !#'< '.'&B#') ? 3.6&
"ad no cell buffering occurred, then the p" would be
p" ? 6.1 , log !#5< '.'&B#') ? 3.3'
)s *ou can see, reall* not much of a change.
Chronic Respiratory Al;alosis
If respirator* al/alosis persist for longer than #. 6 hours, the /idne* will respond b* lowering h*drogen secretion, e1cretion of
titratable acids, ammonium production and ammonium e1cretion. There will also be an increase in the amount of "$%&. e1creted
due to decreased reabsorption of filtered "$%&. .
$ompletion of this process occurs after #.& da*s after which a new stead* state is achieved.
-enal compensation result in a . me$/% reduction in plasma )HCO3-* for e"ery # mmHg reduction in !CO2.
In comparison, to acute respirator* al/alosis, this compensation offers a much better protection of the arterial p". To put this into
perspective, consider the same #' mm"g fall in ($%# as before in the acute scenario. Iow, due to renal compensation, the
plasma +"$%&.- falls b* C meq<> to 16 meq<>. The p" now in the chronic situation would be :
p" ? 6.1 , log !16< '.'&B#') ? 3.4&.
Compensatory Responses: summary and ta;e home points
(. $ompensator* responses never return the ph to normal or overshoot.
0. The basis of compensator* responses is to maintain the ($%#<+"$%&.- ratio.
+. Therefore, the direction of the compensator* response is alwa*s the same as that of the initial change.
2. $ompensator* response to respirator* disorders is two.fold= a fast response due to cell buffering and a significantl* slower response due
to renal adaptation.
7. $ompensator* response to metabolic disorders involves onl* an alteration in alveolar ventilation.
&. :etabolic responses cannot be defined as acute or chronic in terms of respirator* compensation because the e1tent of compensation is
the same in each case.
Below is table summari;ing compensator* responses and their mechanisms.
5
!rimary disorder
Initial
chemical
chane
Compensatory
response
Compensatory @echanism "=pected le9el of compensation
@etabolic
Acidosis
G#CO+, G!CO0 #yper9entilation
!CO0 % A('7 3 *#CO+,-B ) 6
F 0
G!CO0 % ('0 3H *#CO+,-
!CO0 % last 0 diits of p#
@etabolic
Al;alosis
I#CO+, I!CO0 #ypo9entilation
!CO0 % A/'8 3 *#CO+,-B ) (& F 0
I!CO0 % /'5 3 H *#CO+,-
Respiratory
Acidosis
I!CO0 I#CO+,
Acute
Intracellular Bufferin Ahemolobin,
intracellular proteinsB
I*#CO+,- % ( m"$.4 for e9ery (/
mm # H!CO0
Chronic
Generation of ne> #CO+, due to the increased
e=cretion of ammonium'
I*#CO+,- % +'7 m"$.4 for e9ery (/
mm # H!CO0
Respiratory
Al;alosis
G!CO0 G#CO+,
Acute Intracellular Bufferin
G*#CO+,- % 0 m"$.4 for e9ery (/
mm # H!CO0
Chronic
Decreased reabsorption of #CO+,, decreased
e=cretion of ammonium
G*#CO+,- %2 m"$.4 for e9ery (/
mm # H!CO0
)lso: In acute respirator* acidosis, Jp" ? '.''C B K ($%#
In chronic respirator* acidosis, Jp" ? '.''& B K ($%#.
Calculations
There are various calculations that are commonl* used diagnosticall* in interpreting acid base disorders and distinguishing
between different causes of acid base disorders. $alculating the anion gap is an approach that must be ta/en in all cases of
metabolic acidosis. %ther calculations such as osmolar gap and urine anion gap, are used when clinicall*, the cause of an acid
base disorder is in doubt.
This teaching module will discuss the various diagnostic calculations that can be useful in interpreting acid base disorders.
6mphasis will be placed on the underl*ing rational behind each formula to increase comprehension and deduction and minimi;e
memori;ation.
Topics to be covered are:
)nion Lap
9elta 2atio
Grine )nion Lap
%smolar Lap
Anion Gap
Dhen acid is added to the bod*, the +",- increases and the +"$%&.- decreases. In addition, the concentration of the
anion, which is associated with the acid, increases. This change in the anion concentration provides a convenient wa* to
anal*;e and help determine the cause of a metabolic acidosis b* calculating what is termed the anion ap.
The anion gap is estimated b* subtracting the sum of $l. and "$%&. concentrations from the plasma Ia concentration.
Ia , Gnmeasured cations ? Cl, ) #CO+, ) Gnmeasured anions
Anion ap % *:a- < A*Cl,- ) *#CO+,-B
The ma0or unmeasured cations are calcium, magnesium, gamma globulins and potassium. The ma0or unmeasured anions
are negativel* charged plasma proteins !albumin), sulphate, phosphates, lactate and other organic anions. The anion gap
is defined as the quantit* of anions not balanced b* cations. This is usuall* equal to 1# F 5 meq<> and is usuall* due to the
neati9ely chared plasma proteins as the charges of the other unmeasured cations and anions tend to balance out.
If the anion of the acid added to plasma is $l. , the anion gap will be normal !i.e., the decrease in +"$%&.- is matched b*
an increase in +$l.-). @or e1ample:
#Cl ) :a#CO+ J :aCl ) #0CO+ J CO0 ) #0O
In this setting, there is a meq. for meq. replacement of e1tracellular "$%&. b* $l. = thus, there is no change in the anion
gap, since the sum of $l.- , +"$%&.- remains constant. This disorder is called a h*perchloremic acidosis, because of the
associated increase in the $l. concentration. LI or renal loss of "$%&. produces the same effect as adding "$l as the
/idne* in its effort to preserve the 6$M will retain Ia$l leading to a net e1change of lost "$%&. for $l..
6
In contrast, if the anion of the acid is not $l. !e.g. lactate, N.h*dro1*but*rate), the anion gap will increase !i.e. the decrease
in +"$%&.- is not matched b* an increase in the +$l.- but rather b* an increase in the +unmeasured anion-:
#A ) :a#CO+ J :aA ) #0CO+ J CO0 ) #0O, where ). is the unmeasured anion.
$auses of elevated )nion gap acidosis is best remembered b* the mnemonic 1U4? or the popular @UD!I4"S
@ ? :ethanol
U ? Gremia
D ? 9) !also )) and starvation)
! ? (araldeh*de
I ? II"
4 ? >actic acidosis
" ? 6th*lene Ll*col
S ? 8al*cilate
1 ? etoacidosis !9),alcoholic /etoacidosis,
starvation)
U ? Gremia !2enal @ailure)
4 ?>actic acidosis
? ? To1ins !6th*lene gl*col, methanol, paraldeh*de,
salic*late)
Because, neati9ely chared plasma proteins account for the normal anion ap, the normal 9alues should
be adKusted do>n>ard for patients >ith hypoalbuminemia'
?he appro=imate correction is a reduction in the normal anion ap of 0'7 me$.l for e9ery (.dl decline in the
plasma albumin concentration Anormal 9alue % 2 .dlB'
8ee practice case C for an e1ample.
?he Delta Ratio AH.HB
The delta ratio is sometimes used in the assessment of elevated anion gap metabolic acidosis to determine if a mi1ed acid
base disorder is present.
Delta ratio % H Anion ap.H *#CO+,- or Oanion ap. J *#CO+,-
Delta Delta % @easured anion ap < :ormal anion ap
Delta del :ormal *#CO+,- < @easured *#CO+,-
9elta 9elta % AAG < (0B
Delta delaaaA02 , *#CO+,-B
In order to understand this, let us re.e1amine the concept of the anion gap.
If one molecule of metabolic acid !")) is added to the 6$@ and dissociates, the one ", released will react with one
molecule of "$%&. to produce $%# and "#%. This is the process of buffering. ?he net effect >ill be an increase in
unmeasured anions by the one acid anion A, Aie anion ap increases by oneB and a decrease in the bicarbonate
by one me$'
Iow, if all the acid dissociated in the 6$@ and all the buffering was b* bicarbonate, then the increase in the )L should be
equal to the decrease in bicarbonate so the ratio between these two changes !which we call the delta ratio) should be
equal to one.
)s described previousl*, more than 4'P of e1cess acid is buffered intracellularl* and b* bone, not b* "$%&. . In contrast,
most of the e1cess anions remain in the 6$@, because anions cannot easil* cross the lipid bila*er of the cell membrane.
As a result, the ele9ation in the anion ap usually e=ceeds the fall in the plasma *#CO+, -' In lactic acidosis, for
e=ample, the H.H ratio a9eraes ('&:(.

On the other hand, althouh the same principle applies to ;etoacidosis, the ratio is usually close to (:( in this
disorder because the loss of /etoacids anions !/etones) lowers the anion gap and tends to balance the effect of
intracellular buffering. )nion loss in the urine is much less prominent in lactic acidosis because the associated state of
mar/ed tissue h*poperfusion usuall* results in little or no urine output.
) delta.delta value below 1:1 indicates a greater fall in +"$%&.- than one would e1pect given the increase in the anion
gap. This can be e1plained b* a mi1ed metabolic acidosis, i.e a combined elevated anion gap acidosis and a normal anion
gap acidosis, as might occur when lactic acidosis is superimposed on severe diarrhea. In this situation, the additional fall
in "$%&. is due to further buffering of an acid that does not contribute to the anion gap. !i.e addition of "$l to the bod* as
a result of diarrhea)
) value above #:1 indicates a lesser fall in +"$%&.- than one would e1pect given the change in the anion gap. This can be
e1plained b* another process that increases the +"$%&.-,i.e. a concurrent metabolic al/alosis. )nother situation to
consider is a pre.e1isting high "$%&. level as would be seen in chronic respirator* acidosis.
Delta ratio Assessment Guidelines
L /'2
#yperchloremic normal anion ap acidosis
L ( #ih AG M normal AG acidosis
( to 0 !ure Anion Gap Acidosis
4actic acidosis: a9erae 9alue ('&
D1A more li;ely to ha9e a ratio closer to ( due to urine ;etone loss
N 0 #ih AG acidosis and a concurrent metabolic al;alosis
or a pre,e=istin compensated respiratory acidosis
7
8ee case & and 3 for e1amples.
Urine Anion Gap
The three main causes of normal anion gap acidosis are:
>oss of "$%&. from Lastrointestinal tract !diarrhea)
>oss of "$%&. from the idne*s !2T)s)
)dministration of acid
9istinguishing between the above & groups of causes is usuall* clinicall* obvious, but occasionall* it ma* be useful to have an
e1tra aid to help in deciding between a loss of base via the /idne*s or the bowel. $alculation of the urine anion ap ma* be helpful
diagnosticall* in these cases.
The measured cations and anions in the urine are Ia,, ,, and $l. = thus the urine anion gap is equal to:
Grine anion gap ? *:a)- ) *1)- , *Cl,-
Grine anion gap ? unmeasured anions 7 unmeasured cations
In normal sub0ects, the urine anion gap is usuall* near ;ero or is positive' In metabolic acidosis, the e1cretion of the I"5, !which is
e1creted with $l. ) should increase mar/edl* if renal acidification is intact. Because of the rise in urinar* $l. , the urine anion gap
which is also called the urinary net chare, becomes negative, ranging from .#' to more than .4' meq<>. The negative value
occurs because the $l. concentration now e1ceeds the sum total of Ia, and ,.
In contrast, if there is an impairment in /idne* function resulting in an inabilit* to increase ammonium e1cretion !i.e. 2enal Tubular
)cidosis), then $l. ions will not be increased in the urine and the urine anion gap will not be affected and will be positive or ;ero.
In a patient with a h*perchloremic metabolic acidosis: A neati9e UAG suests GI loss of bicarbonate Ae diarrheaB, a
positi9e UAG suests impaired renal acidification Aie renal tubular acidosisB'
)s a memor* aid, remember QneGU?iveR . negative G)L in bowel causes.
2emember that in most cases the diagnosis ma* be clinicall* obvious !severe diarrhea is hard to miss) and consideration of the
urinar* anion gap is not necessar*.
8ee case 4 for an e1ample.
%smolar Lap
The %smolar Lap is another important diagnostic tool that can be used in differentiating the causes of elevated anion gap
metabolic acidosis. The ma0or osmotic particles in plasma are Ia, , $l. , "$%&., urea and glucose and as such, plasma osmolarit*
can be estimated as follows:
!lasma osmolarity % 0A:aB ) lucose.(6 ) BU:.0'6
Iote that because $l. and "$%&. are alwa*s bound to Ia, their contributions to osmolarit* are estimated b* doubling the Ia
concentration. (lasma osmolalit* !(osm) can also be measured directl* b* free;ing point depression. The osmolar gap is the
difference between the calculated serum osmolarit* and the measured serum osmolarit*.
Osmolar Gap % @easured !osm < Calculated !osm
The normal osmolar gap is 1'.14 mmol<> "#' .The osmolar gap is increased in the presence of low molecular weight substances
that are not included in the formula for calculating plasma osmolarit*. $ommon substances that increase the osmolar gap are
ethanol, ethylene lycol, methanol, acetone, isopropyl ethanol and propylene lycol'
In a patient suspected of poisoning, a high osmolar gap /particularly if 0 2'1 &ith an other&ise une2plained high
anion gap metabolic acidosis is suggesti"e of either methanol or ethylene glycol into2ication.
%ne must correlate an elevated osmolar gap with other clinical findings because it is a relativel* nonspecific finding that is also
commonl* seen in alcoholic and diabetic /etoacidosis, lactic acidosis and in chronic renal failure. 6levation in the osmolar gap in
these disease states is thought to be due in part to elevations of endogenous gl*cerol, acetone, acetone metabolites, and in the
case of renal failure, retention of unidentified small solutes.
8
Step>ise approach to interpretin the arterial blood as'
(. #M!' The most clinical useful information comes from the clinical description of the patient b* the histor* and ph*sical
e1amination. The "S( usuall* gives an idea of what acid base disorder might be present even before collecting the )BL sample
0. 4oo; at the p#. Is there an acid base disorder presentT
. If p" U 3.&4, then acidemia
. if p" V 3.54, then al/alemia
. If p" within normal range, then acid base disorder not li/el* present.
. p" ma* be normal in the presence of a mi1ed acid base disorder, particularl* if other parameters of the )BL are abnormal.
+. 4oo; at !CO0, #CO+,' Dhat is the acid base process !al/alosis vs acidosis) leading to the abnormal p"T )re both values
normal or abnormalT
. In simple acid base disorders, both values are abnormal and direction of the abnormal change is the same for both parameters.
. %ne abnormal value will be the initial change and the other will be the compensator* response.
+a. Distinuish the initial chane from the compensatory response'
, The initial change will be the abnormal value that correlates with the abnormal p".
. If )l/alosis, then ($%# low or "$%&. high
. If )cidosis, then ($%# high or "$%&. low.
%nce the initial change is identified, then the other abnormal parameter is the compensator* response if the direction of the change
is the same. If not, suspect a mi1ed disorder.
+b. %nce the initial chemical change and the compensator* response is distinguished, then identify the specific disorder. 8ee
table below.
. If ($%# is the initial chemical change, then process is respirator*.
. if "$%&. is the initial chemical change, then process is metabolic.
Acid Base Disorder Initial Chemical Chane Compensatory Response
Respiratory Acidosis I !CO0 I#CO+,
Respiratory Al;alosis G !CO0 G #CO+,
@etabolic Acidosis G #CO+, G !CO0
@etabolic Al;alosis I #CO+, I !CO0
2. If respiratory process, is it acute or chronicO
. )n acute respirator* process will produce a compensator* response that is due primaril* to rapid intracellular buffering.
. ) chronic respirator* process will produce a more significant compensator* response that is due primaril* to renal adaptation,
which ta/es a longer time to develop.
. To assess if acute or chronic, determine the e=tent of compensation. 8ee table.
7. If metabolic acidosis, then loo/ at the Anion Gap.
. If elevated !V than 16), then acidosis due to G>T. !etoacidosis, Gremia, >actic acidosis, To1ins). 8ee table.
. If anion gap is normal, then acidosis li/el* due to diarrhea, 2T).
&. If metabolic process, is degree of compensation ade$uateT
. $alculate the estimated ($%#, this will help to determine if a seperate respirator* disorder is present. 8ee table.
5. If anion gap is elevated, then calculate the Delta,Ratio !K<K) to assess for other simultaneous disorders.
. K<K compares the change in the anion gap to the change in bicarbonate.
. If ratio between 1 and #, then pure elevated anion gap acidosis
. If U 1, then there is a simultaneous normal anion gap acidosis present.
. if V #, then there is a simultaneous metabolic al/alosis present or a compensated chronic respirator* acidosis.
6. If normal anion gap and cause is un/nown, then calculate the Urine Anion Gap AUAGB' This will help to differentiate 2T)s from
other causes of non elevated anion gap acidosis.
. In 2T), G)L is positive.
. In diarrhea and other causes of metabolic acidosis, the G)L is negative. !neGU?ive in diarrhea)
9
!hysioloic "ffects of Acidosis
Respiratory "ffects
#yper9entilation A 1ussmaul respirationsB
Shift of o=yhaemolobin dissociation cur9e to the riht
Decreases 0,+ D!G le9els in red cells, >hich opposes the effect abo9e' Ashifts the
ODC bac; to the leftB ?his effect occurs after & hours of acidemia'
Cardio9ascular "ffects
Depression of myocardial contractility Athis effect predominates at p# L 5'0 B
Sympathetic o9er,acti9ity A tachycardia, 9asoconstriction, decreased arrhythmia
thresholdB
Resistance to the effects of catecholamines Aoccur >hen acidemia 9ery se9ereB
!eripheral arteriolar 9asodilatation
Penoconstriction of peripheral 9eins
Pasoconstriction of pulmonary arteries
"ffects of hyper;alemia on heart
Central :er9ous System "ffects
Cerebral 9asodilation leads to an increase in cerebral blood flo> and intracranial
pressure Aoccur in acute respiratory acidosisB
Pery hih pCo0 le9els >ill cause central depression
Other "ffects
Increased bone resorption Achronic metabolic acidosis onlyB
Shift of 1) out of cells causin hyper;alemia Aan effect seen particularly in
metabolic acidosis and only >hen caused by non oranic acidsB
Increase in e=tracellular phosphate concentration
!hysioloic "ffects of Al;alosis
Respiratory "ffects
Shift of o=yhaemolobin dissociation cur9e to the left Aimpaired unloadin of
o=yen
?he abo9e effect is ho>e9er balanced by an increase in 0,+ D!G le9els in RBCs'
Inhibition of respiratory dri9e 9ia the central M peripheral chemoreceptors
Cardio9ascular "ffects
Depression of myocardial contractility
Arrhythmias
Central :er9ous System "ffects
Cerebral 9asoconstriction leads to a decrease in cerebral blood flo> Aresult in
10
confusion, muoclonus, asteri=is, loss of consciousness and seiQuresB Only
seen in acute respiratory al;alosis' "ffect last only about & hours'
Increased neuromuscular e=citability A resultin in paraesthesias such as
circumoral tinlin M numbnessR carpopedal spasmB Seen particularly in acute
respiratory al;alosis'
Other "ffects
Causes shift of hydroen ions into cells, leadin to hypo;alemia'
Iote: :ost of the above effects are short lasting.
"tioloy of Acid Base Disturbances
This teaching module will give an overview of common causes of specific acid base disoders. )lso included are conditions or scenarios that
commonl* lead to mi1ed acid base disorders.
:etabolic )cidosis
:etabolic )l/alosis
2espirator* )cidosis
2espirator* )l/alosis
:i1ed )cid Base 9isorders
@etabolic Acidosis
A primary metabolic acidosis is characteri3ed by lo& arterial pH /4 +.3'1, reduced plasma HCO3- concentration,
and compensatory al"eolar hyper"entilation resulting in decreased !CO2.
It can be induced b* either increased endogenous acid production, increased e1ogenous acid administration, loss of "$%&., or
b* decreased abilit* to e1crete the normal dietar* ", load.
Differential Dianosis
The differential diagnosis of metabolic acidosis is vast and is best approached if one brea/s down the causes of metabolic
acidosis into normal vs elevated anion ap metabolic acidosis. 8ee below.
"le9ated Anion Gap AN(& me$B :ormal Anion Gap A6,(& me$B
Increased "ndoenous production:
1etoacidosis AAlcohol, Star9ation,
D1AB
4actic Acidosis
Uremia
4oss of Bicarbonate:
Diarrhea
Carbonic anhydrase inhibitors
?ype 0 R?A Apro=imalB
!ancreatic ileostomy
!ancreatic, biliary, intestinal fistula
"=oenous Administration:
ammonium chloride or #C4
Decreased Renal Acid "=cretion:
?ype (AdistalB ,2 R?A
Renal Eailure
Into=ications:
@ethanol, "thylene Glycol,
!araldehyde, Salicylates, I:#
@iscellaneous:
#yper;alemia
Reco9ery from D1A
Clic; submenu or ne=t for select causes of metabolic acidosis
4actic Acidosis
) commonl* encountered cause of elevated anion gap metabolic acidosis, particularl* in the I$G is lactic acid. >actic acidosis is
characteri;ed b* a p" U 3.&6 and lactate level V 7mmol.4
>actic acid is produced under normal aerobic states in cells of the brain, retina, and er*throc*tes. Gnder normal circumstances,
lactate is circulated to the liver, and to a lesser degree the /idne*, where it is converted into glucose or $%# and "#%.
4actate ) +O0 J #CO+, ) 0CO0 ) 0#0O
0 4actate ) 0CO0 ) 0#0O J 0#CO+, ) lucose'
11
In h*po1ic states !low %# suppl*) such as in strenuous muscle activit* !sei;ure) or in low tissue perfusion states from circulator*
failure, lactic acid is also produced anaerobicall* during gl*col*sis. This occurs via the following reaction:
This conversion of p*ruvate to lactate in anaerobic conditions is promoted b* the accumulation of I)9" and the depletion of I)9,
which is needed as an electron acceptor so that gl*col*sis can continue. The conversion to lactate results in the regeneration of
I)9, so that minimal amounts of )T( can be made indefinitel* from gl*col*sis in states of ver* low tissue o1*genation.
>actate accumulation and lactic acidosis results because in states of low tissue perfusion such as shoc/, or in states of
mitochondrion d*sfunction, lactate cannot be rec*cled to the liver for conversion bac/ to glucose or for further brea/down because
both of these reactions as shown above require o1*gen and both ta/e place in the mitochondrion.
There are primaril* # t*pes of lactic acidosis:
?ype A 7 9ue to tissue h*poperfusion and h*po1ia
?ype B 7 Iot due to tissue h*poperfusion and h*po1ia.
?ype A 4actic Acidosis
:ost cases of lactic acidosis are due to reduced o1*gen deliver* as a result of reduced tissue perfusion from shoc; or
cardiopulmonar* arrest. %ther conditions such as acute pulmonary edema, can cause severe h*po1emia leading to reduced %#
deliver*. %ther causes are carbon mono1ide poisoning and se9ere anemia. %ther causes of t*pe ) lactic acidosis which ma* not
necessaril* involve generali;ed tissue h*po1ia are se9ere seiQure, se9ere e=erciQe and hypothermic shi9erin. )ll of which
result in locali;ed s/eletal muscle h*po1ia leading to increased lactic acid production.
The clinical signs usuall* indicate reduced tissue perfusion and include severe h*potension, tach*pnea, oliguria or anuria,
peripheral vasoconstriction and deteriorating mental status. Sepsis, particularl* in criticall* ill patients is a ver* important cause of
lactic acidosis and is often associated with fever !V&C.4W$) or h*pothermia !&4W$). 1ussmaul hyper9entilation !deep sighing
respiration) ma* be observed if the severit* of the acidosis is sufficient to elicit a degree of respirator* compensation. >actic
acidosis is usuall* associated with laborator* abnormalities indicating organ failure or compromise such as abnormal liver function
tests, elevated BGI and elevated creatinine. >actate levels are usuall* greater than 4 meq<>. Gpper limit of nl is 1.6 in plasma.
)nion gap is classicall* elevated, V 16.
?ype B 4actic Acidosis
Gsuall* without clinicall* apparent tissue h*po1ia and can be due to an* number of conditions:
Gnderl*ing diseases: 9:, uremia, liver disease, infections, malignancies
9rugs and to1ins: ethanol, methanol, eth*lene gl*col, salic*lates, metformin
Inborn errors of metabolism: p*ruvate deh*drogenase deficienc*, gl*cogen storage disease, p*ruvate carbo1*lase
deficienc*, etc.
%ther : D,4actic acidosis !short bowel s*ndrome) X, idiopathic
T*pical picture includes acute onset after nausea and vomiting, altered state of consciousness and h*perventilation. >aborator*
findings are variable depending on underl*ing cause.
D,4actic AcidosisX
6asil* missed diagnosis, because the isomer responsible for the acidosis is the 9. isomer which is not detected b* the standard
assa* for lactate. This unique form of lactic acidosis can occur in patients with KeKunoilelal bypass, or less commonl*, small bo>el
resection or other causes of the short bo>el syndrome'
In these settings, the glucose and starch are metaboli;ed in the colon into 9.lactic acid, which is then absorbed into the s*stemic
circulation. The ensuing acidemia tends to persist, since 9.lactate is not recogni;ed b* >.lactate deh*drogenase, the en;*me that
catal*;es the conversion of the ph*siologicall* occurring >.lactate into p*ruvate.
12
Two factors that tend to contribute to the accumulation of 9.lactate s*stemicall* are 1) an o9erro>th of ram positi9e
anaerobes, such as lactobacilli that are most able to produce 9.lactate and #) increased deli9ery of lucose and starch to the
colon in the presence of a shorter small bo>el transit'
(atients t*picall* present with recurring episodes of metabolic acidosis, usuall* after a carboh*drate meal, and characteristic
neurologic abnormalities including confusion, cerebella ata1ia, slurred speech, and loss of memor*.
Criteria for D,lactic acidosis:
(resence of short bowel s*ndrome with an intact colon.
)n acute episode of encephalopathic s*mptoms, such as confusion, slurred speech , ata1ia, unstead* gait, abusive
behavior and<or n*stagmus
:etabolic acidosis with an increased anion gap
Iormal >.lactate levels
8erum 9.lactate levels V & mmom<>
)bnormal colonic flora, with a predominance of Lram positive anaerobic bacteria !>actobacilli, which produce large
amounts of lactic acid)
?reatment for 4actic Acidosis
Treatment of lactic acidosis requires identification of the primar* illness and therap* directed toward correction of that disturbance.
2estoration of tissue o1*gen deliver* through hemod*namic and<or respirator* support is the /e* therapeutic goal in t*pe ) lactic
acidosis, which will reduce further lactate production and allow metabolism of e1cess lactate to "$%&. .
Gnli/e other forms of metabolic acidosis, the use of sodium bicarbonate in lactic acidosis is controversial, particularl* in patients
with circulator* and respirator* failure. (roponents argue that raising the arterial p" ma* improve tissue perfusion, b* reversing
acidemia induced vasodilatation and impaired cardiac contractilit*, and ma* diminish the ris/ of serious arrh*thmias. %thers argue
that the Ia"$%& administration ma* actuall* worsen acidosis, particularl* in patients with respirator* compromise due to the
generation of $%# from the metabolism of Ia"$%&. It is thought that this $%# accumulates in tissues leading to worsening
intracellular acidosis. The intracellular acidosis leads to reduced lactate utili;ation in hepatic cells and a decline in cardiac
contractilit* leading to reduced cardiac output and parado=ically further promotion of lactic acid production. %thers also argue
that Ia"$%& administration carries with it a ris/ of volume overload and o9ershoot metabolic al;alosis after normal
hemod*namic has been restored.
9espite the controvers* most ph*sicians support administration of Ia"$%& for ver* severe acidemia and will give small amounts
of Ia"$%& to maintain the arterial p" above 3.1', since a p" be*ond this value will promote the development of arrh*thmias and
cardiac depression.
?reatment for D,4actic acidosis
8pontaneous regeneration of "$%&. does not occur in 9.lactic acidosis, since 9.lactate cannot be metaboli;ed. Therap* for 9.
lactic acidosis consists of sodium bicarbonate administration to correct the acidemia and oral antibiotics to decrease gram
positive anaerobic colonic bacteria. ) low carboh*drate diet is also helpful in the reducing carboh*drate deliver* to the colon.
1etoacidosis
etoacidosis is a common form of elevated anion gap metabolic acidosis seen in patients with insulin requiring diabetes mellitus,
alcoholics and pts undergoing fasting or starvation and is due to the overproduction of /etone bodies !etosis) leading to
accumulation of /etones in plasma !etonemia) and urine !etonuria).
The basic mechanism for the development of etonemia is as the following. In starvation states where plasma glucose levels are
low or in states of low plasma insulin where upta/e of glucose b* cells is diminished, fatt* acids will be mobili;ed and transported to
tissues !brain, s/eletal muscle, heart) for fatt* acid o1idation and energ* production. @att* acids are also transported to the liver,
where due to diminished citric c*cle activit* resulting from gluconeogenesis, acet*l $o) from fatt* acid o1idation can not be
o1idi;ed and is instead converted to the generation of /etone bodies. These /etone bodies !acetoacetate and N.h*dro1*but*rate)
serve as a source of fuel for other tissues, in particular, the brain. etonemia arises when this process is prolonged due to
prolonged states of glucose unavailabilit*, as the hepatic production of /etone bodies overwhelms the capacit* of e1trahepatic
tissues to o1idi;e them. )ccumulation and ioni;ation of /etones in plasma result in the release of e1cess h*drogen ions which then
lead to acidosis.
Clic; ne=t for causes of 1etoacidosis
Diabetic 1etoacidosis AD1AB
13
Gncontrolled t*pe 1 diabetes mellitus is the most common cause of /etoacidosis. The lac/ of insulin contributes to this condition not
onl* via decreased glucose upta/e but also b* promoting lipol*sis !trigl*ceride brea/down) and fatt* acid o1idation. It is a state that
also includes an increase in counter,reulatory hormones !ie, glucagon, cortisol, growth hormone, epinephrine) which contribute
to h*pergl*cemia b* promoting further gluconeogenesis and to /etonemia b* promoting acet*l 7$%) migration into mitochondrion
where the* can be converted into /etones.
(rogressive rise of blood concentration of these acidic organic substances initiall* leads to a state of /etonemia. Iatural bod*
buffers can buffer /etonemia in its earl* stages. Dhen the accumulated /etones e1ceed the bod*Es capacit* of e1tracting them,
the* overflow into urine !ie, /etonuria). If the situation is not treated promptl*, more accumulation of organic acids leads to fran/
clinical metabolic acidosis !ie, /etoacidosis), with a drop in p" and bicarbonate serum levels. "*pergl*cemia usuall* e1ceeds the
renal threshold of glucose absorption and results in significant gl*cosuria. $onsequentl*, water loss in the urine is increased
!pol*uria) due to osmotic diuresis induced b* gl*cosuria. This incidence of increased water loss results in severe deh*dration, thirst,
tissue h*poperfusion, and, possibl*, lactic acidosis. In addition, beta h*dro1*but*rate induces nausea and vomiting that
consequentl* aggravate fluid loss. ?ypical free >ater loss in D1A is appro=imately & liters or nearl* 1'' m></g of bod* weight.
"*pergl*cemia, osmotic diuresis, serum h*perosmolarit*, and metabolic acidosis result in severe electrol*te disturbances. The
most characteristic disturbance is total body potassium loss. Total bod* potassium loss is usuall* present despite normal or high
serum potassium levels. (otassium levels ma* appear to be high due to the transcellular shift of potassium out of cells. This is not
due to /etoacidosis directl* but rather is due to insulin deficienc* and h*perosmolalit*. ) large part of the shifted e1tracellular
potassium is lost in urine because of osmotic diuresis. )lso, when /etoacids are e1creted, the* are usuall* e1creted with Ia or in
the urine, leading to further loss. Momiting ma* also contribute to potassium loss in these patients. !atients >ith initial
hypo;alemia are considered to ha9e se9ere and serious total body potassium depletion.
In addition, hyponatremia is usually present, and is usuall* due to the dilutional effect of h*perosmolalit* as water is shifted from
intracellular to e1tracellular compartments.
?he direct effect of hyperosmolarity is often counteracted by the lucosuria,induced osmotic diuresis. The diuresis results
in water loss in e1cess of sodium and potassium, which will tend to raise the plasma sodium concentration and plasma osmolalit*
unless there is a comparable increase in water inta/e. As such, hyponatremia is usually mild'
The combined effects of serum h*perosmolarit*, deh*dration, and acidosis result in increased osmolarit* in brain cells that ma*
clinicall* manifest as an alteration in the level of consciousness.
History
#4P of patients present with 9) as first presentation of their diabetes mellitus.
Gsuall* triggered b* illness: GTI, infection, stress !medical or emotional), :I
:a* also be due to poor compliance, or missed in0ections due to vomiting
Insidious increased thirst !ie, pol*dipsia) and urination !ie, pol*uria) are the most common earl* s*mptoms of 9).
Iausea and vomiting ma* occur associated with diffuse abdominal pain
>etharg*, somnolence, confusion ma* develop
9*spnea
8igns
8igns of deh*dration . Dea/ and rapid pulse, dr* tongue and s/in, h*potension, and increased capillar* refill time
%ral odor . $haracteristic fruit* odor !from acetone, a product of acetoacetate metabolism
8igns of acidosis . 9eep sighing breathing, abdominal tenderness, and disturbance of consciousness
Bod* temperature ma* be within the reference range or low, even in the presence of intercurrent infection.
>aborator*
Grine dipstic/ highl* positive for glucose, /etones !dipstic; detect acetoacetate but not beta,hydro=ybutyrate >hich is
the predominant ;etone, therefore test not al>ays positi9e initially for ;etones)
8erum /etones present
)BL : low bicarbonate, low ($%#, p" U 3.&4
14
)nion gap V 16
8erum normal, high or low.
8erum Ia low phos low.
8erum phosphate: usuall* phosphate depleted due to urine losses but are normal or high b* labs due to transcellular
shift out of cells in the setting of acidosis and insulin deficienc*. After treatment >ith Insulin, phosphate le9els usually
lo>
8erum glucose usuall* V &'' mg<dl but below C''mg<dl !unli/e I", where V 1''' mg<dl)
>eu/oc*tosis, even in the absence of infection
Bun<$r high due to prerenal a;otemia
?reatment
The ma0or goals of treatment are 1) rapid fluid volume e1pansion, #) correction of h*pergl*cemia and h*per/etonemia, &)
prevention of h*po/alemia during treatment, and 5) identification and treatment for an* associated bacterial infection
1. Eluids: IM@, in adults, rapid infusion of 1> of '.AP I8 !e.g. over &' min), repeat bolus as necessar* to prevent shoc/.
Dhen B( is stable and urine output adequate, can switch to '.54P I8 at a slower rate. This is done to replace the free
water loss induced b* the osmotic diuresis.
2. Insulin infusion: 1'.#' unit bolus !'.14 u</g), then 4.3 units<hr !'.1 unit</g<hr). This stops the lipol*sis and
gluconeogenesis and allows for the conversion of /etones to bicarbonate. B8 should not be allowed to fall below #4' in
the first 5.4 hours of treatment. If does, change rate to '.'& u</g<hr. Dhen anion gap normal, initiate 8Y insulin, overlap
for 1.#hr with insulin infusion. Dhen blood sugar less than 1C', can add 4.1'P de1trose to IM@.
3. !otassium replacement: If initial V6, then withhold replacement. If U 5.4, then administer 1'.#' meq<hr of . If initial
U &, then administer 5' meq<hr.
4. Bicarb replacement: If p" U 3.1 and<or cardiac instabilit* present, then give bicarb
5. !hosphate replacement: Live .phos if initial (U 1.'mg<dl. !usuall* high initiall*, due to the transcellular shift of
phosphate outside the cell in the setting of acidosis and insulin deficienc*)
Alcoholic 1etoacidosis
)lcoholic /etoacidosis !))) is an acute metabolic acidosis that t*picall* occurs in people who chronicall* abuse alcohol and have
a recent histor* of binge drin/ing, little or no food inta/e, and persistent vomiting. )) is characteri;ed b* elevated serum /etone
levels, high anion gap and a normal or onl* slightl* high plasma glucose
!athophysioloy: )) is a result of prolonged starvation with gl*cogen depletion, increase in counter.regulator* hormone
production, deh*dration, and the metabolism of ethanol itself.
9ue to a ph*sical complaint !abdominal pain, vomiting), dietar* inta/e usuall* ceases in these patients leading to starvation and the
development of increased /etoacid production. The bod*Es response to starvation is a decrease in insulin activit* and an increase in
the production of counter.regulator* hormones such as glucagon, epinephrine, growth hormone and cortisol. 9ecrease in insulin
plus an increase in the concentration of counter.regulator* hormones, primaril* glucagon, result in increased lipol*sis, fatt* acid
mobili;ation and transfer of fatt* acids to the liver. These fatt* aids are ta/en up b* the liver and undergo fatt* acid o1idation in the
mitochondrion which results in the accumulation of acet*l.$o). )s mentioned previousl*, the liver during states of starvation is
activel* undergoing gluconeogenesis, diminishing the citric c*cle b* using up intermediates. )cet*l.$o) which normall* enters the
citric c*cle for further o1idation, accumulates and is instead converted to /etoacids= N.h*dro1*but*rate and acetoacetate.
The metabolism of ethanol leads to an accumulation in reduced nicotinamide adenine dinucleotide !I)9"), which then result in #
processes: 1) Impaired conversion of lactate to p*ruvate or preferential conversion of p*ruvate to lactate, both resulting in
increased lactic acid levels, and #) a shift in the N.h*dro1*but*rate to acetoacetate equilibrium toward N.h*dro1*but*rate.
As a result, S,hydro=ybutyrate is by far, the predominant ;etone in A1A. ?he standard nitroprusside test for
detectin ;etones unfortunately only detects acetoacetate and in A1A may be falsely neati9e or only minimally positi9e,
and can lead to a an underestimation of the deree of ;etoacidosis'
)cid base disorders in ))
15
These patients frequentl* ma* present with a mi1ed acid base disturbance:
6levated anion gap metabolic acidosis secondar* to etoacidosis
:etabolic al/alosis as a result of persistent vomiting
$hronic respirator* al/alosis as a result of liver disease.
:ild degree of lactic acidosis ma* also be present, contributing to the elevated anion gap acidosis.
"istor*
$hronic alcoholic who goes on drin/ing binge
9evelops pancreatitis, gastritis, which leads to abdominal pain, nausea and persistent vomiting
8*mptoms leads to cessation of alcohol consumption and poor oral inta/e 1 to & da*s prior to presentation
8*mptoms ma* also include that of liver disease or portal h*pertension : melena, hematoche;ia, hematemesis, fatigue,
d*spnea
)lcoholic withdrawal: tremors, sei;ure, hallucinations, delirium tremens
8igns
Tach*cardia, tach*pnea, ussmaul respiration, h*potension !possibl*)
)bdominal tenderness !particularl* if pancreatitis present)
"eme.positive stools
(h*sical e1am findings ma* include that of chronic liver disease: spider nevi, ascitis, hepatomegal*, caput medusa,
palmar er*thema, varices, 0aundice, g*necomastia
>aborator* findings
)BL: p" ma* be low high or normal depending on acid base disturbances present. ($%# will be low, "$%&. high. )nion
gap will be elevated, V16
8erum /etones ma* be falsel* negative, or onl* wea/l* positive.
8erum glucose ma* be low, normal or onl* slightl* elevated !in contrast to 9) were glucose levels are significantl*
elevated)
8erum lactate ma* be elevated
:g, phos, depleted low due to increased urinar* e1cretion and poor nutrition. (hos ma* appear normal or high due to
transcellular shift in the setting of acidosis.
Bun and $r elevated due to prerenal a1otemia
)nemia ma* be present due to alcohol induced bone marrow suppression, h*perspenism, or LI bleed
"ct ma* be falsel* elevated due hemoconcentration secondar* to volume loss.
)lcohol levels absent or low
>@Ts ma* be abnormal if liver disease present. )m*lase, lipase elevated if pancreatitis present
?reatment
6stablish )B$s. If the patientEs mental status is diminished, consider administration of o1*gen, thiamine, de1trose, and
nalo1one. 2emember thiamine must be given prior to de1trose to prevent Dernic/e orsa/off.
%nce the diagnosis of )) is established, the mainsta* of treatment is h*dration with 4P de1trose in normal saline
!94I8.) $arboh*drate and fluid replacement reverse the pathoph*siologic derangements that lead to )) b* increasing
serum insulin levels and suppressing the release of glucagons and other counter.regulator* hormones. 9e1trose
16
stimulates the o1idation of I)9" and aids in normali;ing the I)9"<I)9, ratio. @luids alone do not correct )) as
quic/l* as fluids and carboh*drates together.
Insulin contraindicated, because ma* lead to life threatening h*pogl*cemia particularl* as the patientRs endogenous insulin
levels rise with carboh*drate and fluid repletion.
Bicarbonate onl* given if p" U 3.1, and acidosis not responding to IM@.
Star9ation. Eastin
8tarvation, as mentioned previousl* can result in /etoacidosis due to the increase in counter.regulator* hormones and a decrease
in insulin, a balance which promotes fatt* acid o1idation, gluconeogenesis, and /etone production.
"owever in comparison to the potentiall* severe /etoacidosis that develops in uncontrolled diabetes and alcoholic states, /etoacid
levels do not e1ceed 1' meq<> with fasting. This limitation in the /etone formation ma* reflect the abilit* of /etonemia to promote
insulin secretion, eventuall* limiting the release of free fatt* acids and thus /etoacidosis
Renal ?ubular Acidosis
Renal Tubular Acidosis (RTA) refer to a group of disorders intrinsic to renal tubules characterized by an impairment in urinary acidification
which result in retention of H+ ions, reduction in plasma [H!"#$ and a hyperchloremic metabolic acidosis with a normal serum anion gap%
There are " distinct types of RTA, each ha&ing a different pathophysiology leading to decreased acid e'cretion% The urinary anion gap ([(a + )$
* l# ) is usually positi&e in RTA due to an inability to e'crete H+ % This distinguishes RTA from the other causes of normal anion gap metabolic
acidosis such as diarrhea which will ha&e a negati&e urinary anion gap%
Clic; ne=t or submenu for a discussion on each type of R?A'
?ype ( ADistalB R?A
T*pe 1 or distal 2T) is referred to as the classic 2T) and is a disorder of acid e1cretion involving the collectin tubules. The
disorder is characteri;ed b* a hypo;alemic, hyperchloremic metabolic acidosis.
(athoph*siolog*
The disorder is due to defective ", ion secretion in the distal tubule. Impairment in #) ions secretion result in an inability to
acidify the p# beyond 7'7 which retards the e1cretion of titratable acids !"#(%5) and I"5
,
ions, thus resulting in a reduction in net
acid e1cretion. The plasma bicarbonate is significantl* reduced and ma* fall below (/ me$.4'
The impairment in ", ions secretion is most commonl* thought to be due to a defect in the luminal #) ,A?!ase pump located in
the intercalating cells of the collecting tubule. The ", .)T(ase pump is primaril* responsible for the h*drogen secretion in the distal
nephrons.
These patients tend to have urinar* , wasting and h*po/alemia. The etiolog* of the h*po/alemia is unclear but is thought to be
due to increased potassium secretion b* distal tubular cells in the setting of diminished ", ion secretion.
"*percalciuria, h*perphosphatemia, nephrolithiasis !calcium phosphate stones) and nephrocalcinosis are fre$uently associated
>ith untreated type ( R?A' The h*percalciuria is thought to be due to 1) increased calcium phosphate release from bone as a
result of bone buffering of e1cess acid and #) reduction in tubular calcium reabsorption secondar* to chronic acidosis. The
h*percalciuria, al/aline urine, and reduced e1cretion of citrate in the urine !which normall* prevents calcium cr*stalli;ation) promote
the precipitation of calcium phosphate and stone formation. The h*pocitraturia is thought to be due to the effects of acidosis and
h*po/alemia on pro1imal tubule reabsorption.
$auses
:an* different conditions have been associated with t*pe I 2T). 8ee table below. The most common identifiable causes in adults
are autoimmune disorders, such as SKorenTs syndrome . In children, 2T) is most often a primar* hereditar* condition.
8*mptoms
?he loss of calcium salts from bones in these patients can result in failure to thri9e, ric;ets and stuntin of ro>th in
children and osteomalacia or osteopenia in adults. (atients ma* otherwise be as*mptomatic or ma* present with s*mptoms of
severe acidosis or h*po/alemia !pol*uria, pol*d*psia, wea/ness and fatigue)
17
@aKor causes of distal R?A
Idiopathic or sporadic in children
Eamilial
Autosomal dominant
Autosomal recessi9e
Secondary AAc$uiredB
SKorenDs
#ypercalciuria
Rheumatoid Arthritis , S4"
#yperlobulinemia
Ifosfamide, Amphotericin , 4ithium carbonate
Sic;le cell anemia
Cirrhosis, renal transplant
?ype 0 A!ro=imalB R?A
T*pe # 2T) is characteri;ed b* an impairment in pro=imal #CO+, reabsorption resulting in a hypo;alemic hyperchloremic metabolic
acidosis'
(athoph*siolog*
This condition usuall* appears as part of a generali;ed disorder of pro1imal tubular function /nown as Eanconi syndrome which also
include defects in the absorption of glucose, amino acids, phosphate, uric acid, and other organic anions such as citrate.
The reduction in "$%&. reabsorption leads to an increase in bicarbonate loss in the urine. 2emember that a loss of a single bicarbonate
ion is a/in to adding one h*drogen ion to the plasma, therefore this bicarbonate loss in the urine leads to increased h*drogen ion
concentration and a subsequent reduction in arterial p".
Gsuall* about A'P of the filtered "$%&. is absorbed b* the pro1imal tubule, the rest is absorbed b* the distal nephrons. In the setting of
pro1imal impairment of "$%&. , the distal nephrons become overwhelmed b* an increase in "$%&. deliver* and cannot compensate for
the loss in pro1imal function. "owever as urinar* "$%&. loss progresses, plasma "$%&. drops to 14.1C meq<>. This causes the level of
filtered "$%&. to fall and thus there is reduced deliver* of "$%&. ions to the distal nephrons. )t that point, the distal nephrons are no
longer overwhelmed and can regain function, leading to a reduction in bicarbonaturia and a urine which can now be acidic. This is in
contrast to t*pe 1 2T), where urine acidification is limited to a minimum urinar* p" of 4.4.
?hus type 0 R?A is a self limitin disorder in >hich the plasma #CO+, concentration is usually bet>een (2 and 0/ me$.4
due to the establishment of a ne> steady state'
Grinar* , wasting and h*po/alemia are common in t*pe # 2T) and is due to persistent hyperaldosteronism, leading to increased
secretion b* the distal nephrons. "*peraldosteronism in these patients are related to the defect in pro1imal reabsorption of filtered "$%&.
which in effect leads to decreased pro1imal Ia$l reabsorption and a tendenc* for salt wasting.
The factors responsible for the defects in pro1imal transport are incompletel* understood. There are three features of the pro1imal tubules
that are vital to pro1imal reabsorption of "$%&. : 1) the :a), #) e=chaner in the luminal membrane, #) the :a),1) A?!Ase pump in
the basolateral membrane and &) the enQyme carbonic anhydrase, which is located both intracellularl* where it results in the generation
of ", and "$%&. , and in the lumen, where it facilitates "$%&. reabsorption. It has been proposed that one or more of these factors must
be impaired to account for the defect in t*pe # 2T).
$auses
Below is a table showing some of the /nown causes of t*pe II 2T). ) variet* of congenital and acquired disorders can cause t*pe # 2T).
Idiopathic 2T) and c*stinosis are most common in children= carbonic anhydrase inhibitors and multiple myeloma are most often
responsible in adults.
$omplications
)s in t*pe 1 2T), bone disease also occurs due to an increase in bone buffering of e1cess acid and the release of calcium salts from bone.
Also contributin to this problem is ac$uired 9itamin D deficiency, since the pro=imal tubule is a maKor site of formation of
calcitriol'
9efects in pro1imal transport ma* also result in phosphate wasting and hypophosphatemia leading to decreased deposition of mineral in
bone. 2ic/ets in children and osteomalacia or osteopenia in adults are relativel* common in t*pe # 2T), occurring in up to #'P of cases.
18
In contrast to t*pe 1 2T), nephrocalcinosis and nephrolithiasis does not occur, and this is due to normal levels of urinar* citrate in this
condition !in contrast to t*pe #) and the abilit* to acidif* the urine which increases the solubilit* of calcium phosphate.
@aKor Causes of type 0 R?A
Idiopathic or sporadic in children
#ereditary
A' Cystinosis
B' Galactosemia
C' ?yrosinemia
D' Glycoen storae disease, type (
"' CilsonDs disease
Ac$uired disorders
A' @ultiple @yeloma
B' #ypocalcemia and 9itamin D deficiency
C' Drus and ?o=ins: AAcetaQolamide or other carbonic anhydrase inhibitor,
Ifosfamide, StreptoQocin, 4ead, Cadmium, @ercury, outdated tetracyclineB
D' Amyloidosis
"' Renal transplant reKection
?ype 2 R?A
T*pe IM 2T) is the onl* t*pe characteri;ed b* a hyper;alemic, hyperchloremic acidosis. The defect is thought to be
Aldosterone deficiency or resistance'
(athoph*siolog*
)ldosterone deficienc* or resistance impairs the secretion of h*drogen and potassium ion resulting in acidosis and hyper;alemia.
The h*per/alemia is usuall* ver* prominent in this condition and has an important role in metabolic acidosis b* impairing
ammonium production and acid e1cretion in the urine. The h*per/alemia in this setting impairs I"5, production in the pro1imal
tubule b* inducing a state of intracellular al;alosis within the tubular cell. This occurs due to the transcellular e1change of
potassium for h*drogen resulting in the e1it of h*drogen ion from the cell.
The development of intracellular al/alosis reduces I"5, secretion b* the pro1imal tubular, which in combination with decreased
h*drogen secretion distall*, result in decreased ammonium e1cretion and decreased net acid e1cretion. 2eversing this process b*
correcting the h*per/alemia often leads to increased I"5, e1cretion and correction of the metabolic acidosis
The metabolic acidosis seen with h*poaldosteronism is generall* mild, with the plasma +"$%&.- usually abo9e (7 me$.4. Despite
the impairment in distal #) secretion, the urine p# in this disorder is enerally but not al>ays belo> 7'+, in contrast to t*pe
1 2T). The abilit* to acidif* the urine in this condition is due to the inadequate amount of I"& available for buffering of protons.
6ven if onl* a few protons are secreted distall*, urinar* p" will fall in the absence of buffers. This is in contrast to t*pe 1 2T) where
distal ", secretion is impaired and an* protons secreted will be buffered b* available I"& , thus maintaining an al/aline urine.
$auses
T*pe 5 2T) due to aldosterone deficienc* has multiple etiologies. #yporeninemic hypoaldosteronism is the most common cause
and is usuall* asscoiated with mild to moderate renal insufficenc*. It is most commonl* found in diabetes nephropathy and
chronic interstitial nephritis. I8)I98, )$6 inhibitors, trimetoprim and heparin can all reduce aldosterone production and
produce a t*pe 5 2T). 9rug.induced t*pe 5 2T) is usuall* seen in patients with pre.e1isting renal insufficienc*.
(atients with tubular resistance to aldosterone will present ver* similarl* to h*poreninemic h*poaldosteronism. It is thought to be
due to a tubulointerstial process that damages the distal tubule causing retention of h*drogen and potassium ions despite adequate
aldosterone. B!# and sic;le cell disease are the most common causes. Spironolactone has also been /nown to cause an
aldosterone resistant state.
8*mptoms
T*pe IM 2T) is usuall* as*mptomatic with onl* mild acidosis, but cardiac arrh*thmias or paral*sis ma* develop if h*per/alemia is
e1treme.
19
Dianosis of R?A
T*pe I 2T)
The findings of h*po/alemic, normal anion gap metabolic acidosis with an inappropriately hih urine p# AN7'7B and postive urine
anion gap confirm the diagnosis' In patients with a normal plasma bicarbonate concentration, the failure to lower urinar* p" to less
than 4.4 after an acute acid challenge with I"5$l defines the s*ndrome of incomplete classic distal R?A
T*pe II 2T)
The diagnosis of t*pe # 2T) is made b* measurement of the urine p" and fractional bicarbonate e1cretion during a bicarbonate
infusion.The plasma bicarbonate concentration is raised toward normal !1C.#' meq<>) with an intravenous infusion of sodium
bicarbonate at a rate of '.4 to 1.' meq</g<hour. The urine p" , even if initiall* acidic, will rise rapidl* once the reabsorptive threshold
for bicarbonate is e1ceeded. As a result, the urine p# >ill be abo9e 5'7 and the fractional e=cretion of bicarbonate >ill
e=ceed (7U .
T*pe IM 2T)
The findings of hyper;alemic, normal anion gap metabolic acidosis with an appropriately lo> urine p# AL7'7B and positive urine
anion gap confirm the diagnosis. The diagnosis is further supported b* a bicarbonate fractional e1cretion of less than 1'P in the
setting of bicarbonate infusion.
Comparison of R?A
Eindin ?ype ( R?A ?ype 0 R?A ?ype 2 R?A GI Bicarbonate
loss
Basic defect Decreased distal
acidification
Diminished
pro=imal #CO+,
reabsorption
Aldosterone
deficiency or
resistance
:ormal Anion,ap acidosis Ves Ves yes Ves
Urine anion ap !ositi9e !ositi9e !ositi9e :eati9e
@inimum urine ph N 7'7 Pariable, N 7'7 if
i9en an al;ali
load
L 7'7 7 to &
Serum 1 4o> 4o> #ih 4o>
U filtered bicarbonate
e=creted
L (/ N (7 L (/ L (/
!lasma *#CO+,-, untreated @ay be belo> (/
me$.4
Usually (2, 0/
me$.4
Usually abo9e (7
me$.4
Daily acid e=cretion 4o> :ormal 4o> #ih
GER :ormal :ormal 4o> :A
Stones.nephrocalcinosis Ves :o :o :o
Eanconi syndrome :o Ves :o :o
Treatment of 2T)
T*pe 1 2T)
Treatment of acidosis is generall* indicated in t*pe 1 2T) to allow normal growth to occur in children, to minimi;e stone formation,
nephrocalcinosis, and possible osteopenia due to calcium loss from bone, and to diminish inappropriate urinar* losses.
Al;ali supplement is the standard therapy% +nough al,ali is usually prescibed to titrate the fraction of daily acid load that is not e'creted%
In adults, this is usually (,0 me$.;.day%
(atients are generall* treated with Ia"$%& or sodium citrate. :an* patients do not need potassium replacement since correction
of acidemia leads to mar/ed improvement in potassium wasting. "owever patients with significant h*po/alemia, calcium stones, or
nephrocalcinosis require potassium and are treated with potassium citrate or (ol*citra !potassium citrate plus sodium citrate).
20
T*pe # 2T)
)l/ali therap* is required for normal growth in children and to prevent or treat osteopenia<osteomalacia in adults. 2eversal of
acidemia is difficult since the e1ogenous al/ali is rapidl* e1creted in the urine. )s a result, much higher doses of al/ali are required
in comparison to t*pe 1 and 5 2T). About (/,(7 me$.;.day of al;ali is typically re$uired to stay ahead of urinary e=cretion'
The preferred therap* is potassium citrate which also helps with potassium losses in this disorder. ?hiaQides are also sometimes
used with lo> salt diet to reduce the amount of al/ali required. Thia;ides induced volume contraction can be used to enhance
pro1imal "$%&. reabsorption leading to improvement in bicarbonaturia and renal acidification. If h*pophosphatemia is present,
vitamin 9 and phosphate supplement is also required.
T*pe 5 2T)
?herapy is aimed mainly at reducin serum potassium, as acidosis will usually impro&e once the hyper,alemic bloc, of ammonium
production is remo&ed% All patients should be placed on a low potassium diet% Any drugs that suppresses aldosterone production or bloc,s
aldosterone effects should be discontinued% -ineralocorticoid replacement with fludrocortisone will impro&e hyper,alemia and acidosis but is
not appropriate with patients with hypertension or a history of heart failure% These patients are instead treated with a lo> potassium diet and a
loop diuretic%
Uremic Acidosis
:etabolic acidosis is a common complication of renal disease and results from an inabilit* of the diseased /idne* to e1crete the
dail* dietar* acid load. To understand the effects of acid base with progressive renal failure, it is first necessar* to review the normal
handling of acids.
The dail* dietar* acid load is primaril* due to the generation of "#8%5 from the metabolism of sulphur containing amino acids. This
acid is rapidl* buffered b* "$%&. and other buffers, leading to the formation of sodium sulphate salts.
"#8%5 , #Ia"$%& ..... I)#8%5 , #"#$%& ..... #$%# , #"#% , I)#8%5.
To maintain the stead* state, both the #", and the 8%5#. must be e1creted in the urine. The e1cretion of ", occurs via the
e1cretion of titratable acids and more importantl*, I"5,. Dhilst, the e1cretion of 8%5#. anions depends on the capacit* of the
/idne* to filter and reabsorb the anions.
In initial stages of chronic renal disease, as the number of functioning renal tubules are reduced, the tubular functions of the /idne*
are diminished and the /idne*Rs abilit* to produce I"5, ions is affected, thus resulting in a reduction of h*drogen ions e1creted
and an increase in the amount of "$%&. ions e1creted. The e1cretion of bicarbonate ions results in a reduction in plasma +"$%&.-
and thus metabolic acidosis. %n the other hand, initiall* in $9, ultrafiltration occurs and glomerular filtration rate reduces at a
much slower pace than is the loss of tubular function. Therefore, the e1cretion of sulphate and other organic and inorganic acid
anions is not affected as their filtration b* the /idne* is maintained. In addition, the /idne*s lose the capacit* to reabsorb these
anions due to loss in tubular function leading to further anion e1cretion. To maintain electroneutralit*, the /idne*s retain $l. with
each bicarbonate ion lost and thus earl* renal disease is associated with a h*perchloremic metabolic acidosis. The anion gap is not
affected due to the continued e1cretion of organic acids b* the /idne*s.
In advanced /idne* disease as L@2 falls below #'ml<min, the /idne*s capacit* to filter the anions of organic acids is significantl*
diminished and thus there is retention of phosphates, sulphates, urate and hippurate anions in the plasma that significantl* raise
the anion gap resulting in an elevated anion gap metabolic acidosis.
To summarize: "arly chronic ;idney disease is associated >ith a hyperchloremic normal anion ap metabolic acidosis
>hile end stae renal disease AuremiaB is associated >ith an ele9ated anion ap metabolic acidosis'
In some cases of end stage renal disease, patients may also present &ith ele"ated anion and normal anion gap
acidosis simultaneously.
The acidosis associated with renal disease is usuall* not severe and this is due to the increased buffering of retained ", ions b*
bone. This process is manifested b* the release of calcium salts from bone and their e1cretion in urine. This calcium loss over time
can lead to osteopenia.
Treatment
To prevent bone loss and possible osteopenia, al/ali therap* is generall* recommended even for mild metabolic acidosis
associated with chronic renal disease. It is assumed that al/ali replacement will prevent the harmful effects of prolonged positive
", balance, including the persistent buffering of ", ions b* bone.
21
%ral al/ali is t*picall* used to maintain the +"$%&.- over #' meq<>. This can be accomplished with relativel* modest amounts of
al/ali !1.' to 1.4 m6q</g per da*). Gsuall* this is amount of new bicarbonate generated each da*.
Therapies include sodium bicarbonate and 8hohl !sodium citrate). 8odium citrate !8hohl solution) has been shown to enhance the
absorption of aluminum from the gastrointestinal tract and should never be administered to patients receiving aluminum.containing
antacids because of the ris/ of aluminum into1ication.
@etabolic Al;alosis
(rimar* metabolic al/alosis is characteri;ed b* an elevation in the arterial p", an increase in the plasma "$%&. concentration, and
a compensator* h*poventilation, resulting in a rise in the p$%#. It is often accompanied b* hypochloremia and hypo;alemia.
!athoenesis
:etabolic )l/alosis can be induced b* a loss of hydroen ions, transcellular #) shift, e=oenous al;ali administration or by
contraction al;alosis. These factors are /nown as initiator factors because the* are said to initiate the al/alosis. Gnder normal
circumstances, al/alosis should never develop because the /idne* is e1cellent at e1creting e1cess bicarbonate. "owever in
conditions where /idne* function might be impaired, e1cretion of bicarbonate ma* become compromised. :etabolic al/alosis is
alwa*s associated with an initiating factor and and an impairment in /idne* function referred to as the maintenance factor, that is
thought to maintain the al/alosis . 8ee table below.
The most common maintenance factor is a reduction in "CP that leads to a reduction in L@2 and an increase in Ia and "$%&.
reabsorption. )nother factor that maintains al/alosis is #ypo;alemia. )l/alosis can be both a cause and a result of h*po/alemia,
as will be discussed. @ineralocorticoid e=cess is another factor that initiates metabolic al/alosis. In those cases, the al/alosis is
maintained b* the development of h*po/alemia as will be discussed.
:etabolic al/alosis that is associated with a reduction in volume responds ver* well to treatment with normal saline and is said to
be saline responsi9e. :ineralocorticoid or h*po/alemia induced al/alosis does not respond to volume administration and is said
to be saline unresponsi9e' This will be discussed.
Initiatin Eactors @aintenance Eactors
Saline
Responsi9e
Saline
Unresponsi9e
Causes of metabolic Al;alosis
(B 4oss of hydroen
A' Gastrointestinal loss
(' Remo9al of astric secretions: Pomitin or nasoastric suction
0' Chloride,losin diarrhea
+' Gastrocolic fistula
2' Pillous adenoma
7' Antacid therapy, particularly if combined >ith cation e=chane resin
B' Renal loss
(' loop or thiaQide diuretics
0' @ineralocorticoid e=cess A!rimary Aldo, Cushins, steroids, licoriceB
+' !ost chronic hypercapnia
2' #ypercalcemia, includin the mil; of al;ali syndrome
C' #) mo9ement into cells
(' #ypo;alemia
0B "=oenous Al;ali
A' Administration of :a#CO+, sodium citrate, luconate, acetate, antacids
B' @assi9e blood transfusion
C' Antacids , @il; al;ali syndrome
+B Contraction al;alosis
A' 4oop or thiaQide,type diuretics
B' S>eat losses in cystic fibrosis
C' Gastric losses in achlorhydria
2B @iscellaneous
A' BartterDs syndrome
B' GitelmanDs syndrome
GI #ydroen 4oss and Reduction in "CP
>oss of h*drogen ions leading to metabolic acidosis most commonl* occurs via the LI tract in the form of 9omitin or nasoastric
suction. Lastric 0uice contains a high concentration of "$> and lesser concentration of $>. 6ach meq of ", ion secreted
generates 1 meq of "$%&. which is then absorbed in the plasma. Gnder normal conditions the increase in the plasma "$%&.
concentration is onl* transient, since the entr* of acid into the duodenum stimulates an equal amount of "$%&. secretion from the
pancreas. "owever there is no stimulus to "$%&. secretion if gastric 0uice is removed during vomiting and IL suction. The net
result is an increase in the plasma +"$%&.- and metabolic al/alosis.
22
(' 4oss of hydroen ions from
GI
0' "=oenous addition of
al;ali
+' ?ranscellular #) shift
2' Contraction al;alosis
(' Reduced "CP < decreased GER
and increased absorption of #CO+,
0' #ypo;alemia
(' @ineralocorticoid e=cess
0' Se9ere #ypo;alemia
#ypo;alemia
Gnder normal conditions, the e1cess "$%&. generated would be e1creted in the urine b* the /idne* and thus al/alosis would not
be maintained. "owever vomiting or nasogastric suction also results in a decrease in the e1tracellular fluid compartment and the
effective circulating volume !6$M). The reduction in the 6$M leads to decreased L@2 !less bicarb filtered), and also serves as a
stimulus to increase angiotensin and aldosterone production leading to an increase in Ia and "$%&. reabsorption b* the pro1imal
tubules. )n increase in Ia reabsorption leads to increased "$%&. reabsorption because of the increase in h*drogen secretion as
Ia is e1changed for ", across the Ia.", transporter in the pro1imal tubule. The secreted h*drogen ions combine with filtered
"$%&. leading to reabsorption as previousl* described. Aldosterone primarily acts distally to increase #) and 1 secretion
resultin in increased acid and potassium e=cretion. The net result is a h*po/alemic metabolic al/alosis. The almost complete
reabsorption of "$%&. in the setting of reduced 6$M, leads to the parado=ical findin of an acidic urine despite the presence of
e1tracellular al/alosis.
Contraction Al;alosis and #ypo;alemia
$ontraction al/alosis occurs whenever there is a loss in bodil* fluid that does not contain "$%&. . In this setting, which is most commonl*
due to diuretics, the e1tracellular volume contracts around a fi1ed quantit* of "$%&. resulting in a rise in +"$%&.-. Iote that in this setting,
the total bod* bicarbonate is the same as shown in the figure below.
The direct effect of contraction is largel* minimi;ed b* the release of ", from cell buffers, thereb* lowering the plasma +"$%&.-
toward normal. "owever, if 6$@ reduction b* diuretics result in h*povolemia, then as in vomiting, the release of angiotensin and
aldosterone will be stimulated. This then leads to an increase in "$%&. absorption and increased " and secretion. The increase
in potassium secretion result in the development of hypo;alemia which also pla*s a ver* important role in maintaining the
al/alosis.
#ypo;alemia
"*po/alemia is ver* commonl* associated with metabolic al/alosis. This is due to # factors: 1) the common causes of metabolic
al/alosis !vomiting, diuretics, mineralocorticoid e1cess) directl* induce both ", and loss !via aldosterone) and thus also cause
h*po/alemia and #) h*po/alemia is a ver* important cause of metabolic al/alosis. "*po/alemia causes metabolic al/alosis b*
three mechanisms. The initial effect is b* causing a transcellular shift in which leaves and ", enters the cells, thereb* raising the
e1tracellular p". The second effect is b* causing a transcellular shift in the cells of the pro1imal tubules resulting in an intracellular
acidosis, which promotes ammonium production and e1cretion. Thirdl*, in the presence of h*po/alemia, h*drogen secretion in
the pro1imal and distal tubules increases. This leads to further reabsorption of "$%&.. The net effect is an increase in the net acid
e1cretion.
!osthypercapnia
The normal stimulus to respirator* acidosis is a compensator* increase in "$%&. reabsorption b* the /idne* and thus an increase
in plasma +"$%&.-. Treatment with mechanical ventilation in this disorder leads to a rapid reduction in the p$%#. The plasma
"$%&. will however remain elevated, resulting in the development of metabolic al/alosis. The maintenance of al/alosis in this
setting is unclear. "owever chronic respirator* acidosis is thought to be associated with $l. loss in the urine leading to h*povolemia
and h*pochloremia. 2estoration of $l. and volume balance tends to correct the disorder.
@ineralocorticoid e=cess
23
The common causes of metabolic al/alosis cause and maintain metabolic al/alosis due to hypo9olemia induced secondary
hyperaldosteronism which leads to increased acid e1cretion and h*po/alemia. $onditions of mineralocorticoid e1cess such as
$onnEs s*ndrome, e1cess steroid administration and $ushingEs s*ndrome produce a state of h*peraldosteronism which also leads
to metabolic al;alosis and hypo;alemia' In these conditions, the e1tracellular volume is e1panded and the patient ma* have
h*pertension. In these patients, metabolic al/alosis is perpetuated b* the effects of hypo;alemia !not h*povolemia) which leads to
increased ammonium production, h*drogen secretion and bicarbonate reabsorbtion
Dianosis of @etabolic Al;alosis
%nce it has been determined that a patient has metabolic al/alosis, the etiolog* is usuall* obvious from the histor*. If there is no
pertinent histor*, then one can assume that the al/alosis is due to one of the three most common causes: 1) vomiting, #) diuretics,
&) mineralocorticoid e1cess. To differentiate between these conditions, it is usuall* helpful to measure the urinary chloride
concentration.
In causes of metabolic al/alosis associated with a reduction in the 6$M, there will be a stimulus for avid Ia and $l reabsorption to
replenish e1tracellular volume. In these setting urinary Cl should be e=pected to be 9ery lo>, less than 07 me$.4.
Grinar* Ia is not a reliable measure of e1tracellular volume in this setting because if the al/alosis is such that not all of the filtered
"$%&. can be reabsorbed, then some will be e1creted with Ia and the urinar* Ia ma* be high. Thus, it ma* appear that the
volume status is euvolemic or h*pervolemic when it is not.
If the urinar* $l is low, indicating a h*povolemic state, then administration of Ia$l and water to replenish the e1tracellular volume
should stop the stimulus for aldosterone production and in turn should lead to appropriate e1cretion of e1cess "$%&. and
improvement of h*po/alemia. Thus, leading to correction of the metabolic al/alosis. 8uch causes of metabolic al/alosis are said to
be saline responsi9e' 8ee table below.
In contrast, states of mineralocorticoid e=cess are associated >ith an e=panded 9olume and sometimes h*pertension. The
urinary Cl >ill be hih AN 2/ me$.4B' In these patients, administration of saline would further e1pand the e1tracellular volume and
worsen h*pertension. It would not correct the al/alosis which is primaril* due to h*po/alemia. 8uch causes of metabolic al/alosis
are said to be saline resistant.
Urine Cl L 07 me$.4
Saline Responsi9e
Urine Cl N 2/ me$.4
Saline Unresponsi9e
$auses of saline resistant metabolic al/alosis can further be distinguished based on whether or not the patient is h*pertensive.
:ineralocorticoid e1cess states tend to be associated with h*pertension while e1ogenous al/ali load, Barrters and LitelmanEs
s*ndrome are associated with normal blood pressure.
?reatment
8aline . 2esponsive metabolic al/alosis
Re,e=pand 9olume >ith :ormal Saline ! (rimar* Therap*)
8upplement with (otassium to treat h*po/alemia !al/alosis associated with se9ere h*po/alemia will be resistant to
volume resuscitation until is repleted)
", bloc/ers or ((Is if vomiting<IL suction to prevent further losses in ", ions
9iscontinue diuretics
)ceta;olamide if I8 contraindicated due to $"@. !:onitor for h*po/alemia)
"$l or I"5$l in emergenc*. !"$l can cause hemol*sis, I"5$l should not be used in liver disease)
"emodial*sis in patients with mar/ed renal failure
24
!rimary mineralocorticoid e=cess
"=oenous Al;ali load
BarrterDs or GitelmanDs syndrome
Se9ere #ypo;alemia A1L 0'/B
Pomitin or nasoastric suction
Diuretics
!osthypercapnia
Cystic Eibrosis
4o> chloride inta;e
8aline 7 Gnresponsive metabolic al/alosis !:ineraldocorticoid e1cess)
8urgical removal of mineralocorticoid producing tumor
)ldosterone inhibitor
)$6 inhibitor.
9iscontinue steroids
!otassium repletion !onl* intervention needed to treat the al/alosis)
Respiratory Acidosis
Respiratory acidosis is a clinical disorder characterized by a low arterial pH (< .!"#$ an elevation in the p%&' (hypercapnia# and a
compensatory increase in the plasma (H%&!)*.
"*percapnia also occurs in metabolic al/alosis, but this is rather a response to the high arterial p", which distinguishes the two.
!athophysioloy
)s mentioned previousl*, brea/down of carboh*drates and fats result in the endogenous production of up to #' mol of $%#. This $%#, if
not e1creted via ventilation will combine with "#% to form carbonic acid in the following reaction:
CO0 ) #0O W #0CO+ ACAB W #) ) #CO+,
)n* increase in ($%# due to increased $%# production is rapidl* handled b* increased alveolar ventilation. Because of the lungRs
e1cellent capacit* to e1crete e1cess $%#, increases in ($%# are alwa*s due to h*poventilation and never to increased $%# production.
"*poventilation can occur with an* interference in the respirator* process. 8ee table. $ommon etiologies are neuromuscular disorders,
$I8 depression, disorders of the chest wall, chronic obstructive lung disease and acute airwa* obstruction.
@or a discussion on the compensator* mechanisms of respirator* acidosis, clic/ here.
Causes of respiratory acidosis
AB C:S depression
(' Opioids
0' O=yen in patient >ith chronic hypercapnia
+' Central sleep apnea
2' C:S lesion
7' "=treme obesity A!ic;>ic;ian syndromeB
BB :euromuscular disorders
(' @yasthenia ra9is
0' Guillain,Barre
+' A4S
2' !oliomyelitis
7' @uscular dystrophy
&' @ultiple Sclerosis
CB Chest >all or ?horacic Cae Abnormality
(' 1yphoscoliosis
0' Elail Chest
+' @y=edema
2' Rib Eracture
7' Scleroderma
2B Disorders affectin as e=chane
(' CO!D
0' Se9ere asthma or pneumonia
+' !neumothora= or #emothora=
2' Acute pulmonary edema
7B Air>ay obstruction
(' Aspiration of forein body
0' Obstructi9e sleep apnea
+' 4arynospasm
Symptoms
8*mptoms are caused b* acute respirator* acidosis and not b* chronic respirator* acidosis and usuall* include neurologic abnormalities.
Initial s*mptoms include headache, blurr* vision, restlessness, and an1iet*, which can progress to tremors, asteri1is, delirium, and
somnolence or coma !$%# narcosis). 8evere h*percapnia increases cerebral blood flow and cerebrospinal fluid pressure. 8igns of
increased intracranial pressure such as papilledema ma* be seen.
The tendenc* to develop neurologic abnormalities in acute respirator* acidosis is due to the rapid reduction in $8@ p". $%# is lipid soluble
and rapidl* crosses the blood brain border, leading to a decline in $8@ p". In contrast, "$%&. is a polar compound that does not readil*
25
cross the blood border and thus is not available to counteract the actions of $%#. Thus acute respirator* acidosis promotes a greater fall in
$8@ p" than acute metabolic acidosis, which ma* e1plain wh* neurologic abnormalities are seen less often in the latter. In chronic
respirator* acidosis, the $%# accumulates at a much slower rate, allowing renal compensation to return the arterial p" and ultimatel* $8@
p" toward normal. Therefore neurologic abnormalities are also seldom seen in chronic respirator* acidosis.
?reatment
Treat underl*ing disorder
8uppl* o1*gen
$orticosteroids and bronchodilators to reduce airwa* inflammation and resistance.
:echanical ventilator if ventilation fails.
Respiratory Al;alosis
2espirator* )l/alosis is an acid base disturbance characteri;ed b* elevated arterial p", h*perventilation resulting in a low p$%# and a
usuall* compensator* decrease in plasma "$%&. concentration.
!athophysioloy
2espirator* )l/alosis results from an elevation in alveolar ventilation that causes a fall in the partial pressure of dissolved carbon dio1ide.
The fall in ($%# causes a compensator* fall in plasma "$%&. concentration as was decribed previousl*.
The causes of 2espirator* )l/alosis are shown in the table below. It is ver* commonl* induced b* what the bod* or patient perceives as a
stressor. The stressor which is often associated with an1iet*, pain, and infection stimulates the $I8 leading to h*perventilation. %ther
common causes are h*po1emia, sepsis, liver failure and (6. )spirin into1ication is an interesting cause of respirator* al/alosis which can
also cause an elvated anion gap acidosis.
AB C:S stimulation
(' pain
0' An=iety, !sychosis
+' Ee9er
2' CPA
7' @eninitis, encephalitis
&' ?umor, trauma
5' Drus: Salicylate Aalso causes metabolic acidosisB, methyla=anthines, theophylline,
aminophyllines'
6' !renancy, proesterone
BB #ypo=emia or tissue hypo=ia
(' #ih altitude
0' !ulmonary disease: pneumonia, interstitial fibrosis, !", pulmonary edema
+' C#E
2' #ypotension
7' Se9ere anemia
&' Aspiration
CB Chest Receptors stimulation
(' Elail Chest
0' #emothora=
+' !"
2B @iscellaneous disorders
('Gram neati9e septicemia A9ery early clinical sin of septicemiaB
0' #epatic failure
+' @echanical hyper9entilation
2' #eat e=posure
7' Reco9ery from metabolic acidosis
$linical :anifestations
$linical manifestations of respirator* al/alosis var* according to duration and severit* and depend on the underl*ing disease process.
In acute respirator* al/alosis, acute onset of h*pocapnia can cause cerebral vasoconstriction. Therefore, an acute decrease in ($%#
reduces cerebral blood flow and can cause neurologic s*mptoms, including di;;iness, mental confusion, s*ncope, sei;ures, paresthesias,
numbness around the mouth. This acute drop in ($%#, result in a substantial drop in $8@ p" not seen in chronic respirator* al/alosis or
metabolic al/alosis. In metabolic al/alosis, the change in $8@ p" occurs much slower due to the relative inabilit* of "$%&. to cross the
blood brain barrier in comparison to $%#.
In addition some complaints ma* be unrelated to the change in p". @or e1ample, patients with ps*chogenic h*perventilation often complain
of chest tightness, headache, d*spnea, and other somatic s*mptoms that ma* be related to an1iet* and not al/alemia.
)cute respirator* al/alosis also causes intracellular shift of potassium and phosphates potentiall* resulting in h*po/alemia and
26
h*pophosphatemia. The h*po/alemia is usuall* mild. "*pocalcemia t*picall* results, due to an increase in albumin bound calcium and ma*
lead to tetan* and a positive $hvoste/ or Trousseau sign.
Treatment
Treat the underl*ing cause: o1*gen, diuretics, etc.
@or an1ious patient, reassurance, rebreathing into paper bag !raises the inspired ($%#).
Teach breath holding techniques during episodes.
If intubated, reduce minute ventilation b* ad0usting rate, tidal volume.
Gsuall* self limited since muscles wea/ness will suppress ventilation.
If the (a$%# is corrected rapidl* in patients with chronic respirator* al/alosis, metabolic acidosis ma* develop due to the previous
compensator* drop in serum bicarbonate.
@i=ed Acid Base Disorders
:i1ed acid base disorders occur when there is more than one primar* acid base disturbance present simultaneousl*. The* are
frequentl* seen in hospitali;ed patients, particularl* in the criticall* ill.
Chen to suspect a mi=ed acid base disorder:
1. The e1pected compensator* response does not occur
#. $ompensator* response occurs, but level of compensation is inadequate or too e1treme
&. Dhenever the ($%# and +"$%&.- becomes abnormal in the opposite direction. !i.e. one is elevated while the other is
reduced). In simple acid base disorders, the direction of the compensator* response is alwa*s the same as the direction
of the initial abnormal change.
5. p" is normal but ($%# or "$%&. is abnormal
4. In anion gap metabolic acidosis, if the change in bicarbonate level is not proportional to the change of the anion gap. :ore
specificall*, if the delta ratio is greater than # or less than 1.
6. In simple acid base disorders, the compensator* response should never return the p" to normal. If that happens, suspect
a mi1ed disorder.
:i1ed metabolic disorders
1. Anion Gap and :ormal Anion Gap Acidosis.
This mi1ed acid base disorder is identified in patients with a delta ratio less than ( which signifies that the reduction in
bicarbonate is greater than it should be, relative to the change in the anion gap. Thus, implicating that there must be
another process present requiring buffering b* "$%&., i.e a concurrent normal anion gap acidosis.
61ample:
>actic acidosis superimposed on severe diarrhea. !note: the delta ratio is not particularl* helpful here since the
diarrhea will be clinicall* obvious)
(rogressive 2enal @ailure
9) during treatment
T*pe IM 2T) and 9)
#. Anion Gap Acidosis and @etabolic Al;alosis
This mi1ed acid base disorder is identified in patients with a delta ratio reater than (, which signifies a reduction in
bicarbonate less than it should be, relative to the change in the anion gap. This suggests the presence of another
process functioning to increase the bicarbonate level without affecting the anion gap, i.e. metabolic al/alosis.
61amples:
>actic acidosis, uremia, or 9) in a patient who is activel* vomiting or who requires nasogastric suction.
(atient with lactic acidosis or 9) given sodium bicarbonate therap*.
27
&. :ormal Anion Gap Acidosis and @etabolic Al;alosis
This diagnosis can be quite difficult, because the low "$%&. and low ($%# both move bac/ toward normal when
metabolic al/alosis develops. )lso, unli/e elevated anion gap acidosis, the anion gap will not indicate the presence of the
acidosis.
61ample:
In patients who are vomiting and with diarrhea !note: all acid base parameters ma* fall within the normal range)
:i1ed respirator* and respirator*7metabolic disorders
"aving a good /nowledge of compensator* mechanisms and e1tent of compensation will aid in identif*ing these disorders.
2emember= compensation for simple acid.base disturbances alwa*s drives the compensating parameter !ie, the ($%#, or
+"$%&.-) in the same direction as the primar* abnormal parameter !ie, the +"$%&.- or ($%#). Chene9er the !CO0 and *#CO+-
are abnormal in opposite directions, ie, one abo9e normal >hile the other is reduced, a mi=ed respiratory and metabolic
acid,base disorder e=ists'
Rule of thumb:
Dhen the ($%# is elevated and the +"$%&.- reduced, respirator* acidosis and metabolic acidosis coe1ist.
Dhen the ($%# is reduced and the +"$%&.- elevated, respirator* al/alosis and metabolic al/alosis coe1ist
The above e1amples both produce ver* e1treme acidemia or al/alemia and are relativel* eas* to diagnose. "owever more often,
the disorder is quite subtle. @or e1ample, in cases of metabolic acidosis, the "$%&. is low and ($%# low. If the ($%# is normal or
not aqequatel* reduced, this ma* indicate a subtle coe1isting respirator* acidosis.
:i1ed acid base disorders usuall* produce arterial blood gas results that could potentiall* be e1plained b* other mi1ed disorders.
%ftentimes, the clinical picture will help to distinguish. It is important to distinguish mi1ed acid base disorders because wor/ up and
management will depend on accurate diagnosis.
1. Chronic Respiratory Acidosis >ith superimposed Acute Respiratory Acidosis
61ample:
)cute e1acerbation of $%(9 secondar* to acute pneumonia
$%(9 patient with worsening h*poventilation secondar* to o1*gen therap* or sedative administration
#. Chronic Respiratory Acidosis and Anion Gap @etabolic Acidosis
61ample:
$%(9 patient who develops shoc/ and lactic acidosis
&. Chronic Respiratory Acidosis and @etabolic Al;alosis
61ample:
(ulmonar* insufficienc* and diuretic therap*
or $%(9 patient treated with steroids or ventilation !important to recogni;e as al/alemia will reduce acidemic
stimulus to breathe)
5. Respiratory Al;alosis and @etabolic Acidosis
61ample:
8alic*late into1ication
Lram negative sepsis
)cute cardiopulmonar* arrest
8evere pulmonar* edema
(lease note that it is impossible to have more than one respirator* disorder in the same mi1ed disorder!i.e. concurrent respirator*
al/alosis and respirator* acidosis)
!ractice Cases
28
These case studies are pro&ided to gi&e you practice dealing with some of the topics that were discussed in the acid base tutorial% +ach case
contains a clinical presentation followed by e&aluati&e studies% Answers are pro&ided after each case but it would probably be best if you
formulate your own answer to each .uestion before reading below for the answer.
Case (
) 55 *ear old moderatel* deh*drated man was admitted with a two da* histor* of acute severe diarrhea. 6lectrol*te results: Ia,
1&5, , #.A, $l. 1'C, "$%&. 16, BGI &1, $r 1.4.
)BL: p" 3.&1 p$%# && mm"g
"$%& 16 p%# A& mm"g
Dhat is the acid base disorderT
)nswer !using the step by step approach)
1. #istory: Based on the clinical scenario, li/el* acid base disorders in this patient are:
Iormal anion gap acidosis from diarrhea or
6levated anion gap acidosis secondar* to lactic acidosis as a result of h*povolemia and poor perfusion.
0' >oo/ at the p#.
The p" is low, !less than 3.&4) therefore b* definition, patient is acidemic.
+. Dhat is the processT >oo/ at the !CO0, #CO+, .
($%# and "$%&. are abnormal in the same direction, therefore less li/el* a mi1ed acid base disorder. Ieed to distinguish the
initial change from the compensator* response. ) low ($%# represents al/alosis and is not consistent with the p". ) low "$%&.
represents acidosis and is consistent with the p", therefore it must be the initial change. The low ($%# must be the compensator*
response. 8ince the primar* change involves "$%&., this is a metabolic process, i.e. :etabolic )cidosis.
2. $alculate the anion ap
The anion gap is Ia . !$l , "$%&.) ? 1&5 .!1'C , 16) ? 1'
8ince gap is less than 16, it is therefore normal.
7. Is compensation ade$uateT $alculate the estimated ($%#.
Gsing DinterEs formula= ($%# ? 1.4 B +"$%&.-) , C F # ? 1.4 B16 , C F # ? &'.&5.
8ince the actual ($%# falls within the estimated range, we can deduce that the compensation is adequate and there is no seperate
respirator* disorder present.
Assessment: Iormal anion gap acidosis with adequate compensation most li/el* secondar* to severe diarrhea.
Case 0
) ## *ear old female with t*pe I 9:, presents to the emergenc* department with a 1 da* histor* of nausea, vomiting, pol*uria, pol*d*psia
and vague abdominal pain. (.6. noted for deep sighing breathing, orthostatic h*potension, and dr* mucous membranes.
>abs: Ia 1&# , 6.', $l A&, "$%&. 11 glucose 3#', BGI &C, $r #.6.
G): p" 4, 8L 1.'1', /etones negative, glucose positive . (lasma /etones trace.
)BL: p" 3.#3 "$%&. 1' ($%# #&
Dhat is the acid base disorderT
)nswer !using the step by step approach)
1. #istory: Based on the clinical scenario, li/el* acid base disorders in this patient are:
6levated anion gap acidosis secondar* to 9), or
6levated anion gap acidosis secondar* to lactic acidosis in the setting of vomiting and pol*uria which ma* lead to
h*povolemia, and<or
:etabolic al/alosis in the setting of vomiting
29
0' >oo/ at the p#.
The p" is low, !less than 3.&4) therefore b* definition, patient is acidemic.
+. Dhat is the processT >oo/ at the !CO0, #CO+, .
($%# and "$%&. are abnormal in the same direction, therefore less li/el* a mi1ed acid base disorder but not *et ruled out.
)gain, need to distinguish the initial change from the compensator* response. ) low "$%&. represents acidosis and is consistent
with the p", therefore it must be the initial change. To maintain the ($%#<"$%&., the ($%# is reduced in response. The low ($%#
must be the compensator* response. 8ince the primar* change involves "$%&., this is a metabolic process, i.e. :etabolic
)cidosis.
2. $alculate the anion ap
The anion gap is Ia . !$l , "$%&.) ? 1&# .!A& , 11) ? #C
8ince gap is greater than 16, it is therefore abnormal.
7. Is compensation ade$uateT $alculate the estimated ($%#.
Gsing DinterEs formula= ($%# ? 1.4 B +"$%&.-) , C F # ? 1.4 B11 , C F # ? ##.4 . #6.4.
8ince the actual ($%# falls within the estimated range, we can deduce that the compensation is adequate and there is no seperate
respirator* disorder present.
&. 8ince anion gap elevated, calculate the delta,ratio to rule out concurrent metabolic al/alosis.
Delta ratio ? K )nion gap ? !)L . 1#) pppppp? !#C . 1#) pp? 16 ? 1.#
DepppppppppK +"$%&.-pa!#5 . +"$%&.-)ppppp!#5 . 11) pp 1&
8ince the delta gap is between 1 and #, we can deduce that this is a pure metabolic acidosis.
Assessment: $ompensated elevated anion gap acidosis most li/el* secondar* to 9).
Iote the absence of /etones in the urine. This is sometimes seen in earl* 9) due to the predominance of beta.h*dro1*but*rate.
The dipstic/ test for /etones detect acetoacetate but not beta.h*dro1*but*rate.
Case +
) previousl* well 44 *ear old woman is admitted with a complaint of severe vomiting for 4 da*s. (h*sical e1amination reveals
postural h*potension, tach*cardia, and diminished s/in turgor. The laborator* finding include the following:
6lectro*es: Ia 15' , &.5, $l 33 "$%&. A, $r #.1
)BL: p" 3.#& , ($%# ##mm"g
)nswer !using the step b* step approach)
1. #istory: Based on the clinical scenario, li/el* acid base disorders in this patient are:
6levated anion gap acidosis secondar* to lactic acidosis in the setting of severe persistent vomiting which ma* lead to
h*povolemia, and<or
:etabolic al/alosis in the setting of persistent vomiting
0' >oo/ at the p#.
The p" is low, !less than 3.&4) therefore b* definition, patient is acidemic.
+. Dhat is the processT >oo/ at the !CO0, #CO+, .
($%# and "$%&. are abnormal in the same direction, therefore less li/el* a mi1ed acid base disorder but not *et ruled out.
)gain, need to distinguish the initial change from the compensator* response. ) low "$%&. represents acidosis and is consistent
with the p", therefore it must be the initial change. The low ($%# must be the compensator* response. 8ince the primar* change
involves "$%&., this is a metabolic process, i.e. :etabolic )cidosis.
2. $alculate the anion ap
The anion gap is Ia . !$l , "$%&.) ? 1&5 .!33 , A) ? 5C
8ince gap is greater than 16, it is therefore abnormal.
30
7. Is compensation ade$uateT $alculate the estimated ($%#.
Gsing DinterEs formula= ($%# ? 1.4 B +"$%&.-) , C F # ? 1.4 B A , C F # ? 1A.4 . #&.4.
8ince the actual ($%# falls within the estimated range, we can deduce that the compensation is adequate and there is no seperate
respirator* disorder present.
&. 8ince anion gap elevated, calculate the delta,ratio to rule out concurrent metabolic al/alosis.
Delta ratio ? K )nion gap ? !)L . 1#) pppppp? !5C. 1#) pp? &6 ? #.6
DepppppppppK +"$%&.-pa!#5 . +"$%&.-)ppppp!#5 . A) pp 15
8ince the delta ratio is greater than #, we can deduce that there is a concurrent metabolic al;alosis. This is li/el* due to
vomiting.
)nother possibilit* is a pre.e1istent high "$%&. level due to compensated respirator* acidosis. But we have no reason to suspect
respirator* acidosis based on the histor*.
Assessment: :i1ed elevated anion gap metabolic acidosis and metabolic al/alosis li/el* due to lactic acidosis and vomiting.
Case 2
) 3' *ear old man with histor* of $"@ presents with increased shortness of breath and leg swelling.
)BL: p" 3.#5, ($%# 6' mm"g, (%# 4# "$%&. #3
Dhat is the acid base disorderT
)nswer !using the step b* step approach)
1. #istory: Based on the clinical scenario, li/el* acid base disorders in this patient are:
)cute respirator* acidosis secondar* to acute pulmonar* edema
0' >oo/ at the p#.
The p" is low, !less than 3.&4) therefore b* definition, patient is acidemic.
+. Dhat is the processT >oo/ at the !CO0, #CO+, .
($%# and "$%&. are abnormal in the same direction, therefore less li/el* a mi1ed acid base disorder but not *et ruled out.
Ieed to distinguish the initial change from the compensator* response. "$%&. is on the high side of normal and is not consistent
with the p". ($%# is high and represents acidosis and is consistent with the p". Therefore it must be the initial change. The high
normal "$%&. must be the compensator* response. 8ince the primar* change involves ($%#, this is a respirator* process, i.e.
2espirator* )cidosis.
2. Is respirator* process acute or chronic, estimate e1pected e=tent of compensation.
If acute, e1pected compensation is O+#CO+,- ? 1 m6q<> for ever* 1' mm "g H($%# .
$hange in ($%# ? 6'. 5' ?#'.
Therefore elevation in +"$%&.- ? #'<1' B 1 ? #.
This should increase the +"$%&.- to #6. 8ince the actual ($%# is close to the estimated value, we can conclude that this is acute
respiratory acidosis.
Based on the ($%#, we ma* also calculate the e1pected p" in acute respirator* acidosis.
H p" ? '.''C B H($%# ? '.''C B !6' . 5'B ? '.16
Therefore e1pected p" ? 3.5 . '.16 ? 3.#5.
8ince the actual p" is consistent with e1pected value, acid base disorder li/el* due solel* to acute respirator* acidosis and other
acid base disorders are most li/el* not present.
Assessment: )cute respirator* acidosis li/el* secondar* to pulmonar* edema.
Case 7
) #C *ear old female with histor* of 80ogrenRs s*ndrome presents to her ($( for a chec/ up visit. In review of s*stems, she reports
a # da* episode of water* diarrhea # da*s ago. 8he is otherwise doing well. (h*sical e1amination is unremar/able. 8he is noted to
have the following serum chemistr*:
31
Ia 1&C, 5.#, $l 1'C, "$%&. 15
Because of her histor*, the ph*sician decides to chec/ her urine electrol*tes.
Grine chemistr*: &1, Ia 1'', $l 1'4
Dhat is the acid base disorderT Dhat is the li/el* causeT
)nswer
(' #istory: Iote that in this scenario, we are not given an arterial blood gas. Therefore we must deduce the diagnosis primaril*
from the histor* and the limited wor/up available.
The patients presents to an outpatient visit ver* as*mptomatic. Besides the histor* of diarrhea, there is nothing else in the histor* to
suggest an active acid base disorder. "owever, her serum electrol*tes indicate a low "$%&. concentration which suggests
acidosis.De can safel* rule out a chronic respirator* al/alosis as basis of the low "$%&. since h*perventilation would be evident
on e1am. In the absence of other data, we have to assume that the patient has a metabolic acidosis.
De are not given serum electrol*tes and therefore we cannot calculate the anion gap, but based on the histor*, we can assume
that the patient does not have lactic acidosis, /etoacidosis, uremia and has not ingested an* to1ins.
)ssuming the patient has normal anion gap acidosis, our differential becomes diarrhea vs 2T). De have to consider 2T) in this
patient, because of the histor* of 80ogrenEs.
0. Urine Anion Gap. De are given urine electrol*tes and thus to distinguish between 2T) and diarrhea, we can calculate the urine
anion gap , otherwise /nown as the Grinar* Iet $harge. 2emember that the G)L is an indirect measure of ammonium e1cretion,
which should be ver* high in the presence of acidosis if renal function is not impaired.
G)L ? Ia , . $l
G)L ? 1'' , &1 . 1'4 ? #6.
) positive G)L suggest 2T) because in the setting of diarrhea, ammonium chloride concentration in the urine would be high and
the G)L would be negative. ) postive value suggests that the /idne* is unable to adequatel* e1crete ammonium, leading to a
reduction in net acid e1cretion and thus metabolic acidosis.
Assessment: :etabolic acidosis li/el* secondar* to renal tubular acidosis.
Iote that further wor/up is needed in order to distinguish the different t*pes of 2T). 80ogrenEs is most commonl* seen in t*pe I 2T)
and is associated with h*po/alemia and a urine p" that that does not fall be*ond 4.&, even in the setting of increased acid load.
$hec/ing the urine p" after administration of I"5$l would establish the diagnosis.
Case 6
) 3# *ear old man with histor* of $%(9 presents to the hospital with alcoholic /etoacidosis.
8erum chemistr*: Ia 1&6, 4.1, $l C4, "$%&. #4, BGI #C, $r 1.5,
)BL: p" 3.#', ($%# 6', "$%&. #4, (%# 34
Grine /etones #,
If the patientRs previous anion gap was 1#, what was his bicarbonate concentration prior to the onset of /etoacidosisT
Answer
The patient is acidemic, with a high ($%# and a "$%&. that is slightl* elevated. This would seem to suggest an acute respirator*
acidosis. "owever we are told that the patient has developed alcoholic /etoacidosis which should produce an elevated anion gap
metabolic acidosis. In that case we would e1pect the bicarbonate level to be ver* low, but it is not. This would suggest that the
patient either has a concurrent metabolic al/alosis or that the bicarbonate level was ver* high prior to the onset of metabolic
acidosis.
The patient is not vomiting or ta/ing diuretics and there is no reason to supect a metabolic al/alosis. De are told of the histor* of
$%(9, which is commonl* associated with chronic respirator* acidosis. In these patients, bicarbonate levels are ver* high due to
renal compensation. Therefore we suspect that the patient had a high bicarbonate level prior to the onset of )). The metabolic
acidosis from )) caused a drop in his bicarbonate level, down to a normal level.
32
The anion gap is Ia . !$l , "$%&.) ? 1&6 .!C4 , #4) ? #6, this confirms our suspicion of an elevated anion gap metabolic acidosis.
In patients with /etoacidosis, we suspect a 1:1 change in the elevation of the anion gap vs the reduction of the bicarbonate level.
That is, the elevation in the anion gap will be matched b* an equal reduction in bicarbonate. 8ee delta ratio.
If the previous anion gap was 1#, then change in )L ? #6 .1# ?15.
The change in bicarbonate should also be 15, therefore the previous bicarbonate level should be 15 , #4 ? &A.
Case 5
) 4' *ear old insulin dependent diabetic woman was brought to the 69 b* ambulance. 8he was semi.comatose and had been ill for
several da*s. $urrent medication was digo1in and a thia;ide diuretic for $"@.
>ab results
8erum chemistr*: Ia 1&#, #.3, $l 3A, "$%&. 1A Llu C14,
>actate '.A urine /etones &,
)BL: p" 3.51 ($%# &# "$%&. 1A p%# C#
Dhat is the acid base disorderT
)nswer !using the step b* step approach)
1. #istory: Based on the clinical scenario, possible acid base disorders in this patient are:
6levated anion gap acidosis secondar* to 9)
:etabolic al/alosis in the setting of thia;ide diuretics use.
0' >oo/ at the p#.
Iote that the p" is normal which would suggest no acid base disorder. But remember, p" ma* be normal in the presence of a
mi1ed acid base disorder.
+. Dhat is the processT >oo/ at the !CO0, #CO+, .
($%# is low indicating a possible respirator* al/alosis. The "$%&. is also low indicating a possible metabolic acidosis. Because
the p" is normal, we are unable to distinguish the initial, primar* change from the compensator* response.
De suspect however that the patient has 9), and therefore should have a metabolic acidosis with an anion gap that should be
elevated. De can confirm this b* calculating the anion gap.
2. $alculate the anion ap
The anion gap is Ia . !$l , "$%&.) ? 1&# .!3A , 1A) ? &5
8ince gap is greater than 16, it is therefore abnormal and confirms the presence of metabolic acidosis.
Dh* is the p" normalT If the patient has metabolic acidosis, we suspect a low ph unless there is another process acting to
counteract the acidosis, i.e al/alosis.
7. To rule out a metabolic al/alosis, let us chec/ the delta ratio.
Delta ratio ? K )nion gap ? !)L . 1#) pppppp? !&5 . 1#) pp? ## ? 5.5
DepppppppppK +"$%&.-pa!#5 . +"$%&.-)ppppp!#5 . 1A) pp 4
8ince the delta ratio is greater than #, we can deduce that there is a concurrent metabolic al;alosis. This is li/el* due to to the
use of thia;ide diuretic. Iote that 9) is often associated with vomiting, but in this case=vomiting was not mentioned.
)nother possibilit* is a pre.e1istent high "$%&. level due to compensated chonic respirator* acidosis. But we have no reason to
suspect chronic respirator* acidosis based on the histor*.
Assessment: :i1ed elevated anion gap metabolic acidosis and metabolic al/alosis li/el* due to 9) and thia;ide diuretics.
$ase C
) 6' *ear old homeless man presents with nausea, vomiting and poor oral inta/e # da*s prior to admission. The patient reports a &
da* histor* of binge drin/ing prior to s*mptoms.
33
>abs : 8erum chemistr*: Ia 1&#, 4.', $l 1'5, "$%&. 16 , BGI #4, $r 1.&, Llu 34
)BL: p" 3.&', ($%# #A, "$%&. 16, (%# A#
8erum albumin 1.'
9oes the patient have an abnormal anion gapT
Ans>er
The patient is acidemic with a low bicarb and low ($%#, suggesting metabolic acidosis. The patient is h*ponatremic with a histor*
of nausea, vomiting and poor inta/e. In this scenario, the metabolic acidosis ma* either be due to normal anion gap acidosis
secondar* to vomiting and<or lactic acidosis, /etoacidosis secondar* to e1treme volume loss and poor inta/e. To rule out lactic
acidosis and /etoacidosis, we need to calculate the anion gap.
)nion gap ? !Ia.!$l ,"$%&.) ? 1&# .!1'5 ,16) ? 1#
Iote that the anion gap appears to be normal, and thus lactic acidosis appears unli/el*. "owever, note also that the patient is
severel* h*poalbuminemic with a serum albumin of 1.'.
Because the anion gap is primaril* determined b* negativel* charged plasma proteins such as albumin, we must ad0ust the normal
value of the anion gap to more accuratel* reflect the albumin deficienc*.
?he appro=imate correction is a reduction in the normal anion ap of 0'7 me$.l for e9ery (.dl decline in the plasma
albumin concentration Anormal 9alue % 2 .dlB
Therefore in this scenario, the normal anion gap should be:
9ecline in albumin ? 5 . 1 ? & g<dl
2eduction in normal anion gap ? & B #.4 ? 3.4
)d0usted anion gap ? 1# . 3.4 ? 5.4.
Iote now that a calculated anion gap of 1# is high when compared to the ad0usted anion gap of 5.4 .
Assessment: This patient has an elevated anion gap metabolic acidosis which ma* be due to lactic acidosis or /etoacidosis.
Acid Base !hysioloy
The normal 6$@ ", concentration is 5' nanomol<>. 2egulation of ", concentration at this low level is essential for normal cellular
processes because of the high reactivit* of ", ions, particularl* with proteins. Dhen there is a change in ", concentration, proteins
gain or lose ", ions, resulting in alterations in charge distribution, molecular configuration, and consequentl* protein function.
Gnder normal conditions, the ", concentration varies little from its normal value due to the processes of acid base regulation.
This teaching module will discuss the role of acid base regulation and includes the following topics:
9ail* )cid >oad
)cid Buffering
2enal )cid 61cretion
(ulmonar* )cid 61cretion
Zou ma* clic/ on each topic individuall*. If *ou are ta/ing the tutorial for the first time, it is preferable that *ou clic/ ne=t to go
through the topics sequentiall*.
Daily Acid 4oad
The dail* acid load is constituted b* oneRs diet, and is comprised primaril* of foods containing acid, and the production of acid as a
result of metabolism. The inta/e of al/ali containing foods and the production of al/ali as a result of metabolism offsets the dail*
acid load but the net effect is dail* addition of acid to the bod* that must be buffered and e=creted to maintain acid base balance.
There are # t*pes of acids that can potentiall* contribute to the dail* acid loadR carbonic or 9olatile acid !#0CO+) and
noncarbonic or non9olatile acids.
34
Carbonic acids
:etabolism of fats and carboh*drates result in the production of 14.#' mol of $%# per da*. Before elimination b* the lungs, most of
the $%# is ta/en up b* red blood cells, reacting with "#% to form carbonic acid as shown below:
CO0 ) #0O W #0CO+ACAB W #) ) #CO+
,
where !$)) is the ver* important en;*me carbonic anhydrase.
Intracellularl*, carbonic acid dissociates to form h*drogen and bicarbonate ions. The latter is pumped out of the cell into plasma. )t
the alveoli, bicarbonate ions re.enter the 2B$ and the above equation is driven to the left, re.producing $%# which is then
eliminated b* the lung.
Gnder normal circumstances, $%# produced via metabolism is primaril* eliminated via alveoli ventilation. )n* increases in $%#
production is matched b* an increase in alveolar ventilation leading to a stable ($%# level.
:on9olatile Acids Polatile Acids A#0CO+B
@etabolism of amino acids,
producin #C4 and #0SO2
@etabolism of fats and
carbohydrates producin CO0
Inta;e of acid containin foods,
sulphates, phosphates
Daily loss of al;ali in feces Aminimal
unless diarrheaB
:oncarbonic acids
Ioncarbonic acids on the other hand are primaril* derived from the metabolism of proteins and dietar* inta/e of foods containing
sulphates !"#8%5) and phosphates !"#(%5
.
) and are primaril* responsible for the dail* acid load that requires e1cretion b* the
/idne*s.
) normal diet results in the generation of 4' .1'' meq of ", per da*. :ost of this comes from the metabolism of sulphur containing
amino acids such as c*steine and methionine which *ield sulphuric acid and from metabolism of l*sine, arginine and histidine which
*ield h*drochloric acid.
Ingestion of al/ali containing foods !e.g. citrate), and metabolism of amino acids such as aspartate and glutamate that lead to al/ali
production offset the dail* acid load but the net effect is dail* acid addition.
Acid Bufferin
%ne of the ma0or wa*s in which large changes in ", concentration are prevented is b* buffering. The bod* buffers which are
primaril* wea/ acids, are able to ta/e up or release ", so that changes in the free ", concentration are minimi;ed. Buffers are
located in the e1tracellular fluid !6$@), intracellular fluid and bone.
"=tracellular Buffers
The most important buffer in the 6$@ and the bod* is #CO+, !bicarbonate) which combines with e1cess ", ions to form carbonic
acid.
Ta/e for instance an acid load of "#8%5 produced via metabolism of methionine:
#0SO2 ) 0:a#CO+ J :A0SO2 ) 0#0CO+ J0CO0 ) 0#0O ) :A0SO2'
Iote in this buffering reaction that bicarbonate reacts with a strong acid to form a wea/er acid!"#$%&) which then dissociates into
$%# and "#%. The $%# produced here does not reform "#$%& because it is then e1creted b* the lungs. Iote that "$%&. is used
up in this reaction. 8o that p" is not affected, the "$%&. used up in this process must be regenerated and the I)#8%5 must be
e1creted b* the /idne*s.
The $%#<"$%&. buffer s*stem is considered ver* effective because of the vast quantit* of bicarbonate in the bod* and the abilit* to
e1crete the $%# formed via ventilation.
%ther less important buffers in the 6$@ are plasma proteins and inorganic phosphates.
35
Intracellular Buffers
The primar* intracellular buffers are proteins, organic and inorganic phosphates and in the 2B$, hemolobin A#B,B' Dhereas
buffering b* plasma "$%&. occur almost immediatel*, appro1imatel* 0,2 hours is required for buffering b* cell buffers due to slow
cell entr*.
"emoglobin is a ver* important buffer in 2B$s, particularl* in the role of carbonic acid buffering.
It should also be noted that transcellular upta/e of h*drogen ions b* cells result in the passage of Ia, and , ions out of cells to
maintain electroneutralit*. This process can substantiall* affect potassium balance as will be discussed later.
Bone
Bone represents an important site of buffering acid load. )n acid load, is associated with the upta/e of e1cess ", ions b* bone
which occurs in e1change for surface Ia, and , and b* the dissolution of bone mineral, resulting in the release of buffer
compounds, such as Ia"$%&, $a"$%&, and $a"(%5.
It has been estimated that at least 2/U of the bufferin of an acute acid load ta;es place in bone' Chronic acidosis
can ha9e 9ery ad9erse effects on bone mineraliQation due to this process and can result in bone diseases such as ric;ets,
osteomalacia and osteopenia.
2enal )cid 61cretion
The process of renal acid e1cretion is comple1. In order to conceptuali;e this process, lets consider the follow equation:
"$l , Ia"$%& [ Ia$l , "#$%& [ $%# , "#% , I)$l.
The above equation represents the process of buffering of the dail* nonvolatile acid load. Buffering minimi;es the effect that strong
acids such as "$l would have on the p". Ionetheless the p" will be affected if the bicarbonate lost in this process is not
regenerated, because as we will learn= loss of bicarbonate from the 6$@ lowers the e1tracellular p", leading to acidosis. %ne wa*
to regenerate the lost bicarbonate would be for the /idne* to reverse the above equation, and e1crete "$l in the urine as free ",
ions. Gnfortunatel* this would require a urine p" of 1.', an impossible tas/ since the minimum attainable urine p" is 5.' to 5.4.
In order to maintain acid base balance, the /idne* must accomplish two tas/s:
(B Reabsorption of all filtered bicarbonate
0B "=crete the daily acid load
The /idne* achieves these three tas/s effectivel* via the processes of hydroen secretion, bicarbonate reabsorption and
e1cretion of h*drogen ions with urinary buffersA titratable acids and ammoniumB '
#ydroen Ion Secretion
The /idne* is responsible for e1creting the nonvolatile acid load, which as previousl* mentioned, is equivalent to about 4'.
1''meq<> of h*drogen ions per da*. "*drogen ions are buffered in the blood and are not filtered b* the /idne* as free ions.
"*drogen ions are instead e1creted in the urine via the process of hydroen ion secretion. In the tubular fluid, the secreted
h*drogen ions combine with urinar* buffers to be e1creted as titratable acids and ammonium or combine with filtered bicarbonate
leading to bicarbonate reabsorption'
Bicarbonate Reabsorption
The /idne* filters appro1imatel* 5&#' meq<da* of "$%&. !#5 meq<> 31C'><da*). Gnder normal circumstances, the /idne*
is able to completel* reabsorb all the filtered bicarbonate. This is vitall* important, since an* loss of bicarbonate in the
urine would disturb acid base balance.
The process of bicarbonate reabsorption occur predominantl* in the pro1imal tubule !about A'P). The rest occur in the
thic/ ascending limb and in the collecting tubule. )ll involve hydroen ion secretion as shown in the diagram below. To
completel* reabsorb bicarbonate,the /idne* must secrete 5&#' meq<da* of h*drogen ions in addition to the amount
required to e1rete the dail* acid load.
36
The primar* step in pro1imal h*drogen secretion is the secretion of ", b* the :a) , #) antiporter in the luminal
membrane. "*drogen ions are generated b* the intracellular brea/down of "#' to %". and ",.
"*drogen ions secreted combine with filtered "$%&. ions to form carbonic acid and then $%# , "#%, which are then
passivel* reabsorbed.
Technicall*, "$%&. ions reabsorbed in this process are not the same as the ones filtered. Iote that a new "$%&. ion is
generated from the intracellular brea/down of "#' to %". and ", and subsequent reaction of %". with $%# to form
"$%&. . This new bicarbonate then crosses the basolateral membrane via a Ia, . &"$%&. cotransporter.
The net effect is one mol of bicarbonate ion returned to s*stemic circulation for ever* ", ion that is secreted and
reabsorption of virtuall* all filtered bicarbonate.
8imilar processes occur in the thic/ ascending loop of "enle and intercalating cells of the collecting duct. In contrast to the
pro1imal tubule, h*drogen ion secretion in the collecting tubule is mediated b* a #) A?!ase pump in the luminal
membrane and a $l."$%&. e1changer in the basolateral membrane as shown in the diagram above. The ", )T(ase
pump is influenced b* aldosterone, which stimulates increased ", secretion. #ydroen ion secretion in the collectin
tubule is the process primarily responsible for acidification of the urine, particularl* during states of acidosis. The
urine p" ma* fall as low as 5.'.
(ro1imal reabsorption of bicarbonate can be affected b* man* factors, in particular, potassium balance, 9olume status
and renin.aniotensin le9els. Therefore these factors can have ver* significant effects on acid base balance. Their
specific effects will be discussed later.
Grinar* Buffering
?he role of urinary bufferin ser9es t>o purposesR to aB e=crete the daily acid load and bB reenerate bicarbonate
lost durin e=tracellular bufferin' It is a process >hereby seceted hydroen ions are buffered in the urine by
combinin >ith >ea; acids !titratable acidit*B or >ith I"& !ammoniaB to be e=creted' It is a necessary process
because the ;idney cannot easily e=crete free hydroen ions'
?itratable Acidity
The ma0or titratable acid buffer is "(%5
#.
. %ther less important buffers are creatinine and uric acid. In 9), /etoanions also
serve as a source of titratable acids.
Below is a diagram outlining this process.
37
61cretion of titratable acids is dependent on the quantit* of phosphate filtered and e1creted b* the /idne*s, which is
dependent on oneEs diet,and also (T" levels. )s such, the e1cretion of titratable acids is not regulated b* acid base
balance and cannot be easil* increased to e1crete the dail* acid load. Ammonium production can however be
regulated to respond to acid base status, as will be discussed ne1t.
Ammonium "=cretion
Dith increased acid load, there is increased h*drogen ion secretion, causing the urine p" to fall below 4.4. )t this point, virtuall* all
the urinar* phosphate e1ist as "#(%5. and further buffering cannot occur unless there is an increase in urinar* phosphate
e1cretion. )s mentioned previousl*, phosphate e1cretion is mainl* dependent on dietar* phosphate inta/e and (T" levels and is
not regulated in response to the need to maintain acid base balance. Dithout further urinar* buffering, adequate acid e1cretion
cannot ta/e place. ?he maKor adaptation to an increased acid load is increased ammonium production and e=cretion' The
abilit* to e1crete ", ions as ammonium adds an important degree of fle1ibilit* to renal acid base regulation, because the rate of
I"5, production and e1cretion can be regulated in response to the acid base requirements of the bod*. Also of importance is the
role of ammonium production in the further eneration of bicarbonate ions'
The process of ammonium e1cretion ta/es place in & steps.
Ammonium Eormation AammoniaenesisB !pro1imal tubule)
Ammonium Reabsorption !:edullar* 2ec*cling)!thic/ ascending loop)
Ammonium ?rappin !collecting tubule)
Ammoniaenesis
The process of ammoniagenesis occurs within pro=imal tubular cells. Llutamine made in the liver, is received from
peritubular capillaries and is metaboli;ed into alpha./eto glutarate and I"5,, in a reaction that involves the en;*me
glutaminase.
The ammonium is secreted into the tubular lumen b* substituting for ", on the Ia, . ", e1changer. In the tubular fluid,
I"5, circulates partl* in equilibrium with I"&.
The alpha./etoglutarate is metaboli;ed further into two "$%&. ions, which then leave the cell and enter s*stemic
circulation b* crossing the basolateral membrane.
!lease note that the eneration of ne> #CO+, ions is probably the most important feature of this process'
This will be e1plained ne1t.
Below is a diagram outlining )mmonium formation .
38

?he Role of Ammonium "=cretion

Dhat happens ne1t to ammonium is somewhat comple1. 8o before continuing , let us re.e1amine the rational behind
ammonium e1cretion.
Iow remember= free h*drogen ions are not filtered b* the /idne*. Instead, the* are secreted into the tublar fluid. Because
free h*drogens cannot be e1creted in the urine easil*, there are e1creted with wea/ acids such as "#(%5. which function
as urinar* buffers. Iow in the presence of an increased acid load, the phospate ions are used up and the /idne* then
increases its production of ammonium .
Iotice that ammonium, not ammonia is produced in the pro1imal tubule. Therefore *ou might as/ *ourself, how does
ammonium production increase h*drogen e1cretion if it cannot bind to h*drogen ions secreted in the pro1imal tubular
lumenT
The answer to this is somewhat controversial in the literature. Below is one school of thought that has gained popularit*.
)s was mentioned previousl*, new bicarbonate ions are produced during ammoniagenesis. The generation of new
bicarbonate ions conceptuall* is a/in to inceased h*drogen e1cretion. Therefore the real function of ammoniagenesis is
not as a urinar* buffer of h*drogen ions as is commonl* inaccuratel* described. ?he real function of ammoniaensis is
to increase the eneration of ne> bicarbonate ions'
@or simplicit*, this rational will be the basis of the remaining discussion on ammonium e1cretion.
)mmonium before it is e1creted is first re.absorbed in the thic/ ascending limb, circulated in the medullar* interstitium and
then pumped bac/ in the collected tubule as ammonia. In the collecting tubule, ammonia then ta/es up h*drogen ions
secreted into the lumen b* intercalated cells, to form ammonium.
Iow the second question *ou might as/ is wh* so man* steps leading to the same resultT
In order for ammoniaenesis to be effecti9e in the eneration of ne> #CO+,, the :#2) produced must be
e=creted in the urine. If I"5, were to enter the circulation, it would end up in the liver where metabolism would lead to
the formation of urea as showed in the following equation:
I"5, , # "$%&. ?V urea , $%# , & "#%
Iotice that the formation of urea consumes # molecules of bicarbonate. Therefore, in essence, the bicarbonate generated
in the pro1imal tubule would be negated or cancelled out, and ammoniagenesis would not increase net acid e1cretion.
)s mentioned previousl*, I"5, secreted in the pro1imal tubule is in equilibrium with a small quantit* of I"&. This I"& is
capable of diffusing out of the lumen into the peritubular capillaries. If this were allowed to continuall* happen, a large
39
quantit* of ammonium would be lost to the circulation and its metabolism in the liver would consume the "$%&.
generated.
This effect is minimi;ed b* having an acidic urine ph which /eeps I"5, in its protonated form. "owever, the urine does
not become ma1imall* acidified until the collecting tubule where secretion of h*drogen ions b* intercalated cells
significantl* reduce the urine p". Therefore the /idne* prevents loss of ammonium b* reabsorbing I"5, in the thic/
ascending limb and pumping it into the collecting duct where the urine p" is ver* low, facilitating ammonia in its protonated
form. This process is enhanced during periods of acidosis when h*drogen secretion b* the intercalated cells is significantl*
increased.
@edullary Recyclin and Ammonium ?rappin'
)fter ammoniagenesis, ammonium is ta/en up into the medullar* interstitium via a process called medullar* rec*cling. It is then pumped
bac/ into the tubular fluid at the level of the collecting duct, where it undergoes what is called ammonium trapping after which it is e1creted.
Below is an outline of this process.
1. )mmonium is first reabsorbed at the level of the thic/ ascending limb b* substituting for , on the Ia, ., .#$l. carrier.
#. The less acidic tubular cell then causes I"5, to dissociate into I"& and ",.
&. The luminal membrane in the thic/ ascending limb is impermeable to I"& and thus I"& cannot diffuse bac/ into the lumen. It
instead diffuses out into the medullar* interstitium into those compartments which have the lowest I"& concentration, i.e. the
8& segment of the pro1imal tubule and the medullar* interstitium of the collecting tubule.
5. )t the 8& segment of the pro1imal tubule, I"& re.enters the lumen where it is protonated bac/ to I"5 and is again rec*cled bac/
into the medullar* interstitium via reabsorption at the thic/ ascending limb. This leads to a high concentration of I"& in the
medullar* interstitium.
4. Because of the ver* low I"& concentration in the collecting tubular fluid !as a result of removal in the loop of "enle), and a
ma1imall* acidic urine p" in the collecting duct that further reduces tubular I"&, there is a large gradient for I"& secretion into
the collecting tubular lumen.
6. In contrast to the thic/ ascending limb, the tubular lumen is permeable to I"& but not to I"5. )s a result, I"& secretion into the
collecting duct lumen leads to \ammonium trapping] as I"5, formed from the ver* acidic urine is unable to diffuse bac/ into the
cell.
3. I"5 is then e1creted in the urine, usuall* with a $l. anion.
40
:ote that this process is primarily dependent on acidification of the urine in the collectin tubule as a result of hydroen
secretion by intercalated cells'
In states of acidosis, >here hydroen secretion is sinificantly increased in the collectin tubule, this process is reatly
enhanced'
In states of al;alosis, the process is appropriately hindered as a result of the al;alemic urine'
2enal )cid 61retion= Ta/e "ome (oints
(. The net quantit* of ", ions e1creted in the urine is equal to the amount of ", e1creted as titratable acidit* and I"5, minus an*
", added to the bod* because of urinar* "$%&. loss.
:et acid e=cretionA:A"B % titratable acidity ) :#2
)
, urinary #CO+
,
Iote that normall* there is no urinar* "$%&. and therefore:
:et acid e=cretionA:A"B % titratable acidity ) :#2
)

0. Titratable acidit* is dependent on the dietar* inta/e of phosphate and cannot be regulated to increase acid e1cretion
+. The /idne* Es main response to an increased acid load is to increase ammonium production and e1cretion
2. ) ver* important feature of titrable acidit* and ammonium e1cretion is the regeneration of bicarbonate ions.
7. The /idne* must reabsorb all filtered "$%&. in order to maintain acid base balance.
&. "*drogen ion secretion in the collecting tubule is ver* important in ma1imall* acidif*ing the urine.
5. In states of acidosis, ma1imal acidification of the urine in the collecting tubule must occur for adequate ammonium e1cretion.
6. In states of acidosis, ammonium e1cretion is increased b* increasing ammonium production and increased h*drogen ion
secretion in the collecting duct.
8. )ldosterone stimulates secretion of h*drogen ion in the collecting duct .
(/. )lthough the e1tracellular p" is the primar* ph*siologic regulator of net acid e1cretion, in pathoph*siologic states, the effective
circulating volume, )ldosterone, and the plasma , concentration all can affect acid e1cretion, independent of the s*stemic p".
!umonary Acid "=cretion
The main ph*siologic stimuli to respiration are an elevation in the ($%# and a reduction in the (%# !h*po1emia). The $%#
stimulus to ventilation occurs in the chemosensitive areas in the respirator* center in the brain stem, which responds to $%#
induced changes in the cerebral interstitial p". This effect is important in removing the 14 mol of $%# produced dail* from
metabolism of fats and carboh*drates, via alveolar ventilation. In acid base disorders, the initial rise or fall in alveolar ventilation is
mediated primaril* b* the peripheral chemoreceptors in the carotid or aortic bodies, which immediatel* sense the change in p".
$hanges in ($%# are sensed via central chemo.receptors as $8@ ph is altered. In general, ($%# is regulated b* alveolar
ventilation. "*perventilation !increase in alveolar ventilation) enhances $%# e1cretion and lowers the ($%# while h*poventilation
!reduction in ventilation) reduces $%# e1cretion and raises the ($%#.
The effects of acid base balance on alveolar ventilation and vice versa will be discussed in more detail when specific acid base
disorders are described.
41