Quantitative Acid-Base Chemistry

& Acid-Base Physiology

(They are not the same)

P Wilkes MD, PhD, FRCP

University of Ottawa Heart Institute
 Guiding Principles
 Physiology will not violate the laws of
chemistry and physics
 There is a difference between cause and
effect vs. correlation (physics vs. math)
 In many ways – you do not know anything
unless you know everything
(If the devil is in the details – so is salvation)
Learning Objectives
 The Chemistry
 The Physiology
 The Clinical Approach
The ‘Chemistry’ in the Text Books
‘The CO2 Hydration Reaction’
Chemical Description:
CO2 + H20 H2CO3 HCO3- + H+

Mathematical Description, the

Henderson-Hasselbalch equation:

pH = pK + log [HCO3-]
(.PCO2)
[HCO3-]
PCO2=60 PCO2=40
Resp acidosis
Metab alkalosis
30
PCO2=30

24

Metab acidosis

14 Resp alkalosis

7.0 7.4 7.6

 PCO2=60 PCO2=40

30
Hg
[HCO3-] PCO2=30

24

14

7.0 pH 7.4 7.6

 BE = (1-0.014Hgb)(HCO3-24)+(1.43Hgb +7.7)(pH-7.4)

PCO2=40

30 PCO2=30

[HCO3-]

24
Base Measured
Excess Decrease
in [HCO3-]
14

7.0 7.4 7.6

pH
 CO2 Hydration Reaction
 What is the pH of water equilibrated to PCO2 =
40 mmHg?
? 7.4
? Higher
? Lower
 Answer 4.4
 What is the HCO3?
? 24 mEq/L
? Higher
? Lower
 Answer < 1 mEq/L
 What is Going On?
 The Problem:
The CO2 hydration reaction does not
predict what we measure in blood!!
Nevertheless, the Henderson-
Hasselbalch equation does??
 The Answer:
The CO2 hydration reaction is either
wrong or incomplete
 Modern Quantitative Acid – Base
Chemistry
(The Real Chemistry)
Can J Physio Pharmacol 61: 1444 - 1461, 1983

Peter A Stewart
 Physical Chemistry of CO2 and Water
Condition: PCO2 = 40 mmHg
Equations: [H+][OH-] = K’w
At pH 7.4
(i.e. [H+] = 4x10-5 mEq/L)
CO2(K1) = [HCO3-][H+]
HCO3 = 24 mEq/L [HCO3-](K2) = [CO3=][H+]
How do you account
for electrical neutrality? [H+] - [HCO3-] - [CO3=] - [OH-] = 0

Solving: [H+] = 0.036 mEq/L, pH = 4.44 !!

[HCO3-] = 0.036 mEq/L
[CO3=] and [OH-] < 1 x 10-6 mEq/L

[H+], [HCO3-], [CO3=], [OH-] are determined ONLY by PCO2 &

Dissociation Constants
 How to Make Bicarb ?

NaOH = 5
40
HCO3 mmol/L

30 NaOH = 20

20
NaOH = 40
10

0 Necessary Condition
0 10 20 30 40 50
[fixed60+ charge]
PCO2 (mmHg) &
PCO2
The Fixed Positive Charge and Other Acids

 Plasma [Na+] + [K+] – [Cl-]

140 mEq/L + 4 mEq/L – 100 mEq/L
~ 44 mEq/L positive charge
 This is the Strong Ion Difference (SID)
 Other Acids ?

 Albumin
 Phosphate
 Albumin + Phosphate = [Atot]
 ~ Total Protein (g/L) x 0.25 = Atot (mEq/L)
 The Chemically Complete
Solution
 Multiple components
CO2 hydration reaction
Weak Acids (Blood is thicker than water)
Electrical Neutrality
 Systems Approach:
Solve All Equations Simultaneously
Independent vs. Dependent Variables
Water dissociation equilibrium
[H+] x [OH-] = K’w
Weak acid dissociation equilibrium
[H+] x [A-] = KA x [HA]
Conservation of mass for “A”
[HA] + [A-] = [ATOT]
Bicarbonate ion formation equilibrium
[H+] x [HCO3-] = KC x pCO2
Carbonate ion formation equilibrium
[H+] x [CO32-] = K3 x [HCO3-]
Electrical neutrality
[SID] + [H+] - [HCO3-] - [A-] - [CO32-] - [OH-] = 0
SID – HCO3 – [A-] ~0
Na + K – Cl – HCO3 ~ [A-] (Is this familiar?)
[A-] is the anion gap
• Only the whole set of six equations
can explain the quantitative
properties of the system, and
permit evaluation of any of the
dependent variables
• No one of the six equations is
more, or less, important than the
others. All six are essential
Solve for [H+] and get a big wet kiss:

Please put away all calculators, you have 30

seconds beginning now

[H+]4 + {KA+[SID]} [H+]3 +

{KA([SID]-[Atot])-(K1.CO2+K’w)} [H+]2 -
{KA(K1.CO2+K’w)+K2.K1.CO2} [H+] -
KA.K2.K1.CO2 = 0

A[X]4 + B[X]3 + C[X]2 + D[X] + E = 0

 A Fourth Order
Polynomial !?!
DUOH !?!
Now what do I do??
 I know – Use a computer ! ?
Insert: SID = Na+K-Cl = 140 + 4 -100
= 44 mEq/L
PCO2 = 40 mmHg
Tprot = 80 g/L = 20 mEq/L

[H+]4 + {KA+ [44] } [H+]3 +

{KA( [44] - [20] )-(K1.40+K’w)} [H+]2 -
{KA(K1.40+K’w)+K2.K1.40} [H+] -
KA.K2.K1.40 = 0

[H+] = 3.98 x 10–8

-Log 3.98 x 10-8 = 7.4
Why Does the Henderson-Hasselbalch Equation
Seem to Work?
Water dissociation equilibrium
[H+] x [OH-] = K’w
Weak acid dissociation equilibrium
[H+] x [A-] = KA x [HA]
Conservation of mass for “A”
[HA] + [A-] = [ATOT] (20 mEq/L)
Bicarbonate ion formation equilibrium
[H+] x [HCO3-] = KC x pCO2 (40 mmHg)
Carbonate ion formation equilibrium
[H+] x [CO32-] = K3 x [HCO3-]
Electrical neutrality
[SID] (44 mEq/L) + [H+] - [HCO3-] - [A-] - [CO32-] - [OH-] = 0
[H+] is determined by SID, PCO2 and Atot
[H+] = 3.98x10-8 Eq/L (pH=7.4) in all 6 equations only if
SID=44 mEq/L, PCO2=40mmHg and Atot=20 mEq/L
Therefore [HCO3] must be ~ 24 mM/L
(math not chemistry)
 Paradigm Shift
[H+] = 3.98 x 10-8 Eq/L (i.e. pH=7.4) AND HCO3 = 24 mmol/L because:
SID = 44 mEq/L
PCO2 = 40 mmHg
Tprot = 80 g/L (~20 mEq/L)

1) [H+] and [HCO3] DO NOT INFLUENCE EACH OTHER

2) The CO2 hydration reaction:
a) incomplete chemical description of the system
b) predicts acid-base but does not offer a cause/effect explanation
3) You must understand normal acid-base before you can understand
abnormal acid-base
 Does the Equation Work?

7.7
7.6
pH Calculated

y = 1.1101x - 0.8447
7.5 R2 = 0.8092
7.4
7.3
7.2
7.1
7.2 7.3 7.4 7.5 7.6 7.7
pH Measured

(Wilkes AJP:1998)
Independent vs. Dependent
In Vitro In Vivo

Independent

PCO2 = ƒ(VCO2, VA)

SID = ƒ(dIn/dOut, Vd), Na, Cl
Atot = ƒ(dIn, dOut, Vd)
CO2 Na+, Cl-

Dependent
Protein
H, HCO3, CO3, Prot, ProtH, OH
(not functions of dIn, dOut or Vd)
 Summary

Cause and Effect [H+]

PCO2 [OH-]
[H+] = ƒ([SID], PCO2, [Tprot]) [HCO3-]
[SID]
A(X)4 + B(X)3 + C(X)2 + D(X) + E = 0
[CO3=]
[Tprot]
[Prot.H]

[Prot-]
 Conceptual Consequences
 The model predicts what we measure
 H+ and HCO3 are both determined by
chemistry IN PLASMA, NOT physiology
 H+ and HCO3 are not determined by intake
or loss – the kidney is irrelevant!!
 What does physiology control?
1) The concentrations of Na, K, Cl
and thus the strong ion difference
2) PCO2
3) Total weak acid concentration
 Influence of [SID]

[Na+] = 137 mEq/L [Na+] = 143 mEq/L

[K+] = 4 mEq/L [K+] = 4 mEq/L
[Cl-] = 105 mEq/L [Cl-] = 96 mEq/L
[SID] = 36 mEq/L [SID] = 51 mEq/L
PCO2 = 40 mmHg PCO2 = 40 mmHg
[Tprot] = 80 g/L [Tprot] = 80 g/L

pH = 7.29 pH = 7.51
[HCO3-] = 20 mEq/L [HCO3-] = 34 mEq/L
[Prot-] = 16 mEq/L [Prot-] = 17 mEq/L
‘Electrolyte’ Acidosis
Usually iatrogenic
Assumed to be ‘benign’
However:
Gut hypoperfusion/Post Op N/V
(Gan, Anesth.1999; Williams, Anesth Analg. 1999)

Impaired Renal Blood Flow, GFR

(Wilcox, J Clin Invest, 1983)

Difficulty diagnosing Lactacidosis?

 First Patient
 74 yo male, 48 hrs post MI, on BIPAP
 S. aureus infection, osteomyolytis (by
MRI for neck pain) vs. endocarditis (by
ECHO)
 Mod MR, EF 50%, no inotropes, stable
BP (No Swan)
 COPD, DM, Creat 173
 7.29/42/80/20/-6.7 AG = 15
 Are you worried ?
 First Patient: Approach
 Electrolytes:
Na = 132, K = 4.9, Cl = 102
SID = 34 mEq/L
 Total Protein:
64 g/L ~ 15 mEq/L
 Electrical Neutrality:
SID – HCO3 – Prot- ~ 0
34 - 20 - 15 = -1
 Lactate = 1.5 mEq/L
 Electrolyte based acidosis, low SID
 SID and Acid-Base
160 160
140 140
[Prot-]
[Prot-]
120 120
[HCO3-] [HCO3-]
100 100
[Na +]
80 80 [Na +]
60 [Cl-] 60
[Cl-]
40 40
20 20
0 0
Cations Anions Cations Anions

Very common cause of met acidosis

Iatrogenic hyperchloremic metabolic acidosis
How does this occur?
 Influence of Plasma Protein

Normal Protein = 80 g.L-1 Low Protein = 40 g.L-1

SID = 44 mEq.L-1 SID = 44 mEq.L-1
PCO2 = 40 mmHg PCO2 = 40 mmHg

pH = 7.42 pH = 7.533
[HCO3-] = 27 mmol.L-1 [HCO3-] = 35 mEq.L-1
[Prot-] = 16.8 mEq.L-1 [Prot-] = 8.7 mEq.L-1
 Hypoproteinemic Metabolic
Alkalosis
160 160
140
Prot- 140
Prot-
120 120
HCO3 HCO3
100 100
80 80
60 Na Cl 60 Na Cl
40 40
20 20
0 0
Cations Anions Cations Anions
 Hypoproteinemia
 Decrease in COP (Schupbach et al., Vox Sang
35:332, 1978; Zabala Ann Ital Chir LXIV 4:387, 1993)
 Fluid Shifts/Retention
 Glomerular Filtration Pressure

 Metabolic Alkalosis (McAuliffe et al., Am J Med

81:86, 1986)
 Consequences of
Hypoproteinemic Metabolic
Alkalosis
Hypoventilation (McAuliffe AJM, 1986)
Hyperventilation ! (Rossing, J Lab Clin Med, 1988)
Difficulty assessing acid-base status
Anion gap = (Na + K – Cl – HCO3-) = Prot-
Hides lactacidosis
 Case #3: POD #1 2200 hr,
Emergency CABG

 LV III, Inotropic support, IABP

 105/60, 38/20, CI = 2.0, SVR = 1200
 ABG = 7.45/40/155/29/-2.2
 Anion gap = Na + K – Cl – HCO3 = 17
 Are you concerned ?
 Third Patient: Approach
Step 1: Electrolytes and SID
Na = 139
K = 3.5
Cl = 96
SID = 46 mEq/L

Step 2: Total Protein = 40 g/L

Convert to mEq/L: 40 g/L x 0.25 = 10 mEq/L
 Third Patient: Approach
Step 3: Electrical Neutrality
SID – HCO3 – Prot- ~ 0 + 5 mEq/L
46.5 – 29 – 10 = 7.5 mEq/L

Either: Lab variation (~ 2%)

Unmeasured acid

Lactate = 8 mEq/L (Type A)

Dead gut on laparotomy
 The Danger of Hypoproteinemic
Alkalosis
160 160
140 - 140 [Prot-]
[Prot ]

120 - 120 [Lact-]

[HCO3 ]
[HCO3-]
100 100
80 80
[Na +]
[Cl-] [Na +] [Cl-]
60 60
40 40
20 20
0 0
Cations Anions Cations Anions
How does Stewart approach affect
concept of Anion Gap ?

AG = Na+K-Cl-HC03
160 = [Prot-]
140
Prot AG = [A-]
120 SID HCO3
100
from [HA]Ka = [A-][H+]
80
Na Cl [Atot] = [HA] + [A-]
60
[A-] = KaAtot
40
Ka+[H+]
20
0 Therefore: AG can be
Cations Anions measured directly
 How does the Stewart approach affect
concept of BE?
 From BE = (1-0.014Hgb)(HCO3-24)+(1.43Hgb +7.7)(pH-7.4)
BE = 0 when pH = 7.4 and [HCO3] = 24
 From Stewart:
pH and [HCO3] are dependent upon prevailing PCO2, SID and Atot
Therefore BE is also a function of PCO2, SID and Atot
 Atot and SID can both be altered by pathophysiology such that
neither pH or HCO3 change
 Both Atot and SID should be assessed during a clinical evaluation
 Information from BE
BE = (1-0.014Hgb)(HCO3-24)+(1.43Hgb +7.7)(pH-7.4)
HgB = 14

pH = 7.4 pH = 7.3 pH = 7.24 pH = 7.38

HCO3 = 24 HCO3 = 16 HCO3 = 16 HCO3 = 25
PCO2 = 40 PCO2 = 30 PCO2 = 35 PCO2 = 40
BE = 0 BE = -9.2 BE = -10.9 BE = +1.2
Na = 140 Na = 140 Na = 130 Na = 140
K=4 K=4 K=4 K=4
Cl = 100 Cl = 100 Cl = 105 Cl = 100
AG = 16 AG = 24 AG = 9 AG = 15

Lact = 10 SID = 29
SID = 44 SID = 44
SID = 44 (-10) Tprot = 15
Tprot = 20 mEq/L Tprot = 10 mEq/L
Tprot = 20 mEq/L SID-HCO3–TP~ 0
SID-HCO3-TP~0 SID-HCO3-TP~10
SID-HCO3-TP~0 29 – 16 – 15 = -2
44 – 24 – 20 ~ 0 44 – 25 – 10 = 9
34 – 16 – 20 = 2 Lact = 0
Lact = 10
 Model Summary

SID (electrolyte or metabolic)  acidosis

SID (electrolyte)  alkalosis

Weak acid (protein)  alkalosis

(Weak acid (phos-, protein)  acidosis)

PCO2  acidosis
PCO2  alkalosis
Compensatory Responses
 Metabolic acidosis Hyperventilate
Lower PCO2
 Metabolic alkalosis
 2nd low protein Decrease SID
by increase Cl
 2nd increased SID Hypoventilate
Increase PCO2
 Respiratory acidosis Increase SID by
decreasing Cl
 Respiratory alkalosis ?increase protein
?decrease SID
 Permissive Hypercapnia
(Wilkes, unpublished)

100 PCO2 (mmHg)

90
80
[HCO3-] (mEq/L)
70
60
50
40 [SID] (mEq/L)
30
20
10
0
0 5 10 15 20 25 30
Days
 Permissive Hypercapnia
(Wilkes, unpublished)

160
140 [Na+],(mEq/L)
120
mEq.L-1

100
80 [Cl-], (mEq/L)
60
[SID], (mEq/L)
40
20
0
0 5 10 15 20 25 30

Days
Respiratory Acidosis
 Compensatory response to
hypercapnea in severe COPD is to
increase SID by lowering Cl (Alfero 1996)
Influence of [Atot] on [SID]
(Wilkes AJP 1998)

[Na ], [Cl ], [SID] (mEq.L ) 160

[Na+]=0.18[Atot]+134.6
-1

140
120
-
[Cl ]=-0.66[Atot]+110.7
100
80
-

60 [SID]=0.99[Atot]+24.7
+

40
20
8 10 12 14 16 18 20
Atot (mEq.L-1)
Influence of [Atot] on [Prot-], [HCO3-]
and [H+]
60

50
[Prot ], [HCO3 ], [H ]
+

40
-

[H+], nEq.L-1
30
[HC03-], mEq.L-1
20
-

[Prot-], mEq.L-1
10

0
8 10 12 14 16 18 20
-1
Atot (mEq.L )
 The Law of Electrical Neutrality
A Law of Physics – it ALWAYS exist

SID + H+ - HCO3- - Prot- - Phos- - CO3= - OH- =0

SID – HCO3- - Prot- - Phos- ~ 0
{HCO3- + Prot- + Phos-} ~ SID
{HCO3- - Prot- - Phos-} ~ {Na + Mg + Ca + K – Cl – Lact}

What if electrical neutrality APPEARS not to exist?

Influence of Apparent Charge Imbalance
[SID] - [HCO3-] - [Prot-] ~ 0
(Wilkes, AJP, 1998)

0.3
y = -0.0146x + 0.0214
0.2
R2 = 0.8599
pH(msd-calc)

0.1
if UMI = 0, dpH = 0.0214
0
-0.1
-0.2
-0.3
-15 -10 -5 0 5 10 15 20
Un-Measured Ions (UMI), (mEq/L)
 Explanations of The Strong Ion Gap

SID + H+ - HCO3- - Prot- - CO3= - OH- =0

SID – HCO3- - Prot- = 0
SID = HCO3- + Prot-
If SID = HCO3- + Prot- (Strong Ion Gap)?

1. Measurement error (Na, Cl + 2%) (Jones 1993)

2. Error of omission - lactate, ketoacids,
krebs cycle intermediates (Gilfix 1993, Forni 2005,
Moviat 2008)

3. Ionic concentration vs. activity (Stewart 1978)

Acids – Bases & Salts & Ionic Activity

If NS is equal parts Na and Cl (SID=0) how

can you explain the pH = 5.5?
1) Electrical neutrality refers to ionic
activity (functional concentration) not
ionic concentration (actual concentration)
2) NS is also equal parts HCl and NaOH
and HCl is a stronger acid than NaOH is
base (Wilkes, 2009)
 Strong Ion Gap (SIG)
In the Critically Ill (Kellum 1998)
 Increased SIG in pts with:
 Sepsis (Reeves, 1983, Mehta 1986)

 Liver disease (Kellum 1995, Kirschbaum 1997)

 Critical illness (Mehta 1986)

 Animal studies with endotoxemia (Kellum

1995)

 Critically ill pts with ARF (Rocktaeschel 2003)

 May be a predictor of mortality (Kellum 2004)
Clinical Outcome (Gunnerson CC: 2005)
Definitions of Acid-Base Disturbances
 Consistent definitions are a necessity to
assess incidence and outcome
 Respiratory disturbances are straight
forward
 Metabolic acidosis secondary to high
chloride is not equivalent to high lactate
 Organic vs. electrolyte

 Metabolic alkalosis from elevated SID or

hypoproteinemia
 Organic vs. electrolyte
 SID and the ICU
 Need to define acid-base disorders
based on physical principles, not HCO3
and H+
 Clinical outcome may be a function of
underlying physical principle more so
than the actual pH
 Need to define what is normal for a
given population
 We still do not have a complete
understanding of the physical chemistry
 Basic Clinical Approach at 02:00
 pH=7.05, HCO3=12, BE=-12, PCO2=30
 ETT, O2, #14 iv and volume, inotropes, Sx and/or antibx
 Most other cases
 Measure electrolytes – calculate SID
Normal is 40-44 mEq/L
Measure TPrt x 0.25 = Atot (mEq/L)
Estimate electrical neutrality from
[SID] – Atot – [HCO3] + 5
If >5 then check lactate
If lactate normal then +SIG (equally bad)
 Case 2: POD # 0, Elective CABG
 PMHx:
79 yo male with peripheral, cerebral vascular
disease
 Intra Op:
SVG x 2, off CPB with mil/levo
increased abdominal girth
CI=1.8, SVR=1477, BP=115/55, Ppa 50/20
7.35/36/104/20/-5.4 AG = 9.2
 Are you worried ?
 Second Patient: Approach
1) Electrolytes:
Na = 136
K = 5.2
Cl = 112
SID = 29.2 mEq/L
2) Total Protein = 33 g/L ~ 7.6 mEq/L
3) Electrical Neutrality:
29.2 – 20 – 7.6 = 1.6 mEq/l
4) Lactate = 2 mEq/L
5) Compensated hypoproteinemic alkalosis
(Wilkes, AJP, 1998)
Questions