Regulation of Acid Base Balance. Abnormalities with case studies.

1. Presenter: Dr. Abhirup Sarkar
Junior Resident
Department of Laboratory Medicine
AIIMS, New Delhi
Moderator: Dr. Sudip Kumar Datta

2. Overview
 To what extent acid base balance is maintained in human body?
 Why regulation of acid base balance is important?
 Source of acid in body.
 Mechanisms for regulation of acid base balance:
Three-tier mechanism.
 Chemical buffer system.
 Respiratory regulation.
 Renal regulation.
 Approach to the acid base disorders.
 Concept of Anion Gap, Urine Anion Gap, Delta Ratio.
 Examples of acid base disorders with case studies.

3. Introduction
 Various human body fluids maintain specific H+ concentration.
 Precise control of extracellular fluid H+ concentration is maintained in
the body.
 Narrow range of 7.35 – 7.45.

4. Why regulation of pH is important ?
 pH change alters tertiary structure of the body proteins causing:
 Malfunctioning of cellular transmembrane ion channels.
 Change in the active site of enzyme and hinders enzyme activity.
 Hinders hormone activity.
 Intracellular pH is to be maintained at pH of neutrality, so that the
metabolite intermediates become charged and trapped in the cell.
 Extracellular slightly higher pH maintains the H+ gradient favouring
the exit of H+ from the cell.

5. Compatible range for life
• < 7.35 = Acidemia , > 7.45 = Alkalemia
• Death occurs at blood pH below 6.8 and above 8.0

6. Source of Acid
The various acids produced by the body are classified as volatile acid and
as fixed acids.
 Volatile acid
CO2 : end-product of complete oxidation of carbohydrates and fatty acids
create an equivalent amount of carbonic acid (H2CO3) by dissolving in
water
~ 12,000 – 24,000 mmol /day

7.  Fixed Acid:
non-volatile. ~50 mmol/L.
• Sulfuric acid (amino acids)
• Phosphoric acid (phospholipids)
Products of Normal Catabolism
• Acetoacetic acid (DKA)
• β-Hydroxybutyric acid (DKA)
• Lactic acid (anaerobic respiration)
Products of Extreme Catabolism
• Salicylic acid (aspirin)
• Formic acid (from methanol)
• Oxalic acid (from ethylene glycol)
Ingested Substances

8. Defending Against Change in pH
Three primary systems regulate the H+ concentration in the body fluids
First Line
• Chemical
Buffer
Systems
Second
Line
• Respiratory
Regulation
Third Line
• Renal
Regulation

9. Chemical Buffer Systems
 Buffer is a system that resists any alteration in its pH when a small
amount of acid or alkali is added to it.
 It comprises two major components: a weak acid (HA) and its
conjugate base (A-).

10. Name of Buffer Contribution in Chemical
Buffering
Bicarbonate Buffer 53%
Haemoglobin Buffer 35%
Phosphate and Serum Protein
Buffers
12%

11. Bicarbonate Buffer System
 The principal extracellular buffer.
 53% of total chemical buffer action.
 Contains two ingredients:
(1) a weak acid, H2CO3 : Proton donor.
(2) a bicarbonate salt : sodium bicarbonate (NaHCO3) : Proton acceptor.

12. Base entering the blood stream
Acid entering the blood stream

13. Henderson–Hasselbalch equation
 Used for estimating the pH of a buffer solution.
[HA] is the molar concentration
of the undissociated weak acid,
[A⁻] is the molar concentration
(molarity, M) of this acid’s
conjugate base and Ka is the
acid dissociation constant

14. Henderson–Hasselbalch equation
 When applied to relate the pH of blood to constituents of the
bicarbonate buffering system:

15. Henderson–Hasselbalch equation

16. Even though pK 6.1 is far away from 7.4 , it is remarkably
effective because it operates in an open system; that is, the
two buffer components can be added to or removed from
the body at controlled rates.

18. Phosphate Buffer
 Plays major role in buffering renal tubular fluid and intracellular
fluids, but not in extracellular fluid.
 Components are : H2PO4
− and HPO4
= . It has a pK of 6.8.
 Intracellular concentration is high compared to extracellular
concentration.
 Concentration in tubular fluid is also high.

19. Protein Buffer
 Depends on the ability of amino acids to respond to pH changes by
accepting or releasing H+
 Histidine and Cysteine, have R groups (side chains) that will donate
H+ if the pH increases outside the normal range. Their buffering
effects are very important in both the ECF and the ICF.

20. Buffer System in RBC

21. Buffer System in RBC

22. Respiratory Regulation
 Buffering power of the respiratory system is one to two times as great
as the buffering power of all other chemical buffers in the extracellular
fluid combined.
 If the metabolic formation of CO2 remains constant, the only other
factor that affects PaCO2 in extracellular fluid is the rate of alveolar
ventilation.

24. Renal Regulation
1. Bicarbonate Reabsorption
2. Phosphate Buffer System
3. Ammonium Buffer System

25. Bicarbonate Reabsorption

26. Bicarbonate Reabsorption

27. H+ secretion in Urine & “New” HCO3
- generation by
Phosphate Buffer System

28. H+ secretion in Urine & “New” HCO3
- generation by
Ammonium Buffer System

29. Factors Influencing Renal Regulation
Most Important

30. Approach to a Case of Acid Base Disorder
 The most clinical useful information comes from the clinical
description of the patient by the history and physical examination.
 Look at the pH. Is there an acid base disorder present?
- If pH < 7.35, then acidaemia
- If pH > 7.45, then alkalemia
 Look at PCO2, HCO3
-. What is the acid base process (alkalosis vs
acidosis) leading to the abnormal pH?
 Distinguish the initial change from the compensatory response.
- The initial change will be the abnormal value that correlates with
the abnormal pH.

31.  Once the initial chemical change and the compensatory response is
distinguished, then identify the specific disorder.
 If respiratory process, is it acute or chronic?
- To assess if acute or chronic, determine the extent of compensation.
 If metabolic acidosis, then look at the Anion Gap and Delta Ratio.
 If normal anion gap and cause is unknown, then calculate the Urine
Anion Gap.

32. Predicted Compensation
Winter’s Formula

33. Predicted Compensation…..cont.

34.  In general, compensatory responses return the pH toward, but
not to, the normal value.
 Exception: “Chronic respiratory alkalosis when prolonged” can be
fully compensated by renal acidosis and pH can become normal.
 Normal pH with abnormal PaCO2 and [HCO3
-] points towards mixed
acid-base disturbances.

35. Base Excess and Standard Base Excess
 Introduced in 1957
 Base excess is amount of acid or alkali to return in vitro blood to
normal pH (7.40) under standard conditions ( at 37oC at a PaCO2 of 40
mmHg)
 Normal Base excess is between -3 and +3mEq/L
 Standard base excess is dose of acid or alkali to return the ECF to
normal pH (7.40) under standard conditions. ( at 37oC at a PaCO2 of 40
mmHg)
 This is the base excess calculated for anaemic blood (Hb = 5g/dL).Based
on the principle that this closely represents the behaviour of the whole
body, as Hb effectively buffers the plasma as well as the ECF (plasma +
ECF is represented by anaemic blood)

37. Anion Gap
 In normal individuals, the total serum cations are balanced with the total
serum anions.
Total cations = Measured cations (Na+) + Unmeasured cations
Total anions = Measured anions (HCO3
- , Cl-) + Unmeasured anions
The normal Anion Gap is 10 ± 2 mEq/L.

38. Increased Anion Gap
 Increase in unmeasured anions More Common
 Decrease in unmeasured cations.
 If there is acute increase in pH, i.e., alkalosis an increase in the
effective anionic charge on albumin (as it will release proton)
If there are gross changes in serum albumin (major UA) level
AGcorrect = AG + {(4 − [albumin]) × 2.5}

39. Decreased Anion Gap
 An increase in unmeasured cations: Addition to the blood of abnormal
cations, such as lithium (lithium intoxication) or cationic
immunoglobulins (plasma cell dyscrasias).
 Decrease in unmeasured anions: a reduction in the major plasma anion
albumin concentration (nephrotic syndrome). A fall in serum albumin
by 1 g/dL from the normal value (4.5 g/dL) decreases the AG by 2.5
mEq/L.
 A decrease in the effective anionic charge on albumin by acidosis as it
will accept proton.
Laboratory Error:
1. Hyperviscosity and hyperlipidemia  Underestimation of Na+
2. Bromide intoxication  Overestimation of Cl-

40.  When high AG with Metabolic Acidosis. 4 major causes are considered:
 When non-AG Metabolic Acidosis 2 major causes are considered

41. Urine Anion Gap = [Na+ + K+]u – [Cl−]u
 The most important unmeasured ion in urine is NH4
+ since it is
the most important form of acid excretion by the kidney. Urine
NH4
+ is difficult to measure directly.
 A positive urine anion gap suggests a low urinary NH4
+ (e.g. renal
tubular acidosis).
 A negative urine anion gap suggests a high urinary NH4
+ (e.g.
diarrhoea). In chronic metabolic acidosis, ammonium excretion
should be elevated if renal tubular function is intact.

42. Metabolic
Acidosis
Blood Anion
Gap
Normal
Urinary
Anion Gap
Positive:
RTA
Negative: GI
loss
Increased
Ketoacidosis
Lactic
acidosis
Toxin
Renal failure

43. Delta Ratio
 The Delta Ratio is a formula that can be used to assess to evaluate
whether a mixed metabolic acidosis (pure high/normal AG or mixed) is
present.
 < 0.4 due to a pure NAGMA
 0.4 - 0.8 due to a mixed NAGMA + HAGMA
 0.8 - 2.0 due to a pure HAGMA. Lactic acidosis: average value 1.6 . DKA
more likely to have a ratio closer to 1 due to urine ketone loss
 >2.0 due to a mixed HAGMA + metabolic alkalosis
NAGMA=Non-Anion Gap Metabolic Acidosis
HAGMA=High Anion Gap Metabolic Acidosis

44. Case 1
A 19 year old female insulin dependent diabetic patient on medication
was brought to Emergency Department. She is now feeling lethargic and
slightly disoriented and taking long deep breathing. There was a history
of poor compliance with medical therapy.
She is afebrile. Chest is clear. Circulation was adequate.
Na+ 136 mmol/l
K+ 5.1 mmol/l
Cl- 101 mmol/l
Glucose 342 mg/dl
Urea 32 mg/dl
Creatinine 1.1 mg/dl
pH 7.26
PaCO2 17 mmHg
PaO2 128 mmHg
HCO3 7.1 mmol/l

45.  pH 7.26 Acidemia
 PaCO2 17
 HCO3 7.1
 Predicted PaCO2= (7.1 x 1.5) + 8 ± 2 = 16.65 to 20.65
PaCO2 is inside the predicted range. So respiratory compensation is as
predicted and there is no mixed disorder.
 Anion Gap = 136 – 101 -7.1 = 27.9 High Anion Gap
 Delta Ratio = (27.9-12)/(24-7.1) =0.94 (0.8 - 2.0 due to a pure HAGMA)
Decrease in HCO3 corresponds with pH
change. PaCO2 change is compensatory.
Metabolic Acidosis with Respiratory
Compensation.

46. Cont..
Insulin deficiency
Increase in counter-regulatory hormones (glucagon, cortisol, GH, epinephrine)
Enhances hepatic
gluconeogenesis
Increased
glycogenolysis
Lipolysis
Increases serum free
fatty acids
Hepatic metabolism
of free fatty acids
Accumulation of acidic intermediate
and end metabolites. e.g. acetone,
beta-hydroxybutyrate, and
acetoacetate
Exceeds the capacity of
body to buffer and leads to
ACIDEMIA

47.  Na+ 136 mmol/l
 K+ 5.1 mmol/l
 Cl- 101 mmol/l
 Glucose 342 mg/dl
 Urea 32 mg/dl
 Creatinine 1.1 mg/dl
Despite a total-body potassium deficit,
the serum potassium at presentation is
mildly elevated.
This is due to the extracellular shift of
potassium in exchange of hydrogen,
which is accumulated in acidosis, in
spite of depleted total body
potassium.

48. Case 2
The patient is a 35 year -old female with AIDS brought to the emergency
room with a fever of 39oC and a three month history of copious
diarrhoea.
On physical exam the patient is a well-developed, thin female in
moderate distress. Vital signs-(supine) blood pressure 100/60, pulse 100
and (standing) blood pressure 80/40, pulse 125, respirations 18 and she
was afebrile. The abdomen was supple and minimally tender to
palpation. Bowel sounds were hyperactive.

49. Na+ 136 mmol/l
K+ 3.4 mmol/l
Cl- 112 mmol/l
Glucose 105 mg/dl
Urea 64 mg/dl
Creatinine 1.5 mg/dl
pH 7.33
PCO2 27 mmHg
PO2 90 mmHg
HCO3 14 mmol/L

50.  pH 7.33 Acidemia
 PaCO2 27
 HCO3 14
 Predicted PaCO2= (14 x 1.5) + 8 ± 2 = 27 to 31
PaCO2 is inside the predicted range. So respiratory compensation is as
predicted and there is no mixed disorder.
 Anion Gap = 136 – 112 - 14 = 10 Normal Anion Gap
 Delta Gap = (10-12)/(24-14) = -0.2 (< 0.4 due to a pure NAGMA)
Decrease in HCO3 corresponds with pH
change. PaCO2 change is compensatory.
Metabolic Acidosis with Respiratory
Compensation.

51.  In diarrhoea, stools contain a higher [HCO3
−] than plasma so that
metabolic acidosis develops along with volume depletion.
 Reciprocal changes in [Cl−] and [HCO3
−] result in a normal Anion
Gap.
Increase in [Cl−] above the normal value approximates the decrease in
[HCO3
−].

52. Case 3
The patient is a 28 year-old female who presents with a complaint of
muscular weakness and fatigue. She has lost 30 pounds since her last
office visit one year ago. She has no other complaints.
On physical exam she is a cachectic female appearing fatigued. Blood
pressure 100/76 mmHg, pulse 88/min, respirations 16/min and she was
afebrile. Clinical exam was remarkable for an erythematous pharynx and
scraped or raw areas on the knuckles of right hand.

53. Na+ 133 mmol/l
K+ 2.8 mmol/l
Cl- 85 mmol/l
Glucose 77 mg/dl
Urea 41 mg/dl
Creatinine 0.8 mg/dl
pH 7.48
PaCO2 48 mmHg
PO2 80 mmHg
HCO3 36 mmol/L

54.  pH 7.48 Alkalemia
 PaCO2 48
 HCO3 36
 Predicted PaCO2 = (36-24)x 0.75 + 40 = 49
 Actual PaCO2 is in the predicted range.
 Anion Gap = 136 – 36 -85 =12 Normal
Increase in HCO3 corresponds with pH
change. PaCO2 change is compensatory.
Metabolic Alkalosis with Respiratory
Compensation.

55. Causes of Metabolic Alkalosis

56. Chloride responsive and Non-responsive Metabolic
Alkalosis
 Chloride responsive : In cases of metabolic alkalosis associated with a
reduction in the ECV, there will be a stimulus for avid Na+ and Cl-
reabsorption in expense of H+ to replenish extracellular volume. In
these setting urinary Cl will be low, less than 20 mEq/L.
Administration of NaCl and water stops the stimulus for aldosterone
production and thus leading to correction of the metabolic alkalosis.
 Chloride non-responsive : States of mineralocorticoid excess are
associated with an expanded volume and sometimes hypertension.
The urinary Cl will be high (> 40 mEq/L). In these patients,
administration of saline would further expand the extracellular volume
and worsen hypertension. In cases of exogenous base ingestion also,
the alkalosis will not be corrected by administration of NaCl.

57. Case 4
 A 68 year-old male known smoker with a history of COPD presents to
the emergency room complaining of worsening dyspnoea and an
increase in the frequency and purulence of his sputum production over
the past 2 days. Before he is placed on supplemental oxygen, a room air
arterial blood gas is drawn and it reveals:
pH 7.37
PaCO2 57mmHg
PaO2 70
HCO3
- 32

58.  pH 7.37 Slight Acidemia
 PaCO2 57
 HCO3 32
 Predicted HCO3 = (57-40) x 0.4 + 24 = 30.8
 Predicted HCO3 is near actual HCO3
Increase in PaCO2 corresponds with pH
change. HCO3 change is compensatory.
Chronic respiratory acidosis with
Metabolic Compensation.

59. Case 5
 A 24 year-old woman is found in a road by some bystanders. She is
brought into the ER and upon arrival, doctors found her with an
oxygen saturation of 88% on room air and pinpoint pupils on exam.
 A room air arterial blood gas is performed and reveals:
pH 7.25
PaCO2 60mmHg
PaO2 65 mmHg
HCO3
- 26mmol/l,
 On her chemistry panel:
Sodium 137 mmol/l
Chloride 100 mmol/l
Bicarbonate 26 mmol/l

60.  pH 7.25 Acidemia
 PaCO2 60
 HCO3 26
 Predicted HCO3 = (60-40) x 0.1 + 24 = 26
 Predicted HCO3 is actual HCO3
Increase in PaCO2 corresponds with pH
change. No/very little change in HCO3.
Acute respiratory acidosis

61. Causes of Respiratory Acidosis

62. Case 6
 A 35-year-old reports to the Emergency Department in the early
morning with shortness of breath. She has cyanosis of the lips. She has
had a productive cough for 2 weeks. Her temperature is 102.2o F, blood
pressure 110/76mmHg, heart rate 108/min, respirations 32/min, rapid
and shallow. Breath sounds are diminished in both bases, with coarse
rhonchi in the upper lobes. Chest X-ray indicates bilateral pneumonia.
 ABG results are:
pH= 7.49
PaCO2= 28 mmHg
HCO3= 22 mmol/l
PaO2= 54 mmol/l

63.  pH 7.49 Alkalemia
 PaCO2 28
 HCO3 22
 Predicted HCO3 = 24 - (40-28) x 0.2 = 21.6
 Actual HCO3 is in the predicted range.
Decrease in PaCO2 corresponds with pH
change. Change in bicarbonate is minimal.
Acute Respiratory Alkalosis

64. Causes of Respiratory Alkalosis

65. Some examples of Mixed Disorders
 Metabolic Acidosis + Metabolic Alkalosis : Renal failure, diabetic
ketoacidosis, lactic acidosis with vomiting or diuretics.
 Respiratory Acidosis + Metabolic Alkalosis: Chronic obstructive
pulmonary disease (COPD) with respiratory acidosis and a thiazide or
loop diuretic for treatment of cor pulmonale will cause metabolic
acidosis.
 Respiratory Alkalosis + Metabolic Alkalosis: Pregnant individuals
usually have respiratory alkalosis elevated diaphragm, however, when
they develop profuse vomiting, a superimposed metabolic alkalosis
develops.

66. Summary

68. See the pH : Acidemia or Alkalemia?
Primary problem : Respiratory or Metabolic?
Compensation? Whether mixed disorder?
Calculate Anion Gap, Delta Ratio, Urinary
anion Gap where necessary
pCO2 or [HCO3] change
corresponds with pH
change?
Compensatory change in
pCO2 or [HCO3] are in
expected range? Or some
other pH disturbances?
pH <7.35 or >7.45?