1. Biochemical basis of acidosis and alkalosis: evaluating acid base disorders
Eric Niederhoffer, Ph.D.
SIU-SOM

2. Outline Approach Respiratory Metabolic history physical examination
differentials
clinical and laboratory studies
compensation
Respiratory
acidosis
alkalosis
Metabolic
There can only be one respiratory acid base disorder but multiple metabolic disorders at one time. This guide is based upon information from Merck manual online, emedicine.com, and recent literature.

3. Approach
History - subjective information concerning events, environment, trauma, medications, poisons, toxins
Physical examination - objective information assessing organ system status and function
Differentials - potential reasons for presentation
Clinical and laboratory studies - degree of changes from normal
Compensation - assessment of response to initial problem

4. Evaluation of Acid-Base Conditions
Examine serum electrolytes (increased or decreased total CO2, increased AG, abnormal HCO3- gap) and ABGs (directional changes in pH, HCO3-, and PCO2).
Examine ABG data for mixed acid-base conditions.
Complete clinical assessment of history, physical examination, previous ABGs and serum electrolytes, along with other laboratory data.
Identify underlying clinical cause(s) for each acid-base disorder.
Treat the clinical conditions.
Unless it’s of a mild degree, a single acid-base disorder will not have a normal pH.

5. Reference ranges and points
Parameter Reference range Reference point
Na mEq/L
K mEq/L
Cl mEq/L
CO2, total mEq/L pH
PCO mm Hg 40 mm Hg
PO mm Hg
HCO mEq/L 24mEq/L
Anion gap 8-16 mEq/L 12 mEq/L
Bicarbonate gap -6-6 mEq/L
Osmolar gap <10 mOsm/L
PAO2=FIO2(Patm-47)-(PaCO2)/0.8 or FIO2(Patm-47)-1.2(PaCO2) CO2 total (or measured HCO3-) is from venous sample
Venous blood gases (VBG) has PCO2 and HCO3- higher by 3 to 8 mm Hg and 1 to 2 mEq/L, respectively
Anion gap = [Na+] + [UC] – [Cl-] – [HCO3-] – [UA] where UC are K+, Ca2+, and Mg2+ ([UC] = 11 mEq/L) and UA are PO43-, SO42-, proteins and organic acids ([UA] = mEq/L). Reference point AG decreases by 2.5 mEq/L for every 1 g/dL decrease in serum [albumin].
Osmolar gap = Osmolalitymeasured – 2]Na+] –[Glucose] – [Urea] Osmolarity and osmolality are not the same, but close.
Base deficit: ∆⇑anion gap = ∆⇓HCO3-
Bicarbonate gap: (AGpatient – AGnormal) – (HCO3-normal – HCO3-patient) Delta ratio: (AGpatient – AGnormal)/(HCO3-normal – HCO3-patient)

6. Evaluation of Serum Electrolytes
Total CO2
Increased, >30 mEq/L
metabolic alkalosis
HCO3- retention for respiratory acidosis
Normal
Decreased, <24 mEq/L
metabolic acidosis (AG or HCA)
HCO3- excretion for respiratory alkalosis
Anion Gap
Increased, >20 mEq/L
consider potential cause
Normal
Decreased, <8 mEq/L
consider hypoproteinemia, abnormal proteins or cations
Bicarbonate Gap
Positive, > 6 mEq/L
metabolic alkalosis and/or
HCO3- retention for respiratory acidosis
Negative, < -6 mEq/L
hyperchloremic acidosis (HCA) and/or
HCO3- excretion for respiratory alkalosis
Generally, if total CO2 > 45 mEq/L, this suggests metabolic alkalosis. If total CO2 < 12 mEq/L, this suggests metabolic acidosis.

7. Evaluation of Arterial Blood Gas
Primary process
Compensatory response
Respiratory acidosis
Respiratory alkalosis
Metabolic acidosis
Metabolic alkalosis
PaCO2 (PCO2) = VO2 x 0.863/VA, where VO2 is rate of CO2 production and VA is alveolar ventilation
You cannot reliably get the PaCO2 from clinical observations because you don’t know the patient’s VO2 or VA and cannot get the ratio. (From Martin, L All you really need to know to interpret arterial blood gases. 2nd ed., Lippincott Williams & Wilkins, New York,) “There is no predictable correlation between PaCO2 and the clinical picture. Any combination of respiratory rate, depth, or effort can reflect any PaCO2 value, and vice versa.” Patients with respiratory problems can have decreased, normal, or increased PCO2. Patients who appear normal can have decreased, normal, or increased PCO2.

8. Delta ratio 𝛥 ratio = 𝛥Anion gap/𝛥[HCO3-] = (AG – 12)/(24 - [HCO3-])
Assessment
<0.4
Hyperchloraemic normal anion gap acidosis
0.4 – 0.8
Combined high AG and normal AG acidosis
Note that the ratio is often <1 in acidosis associated with renal failure
1 - 2
Uncomplicated high-AG acidosis
Lactic acidosis: average value 1.6
DKA more likely to have a ratio closer to 1 due to urine ketone loss (if patient not dehydrated)
>2
Pre-existing increased [HCO3-]:
concurrent metabolic alkalosis
pre-existing compensated respiratory acidosis
The delta ratio can be used to check for coexisting metabolic alkalosis.
This is based upon the assumption that for every H+ released from an acid, there will be reaction with HCO3- to produce CO2 and H2O. So the increase in acid anions created will be balanced by the decrease in HCO3-. Ideally, the ratio of these two quantities is 1. But it is more complicated in actual situations so we can look to the ratio as an indication of the presence of other acid base disorders.

9. Compensation Primary Disturbance pH HCO3- PCO2 Compensation
Respiratory acidosis
<7.35
Compensatory increase
Primary increase
Acute: 1-2 mEq/L increase in HCO3- for every 10 mm Hg increase in PCO2
Chronic: 3-4 mEq/L increase in HCO3- for every 10 mm Hg increase in PCO2
Respiratory alkalosis
>7.45
Compensatory decrease
Primary decrease
Acute: 1-2 mEq/L decrease in HCO3- for every 10 mm Hg decrease in PCO2
Chronic: 4-5 mEq/L decrease in HCO3- for every 10 mm Hg decrease in PCO2
Metabolic acidosis
1.2 mm Hg decrease in PCO2 for every 1 mEq/L decrease in HCO3-
Metabolic alkalosis
mm Hg increase in PCO2 for every 1 mEq/L increase in HCO3-
, PCO2 should not rise above 55 mm Hg in compensation
Anion gap = [Na+] – [Cl-] – [HCO3-] Unless it’s of a mild degree, a single acid-base disorder will not have a normal pH.
Osmolar gap = Osmolalitymeasured – 2]Na+] –[Glucose] – [Urea] Osmolarity and osmolality are not the same, but close.
Base deficit: ∆⇑anion gap = ∆⇓HCO3-
There is some debate as to the value of PCO2 during compensation, some evidence suggests ≤85 mm Hg as an upper limit.
pH = 6.1 +log([HCO3-]/0.03PCO2)

10. Respiratory acidosis PCO2 greater than expected Acute or chronic
Causes
excess CO2 in inspired air
(rebreathing of CO2-containing expired air, addition of CO2 to inspired air, insufflation of CO2 into body cavity)
decreased alveolar ventilation
(central respiratory depression & other CNS problems, nerve or muscle disorders, lung or chest wall defects, airway disorders, external factors)
increased production of CO2
(hypercatabolic disorders)
Examples:
Central respiratory depression & other CNS problems - drug depression of respiratory center (eg by opiates, sedatives, anaesthetics)
Nerve or muscle disorders - myasthenia gravis
Lung or chest wall defects - restrictive lung disease
Airway disorders – bronchospasm/asthma
External factors - Inadequate mechanical ventilation
Hypercatabolic disorders – malignant hyperthermia
see for more examples.

11. Racid acute Na+ 138 mEq/L pH 7.33 K+ 4.2 mEq/L PO2 61 mm Hg
A 65-year-old man comes to the physician with a 3-hour history of shortness of breath after feeling ill for the past week. His BMI is 30 kg/m2. His temperature is 38.3°C (101°F), pulse is 96/min, respirations are 20/min and shallow, and blood pressure is 145/90 mm Hg.
Na+ 138 mEq/L pH 7.33
K+ 4.2 mEq/L PO2 61 mm Hg
Cl- 101 mEq/L PCO2 50 mm Hg
CO2, total 28 mEq/L HCO3- 26 mEq/L
History suggests hypoventilation, supported by increased PCO2 and lower than anticipated PO2.
Respiratory acidosis (acute) due to no renal compensation.
(A-a) O2 difference = 0.21(760 – 47) -50/ = 27 mm Hg

12. Description Na+ 138 mEq/L pH 7.33 K+ 4.2 mEq/L PO2 61 mm Hg
Cl- 101 mEq/L PCO2 50 mm Hg
CO2, total 28 mEq/L HCO3- 26 mEq/L
AG = 11 mEq/L BG = 1 mEq/L
1-2 mEq/L increase in HCO3- for every 10 mm Hg increase in PCO2.
PCO2 increase = = 10 mm Hg.
HCO3- increase predicted = (1-2) x (10/10) = 1-2 mEq/L
add to 24 mEq/L (reference point) = mEq/L

13. Racid chronic Na+ 145 mEq/L pH 7.33 K+ 4.5 mEq/L PO2 52 mm Hg
A 56-year-old woman with COPD is brought to the physician with a 3-hour history of shortness of breath. Her temperature is 37°C (98.6°F), pulse is 90/min, respirations are 22/min and shallow, and blood pressure is 135/80 mm Hg.
Na+ 145 mEq/L pH 7.33
K+ 4.5 mEq/L PO2 52 mm Hg
Cl- 99 mEq/L PCO2 62 mm Hg
CO2, total 34 mEq/L HCO3- 32 mEq/L
History suggests hypoventilation, supported by increased PCO2.
Respiratory acidosis (chronic) with renal compensation.
(A-a) O2 difference = 0.21(760 – 47) – 62/0.8 – 62 = 21 mm Hg

14. Description Na+ 145 mEq/L pH 7.33 K+ 4.5 mEq/L PO2 52 mm Hg
Cl- 99 mEq/L PCO2 62 mm Hg
CO2, total 34 mEq/L HCO3- 32 mEq/L
AG = 14 mEq/L BG = 10 mEq/L
3-4 mEq/L increase in HCO3- for every 10 mm Hg increase in PCO2.
PCO2 increase = = 22 mm Hg.
HCO3- increase predicted = (3-4) x (22/10) = 7-9 mEq/L
add to 24 mEq/L (reference point) = mEq/L

15. Respiratory alkalosis
PCO2 less than expected
Acute or chronic
Causes
increased alveolar ventilation
(central causes, direct action via respiratory center; hypoxaemia, act via peripheral chemoreceptors; pulmonary causes, act via intrapulmonary receptors; iatrogenic, act directly on ventilation)
Examples:
Central causes (direct action via respiratory center) - various drugs (eg, analeptics, propanidid, salicylate intoxication)
Hypoxaemia (act via peripheral chemoreceptors) - respiratory stimulation via peripheral chemoreceptors
Pulmonary causes (act via intrapulmonary receptors) – pulmonary embolism
Iatrogenic (act directly on ventilation)– excessive controlled ventilation
see for more examples.

16. Ralk acute
A 17-year-old woman is brought to the physician with a 3-hour history of epigastric pain and nausea. She admits taking a large dose of aspirin. Her respirations are 20/min and full.
Na+ 136 mEq/L pH 7.55
K+ 3.7 mEq/L PO2 104 mm Hg
Cl- 101 mEq/L PCO2 25 mm Hg
CO2, total 23 mEq/L HCO3- 22 mEq/L
History suggests hyperventilation, supported by decreased PCO2.
Respiratory alkalosis (acute) due to no renal compensation.
(A-a) O2 difference = 0.21(760 – 47) – 25/0.8 – 104 = 15 mm Hg

17. Description Na+ 136 mEq/L pH 7.55 K+ 3.7 mEq/L PO2 104 mm Hg
Cl- 101 mEq/L PCO2 25 mm Hg
CO2, total 23 mEq/L HCO3- 22 mEq/L
AG = 12 mEq/L BG = -2 mEq/L
1-2 mEq/L decrease in HCO3- for every 10 mm Hg decrease in PCO2.
PCO2 decrease = = 15 mm Hg.
HCO3- decrease predicted = (1-2) x (15/10) = 2-3 mEq/L
subtract from 24 mEq/L (reference point) = mEq/L

18. Ralk chronic
A 81-year-old woman with a history of anxiety is brought to the physician with a 2-day history of shortness of breath. She has been living at 9,000 ft elevation for the past 1 month. Her respirations are full at 20/min.
Na+ 133 mEq/L pH 7.48
K+ 4.9 mEq/L PO2 69 mm Hg
Cl- 105 mEq/L PCO2 22 mm Hg
CO2, total 17 mEq/L HCO3- 16 mEq/L
History suggests hyperventilation, supported by decreased PCO2.
Respiratory alkalosis (chronic) with renal compensation.
(A-a) O2 difference = 0.21(760 – 47) – 22/0.8 – 69 = 54 mm Hg

19. Description Na+ 133 mEq/L pH 7.48 K+ 4.9 mEq/L PO2 69 mm Hg
Cl- 105 mEq/L PCO2 22 mm Hg
CO2, total 17 mEq/L HCO3- 16 mEq/L
AG = 12 mEq/L BG = -8 mEq/L
4-5 mEq/L decrease in HCO3- for every 10 mm Hg decrease in PCO2.
PCO2 decrease = = 18 mm Hg.
HCO3- decrease predicted = (4-5) x (18/10) = 7-9 mEq/L
subtract from 24 mEq/L (reference point) = mEq/L

20. Metabolic acidosis Plasma HCO3- less than expected
Gain of strong acid or loss of base
Alternatively, high anion gap or normal anion gap metabolic acidosis
Causes
high anion-gap acidosis (normochloremic)
(ketoacidosis, lactic acidosis, renal failure, toxins)
normal anion-gap acidosis (hyperchloremic)
(renal, gastrointestinal tract, other)
Examples:
Ketoacidosis – alcoholic ketoacidosis
Lactic acidosis - Type A lactic acidosis (impaired perfusion)
Renal failure – uremic acidosis
Toxins – salicylates
Renal – renal tubular acidosis
Gastrointestinal gract – severe diarrhea
Other - Addition of HCl, NH4Cl
see for more examples.

21. Macid increased AG Na+ 135 mEq/L pH 7.19 K+ 4.0 mEq/L PO2 80 mm Hg
A 75-year-old man with severe congestive heart failure is brought to the emergency department. He takes none of his prescribed medications. His respirations are 24/min and blood pressure is 80/50 mm Hg. He has decreased urine output; his baseline creatinine concentration has been 1.6 mg/dL.
Na+ 135 mEq/L pH 7.19
K+ 4.0 mEq/L PO2 80 mm Hg
Cl- 97 mEq/L PCO2 21 mm Hg
CO2, total 8 mEq/L HCO3- 8 mEq/L
Lactate 20 mEq/L
Urea 54 mg/dL
Creatinine 2.5 mg/dL
History suggests congestive heart failure (poor perfusion).
Metabolic acidosis with appropriate respiratory compensation.
(A-a) O2 difference = 0.21(760 – 47) – 21/0.8 – 80 = 44 mm Hg

22. Description Na+ 135 mEq/L pH 7.19 K+ 4.0 mEq/L PO2 80 mm Hg
Cl- 97 mEq/L PCO2 21 mm Hg
CO2, total 8 mEq/L HCO3- 8 mEq/L
Lactate 20 mEq/L
Urea 54 mg/dL AG = 30 mEq/L
Creatinine 2.5 mg/dL BG = 2 mEq/L
1.2 mm Hg decrease in PCO2 for every 1 mEq/L decrease in HCO3-.
HCO3- decrease = = 16 mEq/L
PCO2 decrease predicted = 1.2 x 16 = 19 mm Hg.
subtract from 40 mm Hg (reference point) = 21 mm Hg

23. Macid normal AG
A 2-year-old girl is brought to the physician because of a 1-week history of diarrhea. She is at the 30th centile for height and weight. Physical examination shows no abnormalities. Laboratory studies show a fractional excretion of HCO3- of 2.5%.
Na+ 139 mEq/L pH 7.34
K+ 4.3 mEq/L PO2 96 mm Hg
Cl- 112 mEq/L PCO2 29 mm Hg
CO2, total 16 mEq/L HCO3- 15 mEq/L
Urine pH 5.0
History suggests intestinal electrolyte loss.
Metabolic acidosis with respiratory compensation.
(A-a) O2 difference = 0.21(760 – 47) – 29/0.8 – 96 = 18 mm Hg

24. Description Na+ 139 mEq/L pH 7.34 K+ 4.3 mEq/L PO2 96 mm Hg
Cl- 112 mEq/L PCO2 29 mm Hg
CO2, total 16 mEq/L HCO3- 15 mEq/L
Urine pH 5.0
FEHCO3- 2.5%
AG = 12 mEq/L BG = -9 mEq/L
1.2 mm Hg decrease in PCO2 for every 1 mEq/L decrease in HCO3-.
HCO3- decrease = = 9 mEq/L
PCO2 decrease predicted = 1.2 x 9 = 11 mm Hg.
subtract from 40 mm Hg (reference point) = 29 mm Hg

25. Metabolic alkalosis Plasma HCO3- greater than expected
Loss of strong acid or gain of base
Causes (2 ways to organize)
loss of H+ from ECF via kidneys (diuretics) or gut (vomiting)
gain of alkali in ECF from exogenous source (IV NaHCO3 infusion) or endogenous source (metabolism of ketoanions) or
addition of base to ECF (milk-alkali syndrome)
Cl- depletion (loss of acid gastric juice)
K+ depletion (primary/secondary hyperaldosteronism)
Other disorders (laxative abuse, severe hypoalbuminaemia)
Examples:
Addition of base to ECF – milk-alkali syndrome, excessive NaHCO3 intake, recovery phase from organic acidosis, massive blood transfusion
Cl- depletion - loss of acid gastric juice, diuretics, post-hypercapnia, excess fecal loss
K+ depletion – primary/secondary hyperaldosteronism, Cushing syndrome, some drugs, kaliuretic diuretics
see for more information.

26. Urinary Chloride Spot urine Cl- less than 10 mEq/L
often associated with volume depletion
respond to saline infusion
common causes - previous thiazide diuretic therapy, vomiting (90% of cases)
Spot urine Cl- greater than 20 mEq/L
often associated with volume expansion and hypokalemia
resistant to therapy with saline infusion
causes: excess aldosterone, severe K+ deficiency, current diuretic therapy, Bartter syndrome

27. Malk low Urine Cl-
An 24-year-old woman is brought to the physician with a 3-month history of weakness and fatigue. She has binges of eating followed by self-induced vomiting. Blood pressure is 90/60 mm Hg. Physical examination shows erosions of the lingual surface of the teeth.
Na+ 137 mEq/L pH 7.52
K+ 2.6 mEq/L PO2 78 mm Hg
Cl- 90 mEq/L PCO2 49 mm Hg
CO2, total 41 mEq/L HCO3- 39 mEq/L
Urine Cl- 5 mEq/L
History and physical examination suggests bulimia nervosa.
Metabolic alkalosis with respiratory compensation.
The cause is most likely bulimia nervosa.
(A-a) O2 difference = 0.21(760 – 47) – 49/0.8 – 78 = 10 mm Hg

28. Description Na+ 137 mEq/L pH 7.52 K+ 2.6 mEq/L PO2 78 mm Hg
Cl- 90 mEq/L PCO2 49 mm Hg
CO2, total 41 mEq/L HCO3- 39 mEq/L
Urine Cl- 5 mEq/L
AG = 8 mEq/L BG = 11 mEq/L
mm Hg increase in PCO2 for every 1 mEq/L increase in HCO3-.
HCO3- increase = = 15 mEq/L
PCO2 increase predicted = x 15 = 9-12 mm Hg.
add to 40 mm Hg (reference point) = mm Hg

29. Malk high Urine Cl-
An 83-year-old woman is brought to the physician with a 1-week history of weakness, nausea, and poor appetite. Her current medications are aspirin and hydrochlorothiazide. Her blood pressure is 110/70 mm Hg.
Na+ 130 mEq/L pH 7.48
K+ 1.9 mEq/L PO2 66 mm Hg
Cl- 77 mEq/L PCO2 49 mm Hg
CO2, total 38 mEq/L HCO3- 36 mEq/L
Urine Cl- 74 mEq/L
History and physical examination suggest electrolyte imbalance.
Metabolic alkalosis with respiratory compensation.
The cause most likely is current diuretic therapy.
(A-a) O2 difference = 0.21(760 – 47) – 49/0.8 – 66 = 23 mm Hg

30. Description Na+ 130 mEq/L pH 7.48 K+ 1.9 mEq/L PO2 66 mm Hg
Cl- 77 mEq/L PCO2 49 mm Hg
CO2, total 38 mEq/L HCO3- 36 mEq/L
Urine Cl- 74 mEq/L
AG = 17 mEq/L BG = 17 mEq/L
mm Hg increase in PCO2 for every 1 mEq/L increase in HCO3-.
HCO3- increase = = 12 mEq/L
PCO2 increase predicted = x 12 = 7-9 mm Hg.
add to 40 mm Hg (reference point) = mm Hg

31. Review Questions What is an effective approach to acid base problems?
What are the reference ranges and reference points?
What are the anion, bicarbonate, and osmolar gap?
What is the delta ratio?
What is compensation?
What are the characteristics of respiratory acidosis and alkalosis?
What are the characteristics of metabolic acidosis and alkalosis?
What is the utility of spot urine Cl-?