Standard Approach

This section outlines the chemical principles underlying blood gas interpretation and provides a reasonably standard approach.

Principles

Anion Gap

The \(Anion \ Gap = Na^+ - Cl^+ - HCO_3^-\):

  • Normal is 12 (8-16)
    A value rather than range is specified to permit further changes.
  • Low sensitivity and specificity
  • Accuracy falls further in the setting of hypoalbuminaemia, and so should be corrected:
    • \(AGc = AG + 0.25 \times (40 - [albumin])\)
    • i.e. For every 4 g/L ↓ (or ↑) in serum albumin, the normal anion gap ↓ (or ↑) by 1
  • The anion gap rises when anions other than bicarbonate contribute to negative charge
    • In an inorganic acidosis, chloride ↑ and bicarbonate ↓ proportionally such that the AG remains normal
    • Other acid anions produce an H+ that reacts with HCO3- and the bicarbonate ↓, and the AG ↑

The Anion Gap is sometimes written including potassium. This makes the:

  • \(Anion \ Gap = Na^+ + K^+ - Cl^+ - HCO_3\)
  • Equation marginally more accurate
    Predominantly in patients who experience wild swings in their serum potassium, typically renal patients.
  • Maths marginally harder
  • Normal value 16 (12-20)
  • CICM examiner sad
    Thus, the uncorrected version is used here.

Causes of a negative anion gap include:

  • Excess unmeasured cation
    • Lithium
    • Magnesium
    • Calcium
    • Cationic drugs
      • Polymyxin B
  • Halides
    Incorrectly read as chloride by the electrode.
  • Erroneous measurements
    • Measurement error of each of the composite electrolytes
    • Effect of other substances
      • Chloride impersonators
        Halides, such as bromide and iodide.
      • Unmeasured cations
        Lithium, calcium, magnesium.
      • Cationic drugs
      • Protein
        Anionic proteins will ↑ the AG whilst not causing significant acidosis:
        • Gamma-globulinaemia
        • ↑ Serum paraprotein
        • ↑ Phosphate
        • ↑ Sulfate

Delta Ratio

The \(Delta \ Ratio = {\uparrow AG \over \downarrow HCO_3^-}\):

  • Relates the change in the AG to the change in the bicarbonate
  • If the ↑ in AG is matched by the ↓ in HCO3-, then bicarbonate has theoretically buffered the entire acid load
    This relies on several assumptions that do not occur in practice:
    • Bicarbonate is not the only extracellular buffer
    • ~50% of metabolic acidosis is buffered intracellularly
    • Measurement error exists in measuring the five components of the ratio
      Sodium, potassium, chloride, albumin, bicarbonate.
Interpretation of the Delta Ratio
Ratio Interpretation
<0.4 NAGMA
0.4-0.8 Mixed HAGMA and NAGMA
0.9-1.2 Pure HAGMA
>1.2 HAGMA with pre-existing metabolic alkalosis
An ↑ DR indicates an ↑ degree of metabolic alkalosis.

Standardised Base Excess

  • The base excess is the amount of strong acid or base that would have to be added to a sample of whole blood to produce a pH of 7.4 at a PaCO2 of 40mmHg at 37°C
    This quantifies the metabolic portion of an acid-base disturbance.
  • The standardised base excess is the base excess normalised to a haemoglobin of 48g/L
    This generalises the result to the extracellular fluid compartment by attenuating the buffering effect of haemoglobin

Osmolar Gap

The \(Osmolar \ Gap = Osm_{measured} - (2 \times Na^+ + Urea + Glucose)\):

  • Difference between:
    • Total (measured) osmoles
    • Measurable osmoles
  • Normal <10
    Should be ~6.
  • An ↑ OG with a normal AG occurs with any substance that does not dissociate at physiological pH
    This may occur in absence of acidosis if the osmole is not metabolised to produce an acid.
  • Osmolality relates only to concentration, and is unrelated to molecular size or weight
  • To affect the OG, osmoles must be present in a sufficient concentration to make a meaningful contribution to total osmolality
  • Osmoles that are metabolised to unmeasured anions will also ↑ the AG as they are metabolised, causing a concurrent ↓ in the OG
    This occurs during metabolism of toxic alcohols.
  • The reverse happens late in DKA resuscitation, where regeneration of NAD+ causes a greater production of acetoacetate from ketones, part of which spontaneously dissociates to form acetone which ↑ the osmolar gap
Abnormalities of the Osmolar Gap
↑ Osmolar Gap Normal Osmolar Gap
↑ Anion Gap

Toxins:

  • Methanol
    Metabolised to formic acid.
  • Metabolised glycols
    • Ethylene glycol
    • Propylene glycol
  • Salicylates
    Metabolised to pyruvate, lactate, acetate.

Metabolic:

  • Lactic acidosis
  • Ketoacidosis
  • AKI
  • CKD
  • Toxic alcohols after metabolism
  • Spurious AG
    Significant unmeasured anion.
    • e.g. Hyperalbuminaemia
Normal Anion Gap
  • Mannitol
  • Glycine
  • Organic solvents
    • Acetone
  • Non-metabolised glycols
    • Polyethylene glycol
  • Maltose
  • Ethanol
  • Toxic alcohols prior to metabolism
  • Pseudohyponatraemia
    • Hypertriglyceridaemia
    • Hyperproteinaemia
Metabolic causes of a ↑ AG and ↑ OG typically cause a smaller ↑ in OG than toxins

As the osmolar gap may vary in absence of acidosis, causes of an abnormal osmolar gap are also presented here.

Correcting sodium for glucose allows the presence of an underlying sodium disorder to be quantified. A variety of calculations exist, consider:

\(Na_{corr} = Na_{serum} - {Glucose \over 4}\)

Where:

  • \(Na_{corr}\) is the corrected sodium in mmol/L
  • \(Na_{serum}\) is the measured sodium in mmol/L
  • \(Glucose\) is the BSL in mmol/L

Note that the serum sodium is a true indication of the current electrolyte composition of the serum, and so the uncorrected value should be used for other calculations, such as the anion gap.

Strong Ion Difference

  • Net charge of substances that remain fully ionised at physiological pH

The normal strong ion difference is +42meql/L, and the full list contains:

  • Cations
    • Sodium
    • Potassium
    • calcium
    • Magnesium
  • Anions
    • Chloride
    • Lactate
    • Acetoacetate
    • β-hydroxybutyrate

Urinary Anion Gap

\(AG_{urine} = Na^+ + K^+ - Cl^-\):

  • Ammonium is the major adjustable urinary cation, and so the urinary AG acts as an index of NH4+ excretion
  • Indicates whether a NAGMA is due to renal or non-renal cause
    This is usually (but not always) obvious clinically.
  • If the urinary AG is:
    • Negative then chloride exceeds the measured cations
      NH4+ is being eliminated which is an appropriate renal response to acidosis. The problem lies elsewhere.
    • Positive then there is inappropriate chloride retention/loss of base

Derivation of the urinary anion gap equation:

  • Urine normally contains:
    • Cations
      Sodium, potassium, ammonium (NH4+), calcium, magnesium.
    • Anions
      Chloride, bicarbonate, sulphate, phosphate, organic anions.
  • Sodium, potassium, and chloride are the only commonly measured ions, the rest are unmeasured
  • Total anion change must equal total cation charge:
    \(Cl^- + Unmeasured_{anions} = Na^+ + K^+ + Unmeasured_{cations}\)
  • Therefore:
    \(AG_{urine} = Unmeasured_{anions} - Unmeasured_{cations} = Na^+ + K^+ - Cl^-\)

Approach

Although not part of acid-base assessment, now is a good time to determine any abnormalities of gas exchange:

  1. Determine PAO2 using the AGE
    \(PAO_2 = FiO_2 \times (P_{atm} - 47) - {PaCO_2 \over R}\)
    • Normal A-a gradient is \(10mmHg + 0.1 \times Age\)
    • The A-a gradient can be expected to increase by 5-7mmHg for every 10% ↑ in FiO2
    • An ↑ A-a gradient indicates ↓ PaO2 is secondary to shunt or diffusion limitation, rather than alveolar hypoventilation or ↓ FiO2
  2. Determine P/F ratio

The A-a gradient is not actually that helpful in practice, since shunt is almost always the primary cause.

Assuming standard atmospheric pressure an a normal respiratory quotient, the AGE can be abbreviated to: \(PAO_2 = FiO_2 \times 713 - PaCO_2 \times 1.25\)

This details a reasonably standard approach to blood gas interpretation:

  1. Determine the primary process
    Is it metabolic or respiratory?
    • Evaluate pH and PaCO2

If both pH and PaCO2 are normal then a dual metabolic problem is possible.

  1. Determine compensation
    • Metabolic compensation for respiratory disorder
      • Full compensation may occur:
        • For PaCO2 between 25-80mmHg
        • Over ~5 days
      • Some compensation is evident with an appropriate change in the SBE
    • Respiratory compensation for metabolic disorder
      • Full compensation does not occur
      • PaCO2 in mmHg should ≃ the last 2 digits of pH (after the decimal point)
        This rule of thumb is invalid in severe acidosis or dual disorders.

Compensation rules are messy in practice - the overlapping, dynamic effect of both disease and treatment means patients rarely behave as expected.

Metabolic Compensation Rules
Acute Acidosis ↑ 1
Acute Alkalosis ↓ 2
Chronic Acidosis ↑ 4
Chronic Alkalosis ↓ 5
Indicates the change in HCO3- in mmol/L for every 10mmHg change in PaCO2
Respiratory Compensation Rules
Acidosis \(PaCO_2 = (1.5 \times HCO_3^-) + 8\)
Alkalosis \(PaCO_2 = (0.7 \times HCO_3^-) + 20\)
  1. Determine severity
    • Metabolic disorders
      • Mild: SBE 4-9
      • Moderate: SBE 10-14
      • Severe: SBE >14

The SBE determines severity in both directions; i.e. an SBE of 12 is moderate alkalosis, an SBE of -12 is moderate acidosis.

  1. Determine contributors
    • Contribution of unmeasured anions to acidosis
      Unmeasured anions will ↑ the anion gap.
      • Calculate albumin-corrected AG.
        • If ↑, look for unmeasured anions
        • If low or negative, consider:
          • Laboratory error
          • Lithium
          • IgG myeloma
      • If ↑ AG, are unmeasured anions the only cause?
        Two approaches:
        1. Calculate the Delta Ratio
        2. Determine if the AG changed proportionally to the SBE:
          • Calculate the change in AG (ΔAG)
          • If \(\Delta AG = SBE\) then a single metabolic disorder is present
            The change in SBE is explained entirely by the AG.
          • If \(\Delta AG \neq SBE\) then a NAGMA is also present
    • Contribution of osmoles
      • Calculate osmolar gap
    • Contribution of renal acid handling
      • Relevant in NAGMA
      • Calculate urinary anion gap

Calculating the change in AG relative to SBE is conceptually similar to the Delta Ratio, with a Copenhagen flavour.

\(\Delta AG = AG - 12^*\)

*In the setting of abnormal albumin the alternative normal value should be used.

Examination

For the purposes of an exam:

  • If the FiO2 is given, you should calculate the A-a gradient
  • If there is a metabolic acidosis, you should calculate the AG
  • If the AG is ↑, you should calculate the delta ratio
  • If there is a measured osmolality, then you should calculate the osmolar gap

  • Urinary pH = RTA
  • Polyuria post-TBI = Mannitol
  • ‘Young female’ = Pregnancy
  • Hyperglycaemia = DKA or HHS
  • Flucloxacillin/paracetamol with renal or hepatic dysfunction = Pyroglutamic acidosis
  • Hypercholesterolaemia = Myxoedema coma
  • Osmolality = Toxic alcohols

References

  1. Brandis, K. Acid-base pHysilogy. 2015.
  2. Bersten, A. D., & Handy, J. M. (2018). Oh’s Intensive Care Manual. Elsevier Gezondheidszorg.
  3. Marts LT, Hsu DJ, Clardy PF. Mind the Gap. Annals ATS. 2014 May;11(4):671–4.