Mixed Acid–Base Disorders and Physiological Interpretation

Mixed acid–base disorders are often the expected result of critical illness: ventilation changes, organs adapt, fluids alter composition, and several metabolic processes coexist. The task is to reconcile those processes with a coherent set of measurements. A normal pH, a familiar compensation formula, or agreement between two calculated quantities cannot complete that task alone. This chapter integrates the mechanisms established in Chapters 52–56 through explicit assumptions, independent evidence, and serial constructed cases.

57.1 Describe the Net State Without Losing the Individual Processes

Acidemia and alkalemia describe the measured blood pH relative to its reference interval. Acidosis and alkalosis describe acidifying and alkalinizing processes. These statements occupy different levels of explanation. Two opposing processes can leave pH near its usual range while both remain clinically substantial.

A low bicarbonate concentration together with a low arterial carbon dioxide tension might reflect metabolic acidosis with a respiratory response, sustained respiratory alkalosis with renal adaptation, two primary processes, or a sampling problem. A high bicarbonate concentration with hypercapnia presents the corresponding ambiguity. Direction alone is therefore insufficient; magnitude, prior state, timing, and composition provide the additional information.

The word mixed should identify more than one physiologically supported process. It should not become a label applied automatically whenever a value falls outside a narrow predicted band. A population relationship may be imperfect for the individual, and a changing patient may not have reached the steady state that the relationship assumes.

Nor does a pH within the laboratory interval establish complete compensation. Chronic respiratory disorders can bring pH toward that interval through adaptation, while coincident metabolic changes can move it further. Conversely, marked acidemia can contain an important alkalinizing process that is simply smaller than the opposing disturbance. Describing only the net direction hides that contribution.

Begin with the observed state, then ask which processes could produce it. The explanation should account for ventilation and carbon dioxide transport, renal and gastrointestinal exchanges, electrolyte delivery, organic-anion production and disposal, and the buffers present. The history determines which possibilities are plausible; the measurements test whether they are sufficient.

This sequence preserves an essential distinction: a sample can show the chemical effect of a process without proving its cause, and a plausible cause can be active before its full effect appears in blood. Serial assessment connects the two rather than forcing the patient into a single static label.

57.2 Identify Which Numbers Were Measured and Which Were Calculated

A blood-gas analyzer generally measures pH and PCO₂, then calculates bicarbonate using their equilibrium relationship. The displayed bicarbonate is not an independent third confirmation. Base excess and standard bicarbonate may also depend on those measured inputs, hemoglobin assumptions, and analyzer algorithms. Several abnormal outputs can therefore arise from one underlying measurement or model error.

Using rounded plasma constants near 37°C, bicarbonate in mmol/L, and PCO₂ in mmHg:

The coefficient 0.03 has units mmol/(L·mmHg), and 6.1 is the apparent pK′. If pH is 7.40 and PCO₂ is 40 mmHg, calculated bicarbonate is approximately 0.03 × 40 × 10^1.30 = 23.94 mmol/L, conventionally rounded to 24. Recalculating it checks arithmetic coherence; it does not independently verify the pH or PCO₂ electrodes.

Chemistry total CO₂ is obtained by a different analytical route. Most is bicarbonate, with dissolved CO₂ and smaller additional forms contributing. In the same illustrative state, dissolved CO₂ is approximately 1.2 mmol/L, so a simple bicarbonate-plus-dissolved-CO₂ estimate is about 25.2 mmol/L. Total CO₂ and calculated bicarbonate should be related, but exact equality is not required.

Nasir and colleagues compared 1,820 contemporaneous venous chemistry and arterial blood-gas sample pairs. Despite close correlation, agreement was insufficient to treat their measurements as interchangeable in every individual. The result concerns those methods and specimens rather than a universal correction between all analyzers. 1

For conventional anion-gap calculations, the chemistry panel’s total CO₂ is commonly used as a bicarbonate approximation. State that convention when combining chemistry and gas data. In the cases below, gas bicarbonate is calculated, while the gap uses contemporaneous chemistry total CO₂. This avoids silently switching the denominator or pretending that both bicarbonate numbers were directly measured.

57.3 Establish a Coherent Specimen Before Explaining a Complex Disorder

Measurements belong to a specimen, time, and physiological compartment. Arterial blood is appropriate for interpreting pulmonary carbon dioxide elimination. Central venous blood includes the effects of tissue delivery, production, and washout. Peripheral venous blood samples a different drainage territory. A fixed numerical conversion cannot make all three interchangeable during circulatory failure.

Adrogué and colleagues demonstrated that arterial and central venous pH and PCO₂ could diverge substantially during severe circulatory compromise, particularly when ventilation continued despite poor flow. This does not make central venous blood a direct intracellular measurement or establish that every patient requires paired sampling. It shows that compartment identity is part of the interpretation. 2

Timing can create a second form of false mixture. Combining a gas drawn before a ventilator change with chemistry drawn after fluid administration may construct a sample that never existed. Even simultaneously requested tests may have different collection times. Temperature-adjusted gas values must also be distinguished from values reported at 37°C, and a pressure in kPa requires a different solubility coefficient from one in mmHg.

Air exposure can change gas tensions; ongoing cellular metabolism can change a delayed specimen. Biswas and colleagues experimentally demonstrated effects of air bubbles and storage conditions, with different sensitivities among reported variables. Their historical equipment and conditions do not supply a universal acceptable delay for current devices. 3

Chemistry specimens have separate vulnerabilities. Bandi demonstrated CO₂ loss during particular processing and air-exposure conditions, including effects of incompletely filled tubes. The amount cannot be corrected with a universal subtraction or addition. 4 Dilution by line fluid or excessive liquid anticoagulant, assay interference, and labeling errors create further possibilities.

A surprising result should therefore trigger reconciliation of the collection, handling, method, and clinical timeline. This work is part of physiological interpretation, because a sophisticated equation cannot rescue an incoherent set of inputs.

57.4 Use Expected Compensation as an Empirical Comparison

Compensation relationships summarize observed responses to selected disturbances. They are not equilibrium identities like Henderson–Hasselbalch. They ask whether the other component is broadly compatible with an assumed primary process, a relevant baseline, sufficient time, and adequate organ capacity.

For metabolic acidosis, a conventional teaching approximation, often called Winter’s rule, estimates an arterial PCO₂ in mmHg from bicarbonate in mmol/L:

This is presented as a clinical approximation rather than a newly derived law or an exact individual prediction. Historical work by Albert, Dell, and Winters belongs to the empirical investigation of metabolic acidosis; the numerical teaching rule should not be mistaken for a consequence of charge conservation. 5

If bicarbonate is 12 mmol/L, the central estimate is 1.5 × 12 + 8 = 26 mmHg, with an illustrative band of 24–28 mmHg. A measured PaCO₂ of 40 mmHg suggests a respiratory acidifying contribution or limited respiratory response relative to that assumed metabolic state. A value of 20 mmHg suggests an additional respiratory alkalinizing contribution. Neither calculation identifies the reason: respiratory drive, mechanical limitations, sedation, ventilation settings, timing, and sample quality remain relevant.

A PaCO₂ within the approximation does not exclude two opposing metabolic processes. Their net bicarbonate may generate an apparently appropriate respiratory prediction while an increased gap, relative chloride excess, or reduced weak-acid concentration reveals additional chemistry. The comparison addresses one relationship, not the completeness of the entire diagnosis.

The same restraint applies to expected changes during respiratory disorders and metabolic alkalosis. Different empirical fits and teaching conventions have different populations, ranges, and uncertainty. A deviation is a reason to examine the assumptions and seek a mechanism; its size alone does not prove a new disease or specify a correction target.

57.5 Adaptation and the Prior State Change the Meaning of a Deviation

Immediate buffering, respiratory responses, renal adaptation, and tissue exchange occur on overlapping time scales. A newly changed PCO₂ can therefore coexist with bicarbonate shaped by an earlier respiratory state. Applying a steady-state rule immediately after the change may falsely diagnose a new metabolic process or miss one already present.

The prior gas is especially useful in chronic hypercapnia. A high bicarbonate concentration can be an appropriate response to sustained carbon dioxide retention. If PCO₂ rises further, the short-term change occurs on top of that adapted baseline rather than starting again from a hypothetical bicarbonate of 24 mmol/L. If PCO₂ falls, retained bicarbonate and altered renal handling do not disappear instantly.

González and colleagues prospectively studied 28 carefully selected stable outpatients with chronic hypercapnia. Their bicarbonate–PCO₂ slope was approximately 0.48 mmol/L per mmHg within the studied range, illustrating that a commonly taught fixed chronic slope is an approximation. Patients with other acid–base influences were excluded; the fit cannot be assigned uncritically to unstable patients with kidney failure or ongoing losses. 6

Sustained hypocapnia likewise changes renal balance. In controlled human work, Krapf and colleagues demonstrated lower bicarbonate during chronic hyperventilation, including in subjects with experimentally induced metabolic acidosis. Their hypobaric-hypoxia protocol and small selected population define the conditions of that evidence. 7 A low bicarbonate therefore cannot automatically be counted as a second primary disorder whenever PCO₂ is low.

Historical observations during recovery from metabolic acidosis also found that low PCO₂ could persist after pH normalized or became alkaline. The heterogeneous, largely pediatric observations mostly used venous samples and calculated PCO₂. They illustrate a changing recovery trajectory rather than establish modern arterial compensation limits or a universal duration of adaptation. 8

Adaptation is also constrained by renal function, potassium and chloride balance, effective circulating conditions, and medications. The history may support persistent adaptation, a superimposed loss, or both. These distinctions become clearer when actual serial values are compared with the timing of changes in ventilation, gastric drainage, fluid composition, diuresis, and extracorporeal treatment.

57.6 Examine the Gap Even When Bicarbonate or pH Looks Reassuring

An anion gap estimates charge omitted from the selected calculation, not a physical failure of electroneutrality. Here potassium is omitted and chemistry total CO₂ approximates bicarbonate:

All concentrations are in mmol/L, numerically equivalent to mEq/L for these monovalent contributors. The laboratory’s ion methods and reference interval, and the patient’s previous values, must be matched to the same convention.

Albumin contributes much of the usual omitted anionic charge. Low albumin can conceal additional anions even when the observed gap remains near its reference interval. An approximate adjustment adds 2.5 mEq/L per 1 g/dL by which albumin falls below a selected reference. This relationship was derived from clinical measurements; it is not a direct assay of accumulated acid. 9

For illustration, sodium is 140 mmol/L, chloride 108 mmol/L, and total CO₂ 24 mmol/L, producing an observed gap of 8 mEq/L. If albumin is 2 rather than an illustrative reference of 4 g/dL, the adjustment adds 5 mEq/L and gives 13 mEq/L. Whether that is increased depends on the matched method and baseline. The important point is that an apparently ordinary observed gap can underestimate the omitted-charge signal when albumin is low.

Measure lactate, ketoanions, or a suspected exposure directly when the history supports them. Lactate is usually included within the conventional gap’s omitted charge; adding the lactate concentration to the gap as a second acid burden would count overlapping information twice. A gap that fails to track lactate exactly may reflect other anions, baseline differences, albumin, distribution, excretion, or measurement error.

Likewise, the albumin adjustment does not establish that its numerical increment is a newly measured toxic anion. It makes a comparison on a specified protein scale, with the uncertainty inherent in that approximation.

57.7 Reconcile Opposing Strong-Ion and Weak-Acid Influences

The net metabolic result can combine substantial opposing effects. Relative chloride excess and accumulated strong anions can be acidifying, while reduced albumin has an alkalinizing influence under specified conditions. Phosphate retention introduces another weak-acid contribution. Their combined expression may leave bicarbonate or base excess much less abnormal than any one component suggests.

Fencl and colleagues demonstrated such concealment in ICU samples: analyses that included proteins and electrolyte composition identified opposing abnormalities in samples with apparently reassuring net findings. Albumin adjustment improved recognition of omitted anionic charge. This observational chemical analysis did not establish that treating every calculated component improves patient outcomes. 10

Strong-ion accounting can make the components explicit, provided the ion list and units are stated. Sodium, potassium, chloride, and lactate are monovalent; ionized calcium and magnesium contribute two equivalents per millimole. Total calcium should not silently replace the freely ionized fraction. Albumin charge depends on pH, and albumin in g/L must not be inserted into a formula intended for g/dL.

The apparent strong ion difference uses measured ions; the effective difference includes bicarbonate and modeled weak-acid charge. Their residual, the strong ion gap, is not independent chemical confirmation of the conventional gap when both rely on many of the same measurements. Their omitted species also differ: a strong ion gap calculated after subtracting measured lactate does not contain the same lactate contribution as a conventional gap that omits it.

Dubin and colleagues found that including albumin-corrected gap information substantially narrowed differences among diagnostic frameworks in a large observational ICU cohort. Agreement between frameworks does not create multiple independent measurements of acid, and choosing one was not tested as an outcome-improving intervention. 11

Use the alternative description to expose missing composition or inconsistent assumptions. Do not sum base deficit, gap excess, lactate, and weak-acid effects as though each were a separate measured amount that must be replaced.

57.8 Delta Comparisons Depend on Baseline, Distribution, and Anion Loss

A rise in gap accompanied by a fall in bicarbonate suggests that retained anions and buffering are linked. Delta comparisons ask whether their magnitudes fit that simplified picture. They require a reference state before either subtraction has a clear meaning.

Define ΔAG as current gap minus baseline gap, using a consistent albumin convention. Define ΔHCO₃ as baseline bicarbonate approximation minus its current value. The commonly used ratio is ΔAG/ΔHCO₃. It becomes unstable when the denominator is small and changes if generic rather than individual baselines are selected.

Suppose a patient’s stable baseline adjusted gap was 14 mEq/L and total CO₂ 26 mmol/L. Current values are 26 mEq/L and 18 mmol/L. The changes are 12 and 8, so the ratio is 12/8 = 1.5. Substituting hypothetical generic baselines of 12 and 24 gives changes of 14 and 6, and a ratio of 14/6 ≈ 2.33. The current sample is unchanged; only the assumed reference has altered the apparent mixture.

Lu and colleagues studied ICU patients with sepsis and found that using individual baseline gap and bicarbonate values materially changed the mean delta ratio compared with generic normal values. The wide variation also cautions against using a single ratio to identify a unique second process. 12

Distribution and excretion provide further limits. Buffered proton equivalents and organic anions need not remain in the same compartments. Ketoanions lost with sodium or potassium remove potential base and can produce persistent hyperchloremic acidosis as the gap falls. Human observations across diabetic-ketoacidosis admissions demonstrated a broad spectrum of gap and hyperchloremic patterns, influenced by renal handling and volume depletion. 13

Thus, a mismatch can suggest concurrent bicarbonate loss or an alkalinizing process, but it can also reflect the underlying disorder’s kinetics and baseline. Use the comparison to formulate and test an explanation rather than assign rigid diagnostic categories from a ratio alone.

57.9 Serial Case: A Normal Initial pH Conceals Two Contributions

Consider constructed contemporaneous samples in a patient with sepsis, adrenergic stimulation, reduced kidney function, and increased respiratory drive. Initially arterial PCO₂ is 20 mmHg and gas-calculated bicarbonate 12 mmol/L. Chemistry total CO₂ is 13 mmol/L, sodium 140 mmol/L, chloride 106 mmol/L, albumin 2 g/dL, and lactate 8 mmol/L. Use rounded 37°C constants and an illustrative albumin reference of 4 g/dL.

The gas relationship gives pH ≈ 6.1 + log₁₀[12/(0.03 × 20)] = 7.40. The observed chemistry gap is 140 − 106 − 13 = 21 mEq/L, and the albumin-adjusted value is 26 mEq/L. The normal pH therefore coexists with a substantial omitted-anion signal and elevated measured lactate.

The conventional metabolic-acidosis comparison gives expected PCO₂ about 26 mmHg, with the previously stated approximate band. A measured 20 mmHg supports an additional respiratory alkalinizing contribution in this context. It does not identify whether inflammation, pain, a central stimulus, or another mechanism explains the drive. Sampling dilution must also be excluded rather than relying on the normal pH alone.

Later, gas bicarbonate is 14 mmol/L and PCO₂ 28 mmHg, giving pH ≈ 7.32. Contemporaneous total CO₂ is 15 mmol/L, sodium remains 140 mmol/L, chloride is 112 mmol/L, albumin remains 2 g/dL, and lactate has fallen to 3 mmol/L. The gap is now 13 mEq/L and its adjusted value 18 mEq/L.

Lactate and the gap have fallen, yet arterial pH is lower. Reduced respiratory alkalinization and an increasing chloride-associated component explain how those directions can coexist. Controlled physiological observations establish that chloride-rich fluid can generate such compositional changes, although this constructed trajectory does not prove that fluid alone caused them. 14 The lower pH cannot be read as evidence that lactate metabolism necessarily worsened.

57.10 Serial Case: Chronic Hypercapnia, New Losses, and CO₂ Reversal

Now consider a patient with a documented stable respiratory baseline. Arterial PCO₂ is 60 mmHg and calculated bicarbonate 32 mmol/L, giving pH ≈ 6.1 + log₁₀(32/1.8) = 7.35. Chemistry total CO₂ is approximately 34 mmol/L; sodium is 140 mmol/L and chloride 98 mmol/L, giving a gap of 8 mEq/L. Potassium is 4.2 mmol/L and albumin 3.5 g/dL. This is a specified observed baseline, not a claim that every patient at that PCO₂ should have these values.

After gastric losses and diuretic-associated electrolyte changes, PCO₂ is still 60 mmHg but bicarbonate is 44 mmol/L. Calculated pH is approximately 7.49. Chemistry total CO₂ is about 46 mmol/L; sodium is 140 mmol/L and chloride 86 mmol/L, giving a conventional gap of 8 mEq/L. Albumin and the analytical method are assumed unchanged, and potassium has fallen to 2.9 mmol/L.

The rise in bicarbonate and pH at unchanged PCO₂ supports a new alkalinizing influence beyond the previous respiratory adaptation. The loss history, relative hypochloremia, and potassium change provide independent physiological context. No fixed chronic compensation slope is needed to recognize the departure from the patient’s own baseline. The gap does not have to increase when the principal new process is not accumulation of an omitted acid anion.

At a later stage after carbon dioxide elimination changes, PCO₂ is 40 mmHg and bicarbonate remains 38 mmol/L. The resulting pH is approximately 6.1 + log₁₀(38/1.2) = 7.60. Total CO₂ is approximately 39 mmol/L, sodium 140 mmol/L, and chloride 93 mmol/L, again giving a gap of 8 mEq/L. Albumin remains unchanged. These values are another constructed state, not a predicted time course or a ventilation target.

The striking alkalemia now reflects a different relationship between gas elimination and persistent metabolic conditions. Previous renal adaptation may contribute, while ongoing chloride and potassium deficits or continued losses can maintain the disturbance. Calling it entirely posthypercapnic or entirely diuretic-induced would require more evidence than the final gas provides. The sequence explains why changing ventilation can expose an alkalinizing component that was less conspicuous during hypercapnia.

57.11 Constructed Case: An Apparent Mixed Disorder May Be Analytical

Suppose a chemistry panel reports sodium 138 mmol/L, chloride 104 mmol/L, and total CO₂ 10 mmol/L. The conventional gap is 138 − 104 − 10 = 24 mEq/L. Simultaneous arterial blood has pH about 7.40, PCO₂ 40 mmHg, and calculated bicarbonate approximately 24 mmol/L. The patient’s established same-method chemistry baseline had total CO₂ 25 mmol/L and a gap of 9 mEq/L.

One tempting explanation is a concealed gap acidosis combined with a powerful alkalinizing process. However, these measurements first require analytical reconciliation. Ordinary dissolved CO₂ cannot explain a 14-mmol/L difference between chemistry total CO₂ and gas bicarbonate. Nor does the gas calculation prove its own electrodes correct: independent verification of both routes is needed.

Review the actual collection times and handling, repeat appropriately collected samples when necessary, and examine method-specific interference. Excess liquid heparin can create spuriously low PCO₂ and bicarbonate, as demonstrated in a clinical report, so a gas pattern itself can falsely resemble combined respiratory alkalosis and metabolic acidosis. 15

The chemistry result can also be wrong. Goldwasser and colleagues documented falsely low enzymatic total CO₂ from an endogenous assay interferent, with a misleading high gap and comparatively normal gas findings. Their investigation used alternative analytical measurements and reaction behavior rather than declaring the blood gas automatically superior. It was a mechanistic case report, not a prevalence estimate. 16

If an independently checked repeat chemistry in the constructed case gives total CO₂ 25 mmol/L, the calculated gap returns to 9 mEq/L without any inferred removal of 15 mEq/L of acid. The low total CO₂ and high gap had been two consequences of the same input error. This is exactly why correlated calculations must not be counted as independent confirmations of a complex physiological diagnosis.

57.12 Build an Explanation That Survives the Next Sample

A complete interpretation states the measured net pH, the respiratory contribution, the metabolic components supported by composition, and the uncertainty attached to each. It should also explain why the current state differs from the patient’s prior state. An isolated label such as compensated, mixed, or triple disorder is less useful if the proposed mechanisms cannot account for the observed sequence.

Start with evidence that is genuinely distinct. A gastric-loss history, serial chloride and potassium changes, a directly measured lactate concentration, and documented chronic hypercapnia supply different information. Calculated bicarbonate, base excess, and a gap containing that bicarbonate share inputs and constraints. Agreement among them may establish coherence, but it does not multiply the number of measured abnormalities.

Next ask what the explanation predicts. If an organic-anion process is improving, its direct marker and appropriately interpreted gap may decline, while chloride-related acidosis persists. If ventilation changes before renal adaptation reverses, PCO₂ and pH may move rapidly while bicarbonate remains influenced by the earlier state. If a result is an artifact, a properly selected independent method may remove the discrepancy without a physiological intervention.

These predictions remain conditional. Organ failure, changing volume, metabolism, and treatment can alter several processes simultaneously. A departure from the predicted course should prompt reconsideration of the mechanism, timing, or measurements rather than a reflex effort to normalize every calculated value.

Arterial interpretation also has a boundary: it describes circulating arterial conditions and gas exchange, not the full intracellular environment or cumulative whole-body acid inventory. Improving arterial pH does not independently establish recovered tissue perfusion or completed acid removal. Clinical trajectory, circulation, ventilation, renal handling, and relevant external balances remain necessary.

The aim is a coherent, testable account of the patient’s physiology. Equations strengthen that account when their assumptions are visible; they weaken it when precision hides shared inputs, uncertain baselines, or a changing system. Serial evidence determines whether the explanation remains adequate.

References

1. Nasir NM, Sthaneshwar P, Yunus PJ, Yap SF. Comparing measured total carbon dioxide and calculated bicarbonate. Malaysian Journal of Pathology. 2010;32:21–26. PMID:20614722

2. Adrogué HJ, Rashad MN, Gorin AB, Yacoub J, Madias NE. Assessing acid–base status in circulatory failure: differences between arterial and central venous blood. New England Journal of Medicine. 1989;320:1312–1316. doi:10.1056/NEJM198905183202004

3. Biswas CK, Ramos JM, Agroyannis B, Kerr DN. Blood gas analysis: effect of air bubbles in syringe and delay in estimation. British Medical Journal (Clinical Research Edition). 1982;284:923–927. doi:10.1136/bmj.284.6320.923

4. Bandi ZL. Estimation, prevention, and quality control of carbon dioxide loss during aerobic sample processing. Clinical Chemistry. 1981;27:1676–1681. PMID:6793263

5. Albert MS, Dell RB, Winters RW. Quantitative displacement of acid–base equilibrium in metabolic acidosis. Annals of Internal Medicine. 1967;66:312–322. doi:10.7326/0003-4819-66-2-312

6. González SB, Menga G, Raimondi GA, Tighiouart H, Adrogué HJ, Madias NE. Secondary response to chronic respiratory acidosis in humans: a prospective study. Kidney International Reports. 2018;3:1163–1170. doi:10.1016/j.ekir.2018.06.001

7. Krapf R, Beeler I, Hertner D, Hulter HN. Chronic respiratory alkalosis: the effect of sustained hyperventilation on renal regulation of acid–base equilibrium. New England Journal of Medicine. 1991;324:1394–1401. doi:10.1056/NEJM199105163242003

8. Winters RW, Lowder JA, Ordway NK. Observations on carbon dioxide tension during recovery from metabolic acidosis. Journal of Clinical Investigation. 1958;37:640–645. doi:10.1172/JCI103647

9. Figge J, Jabor A, Kazda A, Fencl V. Anion gap and hypoalbuminemia. Critical Care Medicine. 1998;26:1807–1810. doi:10.1097/00003246-199811000-00019

10. Fencl V, Jabor A, Kazda A, Figge J. Diagnosis of metabolic acid–base disturbances in critically ill patients. American Journal of Respiratory and Critical Care Medicine. 2000;162:2246–2251. doi:10.1164/ajrccm.162.6.9904099

11. Dubin A, Menises MM, Masevicius FD, et al. Comparison of three different methods of evaluation of metabolic acid–base disorders. Critical Care Medicine. 2007;35:1264–1270. doi:10.1097/01.CCM.0000259536.11943.90

12. Lu D, Song H, Amy Liu IL, Shi J, Treger RM. The Δ anion gap/Δ bicarbonate ratio in lactic acidosis: time for a new baseline? Kidney360. 2024;5:1251–1261. doi:10.34067/KID.0000000000000513

13. Adrogué HJ, Wilson H, Boyd AE III, Suki WN, Eknoyan G. Plasma acid–base patterns in diabetic ketoacidosis. New England Journal of Medicine. 1982;307:1603–1610. doi:10.1056/NEJM198212233072603

14. Scheingraber S, Rehm M, Sehmisch C, Finsterer U. Rapid saline infusion produces hyperchloremic acidosis in patients undergoing gynecologic surgery. Anesthesiology. 1999;90:1265–1270. doi:10.1097/00000542-199905000-00007

15. Bloom SA, Canzanello VJ, Strom JA, Madias NE. Spurious assessment of acid–base status due to dilutional effect of heparin. American Journal of Medicine. 1985;79:528–530. doi:10.1016/0002-9343(85)90044-0

16. Goldwasser P, Manjappa NG, Luhrs CA, Barth RH. Pseudohypobicarbonatemia caused by an endogenous assay interferent: a new entity. American Journal of Kidney Diseases. 2011;58:617–620. doi:10.1053/j.ajkd.2011.06.003