TheraCALC · Acid-Base Methodology & Validation

1 — Acid-Base Interpretation Framework

The calculator follows a five-step algorithm modeled on approaches commonly used in internal medicine and critical care education. Each major step is surfaced in the "How We Got Here" tab with the formula applied, the computed value, and a brief clinical interpretation.

Step	Focus	What the calculator evaluates
1	pH	Determine acidemia (pH < 7.35), alkalemia (pH > 7.45), or near-normal pH
2	Primary process	Compare HCO₃ and PaCO₂ to identify the primary driver as metabolic (HCO₃ change) or respiratory (PaCO₂ change)
3	Anion gap	Calculate AG = Na − Cl − HCO₃. Correct for albumin (+2.5 mEq/L per 1 g/dL below 4.0). Assess delta-delta ratio
4	Compensation	Apply the appropriate bedside compensation formula. Values outside the expected range may suggest a concurrent process
5	Mixed-process screening	Integrate delta-delta ratio, urine indices (Cl, Na, K, UAG, TTKG), osmol gap, and Henderson-Hasselbalch cross-check

2 — Primary Disorder Classification

When pH is available it is the primary driver of classification. BMP-only interpretation uses the HCO₃ pattern alone and is labeled as estimated throughout the interface.
Near-normal pH (7.35–7.45) with opposing HCO₃ and PaCO₂ abnormalities is handled by identifying the dominant driver based on its relative deviation from normal.

Condition	Classification
pH < 7.35, HCO₃ < 22	Metabolic acidosis
pH < 7.35, PaCO₂ > 45	Respiratory acidosis
pH > 7.45, HCO₃ > 26	Metabolic alkalosis
pH > 7.45, PaCO₂ < 35	Respiratory alkalosis
pH 7.35–7.45 with PaCO₂ < 35 and HCO₃ < 22	Mixed pattern: respiratory alkalosis + metabolic acidosis (e.g., salicylate toxicity, early sepsis)
pH 7.35–7.45 with PaCO₂ > 45 and HCO₃ > 26	Mixed pattern: respiratory acidosis + metabolic alkalosis
BMP only: HCO₃ < 22	Metabolic acidosis (estimated — ABG required to confirm)
BMP only: HCO₃ > 26	Metabolic alkalosis (estimated — ABG required to confirm)

3 — Anion Gap, Albumin Correction & Delta-Delta Ratio

3.1 Anion gap and albumin correction

Formula / concept	Detail
Anion gap formula	AG = Na⁺ − Cl⁻ − HCO₃⁻ (normal range: approximately 8–12 mEq/L)
Albumin correction	Corrected AG = raw AG + 2.5 × (4.0 − albumin in g/dL). Each 1 g/dL of albumin below 4.0 can mask about 2.5 mEq/L of true AG elevation
Thresholds	Raw AG > 12 mEq/L or corrected AG > 14 mEq/L is flagged as elevated. Corrected AG is used whenever albumin has been entered
Prompts	If AG > 6 without albumin entered, the disclosure strip prompts for albumin. If corrected AG > 14 without serum osmolality, osmol gap entry is prompted

3.2 Delta-delta ratio

In a pure elevated-AG process, each mEq/L rise in AG corresponds to a 1 mEq/L fall in HCO₃. The delta-delta ratio detects when these do not match, indicating a concurrent metabolic process.

Delta-delta value	Interpretation
< 0.4	Pattern consistent with pure normal-AG (hyperchloremic) metabolic acidosis
0.4 – 1.0	Pattern suggests elevated-AG acidosis with concurrent normal-AG acidosis
1.0 – 2.0	Pattern consistent with a predominantly elevated-AG process — HCO₃ drop matches AG rise
> 2.0	Pattern suggests elevated-AG acidosis with concurrent metabolic alkalosis

4 — Compensation Formulas

Expected compensation is calculated from commonly used bedside formulas and displayed as a range rather than a single point. An observed value outside the expected range may suggest a concurrent process; the tool uses "may suggest" language, not "confirms."

Primary disorder	Expected compensation	Tolerance / notes
Metabolic acidosis	PaCO₂ ≈ 1.5 × HCO₃ + 8 (Winters formula)	±2 mmHg around the calculated value
Metabolic alkalosis	PaCO₂ ≈ 0.7 × (HCO₃ − 24) + 40	±2 mmHg; capped at approximately 55 mmHg
Acute respiratory acidosis	HCO₃ rises by about (PaCO₂ − 40) / 10	±2 mEq/L; onset < 24 hours
Chronic respiratory acidosis	HCO₃ rises by about 3.5 × (PaCO₂ − 40) / 10	±3 mEq/L; onset over days–weeks
Acute respiratory alkalosis	HCO₃ falls by about 2 × (40 − PaCO₂) / 10	±3 mEq/L
Chronic respiratory alkalosis	HCO₃ falls by about 5 × (40 − PaCO₂) / 10	±3 mEq/L

Respiratory acidosis annotation For respiratory acidosis, the "How We Got Here" tab annotates whether HCO₃ falls within the acute range, the chronic range, or between them — displayed as "consistent with acute event," "consistent with chronic hypercapnia," or "acute-on-chronic pattern." This distinction is directly relevant to COPD management decisions.

5 — Mixed Disorder Detection

Mixed disorders are identified from five pattern triggers. Each detected pattern is displayed with the specific findings that triggered it, a confidence label reflecting available data, and any limitations such as albumin not being entered.

Pattern	Trigger	Examples
Elevated-AG acidosis + metabolic alkalosis	Corrected AG > 14 and HCO₃ > 26 (or delta-delta > 2)	DKA with vomiting; uremia with contraction alkalosis
Elevated-AG acidosis + normal-AG acidosis	Corrected AG > 14 and delta-delta < 1.0	Lactic acidosis with concurrent diarrhea; sepsis with large-volume normal saline
Respiratory acidosis + metabolic alkalosis	PaCO₂ > 45, HCO₃ > 30, and pH near-normal	COPD with diuretics; post-hypercapnic alkalosis
Respiratory alkalosis + metabolic acidosis	PaCO₂ < 35, HCO₃ < 20, and pH 7.38–7.45	Salicylate toxicity; early sepsis
Triple disorder (rare)	Elevated AG, delta-delta < 1.0, and HCO₃ higher than normal-AG acidosis alone would predict	DKA with concurrent GI loss and vomiting

6 — Clinical Cutoffs & Action Thresholds

Key clinical values used as thresholds throughout the calculator are defined centrally so changes propagate consistently to every output that depends on them.

Parameter	Threshold	Purpose
Anion gap (raw)	> 12 mEq/L	Flags as elevated; prompts albumin entry
Anion gap (albumin-corrected)	> 14 mEq/L	Elevated corrected AG; triggers AGMA workup
pH — critical low	< 7.10	Critical urgency trigger; bicarbonate consideration threshold
pH — urgent low	< 7.20	Urgent intervention range
pH — urgent high	> 7.60	Emergent alkalemia; HCl therapy consideration in selected ICU cases
pH — critical high	> 7.65	Critical urgency trigger
Potassium — critical low	< 2.5 mEq/L	Critical hypokalemia; arrhythmia risk
Potassium — high	> 5.5 mEq/L	Hyperkalemia intervention trigger
Potassium — urgent high	> 6.5 mEq/L	Critical urgency escalation; EKG prompt
Lactate — elevated	> 2.0 mmol/L	Perfusion concern
Lactate — critical	> 4.0 mmol/L	Perfusion emergency; urgent action
Osmolal gap — borderline	> 10 mOsm/kg	Borderline elevation; limited specificity alone
Osmolal gap — significant	> 20 mOsm/kg	High concern for toxic alcohol or mannitol
Urine chloride — responsive	< 25 mEq/L	Chloride-responsive metabolic alkalosis pattern
Urine chloride — resistant	> 40 mEq/L	Chloride-resistant (mineralocorticoid-mediated) alkalosis pattern
CrCl — acetazolamide gate	< 30 mL/min	Acetazolamide considered contraindicated below this threshold
CrCl — arginine HCl gate	< 50 mL/min	Arginine HCl considered contraindicated below this threshold

7 — Derived Calculations

7.1 Osmolal gap

Calculated osmolality = (2 × Na⁺) + (BUN / 2.8) + (glucose / 18). Gap = measured serum osmolality − calculated osmolality.

Gap value	Interpretation
< 10 mOsm/kg	Normal
10–20 mOsm/kg	Borderline — consider ethanol or early toxic alcohol ingestion
> 20 mOsm/kg	Significant — high concern for toxic alcohol (methanol, ethylene glycol), mannitol, or ethanol

7.2 Transtubular Potassium Gradient (TTKG)

Valid only when urine osmolality exceeds serum osmolality (concentrated urine). Suppressed automatically when urine is dilute.

Scenario	TTKG	Interpretation
Hypokalemia	> 4	Renal potassium wasting (aldosterone, diuretics, RTA)
Hypokalemia	< 2	Extrarenal loss (GI, skin)
Hyperkalemia	< 7	Impaired aldosterone; consider Type 4 RTA or adrenal insufficiency
Hyperkalemia	> 11	Appropriate kaliuresis

7.3 Urine Anion Gap (UAG)

UAG = urine Na⁺ + urine K⁺ − urine Cl⁻. Estimates unmeasured urinary ammonium excretion to differentiate causes of normal-AG metabolic acidosis.

UAG	Interpretation
Strongly negative (< −20 mEq/L)	High ammonium excretion — consistent with GI bicarbonate loss (diarrhea, ileostomy)
Positive (> 0 mEq/L)	Low ammonium excretion — consistent with RTA; subtype by urine pH and potassium

7.4 A-a Oxygen Gradient

Formula: A-a = [(FiO₂/100) × 713 − PaCO₂/0.8] − PaO₂. Age-adjusted upper limit of normal: approximately 4 + (age/4) mmHg. FiO₂ outside 21–100% is flagged and A-a suppressed. Requires PaO₂ from ABG.

7.5 Corrected Sodium for Hyperglycemia

Corrected Na⁺ = Measured Na⁺ + 1.6 × (glucose − 100) / 100 mg/dL. Shown when glucose > 200 mg/dL. Glucose > 600 mg/dL prompts DKA vs HHS differentiation.

8 — Renal Function & Drug Dosing Gates

Cockcroft-Gault CrCl is used for three drug-specific safety gates: acetazolamide (CrCl < 30 mL/min: considered contraindicated), arginine HCl (CrCl < 50 mL/min: considered contraindicated), and potassium replacement rate adjustment.
Formula: CrCl = [(140 − age) × weight × (0.85 if female)] / (72 × SCr).

Cockcroft-Gault limitation This equation may overestimate GFR in frail or sarcopenic patients. Cystatin C-based eGFR is preferred in those populations where available. This is disclosed in the caveats section when creatinine is elevated.

9 — Input Plausibility Checks

The calculator cross-checks entered values for internal consistency. Warnings appear in the caveats section and do not block calculation.

Check	Trigger	What the clinician sees
Henderson-Hasselbalch cross-check	Calculated pH differs from entered pH by more than 0.08 units	Amber caveat: pH inconsistent with HCO₃ and PaCO₂ — verify the entered values
Physiologic pH range	pH below 6.5 or above 8.0	Amber caveat: outside the survivable range — verify entry
PaCO₂ range	PaCO₂ below 10 or above 120 mmHg	Amber caveat: outside plausible range — verify entry
FiO₂ validity	FiO₂ below 21% or above 100%	A-a gradient suppressed; amber caveat displayed
TTKG validity	Urine osmolality at or below serum osmolality	TTKG suppressed; dilute urine renders result unreliable
CrCl availability	Creatinine entered but age or weight missing	Caveat names the specific missing field and lists affected drug dosing gates

10 — Data Confidence & Urgency Indicators

10.1 Data confidence badge

Badge	When it appears
BMP ONLY	No pH or PaCO₂ entered; banner shows "(BMP-estimated)" after the disorder label
ABG CONFIRMED	pH and PaCO₂ present
ABG + ALBUMIN	pH, PaCO₂, and albumin all present
URINE-INFORMED	pH, PaCO₂, and urine electrolytes present
MULTI-SOURCE	pH, PaCO₂, albumin, and urine data all present

10.2 Action urgency indicator

Urgency level	Triggered by
Urgent action (red bar)	pH below 7.10, pH above 7.65, potassium above 6.5 mEq/L, or lactate above 4.0 mmol/L
Urgent (orange bar)	pH below 7.20, potassium below 2.5 or above 6.0 mEq/L, mixed disorder, or creatinine above 4.0 mg/dL
Routine	None of the above applies

11 — Clinical Presets

The calculator includes 18 clinical teaching presets covering major acid-base patterns encountered in inpatient practice. Each includes age, weight, and creatinine for full CrCl calculation.

Category	Presets
Elevated-AG metabolic acidosis	DKA / HAGMA ketoacidosis, lactic acidosis (shock), ethylene glycol, methanol, isopropanol (osmol gap without acidosis), uremic acidosis
Normal-AG metabolic acidosis	Diarrheal NAGMA, RTA Type 1 (distal; urine pH 6.5), RTA Type 4 (hyperkalemic), chronic diarrhea on CKD
Metabolic alkalosis	Vomiting-induced alkalosis (urine Cl⁻ 15 mEq/L; chloride-responsive)
Mixed and respiratory	Salicylate (respiratory alkalosis + metabolic acidosis; near-normal pH), sepsis (early respiratory alkalosis + metabolic acidosis), COPD exacerbation (chronic respiratory acidosis)

12 — Internal Validation Summary

Calculation logic has been verified against known clinical scenarios prior to deployment. Automated testing covers the clinical presets and targeted logic scenarios listed below.
These tests represent internal unit testing and do not replace prospective clinical validation. External validation against patient-level data is a future goal.

Category verified
Primary classification — all four disorder types and normal patterns
Near-normal pH mixed classification (salicylate and early sepsis patterns)
BMP-only inference and confidence badge assignment
Anion gap calculation and albumin correction
Delta-delta ratio calculation and interpretation thresholds
All six compensation formulas with range display and mixed-detection logic
Acute vs chronic respiratory acidosis annotation
Mixed-disorder pattern detection, including rare triple-disorder patterns
Action urgency independent of biochemical severity
Henderson-Hasselbalch plausibility checks (true positives and negatives)
FiO₂ validity gate and A-a gradient suppression
TTKG suppression when urine osmolality is dilute
Osmolal gap calculation
HHS vs DKA differentiation at very high glucose
CrCl drug gates — acetazolamide, arginine HCl, potassium rate adjustment
Female CrCl 0.85 multiplier applied correctly
Urine chloride subtyping; UAG and TTKG calculation
BMP-only gating of intervention and dose text
Runtime across all teaching presets without errors
User interface input/output linkage checks

13 — Known Limitations & Clinical Caveats

BMP-only classification. Without pH and PaCO₂, the calculator cannot confirm acidemia or alkalemia, verify compensation, or reliably detect mixed disorders. BMP-only outputs are labeled as provisional.
Compensation formula variance. Winters formula and standard respiratory compensation ranges are bedside approximations derived from population studies. Individual variation is expected; the tool consistently uses "may suggest" rather than "confirms."
Creatinine clearance in frail patients. Cockcroft-Gault may overestimate GFR when muscle mass is reduced. Cystatin C-based eGFR is preferred in those populations where available.
Pediatric use. Adult normal ranges and thresholds are used throughout. Pediatric acid-base interpretation is outside the current scope of this tool.
No prospective clinical validation. The calculator has been verified through internal unit testing but has not yet been evaluated against a prospective patient-level dataset.
Mixed-disorder confidence. Detection relies on compensation thresholds that carry inherent variance. Post-bicarbonate administration, chronic compensated states, or simultaneously evolving disorders may affect accuracy.
One-compartment assumption. Standard acid-base formulas assume equilibrated distribution. They are less reliable during rapid flux states or immediately following bicarbonate administration.

14 — References

Winters RW. Posterior and anterior anion gap acidosis. JAMA. 1967;199(11):80-82.
Emmett M, Narins RG. Clinical use of the anion gap. Medicine (Baltimore). 1977;56(1):38-54.
Battle DC, et al. The use of the urinary anion gap in the diagnosis of hyperchloremic metabolic acidosis. N Engl J Med. 1988;318(10):594-599.
Narins RG, Emmett M. Simple and mixed acid-base disorders: a practical approach. Medicine (Baltimore). 1980;59(3):161-187.
Kraut JA, Madias NE. Approach to patients with acid-base disorders. Respir Care. 2001;46(4):392-403.
Fencl V, et al. Diagnosis of metabolic acid-base disturbances in critically ill patients. Am J Respir Crit Care Med. 2000;162(6):2246-2251.
Adrogué HJ, Madias NE. Management of life-threatening acid-base disorders. N Engl J Med. 1998;338(1):26-34.
Kraut JA, Madias NE. Metabolic acidosis: pathophysiology, diagnosis and management. Nat Rev Nephrol. 2010;6(5):274-285.
Khanna A, Kurtzman NA. Metabolic alkalosis. J Nephrol. 2006;19 Suppl 9:S86-96.
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16(1):31-41.
US Food and Drug Administration. Guidance for Industry: Pharmacokinetics in Patients with Impaired Renal Function. 2024.

Reporting Discrepancies & Contact

If you identify a calculation discrepancy, logic inconsistency, or scenario the calculator does not handle well, please report it using the feedback button on the calculator. Clinical input from practicing pharmacists is the most valuable driver of improvement.
Include: the specific section and inputs used; exact values entered; what you expected vs what the calculator returned; and a reference or comparator where applicable. No PHI is required.
Contact: [email protected] — all reports reviewed by the clinical pharmacist developer.

Acid-Base Clinical Calculator — Methodology & Validation