Winters vs Rose: How Much pCO2 Falls

References

Chapter 19, Part 1 

Metabolic acidosis  June 14, 2023

American Society of Nephrology | Medical Students - Kidney TREKS this is the program that Josh mentioned at Mount Desert Island! 

Effects of pH on Potassium: New Explanations for Old Observations - PMC here’s the review melanie from Peter Aronson that clarifies the fact that there are no H+-K+ antiporters outside the kidney but rather coupled transport-

We discussed whether we like “Winter’s formula” Quantitative Displacement of Acid-Base Equilibrium in Metabolic Acidosis | Annals of Internal Medicine 

Dr. R. W. Winters was charged with larceny https://www.nytimes.com/1982/05/16/nyregion/ex-columbia-u-doctor-charged-with-larceny.html

JCI - The Maladaptive Renal Response to Secondary Hypocapnia during Chronic HCl Acidosis in the Dog this was a classic experiment exploring the respiratory response to an infusion of HCl but the animals were maintained in a high pCO2 milieu (not generalizable to humans!)

Here’s the thoughtful Pulmcrit post (by Josh Farkas)  that Josh mentioned regarding correction of anion gap for hypoalbuminemia: Mythbusting: Correcting the anion gap for albumin is not helpful

JC mentioned that the anion gap does change in cirrhosis when the albumin is very low but using the correction factor may not change the clinical findings Acid-base disturbance in patients with cirrhosis: relation to hemodynamic dysfunction

Diagnostic Importance of an Increased Serum Anion Gap | NEJM Melanie mentioned the work of Patricia Gabow on the anion gap. In this review, she refers to work that she had done to try to identify all the organic anions in the anion gap but it falls short. 

Also, check out this critical look at the delta/delta: The Δ Anion Gap/Δ Bicarbonate Ratio in Lactic Acidosis: Time for a New Baseline?

Roger mentioned near drowning in the Dead Sea and the unusual electrolytes in that instance. Near-Drowning in the Dead Sea: A Retrospective Observational Analysis of 69 Patients

We discussed this classic NEJM article by Daniel Batlle The Use of the Urinary Anion Gap in the Diagnosis of Hyperchloremic Metabolic Acidosis

Amy mentioned this review from  Uribarri  and Oh in JASN on the urine anion gap: The Urine Anion Gap: Common Misconceptions

Joel has a great blog post on the urine osmolar gap. urine osmolar gap – Precious Bodily Fluids 

Anna’s VoG on the bicarb deficit:  Kurtz, I Acid-Base Case Studies, 2nd Edition. Trafford Publishing 2004.  And the Fernandez paper that derived a better equation

Reference for Josh’s VoG: Key enzyme in charge of ketone reabsorption of renal tubular SMCT1 may be a new target in diabetic kidney disease

Severe anion gap acidosis associated with intravenous sodium thiosulfate administration

Unexpectedly severe metabolic acidosis associated with sodium thiosulfate therapy in a patient with calcific uremic arteriolopathy

Sodium Thiosulfate Induced Severe Anion Gap Metabolic Acidosis

Sodium Thiosulfate and the Anion Gap in Patients Treated by Hemodialysis

Outline: Chapter 19 Metabolic Acidosis

Overview

Low arterial pH

Reduced HCO3

Compensatory hyperventilation (↓ pCO2)

Bicarb < 10 strongly suggests metabolic acidosis (renal compensation for respiratory alkalosis does not go that low)

Pathophysiology

H+ + HCO3- <=> H2CO3 <=> CO2 + H2O

Acidosis results from H+ addition or HCO3 loss

Response to Acid Load

Extracellular buffering

Example: Add 12 mmol H+/L → HCO3 falls from 24 → 12 → pH drops to 7.1 (40 to 80 nmol/L)

Intracellular and bone buffering

55–60% buffered intracellularly and in bone

12 mEq/L acid load only reduces serum HCO3 by ~5 mEq/L

H+ into cells → K+ out (hyperkalemia)

Notably in diarrhea or renal failure

Less effect with organic acidosis (e.g., DKA, lactic acidosis)

Respiratory compensation

Stimulates chemoreceptors → ↑ tidal volume (more than RR)

Decreases pCO2, increases pH

Begins within 1–2 hours; peaks at 12–24 hours

Winters formula alternative: for every 1 mEq ↓ HCO3, pCO2 ↓ by 1.2

Chronic: respiratory compensation is blunted by renal adaptation

Renal hydrogen excretion

50–100 mEq/day acid generated from diet

90% filtered HCO3 reabsorbed in PT

Acid secreted:

10–40 mEq via titratable acid (TA)

30–60 mEq via NH3/NH4 (can ↑ to 250 mEq in acidosis)

TA: phosphate (DKA → ketones act as TA)

Max excretion up to 500 mEq/day in severe acidosis

Generation of Metabolic Acidosis

Mechanisms

Inability to excrete H+ (slow)

Addition of H+ or loss of HCO3 (rapid)

Anion Gap (AG)

Normal: 5–11 (falling due to rising Cl-)

Mostly due to negatively charged proteins (albumin)

Adjust for albumin: AG ↓ 2.5 per 1 g/dL albumin ↓

Revised: AG = unmeasured anions - unmeasured cations

↑ AG = addition of unmeasured anions (e.g., lactate, ketones)

Hyperchloremic acidosis: ↓ HCO3 replaced by ↑ Cl (normal AG)

Delta–Delta Analysis

Adjust AG for albumin

Normal ΔAG:ΔHCO3 = 1.6:1 (early 1:1)

<1 → high + normal AG acidosis

Other causes of AG variation

High AG without acidosis: hemoconcentration, alkalosis

Low AG: hypoalbuminemia, ↑ unmeasured cations (lithium, IgG, lab artifact)

Urine Anion Gap (UAG)

Normal = ~0; should be very negative (< -20) in acidosis

Type 1 & 4 RTA → UAG positive or near zero

Invalid in ketoacidosis or volume depletion (Na retention → ↓ distal acidification)

Urine Osmolal Gap

Estimate NH4+ via osmolar gap

Requires urine Na, K, glucose, urea

Etiologies and Diagnosis

Lactic Acidosis

Pyruvate → lactate (LDH; NADH → NAD+)

Normal production: 15–20 mmol/kg/day

Metabolized in liver/kidney → pyruvate → glucose or TCA

Normal lactate: 0.5–1.5 mmol/L; acidosis if > 4–5 mmol/L

Causes:

↑ production: hypoxia, redox imbalance, seizures, exercise

↓ utilization: shock, hepatic hypoperfusion

Malignancy, alcoholism, antiretrovirals

D-lactic acidosis

Short bowel/jejunal bypass

Glucose → D-lactate (not metabolized by LDH)

Symptoms: confusion, ataxia, slurred speech

Special assay needed

Tx: bicarb, oral antibiotics

Treatment

Underlying cause

Bicarb controversial: may worsen intracellular acidosis, overshoot alkalosis, ↑ lactate

Target pH > 7.1; prefer mixed venous pH/pCO2

Ketoacidosis (Chapter 25 elaborates)

FFA → TG, CO2, H2O, ketones (acetoacetate, BHB)

Requires:

↑ lipolysis (↓ insulin)

Hepatic preference for ketogenesis

Causes:

DKA (glucose > 400)

Fasting ketosis (mild)

Alcoholic ketoacidosis

Poor intake + EtOH → ↓ gluconeogenesis, ↑ lipolysis

Mixed acid-base (vomiting, hepatic failure, NAGMA)

Congenital organic acidemias, salicylates

Diagnosis:

AG, osmolar gap (acetone, glycerol)

Ketones: nitroprusside only detects acetone/acetoacetate

BHB can be 90% of total (false negative)

Captopril → false positive

Treatment:

Insulin +/- glucose

Renal Failure

↓ excretion of daily acid load

GFR < 40–50 → ↓ ammonium/TA excretion

Bone buffering stabilizes HCO3 at 12–20 mEq/L

Secondary hyperparathyroidism helps with phosphate buffering

Alkali therapy controversial in adults

Ingestions

Salicylates

Symptoms at >40–50 mg/dL

Early: respiratory alkalosis → Later: metabolic acidosis

Treatment: bicarb, dialysis (>80 mg/dL or coma)

Methanol

Metabolized to formic acid → retinal toxicity

Osmolar gap elevated

Tx: bicarb, ethanol/fomepizole, dialysis

Ethylene glycol

→ glycolic/oxalic acid → renal failure

Same treatment + thiamine/pyridoxine

Other

Toluene, sulfur, chlorine gas, hyperalimentation (arginine, lysine)

GI Bicarbonate Loss

Diarrhea, bile/pancreatic drainage → loss of alkaline fluids

Ureterosigmoidostomy → Cl-/HCO3- exchange in colon

Cholestyramine → Cl- for HCO3-

Renal Tubular Acidosis (RTA)

Type 1 (Distal)

↓ H+ secretion in collecting duct → urine pH > 5.3

Etiologies: Sjögren, RA, amphotericin

Features: nephrocalcinosis, stones, hypokalemia

Diagnosis: NAGMA, persistent ↑ urine pH

Treatment: alkali (1–2 mEq/kg/d adults; 4–14 kids), K+ if needed

Type 2 (Proximal)

↓ HCO3 reabsorption

Bicarb threshold reduced → self-limited

Causes: multiple myeloma, Fanconi, ifosfamide

Features: rickets/osteomalacia, no stones, pH variable

Diagnosis: NAGMA, pH < 5.3, high FE HCO3 when HCO3 loaded

Treatment: alkali (10–15 mEq/kg/d), thiazides

Type 4

Aldo deficiency/resistance → hyperkalemia + mild acidosis

K+ inhibits NH4 generation

Tx: correct K+, consider loop diuretics

Symptoms

Hyperventilation (dyspnea)

pH < 7.0–7.1 → arrhythmias, ↓ contractility

Neurologic: lethargy → coma (CSF pH driven)

Skeletal growth issues in children

Treatment Principles

No alkali needed for keto/lactic acidosis unless pH < 7.2

Bicarbonate Deficit

Deficit = HCO3 space * (desired - actual HCO3)

HCO3 space: 50–70% of body weight

Watch for:

K+ shifts: beware hypokalemia when correcting acidosis

Na+ load in CHF

Dialysis if necessary