Acid-Base Equilibrium

Introduction

An arterial blood gas (ABG) test measures the following in arterial blood.

Acidity (pH),
Oxygen tension (PaO2),
Carbon dioxide tension (PaCO2),
Oxyhemoglobin saturation (SaO2),
Bicarbonate (HCO3), and
Haemoglobin level

Lab value skeleton

It represents commonly used lab values to assess a patient's laboratory test results quickly.

Normal Physiology

The body's primary role in acid-balance balance is maintaining a stable pH of 7.4 to function all enzymes optimally. The clinical consequence of acid-base dysregulation is poor vascular tone, skeletal muscle weakness, myocardial suppression, electrolyte abnormalities and impaired cellular respiration. The net acid production is equal to the net acid elimination from the body. The three stages of acid metabolism are 1. Production, 2. Transportation, and 3. Elimination through Lungs and kidneys.

Production: Two types of acids produced in the body are volatile (CO2) and non-volatile (all other acids)

Carbohydrates ---> CO2
Proteins ---> H2SO4
Phospholipids ---> H3PO4
Pathological production of acids - Diabetes produces ketones, Hypotension and hypoxia produce lactate

Transportation: The acid transport mechanism in the blood are

By the binding of acids to plasma proteins, such as albumin, or
By binding to the bicarbonate buffer system. A buffer has the property of resisting changes in pH. Bicarbonate ions can bind to excess hydrogen ions in the blood to form carbonic acid, which can then dissociate into the water and carbon dioxide.

Elimination: The liver can metabolize certain acids, such as lactic acid and ketone bodies, and convert them into less acidic compounds that can be excreted from the body. The other organs responsible for acid elimination from the body are

Lungs; CO2 expiration
Kidneys; 1. bicarbonate absorption in the PCT, 2. H+ secretion in the DCT (aldosterone mediated), and 3. NH4+ secretion in the collecting duct.

The Trans-cellular shift of K+ ion in metabolic acidosis; The acidosis causes a shift in the potassium balance between the intracellular and extracellular compartments. The H+ ions move into the cells in exchange for K+ ions moving out of the cells, resulting in hyperkalemia. For every 0.1 drop in pH, K+ increases by 0.6

Acidemia ---> Hyperkalemia (pH 0.1 --> K 0.6)

Alkalemia ---> Hypokalemia

The ABG value represents in the order; pH/PaCO2/PaO2/HCO3/O2Sat

Phosphate is absorbed in the PCT, blocked by a high level of PTH, resulting in phosphate acting as a buffer in the renal tubules (distal).

Acid-Base disorder

Acidemia versus Acidosis: Acidemia or alkalemia refers to a physiologic state based on arterial pH (<7.4 acidemia, and >7.4 alkalemia). Acidosis and alkalosis, on the other hand, are terms used to describe the processes that can cause acidemia or alkalemia. Both acidosis and alkalosis can have a range of causes, including respiratory or metabolic disturbances, and can be life-threatening if not managed appropriately. A patient can be acidemic or alkalemic, but not both. However, a patient can have one or more acidosis and one or more alkalosis.

There are two primary types of acid-base disorders; 1. Respiratory, and 2. Metabolic.

Respiratory Acidosis; PaCO2 >40
Respiratory Alkalosis; PaCO2 <40
Metabolic Acidosis; HCO3- <24
Metabolic Alkalosis HCO3- >24

ABG reading steps; Example (1) pH; 7.35/PaCO2; 38/HCO3; 20

Determine acedemia or alkalemia. Here pH is below 7.4, hence Acidemia
Determine which process (acidosis or alkalosis) is in the same direction as the pH disorder (acidemia or alkalemia). Here metabolic acidosis (bicarbonate below 24) is in the direction of the pH disorder (acidemia). The diagnosis is Metabolic Acidosis.
Look for compensation. Here metabolic acidosis. Use winter's formula. The required PaCO2 is 38. The diagnosis is Metabolic acidosis compensated with Respiratory alkalosis.

Compensation

The compensation formula

Metabolic acidosis; Use winter's formula (PaCO2 = 1.5 (HCO3-) + 8)
Metabolic alkalosis; PaCO2 = 40 + 0.7 (HCO3-24)
Acute Respiratory acidosis; HCO3 = 24 + (PaCO2-40)/10
Acute Respiratory alkalosis; HCO3 = 24 - 2(40-PaCO2)/10
Chronic Respiratory acidosis; HCO3 = 24 + 4(PaCO2-40)/10
Chronic Respiratory alkalosis; HCO3 = 24 - 5(40-PaCO2)/10

Remember,

Compensation does not return the pH to normal,
Patients never "overcompensate",
Compensation for metabolic alkalosis is relatively poor, and
By predicting the normal compensatory response to primary acid-base disorders, the mixed disorder can be identified (if a given patient is not compensating as predicted, a second or third abnormality must be present).

Example (2): pH; 7.35/PaCo2; 30/HCO3; 10

Determine (pH) acidemia or alkalemia; Here Acidemia
Determine the process (acidosis or alkalosis) in the same direction with the pH; Metabolic; Here, Metabolic Acidosis.
Look for compensation; The required PaCO2 is 23, but here it is 30. Therefore a second disorder is present. PaCO2 is higher than predicted; hence the second disorder here is Respiratory acidosis. The diagnosis is "Metabolic acidosis + Respiratory acidosis".

Anion gap

The electrical equilibrium of the body, also known as the body's electrochemical balance, is essential for proper physiological functioning.

Cations (positively charged ions) = Anions (negatively charged ions)
AG = Measured cations - Measured anions = (Na+) + (K+) - (Cl-) + (HCO3-)
K+ value is very low as compared to Na+; hence the AG is measured quickly as

AG = (Na+) - (Cl-) + (HCO3-) = 12

Example (3); pH; 7.32/PaCO2; 28/HCO3; 14, Na+; 140, Cl-; 116

Answer: Normal Gap Metabolic Acidosis

Example (4); pH; 7.28/PaCO2; 24/HCO3; 12, Na+; 128, Cl-; 94

Answer: Elevated Metabolic Acidosis

Example (5); A diabetic patient with acute dyspnoea; pH; 7.47/PaCO2; 20/HCO3; 14, Na+; 135, Cl-; 14

Answer: Respiratory alkalosis + Normal Gap Metabolic Acidosis

Example (6); A female patient is brought in an unconscious state; pH; 7.09/PaCO2; 34/HCO3; 10, Na+; 135, Cl-; 112, Albumin; 2.

Answer: Elevated Gap Metabolic Acidosis + Respiratory Acidosis

Mixed disorders

In high anion gap metabolic acidosis, an excess of unmeasured anions can decrease the pH. An equal amount of cations or bicarbonate (buffer) must be utilised in a 1:1 ratio to maintain electrical neutrality. The delta ratio compares the increase in AG to the decrease in HCO3.

Delta ratio = (AG - 12) / (24 - HCO3)

As other buffers, like intracellular proteins, partly buffer pathological acids, hence the delta ratio is often greater than 1.

The expected Delta ratio is as follows

Lactic acidosis ~ 1.6 (1 to 2)
Ketoacidosis ~ 1 (0.8 - 1.2)
Kidney disease - Variable

The Delta ratio interpretations are as follows

Lower than expected; HAGMA + NAGMA
Within expected range; HAGMA alone
Higher than expected; HAGMA + Metabolic alkalosis

Explanation;

Example (7); 75-year-old woman with Acute diarrhoeal disease. pH; 7.29/PaCO2; 30/HCO3; 14. Na+: 128, Cl-: 94

Answer: HAGMA + NAGMA (as the Delta ratio is less than one, 0.8)

Example (8); 35-yrs-old with Type 1 DM came with vomiting and abdominal pain. pH; 7.27/PaCO2; 27/HCO3; 12. Na+; 140, Cl-; 98

Answer; Here Delta ratio is 1.5. Even though the clinical picture is of ketoacidosis, but delta ratio is not falling in 0.8 - 1.2, hence suspect a concurrent metabolic alkalosis.

Elevated gap metabolic acidosis + Metabolic alkalosis

In this case, HAGMA is due to ketoacidosis, and Metabolic alkalosis is due to vomiting.

Example (9); 48-year-old alcoholic found unconscious in a pool of vomitus. pH; 7.17/ PaCO2; 65/ HCO3; 22, Albumin; 1.6, Na+; 136, Cl-; 98

Answer; The respiratory acidosis is not compensated appropriately, and bicarb is low, meaning additional metabolic acidosis is present. The adjusted (for low albumin) AG is elevated (22). Delta ratio is 5

Respirtory Acidosis + Elevated Gap Metabolic acidosis + Metabolic Alkalosis

This patient has ketoacidosis from alcoholism. intoxication causes central respiratory suppression and metabolic alkalosis from vomiting.

Metabolic Acidosis

Three mechanisms can produce metabolic acidosis

(dilution acidosis is because of large volume of NS)

Increased acid generation
1. 1. - - Lactate, Ketones and alcohol
Loss of bicarbonate
1. 1. - - Diarrhoea and Type 1 RTA (distal RTA, Sjogren)
Diminished renal acid excretion
1. 1. - - Type 2 (proximal, infants, Fanconi) & Type 4 RTA (hypoaldosteronism)

HAGMA

High anion gap metabolic acidosis (HAGMA) occurs when there is an excess of acid in the blood, which can be due to various causes, including kidney disease, diabetes (keto acids), lactic acidosis, ingestion of toxic substances, and certain medications.

Ketoacidosis (alternate fuel synthesised by the Liver) produced in

Diabetes
Starvation
Alcoholism

The first step in any alcohol (Methanol, Ethanol or Glycol) metabolism is the conversion to acetaldehyde by the Alcohol dehydrogenase (ADH) enzyme. This reaction requires the coenzyme NAD+ (nicotinamide adenine dinucleotide) and results in the release of hydrogen ions (H+). And next step is further oxidation by the Aldehyde dehydrogenase enzyme.

Methanol --> Formaldehyde --> Formate

Ethanol --> Acetaldehyde --> Acetate

Ethylene glycol --> Glycoaldehyde --> Glycolate

Propylene glycol --> Lactaldehyde --> Lactate

The affinity of ADH to ethanol is higher than that of formaldehyde or glycolaldehyde. So ethanol infusion is given to slow down the formation of formate or glycolate in case of poisoning with methanol or glycol. Formeprazole inhibits alcohol dehydrogenase but is not available widely.

Serum Osmolar gap:

It measures the difference between the calculated and measured levels of osmolality in the blood. To calculate the expected osmolality, one can use the following formula:

2 x [Na+] + glucose/18 + BUN/2.8

A normal serum osmolar gap is typically less than 10 mOsm/kg. A high serum osmolar gap (>20) indicates suspected toxic alcohol ingestion.

BUN vs Urea: Urea is produced in the liver when proteins are metabolised: Protein → Amino acids → Ammonia (toxic) → Urea (liver) → Excreted by kidneys. The urea molecule is CO(NH2)2. Americans use BUN instead of Urea because nitrogen reflects protein metabolism. Although urea contributes to measured osmolality, it is a freely permeable solute across cell membranes (Raises osmolality, does not increase tonicity).

Molecular weight of urea = 60, Nitrogen component = 28. If the laboratory reports urea instead of BUN: Calculated Osmolality=2[Na] + Glucose/18 + Urea/6. And BUN=Urea× 28/60

High BUN with normal creatinine (More production → GI bleed, high-protein diet, steroids. More reabsorption → dehydration, hypovolemia.)

Dehydration (Reduced renal perfusion → kidneys reabsorb more water. Urea passively follows water reabsorption. Creatinine is not reabsorbed)
Upper GI bleed (Digested blood acts like a large protein meal. Elevated BUN out of proportion to creatinine may suggest upper GI bleeding.)
High protein intake (More dietary protein → more amino acid metabolism.)
Steroids (Steroids cause protein catabolism. Muscle and tissue proteins are broken down.)

NAGMA

A low HCO₃⁻ with NAGMA) is caused by excessive bicarbonate loss from either the GI tract (e.g., diarrhoea) or the kidneys (e.g., Renal Tubular Acidosis, RTA). The UAG) helps differentiate between these causes:

UAG=(Urine Na+ plus Urine K+ minus Urine Cl−

The kidneys excrete acid primarily as ammonium (NH₄⁺), mainly as NH₄Cl. Simultaneously, new HCO₃⁻ is generated and returned to the bloodstream.

When metabolic acidosis develops, the kidneys respond by increasing ammoniagenesis: Acidosis → ↑ NH₄⁺ production → ↑ NH₄⁺ excretion → ↑ new HCO₃⁻ generation. Because NH₄⁺ is not routinely measured in urine, the UAG serves as an indirect marker. Since NH₄⁺ is excreted with chloride, urinary chloride concentration reflects urinary ammonium excretion.

Negative UAG: High urinary chloride -> means High NH₄⁺ excretion (Appropriate renal response to acidosis) -> Suggests extrarenal bicarbonate loss. So high NH₄⁺ excretion (negative UAG) → kidneys are functioning appropriately; think diarrhoea or other GI bicarbonate losses (Enteric fistula/Pancreatic drainage)

Positive UAG: Low urinary chloride -> means Low NH₄⁺ excretion (inadequate renal acid excretion) -> Suggests a renal cause, particularly RTA. So low NH₄⁺ excretion (positive UAG) → kidneys are failing to excrete acid; think renal tubular acidosis (RTA).

Large-volume or chronic diarrhoea causes loss of bicarbonate, sodium, potassium, and bicarbonate precursors (e.g., citrate, lactate, butyrate) in stool, leading to hyperchloremic metabolic acidosis. To compensate, the kidneys markedly increase NH₄⁺ excretion. NH₄⁺ is excreted as NH₄Cl (acidic). As urinary chloride rises disproportionately, resulting in a negative UAG. Diarrhoea caused by cholera is more commonly associated with high stool concentrations of true bicarbonate. Diarrhoea can cause

Volume depletion
Acid-base disturbance (stool is alkaline)
Electrolytes abnormalities

The key concept is that Ammonium excretion = renal acid excretion.

The best test is actually: Urine Osmolal Gap, because it estimates NH₄⁺ more accurately than UAG.

NAGMA + Hypokalemia + Positive UAG → Distal RTA
NAGMA + Hyperkalemia + Positive UAG → Type 4 RTA
NAGMA + Negative UAG → Think diarrhoea until proven otherwise
Negative UAG = kidneys are appropriately dumping NH₄⁺ (extrarenal cause).
Positive UAG = kidneys cannot dump NH₄⁺ (renal tubular acidosis)

Metabolic alkalosis

(detailed in the NAGMA and Met Alkalosis page)

Respiratory acidosis

Alveolar ventilation V/s Alveolar gas equation

The Dalton Law; states that in a mixture of non-reacting gases, the total pressure exerted is equal to the sum of the partial pressures of the individual gases.

Alveolar ventilation equation: It relates the volume of air that reaches the alveoli per unit of time. The equation is as follows: VA = (Vt - Vd) x f

Where: VA is the alveolar ventilation rate (the volume of air that reaches the alveoli per unit of time), Vt is the tidal volume, Vd is the dead space volume, and f is the respiratory frequency (the number of breaths per unit of time).

Alveolar gas exchange equation: The equation is as follows: PAO2 = FiO2 (Pi - PH2O) - (PACO2 / RQ).

The A-a gradient

Hypoxemia versus Hypoxia; Hypoxemia is the reduction of oxygen in the blood; on the other hand, hypoxia is the insufficient oxygen supply to the body tissue. The A-a gradient is a measure of the efficiency of oxygen transfer from the lungs to the bloodstream and can help to determine the cause of hypoxemia. An elevated A-a gradient suggests impaired oxygen transfer due to V/Q mismatch, while a normal or low A-a gradient suggests impaired oxygen transfer due to shunt.

Pulmonary ventilation; Typically assessed by PaCO2
Gas exchange; The A-a gradient reflects the efficiency of oxygen transfer from the lungs to the bloodstream
Oxygen transportation; 2% of oxygen is dissolved in the blood (measured as PaO2), and 98% binds to Hb ("O2 sat"). O2 sat can be reported as SpO2 (from pulse oximetry) or SaO2 (from ABG).
Tissue diffusion
Cellular respiration

Example (x1); 83-year-old lady admitted with breathing difficulty and hypoxia. pH; 7.53/PaCO2; 26/PaO2; 41 on RA.

Answer; Step 1; Check the A-a gradient. PAO2 = FiO2 (Pi - P H2O) - PaCO2/RQ

= 21 (760 - 47) - PaCO2/0.8 = 150 - 26/0.8 = 77

Step 2; Estimated A-a gradient = (Age/4) + 4 = (83/4) + 4 =25

The PaO2 and PCO2 are very low. Here A-a gradient is increased, therefore, the hypoxemia is not related to hypoventilation (it is evident in ABG that low PaCO2). The Most likely diagnosis is Pneumonia or Aspiration pneumonitis.

Example (x2); 56-year-old male patient admitted with dyspnoea for three days. pH; 7.31, PaCO2; 60, PaO2; 57.

Answer; Step 1; Check the A-a gradient. PAO2 = FiO2 (Pi-P H2O) - PaCO2/RQ

PAO2 = 150 - 60/0.8. The A-a gradient = PAO2 - PaO2 = 75 - 57 =18

Step 2; Estimate A-a gradient = (Age/4) + 4 = (56/4) + 4 = 18

It means the cause of hypoxemia must be hypoventilation.

The Most likely diagnosis is COPD exacerbation. The patient with COPD exacerbation and hypoventilation will have improved outcomes if treated with BiPAP.

The Saturation Gap

Oxygen transport:

Oxygen dissolved in blood ~ 1.5% = measured as PaO2.

Oxygen bound to Hb ~ 98% = measured as 1) SpO2 (from pulse oxy) or 2) SaO2 (calculated from ABG) - both collectively called "O2 sat". Pulse oximeter work with the principle of spectrophotometry.

When there is a difference between the SpO2 (pulse oximetry) and the calculated oxygen saturation (SaO2) based on the oxygen-haemoglobin dissociation curve, this difference is called the saturation gap (if >5%). The saturation gap can be caused by

abnormal haemoglobin variants, such as methemoglobin (SpO2 < SaO2) or carboxyhemoglobin (SpO2 > SaO2),
poor perfusion to the tissues, or
inaccurate pulse oximetry readings.

Example: A code blue is called after a 680-year-woman undergoing TEE prior to elective cardioversion for atrial fibrillation developed dyspnoea and confusion. On exam, she is in respiratory distress and is cyanotic. O2 saturation is 85% (SpO2) with 10-litre oxygen via face mask. pH 7.45/PaCO2 36/HCO3 24/ PaO2 340/ SaO2 100.

Answer: [cyanosis is common with met Hb (carboxy Hb sometime has a cherry red appearance)]

Step 1; calculate A-a gradient

PAO2 = FiO2 (Pi-PH2O) - [PaCO2/RQ] = 0.60 (760-47) - [36/0.8] = 383

A-a gradient = PAO2-PaO2 = 383-340 = 43

Step 2: Expected A-a gradient = age/4+4 + 50 (FiO2-0.21) = 41

Step 3: Saturation gap = | SpO2-SaO2 | = | 85%-100% | = 15% , seen in methemoglobinemia

Sources of Error

Error in the method used to withdraw the arterial blood
Consumption of oxygen by leukocytes results in low PaO2. This error is minimal if the sample is placed on ice and analyzed within 15 minutes
(acidic)Heparin decreases pH and dilute PaCO2. This error is minimal if heparin solution used should be minimized and at least 2 mL of blood should be obtained
Air bubbles can cause a falsely high PaO2 and a low PaCO2. This error can be decreased by gently tapping on the syringe to remove the bubbles after the sample has been withdrawn and analyzing the sample as soon as possible
Failure to check collateral circulation (Allen's test).

Courtesy: Tintinalli, Eric Strong MD

-End-

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