Normal Acid-Base Balance

Introduction

• Acid-base homeostasis, dictated by the concentration of hydrogen and bicarbonate ions in plasma, must be precisely regulated to optimize enzymatic activity, cellular metabolism, and oxygen transport;¹ even minimal deviations can significantly alter metabolic stability and lead to widespread organ dysfunction.²
• To discuss acid-base balance, a sound understanding of the following definitions is needed:
  • Acid: A molecule that can act as a proton donor.
  • Base: A molecule that can act as a proton acceptor.
• In physiologic solutions, a proton is analogous to a hydrogen ion, [H+], and Arrhenius’ definitions become pertinent, where:
  • An acid is a compound that reacts with water to form hydrogen [H+] ions.
  • A base is a compound that reacts with water to form hydroxide [OH-] ions.
• This can be further described by an acid or base’s strength, which includes “strong” and “weak”:
  • A strong acid readily and irreversibly gives up a [H+], with a strong base avidly binding a [H+].
  • This contrasts with biologic molecules, which function as either a weak acid or a weak base and reversibly donate or bind a [H+], respectively.
• At physiologic temperature (37°C), the normal hydrogen ion concentration in arterial blood and extracellular fluid is 35-45 nmol/L, equivalent to an arterial pH 7.35-7.45; a normal plasma bicarbonate ion concentration is 24 ± 2 mEq/L.
• Physiologic changes due to acid-base disturbance are mitigated by three inter-related systems: chemical buffers, ventilation, and renal response;3 understanding these regulatory bodies is fundamental to maintaining acid-base stability in the anesthetized or critically ill patient.
• Of note, acid-base disturbances (e.g., metabolic acidosis, etc.) will not be discussed in this summary.

Chemical Buffers

• A buffer is defined as a substrate within a solution that prevents extreme fluctuations in pH and is composed of a base molecule and its weak conjugate acid; base molecules of the buffer system bind excess hydrogen ions, while the weak acid protonates excess base molecules.¹ The dissociation ionization constant, or [pK^a], indicates an acid’s strength and is derived from the Henderson-Hasselbach equation:
  Where:

• • pH indicates the measure of acidity or alkalinity of a solution.
  • pK^a is the pH at which an acid is 50% protonated and 50% deprotonated.
  • [A–] is the molar concentration of the conjugate base.
  • [HA] is the molar concentration of a weak acid.
• As previously stated, buffers provide immediate resistance against pH changes, and there are several physiologically significant buffer systems,² including:
  • Bicarbonate (H₂CO₃/HCO₃^–)
  • Hemoglobin (HbH/Hb^–)
  • Other intracellular proteins (PrH/Pr^–)
  • Phosphates (H₂PO₄^2–/HPO₄^2–)
  • Ammonia (NH₃, NH₄⁺)
• In the extracellular space, the bicarbonate buffer system is most significant, as it relates pH, bicarbonate, and pCO₂; this is rapidly affected by and responsive to ventilation. The bicarbonate pair is highly effective due to its abundance and dual regulation by the lungs and kidneys.³ In this system, carbon dioxide, generated via aerobic metabolism, slowly combines with water to form carbonic acid; carbonic acid spontaneously and rapidly deprotonates to form bicarbonate. Normally, less than 1% of dissolved carbon dioxide undergoes the above reaction; however, the catalytic enzyme carbonic anhydrase, found in the endothelium, lungs, and kidneys, facilitates the rapid conversion of carbonic acid.
• Of note, the bicarbonate buffer system is ineffective in mitigating increases in PaCO2, and changes in bicarbonate concentration, [HCO3-], do not reflect the severity of respiratory acidosis.2
• In the intracellular space, the hemoglobin buffer system is dominant, as it plays a critical role in binding hydrogen ions during CO2 transport. 4 Other intracellular buffers include protein and phosphate, which make significant contributions within the renal tubular lumen. The hemoglobin protein serves as an effective buffer system due to its multiple histidine residues,1 which, at a pH of 5.7-7.7 (pKa 6.8), contain multiple protonable sites on their imidazole side chains. Buffering by hemoglobin is contingent upon the bicarbonate system to facilitate the movement of intracellular carbon dioxide. At the lungs, the opposite occurs. Chloride ions move out of red blood cells as bicarbonate enters, which is then converted to carbon dioxide; subsequently, carbon dioxide is released back into the plasma for elimination by the lungs.1 This allows for large volumes of extrapulmonary carbon dioxide to be transported for elimination as plasma bicarbonate.
• Within this lens, oxygenated and deoxygenated hemoglobin have different affinities for hydrogen ions and carbon dioxide. Deoxyhemoglobin accepts more hydrogen ions, shifting towards the production of more bicarbonate and facilitating the removal of carbon dioxide from peripheral tissues for release into the lungs.1 Conversely, oxyhemoglobin favors hydrogen ion release, shifting towards carbon dioxide formation. At physiologic pH, a small amount of carbon dioxide is carried as carbaminohemoglobin.
• Deoxyhemoglobin has a greater affinity–approximately 3.5 times1– for carbon dioxide, so venous blood carries more carbon dioxide than arterial blood via the Haldane effect. This mechanism accounts for the observed difference in carbon dioxide content between venous (27.7 mmol/L) and arterial (25.6 mmol/L) blood.
• Please see the OA summary on carbon dioxide transport for more details.
• In this vein, and in contrast to the bicarbonate buffer system, hemoglobin can buffer against both carbonic and non-carbonic volatile acids.2

Respiratory Regulation

• The lungs maintain pH by regulating carbon dioxide elimination. This is mediated via changes in alveolar ventilation in response to both central (anterolateral medulla oblongata) and peripheral (carotid and aortic bodies) chemoreceptors; these chemoreceptors respond to changes in cerebrospinal fluid pH.2 Respiratory compensation is rapid, occurring in minutes, and is of special importance during anesthesia, where ventilatory drive is commonly depressed by opioids or inhalational agents.3
• Minute ventilation increases 1-4L/min for every acute one mmHg increase in PaCO2. This relationship remains linear except at the extremes of PaCO2, where either the apneic threshold or CO2 narcosis is reached.1 Similarly, the pulmonary response is typically less in metabolic alkalosis than in metabolic acidosis, due to progressive hypoventilation that leads to hypoxemia when breathing room air. Given this, because oxygen-sensitive chemoreceptors limit the compensatory decrease in minute ventilation, PaCO2 typically does not rise above 55 mmHg in response to metabolic alkalosis in patients not receiving supplemental oxygen.1,2
• Please see the OA summary on hypercarbia for more details. Link

Renal Regulation

• In contrast to respiratory regulation, renal regulation provides long-term compensation over hours to days via the following:
• Reabsorption of filtered bicarbonate:
  • Nearly all bicarbonate filtered at the glomerulus is reabsorbed in the proximal tubule (80-90%), preventing its loss as a crucial buffer.
  • The remaining 10-20% are reabsorbed via the distal tubule.
  • This occurs via:¹
    • Carbon dioxide combines with water in the renal tubular cell.
    • Through carbonic anhydrase, bicarbonate is produced and enters the bloodstream, while a hydrogen ion, [H+], is exchanged with sodium and released into the renal tubule.
    • There, [H+] combines with filtered bicarbonate, which then dissociates into carbon dioxide and water via carbonic anhydrase in the luminal brush border.
    • Carbon dioxide then diffuses back into the renal tubular cell.
• Generation of new bicarbonate and ammonium:
  • Nonvolatile acid secretion depends heavily on ammonium (NH₄⁺) formation, which occurs via deamination of glutamine within the mitochondria of proximal tubular cells.²
  • Excretion of ammonium generates new bicarbonate, which is added to the plasma.^3,5
  • Titratable acids, such as phosphate (H₂PO₄^2-), are also significant and contribute to net acid secretion.
• Distal hydrogen ion secretion:
  • Intercalated cells in the distal nephron secrete hydrogen ions, enabling the kidney to excrete large amounts of acid despite steep gradients.
• Collectively, this allows the kidneys to provide highly effective protection against alkalosis, except in the presence of sodium deficiency or mineralocorticoid excess.¹

Physico-chemical (Stewart) Approach & Strong Ion Difference (SID)

• In 1981, Canadian physiologist Peter Stewart introduced a novel paradigm of acid-base balance that challenged the traditional approach.⁷ In it, he proposed pH was composed of three independent variables:⁴
  • PaCO₂
  • Strong ion difference (SID)
  • Total weak acids (A_tot)
  • Composed primarily of albumin and phosphate.

The strong ion difference, or SID, was defined as:

• Ultimately, this framework proposed:⁴
  • A decrease in SID produces metabolic acidosis.
  • An increase in SID produces metabolic alkalosis.
• The Stewart Approach sought to illustrate metabolic disturbances typically unaccounted for via the traditional approach, such as:
  • Chloride-rich fluids
  • Hypoalbuminemia
  • Lactic acidosis
  • Unmeasured anions
• Ultimately, reflecting the origins of pathology common in both critical illness and anesthesiology.

Acid-Base Model Strengths and Limitations

• In anesthetic practice, both the traditional Hendersen-Hasselbach and Stewart approaches have clinical utility, with varying strengths and weaknesses.

For the traditional (Hendersen-Hasselbach) model, strengths include:

• It is a simple, intuitive framework that is widely taught and readily applied during bedside evaluation.³
• Rapid interpretation of arterial blood gas results enables clinicians to quickly categorize a disturbance and its etiology.³
• It is highly effective for time-sensitive decision-making, such as intraoperative ventilator adjustments or the rapid deterioration of clinical status.³
• It has been clinically validated for decades and is strongly aligned with established compensation formulas (e.g., Winter’s formula).⁵

Conversely, weaknesses include:

• It provides descriptive (rather than causative) insight, making it difficult to identify the underlying mechanism of bicarbonate changes.³
  • In essence, provides a what, but not a why.
• It does not incorporate strong ions or weak acids, limiting the ability to analyze chloride load, albumin changes, or lactate accumulation.^6,7
• It may miss mixed or complex disturbances, such as strong ion acidosis, hypoalbuminemic alkalosis, or fluid-induced abnormalities.^6,7
• It is less effective during massive resuscitation, sepsis, transfusion, or major surgery, where electrolytes and proteins fluctuate significantly.⁶

For the physico-chemical (Stewart) model, strengths include:

• Mechanistic and quantitative, identifying pH as a function of three independent variables: PaCO₂, SID, and A_tot.⁴
• It clarifies electrolyte-driven disturbances, including chloride-mediated acidosis, lactate effects, and the impact of hypoalbuminemia.^4,6
• It is highly valuable in complex or critically ill patients, such as those undergoing major surgery, trauma resuscitation, ECMO, shock, or sepsis.⁶
• It detects unmeasured anions (e.g., in sepsis, renal failure, toxin ingestion) more reliably than bicarbonate-based interpretation.⁴

Conversely, weaknesses include:

• It is mathematically complex, requiring an understanding of electroneutrality and physicochemical relationships.⁴
• It is sensitive to small laboratory variations, since SID is calculated from differences between large ion concentrations.⁴
• It lacks simple bedside heuristics comparable to traditional compensation formulas, limiting rapid use in emergencies.³
• It is not universally adopted, with variability in clinician familiarity and comfort.⁶
• There is limited evidence of superiority in outcomes compared with traditional models, making it most useful as a complement rather than a replacement.^6,7

Clinical Applications in Anesthesiology

• Understanding acid-base physiology is a crucial skill set for practicing anesthesiologists, as it is a direct byproduct of our care and medical decision-making. The following are all examples of how acid-base balance is impacted and affected by the applied practice of anesthesiology:
• Ventilation, CO₂ management, and effects of anesthetic agents
  • Direct manipulation of PaCO₂ through controlled ventilation can facilitate or worsen respiratory acidosis or alkalosis if not properly managed.
    • This is particularly important during neuroanesthesia, laparoscopic and robotic surgery, and critical care, where alterations in cerebral blood flow and hemodynamics^3,5 can cause significant harm if mismanaged.
  • Volatile anesthetics depress ventilation and can increase PaCO₂, leading to respiratory acidosis if not appropriately compensated.
  • Propofol can cause metabolic derangements (albeit rare) through Propofol infusion syndrome, reiterating the importance of frequent metabolic monitoring.
• Fluid therapy
  • Perioperative fluid selection can substantially affect acid-base balance, and the Stewart model illustrates how normal saline (SID = 0) reduces a patient’s SID, potentially facilitating hyperchloremic metabolic acidosis.^4,6
  • Conversely, selecting Plasma-Lyte or lactated Ringer’s solution with SIDs closer to plasma better preserves acid-base stability.
  • This is of high importance during large-volume intra-operative resuscitation, trauma, or sepsis.
• Albumin, hemodilution, and blood products
  • Major surgery can cause hemodilution, decreasing albumin concentration.
  • According to Stewart’s model, albumin is classified as a weak acid, resulting in reduced A_tot and a shift toward metabolic alkalosis.⁴
  • Blood products contain citrate and vary in sodium, chloride, and hydrogen ion concentrations, all of which may affect SID and acid-base balance.⁶

Conclusion

• Acid-base balance reflects the interplay of a tightly controlled and cohesive system that underpins the physiologic milieu.
• A sound understanding of the physiologic norm, as well as the frameworks through which we interpret, diagnose, and treat derangements, is crucial.
• As anesthesiologists, we encounter this in many aspects of our daily practice, including ventilatory management, fluid therapy, transfusion strategies, and perioperative critical care.