Acid-Base Disorders

Physical-Chemical Interpretation of the Acid-Base System

The Canadian scientist Peter Stewart published his book “How to Understand Acid-Base Physiology” in 1981. In it, he presented an integrated model of how electrolytes, water balance, carbon dioxide, and proteins work together to determine acid-base balance. Over the next 20 years, a large number of scientific articles grounded the model in the clinical interpretation and treatment of acid-base disorders. The model is called “the Stewart approach” or the “physico-chemical model.” It is based on the physical-chemical properties of various electrolytes (strong and weak ions), takes thermodynamic principles like conservation of mass into account, and mathematically shows how the system is connected. The result is an extremely useful model that explains phenomena we observe daily in perioperative and intensive care. It explains why hyperchloremia makes the patient acidic, why low albumin levels cause alkalosis, and helps us understand the acid-base effect of different infusion solutions. The kidney’s role in acid-base regulation suddenly becomes understandable. Stewart shows how changes in bicarbonate and proton concentration are secondary to changes in three primary variables—namely PCO₂, the balance between strong cations and strong anions, and the total amount of weak acid in the system. Forget all explanations about bicarbonate regulating acid-base status, and get to know the body’s most underrated electrolyte—the chloride ion! Stewart’s book is a pleasure to read even today—delightfully educational and a clear step-by-step analysis of a fairly complex subject. It can be obtained via www.acidbase.org.

Why is Proton Concentration Important?

A proton (H⁺) is a hydrogen atom (H) that has lost an electron (e^–), making it positively charged. The proton is about 10,000 times smaller than a water molecule. This extreme smallness combined with the positive charge creates a huge voltage gradient. Therefore, the proton becomes chemically very reactive and affects hydrogen bonds, conformation, charge, and function of proteins. On the other hand, the much larger hydroxyl ion (OH^–) is not as interesting from a biological perspective—its lower voltage gradient makes it less likely to affect the biochemical, protein-based machinery. The proton concentration, [H⁺], is regulated with fantastic precision. The normal [H⁺] in blood is 36-43 nM, [OH^–] is at the µ-M level, and our “usual” electrolytes such as Na, K, and Cl are in mM. Hydrogen ion concentration can also be expressed as the negative 10-logarithm, so that:

pH = -log₁₀ [H⁺]

Normal pH in arterial blood is 7.35-7.45. The use of the pH concept can be convenient in some respects, but it may cause one to miss the magnitude of the proton concentration change one really wants to describe.

Which Variables Determine [H+]?

There are three independent or primary variables that determine the hydrogen ion concentration in biological systems. These are:

• The partial pressure of CO₂.
• The total amount of weak acid (A_TOT), where A_TOT = HA + A^–, i.e., dissociated and non-dissociated weak acid. In plasma, virtually all weak acid is albumin and phosphate.
• The concentration difference between strong cations and strong anions—the so-called “strong ion difference” or SID. SID is primarily determined by the balance between [Na⁺] and [Cl^–].

Partial Pressure of CO2

CO₂ is produced through metabolism, and its concentration is therefore highest intracellularly. On a whole-body level, the concentration is determined by the balance between CO₂ production and CO₂ elimination. Produced CO₂ dissolves physically in water (the concentration becomes proportional to the solubility coefficient and the partial pressure of CO₂) and reacts chemically in two ways—first, with water to form carbonic acid:

CO₂ + H₂O ↔ H₂CO₃

and directly with a hydroxyl ion to form bicarbonate:

CO₂ + OH^– ↔ HCO₃^–

Both reactions are reversible and slow but are catalyzed by the enzyme carbonic anhydrase so that equilibrium is reached within microseconds. The carbonic acid, H₂CO₃, formed can dissociate in two steps to bicarbonate ion and carbonate ion:

H₂CO₃ ↔ H⁺ + HCO₃^– ↔ H⁺ + H⁺ + CO₃^2-

Carbon dioxide diffuses easily through water and cell membranes, and mass flow moves with the partial pressure gradient. As venous blood carries away CO₂, the partial pressure drops, maintaining diffusion from the interstitial space and thus from the intracellular compartment. The bicarbonate ion, on the other hand, is charged and can only pass through cell membranes via ion channels or transport proteins.

The higher the PCO₂, the higher the resulting [H⁺] and the lower the pH.

Definition of Strong and Weak Ions

Strong ions are fully dissociated and do not participate in equilibrium reactions. Weak ions, however, switch between dissociated and associated forms in equilibrium reactions. The equilibrium position is dynamically dependent on the surrounding environment. In all biological systems, the concentration of strong positive ions is higher than the concentration of strong negative ions. This concentration difference is called the Strong Ion Difference or SID and is of fundamental importance for acid-base status. To maintain electrical neutrality, the charge space defined by SID will be exactly filled by weak anions . One of these ion species is bicarbonate, HCO₃^–. The space for HCO₃^– is thus proportional to SID, but also inversely proportional to PCO₂ and the total amount of weak acid. Since [HCO₃^–] is in equilibrium with [H⁺], the proton concentration will adjust if the bicarbonate concentration changes. However, the amount of HCO₃^– cannot affect SID; a weak ion cannot influence the amount or behavior of a strong ion. This means that SID is an independent or primary variable, while HCO₃^– is a dependent or secondary variable.

If the hydrogen ion concentration has changed, it is because one or more of these three primary variables has changed. Changes in [H⁺], [HCO₃^–], [CO₃^2-], [OH^–], or other weak ions are always secondary to changes in one of the independent variables.

The higher the SID, the lower the resulting [H⁺] and the higher the pH. In plasma, SID is primarily determined by the concentration difference between Na⁺ and Cl^– and is therefore around 40 mEq/L. Eq stands for charge equivalents, and since both ion species are monovalent, we might as well write SID = 40 mmol/L.

Weak Acids – Albumin and Phosphate

Intracellularly, the entire cellular machinery is housed, resulting in a high concentration of protein, many of which are weak acids. In the extracellular space, there is generally little protein. In plasma, weak acids consist mainly of albumin and phosphate. A weak acid can be written as HA and dissociates according to the reaction HA ↔ A^– + H⁺. The term “total amount of weak acid” refers to both dissociated and non-dissociated forms of the acid; A_TOT = HA + A^–.

Albumin contains 23 constituent amino acids that act as weak acids. This means that an albumin molecule can switch between a fully dissociated form (Alb^–), where it carries 23 negatively charged amino acid residues, and a fully associated form (Alb-H), where all the amino acids have bound their respective protons. Depending on the surrounding environment (read pH and size of SID), each gram of albumin will contribute a different amount of negative charges. If the concentration of the weak acid albumin increases, the amount of free protons will increase, and the pH will decrease. The number of negative charges exposed per gram of albumin is determined by the three independent variables—PCO₂, SID, and A_TOT. If the albumin concentration decreases, it means there is a shortage of weak acid, resulting in an alkalinizing process. Phosphate, which normally exists at a concentration of 1 mM, is also a weak acid and is in equilibrium between dissociated and associated forms, just like albumin, but with its own dissociation constant.

Spontaneous Dissociation of Water

The most abundant substance in the body, water, spontaneously dissociates according to the following reaction:

H₂O ↔ H⁺ + OH^–. The reaction is temperature-dependent and extremely far to the left. The requirement for electrical neutrality combined with the three variables PCO₂, SID, and A_TOT also dictates the equilibrium for water dissociation.

How Does the Body Regulate Acid-Base Balance?

The body regulates PCO₂ through ventilation. The higher the PCO₂, the more carbonic acid is produced and, in turn, more hydrogen ions. The kidneys regulate SID by controlling [Cl^–] relative to [Na⁺]. An increase in SID (e.g., by reducing chloride ion concentration) alkalinizes, while a decrease in SID (e.g., by increasing chloride or lactate concentration) acidifies. The total amount of weak acid consists of proteins and a small amount of phosphoric acid. In blood plasma, albumin is the dominant weak acid. Albumin concentration is actively regulated, but not to achieve a particular acid-base effect—rather to maintain colloid osmotic pressure, act as a carrier protein for hormones, etc. However, a change in albumin concentration, regardless of cause, will affect acid-base balance. A reduced albumin concentration means a lower total amount of weak acid, leading to a lower concentration of free hydrogen ions. Therefore, hypoalbuminemia leads to an alkalinizing process.

The Role of the Kidneys

To compensate for acidosis, the kidneys attempt to increase SID in the blood by excreting more chloride ions than sodium ions. Since electrical neutrality must be maintained in individual renal tubular cells, as well as in urine and blood, each negatively charged chloride ion is excreted along with a weak cation. If the chloride ion were excreted together with a strong cation (such as Na⁺ or K⁺), the SID in the body would remain unchanged, resulting in no correction of acidosis. The body can co-excrete Cl^– with H⁺ to achieve this, or together with NH₄⁺ if there is a need to eliminate nitrogen. The purpose of renal ammonium ion synthesis is not to “buffer” the body, but to increase the body’s SID while simultaneously achieving negative nitrogen balance. Chloride excreted together with H⁺ alkalinizes the patient by raising the primary variable SID—not by the body getting rid of a proton. Body water still provides, in practice, an inexhaustible source of protons through dissociation. Proton concentration is instead determined by the three primary variables. An example of this is that the body can lower S-[Cl^–] by 5 mM. If we simplistically assume that the change only occurred in plasma (in fact, it affects large parts of the extracellular space), it means that a plasma volume of 4 L has lowered its chloride content by 5 mM and removed 20 mM acid in the form of Cl^– and 20 mM H⁺ via urine. This increase in the body’s SID results in a decrease in [H⁺] by approximately nM. Therefore, proton concentration is not determined by counting how many protons move into or out of a compartment, but by how the resulting independent variables dictate conditions for new equilibrium positions in proton transfer reactions. Even if we remove 20 mM H⁺, parts of it will be replaced as water dissociation is adjusted.

A healthy kidney is capable of effectively lowering S-[Cl^–]. A patient with acidosis who does not develop compensatory hypochloremia should be suspected of having impaired kidney function. If we administer chloride-rich fluids to a patient who is already acidic, we create a difficult situation for the kidneys. Ideally, we would use infusion solutions that have the same chloride concentration as the extracellular space of a healthy person—around 100 mM. Renal perfusion is also affected by chloride concentration, and hyperchloremia, even at maintained pH, lowers renal perfusion through vasoconstriction. The result is reduced urine output and increased release of inflammatory cytokines.

Physiological or Physical-Chemical?

Hyperventilation secondary to acidemia, hypoxemia, or pain leads to decreased PCO₂. The fact that [HCO₃^–] and [H⁺] also decrease is a physical-chemical consequence of this. In chronic respiratory failure with acidosis due to CO₂ retention, the kidney, as a compensatory measure, excretes more chloride ions than sodium ions, thereby increasing SID in the blood. An increased SID provides more space for weak anions, including [HCO₃^–], whose equilibrium with protons will lower [H⁺]. The increase in SID is physiological, but the resulting increase in bicarbonate is physical-chemical.

Analysis of Acid-Base Status

Acid-base status is determined by the interaction between three primary variables—PCO₂, SID, and A_TOT. Traditionally, we have analyzed patients’ acid-base status based on a division into two categories of regulation and disturbance: respiratory and “metabolic.” The result includes difficulties (conceptually, analytically, and pedagogically) in handling parallel metabolic disturbances. Classical acid-base analysis does not provide good tools to quantify how much of an acidosis is due to hyperchloremia and how much is counteracted by concurrent hypophosphatemia or low albumin levels. The term “metabolic” as opposed to respiratory is also misleading as it equates disturbances related to lactate and ketone body production (truly metabolic) with pure electrolyte disturbances, which are often the result of fluid therapy (iatrogenic) and electrolyte and fluid shifts.

Base Excess

Base excess (BE) can reveal whether there is a non-respiratory disturbance or not—and quantify its magnitude. BE answers the question: “How much strong acid or strong base do I need to add to this blood sample for pH to return to 7.40, assuming PCO₂, temperature, and Hb were normal?” The normal range is +3 to -3 mEq/L. A blood gas analysis with BE -7 means that there is a non-respiratory acidosis that requires 7 mmol/L of strong base to correct (a minus in front of BE thus means a “lack of base excess…”). BE is calculated by the blood gas machine using the van Slyke equation based on measured values of [H⁺], [HCO₃^–], and PCO₂. BE quantifies the cumulative effect of disturbances in the two variables SID and A_TOT. Here, a two-dimensional analysis tool meets a reality in 3D. If a patient has a lactate elevation of 5 mM, with normal S-[Na⁺] and S-[Cl^–], it means that SID has decreased by 5 mEq/L from the baseline; SID at the start was 140-100=40, and after the lactate increase, it is 140-100-5=35 mEq/L. If nothing has happened to S-[Phosphate] or S-[Albumin], the variable A_TOT is still normal. In this situation, the resulting BE will be -5 mEq/L. DBE=DSID if D[Albumin]=0. You could also imagine lactate rising to 5 mM in a patient with hypochloremia at 95 (if the normal value for the current measurement method is 100). SID has then decreased by 5 units due to the lactate increase, while the chloride deficiency of 5 mM increases SID by the same amount. SID is still normal, and BE is 0. An acidifying decrease in SID, for example due to hyperchloremia, can also coexist with an alkalinizing hypoalbuminemia that completely “cancels out” each other and leaves BE normal; S-[Cl^–] increased by 5 mM and S-[Albumin] lowered to 22 g/L.

Determining SID

If you’re in a hurry, read under “Simplified SID Determination”! Strong Ion Difference is the difference in charge between strong positive ions (=strong cations) and strong negative ions (=strong anions):

SID=S _{strong cations} – S_{strong anions} mEq/liter

SID is about 40-42 mEq/L (depending on the methods used to determine the electrolytes involved). Since electrical neutrality prevails, the sum of all positive charges (strong and weak) is exactly equal to the sum of all negative charges (strong and weak):

S _{strong cations} + S _{weak cations} – S_{strong anions} – S_{weak anions} = 0

([Na⁺]+[K⁺]+[Ca²⁺]+[Mg²⁺])+([NH₄⁺]+[H⁺]) – ([Cl^–]+[lactate^–]+[XA^–]) – ([HCO₃^–]+[Alb^–]+[Phosphate^–]+[OH^–]+[CO₃^2-]) = 0

The charge concentration (mEq/L) of a divalent ion is 2 times its concentration in mol/L. [NH₄⁺], [OH^–] and [CO₃^2-] are measured in mM, while [H⁺] is measured in nM—the other ions are in mM. If we briefly disregard ions in mM concentration, we can write:

([Na⁺]+[K⁺]+[Ca²⁺]+[Mg²⁺])-([Cl^–]+[lactate^–]+[XA^–])-([HCO₃^–]+[Alb^–]+[Phosphate^–]) = 0 or

SID = [HCO₃^–]+[Alb^–]+[Phosphate^–]

We can then see that [HCO₃^–] is proportional to SID. This means that if SID increases or decreases, [HCO₃^–] will move in the same direction.

SID Apparent (SIDa)

The actual charge difference between known strong cations and strong anions can be calculated as SID_a = ([Na⁺]+[K⁺]+[Ca²⁺]+[Mg²⁺]) – ([Cl^–]+[lactate^–]). SID_a stands for “apparent”.

SID Effective (SIDe)

SID_a defines the space that weak anions fill. Another way to represent this is to calculate SID_e, where “e” stands for “effective”. We can then estimate the size of the “pen” by counting the sheep that fill it. The three most common weak anions are used to calculate SID_e:

SID_e = [HCO₃^–]+[Alb^–]+[Phosphate^–]

The bicarbonate concentration is obtained from the blood gas analysis, but we need to calculate how many negative charges albumin and phosphate contribute per liter. The values of albumin (g/L) and phosphate (mM) are analyzed by the chemistry lab. There are accepted equations that, using experimentally determined dissociation constants and current pH, calculate the charge contribution from these two weak anions:

[XA-], SIG, and Osmolarity

The difference between SID_a and SID_e is the remaining, thus far “unknown,” negative charges—[XA^–]:

SID_a – SID_e = [XA^–] [XA^–] is the concentration of unknown anions. Examples of [XA^–] are strong organic anions that are intermediate metabolites in the citric acid cycle (e.g., oxalate^–) or toxic strong anions such as salicylate ion in ASA intoxication or formate^–—the deprotonated form of formic acid produced during methanol metabolism.

SID_a – SID_e = [XA^–] = SIG

Another term for this is the Strong Ion Gap, SIG. The normal value for [XA^–] varies slightly depending on the methods used for analyzing the electrolytes included in the calculation but is typically between 2-5 mEq/L, excluding lactate. Today, the determination of lactate is standard in point-of-care blood gas machines, so it should not be treated as an “unknown” anion. In complex acid-base disturbances, it is valuable to calculate [XA^–].

Calculating [XA^–] undeniably takes time and requires the determination of albumin, phosphate, and magnesium levels. It may be justified to calculate it for a patient with unclear acidosis that is not fully explained by lactate or relative hyperchloremia. Acute renal failure with acidosis often results from a combination of dilution with hyponatremia and the accumulation of various organic anions, including phosphate (previously referred to as “non-volatile acids”). Following [XA^–] can be a way to evaluate whether the treatment is effective before possibly starting CRRT. A very low or even negative value of [XA^–] indicates the presence of one or more unknown strong cations. This could be due to lithium intoxication. Calculating [XA^–] is also interesting when tracking unknown substances using calculated and measured osmolarity. The principle is to compare the difference between the osmolarity determined by freezing point depression and the osmolarity that can be calculated by adding known electrolytes as well as glucose and urea. An osmolar “gap” indicates that there are one or more other substances present in increased amounts. This could involve toxic alcohols.

Simplified SID Determination

Evaluate S-[Na⁺], S-[Cl^–], and S-[Lactate^–]. If one or more of the variables deviates from the respective average—what do you estimate the resulting SID to be? Normal, lowered, or elevated?

How much does the current value of S-[Na⁺] deviate from the normal average? How does this change affect SID?

How much does the current value of S-[Cl⁺] deviate from the normal average? How does this change affect SID?

Are there abnormal concentrations of K⁺ and lactate^–, and how do these affect SID?

Example: S-[Na⁺] is 134, S-[Cl^–] is 108, and S-[lactate^–] 3 mM.

The normal value for S-[Na⁺] is 137-145, with an average of 141 mM, and the current value has thus lowered SID by 141-134=7 mEq.

The normal value for S-[Cl^–] is 100-110, with an average of 105 mM, and the current value has thus lowered SID by 108-105=3 mEq/L.

The normal value for S-[lactate^–] is 0.5-1.7, with an average of 1.1 mM, and the current value has thus lowered SID by 3-1.1=1.9 mEq/L.

The sum of the changes in SID is thus DSID=-7-3-1.9=-11.9 mEq/L.

Does your estimated DSID match BE? If DSID is more negative than BE, there is a simultaneous deficiency of albumin. If BE is more negative than DSID, you need to calculate [XA^–] via SID_e and SID_a, as it indicates the presence of other strong anions.

Water Disorders – Dilution and Dehydration

Increased water content dilutes all electrolytes and weak acids. The difference between strong cations and strong anions is also diluted. Water overload, therefore, leads to a lowered SID and acidosis. The dilution of albumin provides a parallel alkalosis, but this is overshadowed by the SID decrease, and the net effect is seen as negative BE.

a x [strong cations] – a x [strong anions] = a x [SID]; where ‘a’ is the dilution factor.

Dehydration increases concentrations with elevated SID and alkalinization, along with an increase in albumin concentration, which provides a (milder) acidifying effect. In clinically relevant dehydration, there is often concurrent hypovolemia, which can lead to hypoperfusion and lactate production.

Hyponatremia—water overload—lowers SID and causes acidosis.

Hypernatremia—water deficit—increases SID and causes alkalosis.

A change in water content causes proportional changes in both [Na⁺] and [Cl^–]. To assess whether other disorders are due to dilution or dehydration, one can calculate a corrected chloride concentration (which answers the question “what would [Cl^–] have been if [Na⁺] were normal?”). Such a corrected chloride ion concentration can be calculated as:

Example: S-[Na⁺]=122 mM and S-[Cl^–]=91 mM. [Cl^–]_c = 91 x 141 / 122=105 mM. The corrected chloride ion concentration is normal in this case and follows the dilution of sodium. The difference between S-[Na⁺] and S-[Cl^–] has dropped from 141-105=36 in the baseline to 122-91=31 after dilution. SID has therefore decreased by 5 mEq/L. At the same time, S-[Alb^–] has also decreased, partially compensating for the acidifying effect of the SID reduction, but the net effect is acidosis, which will also be reflected in BE.

Chloride Disorders

Hypochloremia—A lowered chloride value increases SID and alkalinizes the body. It is seen physiologically as renal compensation for acidosis, for example in chronic respiratory failure (COPD). It can occur with chloride losses via a gastric tube, stoma, or intestine. What makes gastric contents acidic is that parietal cells in the stomach secrete Cl^– into the lumen (together with H⁺ to maintain electrical neutrality), creating a very low SID in gastric fluid. Proton pump inhibitors inhibit this. Pancreatic secretions have a high sodium content and, therefore, high SID. The mixture of gastric contents and pancreatic secretions in the duodenum achieves normal SID, and most of the salts are reabsorbed later in the small intestine. In hypochloremia, it is important to assess the indication for the gastric tube—can it be removed? With high stoma output, there is a loss of water and salts. It is often obvious what is lost most (Na⁺ or Cl^–) when you look at the blood gas analysis. In case of doubt, sodium and chloride concentrations in the stoma fluid can be determined.

Another common cause of hypochloremia is diuretic therapy. Furosemide has complex electrolyte effects, but the dominant effect is chloride loss, and the same applies to thiazide diuretics. Acetazolamide (Diamox) is a non-competitive carbonic anhydrase inhibitor that causes increased excretion of Na⁺ relative to Cl^–. The result is lowered SID in plasma (and alkalinized urine as U-[Cl^–] decreases). Acetazolamide may be indicated if diuretic therapy continues and bothersome alkalosis occurs.

Hyperchloremia—Seen as physiological compensation for chronic hyperventilation, which is practically only seen at high altitude. By far, the most common cause of hyperchloremia is infusion with chloride-rich fluids (infusion fluids with SID <24). If normal S-[Cl^–] is 100 mM, any infusion with a higher chloride concentration will increase the chloride level in the body. We do not always see this because patients’ kidneys often manage to excrete the unwanted chloride load (see also the section on infusion fluids). If high S-[Cl^–] occurs despite balanced fluids being used, it is reasonable to suspect the onset of renal failure or at least a suboptimal environment for the kidneys. Intraoperatively, this could imply hidden hypovolemia, poor renal arterial perfusion, or impaired venous outflow obstruction (high pressures during laparoscopy).

Potassium

Potassium is primarily found intracellularly. Energy-consuming pumps maintain the gradient by pumping potassium into the cells and sodium out into the extracellular space. Potassium is a strong cation and helps create a normal SID. When S-[K⁺] increases, SID increases, which alkalinizes the extracellular space. In acidosis, regardless of cause, the function of the Na-K-H-ATPase fails, resulting in elevated S-[K⁺]. A low potassium level reduces SID and contributes to acidosis. When potassium replacement is needed, it is important to simultaneously assess chloride levels to choose the right potassium preparation. The common KCl preparation is the cheapest but causes significant chloride load, especially as most of the potassium moves intracellularly while the chloride ions remain in the extracellular space. The same applies to the sustained-release tablets Kaleorid, where the active substance is potassium chloride. Keep in mind that potassium-rich fluid must be administered via a central venous catheter (CVC), as it is highly irritating to blood vessels, and with frequent monitoring of S-[K⁺] to avoid the risk of lethal arrhythmias!

In acidosis, hyperchloremia, or renal failure, it may be better to replace potassium in the form of Addex Potassium. There, the chloride ions have been replaced by phosphate and acetate. Phosphate is a weak acid and will increase A_TOT (but the extent is almost never of clinical significance). Acetate is an organic strong anion that can be metabolized in all tissues to CO₂ and water. The oral solution Kajos consists of potassium citrate. Citrate is metabolized in the same way as acetate.

Lactate

Lactate is an organic strong anion. This means that at pH levels compatible with life, lactate is almost completely deprotonated. An increase in lactate by, for example, 2 mM decreases SID by 2 mEq/L, thereby producing a negative BE of -2 mEq/L. Lactate elevation is most commonly seen when tissue is forced into anaerobic metabolism. This can occur in global hypoxia but perhaps more often in regional or systemic hypoperfusion, as seen in hypovolemia. If lactate elevation is seen in conjunction with infection—initiate sepsis treatment according to goal-directed therapy (EGDT). Look for ischemia! Vascular catastrophe in the abdomen? Liver failure with decreased ability to metabolize lactate produced elsewhere in the body? Seizures? Metformin treatment? Intoxication? Cyanide? CO poisoning? Sometimes moderately elevated lactate levels are explained by a strong catecholamine response (endogenous and/or exogenous), such as physical activity, beta-agonist therapy, norepinephrine, or adrenaline—but these should be considered exclusion diagnoses. Lactate is metabolized in the liver and is an energy substrate—when oxygen is available, and functioning enzymes are present, it is metabolized to CO₂ and water.

See also: deranged physiology

About Infusion Solutions and Acid-Base

It is impossible to predict the effect of infusing a certain fluid into a patient based on the product’s stated pH value. However, if you analyze the content of and impact on the three independent variables—PCO₂, SID, and A_TOT—it becomes simple. Infusion fluids stored in non-gas-tight containers equalize the gas content with the surrounding atmosphere. This means that they have negligible CO₂ content, and infusion thus dilutes the body’s CO₂—though the clinical effect is negligible. The electrolyte composition and weak acid content of the infusion fluid are, however, significant.

An infusion fluid with a SID lower than the extracellular space SID will lower SID in plasma and cause acidosis. If the infusion fluid contains no weak acid, A_TOT in plasma will decrease, contributing to alkalosis. Studies show that infusion solutions without weak acid and with SID of 24 mEq/L provide a balanced reduction of the body’s SID (acidifying) that is precisely offset by the dilution of circulating albumin and phosphate (alkalinizing). Infusion fluids with SID > 24, therefore, cause increasing alkalosis, while SID < 24 mEq/L causes acidosis.

Sugar Solutions

Infusing sugar solutions without added electrolytes has the same acid-base effect as increasing the body’s water content. SID decreases, resulting in acidosis. Both S-[Na⁺] and S-[Cl^–] are diluted, but the concentration difference between them also decreases. Since the solution does not contain any weak acid, S-[Albumin] will also decrease through dilution. This creates an alkalosis component. The net effect is acidosis.

Sodium Chloride Solution

Sodium chloride 9 mg/mL has an osmolarity of 308 mOsm/L as the content of Na⁺ and Cl^– is the same—154 mM of each. The solution’s SID is 0 mEq/L, and it contains no weak acid. For each given liter, the concentration difference between sodium and chloride in the extracellular space decreases, resulting in a lowered SID with hyperchloremic acidosis. Simultaneous dilution of weak acids (albumin and phosphate) creates an alkalinizing effect. The significant lowering of SID dominates, and the net effect is acidifying. It is justified to use NaCl if there is known hypochloremia or another alkalosis that requires treatment. Drug preparations are often made in physiological NaCl because it does not cause precipitation. Many synthetic colloid preparations are dissolved in NaCl. Only 2 liters of sodium chloride 9 mg/mL are needed in a healthy person to cause measurable acidosis with lowered BE!

Ringer Acetate

Ringer acetate was developed to have a lower, more physiological chloride content. Crystalloids with this composition are therefore called “balanced.” Some of the chlorides have been replaced with acetate ions. Acetate is an organic anion that behaves like a strong anion at physiological pH. The electrolyte content per liter is Na⁺ 130 mmol, K⁺ 4 mmol, Ca²⁺ 2 mmol, Mg²⁺ 1 mmol, Cl^– 110 mmol, and acetate^– 30 mmol. In the packaging, SID is 0 mEq/L, but metabolism of acetate to CO₂ and H₂O starts immediately upon infusion. The resulting SID is 30 mEq/L. The introduced carbon dioxide needs to be ventilated out to prevent PCO₂ from increasing. Internationally, Ringer Lactate is used, which was developed using the same principle. Lactate is metabolized mainly in the liver, while acetate is processed in several tissues. Since the solution lacks weak acid and provides SID > 24, it theoretically has an alkalinizing effect. However, the chloride content is higher than in plasma, which can cause problems for the kidneys—sometimes a transient hyperchloremic acidosis is observed. Several synthetic colloids are available with Ringer Acetate as the carrier solution.

Other Balanced Crystalloids

Plasmalyte is a crystalloid in which the electrolyte composition has been made similar to that found in plasma. The electrolyte content per liter is Na⁺ 140 mmol, K⁺ 5 mmol, Mg²⁺ 1.5 mmol, Cl^– 98 mmol, acetate^– 27 mmol, and gluconate^– 23 mmol. The resulting SID after the metabolism of acetate and gluconate is 50. This solution alkalinizes the patient by both raising SID and diluting albumin.

Albumin Solutions

In Sweden, human albumin is available in three concentrations—40, 50, and 200 g/L. Albumin is given as a volume expander or when a low albumin level needs to be raised. Normal S-albumin varies with age and is about 40 g/L. Critically and/or long-term ill patients often have markedly lower albumin concentrations, resulting in hypoalbuminemic alkalosis. Administering albumin causes acidification. Albumin 200 g/L is hyperoncotic and can mobilize fluid from the interstitium. Different manufacturers have chosen to dissolve albumin in either NaCl or balanced crystalloid. The effect is simple or combined acidosis: either SID 30 and added weak acid, or SID 0 and added weak acid.

Gelatin Solutions

A synthetic colloid where the oncotic active substance consists of succinylated gelatin. The molecule functions as a large complex weak acid with the ability to carry multiple negative charges or protons, depending on pH. From an acid-base perspective, it therefore resembles albumin. Available preparations have an electrolyte content of 154 mmol Na⁺ and 120 mmol Cl^– per liter. To achieve electrical neutrality, the gelatin contributes 34 mEq negative charge per liter of solution.

Dextrans and Hydroxyethyl Starch

These groups of molecules are themselves acid-base neutral. Both are marketed dissolved in either NaCl or balanced crystalloid solutions. The effect on SID is determined by the carrier solution’s electrolyte composition. Dextrans and hydroxyethyl starch (HES) increase oncotic pressure in plasma and can mobilize water from the interstitium. The resulting dilution of albumin causes alkalinization, which decreases over time as dextran and HES are broken down, excreted, and leave the bloodstream.

Blood Products

To prevent coagulation during the preparation of plasma and platelet concentrates, sodium citrate is used. Citrate is an organic strong anion that chelates calcium. Infused citrate, therefore, lowers SID in the same way as lactate or chloride ions. During massive transfusion, citrate levels can acutely rise and acidify the patient. However, citrate is metabolizable, and its end products are CO₂ and H₂O. As citrate levels decrease, SID normalizes, and the final result depends on how much SID-raising Na⁺ has been added during the transfusions. If the acute acidosis has been treated too aggressively with buffer solutions, the result can be a significant alkalosis after hemorrhage control.

If Ca²⁺ is a strong cation, how can it bind to citrate? The fit in the chelate binding is so good for calcium that binding actually occurs. In addition to its role in the coagulation cascade, calcium also functions as a second messenger intracellularly and can, therefore, act as a ligand for specifically adapted receptors. Similar functions are seen for Mg²⁺, but not for Na⁺, K⁺, or Cl^–.

Buffer Treatment

If you want to alkalinize a patient by adding substances, there are two approaches. Either you increase SID by administering a strong cation, or you add a weak base that balances the existing A_TOT. The accompanying anions are either weak (e.g., HCO₃^–) or organic strong anions that must be metabolized.

Sodium Bicarbonate

The preparation contains Na⁺ in a high concentration (600 mEq/L), whose charges are balanced by an equal amount of HCO₃^–. A 100 mL bottle contains 60 mmol of Na. The SID in the solution is thus 600 mEq/L. The high osmolarity means that the solution is irritating to vessels. Administered sodium effectively raises [Na⁺] in the extracellular space and increases SID, which lowers [H⁺]. Bicarbonate reacts with protons, and the system’s carbonic acid content increases. The effect is the same as a temporary increase in CO₂ production—PCO₂ rises unless ventilation is simultaneously increased. If the patient is unable to increase ventilation, we have alkalinized through SID increase and acidified through CO₂ retention. If PaCO₂ is high enough, respiratory depression can occur with respiratory collapse, worsening the acidosis. Increased PaCO₂ causes cerebral vasodilation, which can be problematic in already elevated intracranial pressure. Administered sodium increases osmolarity and volume load for the circulation as a whole. However, in a patient who needs sodium supplementation but where further chloride load is not appropriate, sodium bicarbonate is often a good alternative.

Tribonate

Tribonate has a lower Na content, balanced by both acetate (a strong anion), bicarbonate, and phosphate (weak anions). An active alkalinizing component, in addition to sodium, is trometamol (abbreviated THAM). It is a non-toxic alcohol that is metabolized to a small extent. Trometamol acts as a weak base and distributes throughout body water—even intracellularly. The effect is to partially balance the body’s A_TOT. Phosphate is added to counteract hypophosphatemia that can occur during acidosis recovery. Tribonate has less impact on PCO₂ than sodium bicarbonate, has lower sodium content, but in the long run depends on renal function for THAM elimination. The osmolality is 800 mOsm/kg and less irritating to vessels than sodium bicarbonate.

100 mL contains 19.5 mmol Na⁺, 15.5 mmol HCO₃^–, phosphate 2 mmol, acetate^– 20 mmol, and 30 mmol THAM.

Hydrochloric Acid

In the case of treatment-requiring alkalosis, physiological sodium chloride solution is the first-line choice. Administering a fluid with SID 0 is an effective way to acidify the patient. If the patient cannot tolerate the volume load this entails, chloride ions balanced with a weak cation can be given. This means HCl or NH₄Cl. Ammonium chloride is questionable for use in severe liver failure. Both solutions need to be diluted and administered only in a line that has a controlled central venous position. Preparation suggestion: HCl 5 mmol/mL = stock solution, 20 mL (100 mmol) diluted in 480 mL 5% glucose to a working solution of 500 mL with 0.2 mmol/mL. Infusion rate up to 1 mL/kg/h (0.2 mmol/kg/h) but rarely over 100 mL/h. The working solution has a SID of -200 mEq/L. Frequent blood gas control!

What Are the Effects of Disturbed [H⁺]?

High [H⁺], i.e., an acidic environment, affects most enzyme functions. One example is the coagulation system, where lowered pH slows the activation of coagulation factors and ultimately the formation of fibrin. Lowered pH (regardless of cause) is a potent vasodilator everywhere except in the pulmonary vascular bed. A locally acidic environment causes vasodilation with the goal of increasing nutritive flow. Problems arise when the pH drop is global, as it leads to general vasodilation with too low perfusion pressures and decentralized blood volume. The pulmonary vascular bed responds oppositely, with vasoconstriction in response to lowered pH. This increases PVR, which can worsen right ventricular failure and, in small children, force the circulation to revert to a fetal flow. Acidosis shifts the hemoglobin-oxygen dissociation curve to the right, meaning that oxygen is more easily unloaded in peripheral tissue. Alkalosis shifts the curve to the left, which can lead to problems with peripheral oxygenation despite good saturation.

When Should I Treat an Acid-Base Disturbance?

In our choice of fluid and electrolyte therapy, we should always consider how we can best maintain or restore homeostasis. If [H⁺], which is normally a high priority for the organism, is disturbed, it provides an indication of the degree of physiological disturbance. It is always more important to understand why pH is disturbed so that we avoid worsening the situation over hours and days than to quickly restore it. One exception is ongoing massive bleeding with clinical signs of coagulopathy. In life-threatening bleeding, the conditions for coagulation must be optimized, which, in addition to ensuring that there are coagulation factors, platelets, and a temperature above 35°C, also involves correcting acidosis so that pH at least rises above 7.20. Another exception concerning the degree of urgency applies to circulatory shock with poor response to catecholamines, where it is often justified to raise pH. Cardiac arrest is an extreme example of this. In acute hyperkalemia and acidosis, one of the treatment options is to normalize pH. The Na-K-H-ATPase functions much faster at normal pH and can then move K⁺ intracellularly.

References

• Kellum J A, Elbers P WG (editors): Stewart’s Textbook of Acid-Base.
• Fencl V, Figge J: Diagnosis of Metabolic Acid-Base Disturbances in Critically Ill Patients. Am J Respir Crit Care Med Vol 162. Pp 2246-2251, 2000.
• Ingelfinger JR: Integration of Acid–Base and Electrolyte Disorders. N Engl J Med 2014;371:1821-31.