By Per Möller, Senior Physician in Anesthesia & Intensive Care. Sahlgrenska University Hospital, Eastern Section.
Physico-chemical interpretation of the acid-base system
The Canadian science scientist Peter Stewart published his book “How to understand acid-base physiology” in 1981. In that he presented an integrated model of how electrolytes, water balance, carbon dioxide and proteins interact to determine acid-base balance. Over the next 20 years a large number of scientific articles came up which anchored the model in clinical interpretation and treatment of acid-base disorders. The model is called “the Stewart approach” or “Physico-chemical model”. It is based on physicochemical properties of different electrolytes (strong and weak ions), taking into account thermodynamic principles such as mass preservation and mathematically showing how the system is connected. The result is an extremely useful model explaining phenomena we see daily in perioperative care and intensive care. It explains why hyperchloremia makes the patient angry, why low albumin levels gives an alkaline and helps us understand the acid-base effect of different infusion solutions. The role of the kidney in acid-base regulation becomes suddenly understandable. Stewart shows how changes in bicarbonate and proton concentrations 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 the explanations that bicarbonate regulates acid-base status and instead learn to know the body’s most underestimated electrolyte – the chloride ion! Stewart’s book is a pleasure to read even today – exquisite educational and clear step-by-step analysis of a rather complex subject. It is available at www.acidbase.org
A proton (H+) is a hydrogen atom (H) which emits an electron (e–) and thus has been positively charged. The proton is about 10,000 times smaller than a water molecule. This extreme small size in combination with the charge plus one gives a huge voltage gradient. The proton becomes chemically highly reactive and affects hydrogen bonds, conformation, charge and function of proteins. However, the presence of the much larger hydroxyl ion (OH–) is not equally 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 controlled with great precision. Normal [H+] in blood is 36-43 nM, [OH–] is in μ-M levels and our “regular” electrolytes such as Na, K, Cl are counted in mM. The hydrogen ion concentration can also be expressed as negative 10 logarithm so that;
pH = -log10 [H+]
Normal pH in arterial blood is 7.35-7.45. Using the term “pH” can be smooth in some respects, but may result in lack of magnitude of the concentration change of protons that you really want to describe.
There are three independent or primary variables that determine the hydrogen ion concentration in biological systems. These are;
- Partial pressure of CO2.
- The total amount of weak acid (ATOT), where ATOT = HA + A-, that is, dissociated and non-dissociated weak acid. In plasma, all weak acids are albumin and phosphate.
- The concentration difference between strong cations and strong anions – the so-called ‘strong ion difference’ or SID. The SID is determined primarily by the balance between [Na+] and [Cl–].
CO2 is formed by metabolism and the concentration is therefore highly intracellular. At the full 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 for CO2) and reacts chemically in two ways – 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 catalyzed by the enzyme carbanhydrate so that equilibrium is reached within microseconds. The formed carbonic acid, H2CO3, can dissociate in two steps to bicarbonate ion and carbonate ion;
H2CO3 ↔ H+ + HCO3– ↔ H+ + H+ + CO32–
Carbon dioxide diffuses without problems through water and cell membranes and the mass flow moves with the partial pressure gradient. When the venous blood transports CO2, the partial pressure is lowered, which maintains diffusion from the interstitial and thus from the intracellular space. The bicarbonate ion, on the other hand, is charged and can only penetrate cell membranes through ion channels or with transport proteins.
The higher the PCO2, the higher the resulting [H+] and the lower pH.
Strong ions are completely dissociated and are not included in equilibrium reactions. Weak ions, on the other hand, alternate between dissociated and associated forms in equilibrium reactions. The equilibrium state 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 Strong Ion Difference or SID and is of fundamental importance to acid-base status. In order to maintain electron neutrality, the charge space defined by the SID will be precisely filled out by weak anions. One of these ionic layers is bicarbonate, HCO3–. Thus, the space for HCO3 is proportional to SID, but also inversely proportional to PCO2 and total weak acidity. When [HCO3–] is in equilibrium with [H+], the proton concentration will be adjusted if the bicarbonate concentration changes. However, the amount of HCO3 cannot affect SID; A weak ion cannot affect the amount or the 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, the reason for one or more of these three primary variables has changed. Changes in [H+], [HCO3–], [CO32–], [OH–] or other weak ions are always secondary to changes in any of the independent variables.
The higher the SID, the lower the resulting [H+] and the higher pH. In plasma, SID is predominantly 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 layers are monovalent, we can equally write that SID = 40 mmol/L.
Intracellularly, the entire cellular machinery is associated with resulting high concentration of proteins, many of which are weak acids. In the extracellular compartment, it is generally sparingly proteins. 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 form of acid; ATOT = HA + A–.
Albumin has 23 major amino acids that act as weak acids. This means that an albumin molecule can switch between completely dissociated form (Alb–) as it carries 23 minus amino acid residues and fully associated form (Alb-H) when all amino acids have bound each of its protons. Therefore, depending on the surrounding environment (read the pH and size of the SID), each gram of albumin will contribute a variety of minus charges. Increasing the concentration of the weak acid albumin will increase the amount of free protons and decrease the pH. Exactly how many minus charges exposed per gram of albumin are determined by the three independent variables – PCO2, SID and ATOT. Decreasing the albumin concentration means a lack of weak acid and thus an alkalinizing process. Phosphate, usually in the concentration of 1 mM, is also a weak acid and is in equilibrium between dissociated and associated form just like albumin, solid with its own dissociation constant.
The body’s most common substance, water, spontaneously dissociates as follows;
H2O ↔ H+ + OH–. The reaction is temperature dependent and extremely far driven to the left. The requirement for electron neutrality in combination with the three variables PCO2, SID and ATOT also dictates the equilibrium of the water dissociation.
The body controls PCO2 through ventilation. The higher the PCO2, the more carbonic acid and, in the long run, more hydrogen ions. The kidneys control the SID by controlling [Cl–] in relation to [Na+]. An increase in SID, (for example, by reducing chloride ion concentration) alkalinizes and a decrease in SID (e.g., by increased chloride or lactate concentration) acidity. 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 certain acid-base effect but for controlling colloid osmotic pressure, acting carrier protein for hormones, and more. However, a change in albumin concentration, for whatever reason, will have an effect on the acid-base balance. A decreased albumin concentration means a smaller total of weak acid, ultimately leading to a lower concentration of free hydrogen ions. Hypoalbuminemia thus leads to an alkalinizing process.
To compensate for an acidosis, the kidneys try to increase SID in the bloodstream. This occurs by secreting more chloride ions than sodium ions. Since electron neutrality has to be maintained in individual kidney tubular cells as well as in urine and blood, each negatively charged chloride ion will be secreted together with a weak cation. Had the chloride ion been secreted together with a strong cation (like Na+ or K+), the SID in the body would remain unchanged and did not cause any correction of the acidosis. The body may choose to purge Cl– with H+ to achieve this, or together with NH4+ if there is a need to get rid of nitrogen. Thus, the purpose of renal ammonium synthesis is not to “buffer” the body without raising the body’s SID and at the same time obtaining a negative nitrogen balance. Chloride secreted together with H+ alkalinizes the patient by raising the primary variable SID – not by shedding the body with a proton. Body water, however, still means an inexhaustible proton source through dissociation. The proton concentration is instead determined by the three primary variables. An example of this is that the body can lower S- [Cl–] with 5 mM. If simplified, we think that the change has only taken place in plasma (in fact, it has affected large parts of the extracellular compartment) means that a 4 L plasma volume 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 body SID results in decreased [H+] on the order of nM. Thus, proton concentration is not determined by counting how many protons moved in or out in a compartment, but how the resulting independent variables dictate the conditions for new equilibrium positions in proton transfer reactions. Even if we remove 20 mM H+, some of these will be replaced by, among other things, adjusting the water dissociation.
A well-functioning kidney can effectively reduce S – [Cl–]. A patient with acidosis who does not develop a compensatory hypochloremia should be suspected to have kidneys that are not functioning well. If we give chloride-rich fluids to a patient who is already acidotic, 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. The renal perfusion itself is also affected by chloride concentration and hyperchloremia, even at maintaining the pH, lowers renal perfusion through vascular constriction. The result is reduced diuresis and increased release of inflammatory cytokines.
Hyperventilation secondary to acidemia, hypoxia or pain leads to decreased PCO2. The fact that [HCO3–] and [H+] also decrease are physico-chemical consequences of this. In chronic respiratory failure with acidosis due to CO2 purge, the kidney, as a compensatory measure, will excrete more chloride ions than sodium ions, thus increasing the SID in the bloodstream. An increased SID means greater space for weak anions, including [HCO3–] whose equilibrium with protons will lower [H+]. The increase in SID is physiological but the resulting bicarbonate increase is physicochemical.
The acid-base status is thus determined by the interaction between three primary variables – PCO2, SID and ATOT. Traditionally, we have analyzed patients’ acid-base status based on a division into two categories of regulation and disorder; respiratory and “metabolic”. The result is, among other things, problems with (conceptual, analytical and educational) dealing with parallel metabolic disorders. The classical acid-base analysis has no good tools to quantify the amount of an acidosis that is a hyperchloremia and how much it is counteracted by a cohort hypophosphataemia or low albumin value. The term “metabolism” as opposed to respiratory is also misleading as it equates to disorders related to lactate and keton bodies production (true metabolism) with pure electrolyte imbalances, which are often the result of fluid therapy (iatrogen) and electrolyte and fluid shifts.
Base excess (BE) can reveal if there is a non-respiratory disorder or not – as well as quantify how large it is. BE is the answer to the question; “How much strong acid or strong base do I need to supply this blood sample for the pH to return to 7.40 if we assume that PCO2, temperature and Hgb were normal?”. Normal value 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 be corrected (one minus in front of BE thus means “lack of base surplus …”). 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 sum effect of disruptions in the two variables SID and ATOT. Here, an analysis tool in two dimensions meets a reality in 3D. If a patient has a 5 mM lactate increase, with normal S- [Na+] and S- [Cl–], this means that SID has decreased 5 mEq/L from the initial state; The SID at start was 140-100 = 40 and is after the lactate increase 140-100-5 = 35 mEq/L. If nothing has happened with S-[Phosphate] or S-[Albumin], the ATOT variable is still normal. In this mode, resulting BE will be -5 mEq/L.
δBE = δSID about δ [Albumin] = 0.
One may also think that lactate rises to 5mM in a patient with a hypochloremia of 95 (if the normal value of the current measurement method is 100). The SID has then decreased by 5 units due to the lactate increase while the chloride deficiency of 5 mM increases SID by as much. SID is still normal and BE is 0. An acidifying decrease in SID, for example by hyperchloremia, can also coexist with an alkaline hypoalbuminemia that completely “disassembles” and leaves BE normally; S- [Cl–] increased with 5 mM and S- [Albumin] decreased to 22 g/L.
If you are in a hurry, see “Simplified SID Decision”! 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 incoming electrolytes). Since electron neutrality prevails, the sum of all positive charges (strong as weak) is exactly equal to the sum of all negative charges (strong and weak);
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–] + [CO32–]) = 0
The concentration of charge (mEq/L) from a divalent ion becomes 2 x its concentration in mole/L. [NH4+], [OH–] and [CO32–] are counted in μM and [H+] in nM – other ionic layers in mM. If we briefly ignore ions in ΔM concentration we can write;
([Na+] + [K+] + [Ca 2+] + [Mg 2+]) – ([Cl–] + [lactate–] + [XA–]) – ([HCO3–] + [Alb–] + [Phosphate]) = 0 or
SID = [HCO3–] + [Alb–] + [Phosphate]
We then see that [HCO3–] is proportional to SID. This means that if the SID increases or decreases, [HCO3–] will move in the same direction.
The actual charge difference between known strong cations and strong anions can be calculated as
SIDa = ([Na+] + [K+] + [Ca2+] + [Mg2+]) – ([Cl–] + [lactate]). SIDa is then “apparent”.
SIDa defines the space that the weak anions can fill out. Another way to designate this is to figure out SIDe where “e” stands for “effective”. We can then estimate the size of the gap by calculating the amount of the gap that fills it. The three most common weak anions are used to calculate SIDe;
SIDe = [HCO3–] + [Alb–] + [Phosphate–]
The bicarbonate concentration is derived from the blood gas analysis, but how many minuses albumin and phosphate contribute per liter, we need to calculate. The value of albumin (g/L) and phosphate (mM) is analyzed by the chemistry lab. There are accepted equations which, using experimentally determined dissociation constants and prevailing pH, determine the charge contribution from these two weak anions;
[Alb–] = [Alb] × (0.123 × pH-0.631) mEq/L
[Phosphate–] = [Phosphate] × (0.309 × pH-0.469) mEq/L
The difference between SIDa and SIDe is the remaining, for the analysis so far “unknown”, negative charges – [XA–];
SIDa – SIDe = [XA–]
[XA–] is the concentration of unknown anions. Examples of [XA–] are strong organic anions which are intermediate metabolites in the citric acid cycle (e.g. oxalate) or toxic strong anions such as salicylate ion in salicylate intoxication or formate – the deprotonated form of formic acid formed in methanol metabolism.
SIDa – SIDe = [XA–] = SIG
Another term is Strong Ion Gap, SIG. The normal value for [XA–] varies slightly depending on the analytical methods for the electrolytes included in the calculation, but is 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 disorders it is valuable to calculate [XA–].
Counting on [XA–] takes undoubtedly some time and assumes we determined albumin, phosphate and magnesium. It may be justified to calculate for a patient with unclear acidosis not completely explained by lactate or relative hyperchloremia. Acute renal failure with acidosis often depends on a combination of dilution with hyponatraemia and accumulation of various organic anions including phosphate (previously referred to as “non-volatile acids”). Following [XA–] can be a way to evaluate if inserted treatment works prior to the possible start of CRRT. A very low, or even negative value of [XA–] indicates the presence of one or more unknown strong cations. There may be lithium toxicity for instance. Calculating [XA–] is also interesting if you track unknown substances using estimated and measured osmolarity. The principle is based on comparing the difference between freezing point reduction osmolarity and the osmolarity that can be calculated by adding known electrolytes as well as glucose and urea. An osmolar “gap” indicates that there is one or more other substances in an increased amount. These can be toxic alcohols such as methanol or ethylene glycole, for instance.
Evaluate S-[Na+], S-[Cl–] and S-[Lactate–]. Deviates one or more of the variables from the respective mean – what do you estimate that the resulting SID will be? Normal, lowered or high?
How much does the current value of S- [Na+] differ from normal mean? How does this change affect the SID?
How much does the current value of S- [Cl+] differ from normal mean? How does this change affect the SID?
Are there different concentrations of K + and lactate – and how are these SIDs affected?
Example: S-[Na+] is 134, S-[Cl–] is 108 and S-[lactate–] 3 mM.
The normal value for S-[Na+] is 137-145, mean 141 mM and the current value has thus lowered SID by 141-134 = 7 mEq.
The normal value for S-[Cl–] is 100-110, average 105 mM and currently has lowered SID by 108-105 = 3 mEq/L.
The normal value for S-[lactate] is 0.5-1.7, average 1.1 mM and the current value has thus lowered SID by 3-1.1 = 1.9 mEq/L.
The sum of the changes of SID is ΔSID = -7-3-1.9 = -11.9 mEq/L.
Does your estimated ΔSID with BE match? If ΔSID is more negative than BE, there is a simultaneous lack of albumin. If BE is more negative than ΔSID, you need to calculate [XA–] via SIDe and SIDa as it indicates the presence of other strong anions.
Increased water content dilutes all the electrolytes and weak acids. Even the difference between strong cations and strong anions is diluted. Water surplus therefore leads to reduced SID and acidosis. The dilution of albumin produces a parallel alkalinization, but it is overshadowed by the SID cut 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.
A dehydration gives increased concentrations with increased SID and alkalinization in parallel with an increase in albumin concentration which gives a (mild) acidification. In clinically relevant dehydration, there is often a concurrent hypovolemia that can lead to hypoperfusion and lactate production.
Hyponatremia – water surplus – reduces SID and acidosis.
Hypernatremia – Water shortage – Increases SID and alkalinization.
A change in water content gives proportional changes in both [Na+] and [Cl–]. In order to evaluate other disorders, dilution or digestion has taken place, calculate a corrected chloride concentration (which answers the question “what had [Cl–] been about [Na+] where normal?”).
Such a corrected chloride ion concentration can be calculated as:
[Cl–] c = [Cl–] measured x [Na+] normal/[Na+] measured
Example: S-[Na+] = 122 mM and S- [Cl–] = 91 mM. [Cl–] c = 91 x 141/122 = 105 mM.
The corrected chloride ion concentration in this case is quite normal and follows the dilution of sodium. The difference between S-[Na+] and S-[Cl–] has fallen from 141-105 = 36 at baseline to 122-91 = 31 after dilution. SID has thus decreased by 5 mEq/L. At the same time, S-[Alb–] has also decreased, which partly compensates for the acidifying effect of the SID reduction, but the net effect becomes an acidosis, which will also be seen on BE.
Hypochloremia – A reduced chloride value increases the SID and alkalines the body. Is seen physiologically as a renal compensation of acidosis, such as during chronic respiratory failure (COPD). It may occur in chloride loss through gastric tube, stoma or intestines. What makes the stomach content acidic is that the parietal cells in the stomach secrete the Cl– into lumen (together with H+ to maintain electron neutrality) and create a very low SID in the gastric fluid. Proton pump inhibitors slow down this process. Pancreatic secretion has a high Na content and therefore high SID. The mixture of gastric and pancreatic secretions in the duodenum usually contains normal SID and most of the salts are then reabsorbed into the small intestine. In hypochloremia, it becomes important to evaluate the indication for the gastric tube – can it be removed? In case of high stoma flow there is a loss of water and salts. It is often evident what is lost to the greatest extent (Na+ or Cl–) when looking at the blood gas analysis. In case of uncertainty, the concentrations of Na+ and Cl– in stoma fluids 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 is true for thiazide diuretics. Acetazolamide (Diamox) is a non-competitive carbanhydrate inhibitor that causes increased secretion of Na+ relative to Cl–. The result is lowered SID in plasma (and alkaline urine when U-[Cl-] decreases). Acetazolamide may be relevant to the continued need for diuretic treatment and troublesome alkalosis.
Hyperchloricemia – is seen as physiological compensation of chronic hyperventilation, which in practice is only seen when staying at high altitude. The most common cause of hyperchloremia is infusion of chloride-rich fluids (SID <24 in infusion fluids). If normal S-[Cl-] is 100 mM, all infusions with higher chloride concentration will increase the level of chloride in the body. The fact that we do not always see this is because the patients’ kidneys usually manage to secrete the unwanted chloride load (see also section on infusion fluids). If high S-[Cl-] occurs despite the use of balanced fluids, it is reasonable to suspect beginning kidney failure or at least one non optimal optimum environment for the kidneys. Peroperatively, it could involve hidden hypovolemia, poor renal arterial perfusion or impaired venous return (high pressure at laparoscopy).
Potassium is predominantly intracellular. Energy-intensive pumps maintain the gradient by pumping potassium into the cells and sodium into the extracellular space. Potassium is a strong cation and helps to create a normal SID. Increasing S-[K+] increases SID, which thus alkalinizes the extracellular space. For acidosis, for whatever reason, the function of the Na-K-H-ATPase fails to cause S-[K+] to rise. Low potassium value reduces SID and contributes to acidosis. In case of potassium substitution, it is important to assess the chloride levels at the same time in order to choose the right potassium preparation. The usual KCl preparation is cheapest but produces a pronounced chloride load, especially as most of the potassium is moved intracellularly while the chloride ions remain in the extracellular compartment. The same applies to prolonged-release tablets Kaleoride where active substance is potassium chloride. Keep in mind that potassium-rich liquid must be given via a central venous catheter as it is highly vascular-resistant and also with frequent controls of S-[K+] to avoid risk of lethal arrhythmias!
In the case of acidosis, hyperchloremia or renal failure, it may be better to substitute potassium in the form of Addex potassium. There, the chloride ions have been replaced with phosphate and acetate. Phosphate is a weak acid and will increase ATOT (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. Oral solution of potassium normally consists of potassium citrate. Citrate is metabolized just like acetate.
Lactate is an organic strong anion. This means that at pH compatible with life, lactate is basically completely deprotonated. An increase of lactate with, for example, 2 mM results in a decrease of SID with 2 mEq/L and thus a turn down of BE with -2 mEq/L. Mostly, lactate increase is seen when tissue metabolism is forced into anaerobic metabolism. This can happen in global hypoxia, but perhaps more often in regional or systemic hypoperfusion as in hypovolemia. If lactate escalation is seen at concomitant infection – start sepsis treatment according to target-related therapy (EGDT). Look for ischemia! Is there any vascular disorder in the abdomen? Liver failure with reduced ability to metabolize lactate produced outside the body? Seizures? Metformin? Intoxication? Cyanide? CO intoxication?
Sometimes moderately elevated lactate values reflects severe catecholamine boost (endogenous and/or exogenous) are explained as physical activity, beta-agonist therapy, norepinephrine or adrenaline administration – but this can be seen as exclusionary diagnoses. Lactate is metabolized in the liver and is an energy substrate – when oxygen is accessed, the functioning enzyme is metabolized to CO2 and water.
It is impossible to predict the effect of infusing a particular fluid into a patient based on the specified pH of the product. On the other hand, if you analyze content and impact on the three independent variables – PCO2, SID and ATOT, it becomes easy. Infusion fluids stored in non-gas-tight packages equalize the gas content with ambient atmosphere. This means that they have a negligible content of CO2 and infusion thus means a dilution of the body’s CO2 – but the clinical effect is non-existent. However, the electrolyte composition and weak acid content of the infusion fluid is important.
Infusion fluids with an SID lower than the SID of the extracellular compartment will lower SID in plasma and cause acidosis. If the infusion fluid contains no weak acid, the ATOT in plasma will decrease and contribute to an alkaline. Attempts show that infusion solutions with weak acid and SID of 24 mEq/L provide a balanced decrease in body SID (acidification) just offset by dilution of circulating albumin and phosphate (alkalinizing). Infusion fluid with SID > 24 therefore gives an increasing alkaline and SID <24 mEq/L an acidosis.
Infusing sugar containing solutions without electrolyte additive gives the same acid-base effect as when increasing the body’s water content. SID is lowered which gives an acidosis. S- [Na+] and S-[Cl–] are both diluted, but the concentration difference between them also decreases. Since the added solution does not contain any weak acid, S-[Albumin] will also be lowered by dilution. This gives a component of alkali. The sum effect becomes an acidosis.
Sodium chloride 9 mg/mL has an osmolarity of 308 mOsm/L when the content of Na+ and Cl– is equal to – 154 mM of each. SID in the solution is 0 mEq/L and contains no weak acid. For each given liter, the concentration difference between sodium and chloride in the extracellular compartment decreases and the result is lowered SID with hyperchloric acidosis. Simultaneous dilution of weak acids (albumin and phosphate) gives an alkalinizing effect. The sharp decrease of SID dominates and the net effect becomes acidifying. It is motivated to use NaCl if you have a known hypochloremia or other alkalis that require treatment. Drug preparations are often made in physiological NaCl as there is no risk of precipitation. Many preparations with synthetic colloids are dissolved in NaCl. It is sufficient with two liters of Sodium chloride 9 mg/mL for a healthy person to cause a measurable acidosis with reduced Base Excess!
Ringer Acetate is designed to have a lower, more physiological chloride content. Crystalloids with this composition are therefore called ‘balanced’. One has replaced a portion of the chlorides with acetates. Acetate is an organic anion that at physiological pH behaves like a strong anion. 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 package, SID is 0 mEq/L but immediately upon infusion, the metabolism of acetate into CO2 and H2O starts. Resulting SID becomes 30 mEq/L. The amount of CO2 added needs to be eliminated by ventilation so as not to increase PCO2. Internationally, Ringer-Lactate is produced according to the same principle. Lactate is metabolized mostly in the liver while acetate is converted into several tissues. Since the solution is completely lacking in acid and gives SID > 24, it theoretically has an alkalinizing effect. However, the chloride content is higher than in plasma which can cause renal problems – sometimes transient hyperchloric acidosis is seen. Several synthetic colloids are available with Ringer-Acetate as a carrier solution.
Plasmalyte is a crystalloid solution where one chose to make the electrolyte composition similar to that found in plasma. Electrolyte contents per liter will then be; Na+ 140 mmol, K+ 5 mmol, Mg2+ 1.5 mmol, Cl– 98 mmol, Acetate– 27 mmol, Gluconate– 23 mmol. Resulting SID after metabolism of acetate and gluconate becomes 50. This solution alkalinizes the patient by both raising SID and dilute albumin.
In Sweden, human albumin is available in three concentrations – 40, 50 and 200 g/L. Albumin is given as volume expander or when you want to raise a low albumin value. Normally, the S-Albumin varies with age and is approximately 40 g/L. Critically and/or long-term ill patients often have significantly lower albumin concentration and hence hypoalbuminemic alkalosis. Adding albumin involves acidification. Albumin 200 g/L is hypertonic and has the potential to mobilize fluid from the interstitial. Different manufacturers have chosen to solve the albumin in either Sodium Chloride or balanced crystalloid. The effect becomes simple or combined acidosis; either SID 30 and added weak acid or SID 0 and added weak acid.
A synthetic colloid in which the oncotically active substance is succinylated gelatine. The molecule acts as a large complex weak acid capable of carrying multiple minus charges or protons, depending on the pH. From an acid-base perspective, it is therefore similar to albumin. Available preparations have an electrolyte content of 154 mmol Na+ and 120 mmol Cl– per liter. Therefore, for electron neutrality to be achieved, the gelatin produces 34 mEq of negative charges per liter of solution.
These groups of molecules are themselves acid-base neutral. Both are marketed in either Sodium Chloride or balanced crystalloid solutions. The effect on SID is determined by the carrier solution’s electrolyte composition. Dextranes and hydroxyethyl starch (HES) increase oncotic pressure in plasma and can mobilize water from interference. Resulting dilution of albumin means an alkalinization that decreases over time as dextran and HES breaks down, is secreted and leaves the bloodstream.
To prevent coagulation in the preparation of plasma and thrombocytes, sodium citrate is used. Citrate is an organic strong anion that chelates Ca2+. The added citrate therefore reduces SID in the same way as lactate or chloride ions. In massive transfusion, citrate levels can become acute and acidify the patient. Citrate, however, is metabolizable and the final products are CO2 and H2O. With decreasing citrate levels, the SID is normalized and the final result is determined by how much SID-increasing Na+ applied during the transfusions. If you treat the acute acidosis aggressively with buffer solutions, the result may be a solid alkaline after hemostasis.
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 acts as a second messenger intracellularly and can thus act as a ligand to specifically adapted receptors. Similar functions are seen for Mg2+ but not for Na+, K+ or Cl–.
If you want to alkalinize a patient by adding substances, there are two approaches. Either, you increase SID by providing a strong cation or adding a weak base that balances existing ATOT. The accompanying anions are either weak (e.g., HCO3–) or organic strong anions which must be metabolized.
The preparation contains Na+ at high concentration (600 mEq/L) whose charges are balanced by equal amount of HCO3. A 100 mL bottle contains 60 mmol Na. SID in solution is 600 mEq/L. The high osmolarity means that the solution is irritating to vessels. Added sodium effectively increases [Na+] in the extracellular space and increases SID which reduces [H+]. Bicarbonate reacts with protons and the system’s carbonic content increases. The effect will be the same as a temporary increase in CO2 production – PCO2 increases if ventilation is not increased simultaneously. If the patient is unable to increase his recovery, we have alkalinized by SID increase and acidified by CO2 retention. If PaCO2 is high enough, breathing depression may occur with respiratory collapse with aggravated acidosis. Increased PaCO2 causes cerebral vascular dilation, which may be problematic at already elevated intracranial pressure. Added sodium implies increased osmolarity and volume load for the circulation as a whole. However, in a patient who is in need of sodium supply but where there is no additional chloride charge, sodium bicarbonate can often be a good option.
Tribonate has a lower sodium content that is balanced by both acetate (strong anion), bicarbonate and phosphate (weak anions). An active alkalinizing component in addition to sodium is trometamol (shortened THAM). It is a non-toxic alcohol that is metabolized to a small extent. Trometamol acts as a weak base and distributes throughout the body water – even intracellularly. The effect is to partially balance the body’s ATOT. The phosphate is added to counteract hypophosphataemia that may occur during acidic acidosis. Tribonate has less impact on PCO2 than sodium bicarbonate, has lower sodium content but is in the long run dependent on renal function to eliminate THAM. Osmolality is 800 mOsm / kg and less vascular resistance than sodium bicarbonate.
100 mL contains 19.5 mmol Na+, 15.5 mmol HCO3, phosphate 2 mmol, acetate– 20 mmol and 30 mmol THAM.
In treatment-requiring metabolic alkalosis, physiological sodium chloride solution is the first choice of fluid to administer. Giving a fluid with SID 0 is an effective way to acidify the patient. If the patient does not tolerate the volume load this implies, chloride ions can be balanced with a weak cation. It means HCl or NH4Cl. Ammonium chloride is dubious for use in severe liver failure. Both solutions need to be diluted and given only in vascular access that has a verified centralized position. Proposal for solution; HCl 5 mmol/mL = stock solution, 20 mL (100 mmol) diluted in 480 mL of 5% Glucose to use solution 500 mL with 0.2 mmol/mL. Infusion rate up to 1 mL/kg/h (0.2 mmol/kg/h) but rarely above 100 mL/h. The usage solution has a SID of -200 mEq/L. Frequent blood gas analysis is strongly recommended!
High [H+], that is, an acidotic environment, affects most enzyme functions. An example is the coagulation system where reduced pH causes activation of coagulation factors and finally formation of fibrin much more slowly. Lowered pH (for whatever reason) is a strong vasodilatory factor everywhere except in the lung vessel bed. Locally acidotic environment provides vasodilatation with the aim of increasing nutritive flow. Problems arise if the pH decrease is global as it leads to general vasodilation with too low perfusion pressure and decentralized blood volume. The lung vessel bed reacts with vasoconstriction at reduced pH. It provides increased PVR that can exacerbate a right ventricle failure and in small children force the circulation to regain a fetal flow. Acidosis displaces the hemoglobin oxygen dissociation curve to the right, which means that oxygen is more readily unloaded into peripheral tissues. Alkalosis displaces the curve to the left, which can lead to problems with peripheral oxygenation despite good saturation.
In our choice of fluid and electrolytic therapy, we should always think about how we best maintain or restore homeostasis. If [H+], which is usually high priority for the organism, is disrupted, it gives an indication of the degree of physiological disorder. It is always important to understand why the pH is disturbed so that over hours and days we avoid deteriorating the situation, rather than quickly restoring it. One exception is ongoing major 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 temperatures above 35 degrees also include making assuring to correct an acidosis so that the pH is at least 7.20. Another exception to the rate of urgency is the circulatory shock with poor effect of catecholamines, where it is often justified to raise the pH. Cardiac arrest is an extreme case of this. In acute hyperkalaemia and acidosis, one of the treatment options is to normalize the pH. Na-K-H-ATPas works much faster at normal pH and can then move K+ intracellularly.
Per Werner Möller. M.D., Specialist in Anesthesia and Intensive Care, DESA.
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