Effect of Intravenously Administered Crystalloid Solutions on Acid‐Base Balance in Domestic Animals

Abstract

Intravenous fluid therapy can alter plasma acid‐base balance. The Stewart approach to acid‐base balance is uniquely suited to identify and quantify the effects of the cationic and anionic constituents of crystalloid solutions on plasma pH. The plasma strong ion difference (SID) and weak acid concentrations are similar to those of the administered fluid, more so at higher administration rates and with larger volumes. A crystalloid's in vivo effects on plasma pH are described by 3 general rules: SID > [${\text{HCO}}_3^{-}$] increases plasma pH (alkalosis); SID < [${\text{HCO}}_3^{-}$] decreases plasma pH (alkalosis); and SID = [${\text{HCO}}_3^{-}$] yields no change in plasma pH. The in vitro pH of commercially prepared crystalloid solutions has little to no effect on plasma pH because of their low titratable acidity. Appreciation of IV fluid composition and an understanding of basic physicochemical principles provide therapeutically valuable insights about how and why fluid therapy can produce and correct alterations of plasma acid‐base equilibrium. The ideal balanced crystalloid should (1) contain species‐specific concentrations of key electrolytes (Na⁺, Cl⁻, K⁺, Ca⁺⁺, Mg⁺⁺), particularly Na⁺ and Cl⁻; (2) maintain or normalize acid‐base balance (provide an appropriate SID); and (3) be isosmotic and isotonic (not induce inappropriate fluid shifts) with normal plasma.

Abbreviations

AG

anion gap

Atot

nonvolatile weak acids

NHE1

Na⁺/H⁺ exchanger

PCO₂

partial pressure of carbon dioxide

pKa

pH at which the acid and conjugate base are equal

SIDa

apparent SID

SIDe

effective SID

SID_if

crystalloid in vivo SID

SID

strong ion difference

SIG

strong ion gap

THAM

trishydroxymethyl aminomethane

UA

unmeasured anion

Intravenous salt solutions (“crystalloids”) are routinely administered to animals and are considered an established standard of care in many veterinary practices. They are administered to maintain or restore vascular volume, electrolyte concentrations, and acid‐base balance and are utilized as diluents for large (>30 kD) molecular weight insoluble molecules to produce a colloidal suspension (“colloids”) that helps preserve plasma colloid osmotic pressure.1 Fluids are drugs, and although often considered to produce beneficial effects, they should only be administered after thorough consideration of the indication for which they are prescribed.2, 3 Reasons for administering IV fluids include the prevention or treatment of dehydration, replacement of ongoing fluid losses, correction of electrolyte imbalances, restoration of tissue perfusion, treatment of hypotension, and correction of acid‐base abnormalities.1, 4 Although the beneficial volume effects of IV fluids have been appreciated for more than 100 years, their impact on the extracellular and intracellular concentrations of electrolytes, acid‐base balance, and survival is only beginning to be appreciated.5, 6, 7, 8, 9, 10

Improvements in hydration status and hemodynamic parameters (macrocirculatory features such as arterial blood pressure, blood flow) are frequently the primary goals of IV fluid therapy. Macrocirculatory improvements, however, do not always insure an improvement in capillary perfusion (microcirculatory effect), cellular homeostasis, or survival.11, 12, 13 The maintenance of normal blood hydrogen ion (H⁺) activity is a key factor linked to survival, and its regulation is one of the most tightly controlled homeostatic processes in the body.14, 15, 16, 17, 18 Use of the term hydrogen ion concentration ([H⁺]), although commonplace in the acid‐base literature, is misleading and should be discouraged because it is hydrogen ion activity (pH) that is measured by pH electrodes. Hydrogen ions are considerably smaller than other chemicals in aqueous solutions but have the highest charge density of any electrolyte in plasma.19 Hydrogen ions (protons) are chemically active because of the electromotive force (activity) they produce. Furthermore, hydrogen ion concentration cannot be accurately determined in vivo because it is calculated assuming an activity coefficient of 1, but its activity coefficient in plasma is uncertain. Comparatively small changes in H⁺ activity (pH) can produce substantial and potentially life‐threatening alterations in cellular metabolism (Fig 1).20, 21 Acidemia (decreased blood pH) and alkalemia (increased blood pH) directly impact morbidity and mortality and are decidedly influenced by the administration of IV fluids.21, 22, 23, 24 This review will summarize the various methods used to identify and describe acid‐base abnormalities, provide a modern definition for what is considered to be a balanced crystalloid solution, and explain how IV fluid therapy can alter acid‐base balance. The use of different IV fluids for the treatment of metabolic acidosis will be reviewed, and the influence of commercially prepared IV fluid solutions on acid‐base balance will be discussed.

Figure 1.

Relationship between approximate pH values and mortality in 754 critically ill human patients.21

Diagnosing and Describing Acid‐Base Disorders

Regrettably, conflicting opinions, ambiguous terminology, computational complexity, and, until recently, the absence of simplified and versatile monitoring equipment have hindered the assessment and diagnosis of acid‐base abnormalities in veterinary clinical practice.25 The various approaches employed for the diagnosis and description of acid‐base abnormalities are based upon changes in blood pH (negative base 10 logarithm of activity) or the principal analytes responsible for its alteration (Fig 2).19, 25 They include (1) the Henderson‐Hasselbalch approach; (2) the anion gap (AG) approach; (3) the Astrup and Siggaard‐Andersen (base excess [BE]) approach; and (4) the physiochemical or Stewart approach.25, 26, 27, 28, 29, 30, 31 The Henderson‐Hasselbalch approach is based on the relationship among pH, PCO₂, and ${\text{HCO}}_3^{-}$ (pH = pK + log [${\text{HCO}}_3^{-}$]/.0308 × PCO₂, where PCO₂ is measured in mmHg at 37°C and is the basis of [${\text{HCO}}_3^{-}$] determination by blood gas analyzers. The anion gap (AG) approach attempts to identify changes in acid‐base balance by determining the difference between the principal cations and anions (AG = ([Na⁺] + [K⁺]) − ([Cl⁻] + [${\text{HCO}}_3^{-}$])).19, 26 An increase in the AG is considered indicative of an increase in fixed (nonvolatile) acid and metabolic (nonrespiratory) acidosis. Increased AG acidosis (e.g, lactic or ketoacidosis) is characterized by decreased plasma bicarbonate concentration without hyperchloremia.27 Increased plasma chloride concentration (i.e, hyperchloremia) is accompanied by a decrease in plasma [${\text{HCO}}_3^{-}$] with no increase in the AG, a condition referred to as “normal AG acidosis” or “hyperchloremic acidosis”.27, 28, 29 Discontent with the Henderson‐Hasselbalch approach prompted Singer and Hastings to introduce the BE concept and propose that plasma pH be determined by 2 independent factors, PCO₂ and net strong (highly dissociable) ion charge, equivalent to the SID.32 Base excess is comparable to the difference between an animal's SID and the normal SID for that species, assuming a fixed and normal plasma protein concentration.33 The Astrup‐Siggaard‐Andersen approach utilizes the PCO₂ and BE.30 The BE is defined as the concentration of titratable acid or alkali required to return the in vitro pH of whole blood to 7.4 at 37°C when the PCO₂ is equal to 40 mmHg. Base excess incorporates the buffering capacity of hemoglobin and was the first measure of metabolic acid‐base status independent of PCO₂.29 Base excess is calculated by most acid‐base analyzers or can be derived from the Siggaard‐Andersen nomogram.30 The physiochemical or Stewart approach posits that [H⁺] and [${\text{HCO}}_3^{-}$] are dependent variables and categorizes acid‐base disturbances based upon changes in the 3 independent factors: PCO₂, SID, and A_tot (Fig 3).15, 31, 34 Bicarbonate is a dependent variable and does not determine hydrogen ion activity; both [${\text{HCO}}_3^{-}$] and hydrogen ion activity are determined by PCO₂, SID, and A_tot. The Stewart approach does not account for the buffering capacity of hemoglobin and is considered “quantitatively cumbersome” and to have “no advantage for diagnostic or prognostic purposes” by some.35 These opinions aside, the Stewart approach is utilized hereafter because (1) hydrogen ion activity and [${\text{HCO}}_3^{-}$] are dependent not independent variables; (2) it incorporates the influence of strong anions and cations on acid‐base balance (anion gap approach); and (3) it provides a more clinically intuitive, descriptive, and quantitative understanding of how variations in plasma constituents and the administration of crystalloid solutions can alter acid‐base balance (Table 1).15, 31, 33, 34, 35, 36, 37, 38, 39

Figure 2.

The different approaches used to diagnose and describe acid‐base disorders can be categorized as descriptive, semiquantitative, and quantitative. The physicochemical (Stewart) approach can be used in all 3 capacities. A_tot = total weak acids; PCO ₂ = partial pressure of carbon dioxide; SBE = standard base excess; SID = strong ion difference; SIG = strong ion gap.26

Figure 3.

Principal independent factors that determine pH.

Table 1.

Stewart approach to acid‐base balance

Independent Variable	Change	Acid‐base Effect	pH
PCO2 mmHg	↑	Respiratory acidosis	↓
	↓	Respiratory alkalosis	↑
SID mEq/L	↑	Metabolic alkalosis	↑
	↓	Metabolic acidosis	↓
Atot mmol/L	↑	Metabolic acidosis	↓
	↓	Metabolic alkalosis	↑

↑ = increase; ↓ = decrease.

Physicochemical or Stewart Approach to Acid‐base Abnormalities

Strong ions behave as though nearly completely dissociated at physiologic pH, and the SID characterizes the net charge that must be balanced by all of the nonvolatile weak acids (A_tot, primarily albumin, and phosphate) in order to maintain electrical neutrality.31 The plasma SID is typically calculated as the difference between all measurable strong cations ([Na⁺] + [K⁺] + [Ca⁺⁺] + [Mg⁺⁺]) and anions ([Cl⁻] + [other strong anions, e.g, lactate]) and is frequently referred to as the apparent SID (SID_a) because this value is representative of the majority of ions found in plasma. The SID_a is normally positive (+40–45 mEq/L), and this net charge is balanced by the negative charge of the fixed weak anion components of phosphate and proteins (A_tot), and bicarbonate.40, 41, 42 As stated earlier, the sum of the nonvolatile weak acids, A_tot, is an independent variable that impacts hydrogen ion activity and therefore pH (Fig 3). An increase in the concentration of lactate and unmeasured anions (other organic acids) from any cause (e.g, hemorrhage, trauma, hypoxia) will increase hydrogen ion activity creating metabolic acidosis.43, 44, 45 Importantly, fluid selection and infusion strategies are key factors that can influence the production of unmeasured anions (UA).46 The [UA] can be derived by subtracting the effective SID (SID_e, the sum of the negatively charged substances) from SID_a, thereby defining the strong ion gap (SIG, SIG = SID_a–SID_e = UA; Fig 4).47 Delayed metabolism or elimination of any UA⁻ decreases SID_e, thereby increasing the SIG and contributing to metabolic acidosis.47 Notably, the SID_a minus SID_e (SIG) is equal to or near zero when plasma pH is 7.4 and PCO₂ is 40 mmHg. The SID_a and SIG have been used clinically in both humans and animals to identify acid‐base imbalances and predicting mortality, respectively.47, 48, 49, 50, 51, 52, 53, 54, 55 Current evidence, however, suggests that directly measured serial arterial lactate concentrations may provide as good or better prognostic ability than SIG for discriminating between survivors and nonsurvivors.53, 54 Simplified versions of the Stewart approach have substantially improved the recognition and contribution of electrolyte abnormalities (alterations in SID) in maintaining acid‐base balance and highlight the importance of fluid selection as a potential therapy.34, 37, 38, 39, 52, 53, 54, 55, 56

Figure 4.

Strong ion gap (SIG) is the difference SID _a and SID _e. The SIG is an accurate measure of the unmeasured anions present in plasma.81

Crystalloids and Balanced Crystalloids

Crystalloid solutions are prepared by diluting relatively small amounts of the salts of physiologically relevant elements (Na⁺, K⁺, Ca⁺⁺, Mg⁺⁺, Cl⁻) in water. These elements are electrically balanced (law of electrical neutrality) but fully dissociate (e.g, strong cations and anions) in water because their pKa (pH at which the acid and conjugate base are equal) value is considerably different (e.g, the pKa of lactic acid = 3.86, and therefore it is fully dissociated) from that of normal plasma pH (7.40). Compounded crystalloids may contain added NaHCO₃ in order to treat (buffer) or resist pH changes from nonrespiratory causes of acidosis. Most commercial manufacturers of crystalloid solutions have abandoned the addition of Na⁺ ${\text{HCO}}_3^{-}$ to replace chloride ion when stored in plastic bags that allow equilibration with atmospheric CO₂ because of the potential to form divalent carbonate (${\text{CO}}_3^{2-}$) and precipitates with calcium and magnesium.57, 58 Most manufacturers have replaced ${\text{HCO}}_3^{-}$ with an organic anion (lactate, acetate, citrate) with the expectation that it will act as a “precursor” or stable surrogate for bicarbonate (Table 2).59, 60 In addition, replacing some of the Cl⁻ with an organic anion maintains electrical neutrality and lowers the solution's [Cl⁻].59 Organic anions are strong anions (pK < 4) combined with Na⁺. Their role is not to generate ${\text{HCO}}_3^{-}$ , as often taught, but to be rapidly metabolized and disappear from solution, thus increasing the in vivo SIDa.60, 61, 62, 63 This requirement is met in most animals but is likely to be species dependent, compromised in sick animals, and dependent upon the rate and amount of organic ion administered.64, 65, 66, 67, 68, 69 The in vivo fate of organic anions as ${\text{HCO}}_3^{-}$ generators in animals with naturally occurring diseases (hypovolemic shock; sepsis) requires further investigation.

Table 2.

Characteristics of crystalloid and colloid solutions

Fluid	pH	Na+ (mEq/L)	Cl− (mEq/L)	K+ (mEq/L)	Ca++ (mEq/L)	Mg++ (mEq/L)	Buffer (mEq/L)	Osmolarity (mOsm/L)	COP (mmHg)	SID (mEq/L)	Viscosity (cP)
0.9% NaCl	5.5	154	154	0	0	0	0	308	0	0	≈1
7.5% Saline	5.5	1283	1283	0	0	0	0	2,566	0	0	≈1
1.4% NaHCO3		167					HCO3	300		167
8.4% NaHCO3	8.0	1,000	1,000	0	0	0	HCO3	2,000	0	1,000	≈1
3% Na Lactatec	7.0	504	7	4	2.7	0	Lactate 504	1,020	0	500	≈1
LRS	6.5	130	109	4	3	0	Lactate 28	273	0	27
Normosol‐Ra	7.4	140	98	5	0	3	Acetate 27 Gluconated23	295	0	27–50	≈1
Plasma‐Lyte Ab	7.4	140	98	5	0	3	Acetate 27 Gluconated23	294	0	27–50	≈1
Plasma‐Lyte 148b	6.0	140	98	5	0	3	Acetate 27 Gluconated23	294	0	27–50	≈1
5% Albumin	5.5	154	154	0	0	0	0	308	19	0	1.2–1.5
6% Het/Saline	5.5	154	154	0	0	0	0	308	3	0	4.3
6% Het/LRS	6.5	143	124	3	5	0.9	28	303	32	28	4.3
6% Tetra/Saline	5.5	154	154	0	0	0	0	308	42	0	≈4
Blood	7.4	≈150	≈105	≈4	≈5	≈2	40	300–305	20–25	40	3.5

Common properties of crystalloid and colloid solutions used for fluid therapy. LRS, Lactated Ringer's solution.

^aHospira, Inc., Lake Forest, IL 60045.

^bBaxter Healthcare Corporation Deerfield, IL 60015.

^c l‐lactate; Het, hetastarch; Tetra, tetrastarch.

^dGluconate is a mixed nonmetabolizable strong ion.

The term “balanced” was originally devised to describe mixtures of various salts in water that produced electrolyte concentrations similar to normal plasma.5, 6, 7, 56, 57, 59 This term, however, has become both confusing and misleading because it is not always apparent what is balanced (e.g, [Na⁺] or [Cl⁻], effective osmolality, pH relative to plasma) and because the fate of organic anions is not always predictable.70, 71 Normal or physiologic saline (0.9% NaCl), Ringer's solution, lactated Ringer's solution (LRS), and compound sodium lactate (Hartmann's) are historically popular resuscitation fluids in both human and veterinary medicine.5, 6, 7, 72, 73, 74 Saline (0.6–0.9% NaCl) evolved from in vitro experiments designed to prevent hemolysis of human red blood cells whereas Ringer's solution was formulated in order to improve the contraction of beating frog hearts in vitro.72, 73 Lactated Ringer's and Hartmann's solutions soon followed by adding lactate to Ringer's solution in order to buffer dehydration‐associated acidosis in humans.74 Although the concentrations of 1 or more electrolytes in each of these 3 solutions are comparable to those found in plasma, none are truly “normal,” “physiologic,” “plasma adapted,” or balanced, especially when different species of animals are considered (Table 2).56, 57, 69, 71 If “balanced” is meant to imply a solution that has an electrolyte composition close to plasma, a normal [Cl⁻], and 1 that maintains normal (effective) osmolality, tonicity, and pH values, then the composition of most commercially prepared “balanced” crystalloids can be challenged.56, 75, 76, 77 I propose that balanced crystalloid solutions should (1) contain species‐specific concentrations of key electrolytes (Na⁺, Cl⁻, K⁺, Ca⁺⁺, Mg⁺⁺), particularly [Na⁺] and [Cl⁻]; (2) maintain or normalize acid‐base balance (provide an appropriate SID); and (3) be isosmotic and isotonic (not induce inappropriate fluid shifts) with normal plasma.

pH of Commercial Crystalloid Solutions

The pH of most commercially prepared crystalloids varies between 4.0 and 6.5 unless specified otherwise (e.g, Normosol‐R¹ [pH 7.4], Plasma‐Lyte A² [pH 7.4], Plasma‐Lyte 148² [pH 7.4]). A solution's in vitro pH is a measure of the degree of acidity or alkalinity of the solution and not the total reservoir (or lack thereof) of hydrogen ions available.78 Three factors determine the in vitro pH of commercially prepared solutions: the container (glass or polyvinyl chloride [PVC]), the temperature‐dependent solubility of CO₂ in water, and the concentration of electrolytes (strong ions) added to the solution. Glass containers are considered to be inert, but autoclaving of PVC packaged solutions generates small quantities of acetic and formic acid, lowering the solution's pH.58, 78, 79 This source of acidity, however, is inconsequential based upon the miniscule amounts of H⁺ produced.73 Carbon dioxide absorbed from air is the largest contributor to hydrogen ion activity and a decrease in pH in commercial solutions. Finally, the addition of physiologically relevant concentrations of salts to water is believed to influence the formation of hydronium ions (H₃O⁺) favoring an increase in hydrogen ion activity and a decrease in pH.79 The concentration of the electrolytes in 0.9% NaCl, for example, is responsible for lowering the pH approximately 0.01 pH unit.79 Sterile distilled water has a pH of approximately 5.6 at sea level and at 25°C due to the absorption of CO₂ from the atmosphere;79 the same process is the largest contributor to hydrogen ion activity in commercial solutions stored in plastic containers.70 Titratable acidity, as measured by the titration of any commercial crystalloid solution with NaOH to pH = 7.4, is clinically negligible in all commercial crystalloids and ranges from 0.126–0.152 mEq/L for 0.9% NaCl.70 The low titratable acidity of 0.9% NaCl implies that it is not the solution's in vitro pH that is responsible for its potential to produce an in vivo metabolic acidosis but rather the solution's effect (0.9% NaCl = 0) on the in vivo SID.56, 57, 59, 71, 79

The Acid‐Base Effects of Intravenous Fluid Therapy

All crystalloids have the potential to significantly alter acid‐base balance because of differences in their physicochemical composition relative to plasma.56, 71

The SID_a of normal plasma is approximately 40–44 mEq/L (mM/L), suggesting that administration of a crystalloid with an in vivo SID (SID_if) of 40–44 mEq/L should maintain plasma SID within the normal reference range. Infusion of a solution with an SID_if of 40–44 mEq/L, however, results in the development of metabolic alkalosis because of progressive dilution of A_tot.56 Acid‐base balance is achieved when the SID_if of the infused fluid is similar to the normal plasma [${\text{HCO}}_3^{-}$] of the species (omnivore versus herbivore) being treated.

The in vitro SID of all crystalloid and colloid solutions is zero (law of electrical neutrality) but ranges from 0 to 50 mEq/L in vivo because of the addition of metabolizable organic anions (e.g, lactate, acetate, citrate, gluconate; Table 2). Because commercially prepared crystalloids do not contain ${\text{HCO}}_3^{-}$, final plasma pH is determined by the net charge difference produced by the crystalloid's SID_if after metabolism of the crystalloid's organic anion(s) in proportion to the rate and volume of fluid administered.70 The rapid infusion of large volumes of any crystalloid, for example, will cause the extracellular fluid (plasma and interstitial fluid) to drift toward the SID_if of the infused crystalloid, changing hydrogen ion activity and pH accordingly. The SID_if of any crystalloid can be calculated by subtracting the major strong anions from strong cations after removal of the metabolizable organic anion (Table 2). Plasma pH can be predictably maintained, increased, or decreased based upon the difference between the crystalloid's SID_if and the animal's baseline [${\text{HCO}}_3^{-}$].80 This usually corresponds to SID_if values ranging from 22 to 32 mEq/L for normal healthy animals (depending upon the species being treated) and can be formulated into general rules: if the crystalloid's SID_if > plasma [${\text{HCO}}_3^{-}$], pH increases; if SID_if < plasma [${\text{HCO}}_3^{-}$], pH decreases; and if SID_if equals plasma [${\text{HCO}}_3^{-}$], pH does not change.81, 82, 83, 84, 85, 86 These general rules also hold true for all commercially prepared colloids except those that contain charged ionic macromolecules (e.g, albumin, gelatins) as apposed to nonionic colloids (e.g, starches, dextrans). Nonionic colloids do not alter acid‐base balance. Ionic colloids (e.g, albumin), particularly those diluted in 0.9% NaCl, have the potential to acidify plasma as a consequence of the increase in A_tot and decrease in SID.85 The clinical importance of the acid‐base effects of current commercially prepared ionic colloidal solutions, however, is minimal compared to that produced by their diluent.

As described above, a crystalloid's SID_if, the rate and total volume of fluid administered, and metabolism of organic anions present in the fluid are the principal determinants of the solution's effect on plasma pH. A lower infusion rate (10 mL/kg/h) of 0.9% NaCl, Hartmann's solution, or a polyionic glucose‐free maintenance solution for 2 hours (total volume = 20 mL/kg) to 60 normal dogs, for example, produced no significant differences in plasma electrolytes, total protein, plasma volume, SIG, or pH.87 The infusion of 30 mL/kg/h LRS (273 mOsm/L) for 1 hour consistently decreased packed cell volume (PCV), total protein (TP), albumin, colloid osmotic pressure (COP), and extracellular tonicity in the plasma of healthy isoflurane‐anesthetized dogs but did not change plasma pH or lactate concentrations.88 Lactate concentrations, however, were increased (>2 mmol/L) for up to 60 minutes when LRS was rapidly administered (180 mL/kg/h) for 1 hour to conscious healthy dogs, suggesting that the capacity for lactate metabolism had been exceeded.67, 69 In addition, IV administration of LRS (4.1 mL/kg/h for 6 hours) increased venous blood lactate concentrations in dogs with stage IIIa and IVa lymphoma.64 Fluids containing gluconate (Normosol‐R¹; Plasma‐Lyte A²; Plasma‐Lyte 148²) may be particularly inefficient for correcting metabolic acidosis in dogs and calves because of gluconate's poor metabolism.61, 62, 69 Other issues associated with the infusion of organic anions, in addition to their impaired or delayed metabolism in various disease states, include but are not limited to poor metabolism (d‐lactate), proinflammatory effects (d‐lactate, acetate), neurologic and cardiac toxicity (d‐lactate), and hypotension (acetate).66, 89, 90

Acute Metabolic Acidosis: Causes, Consequences, and Treatment

Acute metabolic (nonrespiratory) acidosis is caused by diseases that increase the production or decrease the elimination of nonvolatile fixed acids or decrease the body's buffering capabilities. Metabolic acidosis can be characterized by a decrease in SID_a or increase in A_tot with resultant decreases in [${\text{HCO}}_3^{-}$] and secondary (compensatory) decreases in PCO₂ (approximately 0.7 mmHg for each 1 mEq/L decrease in [${\text{HCO}}_3^{-}$]). Metabolic acidosis also may coexist with respiratory acidosis in animals that have impaired pulmonary function.91, 92 Acute metabolic acidosis can be further classified as normal (nonion gap acidosis, hyperchloremic metabolic acidosis) or high anion gap acidosis.28, 93 Lactic acidosis (hyperlactatemia > 2 mmol/L), a high anion gap acidosis, is considered evidence for tissue hypoxia, tissue hypoperfusion, and anaerobic metabolism and is used as a prognostic indicator for increased morbidity and mortality in humans and animals.94, 95, 96, 97, 98, 99, 100, 101, 102, 103 Lactic acidosis in sepsis is multifactorial and may be caused by regional tissue hypoxia and increased aerobic glycolysis secondary to cytokine‐stimulated cellular glucose uptake and catecholamine stimulation of Na‐K ATPase.94, 104, 105

Acidemia decreases cardiac contractility, decreases blood flow (cardiac output), increases susceptibility to cardiac arrhythmias, impairs responsiveness to catecholamines, alters the immune response, and promotes a systemic inflammatory state.94, 106, 107, 108 Severe metabolic acidosis (pH < 7.15) may decrease systemic and increase pulmonary vascular resistance, worsening hypotension and tissue perfusion.109, 110, 111 Intracellular acidification (decreased pHi) also activates Na‐dependent acid/base transporters.112, 113, 114 The Na⁺/H⁺ exchanger (NHE1) is a ubiquitous and integral membrane transporter involved in regulating cell volume and pHi.115, 116 Activation of NHE1 increases intracellular [Na⁺] and [Ca⁺⁺] resulting in alterations in cellular metabolism and cell membrane potential and is likely the principal cause for poor cardiac function, arrhythmias, and increased concentrations of proinflammatory cytokines.114, 115, 116

Treating acute acidemia (pH < 7.2) is not simple and should be based upon identification and control of the pathophysiologic process(s) responsible for its production.117 Ideally, species‐specific crystalloids containing appropriate quantities of electrolytes and metabolizable organic anions are preferred for maintaining tissue perfusion and correcting mild acid‐base abnormalities in otherwise normal healthy animals.36, 59, 70, 77, 118 Alkaline therapies including NaHCO₃ or carbon dioxide‐consuming bases (trishydroxymethyl aminomethane: THAM³) and Carbicarb⁴ (combination of NaHCO₃ and Na₂CO₃) are more effective treatments for acute severe metabolic acidosis than balanced crystalloids because of their high SID_if (Table 2).^{5 ,} 119 Carbicarb⁴ (SID_if = 210; 300 mOsm/L) generates less CO₂ than NaHCO₃ and therefore is less likely to produce intracellular acidosis whereas THAM³ (SID_if = 201; 300 mOsm/L) increases the buffering capacity of blood without generating CO₂ and does not produce hypernatremia or hypokalemia.120, 121, 122, 123 Neither THAM³ nor Carbicarb⁴, however, has therapeutic advantages compared to NaHCO₃ in clinical practice.124, 125 All 3 therapies remain controversial because of selective or uncertain long‐term benefit and the potential for complications.126, 127 More specifically, the Surviving Sepsis Campaign guidelines of 2016 recommend “against the use of sodium bicarbonate therapy to improve hemodynamics or to reduce vasopressor requirements in patients with hypoperfusion‐induced lactic acidemia.”128 In addition, sodium bicarbonate has the potential to produce hypersosmolality, hypernatremia, hypokalemia, decreased ionized calcium concentration, and increased hemoglobin affinity for oxygen.129, 130, 131, 132 Sodium bicarbonate also is believed to produce paradoxical intracellular and CNS acidosis (decreased pHi as plasma pH increases) an effect that is not observed in ventilated animals.133, 134 Regardless, the IV administration or addition of various commercially available or compounded hypertonic or isotonic NaHCO₃ solutions (8.4%: SID = 1,000 mEq/L, 2,000 mOsm/L; 5.0%: SID = 595 mEq/L, 1190 mOsm/L; 1.3%: SID = 154 mEq/L, 310 mOsm/L) have been shown to be more effective than balanced crystalloid solutions for treating diarrheic calves.135, 136 More recently, the co‐administration of NHE exchange inhibitors (e.g, sabiporide) and sodium bicarbonate or hypertonic sodium l‐lactate (3%) has been shown to restore acid‐base balance, improve cardiac performance and hemodynamic parameters, promote urine formation, improve endothelial function, and decrease extracellular fluid accumulation in acidotic, hemorrhaged, hypotensive, endotoxic, and traumatized animals, in addition to preventing intracranial hypertension after severe traumatic brain injury.137, 138, 139, 140, 141, 142, 143 Hypoosmolar sodium L‐lactate also may serve as a potential energy substrate (3.61 kcal/g).144 Collectively, these studies suggest that restoration of vascular volume and tissue perfusion and removal of tissue oxygen debt in conjunction with normalization of plasma pH are key factors in the success or failure of alkalinizing and cell protective therapies.136, 137, 141, 144, 145, 146, 147, 148

Concluding Comments

Misconceptions regarding the interpretation and influence of crystalloid therapy on acid‐base balance can confound fluid selection (Table 3). Balanced crystalloids should (1) contain species‐specific concentrations of key electrolytes (Na⁺, Cl⁻, K⁺, Ca⁺⁺, Mg⁺⁺), particularly Na⁺ and Cl⁻; (2) maintain or normalize acid‐base balance (provide an appropriate SID); (3) be isosmotic and isotonic (not induce inappropriate fluid shifts) with normal plasma; and (4) consider the temperature dependence of H₂CO₃. New insights regarding the mechanisms responsible for acid‐base balance, the role and efficacy of organic anions as buffers, and the importance of a crystalloid's SID_if have helped clarify and determine fluid selection. The administration of large volumes of solutions containing high concentrations of chloride (e.g, 0.9% NaCl) can no longer be supported because of their potential to produce hyperchloremic metabolic acidosis, impair renal function, and increase mortality.75, 147, 148, 149, 150 A small volume of hypertonic sodium bicarbonate solution is an effective treatment for metabolic acidosis and hyperkalemia in dehydrated, hypovolemic, septic animals as long as larger volumes of balanced solutions also are administered to restore tissue perfusion.135, 136 More species‐specific research is required to identify appropriate fluid choices within the context for which they are prescribed.3 Ideally, fluid administration should be continuously monitored, frequently reassessed, and focused upon the restoration cardiovascular function, vascular volume, electrolyte concentrations, effective osmolality, tonicity, plasma SID, and pH.

Table 3.

Misconceptions of acid‐base balance and fluid therapy

Misconception	Fact
The pH of plasma is determined by the partial pressure of carbon dioxide (PCO2) and the bicarbonate ion [H+CO3 −]	Partially true: the plasma pH is determined by 3 primary independent variables: PCO2, Atot, and SID. Changes in [H+CO3 −] are dependent on these same 3 factors
Most commercially available fluids produce no effect on plasma acid‐base balance	All commercially available fluids produce changes in plasma acid‐base balance dependent upon their ability to change in vivo strong ion difference: Their effects on plasma SID become more pronounced when larger fluid volumes are administered rapidly
Fluid administration produces acidosis by dilution of plasma [H+CO3 −]	Fluid administration does dilute [H+CO3 −] producing metabolic acidosis but also dilutes Atot producing metabolic alkalosis. Crystalloid‐induced changes in plasma pH are primarily caused by a change in SID, not dilution
The in vitro pH of commercial crystalloid solutions can acidify the plasma	The titratable acidity of all commercially available IV crystalloid solutions has no clinically relevant effect on plasma pH
Physiologic saline solution (0.9% Na+Cl−) has no effect on plasma pH	0.9% Na+Cl− in vivo SID (SIDif) = 0 and produces hyperchloremic metabolic acidosis; effect is related to dose and administration rate
Physiologic saline solution is harmful to animals	0.9% Na+Cl− effect on [H+] is usually negligible in normal healthy animals unless large volumes (>30 mL/kg) are administered over a short period (<1 h) or administered to animals that already have metabolic acidosis
Lactated Ringer's solution (LRS) is a “balanced” crystalloid	LRS is hypotonic (273 mOsm/L): Tonicity is the effective osmolality of a solution
The lactate in LRS is a bicarbonate precursor or bicarbonate substitute	The role of lactate (like all organic anions) in LRS is to be rapidly metabolized (disappear), thereby increasing SID
The lactate in LRS is an ideal organic anion to substitute for bicarbonate	LRS contains a racemic mixture of d and l‐lactate as an inorganic ion. d‐lactate is proinflammatory and can cause CNS depression
Normosol‐R and Plasma‐Lyte maintain normal plasma pH	Normosol‐R and Plasma‐Lyte have an SIDif = 50 increasing plasma pH
Sodium bicarbonate solution administration produces CNS and intracellular acidosis (paradoxical acidosis)	Possibly true but the effect is dose and rate of administration related, usually transient and clinically irrelevant in animals that are adequately ventilated

[], concentration; pH, negative log of [H⁺]; PCO₂, partial pressure of carbon dioxide; A_tot, weak nonvolatile acids, inorganic phosphate, serum proteins, and albumin; SID, difference between strong cations and strong anions.

“We are still confused – but on a much higher level” W. Churchill.