View metadata, citation and similar papers at core.ac.uk brought to you by CORE

provided by Elsevier - Publisher Connector http://www.kidney-international.org review & 2009 International Society of Nephrology

Assessing acid–base disorders Horacio J. Adrogue´1,2,3, F. John Gennari4, John H. Galla5 and Nicolaos E. Madias6,7

1Department of Medicine, Baylor College of Medicine, Houston, TX, USA; 2Department of Medicine, Methodist Hospital, Houston, TX, USA; 3Renal Section, Veterans Affairs Medical Center, Houston, TX, USA; 4Department of Medicine, University of Vermont College of Medicine, Burlington, VT, USA; 5Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA; 6Department of Medicine, Tufts University School of Medicine, Boston, MA, USA and 7Division of Nephrology, Department of Medicine, Caritas St Elizabeth’s Medical Center, Tufts University School of Medicine, Boston, MA, USA

Effective management of acid–base disorders depends on Management of acid–base disorders begins with accurate accurate diagnosis. Three distinct approaches are currently diagnosis, a process requiring two tasks: First, reliable used in assessing acid–base disorders: the physiological measurement of acid–base variables in the , a complex approach, the base-excess approach, and the fluid containing multiple ions and buffers; this task is an physicochemical approach. There are considerable exercise in chemistry. Second, proper interpretation of the differences among the three approaches. In this review, we data in relation to human health and disease allowing first describe the conceptual framework of each approach, definition of the patient’s acid–base status; this is an exercise and comment on its attributes and drawbacks. We then in . The patient’s history, physical examina- highlight the application of each approach to patient care. tion, and additional laboratory testing and imaging, as We conclude with a brief synthesis and our appropriate, then help the clinician to identify the specific recommendations for choosing an approach. cause(s) of the acid–base disturbance, and from that 1 Kidney International (2009) 76, 1239–1247; doi:10.1038/ki.2009.359; information to undertake appropriate intervention. published online 7 October 2009 Three distinct approaches are currently used in assessing KEYWORDS: base-excess approach; physicochemical approach; acid–base disorders, each with a considerable following physiological approach; Stewart approach worldwide. For the purposes of this review, we name them the physiological approach, pioneered by Van Slyke and co- workers;2,3 the base-excess approach, developed by Astrup and co-workers;4,5 and the physicochemical approach, pro- posedbyStewartandextendedbyhisfollowers.6–9 The last and newest approach has steadily gained acceptance, especially among critical-care physicians and anesthesiologists. The three approaches differ considerably. In this review, we first describe the conceptual framework of each approach, and its attributes and drawbacks. We then highlight the application of each approach to patient care. We conclude with a brief synthesis and our recommendations for choosing an approach.

PHYSIOLOGICAL APPROACH Conceptual framework The physiological approach considers acids as hydrogen ion (H þ ) donors and bases as H þ acceptors.10 It uses solely the carbonic acid/ buffer system for assessing acid- base status, a position rooted in the isohydric principle. Adoption of this buffer system reflects its abundance, physiological preeminence, and the fact that its two components undergo homeostatic control.1–3 Blood pH is viewed as being determined by the prevailing levels of Correspondence: Nicolaos E. Madias, Department of Medicine, Caritas St Elizabeth’s Medical Center, 736 Cambridge Street, Boston, MA 02135, USA. carbonic acid (that is, PaCO2, the respiratory component) E-mail: [email protected] and plasma bicarbonate concentration ([HCO3 ], the meta- Received 24 June 2009; revised 14 July 2009; accepted 14 July 2009; bolic component, Table 1), as stipulated by the Henderson þ published online 7 October 2009 equation, [H ] ¼ 24 PaCO2/[HCO3 ].

Kidney International (2009) 76, 1239–1247 1239 review HJ Adrogue´ et al.: Assessing acid–base disorders

Table 1 | Assessment of the metabolic component of acid-base status Approach Variable Determination Remarks

Physiological Plasma [HCO3 ] Measured pH and PCO2 Interpretation complemented by evaluation of plasma + , [Na ]([Cl ]+[Total CO2]) Base excess Blood base excess (BE) CO2 equilibration method or calculated BE is a measure of the metabolic component of acid–base from measured pH and PCO2 status as reflected in whole blood Interpretation complemented by evaluation of plasma anion gap Standard BE (SBE) Calculated from measured SBE is a measure of the metabolic component of acid- pH, PCO2, and base status as reflected in the extracellular compartment. It is usually calculated automatically from arterial blood gas results, but it can also be obtained using the blood acid–base nomogram with the hemoglobin set at 5 g/dl42 Interpretation complemented by evaluation of plasma anion gap + + ++ ++ Physicochemical SIDa (apparent strong ([Na ]+[K ]+[Ca ]+[Mg ])([Cl ]+[lactate ]) These three formulas for SIDa, as well as additional + + ion difference) ([Na ]+[K ])([Cl ]+[lactate ]+[other strong variants, are currently in use. SIDa is mathematically anions]) equivalent to the plasma buffer base of Singer and ([Na+]+[K+])[Cl] Hastings64 SIDe (effective strong [HCO3 ]+[Alb ]+[Pi ] where: Represents the sum of plasma [HCO3 ] and non- ion difference) [Alb]=[Alb, g/l] [(0.123 pH)0.631] bicarbonate buffers (anionic equivalency of albumin and [Pi]=[Pi, mmol/l] [(0.309 pH)0.469] phosphate) SIG (strong ion gap) SIDa – SIDe An estimate of the concentration of unmeasured anions in plasma that resembles the plasma anion gap Value depends upon the variant of SIDa used ATot (total 2.43 [total , g/dl] Primarily related to albumin concentration concentration For clinical purposes, approximated by the concentration of weak acids of total protein in plasma) All variables and listed are expressed in mEq/l, unless otherwise indicated.

The physiological approach recognizes four acid–base calculated value for each 1 g/dl of plasma albumin below or disorders1,11–13 (Table 2). Metabolic disorders are expressed above the average normal value of 4.5 g/dl, respectively. as primary changes in plasma [HCO3 ], whereas respiratory Changes in blood pH elicit small, directional changes in the disorders are expressed as primary changes in PaCO2. Each anionic charge of plasma albumin and thus the AG, but these 28,29 primary change in either plasma [HCO3 ] or PaCO2 elicits in changes are ignored in clinical practice. The anionic vivo a secondary response in the other variable that tends to charge of plasma albumin decreases by only 1.5 mEq/l when minimize the change in acidity.1,11 These secondary blood pH decreases from 7.40 to 7.10.30 responses, otherwise referred to as compensatory, have been quantitated in animals and humans.14–24 We discourage use Attributes and drawbacks of the term compensatory, because the secondary responses The physiological approach considers the acid–base status of occasionally can yield a maladaptive effect on blood pH.25,26 body fluids as being determined by net H þ balance (that is, Absence of an appropriate secondary response denotes the influx minus efflux) and the prevailing complement of body co-existence of an additional simple acid–base disorder. Use buffers.31,32 The chemistry of acids and bases is blended with of ventilator support in critically ill patients can, of course, the empirically derived secondary responses of the intact alter or prevent expression of the secondary changes in organism to primary changes in PaCO2 or plasma [HCO3 ]. PaCO2 in response to metabolic acid–base disorders. These This approach is simple regarding data collection and clinical ventilator-induced alterations are viewed as complicating application. The standard blood gas analyzer measures pH primary respiratory acid–base disorders. The simultaneous and PCO2, from which plasma [HCO3 ] is calculated presence of two or more simple acid–base disorders defines a (Table 1). Comparing plasma [HCO3 ] with measured 1 mixed acid–base disorder. [TCO2] in venous blood validates this derived variable. Assessment of the metabolic component is complemented Furthermore, most acid–base disorders are first recognized by by evaluating the plasma anion gap (AG), defined as clinicians through abnormalities in venous [TCO2]. þ 27 [Na ]([Cl ] þ [TCO2]), where [TCO2] indicates venous Although PCO2 is universally considered as an appro- total CO2 concentration (Table 1 and Figure 1). The average priate index of the respiratory component, plasma [HCO3 ] normal value for plasma AG differs among health-care has been viewed by some as an unsuitable indicator of the facilities because of methodological variation.27 Normally, metabolic component.33,34 Criticisms include lack of inde- approximately 75% of the plasma AG is determined by pendence of plasma [HCO3 ] from the respiratory compo- plasma albumin concentration.27 Thus, the plasma AG must nent and failure of quantitation of buffers other than be adjusted by subtracting or adding 2.5 mEq/l from the bicarbonate. Plasma [HCO3 ] is certainly affected by changes

1240 Kidney International (2009) 76, 1239–1247 HJ Adrogue´ et al.: Assessing acid–base disorders review

Table 2 | Classification of acid–base disorders Disorder Physiological approach Base-excess approach Physicochemical approach

Metabolic Primary k in [HCO3 ] Primary base deficit (–BE, –SBE) Primary kSIDe, k in pH; secondary k in PaCO2 k in pH; secondary k in PaCO2 kpH Secondary DPaCO2/D[HCO3 ]=k1.2 mm Hg per DPaCO2/DSBE=k1.0 mm Hg per Secondary DPaCO2 not defined response mEq/lk mEq/lk Evaluation of Plasma AG adjusted for plasma Plasma AG adjusted for plasma plasma unmeasured [albumin] [albumin] anions Normal AG acidosis (hyperchloremic Normal AG acidosis (hyperchloremic SID acidosis where SIG=0, (kSIDa=kSIDe), acidosis) acidosis) equivalent to hyperchloremic acidosis High AG acidosis (normochloremic High AG acidosis (normochloremic SIG acidosis where mSIG (unchanged SIDa acidosis) acidosis) and decreased SIDe), equivalent to normochloremic acidosis Effect of [albumin] No significant effect No significant effect Primary m in Atot (hyperalbuminemic on acid–base status acidosis)

Primary m in [HCO3 ] Primary base excess (+BE, +SBE) Primary m in SIDa and SIDe m in pH; secondary m in PaCO2 m in pH; secondary m in PaCO2 m in pH (SID alkalosis) Secondary DPaCO2/D[HCO3 ]=m0.7 mm Hg per DPaCO2/DSBE=m 0.6 mm Hg per Secondary DPaCO2 not defined response mEq/lm mEq/lm Effect of [albumin] No significant effect No significant effect Primary k in ATot (hypoalbuminemic on acid–base satus alkalosis)

Respiratory acidosis Primary m in PaCO2 Primary m in PaCO2 Primary m in PaCO2 k in pH; secondary m in [HCO3 ] k in pH k in pH Secondary D[HCO3 ]/DPaCO2= DSBE=0 (acute) Not considered response m0.1 mEq/l per mm Hg m(acute) DSBE=+SBE (chronic) m0.3 mEq/l per mm Hg m(chronic) DSBE/DPaCO2=m0.4 mEq/l per mm Hg m

Respiratory alkalosis Primary k in PaCO2 Primary k in PaCO2 Primary k in PaCO2 m in pH; secondary k in [HCO3 ] m in pH m in pH Secondary D[HCO3 ]/DPaCO2= DSBE=0 (acute) Not considered response k0.2 mEq/l per mm Hg k (acute) DSBE=SBE (chronic) k0.4 mEq/l per mm Hg k (chronic) DSBE/DPaCO2=k0.4 mEq/l per mm Hg k

AG, anion gap; SBE, standard base excess; SIDa, apparent strong ion difference; SIDe, effective strong ion difference; SIG, strong ion gap (see Table 1 for definitions). Plasma AG can be adjusted for plasma [albumin] by subtracting or adding 2.5 mEq/l from the calculated value for each 1 g/dl of plasma albumin below or above the average normal value of 4.5 g/dl, respectively. Arrows pointing down (k) indicate decreases and arrows pointing up (m) indicate increases. In respiratory acid–base disorders, the term ‘acute’ refers to a duration of minutes to several hours. The term ‘chronic’ refers to a duration of several days or longer.

in PCO2 and vice versa, because HCO3 and H2CO3 are take into account the participation of non-bicarbonate members of a single buffer pair.1–3 Also, sustained changes in buffers.36 PCO2 substantially modify renal acidification thereby decreasing plasma [HCO3 ] in chronic hypocapnia and BASE-EXCESS APPROACH increasing it in chronic hypercapnia.14,15,25,26,32,35Conversely, Conceptual framework þ changes in plasma [HCO3 ] modify alveolar ventilation The base-excess approach also advocates the centrality of H 16,24 4,5,33 resulting in changes in PCO2. However, the interdepen- balance in defining acid–base status. In this approach, the dency of PCO2 and plasma [HCO3 ] does not undermine the three relevant acid–base variables are blood pH, PCO2, and rigor of the physiological approach, because the secondary base excess (BE) (Table 1). Blood BE was introduced to responses of the one variable to changes in the other have replace plasma [HCO3 ] with a measure of the metabolic been quantitated for each disorder (Table 2). Regarding the component that is independent from the respiratory second criticism, non-bicarbonate buffers are not quantitated component. Base excess represents the amount of acid or in the physiological approach, but this does not vitiate alkali that must be added to 1 l of blood exposed in vitro to a diagnosis, because the level of plasma [HCO3 ] always reflects PCO2 of 40 mm Hg to achieve the average normal pH of 7.40. the status of those buffers. Nor does it affect patient Acid is required when blood pH is higher than 7.40 (positive management, because the apparent bicarbonate space, used BE or base excess), whereas alkali is needed when blood pH is to compute acid or alkali replacement, incorporates the lower than 7.40 (negative BE or base deficit). Under normal contribution of non-bicarbonate buffers.36–38 Alterations in circumstances, the average blood BE is zero.39 During in vitro acid–base equilibrium result in changes in the apparent blood titration, any CO2-induced increase in plasma [HCO3 ] bicarbonate space that have been defined experimentally and is attended by an equivalent decrease in the anionic charge of

Kidney International (2009) 76, 1239–1247 1241 review HJ Adrogue´ et al.: Assessing acid–base disorders

Phosphate– Phosphate– Phosphate– Other Other Other cations Other cations Other cations Other anions anions anions

K+ 4K+ 4K+ 4 – SIG AG Proteins– AG SIDa SIDe – AG HCO3 – SIDa SIDe Proteins SIDa 10 – HCO3 24 SIDe – HCO3 4

Na+ Cl– Na+ Cl– Na+ Cl– 140 106 140 106 140 120

Normal High AG (normochloremic) Normal AG (hyperchloremic) metabolic acidosis or or SIG acidosis SID acidosis Figure 1 | Schematic illustration of plasma cations and anions in normal acid–base status, high-anion-gap (normochloremic) metabolic acidosis or SIG acidosis, and normal anion gap (hyperchloremic) metabolic acidosis or SID acidosis. The numbers within the bars give ion concentrations in millimoles per liter. AG, anion gap; SID, strong ion difference; SIDa, apparent strong ion difference; SIDe, effective strong ion difference; SIG, strong ion gap.

non-bicarbonate buffers (largely hemoglobin) that results respiratory disorders represent primary changes in PCO2. from binding the H þ released from carbonic acid; as a result, Recomputing data collected according to the physiological blood BE remains constant. Opposite reactions occur during approach47 allows quantitation of the secondary responses to in vitro decreases in PCO2 again resulting in a constant blood primary changes in SBE or PCO2 (Table 2). Assessment of BE. In contrast, when the PCO2 is varied in vivo as a result of SBE is complemented by evaluating the plasma AG. hypoventilation or hyperventilation, blood BE does not remain constant because a concentration gradient for Attributes and drawbacks bicarbonate develops between blood and interstitial com- This approach champions SBE as a measure of the partment; bicarbonate is lost from plasma into the interstitial contribution of all extracellular buffers to a metabolic acid fluid in hypercapnia causing a negative BE, whereas or alkali load that is independent of the respiratory bicarbonate is added to plasma from the interstitial fluid in component. Some practitioners favor this approach because hypocapnia resulting in a positive BE.19,40 This pitfall was SBE simplifies the estimation of acid or alkali replacement. addressed by introducing the extracellular BE or standard BE The base-excess approach weds the chemistry of acids and (SBE), a measure of the metabolic component that is bases with the anticipated secondary responses to acid–base modeled by diluting the blood sample threefold with its stresses. It is also relatively simple and uses the blood gas own plasma or estimated by using the blood BE at a analyzer to provide all three relevant variables (Table 1). hemoglobin concentration of 5 g/dl.33,41–43 Currently, many Drawbacks of this approach are the failure to include the blood gas analyzers calculate SBE from measured pH, PCO2, contribution of intracellular buffers, and the presumption of and hemoglobin44 (Table 1). a constant 1:3 ratio between blood and interstitial volume, a The base-excess approach recognizes four acid–base ratio that decreases in patients with severe edematous disturbances11–13,45–47 (Table 2). Metabolic disorders are states.40 Most important, the independence of SBE from defined by primary changes in BE or SBE, whereas the respiratory component is limited to acute hypercapnia

1242 Kidney International (2009) 76, 1239–1247 HJ Adrogue´ et al.: Assessing acid–base disorders review

and hypocapnia. Chronic changes in PCO2 elicit parallel accurate estimate of plasma unmeasured anions than plasma changes in SBE by altering renal acidification.14,15,35 Further, AG. Under normal conditions, SIG equals zero. In organic changes in SBE characteristic of metabolic disorders originate acidosis SIDa remains unchanged, but it decreases in in part from the prevailing secondary hypocapnia or hyperchloremic metabolic acidosis. On the other hand, SIDe hypercapnia.25,26 decreases in both types of metabolic acidosis. SIG equals zero in hyperchloremic metabolic acidosis (SID acidosis, 51,53 PHYSICOCHEMICAL APPROACH Figure 1), whereas it increases in organic acidosis (SIG Conceptual framework acidosis, Figure 1) reflecting high levels of unmeasured The physicochemical approach differs fundamentally be- anions, such as lactate and ketoanions. Estimation of ATot for cause, in addition to the influence of PCO2 and non-volatile clinical purposes requires measurement of plasma total weak acids, it proposes that the [H þ ] of living organisms proteins or plasma albumin (Table 1). reflects changes in the dissociation of water induced by the The physicochemical approach defines six acid–base presence of strong ions (that is, ions fully dissociated at the disorders according to primary deviations in each of the pH of body fluids).6–9,48–50 Applying the principles of three independent variables30,51 (Table 2). Abnormal levels of electroneutrality and mass conservation, Stewart examined SIDe or ATot indicate the presence of metabolic acid–base the dissociation of water in a flask, its interaction with solutes disorders. A low SIDe signifies metabolic acidosis (SID that dissociate in solution (including the weak acids normally acidosis) and a high SIDe metabolic alkalosis (SID alkalosis). present in plasma), and the effects of adding CO2.He A low-SIDe metabolic acidosis can occur in association with a concluded that the dissociation of water, and thus the high SIG (for example, ) or a normal prevailing [H þ ], is determined by the interplay of three (that is, zero) SIG (for example, diarrhea) (Figure 1). A high variables defined as independent and proposed to account for ATot signifies metabolic acidosis (hyperalbuminemic acidosis) all acid–base effects in the solution: The strong ion difference and a low ATot metabolic alkalosis (hypoalbuminemic 54–58 (SID), the total concentration of weak acids (ATot, which alkalosis). Increases in PCO2 define 6–8 includes proteins and phosphate), and PCO2. The SID and decreases in PCO2 . Quantitative represents the sum of the concentrations of the strong cations measures of the secondary responses to primary changes in þ þ þþ þþ (Na ,K ,Ca , and Mg ) minus the sum of the SIDe,ATot, and PCO2 are not available. ¼ concentrations of the strong anions (Cl ,SO4 , and anions of organic acids). By virtue of their magnitude, the Attributes and drawbacks concentrations of Na þ and Cl are the main determinants The physicochemical approach provides a detailed descrip- of SID. Stewart developed a set of six equations that, when tion of acid–base variables. Proponents have argued that the solved simultaneously, yield the [H þ ] of the solution.6–8 The increased complexity required for calculating SIG is justified calculated value equals measured acidity using a pH because it yields an index of unmeasured anions after electrode. discounting the contribution of albumin and phosphate. þ In this approach, both [H ] and [HCO3 ] are defined as Some data suggest that SIG better predicts the risk of death in dependent variables, their values being determined exclu- critically ill patients than lactate, AG, or blood BE.53,59 sively by the three independent variables. Bicarbonate is However, most studies have not identified any diagnostic or actually viewed as an irrelevant measure of acid–base status6 prognostic advantage of the physicochemical approach over that simply contributes to filling the gap between strong the other approaches in such patients.60,61 cations and strong anions. The physicochemical approach Compared with the physiological and base-excess ap- proposes that acid–base disorders be assessed using SID and proaches, the physicochemical approach requires additional ATot (collectively representing the metabolic component), and measurements of multiple ions and the use of computer 33,62,63 PCO2 (respiratory component). programs (Table 1). Interpreting SID is cumbersome, Clinical application of this approach involves measure- because its two formulations, SIDa and SIDe, have different ment of blood pH and PCO2, and determination of the two connotations. The SIDa itself is somewhat confusing, variable 30,51,52 formulations of SID and ATot. Subtracting strong electrolytes being used in defining it, such that even the anions from strong cations yields the apparent SID (SIDa). normal baseline differs substantially (Table 1). Despite claims The simplest estimation of SIDa involves subtracting [Cl ] that bicarbonate is an irrelevant anion in terms of acid–base þ þ 52 from the sum of [Na ] and [K ], and under normal assessment, it is a major component of SIDe (Figure 1). conditions, it equals approximately 40 mEq/l (Table 1 and Compared with plasma [HCO3 ] and SBE, the reliability Figure 1). The other formulation of SID, effective SID (SIDe), of SIDa, SIDe, and ATot is precarious, because their represents the sum of plasma [HCO3 ] and the anionic determination requires multiple measurements and calcula- equivalency of albumin and phosphate (Table 1 and Figure 1); tions incorporating several assumptions. it is estimated from blood pH, PCO2, and the plasma The classification of metabolic acid–base disorders is concentrations of albumin and phosphate using a formula or unduly complex. As examples, metabolic acidosis can be 51 a nomogram. The difference between SIDa and SIDe, associated with normal SIDa, low SIDa, normal SIG, high known as strong ion gap (SIG), is proposed as a more SIG, or high ATot. Also, the designation of ATot acidosis and

Kidney International (2009) 76, 1239–1247 1243 review HJ Adrogue´ et al.: Assessing acid–base disorders

ATot alkalosis, based on increased and decreased levels of acid–base disorder is present. The AG is markedly increased plasma albumin, respectively, is largely groundless.33 Despite (28 mEq/l) compared with the expected baseline (approxi- in vitro data showing that changes in albumin affect acidity, mately 4 mEq/l when corrected for plasma albumin concen- there is no evidence that the body and, in particular the liver, tration) indicating the presence of increased unmeasured regulates albumin to maintain acid–base balance. In vivo, anions in plasma. The estimated change in AG (DAG) equals changes in serum albumin do not correlate with changes in 24 mEq/l and approximates the decrease in plasma [HCO3 ]. 63 PCO2 or pH. Contrary to the physiological and base-excess Using the base-excess approach, the SBE of 25 mEq/l in approaches that maintain a sharp distinction between conjunction with a blood pH of 7.05 is indicative of diagnosis and cause, the physicochemical approach attempts metabolic acidosis. The DPaCO2 of 25 mm Hg is appropriate to blend these elements with respect to metabolic distur- for the DSBE of 25 mEq/l (expected value, 1 25, Table 2) bances, a potential source of confusion. and represents secondary hypocapnia. Thus, a single acid- The physicochemical approach is computationally precise base disorder is considered present. The DAG of 24 mEq/l but anchored exclusively in chemistry. The mathematical (evaluated in a manner identical to the physiological precision of this approach does not validate the proposed approach) points to high-anion-gap metabolic acidosis. cause and effect relationship with acid–base variables. To posit Using the physicochemical approach, the decreased SIDe that SID and ATot determine mechanistically plasma [HCO3 ] of 11 mEq/l is diagnostic of metabolic acidosis. The elevated and pH at the physiological level is presumptuous. Experi- SIG of 27 mEq/l indicates that the acidosis is due to mental support for such a cause and effect relationship is accumulation of unmeasured strong anions. Reflecting the 63 lacking. Rather than being causes of acid–base perturbations, low plasma albumin concentration, the decreased ATot changes in SID could be mere reflections of these perturbations. signifies coexisting weak-acid alkalosis (hypoalbuminemic Proponents of the physicochemical approach argue that alkalosis). The decreased PaCO2 points to the presence of rapid infusion of isotonic saline (for example, 30 ml/kg/h), a respiratory alkalosis. No information is available to judge the solution with a SID of zero, generates metabolic acidosis appropriateness of the ventilatory response. Thus, the patient because of a hyperchloremia-induced decrease in SID. This has three acid–base disorders. phenomenon is essentially prevented during rapid infusion of Both the physiological and the base-excess approaches Ringer’s lactate, a solution with an SID of 23 mEq/l.65 The diagnose an identical simple acid–base disorder, namely high- physiological approach offers, however, an equally straight- anion-gap metabolic acidosis. The patient’s clinical history forward explanation. The metabolic acidosis is caused by the coupled with the prevailing and positive tests sizable expansion of the extracellular fluid with a solution for blood and ketones (data not shown) establish the devoid of bicarbonate (that is, isotonic saline) that results in presence of diabetic ketoacidosis. The focus of care is to a decrease in plasma [HCO3 ] without a proportional reverse the organic acidosis. In contrast, the physicochemical 66 decrease in PCO2 (dilution acidosis). Such a dilution of approach identifies three separate acid–base disorders, the extracellular bicarbonate stores is obviated during rapid metabolic acidosis, hypoalbuminemic alkalosis, and respira- infusion of Ringer’s lactate, because the infused lactate tory alkalosis. These diagnoses can be a source of confusion represents a bicarbonate precursor, its generating for the clinician. Is the hypoalbuminemic alkalosis, a equivalent molecules of bicarbonate. Dilution acidosis is, of condition of questionable existence, protective in this case? course, a short-lived phenomenon in patients with normal Must the respiratory alkalosis be treated or is the hypocapnia renal function, because regulatory changes intervene rapidly; it appropriate for the metabolic acidosis? Attempts to address can only be sustained in patients with advanced renal failure. these questions risk mismanagement and divert attention from the key problem, reversing the organic acidosis. CLINICAL APPLICATIONS Let us now evaluate the acid–base status of two clinical cases Case 2 using each of the three approaches. The laboratory data for A 58-year-old man with advanced chronic obstructive each case and the corresponding acid–base diagnoses pulmonary disease and congestive heart failure was admitted according to each approach are shown in Table 3. because of anorexia and failure to thrive. His medications include bronchodilators and diuretics. Case 1 The physiological approach identifies marked elevations in A 27-year-old woman with type 1 diabetes mellitus was plasma [HCO3 ] and PaCO2 in the company of a near normal brought to the emergency department with obtundation, blood pH signifying a mixed acid–base disorder. The PaCO2 severe hyperpnea, and blood pressure of 90/45 mm Hg. of 58 mm Hg exceeds the anticipated ventilatory response to Using the physiological approach, the plasma [HCO3 ]of metabolic alkalosis; for a D[HCO3 ] of 11 mEq/l (35-24), the 4 mEq/l and blood pH of 7.05 signify metabolic acidosis. For expected DPaCO2 is approximately 8 mm Hg (0.7 11, a D[HCO3 ] of 20 mEq/l (24-4), the expected DPaCO2 is Table 2) predicting a PaCO2 of 48 mm Hg (40 þ 8). Thus, 24 mm Hg (1.2 20, Table 2) predicting a PaCO2 of both metabolic alkalosis and respiratory acidosis are present. 16 mm Hg (40-24); the patient’s PaCO2 of 15 mm Hg The increased plasma [HCO3 ] represents the sum of the represents an appropriate ventilatory response. Thus, a single effects of diuretics and chronic hypercapnia on renal

1244 Kidney International (2009) 76, 1239–1247 HJ Adrogue´ et al.: Assessing acid–base disorders review

Table 3 | Clinical examples Mean normal values Case 1 Case 2 Measured variables pH 7.40 7.05 7.41 PaCO2 40 mm Hg 15 58 [HCO3 ] 24 mEq/l 4.0 35 [Na+] 140 mEq/l 129 138 [K+] 4.0 mEq/l 5.0 3.2 [Cl] 104 mEq/l 96 101 [TCO2] 26 mEq/l 5.0 39 [Albumin] 4.5 g/dl 2.0 1.5 Pi 1.2 mmol/l 1.1 0.5

Derived variables AG 10 mEq/l 28 2 SBE 0 mEq/l 25 11 SIDa 40 mEq/l 38 40 SIDe 40 mEq/l 11 40 SIG 0 mEq/l 27 0 Atot 15 mEq/l 7 5

Acid-base diagnoses Physiological approach One disorder: Two disorders: Metabolic acidosis (high AG metabolic acidosis) Metabolic alkalosis Respiratory acidosis Base-excess approach One disorder: Two disorders: Metabolic acidosis (high AG metabolic acidosis) Metabolic alkalosis Respiratory acidosis Physicochemical approach Three disorders: Two disorders: Metabolic acidosis (SIG acidosis) Hypoalbuminemic alkalosis Hypoalbuminemic alkalosis Respiratory acidosis Respiratory alkalosis

acidification. The AG is reduced, the result of severe Instead, it might prompt clinicians to raise plasma albumin . level, a scientifically unsupported measure. Using the base-excess approach, one finds an SBE of No research has been directed toward the potential clinical 11 mEq/l along with the marginally increased blood pH of implications of this divergence in diagnosis. We can only 7.41, which indicates the presence of metabolic alkalosis speculate whether such variable assessment of the acid–base (diuretic-induced). The DPaCO2 of 18 mm Hg (58-40) status and resultant differences in clinical management exceeds the anticipated secondary response to the DSBE of contribute to patients’ morbidity and mortality. 11 mEq/l (0.6 11 B7, predicting a PaCO2 of 47 mm Hg) and signifies coexisting respiratory acidosis. The AG is SYNTHESIS AND RECOMMENDATIONS reduced because of severe hypoalbuminemia. The physiological and base-excess approaches adequately The physicochemical approach indicates that the nor- fulfill both the chemical and the pathophysiological tasks to malcy of SIDa, SIDe, and SIG contrasts with a very assessing acid–base status in a relatively simple and diminished ATot of only 5 mEq/l. The patient’s diagnosis is straightforward manner. Conversely, the physicochemical weak-acid alkalosis (hypoalbuminemic alkalosis). The in- approach addresses these two tasks by introducing consider- creased PaCO2 signifies respiratory acidosis. Two acid–base able complexity, as it requires multiple determinations to disorders are diagnosed. compute its panel of acid–base variables. In our judgment, Both the physiological and base-excess approaches will this approach builds a mathematical superstructure that is lead clinicians to introduce measures to improve alveolar superfluous, impractical, and at times misleading. ventilation as well as reduce the metabolic component and The physiological approach offers quantitative measures thus blood pH by administering potassium chloride and of the secondary responses to primary acid–base perturba- possibly acetazolamide. These two measures complement tions that have been derived from observational and each other because even relative alkalemia reduces the experimental studies in humans (Table 2). A corresponding ventilatory drive. By contrast, the physicochemical approach quantitation is provided by the base-excess approach that is will fail to pursue these therapeutic measures because it based on recomputing data collected according to the cannot judge whether the increase in PaCO2 represents physiological approach (Table 2). Conversely, no quantitative primary hypercapnia, secondary hypercapnia, or both. assessment of the secondary responses to primary changes in

Kidney International (2009) 76, 1239–1247 1245 review HJ Adrogue´ et al.: Assessing acid–base disorders

SID ,A , and PCO is offered by the physicochemical 20. Galla JH. Chloride-depletion alkalosis. In: Gennari FJ, Adrogue´ HJ, Galla e Tot 2 JH, Madias NE (eds). Acid-Base Disorders and their Treatment. Taylor & approach. This situation is a major drawback and risks Francis: Boca Raton, 2005, pp 519–551. misdiagnosis of the secondary responses as independent, 21. Brackett Jr NC, Wingo CF, Muren O et al. Acid-base response to chronic simple acid–base disorders. hypercapnia in man. N Engl J Med 1969; 280: 124–130. 22. Arbus GS, Hebert LA, Levesque PR et al. Characterization and clinical Despite its general adequacy and simplicity, the base- application of the ‘significance band’ for acute respiratory alkalosis. N excess approach uses blood acid–base nomograms obtained Engl J Med 1969; 280: 117–123. 23. Krapf R, Beeler I, Hertner D et al. Chronic respiratory alkalosis. The effect in vitro and assumptions that detract from its overall of sustained hyperventilation on renal regulation of acid-base reliability. Only the physiological approach precisely quanti- equilibrium. N Engl J Med 1991; 324: 1394–1401. tates the two components of the dominant buffer pair in 24. Bushinsky DA, Coe FL, Katzenberg C et al. Arterial PCO2 in chronic metabolic acidosis. Kidney Int 1982; 22: 311–314. blood, which are in equilibrium with the remaining body 25. Madias NE, Schwartz WB, Cohen JJ. The maladaptive renal response to buffers, thereby providing direct and reliable assessment of secondary hypocapnia during chronic HCl acidosis in the dog. J Clin Invest acid–base status in vivo. We conclude that the physiological 1977; 60: 1393–1401. 26. Madias NE, Adrogue´ HJ, Cohen JJ. Maladaptive renal response to approach remains the simplest, most rigorous, and most secondary hypercapnia in chronic metabolic alkalosis. Am J Physiol 1980; serviceable approach to assessing acid–base disorders. 238: F283–F289. 27. Kraut JA, Madias NE. Serum anion gap: its uses and limitations in clinical DISCLOSURE medicine. Clin J Am Soc Nephrol 2007; 2: 162–174. 28. Adrogue´ HJ, Brensilver J, Madias NE. Changes in the plasma anion gap All the authors declared no competing interests. during chronic metabolic acid-base disturbances. Am J Physiol 1978; 235: F291–F297. REFERENCES 29. Madias NE, Ayus JC, Adrogue´ HJ. Increased anion gap in metabolic 1. Adrogue´ HJ, Madias NE. Tools for clinical assessment. In: Gennari FJ, alkalosis: the role of plasma protein equivalency. N Engl J Med 1979; 300: Adrogue´ HJ, Galla JH, Madias NE (eds). Acid-Base Disorders and their 1421–1423. Treatment. Taylor & Francis: Boca Raton, 2005, pp 801–816. 30. Fencl V, Jabor A, Kazda A et al. Diagnosis of metabolic acid-base 2. Henderson LJ. The theory of neutrality regulation in the animal organism. disturbances in critically ill patients. Am J Respir Crit Care Med 2000; 162: Am J Physiol 1907; 18: 427–448. 2246–2251. 3. Van Slyke DD, Wu H, McLean FC. Studies of gas and equilibria 31. Adrogue´ HJ, Madias NE. Measurement of acid-base status. in the blood. V. Factors controlling the electrolyte and water distribution In: Gennari FJ, Adrogue´ HJ, Galla JH, Madias NE (eds). Acid-Base in the blood. J Biol Chem 1923; 56: 765–849. Disorders and their Treatment. Taylor & Francis: Boca Raton, 2005, 4. Astrup P. A simple electrometric technique for the determination of pp 775–788. tension in blood and plasma, total content of carbon 32. Gennari FJ. Regulation of acid-base balance: overview. In: Gennari FJ, dioxide in plasma, and bicar-bonate content in ‘separated’ plasma at a Adrogue´ HJ, Galla JH, Madias NE (eds). Acid-Base Disorders and their fixed carbon dioxide tension (40 mmHg). Scand J Clin Lab Invest 1956; Treatment. Taylor & Francis: Boca Raton, 2005, pp 177–208. 8: 33–43. 33. Siggaard-Andersen O, Fogh-Andersen N. Base excess or buffer base 5. Siggaard-Andersen O, Engel K, Jorgensen K et al. A micro method for (strong ion difference) as measure of a non-respiratory acid-base determination of pH, carbon dioxide tension, base excess and standard disturbance. Acta Anaesthesiol Scand 1995; 39(Suppl 107): 123–128. bicarbonate in capillary blood. Scand J Clin Invest 1960; 12: 172–176. 34. Severinghaus JW. Case for standard-base excess as the measure of 6. Stewart PA. Independent and dependent variables of acid-base control. nonrespiratory acid-base imbalance. J Clin Monit 1991; 7: 276–277. Respir Physiol 1978; 33: 9–26. 35. Madias NE, Adrogue´ HJ, Horowitz GL et al. A redefinition of 7. Stewart PA. How to understand acid-base. In: Stewart PA (ed). A normal acid-base equilibrium in man: Carbon dioxide tension as a key Quantitative Acid-Base Primer for Biology and Medicine. Elsevier: New York, determinant of plasma bicarbonate concentration. Kidney Int 1979; 16: 1981, pp 1–286. 612–618. 8. Stewart PA. Modern quantitative acid-base chemistry. Can J Physiol 36. Adrogue´ HJ, Brensilver J, Cohen JJ et al. Influence of steady-state Pharmacol 1983; 61: 1444–1461. alterations in acid-base equilibrium on the fate of administered 9. Fencl V, Leith DE. Stewart’s quantitative acid-base chemistry: applications bicarbonate in the dog. J Clin Invest 1983; 71: 867–883. in biology and medicine. Respir Physiol 1993; 91: 1–16. 37. Adrogue´ HJ, Madias NE. Management of life-threatening acid-base 10. Lowry TM. The uniqueness of hydrogen. J Soc Chem Indust 1923; disorders. (First of two parts). N Engl J Med 1998; 338: 26–34. 42: 43–47. 38. Adrogue´ HJ, Madias NE. Management of life-threatening acid-base 11. Andersen OS, Astrup P, Bates RG et al. Statement on acid-base disorders. (Second of two parts). N Engl J Med 1998; 338: 107–111. terminology. Report of the ad hoc Committee of the New York Academy 39. Siggaard-Andersen O. Normal values and extreme values. In: The Acid- of Sciences Conference, November 23–24, 1964. Ann Intern Med 1965; Base Status of the Blood, 2nd edn. William and Wilkins: Baltimore, 1964, 63: 885–890. pp 26–29. 12. Winters RW. Terminology of acid-base disorders. Ann Intern Med 1965; 40. Schwartz WB, Relman AS. A critique of the parameters used in the 63: 873–884. evaluation of acid-base disorders ‘whole blood buffer base’ and ‘standard 13. Elkinton JR. Acid-base disorders and the Clinician (Editorial). Ann Intern bicarbonate’ compared with blood pH and plasma bicarbonate Med 1965; 63: 893–899. concentration. N Engl J Med 1963; 268: 1382–1388. 14. Schwartz WB, Brackett Jr NC, Cohen JJ. The response of extracellular 41. Siggaard-Andersen O. An acid-base chart for arterial blood with normal hydrogen ion concentration to graded degrees of chronic hypercapnia: and pathophysiological reference areas. Scand J Clin Lab Invest 1971; 27: the physiologic limits of the defense of pH. J Clin Invest 1965; 239–245. 44: 291–301. 42. Severinghaus JW. Acid-base balance nomogram – A Boston-Copenhagen 15. Gennari FJ, Goldstein MB, Schwartz WB. The nature of the renal de´tente. Anesthesiology 1976; 45: 539–541. adaptation to chronic hypocapnia. J Clin Invest 1972; 51: 1722–1730. 43. Siggaard-Andersen O. Blood acid-base alignment nomogram: scales for 16. Madias NE, Bossert WH, Adrogue´ HJ. Ventilatory response to chronic pH, PCO2, base excess of whole blood of different hemoglobin metabolic acidosis and alkalosis in the dog. J Appl Physiol 1984; concentrations, plasma bicarbonate, and plasma total-CO2. Scand J Clin 56: 1640–1646. Lab Invest 1963; 15: 211–217. 17. Adrogue´ HJ, Madias NE. Influence of chronic respiratory acid-base 44. Siggaard-Andersen O. The Van Slyke equation. Scand J Clin Lab Invest disorders on acute CO2 titration curve. J Appl Physiol 1985; 58: 1231–1238. 1977; 37(Suppl 146): 15–20. 18. Madias NE, Adrogue´ HJ. Influence of chronic metabolic acid-base disorders 45. Siggaard-Andersen O. Terminology. In: The Acid-Base Status of the Blood, on the acute CO2 titration curve. J Appl Physiol 1983; 55: 1187–1195. 2nd edn. William and Wilkins: Baltimore, 1964, pp 16–25. 19. Brackett Jr NC, Cohen JJ, Schwartz WB. Carbon dioxide titration curve of 46. Siggaard-Andersen O. The acid-base status of the whole organism. In: The normal man. Effect of increasing degrees of acute hypercapnia on Acid-Base Status of the Blood, 2nd edn. William and Wilkins: Baltimore, acid-base equilibrium. N Engl J Med 1965; 272: 6–12. 1964: 62–78.

1246 Kidney International (2009) 76, 1239–1247 HJ Adrogue´ et al.: Assessing acid–base disorders review

47. Schlichtig R, Grogono AW, Severinghaus JW. Human PaCO2 and standard 58. Figge J, Mydosh T, Fencl V. Serum proteins and acid-base equilibria: a base excess compensation for acid-base imbalance. Crit Care Med 1998; follow-up. J Lab Clin Med 1992; 120: 713–719. 26: 1173–1179. 59. Balasubramanyan N, Havens PL, Hoffman GM. Unmeasured anions 48. Kellum JA. Metabolic acidosis in the critically ill: lessons from physical identified by the Fencl-Stewart method predict mortality better than chemistry. Kidney Int 1998; 53(Suppl 66): 81–86. excess, anion gap, and lactate in patients in the pediatric intensive care 49. Kellum JA. Determinants of blood pH in health and disease. Crit Care unit. Crit Care Med 1999; 27: 1577–1581. 2000; 4: 6–14. 60. Dubin A, Menises MM, Masevicius FD et al. Comparison of three different 50. Kellum JA. Clinical review: reunification of acid-base physiology. Crit Care methods of evaluation of metabolic acid-base disorders. Crit Care Med 2005; 9: 500–507. 2007; 35: 1254–1270. 51. Corey HE. Stewart and beyond: new models of acid-base balance. Kidney 61. Cusack RJ, Rhodes A, Lochhead P et al. The strong ion gap does not have Int 2003; 64: 777–787. prognostic value in critically ill patients in a mixed medical/surgical adult 52. Lloyd P. Strong ion calculator – a practical bedside application of ICU. Intensive Care Med 2002; 28: 864–869. modern quantitative acid-base physiology. Crit Care Resuscit 2004; 6: 62. Emmett M. Clinical acid-base disorders: traditional versus ‘new’ analytical 285–294. models. Kidney Int 2004; 65: 1112. 53. Kaplan LJ, Kellum JA. Initial pH, base deficit, lactate, anion gap, strong ion 63. Kurtz I, Kraut J, Ornekian V et al. Acid-base analysis: a critique of the difference, and strong ion gap predict outcome from major vascular Stewart and bicarbonate-centered approaches. Am J Physiol Renal Physiol injury. Crit Care Med 2004; 32: 1120–1124. 2008; 294: F1009–F1031. 54. Rossing TH, Maffeo N, Fencl V. Acid-base effects of altering plasma 64. Singer RB, Hastings AB. An improved clinical method for the estimation of protein concentration in human blood in vitro. J Appl Physiol 1986; 61: disturbances of the acid-base balance of human blood. Medicine 1948; 2260–2265. 27: 223–242. 55. McAuliffe JJ, Lind LJ, Leith DE, et al. Hypoproteinemic alkalosis. Am J Med 65. Scheingraber S, Rehm M, Sehmisch C et al. Rapid saline infusion produces 1986; 81: 86–90. hyperchloremic acidosis in patients undergoing gynecologic surgery. 56. Fencl V, Rossing TH. Acid-base disorders in critical care medicine. Annu Anesthesiology 1999; 90: 1265–1270. Rev Med 1989; 40: 17–29. 66. Jaber BL, Madias NE. Marked dilutional acidosis complicating 57. Figge J, Rossing TH, Fencl V. The role of serum proteins in acid-base management of right ventricular myocardial infarction. Am J Kidney Dis equilibria. J Lab Clin Med 1991; 117: 453–467. 1997; 30: 561–567.

Kidney International (2009) 76, 1239–1247 1247