The arterial blood gas algorithm: Proposal of a systematic approach to analysis of acid-base disorders

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Rev Esp Anestesiol Reanim. 2020;xxx(xx):xxx---xxx

Revista Española de Anestesiología y Reanimación www.elsevier.es/redar

REVIEW

The arterial blood gas algorithm: Proposal of a systematic approach to analysis of acid-base disorders夽 S. Rodríguez-Villar a,∗ , B.M. Do Vale b , H.M. Fletcher a a b

Critical Care Department, King´s College Hospital, London, UK Intensive Care Department, Centro Hospitalar Universitário do Porto (CHUP), Porto, Portugal

Received 31 January 2019; accepted 29 April 2019

KEYWORDS Arterial blood gas; Acid-Base disorders; Algorithm of arterial gas analysis

PALABRAS CLAVES Gas arterial; Trastorno ácido-base; Algoritmo para el análisis de gases arteriales

Abstract Abnormalities in the acid-base balance are common clinical problems that can have deleterious effects on cellular function, and can suggest various disorders. Therefore, it is important for the clinician to correctly diagnose the acid-base disorder (s) in order to provide the best treatment. Three approaches have been proposed to evaluate acid-base disorders: a bicarbonate-centric approach; the Stewart approach; and the base excess approach. Although the latter two have many adherents, we will only discuss the bicarbonate-centric approach. This approach is simpler to use at the bedside, involves a physiological evaluation of the acidbase disorder, presents an easily understandable approach to severity assessment, and provides a more solid foundation for the development of effective therapies. Therefore, the following discussion will be limited to an examination of this approach. In this case-centric review, important new concepts will be introduced first; their benefits and limitations discussed; and then their use in the analysis of real cases will be shown. An algorithm with the new concepts has been designed to facilitate a systematic approach acid-base analysis. Crown Copyright © 2019 Published by Elsevier Espa˜ na, S.L.U. on behalf of Sociedad Espa˜ nola de Anestesiolog´ıa, Reanimaci´ on y Terap´ eutica del Dolor. All rights reserved.

El algoritmo de la gasometría arterial: propuesta de un enfoque sistemático para el análisis de los trastornosácido-básicos Resumen Las anomalías en el equilibrio ácido-base son problemas clínicos comunes y pueden tener efectos perjudiciales en la función celular y ser el indicio de varios trastornos. Por lo tanto, es importante para el clínico, el hacer un diagnóstico preciso de los trastornos ácido-base presentes para un tratamiento adecuado.

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Please cite this article as: Rodríguez-Villar S, Do Vale BM, Fletcher HM. El algoritmo de la gasometría arterial: propuesta de un enfoque sistemático para el análisis de los trastornos ácido-básicos. Rev Esp Anestesiol Reanim. 2019. https://doi.org/10.1016/j.redar.2019.04.001 ∗ Corresponding author. E-mail address: [email protected] (S. Rodríguez-Villar). 2341-1929/Crown Copyright © 2019 Published by Elsevier Espa˜ na, S.L.U. on behalf of Sociedad Espa˜ nola de Anestesiolog´ıa, Reanimaci´ on y Terap´ eutica del Dolor. All rights reserved.

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S. Rodríguez-Villar et al. Se han propuesto tres enfoques para evaluar los trastornos ácido-base: un enfoque centrado en el bicarbonato; El enfoque de Stewart y el enfoque de exceso de base. Aunque los dos últimos tienen muchos adeptos, sólo discutiremos el enfoque centrado en el bicarbonato. Este enfoque es más fácil de utilizar desde el punto de vista clínico, tiene una evaluación fisiológica del trastorno ácido-base, presenta una lógica fácilmente comprensible para evaluar la gravedad y proporciona además, una base más sólida para el desarrollo de terapias efectivas. Por lo tanto, nuestro trabajo se limitará a un examen en profundidad de esta teoría. En esta revisión, primero se introducirán conceptos importantes nuevos; sus beneficios y discusión de sus limitaciones; y luego se mostrará su utilización para analizar casos reales. Se ha generado un algoritmo para abordar de forma sistemática el análisis que incorpora estos nuevos conceptos. Crown Copyright © 2019 Publicado por Elsevier Espa˜ na, S.L.U. en nombre de Sociedad Espa˜ nola de Anestesiolog´ıa, Reanimaci´ on y Terap´ eutica del Dolor. Todos los derechos reservados.

Approach to the analysis of acid-based disorders Our approach to the diagnosis of an acid-base disorder involves a stepwise method including 1) validation of the internal consistency of the acid-base parameters available; 2) use of information from the clinical history and physical examination; 3) calculation of the albumin-corrected serum anion gap and the change in the anion gap compared to change in serum bicarbonate (delta anion gap/delta bicarbonate); and 4) determination of the primary initiating mechanism and appropriateness of the secondary adaptive response. For some disturbances, measurements of serum osmolality and urine electrolytes are useful.1---5 Finally, to determine the appropriate therapy, it is necessary to assess the severity of the acid-base disturbance. Currently, therapy is chosen on the basis of a study of arterial or venous blood gases, and aggressive therapy is recommended if blood pH is ≤ 7.20. However, even less severe acidemia can be associated with significant clinical abnormalities.

Normal acid-base parameters First, it is essential to identify normal acid-base parameters to establish the baseline on which changes can be described.1---5 Based on a recent theoretical analysis and a large database review, we suggest that the mean values for serum (total CO2 /HCO3 − ) are approximately 25 mEq/L in healthy men and 24 mEq/L in healthy women at sea level. Additionally, a reasonable reference range for serum (total CO2 /HCO3 − ) is 22---30 mEq/L in healthy adults at sea level.6 Based on studies in a small number of healthy men, a plasma pH of 7.38---7.42 is considered normal.6 Values above 1500 feet, an altitude at which hypoxemia can cause hyperventilation and chronic respiratory alkalosis, have not been well established. If the baseline values (total CO2 /HCO3 − ) are known, those values should be used to assess the acid-base disorder. In their absence, we suggest using the mean values noted above. Values for plasma (HCO3 − ) will be approxi-

Table 1 Validation of the internal consistency of the acidbase data. Relationship between pH & (H+ ) pH 6.8 6.9 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7 7.8

(H+ ) (nanomoles/l) 158 125 100 79 63 50 40 31 25 20 15

mately 1---1.5 mE/L lower. Thus, values < 7.38 (pH < 7.38) are termed acidemia, and values above 7.42 are termed alkalemia.2 Serum (HCO3 − ) < 23 mEq/L is termed hypobicarbonatemia, and serum (HCO3 − ) > 30 mEq/L is indicative of hyperbicarbonatemia.

Assessment of acid-base disorders Errors in the measurement of plasma pH, pCO2 or serum (total CO2 /HCO3 − ) are not uncommon. To identify errors, it is usefule to insert the obtained values into the HendersonHasselbalch equation (Table 1). pH = 6.1 + (HCO3 − )/.03pCO2 If the values do not fit, this could suggest an error in one or more of the parameters, and the measurements should be repeated (Fig. 1). A focused history should be obtained, and a complete physical examination performed.2,3 The primary initiating mechanism should be determined, and the appropriateness of the secondary adaptive response should

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Fig. 1 The first step in our approach is to identify errors and prioritize patient safety. We would start checking the arterial pH, pCO2 and serum bicarbonate for internal consistency using Henderson-Hasselbalch equation. Even an apparently ‘‘normal ABG’’ could potentially carry and acid-base disorder, so it is a good practice to calculate the AG (anion gap) routinely.

be assessed. The serum anion gap (AG), change in the AG from baseline (AG), change in serum levels (HCO3-) and change in serum (HCO3-) from baseline (HCO3-) should be calculated, and the relationship between the (HCO3-) and AG should then be determined.

evolves over hours or days. Therefore, unless the clinician knows precisely when an acid-base disorder began, the written reports should reflect this uncertainty.

Definitions of primary acid-base disorders

Metabolic acidosis is an acid-base disorder initiated by a reduction in plasma or serum levels (HCO3 − ) (Fig. 2). It is associated with a secondary decrease in PCO2 , which represents the physiologic compensatory response.8 It is usually associated with a low plasma pH(pH<7.38) .1,2,8---10 Recently, patients in whom acid is retained in the interstitial compartments without a detectable change in serum levels (HCO3 − ) or plasma pH have been identified. This has been termed subacute or eubicarbonatemic metabolic aci-

The four cardinal acid-base disorders are shown in Table 2. A simple acid-base disorder represents both the primary change in serum levels (HCO3 − ) or PaCO2 and appropriate secondary response.7 Each of the secondary responses evolves over time. For example, the immediate respiratory response to metabolic acidosis, alkalosis, or respiratory acidosis is observed within minutes, but the chronic response

Metabolic acidosis

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S. Rodríguez-Villar et al. Table 2

Primary acid-base disorders and Secondary Compensatory Response.

Acid-Base Disturbance Initiating factor Metabolic Acidosis Respiratory Acidosis

Metabolic Alkalosis Respiratory Alkalosis

Table 3

Secondary compensatory response

Decrease in serum (HCO3 -) Pco2 = 1.5 × HCO3 − +8 ± 2 (Winter’s formula) or decrease in Pco2 of 1 -1.3 mmHg for every 1 mEq/L decrease in serum (HCO3 − ) Increase in Pco2 Increase in serum [HCO3 − ] Early (up to 8 h) increase of 1 mEq/L for every 10 mmHg increase of Pco2 Late ( 24 --- 36 h) increase of 4 mEq/L for every 10 mmHg increase in Pco2 Increase in serum (HCO3 -) Increase in Pco2 of 4 --- 7 mmHg (mean 5 mmHg) for every 10 mEq/L increase in serum [HCO3 -] Decrease in Pco2 Decrease in serum [HCO3 -] Early: decrease of 2 mEq/L for every 10 mmHg decrease in Pco2 Late: ≥ 24 --- 36 h decrease of 5 mEq/L for every 10 mmHg decrease in PCO2

Conditions associated with metabolic acidosis.

Organ System Affected

Pathophysiologic consequence

Cardiovascular System

Decreased cardiac contractility Arterial Vasodilatation Hypotension Venous Vasoconstriction with central pooling of blood Predisposition to cardiac arrhythmias Stimulation of respiration Early- decreased binding to Hg (Bohr effect) Late increased 2.3-DPG with reduced binding of O2 to Hb Increased circulating catecholamines Reduced cellular responsiveness to catecholamines Changes in circulation parathyroid hormone levels Alterations in binding of ligand to calcium sensing receptor Increased ionized Ca2+ Hyperkalaemia, Hypokalaemia Reduced gastrointestinal function Decreased sensorium

Respiratory System and O2 delivery Metabolic

Electrolytes Gastrointestinal System Central Nervous System 2.3-DPG; 2,3 Diphosphoglycerate, Hg; Haemoglobin.

dosis. Importantly, these patients might present adverse effects similar to patients with overt metabolic acidosis. It is hard to identify these patients today, but appropriate methods might be available in the future.11 Metabolic acidosis can also be classified according to duration. Acute metabolic acidosis is arbitrarily defined as lasting from minutes to days, and chronic metabolic acidosis lasts for weeks to years.12 This distinction has not been subject to rigorous examination, and could be redefined in the future. Importantly, the adverse effects of acute and chronic metabolic acidosis differ in many respects, as shown in Table 3. A priori, it has been suggested that most cases of acute, particularly severe, metabolic acidosis are due to diabetic ketoacidosis and lactic acidosis.13 Non-gap metabolic acidosis is a common cause of acute metabolic acidosis, and is attributed to aggressive fluid therapy with chloride-containing solutions (Fig. 3). In addition, chronic kidney disease is probably the most common cause of normal and high anion-gap metabolic acidosis.14---16 The relationship between the severity of the acidosis (as defined by serum HCO3 − ) and PaCO2 varies, depending on the time elapsed between onset and evaluation of the patient. Within the first 8 h, PaCO2 is reduced by 0.85 mmHg for every

1 mEq/L reduction in serum levels (HCO3 ).17 Subsequently, the adaptive response becomes more vigorous, and is complete 24 h after the onset of metabolic acidosis, although complete normalization of blood pH is not apparent. PCO2 is reduced 1---1.3 mmHg for every 1 mEq/L decrement in serum (HCO3 − ). The expected pCO2 can also be determined using Winter´s formula: PCO2 = 1.5 X (HCO3 − ) + 8 ± 2 (Fig. 2). If the measured pCO2 is outside the calculated interval range, then a mixed acid-base disorder is present. Mixed disturbances common, particularly in seriously ill patients.7,8,18,19 Metabolic acidosis is subcategorized into two entities based on AG. In the first entity, the AG can remain unchanged from normal: non-anion gap (hyperchloremic), and the AG (high anion gap acidosis) is increased in the second entity. The AG is calculated by subtracting the sum of chloride and bicarbonate from sodium and potassium2,12,20 (Fig. 2): AG = Na+ +K-(Cl− +HCO3 − ). Many clinicians ignore serum potassium because its concentration is low. However, this is being re-evaluated in some studies.21,22 The AG will vary with fluctuations of serum albumin concentration2,3,7---9,20 and should be corrected for

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Fig. 2 Shows the systematic analysis of metabolic acidosis, initially using Winter’s formula to identify the presence of a simple or complex disorder. Next, the AG (‘‘anionic gap’’) is calculated and adjusted for albumin, prevailing deviations from normal AG values (increase or decrease) are caused by several processes described in flowcharts 7 ( metabolic acidosis with high anion gap) and 8 (hyperchloraemic metabolic acidosis or normal gap anion).

the prevailing serum albumin: corrected AG = AG + 2.5 x (4 - serum albumin g/dl).23 The normal AG can even vary among a cohort of healthy patients (range 10 mEq/L from low to high) and between laboratories, depending on the different methods sed to measure serum chloride. Therefore, it is important for the

5 clinician to know the normal range for their laboratory, and if possible, the normal baseline value for the particular patient.3 Deviations from the prevailing normal AG value (either increases or decreases) are caused by several processes. An AG below normal is infrequent and should alert the clinician to either a laboratory error or one of several disorders (Fig. 3). A high AG is more common, and is normally associated with overproduction or decreased excretion of organic and inorganic acids.24 The relationship between the AG (HCO3 − ) should then be determined. A 1:1 stoichiometry is often assumed between AG and (HCO3 − ), and deviations from 1:1 indicate an accompanying metabolic acid-base disorder (Fig. 4). For example, when (HCO3 − ) exceeds the AG, a normal anion gap (hyperchloremic acidosis) is said to coexist. In contrast, when AG exceeds the (HCO3 − ), ametabolic alkalosis (or other hyperbicarbonatemic disorder) is said to coexist.20 Although the AG/ (HCO3 − ) might be 1:1 in the initial phase of an anion-gap metabolic acidosis, this ratio can potentially change when acidosis persists, and the distribution of protons extends from compartments outside the extracellular fluid can be buffered intracellularly and cause a parallel increase in the ratio.8,20,25 Additionally, the 1:1 relationship found with ketoacidosis might not hold with lactic acidosis. In lactic acidosis, the relationship can be 1.6:1 early in the course of the disorder (owing to the difference between the volume of anion and proton distributions, a reduction in serum chloride secondary to its dilution by Na+ , and water in the cells during the buffering process).21,22,26,27 Evaluation of the serum osmolal gap (SOG) can be useful, and elevation suggests toxic alcohol poisoning (Fig. 4). A simple method to determine a change in the SOG from baseline is: SOG (mOsm/kg) = (measured serum osmolality) --- 2 × (Na + K) + BUN (urea nitrogen) (mg/dL) /2.8 + Glucose (mg/dL)/18. Baseline values for SOG can vary from negative to close to 10---20 mOsm/kg. Additionally, the increment in SOG will depend on the molecular weight of the toxic alcohol present. Finally, time from exposure will affect the concentration of the parent alcohol. Toxic alcohol poisoning can present with elevated SOG, increased AG, an increase in both AG and SOG, or normal values for both (Fig. 4). Other disorders, such as lactic acidosis and ketoacidosis, can be associated with increased SOG and AG8 and should be distinguished from toxic alcohol poisoning.28 In nonanion gap metabolic acidosis, the decrease in serum (HCO3 − ) is matched by an equivalent increment in chloride.15,20 In fact, the AG might decrease as protons reduce their anionic equivalency.29 The main pathophysiologic processes that can cause non-anion gap metabolic acidosis are (Fig. 3) a loss of bicarbonate from the urinary or gastrointestinal tract, or a decrease in net acid excretion (primarily as the result of decreased ammonium [NH4 + ] excretion). In contrast to the high anion gap acidosis associated with chronic kidney disease (CKD), there is no retention of filtered anions. Disorders producing a non-anion gap acidosis are associated with either increased loss of potassium from the body and hypokalemia, or impaired renal excretion and hyperkalemia. Accordingly, non-anion gap acidosis can be divided

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Fig. 3 Describes the main pathophysiological processes that can cause metabolic acidosis with a normal anion-gap (= hyperchloraemic metabolic acidosis): loss of bicarbonate from the urinary/gastrointestinal tract or a decrease in net acid excretion. Finally, deviations from the 200 mOsm/kg urine osmolal gap (increase or decrease) are caused by several processes that are described in flowcharts 9 and 10, and that may or may not be caused by renal dysfunction.

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Fig. 4 )Flow chart for the analysis of metabolic acidosis with high gap anion. It is usually associated with overproduction or decreased excretion of organic and inorganic acids. Evaluation of this type of acidosis is based on calculating the Delta Gap, also called the Delta-Ratio , which rules out the presence of mixed acid-base disorder. Finally, the Serum Osmolal Gap is calculated. This can help identify the presence of unusual substances in plasma, such as methanol or ethylene glycol.

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Fig. 5 List of differential diagnosis of renal and non-renal origin based on the urine osmolal gap (UOG) for the metabolic acidosis with normal anion gap (=hyperchloremic metabolic acidosis).

into acidosis with high or normal serum potassium or acidosis with low serum potassium,29 as shown in the algorithm (Fig. 3). Additionally, the kidneys can play a prominent role. Documenting whether renal bicarbonate reabsorption is impaired and ammonium excretion is appropriate will allow the clinician to identify the kidneys as a contributing factor. To establish the latter, one should assess the quantity of NH4 + excreted in urine. This can be done indirectly by calculating the urine anion or osmolal gap, as described below (Fig. 3), or urine NH4 + can be measured directly.19,29 UrineAnionGap(UAG) = (Na+ +K+ )-Cl− Urine Osmolal Gap (UOSMG) = measured urine osmolality --- 2 x (Na+ + K+ )+ BUN (mg/dL)/2.8 + Glucose (mg/dL)/18 The UAG, is negative by 30 mEq/L when NH+ 4 excretion is appropriate, and less negative or positive when low. Situations in which UAG is abnormal though urinary NH4 + excretion is appropriate can be detected by calculating the UOSMG.18 An UOSMG < 200 mmol/L indicates NH+ 4 excretion is low, whereas an UOSMG > 200 mmol/L indicates it is adequate30---32 (Figs. 3 and 5). Urine NH4 + can be measured directly using a modification of the plasma NH4 + assay. Urine should be refrigerated to prevent urea growth from splitting pathogens.18---29,33

Respiratory acidosis Respiratory acidosis is an acid-base disorder initiated by an elevation in pCO2 (hypercapnia). A secondary increase in serum HCO3 − can occur, and represents the physiologic compensatory response17 (Fig. 6). Respiratory acidosis results mainly from normal or increased CO2 production that cannot be adequately matched by CO2 excretion through pulmonary ventilation. As in metabolic acidosis, clinical history and physical examination should provide invaluable clues to the etiology of

the disorder, and guide the appropriate diagnostic and therapeutic interventions. The adaptive rise in serum (HCO3 − ) in response to an increase in PCO2 can be determined from the formulae in Table 2 (see also Fig. 6). Deviations in serum (HCO3 − ) by > 2 mEq/L from predicted suggests the coexistence of a metabolic disorder. Hypercarbia may cause somnolence (CO2 narcosis), worsen respiratory depression, and precipitate acute respiratory arrest. Pure respiratory acidosis is easily diagnosed; the pCO2 will be elevated; arterial pH will be decreased; and the elevation in serum HCO3 − will be within range of the calculated level using the respective formulas for acute or chronic hypercapnia.

Metabolic alkalosis Metabolic alkalosis is initiated by an elevation in serum (HCO3 − ).1,2,8,9,13 The increase in serum (HCO3 − ) is followed by suppression of ventilation, with a resulting increase in PaCO2 . Although this process is initiated relatively quickly after the rise in serum values (HCO3 − ), an established relationship between these parameters is based on observations 12---24 hours after onset, and assumes that the (HCO3 − ) has been relatively stable. A pCO2 within the appropriate range indicates an adequate compensatory response and a simple acid-base disturbance (Fig. 7). In contrast, if the measured pCO2 is outside the calculated interval range, then a mixed acid-base disorder is present (if >2 mmHg of predicted value, concomitant respiratory acidosis; if <2 mmHg of predicted value, concomitant respiratory alkalosis).13 Combined disturbances are not uncommon. Metabolic alkalosis and respiratory alkalosis are frequently seen in ICU patients with gastric drainage and infection. Similarly, metabolic alkalosis and respiratory acidosis are frequent present in patients with chronic lung disease receiving diuretics. The most common mechanisms responsible for the generation of metabolic alkalosis are either a direct loss of

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Fig. 6 Respiratory acidosis results mainly from normal or increased CO2 production that cannot be adequately matched by the CO2 excretion through pulmonary ventilation. The adaptive rise in serum (HCO3 − ) in response to an increase in PCO2 can be determined from the formulae in Fig. 6.

hydrogen, administration of bicarbonate (or its precursors, e.g., citrate) rich solutions, or volume depletion (Fig. 8). The kidney has the ability to correct metabolic alkalosis by excreting excess HCO3 − . Consequently, the persistence of metabolic alkalosis requires an impairment of the kidney´s ability to excrete the excess load of HCO3 − . This impairment can be due to the confluence of several factors, including a reduction in the effective circulating volume and glomerular filtration rate, chloride depletion, secondary hyperaldosteronism, and hypokalemia.4 When alkalemia is severe (pH > 7.55), mortality can reach 40 % or more. Therefore, clinicians should be vigilant in following these acute patients, and make every effort to maintain serum HCO3 − levels at < 30 mmol/L (mEq/L). Additionally, as noted above, it is very common for both metabolic alkalosis and respiratory alkalosis to coexist. This combination will produce the most severe alkalemia. Metabolic alkalosis can be divided into two broad categories, based on their response to administered chlo-

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Fig. 7 Metabolic alkalosis. pCO2 within the appropriate range indicates an adequate compensatory response and a simple acid-base disturbance. In contrast, if the measured pCO2 is outside the calculated interval range, then a mixed acid-base disorder is present. We can finally classify the aetiology of metabolic alkalosis on the basis of depleted or high/normal intravascular volume, according to flow charts 5 and 6.

ride (Fig. 8): chloride responsive (urine Cl− concentration is usually <20 mmol/L) and chloride-resistant (urine Cl− concentration >20 mmol/L). Serum electrolytes are similar in all cases of metabolic alkalosis, i.e., hypochloremia, elevated serum bicarbonate, and decreased serum K+ . In Cl− responsive metabolic alkalosis associated with volume contraction, the anion gap value can be slightly elevated (by as much as 6 mmol/L). The investigation of metabolic alkalosis starts with an evaluation of the patient’s intravascular volume status based on clinical variables, such as blood pressure, heart rate, orthostatic changes in blood pressure, urine output, mentation, capillary refill time, presence of edema, urea and creatinine levels (Fig. 7). This initial evaluation should help the clinician divide these patients into two major groups: the first with normal or raised intravascular volume

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Fig. 8 The figure shows the differential diagnosis in the context of volume depletion, divided into two broad categories based on response to administered chloride: chloride responsive (urine Cl− concentration is usually <20 mmol/L) and chloride-resistant (urine Cl− concentration >20 mmol/L).

status, and the second with decreased intravascular volume status (Figs. 8 and 9). The conditions most often associated with individuals in the first group are related to high mineralocorticoid pathway activity. Measurements of serum renin and aldosterone activity may provide the definitive evidence for a conclusive diagnosis (see Table 4). The second group of patients most often suffer from conditions associated with loss of body fluids (e.g., vomiting, diuresis, or tubular reabsorptive defects). In this setting, a measurement of urine electrolytes will be helpful in making the distinction. A low urinary Cl− (<20 mmol/L) and a low urinary Na+ (<20 mmol/L) is suggestive of a posthypercapnic state (common among ITU treated patients in which rapid correction of pCO2 by mechanical ventilation does not allow time for the kidney to compensate), remote diuretic use, or remote non-active vomiting. Conversely, a low urinary Cl−

with a high urinary Na+ (>20 mmol/L) is suggestive of active vomiting or excretion of nonreabsorbed anions. A high urinary Cl− (>20 mmol/L) suggests the use of diuretics, Mg2+ deficiency, Barters’ syndrome, Gitelman´s syndrome, alkali administration (such citrate) or hypokalemia.4 With normal or elevated intravascular volume, conditions associated with high mineralocorticoid activity are likely (Fig. 6).

Respiratory alkalosis Respiratory alkalosis is initiated by a reduction in PCO2 with a secondary decrease in serum (HCO3 − ). When mild, the plasma pH might be within the normal range, but when it is more severe, patients usually present with elevated plasma pH (pH > 7.42).1,2,8,18,32

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11 Table 5 Pathophysiologic consequences of severe alkalemia by organ system. Cardiovascular Arterial constriction Reduction in coronary blood flow Reduction in angina threshold Predisposition to refractory supraventricular and ventricular arrhythmias Respiratory Hypoventilation, hypercapnia and hypoxia Metabolic Stimulation of anaerobic glycolysis and organic acid production Hypokalemia Decreased plasma ionized calcium concentration Hypomagnesemia and hypophosphatemia Cerebral Reduction in cerebral blood flow Tetany, seizures, lethargy, delirium and stupor

Fig. 9 The conditions most often associated with individuals with normal or raised intravascular volume status (metabolic alkalosis) are related to high mineralocorticoid pathway activity. Measurements of serum renin and aldosterone activity may provide the definitive evidence for a conclusive diagnosis.

Table 4 activity.

Conditions associated with high mineralocorticoid

Increased renin and aldosterone activity Renal artery stenosis Accelerated hypertension Renin secreting tumors Decreased renin and increased aldosterone activity Primary aldosteronism Adrenal adenoma Bilateral adrenal hyperplasia Dexamethasone responsive adrenal hyperplasia Decreased renin and aldosterone activity Cushing syndrome Exogenous mineralocorticoids Congenital adrenal defect 11- -hydroxylase deficiency Liddle’s syndrome

Acute hypocapnia results in a more marked deviation in blood pH than chronic hypocapnia. Generally, the changes in acid-base parameters occur in two phases, similar to respiratory acidosis. Within the first 10 min, a release of protons from body buffers leads to a small decrease in serum (HCO3 − ) concentration. Serum HCO3 − concentration is reduced by 2 mmol/L for every 10 mmHg decrease in PCO2 . When alkalosis is prolonged by more than 24---36 hours, the suppression of respiration is more pronounced, with HCO3 − being reduced by approximately 5 mmol/L for every 10 mmHg reduction of pCO2 . Of note, mild chronic hypocapnia can result in serum HCO3 − and blood pH within the normal ranges, and therefore might be difficult to detect. An alkalemic pH, particularly when severe, can predispose the patient to arrhythmias due to both a decrease in ionized calcium levels and increase in cellular pH and external pH.4,13 (Table 5 and Fig. 10)

Mixed acid-base disorders The combination of two metabolic disturbances, a metabolic and respiratory disturbance, or two metabolic and one respiratory disturbances (triple acid-base disturbances) are common, particularly in seriously ill patients.18,19 (Table 6). In most disturbances (except for mild chronic hypocapnia), blood pH is outside normal limits. Therefore, any deviation from normal of serum (HCO3 − ) or PCO2 associated with a normal plasma pH suggests the presence of a mixed acid-base disorder. The diagnosis of acid-base disorders is an essential step in the care of patients. The foregoing discussion introduced the basic concepts of acid-base analysis. An algorithm summarizing this approach is shown in Fig. 1. Although not perfect, it should allow the clinician to make a rapid assessment of the acid-base profile of the individual patient. However, the clinician should always be aware of the limitations of any formalized approach, and close patient follow-up is essential.

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pCO2 < 4.7 KPa (35 mmHg)

YES

Respiratory alkalosis

• ACUTE, pH increases x 0.08 ([40-PaCO2]/10) Acute respiratory alterations change pH units by 0.08 for each 10 mmHg deviation (=1KPa) from normal values (pH 7.40) CHRONIC, pH increases by 0.03 x ([40 PaCO2]/10) • Chronic respiratory alterations change pH units by 0.03 for each 10 mmHg deviatio (=1KPa) from normal values (pH 7.40)

Is it a simple or complex (mixed) acid-base disorder?

CHRONIC respiratory alkalosis

Acute respiratory alkalosis (< 48 h from onset): • Is measured HCO3 different (+/- 2) from predicted? HCO3 = 26 (40-pCO2/5) (+/- 2): -If arterial HCO3 is above (2 mmol/L = mEq/L) predicted: concomitant metabolic alkolosis. -If arterial HCO3 is below (2 mmol/L) predicted: concomitant metabolic acidosis. • Is SBE out of normal range? SBE < 3 (acidosis) SBE > (alkalosis)

(> 48 h from onset): • Is measured HCO3 different (+/- 2) from predicted? HCO3 = 26 (40-pCO2/2) (+/- 2): -If arterial HCO3 is above predicted: concomitant metabolic alkalosis -If arterial HCO3 is below predicted: concomitant metabolic acidosis • Is SBE different from predicted? SBE = 0.4x (pCO2-40)

YES

Complex (mixed) acid-base disorder: respiratory alkalosis with secondary metabolic acid-base imbalance.

NO

Simple acid-base disorder: pure respiratory acidosis

Fig. 10 Respiratory alkalosis is initiated by a reduction in PCO2 with a secondary decrease in serum (HCO3 − ). The adaptive reduction in serum (HCO3 − ) in response to a decrease in PCO2 can be determined from the formulae shown. HCO3 − within the appropriate range indicates an adequate compensatory response and a simple acid-base disturbance. In contrast, if the measured HCO3 − is outside the calculated interval range, then a mixed acid-base disorder is present.

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13

Common mixed acid-base disorders in intensive care.

Metabolic acidosis and respiratory alkalosis

Metabolic acidosis and respiratory acidosis Metabolic alkalosis and metabolic acidosis

Metabolic alkalosis and respiratory alkalosis Metabolic alkalosis and respiratory acidosis Mixed non anion gap (hyperchloremic) and high--anion gap acidosis

Multiple acid-base disorders

Severe sepsis and septic shock Salicylate toxicity Congestive heart failure and renal failure Cardiorespiratory arrest Hypoxemic respiratory failure Diuretic therapy and ketoacidosis Vomiting and renal failure Vomiting and lactic acidosis/ ketoacidosis Diuretic therapy and chronic hepatic failure Diuretic therapy and sepsis Diuretic therapy and chronic obstructive pulmonary disease Vomiting and chronic obstructive pulmonary disease Early chronic renal failure Diarrhea and lactic acidosis/ ketoacidosis Renal tubular acidosis and uremic acidosis Hyporeninemic hypoaldosteronism and diabetic ketoacidosis Mixed metabolic acidosis + metabolic alkalosis + respiratory alkalosis and/or acidosis (ex: cirrhotic alcoholic patient that has a vomit episode, determining metabolic alkalosis, goes into starvation Ketoacidosis, and has concomitant respiratory alkalosis from hyperventilation secondary to liver failure). Any combination of the above

Conclusions

References

In this review, we attempted to provide the reader with a stepwise approach to the diagnosis of acid-base disorders using arterial blood gas as a fundamental tool, and the physiologic, bicarbonate-centric approach for analysis. Thus, by revealing and explaining some of the complexities and limitations of the arterial blood gas interpretation, we hope to equip the clinician with a framework to correctly interpret the data, maximize the information that can be extracted from it, and minimize errors or incorrect interpretations. We also discussed some of the current limitations of serum anion gap interpretations and urine anion and osmolar gap measurements; we presented future improvements that should be adopted, such as direct measurements of urinary NH4 + that will likely improve the diagnostic accuracy for renal tubular acidosis and related disorders. Arterial blood gas results must be contextualized in the clinical scenario in order to arrive at a correct diagnosis and implement the appropriate therapeutic modality.34 Thus, the patient’s clinical history and a detailed physical examination are indispensable for the reasoning process.

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Funding Financial support, including any institutional departmental funds, was not sought for the study.

Conflict of interests All faculty and staff in a position to control or affect the content of this paper have declared that they have no competing financial interests.

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