Acs0808 Acid Base Disorders


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Acs0808 Acid Base Disorders

  1. 1. © 2006 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 8 ACID-BASE DISORDERS — 1 8 ACID-BASE DISORDERS John A. Kellum, M.D., and Juan Carlos Puyana, M.D., F.A.C.S. Anticipation and early identification of conditions that alter the There are three mathematically independent determinants of body’s ability to compensate for acid-base disorders are vital in the blood pH: (1) the SID, defined as the difference in concentration management of surgical and critically ill patients. A clear under- between strong cations (e.g., sodium [Na+] and potassium [K+]) standing of metabolic-respiratory interactions and a systematic and strong anions (e.g., chloride [Cl–] and lactate); (2) the total approach aimed at identifying the separate components of acid- concentration of weak acids (Atot), mainly consisting of albumin base disorders not only serves as a diagnostic tool but also helps in and phosphate; and (3) PCO2. These three variables, and only formulating therapeutic interventions. For example, abnormal these three, can independently affect plasma pH. The H+ and acid-base balance may be harmful in part because of the patient’s HCO3– concentrations are dependent variables whose values in response to the abnormality, as when a spontaneously breathing plasma are determined by the SID, Atot, and PCO2. Changes in the patient with metabolic acidosis attempts to compensate by plasma H+ concentration occur as a result of changes in the dis- increasing minute ventilation. Such a response may lead to respi- sociation of water and Atot, brought about by the electrochemical ratory muscle fatigue with respiratory failure or diversion of blood forces generated by changes in the SID and PCO2. The SBE is flow from vital organs to the respiratory muscles, eventually mathematically equivalent to the difference between the current resulting in organ injury.The increased catecholamine levels asso- SID and the SID required to restore the pH to 7.4, given a PCO2 ciated with acidemia may provoke cardiac dysrhythmias in criti- of 40 mm Hg and the prevailing Atot.Thus, an SBE of −10 mEq/L cally ill patients or increase myocardial oxygen demand in patients means that the SID is 10 mEq less than the value required to with myocardial ischemia. In such cases, it may be prudent not achieve a pH of 7.4. only to treat the underlying disorder but also to provide sympto- The essential element of this physicochemical approach is the matic treatment for the acid-base disorder itself. Accordingly, it is emphasis on independent and dependent variables. Only changes important to understand both the causes of acid-base disorders in the independent variables can bring about changes in the and the limitations of various treatment strategies. dependent variables. That is, movement of H+ or HCO3– cannot To treat acid-base disorders, it is not sufficient simply to return affect plasma H+ or HCO3– concentrations unless changes in the one or two laboratory parameters to normal values; one must SID, Atot, or PCO2 also occur. Several reviews of this approach are understand the overall course of the disorder, as well as the spe- available in the literature.3-9 In what follows, we discuss the clini- cific forces involved at any particular time. For example, in a cal application of this approach to the diagnosis and treatment of patient with acute lung injury and moderate hypercapnia, allowing individual acid-base disorders. mild acidemia may be preferable to forcing the lung to achieve a ASSESSMENT OF ACID-BASE BALANCE normal carbon dioxide tension (PCO2). Similarly, prescribing bicar- bonate therapy without anticipating the effects on the body’s own Acid-base homeostasis is defined by the plasma pH and by the compensatory efforts may induce an unwanted rebound alkalemia. conditions of the acid-base pairs that determine it. Normally, arte- A comprehensive understanding of the pathophysiology and a rial plasma pH is maintained between 7.35 and 7.45. Because practical approach to bedside evaluation are complementary com- blood plasma is an aqueous solution containing both volatile acids ponents of care and are equally necessary in the management of an (e.g., CO2) and fixed acids, its pH is determined by the net effects acid-base disorder. of all these components on the dissociation of water. The deter- minants of blood pH can be grouped into two broad categories, respiratory and metabolic. Respiratory acid-base disorders are dis- General Principles orders of PCO2; metabolic acid-base disorders comprise all other conditions affecting pH, including disorders of both weak acids DESCRIPTION AND CLASSIFICATION OF ACID-BASE DISORDERS (often referred to as buffers, though the term is imprecise) and There are three widely accepted methods of describing and strong acids (organic and inorganic) and bases. Any of the follow- classifying acid-base abnormalities. Essentially, they differ from ing indicators serves to identify an acid-base disorder: one another only with respect to assessment of the metabolic com- 1. An abnormal arterial blood pH (pH < 7.35 signifies acide- ponent of the abnormality; all three treat PCO2 as an independent mia; pH > 7.45 signifies alkalemia). variable.The first method quantifies the metabolic component by 2. An arterial PCO2 (PaCO2) that is outside the normal range using the bicarbonate ion (HCO3–) concentration (in the context (35 to 45 mm Hg). of PCO2); the second, by using the standard base excess (SBE); 3. A plasma HCO3– concentration that is outside the normal and the third, by using the strong ion difference (SID). In prac- range (22 to 26 mEq/L). tice, these three methods yield virtually identical results when 4. An arterial SBE that is either abnormally high (≥ 3 mEq/L) employed to quantify the acid-base status of a given blood sam- or abnormally low (≤ −3 mEq/L). ple.1-4 Thus, the only significant distinctions between the methods are conceptual ones, related to how each one approaches the Once identified, an acid-base disorder can be classified accord- understanding of the mechanism of the disorder.5-7 In this chap- ing to a simple set of rules [see Table 1]. A disorder that does not fit ter, we emphasize the physicochemical determinants of pH in the well into the broad categories established by these rules can be blood and the tissues; however, it is a simple matter to convert considered a mixed (or complex) disorder. Some of the basic cat- from one approach to the other if desired. egories can be further divided into various subcategories (see
  2. 2. © 2006 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 8 ACID-BASE DISORDERS — 2 Table 1—Differentiation of Acid-Base Disorders6 Physicochemical Parameter Disorder HCO3– Concentration (mEq/L) PCO2 (mm Hg) SBE (mEq/L) = (1.5 × HCO3-) + 8 Metabolic acidosis < 22 < –5 = 40 + SBE = (0.7 × HCO3-) + 21 Metabolic alkalosis > 26 > +5 = 40 + (0.6 × SBE) Acute respiratory acidosis = [(Pco2 – 40)/10] + 24 > 45 =0 Chronic respiratory acidosis = [(Pco2 – 40)/3] + 24 > 45 = 0.4 × (Pco2 – 40) Acute respiratory alkalosis = 24 – [(40 – Pco2)/5] < 35 =0 Chronic respiratory alkalosis = 24 – [(40 – Pco2)/2] < 35 = 0.4 × (Pco2 – 40) SBE—standard base excess below), but before the issue of classification is addressed in detail, according to the ions that are responsible (e.g., lactic acidosis and three general caveats must be considered. chloride-responsive alkalosis). First, interpretation of arterial blood gas values and blood It is important to recognize that metabolic acidosis is caused by chemistries depends on the reliability of the data. Advances in a decrease in the SID, which produces an electrochemical force clinical chemistry have improved the sensitivity of instruments that acts to increase the free H+ concentration. A decrease in the used to measure electrolyte concentrations (e.g. ion-specific elec- SID may be brought about by the generation of organic anions trodes) and have greatly enhanced the speed and ease of analysis. (e.g., lactate and ketones), by the loss of cations (as with diarrhea), Inevitably, however, prolonged exposure to the atmosphere results by the mishandling of ions (as with renal tubular acidosis), or by in a lowering of the PCO2, and over time, there may be ongoing the addition of exogenous anions (as with iatrogenic acidosis or cellular metabolism. Accordingly, prompt measurement is always poisoning). By contrast, metabolic alkalosis is caused by an inap- advisable. Even with prompt measurement, laboratory errors may propriately large SID (though it may be possible for the SID to be occur, and information may be incorrectly reported. Samples inappropriately large without exceeding the normal range of 40 to drawn from indwelling lines may be diluted by fluid or drug infu- 42 mEq/L). An increase in the SID may be brought about by the sions (a notorious source of error). When the situation is confus- loss of more strong anions than strong cations (as with vomiting ing, it is usually best to repeat the measurement. or diuretic therapy) or, in rare instances, by the administration of Second, interpretation of arterial blood gas values may be prob- more strong cations than strong anions (as with transfusion of lematic in patients with severe hypothermia (e.g., trauma patients large volumes of banked blood containing sodium citrate). undergoing damage-control interventions, who often are severely Because metabolic acid-base disorders are caused by changes hypothermic and sometimes experience severe acidosis), in that in the SID, their treatment necessarily involves normalization of the findings may not reflect the actual blood gas values present. the SID. Metabolic acidoses are corrected by increasing the plas- Because blood samples are “normalized” to a temperature of 37° ma Na+ concentration more than the plasma Cl– concentration C before undergoing analysis, the results obtained in samples (e.g., by administering NaHCO3), and metabolic alkaloses are from a patient whose body temperature is significantly lower than corrected by replacing lost Cl– (e.g., by giving sodium chloride 37° C may not be sufficiently accurate. To obviate this potential [NaCl], potassium chloride [KCl], or even hydrochloric acid problem, the results may have to be adjusted to take the patient’s [HCl]). So-called chloride-resistant metabolic alkaloses [see actual temperature into account. At present, however, such tem- Metabolic Alkalosis, Chloride-Resistant Alkalosis, below] are resis- perature correction is not routinely done, and there has been tant to chloride administration only because of ongoing renal Cl– some controversy regarding whether it has real clinical value.10,11 loss that increases in response to increased Cl– replacement (as Third, whereas the aforementioned four indicators are useful with hyperaldosteronism). for identifying an acid-base disorder, the absence of all four does PATHOPHYSIOLOGY not suffice to exclude a mixed acid-base disorder (i.e., alkalosis plus acidosis) in which the two components are completely Disorders of metabolic acid-base balance occur in one of three matched. Fortunately, such conditions are rare. In addition, apart ways: (1) as a result of dysfunction of the primary regulating from distinguishing a respiratory acid-base disorder from a meta- organs, (2) as a result of exogenous administration of drugs or flu- bolic acid-base disorder, the four indicators and the rules previ- ids that alter the body’s ability to maintain normal acid-base bal- ously mentioned [see Table 1] provide no information on the ance, or (3) as a result of abnormal metabolism that overwhelms mechanism of an acid-base disorder. the normal defense mechanisms. The organ systems responsible for regulating the SID in both health and disease are the renal sys- tem and, to a lesser extent, the gastrointestinal tract. Metabolic Acid-Base Disorders Metabolic acid-base derangements are produced by a signifi- Renal System cantly greater number of underlying disorders than respiratory Plasma flows to the kidneys at a rate of approximately 600 disorders are, and they are almost always more difficult to treat. ml/min. The glomeruli filter the plasma, producing filtrate at a Traditionally, metabolic acidoses and alkaloses are categorized rate of 120 ml/min.The filtrate, in turn, is processed by reabsorp-
  3. 3. © 2006 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 8 ACID-BASE DISORDERS — 3 Gastrointestinal Tract tion and secretion mechanisms in the tubular cells along which it passes on its way to the ureters. Normally, more than 99% of the The GI tract is an underappreciated component of acid-base filtrate is reabsorbed and returned to the plasma.Thus, the kidney balance. In different regions along its length, the GI tract handles can excrete only a very small amount of strong ion into the urine strong ions quite differently. In the stomach, Cl– is pumped out of each minute, which means that several minutes to hours are the plasma and into the lumen, thereby reducing the SID of the required to make a significant impact on the SID. gastric juice and thus the pH as well. On the plasma side, the SID The handling of strong ions by the kidney is extremely impor- is increased by the loss of Cl–, and the pH rises, producing the so- tant because every chloride ion that is filtered but not reabsorbed called alkaline tide that occurs at the beginning of a meal, when reduces the SID. Most of the human diet contains similar ratios gastric acid secretion is maximal.15 of strong cations to strong anions, and thus, there is usually suf- In the duodenum, Cl– is reabsorbed and the plasma pH restored. ficient Cl– available for renal Cl– handling to be the primary reg- Normally, only slight changes in plasma pH are evident because Cl– ulating mechanism. Given that renal Na+ and K+ handling is is returned to the circulation almost as soon as it is removed. If, influenced by other priorities (e.g., intravascular volume and however, gastric secretions are removed from the patient, whether by plasma K+ homeostasis), it is logical that so-called acid handling catheter suctioning or vomiting, Cl– will be progressively lost and by the kidney is generally mediated through management of the the SID will steadily increase. It is important to remember that it is Cl– balance. the loss of Cl–, not of H+, that determines the plasma pH. Although Traditional approaches to the question of renal acid handling H+ is lost as HCl, it is also lost with every molecule of water have focused on H+ excretion, emphasizing the importance of removed from the body. When Cl–, a strong anion, is lost without ammonia (NH3) and its add-on cation, ammonium (NH4+). the corresponding loss of a strong cation, the SID is increased, and However, H+ excretion per se is irrelevant, in that water provides an therefore, the plasma H+ concentration is decreased. When H+ is essentially infinite source of free H+. Indeed, the kidney does not lost as water rather than as HCl, the SID does not change, and excrete H+ to any greater degree in the form of NH4+ than in the thus, the plasma H+ concentration does not change either. form of H2O.The purpose of renal ammoniagenesis is to allow the The pancreas secretes fluid into the small intestine that pos- excretion of Cl– without Na+ or K+. This purpose is achieved by sesses an SID much higher than the plasma SID and is very low supplying a weak cation (NH4+) that is “coexcreted” with Cl–.The in Cl–. Thus, the plasma perfusing the pancreas has its SID mechanisms of renal tubular acidosis are currently being reinter- decreased, a phenomenon that peaks about 1 hour after a meal preted by some authors in the light of a growing body of evidence and helps counteract the alkaline tide. If large amounts of pancre- showing that abnormal chloride conductance, rather than H+ or atic fluid are lost (e.g., as a consequence of surgical drainage), the HCO3 handling per se, is responsible for these disorders.3 resulting decrease in the plasma SID will lead to acidosis. Kidney-Liver Interaction In the large intestine, the fluid also has a high SID, because most of the Cl– was removed in the small intestine and the remaining The importance of NH4+ to systemic acid-base balance, then, electrolytes consist mostly of Na+ and K+. Normally, the body rests not on its carriage of H+ or its direct action in the plasma (normal plasma NH4+ concentration < 0.01 mEq/L) but on its reabsorbs much of the water and electrolytes from this fluid, but coexcretion with Cl–. Of course, production of NH4+ is not when severe diarrhea occurs, large amounts of cations may be lost. restricted to the kidney. Hepatic ammoniagenesis (as well as glut- If this cation loss persists, the plasma SID will decrease and aci- aminogenesis) is also important for systemic acid-base balance, dosis will result. and as expected, it is tightly controlled by mechanisms sensitive to In addition to the acid-base effects of abnormal loss of strong plasma pH.12 Indeed, this reinterpretation of the role of NH4+ in ions from the GI lumen, the small intestine, in particular, may acid-base balance is supported by the evidence that hepatic gluta- contribute strong ions to the plasma. This contribution is most minogenesis is stimulated by acidosis.13 Metabolism of nitrogen by apparent when mesenteric blood flow is compromised and lactate the liver can yield urea, glutamine, or NH4+. Normally, the liver is produced, sometimes in large quantities. Although global releases only a very small amount of NH4+, incorporating most of hypoperfusion may compromise the mesentery, the intestine does its nitrogen into either urea or glutamine. Hepatocytes have not appear to be a source of lactic acid in patients resuscitated enzymes to enable them to produce either of these end products, from a septic state [see Metabolic Acidosis, Positive–Anion Gap and both allow regulation of plasma NH4+ at suitably low levels. Acidosis, Lactic Acidosis, below].16 Moreover, whether the GI tract At the level of the kidneys, however, the production of urea or glu- is capable of regulating strong ion uptake in a compensatory fash- tamine has significantly different effects, in that the kidneys use ion has not been well studied.There is some evidence that the gut glutamine to generate NH4+ and facilitate the excretion of Cl–. may modulate systemic acidosis in experimental endotoxemia by Thus, production of glutamine by the liver can be seen as having removing anions from the plasma17; however, the full capacity of an alkalinizing effect on plasma pH because of the way in which the gut to affect acid-base balance remains to be determined. the kidneys use this substance. METABOLIC ACIDOSIS Further support for this scenario comes from the discovery that hepatocytes are anatomically organized according to their enzy- Traditionally, metabolic acidoses are categorized according to matic content.14 Hepatocytes with a propensity to produce urea the presence or absence of unmeasured anions. These unmea- are positioned closer to the portal venule; those with a propensity sured anions are routinely detected by examining the plasma elec- to produce glutamine are positioned farther downstream. The trolytes and calculating the anion gap (AG) (see below). The dif- upstream (urea-producing) hepatocytes have the first chance at ferential diagnosis for a positive-AG acidosis includes various the NH4+ delivered. However, acidosis inhibits ureagenesis, there- common and rare causes [see Table 2]. Generally speaking, non- by leaving more NH4+ available for the downstream (glutamine- AG acidoses can be divided into three types: renal, gastrointesti- producing) hepatocytes. The leftover NH4+ is thus, in a sense, nal, and iatrogenic [see Table 3]. In the ICU, the most common packaged as glutamine for export to the kidney, where it is used to types of metabolic acidosis are lactic acidosis, ketoacidosis, iatro- facilitate Cl– excretion. genic acidosis, and acidosis secondary to toxins.
  4. 4. © 2006 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 8 ACID-BASE DISORDERS — 4 Table 2 Causes of Positive–Anion Gap Acidosis is set at 40 mm Hg, but the SBE is not corrected for abnormali- ties in Atot. In many hypoalbuminemic patients, Atot is lower than Renal failure normal, and thus, the SID at the equilibrium point will be less Elevated ketone levels (ketoacidosis) than 40 mEq/L. Also, it is rare that the choice would be made to Common causes Elevated lactate levels (lactic acidosis) correct the acid-base abnormality completely. Therefore, the tar- Toxins (methanol, ethylene glycol, salicylate, get SID should be used as a reference value, but in most cases, paraldehyde, toluene) partial correction is all that is required. Sepsis If increasing the plasma Na+ concentration is inadvisable for Dehydration other reasons (e.g., hypernatremia), NaHCO3 administration is Alkalemia inadvisable. It is noteworthy that NaHCO3 administration has not Decreased concentrations of unmeasured cations been shown to improve outcome in patients with lactic acidosis.21 Rare causes (Mg2+, K+, Ca2+) Sodium salts (lactate, citrate, acetate, penicillin, In addition, NaHCO3 administration is associated with certain carbenicillin) disadvantages. Large (hypertonic) doses, if given rapidly, may Rhabdomyolysis actually reduce blood pressure22 and may cause sudden, severe increases in PaCO2.23 Accordingly, it is important to assess the patient’s ventilatory status before NaHCO3 is administered, par- Even extreme acidosis appears to be well tolerated by healthy ticularly if the patient is not on a ventilator. NaHCO3 infusion also persons, particularly when the duration of the acidosis is short. For affects serum K+ and Ca2+ concentrations, which must be moni- example, healthy individuals may achieve an arterial pH lower tored closely. than 7.15 and a lactate concentration higher than 20 mEq/L dur- To avoid some of the disadvantages of NaHCO3 therapy, alter- ing maximal exercise, with no lasting effects.18 Over the long term, native therapies for metabolic acidosis have been developed. however, even mild acidemia (pH < 7.35) may lead to metabolic Carbicarb is an equimolar mixture of sodium carbonate (Na2CO3) bone disease and protein catabolism. Furthermore, critically ill patients may not be able to tolerate even brief episodes of and NaHCO3.24 Like NaHCO3, carbicarb works by increasing the acidemia.19 There do appear to be significant differences between plasma Na+ concentration, except that it does not raise the PCO2. metabolic and respiratory acidosis with respect to patient out- Results with carbicarb in animal studies have been mixed,25 and come, and these differences suggest that the underlying disorder experience in humans is extremely limited. may be more important than the absolute degree of acidemia.20 THAM (tris-hydroxymethyl aminomethane) is a synthetic If prudence dictates that symptomatic therapy is to be provid- buffer that consumes CO2 and readily penetrates cells.26 It is a ed, the likely duration of the disorder should be taken into weak base (pK = 7.9) and, as such, is unlike other plasma con- account. When the disorder is expected to be a short-lived one stituents. The major advantage of THAM is that it does not alter (e.g., diabetic ketoacidosis), maximizing respiratory compensation the SID, which means that there is no need to be concerned about is usually the safest approach. Once the disorder resolves, ventila- having to increase the plasma Na+ concentration to achieve a ther- tion can be quickly reduced to normal levels, and there will be no apeutic effect. Accordingly, THAM is often used in situations lingering effects from therapy. If the SID is increased (e.g., by where NaHCO3 cannot be used because of hypernatremia. administering NaHCO3), there is a risk of alkalosis when the Although THAM has been available since the 1960s, there is sur- underlying disorder resolves. When the disorder is likely to be a prisingly little information available regarding its efficacy in more chronic one (e.g., renal failure), therapy aimed at restoring humans with acid-base disorders. In small uncontrolled studies, the SID to normal is indicated. In all cases, the therapeutic target THAM appears to be capable of reversing metabolic acidosis sec- can be accurately determined from the SBE. As noted (see above), ondary to ketoacidosis or renal failure without causing obvious the SBE corresponds to the amount by which the current SID dif- toxicity27; however, adverse reactions have been reported, includ- fers from the SID necessary to restore the pH to 7.4, given a PCO2 ing hypoglycemia, respiratory depression, and even fatal hepatic of 40 mm Hg. Thus, if the SID is 30 mEq/L and the SBE is −10 necrosis, when concentrations exceeding 0.3 mol/L are used. In mEq/L, the target SID is 40 mEq/L. Accordingly, the plasma Na+ Europe, a mixture of THAM, acetate, NaHCO3, and disodium concentration would have to increase by 10 mEq/L for NaHCO3 phosphate is available. This mixture, known as tribonate administration to correct the acidosis completely. (Tribonat; Pharmacia & Upjohn, Solna, Sweden), seems to have It should be noted that the target SID is the SID at the equilib- fewer side effects than THAM alone does, but as with THAM, rium point between the SID, PCO2, and Atot and that it may not be experience with its use in humans is still quite limited. equal to 40 mEq/L, as in the example given. By convention, PCO2 Anion Gap Determination of anion gap The AG has been used by Table 3—Differential Diagnosis for clinicians for more than 30 years and has evolved into a major tool for evaluating acid-base disorders.28 It is calculated—or, rather, Normal–Anion Gap Metabolic Acidosis estimated—from the difference between the routinely measured concentrations of serum cations (Na+ and K+) and the routinely Urine SID > 0 mEq/L Renal tubular acidosis measured concentrations of anions (Cl– and HCO3–). Normally, GI condition albumin accounts for the bulk of this difference, with phosphate Diarrhea playing a lesser role. Sulfate and lactate also contribute a small Urine SID < 0 mEq/L Pancreatic or small bowel drainage amount to the gap (normally, < 2 mEq/L); however, there are also Iatrogenesis unmeasured cations (e.g., Ca2+ and Mg2+), which tend to offset Parenteral nutrition the effects of sulfate and lactate except when the concentration of Saline either one is abnormally increased. Plasma proteins other than SID—strong ion difference albumin can be either positively or negatively charged, but in the
  5. 5. © 2006 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 8 ACID-BASE DISORDERS — 5 aggregate, they tend to be electrically neutral,29 except in rare pH. These concerns have led some authors to advocate adjusting cases of abnormal paraproteins (as in multiple myeloma). In prac- the normal AG range on the basis of the patient’s albumin35 or tice, the AG is calculated as follows: even phosphate6 concentration. Each 1 g/dl of albumin carries a + + – – charge of 2.8 mEq/L at a pH of 7.4 (2.3 mEq/L, pH = 7.0; 3.0 AG = (Na + K ) – (Cl + HCO3 ) mEq/L, pH = 7.6), and each 1 mg/dl of phosphate carries a charge Because of its low extracellular concentration, K+ is often omit- of 0.59 mEq/L at a pH of 7.4 (0.55 mEq/L, pH = 7.0; 0.61 ted from the calculation. In most laboratories, normal values fall mEq/L, pH = 7.6). Thus, the normal AG for a given patient can into the range of 12 ± 4 mEq/L (if K+ is considered) or 8 ± 4 be conveniently estimated as follows6: mEq/L (if K+ is not considered). In the past few years, the intro- duction of more accurate methods of measuring Cl– concentra- Normal AG = 2(albumin [g/dl]) + 0.5(phosphate [mg/dl]) tion has led to a general lowering of the normal AG range.30,31 or, in international units, Because of the various measurement techniques employed at var- ious institutions, however, each institution is expected to report its Normal AG = 0.2(albumin [g/L]) + own normal AG values. 1.5(phosphate [mmol/L]) Clinical utility of anion gap The primary value of the AG In one study, when this formula for calculating a patient-spe- is that it quickly and easily limits the differential diagnosis in a cific normal AG range was used to determine the presence of patient with metabolic acidosis. When the AG is increased, the unmeasured anions in the blood of critically ill patients, its accu- explanation is almost invariably one of the following five disorders: racy was 96%, compared with an accuracy of 33% with the rou- ketosis, lactic acidosis, poisoning, renal failure, and sepsis.32 tine AG (normal range = 12 mEq/L).6 This technique should be In addition to these disorders, however, there are several condi- employed only when the pH is less than 7.35; even in this situa- tions that can alter the accuracy of AG estimation and are partic- tion, it is only accurate within 5 mEq/L. When more accuracy is ularly frequent in critical illness.33,34 Dehydration increases the needed, a slightly more complicated method of estimating unmea- concentrations of all of the ions. Severe hypoalbuminemia lowers sured anions is required.42,46 the AG, with each 1 g/dl decline in the serum albumin reducing the apparent AG by 2.5 to 3 mEq/L; accordingly, some recom- Strong anion gap Another alternative to relying on the tra- mend adjusting the AG for the prevailing albumin concentra- ditional AG is to use a parameter derived from the SID. By defin- tion.35 Alkalosis (respiratory or metabolic) is associated with an ition, the SID must be equal and opposite to the sum of the neg- increase of as much as 3 to 10 mEq/L in the apparent AG as a ative charges contributed by A– and total CO2. This latter value consequence of enhanced lactate production (from stimulated (A– + total CO2) has been termed the effective SID (SIDe).29 The phosphofructokinase enzymatic activity), reduction in the con- apparent SID (SIDa) is obtained by measuring concentrations of centration of ionized weak acids (A–)(as opposed to Atot, the total each individual ion.The SIDa and the SIDe should both equal the concentration of weak acids), and, possibly, the additional effect of true SID. If the SIDa differs from the SIDe, unmeasured ions dehydration (which, as noted, has its own impact on AG calcula- must be present. If the SIDa is greater than the SIDe, these tion). A low Mg2+ concentration with associated low K+ and Ca2+ unmeasured ions are anions; if the SIDa is less than the SIDe, they concentrations is a known cause of an increased AG, as is the are cations. The difference between the SIDa and the SIDe has administration of sodium salts of poorly reabsorbable anions (e.g., been termed the strong ion gap (SIG) to distinguish it from the β-lactam antibiotics).36 Certain parenteral nutrition formulations AG.42 Unlike the AG, the SIG is normally 0 and is not affected by (e.g., those containing acetate) may increase the AG. In rare cases, changes in the pH or the albumin concentration. citrate may have the same effect in the setting of multiple blood transfusions, particularly if massive doses of banked blood are Positive–Anion Gap Acidosis used (as during liver transplantation).37 None of these rare caus- Lactic acidosis In many forms of critical illness, lactate is es, however, will increase the AG significantly,38 and they usually the most important cause of metabolic acidosis.47 Lactate con- are easily identified. centrations have been shown to correlate with outcomes in In the past few years, some additional causes of an increased patients with hemorrhagic48 and septic shock.49 Traditionally, lac- AG have been reported.The nonketotic hyperosmolar state of dia- tic acid has been viewed as the predominant source of the meta- betes has been associated with an increased AG that remains bolic acidosis that occurs in sepsis.50 In this view, lactic acid is unexplained.39 Unmeasured anions have been reported in the released primarily from the musculature and the gut as a conse- blood of patients with sepsis,40,41 patients with liver disease,42,43 quence of tissue hypoxia, and the amount of lactate produced is and experimental animals that received endotoxin.44 These anions believed to correlate with the total oxygen debt, the magnitude of may be the source of much of the unexplained acidosis seen in hypoperfusion, and the severity of shock.47 This view has been patients with critical illness.45 challenged by the observation that during sepsis, even in profound The accepted clinical utility of the AG notwithstanding, doubt shock, resting muscle does not produce lactate. Indeed, various has been cast on its diagnostic value in certain situations.33,41 studies have shown that the musculature may actually consume Some investigators have found routine reliance on the AG to be lactate during endotoxemia.16,51,52 “fraught with numerous pitfalls.”33 The primary problem with the The data on lactate release by the gut are less clear.There is lit- AG is its reliance on the use of a supposedly normal range pro- tle question that the gut can release lactate if it is underperfused. duced by albumin and, to a lesser extent, phosphate. Concentra- It appears, however, that if the gut is adequately perfused, it does tions of albumin and phosphate may be grossly abnormal in not release lactate during sepsis. Under such conditions, the patients with critical illness, and these abnormalities may change mesentery either is neutral with respect to lactate release or takes the normal AG range in this setting. Moreover, because these up lactate.16,51 Perfusion is likely to be a major determinant of anions are not strong anions, their charge is altered by changes in mesenteric lactate metabolism. In a canine model of sepsis
  6. 6. © 2006 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 8 ACID-BASE DISORDERS — 6 induced by infusion of endotoxin, production of lactate by the gut Table 4 Mechanisms Associated with Increased could not be demonstrated when flow was maintained with Serum Lactate Concentration dopexamine.52 Both animal studies and human studies have shown that the Hypodynamic shock lung may be a prominent source of lactate in the setting of acute Tissue hypoxia Organ ischemia lung injury.16,53,54 These studies do not address the underlying pathophysiologic mechanisms of hyperlactatemia in sepsis, but Increased aerobic glycolysis they do suggest that the conventional wisdom regarding lactate as Hypermetabolism Increased protein catabolism evidence of tissue dysoxia is, at best, an oversimplification. Indeed, Hematologic malignancies many investigators have begun to offer alternative explanations for Hepatic failure Decreased clearance of lactate the development of hyperlactatemia in this setting [see Table 4].54-58 Shock One proposed mechanism is metabolic dysfunction from mito- Thiamine deficiency chondrial enzymatic derangements, which can and do lead to lac- Inhibition of pyruvate dehydrogenase ?Endotoxin tic acidosis. In particular, pyruvate dehydrogenase (PDH), the enzyme responsible for moving pyruvate into the Krebs cycle, is ?Activation of inflammatory cells inhibited by endotoxin.59 Current data, however, suggest that increased aerobic metabolism may be more important than meta- bolic defects or anaerobic metabolism. In a 1996 study, produc- There are two possible explanations for these observations. First, tion of glucose and pyruvate and oxidation were increased in if lactate is added to the plasma, not as lactic acid but rather as the patients with sepsis.60 Furthermore, when PDH was stimulated by salt of a strong acid (e.g., sodium lactate), the SID will not change dichloroacetate, there was an additional increase in oxygen con- significantly, because a strong cation (Na+) is being added along sumption but a decrease in glucose and pyruvate production. with a strong anion. Indeed, as lactate is metabolized and removed, These results suggest that hyperlactatemia in sepsis occurs as a the remaining Na+ will increase the SID, resulting in metabolic consequence of increased aerobic metabolism rather than of tissue alkalosis. Hence, it would be possible to give enough lactate to hypoxia or PDH inhibition. increase the plasma lactate concentration without increasing the Such findings are consistent with the known metabolic effects H+ concentration. However, given that normal metabolism results of lactate production on cellular bioenergetics.61 Lactate produc- in the turnover of approximately 1,500 to 4,500 mmol of lactic acid tion alters cytosolic, and hence mitochondrial, redox states, so that each day, rapid infusion of a very large amount of lactate would be the increased ratio of reduced nicotinamide adenine dinucleotide required to bring about an appreciable increase in the plasma lac- to nicotinamide adenine dinucleotide (NADH/NAD) supports tate concentration. For example, the use of lactate-based hemofil- oxidative phosphorylation as the dominant source of ATP pro- tration fluid may result in hyperlactatemia with an increased plas- duction. Finally, the use of catecholamines, especially epinephrine, ma HCO3– concentration and an elevated pH. also results in lactic acidosis, presumably by stimulating cellular A more important mechanism whereby hyperlactatemia can metabolism (e.g., increasing hepatic glycolysis), and may be a exist without acidemia (or with less acidemia than expected) common source of lactic acidosis in the ICU.62,63 It is noteworthy involves correction of the SID by the elimination of another strong that this phenomenon does not appear to occur with either dobu- anion from the plasma. In a study of sustained lactic acidosis tamine or norepinephrine64 and does not appear to be related to induced by lactic acid infusion, Cl– was found to move out of the decreased tissue perfusion. plasma space, thereby normalizing the pH.65 Under these condi- Although the source and interpretation of lactic acidosis in tions, hyperlactatemia may persist, but compensatory mechanisms critically ill patients remain controversial, there is no question may normalize the base excess and thus restore the SID. about the ability of lactate accumulation to produce acidemia. Traditionally, lactic acidosis has been subdivided into type A, in Lactate is a strong ion because at a pH within the physiologic which the mechanism is tissue hypoxia, and type B, in which there range, it is almost completely dissociated. (The pK of lactate is is no hypoxia.66 This distinction may, however, be an artificial one. 3.9; at a pH of 7.4, 3,162 ions are dissociated for every one ion Disorders such as sepsis may be associated with lactic acidosis that is not.) Because lactate is rapidly produced and disposed of through a variety of mechanisms [see Table 4], some conventional- by the body, it functions as one of the most dynamic compo- ly labeled type A and others type B. A potentially useful method of nents of the SID. Therefore, a rise in the concentration of lactic distinguishing between anaerobically produced lactate and lactate acid can produce significant acidemia. Just as often, however, from other sources is to measure the serum pyruvate concentra- critically ill patients have a degree of hyperlactatemia that far tion. The normal lactate-to-pyruvate ratio is 10:1,67 with ratios exceeds the degree of acidosis observed. In fact, hyperlactatemia greater than 25:1 considered to be evidence of anaerobic metabo- may exist without any metabolic acidosis at all. This is not lism.58 This approach makes biochemical sense because pyruvate because acid generation is separate from lactate production (e.g., is shunted into lactate during anaerobic metabolism, dramatically through “unreversed ATP hydrolysis”), as some have suggest- increasing the lactate-to-pyruvate ratio. However, the precise test ed.64 Phosphate is a weak acid and does not contribute substan- characteristics, including normal ranges and sensitivity and speci- tially to metabolic acidosis, even under extreme circumstances. ficity data, have not yet been defined for patients. Accordingly, this Furthermore, the H+ concentration is determined not by how method remains investigational. much H+ is produced or removed from the plasma but by Treatment of lactic acidosis continues to be subject to debate. changes in the dissociation of water and weak acids. Virtually At present, the only noncontroversial approach is to treat the anywhere in the body, the pH is higher than 6.0, and lactate underlying cause; however, this approach assumes that the under- behaves as a strong ion. Generation of lactate reduces the SID lying cause can be identified with a significant degree of certainty, and results in an increased H+ concentration; however, the plas- which is not always the case. The assumption that hypoperfusion ma lactate concentration may also be increased without an is always the most likely cause has been seriously challenged, espe- accompanying increase in the H+ concentration. cially in well-resuscitated patients (see above). Thus, therapy
  7. 7. © 2006 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 8 ACID-BASE DISORDERS — 7 aimed at increasing oxygen delivery may not be effective. Indeed, tyrate. Hence, it is better to monitor the success of therapy by if epinephrine is used, lactic acidosis may worsen. measuring the pH and the AG than by assaying serum ketones. Administration of NaHCO3 to treat lactic acidosis remains Treatment of DKA includes administration of insulin and large unproven.21 In perhaps the most widely quoted study on this amounts of fluid (0.9% saline is usually recommended); potassium topic, hypoxic lactic acidosis was induced in anesthetized dogs by replacement is often required as well. Fluid resuscitation reverses ventilating them with gas containing very little oxygen.68 These the hormonal stimuli for ketone body formation, and insulin allows animals were then assigned to treatment with NaHCO3 or place- the metabolism of ketones and glucose. Administration of bo, and surprisingly, the group receiving NaHCO3 actually had NaHCO3 may produce a more rapid rise in the pH by increasing higher plasma concentrations of both lactate and H+ than the con- the SID, but there is little evidence that this result is desirable. trol group did. Furthermore, the NaHCO3-treated animals exhib- Furthermore, to the extent that the SID is increased by increasing ited decreases in cardiac output and blood pressure that were not the plasma Na+ concentration, the SID will be too high once the seen in the control group. One possible explanation for these find- ketosis is cleared, thus resulting in a so-called overshoot alkalosis. ings is that the HCO3– was converted to CO2, and this conversion In any case, such measures are rarely necessary and should proba- raised the PCO2 not only in the blood but also inside the cells of bly be avoided except in extreme cases.73 these animals with a fixed minute ventilation; the resulting intra- A more common problem in the treatment of DKA is the per- cellular acidosis might have been detrimental to myocardial func- sistence of acidemia after the ketosis has resolved. This hyper- tion. This hypothesis has not, however, been supported by subse- chloremic metabolic acidosis occurs as Cl– replaces ketoacids, quent experimental studies, which have not documented para- thus maintaining a decreased SID and pH. There appear to be doxical intracellular acidosis or even detrimental hemodynamic two reasons for this phenomenon. First, exogenous Cl– is often effects after NaHCO3 treatment of hypoxic lactic acidosis.69 provided in the form of 0.9% saline, which, if given in large Furthermore, it is not clear how this type of hypoxic lactic acido- enough quantities, will result in a so-called dilutional acidosis (see sis, induced in well-perfused animals, relates to the clinical condi- below). Second, some degree of increased Cl– reabsorption appar- tions in which lactic acidosis occurs.The results of clinical studies ently occurs as ketones are excreted in the urine. It has also been have been mixed, but overall, they do not support the use of suggested that the increased tubular Na+ load produces electrical- NaHCO3 therapy for lactic acidosis.21 chemical forces that favor Cl– reabsorption.74 AKA is usually less severe than DKA. Treatment consists of Ketoacidosis Another common cause of a metabolic acido- administration of fluids and (in contrast to treatment of DKA) sis with a positive AG is excessive production of ketone bodies, glucose rather than insulin.75 Insulin is contraindicated in AKA including acetone, acetoacetate, and β-hydroxybutyrate. Both ace- patients because it may cause precipitous hypoglycemia.76 toacetate and β-hydroxybutyrate are strong anions (pK 3.8 and Thiamine must also be given to keep from precipitating Wernicke 4.8, respectively).70 Thus, their presence, like the presence of lac- encephalopathy. tate, decreases the SID and increases the H+ concentration. Ketones are formed through beta oxidation of fatty acids, a Acidosis secondary to renal failure Although renal failure process that is inhibited by insulin. In insulin-deficient states (e.g., may produce a hyperchloremic metabolic acidosis, especially when diabetes), ketone formation may quickly get out of control. The it is chronic, the buildup of sulfates and other acids frequently reason is that severely elevated blood glucose concentrations pro- increases the AG; however, the increase usually is not large.77 duce an osmotic diuresis that may lead to volume contraction. Similarly, uncomplicated renal failure rarely produces severe aci- This state is associated with elevated cortisol and catecholamine dosis, except when it is accompanied by high rates of acid genera- secretion, which further stimulates free fatty acid production.71 In tion (e.g., from hypermetabolism).78 In all cases, the SID is addition, an increased glucagon level relative to the insulin level decreased and is expected to remain so unless some therapy is pro- leads to a decreased malonyl coenzyme A level and an increased vided. Hemodialysis permits the removal of sulfate and other ions carnitine palmityl acyl transferase level—a combination that and allows the restoration of normal Na+ and Cl– balance, thus increases ketogenesis. returning the SID to a normal (or near-normal) value. However, Ketoacidosis may be classified as either diabetic ketoacidosis those patients who do not yet require dialysis and those who are (DKA) or alcoholic ketoacidosis (AKA). The diagnosis is estab- between treatments often require some other therapy aimed at lished by measuring serum ketone levels. It must be kept in mind, increasing the SID. NaHCO3 may be used for this purpose, pro- however, that the nitroprusside reaction measures only acetone vided that the plasma Na+ concentration is not already elevated. and acetoacetate, not β-hydroxybutyrate. Thus, the measured ketosis is dependent on the ratio of acetoacetate to β-hydroxybu- Acidosis secondary to toxin ingestion Metabolic acidosis tyrate. This ratio is low when lactic acidosis coexists with ketoaci- with an increased AG is a major feature of various types of intox- dosis because the reduced redox state characteristic of lactic aci- ication [see Table 2]. Generally, it is more important to recognize dosis favors production of β-hydroxybutyrate.72 In such circum- these conditions and provide specific therapy for them than it is to stances, therefore, the apparent degree of ketosis is small relative treat the acid-base imbalances that they produce. to the degree of acidosis and the elevation of the AG.There is also a risk of confusion during treatment of ketoacidosis, in that ketone Acidosis secondary to rhabdomyolysis The extensive levels, as measured by the nitroprusside reaction, sometimes rise muscle tissue breakdown associated with myonecrosis may also be even though the acidosis is resolving. This occurs because the a source of positive-AG metabolic acidosis. In this situation, the nitroprusside reaction does not detect β-hydroxybutyrate, and as acidosis results from accumulation of organic acids. The myoglo- β-hydroxybutyrate is cleared, ketosis persists despite improvement binuria associated with the disorder may also induce renal failure. in acid-base balance. Furthermore, conversion of β-hydroxybu- In most cases, the diagnosis is a clinical one and can be facilitated tyrate to acetoacetate may cause an apparent increase in ketone by measuring creatinine kinase or aldolase levels. Early identifica- levels—again, because the nitroprusside reaction detects the rising tion and aggressive resuscitation may prevent the onset of renal levels of acetoacetate but misses the falling levels of β-hydroxybu- failure and improve the prognosis.79
  8. 8. © 2006 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 8 ACID-BASE DISORDERS — 8 Acidosis of unknown origin Several causes of an increased Several reports in the trauma literature have focused on the AG have been reported that have yet to be elucidated. An unex- prognostic value of persistently elevated lactic acid levels during plained AG in the nonketotic hyperosmolar state of diabetes has the first 24 to 48 hours after injury. In one study, involving 76 been reported.39 In addition, even when very careful measurement patients with multiple injuries who were admitted directly to the techniques have been employed, unmeasured anions have been ICU from the operating room or the ED, serum lactate levels and reported in the blood of patients with sepsis,40,41 patients with liver oxygen transport were measured at ICU admission and at 8, 16, disease,42 and animals to which endotoxin had been adminis- 24, 36, and 48 hours.89 In those patients whose lactate levels tered.43 Furthermore, unknown cations also appear in the blood returned to normal within 24 hours, the survival rate was 100%, of some critically ill patients.41 The significance of these findings and in those whose lactate levels returned to normal between 24 remains to be determined. and 48 hours, the survival rate was 75%. However, in those whose lactate levels did not return to normal by 48 hours, the survival Prognostic significance of positive-AG metabolic acidosis rate was only 14%. Thus, the rate of normalization of the serum Several studies have examined whether the presence of unmea- lactate level is an important prognostic factor for survival in a sured anions in the blood is associated with particular outcomes in severely injured patient. critically ill patients. Two such studies focused on trauma patients. In one, the investigators examined 2,152 sets of laboratory data Non–Anion Gap (Hyperchloremic) Acidoses from 427 trauma patients and found that the SIG altered the acid- Hyperchloremic metabolic acidosis occurs as a result of either an base disorder diagnosis in 28% of the datasets.80 Simultaneous increase in the level of Cl– relative to the levels of strong cations measurements of blood gas, serum electrolyte, albumin, and lactate (especially Na+) or a loss of cations with retention of Cl–.The var- values were used to calculate the base deficit, the AG, and the SIG. ious causes of such an acidosis [see Table 3] can be distinguished on Unmeasured anions (defined by the presence of an elevated SIG) the basis of the history and the measured Cl– concentration in the were present in 92% of patients (mean SIG, 5.9 ± 3.3); hyperlac- urine. When acidosis occurs, the kidney normally responds by tatemia and hyperchloremia occurred in only 18% and 21% of increasing Cl– excretion; the absence of this response identifies the patients, respectively.The arterial SBE at ICU admission was poor- kidney as the source of the problem. Extrarenal hyperchloremic ly predictive of hospital survival, and its predictive ability was only acidoses occur because of exogenous Cl– loads (iatrogenic acidosis) slightly improved by controlling for unmeasured ions. In this dataset, or because of loss of cations from the lower GI tract without pro- survivors could not be differentiated from nonsurvivors in the portional loss of Cl– (gastrointestinal acidosis). group as a whole on the basis of the SIG. However, in the subgroup of patients whose lactate level was normal at admission, there was Renal tubular acidosis Most cases of renal tubular acidosis a significant difference in the SIG between survivors and nonsur- (RTA) can be correctly diagnosed by determining urine and plas- vivors, though no such differences were noted in the conventional ma electrolyte levels and pH and calculating the SIDa in the urine measures (i.e., SBE and AG). [see Table 3].90 However, caution must be exercised when the plas- The poor predictive ability of the SBE, the AG, and even the ma pH is greater than 7.35, because urine Cl– excretion may be SIG has been confirmed by studies of general ICU patients. In turned off. In such circumstances, it may be necessary to infuse one study, analysis of data from 300 adult ICU patients demon- sodium sulfate or furosemide.These agents stimulate excretion of strated statistically significant but weak correlations between these Cl– and K+ and may be used to unmask the defect and to probe measures and hospital mortality.81 In another study, however, pre- K+ secretory capacity. treatment SIG was found to be a very strong predictor of outcome Establishing the mechanisms of RTA has proved difficult. It is in 282 patients who had sustained major vascular injury.82 All but likely that much of the difficulty results from the attempt to under- one of the nonsurvivors had an initial emergency department stand the physiology from the perspective of regulation of H+ and (ED) pH of 7.26 or lower, an SBE of −7.3 mEq/L or lower, a lac- HCO3– concentrations. As noted, however (see above), this tate concentration of 5 mmol/L or higher, and an SIG of 5 mEq/L approach is simply inconsistent with the principles of physical or higher. All of the acid-base descriptors were strongly associated chemistry.The kidney does not excrete H+ to any greater extent as with outcome, but the SIG was the one that discriminated most NH4+ than it does as H2O.The purpose of renal ammoniagenesis strongly. The investigators concluded that initial ED acid-base is to allow the excretion of Cl–, which balances the charge of variables, especially SIG, could distinguish survivors of major vas- NH4+. In all types of RTA, the defect is the inability to excrete Cl– cular injury from nonsurvivors. in proportion to excretion of Na+, though the precise reasons for Even though the uncorrected AG and the SBE correlate poor- this inability vary by RTA type.Treatment is largely dependent on ly with the arterial lactate concentration in trauma patients,83 sev- whether the kidney will respond to mineralocorticoid replacement eral investigators have proposed that these parameters be used as or whether there is Na+ loss that can be counteracted by adminis- surrogate measures of the severity of shock or lack of resuscitation. tering NaHCO3. Various studies have shown that the SBE is a poor predictor of lac- Classic distal (type I) RTA responds to NaHCO3 replacement; tic acidosis and mortality both in medical patients and in surgical generally, the required dosage is in the range of 50 to 100 or trauma patients and that it cannot be substituted for direct mEq/day. K+ defects are also common in this type of RTA, and measurement of the serum lactate concentration.33,84,85 Some thus, K+ replacement is also required. A variant of the classic dis- investigators, however, have found that the SBE can be used as a tal RTA is a hyperkalemic form, which is actually more common marker of injury severity and mortality and as a predictor of trans- than the classic type. The central defect in this variant form fusion requirements.86-88 Unfortunately, the SBE can determine appears to be impaired Na+ transport in the cortical collecting only the degree of acid-base derangement, never the cause. In duct. Patients with this condition also respond to NaHCO3 many critically injured patients, abnormalities in body water con- replacement. tent, electrolyte levels, and albumin concentration limit any poten- Proximal (type II) RTA is characterized by defects in the reab- tial correlation between SBE and lactate concentration, even when sorption of both Na+ and K+. It is an uncommon disorder and other sources of acid are absent. usually occurs as part of Fanconi syndrome, in which reabsorption
  9. 9. © 2006 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 8 ACID-BASE DISORDERS — 9 of glucose, phosphate, urate, and amino acids is also impaired. It appears that many critically ill patients have a significantly Treatment of type II RTA with NaHCO3 is ineffective; increased lower SID than healthy persons do, even when these patients have ion delivery merely results in increased excretion.Thiazide diuret- no evidence of a metabolic acid-base derangement.99 This finding ics have been used to treat this disorder, with varying degrees of is not surprising, in that the positive charge of the SID is balanced success. by the negative charges of A– and total CO2. Because many criti- Type IV RTA is caused by aldosterone deficiency or resistance. cally ill patients are hypoalbuminemic, A– tends to be reduced. It is diagnosed on the basis of the high serum K+ and the low urine Because the body maintains PCO2 for other reasons, a reduction in pH (< 5.5).The most effective treatment usually involves removal A– leads to a reduction in SID so that a normal pH can be main- of the cause (most commonly a drug, such as a nonsteroidal anti- tained. Thus, a typical ICU patient may have an SID of 30 inflammatory agent, heparin, or a potassium-sparing diuretic). mEq/L, rather than 40 to 42 mEq/L. If a metabolic acidosis (e.g., Occasionally, mineralocorticoid replacement is required. lactic acidosis) then develops in this patient, the SID will decrease further. If this patient is subsequently resuscitated with large vol- Gastrointestinal acidosis Fluid secreted into the gut umes of 0.9% saline, a significant metabolic acidosis will result. lumen contains more Na+ than Cl–; the proportions are similar to The clinical implication for management of ICU patients is those seen in plasma. Massive loss of this fluid, particularly if lost that if large volumes of fluid are to be given for resuscitation, flu- volume is replaced with fluid containing equal amounts of Na+ ids that are more physiologic than saline should be used. One and Cl–, will result in a decreased plasma Na+ concentration rela- alternative is LRS, which has a more physiologic ratio of Na+ tive to the Cl– concentration and a reduced SID. Such a scenario content to Cl– content and thus has an SID that is closer to nor- can be prevented by using solutions such as lactated Ringer solu- mal (roughly 28 mEq/L, compared with an SID of 0 mEq/L for tion (LRS) instead of water or saline. LRS has a more physiolog- saline). Of course, the assumption here is that the lactate in LRS ic SID than water or saline and therefore does not produce aci- is metabolized, which, as noted (see above), is almost always the dosis except in rare circumstances [see Positive–Anion Gap case. Volume resuscitation also reduces the weak acid concentra- Acidosis, Lactic Acidosis, above]. tion, thereby moderating the acidosis. One ex vivo study con- cluded that administration of a solution with an SID of approxi- Iatrogenic acidosis Two of the most common causes of a mately 24 mEq/L will have a neutral effect on the pH as blood is hyperchloremic metabolic acidosis are iatrogenic, and both progressively diluted.100 involve administration of Cl–. One of these potential causes is par- enteral nutrition. Modern parenteral nutrition formulas contain Unexplained hyperchloremic acidosis Critically ill weak anions (e.g., acetate) in addition to Cl–, and the proportions patients sometimes manifest hyperchloremic metabolic acidosis of these anions can be adjusted according to the acid-base status for reasons that cannot be determined. Often, other coexisting of the patient. If sufficient amounts of weak anions are not pro- types of metabolic acidosis are present, making the precise diag- vided, the plasma Cl– concentration will increase, reducing the nosis difficult. For example, some patients with lactic acidosis SID and causing acidosis. have a greater degree of acidosis than can be explained by the The other potential cause is fluid resuscitation with saline, increase in the lactate concentration,40 and some patients with which can give rise to a so-called dilutional acidosis (a problem sepsis and acidosis have normal lactate levels.101 In many first described more than 40 years ago).91,92 Some authors have instances, the presence of unexplained anions is the cause,40-42 but argued that dilutional acidosis is, at most, a minor issue.93 This in other cases, there is a hyperchloremic acidosis. Saline resuscita- argument is based on studies showing that in healthy animals, tion may be responsible for much of this acidosis (see above), but large doses of NaCl produce only a minor hyperchloremic acido- experimental evidence from endotoxemic animals suggests that as sis.94 These studies have been interpreted as indicating that dilu- much as a third of the acidosis cannot be explained in terms of tional acidosis occurs only in extreme cases and even then is mild. current knowledge.98 However, this line of reasoning cannot be applied to critically ill One potential explanation for unexplained hyperchloremic aci- patients, for two reasons. First, it is common for patients with sep- dosis is partial loss of the Donnan equilibrium between plasma sis or trauma to require large-volume resuscitation; sometimes, and interstitial fluid. The severe capillary leakage that accompa- such patients receive crystalloid infusions equivalent to 5 to 10 nies this loss of equilibrium results in loss of albumin from the vas- times their plasma volumes in a single day. Second, critically ill cular space, which means that another ion must move into this patients frequently are not in a state of normal acid-base balance space to maintain the charge balance between the two compart- to begin with. Often, they have lactic acidosis or renal insufficien- ments. If Cl– moves into the plasma space to restore the charge cy. Furthermore, critically ill patients may not be able to compen- balance, a strong anion is replacing a weak anion, and a hyper- sate for acid-base imbalance normally (e.g., by increasing ventila- chloremic metabolic acidosis results.This hypothesis appears rea- tion), and they may have abnormal buffer capacity as a result of sonable but, at present, remains unproven. hypoalbuminemia. In ICU and surgical patients,95-97 as well as in METABOLIC ALKALOSIS animals with experimentally induced sepsis,98 saline-induced aci- dosis does occur and can produce significant acidemia. Metabolic alkalosis occurs as a result of an increased SID or a The reason why administration of saline causes acidosis is that decreased Atot, secondary either to loss of anions (e.g., Cl– from solutions containing equal amounts of Na+ and Cl– affect plasma the stomach and albumin from the plasma) or increases in cations concentrations of Na+ and Cl– differently. The normal Na+ con- (rare). Metabolic alkaloses can be divided into those in which Cl– centration is 35 to 45 mEq/L higher than the normal Cl– concen- losses are temporary and can be effectively replaced (chloride- tration. Thus, adding (for example) 154 mEq/L of each ion in responsive alkaloses) and those in which hormonal mechanisms 0.9% saline will result in a greater relative increase in the Cl– con- produce ongoing losses that, at best, can be only temporarily off- centration than in the Na+ concentration. So much is clear; what set by Cl– administration (chloride-resistant alkaloses) [see Table may be less clear is why critically ill patients are more susceptible 5]. Like hyperchloremic acidosis, metabolic alkalosis can be con- to this disorder than healthy persons are. firmed by measuring the urine Cl– concentration.
  10. 10. © 2006 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 8 ACID-BASE DISORDERS — 10 Table 5 Differential Diagnosis for intravenous administration of strong cations without strong Metabolic Alkalosis anions. The latter occurs with massive blood transfusion because Na+ is given with citrate (a weak anion) rather than with Cl–. Chloride-responsive alkalosis (urine Cl – concen- Similar results ensue when parenteral nutrition formulations con- tration < 10 mmol/L) tain too much acetate and not enough Cl– to balance the Na+ load. GI loss Vomiting Gastric drainage Respiratory Acid-Base Disorders Chloride-wasting diarrhea (villous adenoma) Respiratory disorders are far easier to diagnose and treat than Diuretic use Hypercapnia metabolic disorders are because the mechanism is always the Chloride-resistant alkalosis (urine Cl– concentra- same, even though the underlying disease process may vary. CO2 tion > 20 mmol/L) is produced by cellular metabolism or by the titration of HCO3– Chloride loss (Cl– < Na+) Mineralocorticoid excess by metabolic acids. Normally, alveolar ventilation is adjusted to Primary hyperaldosteronism (Conn syndrome) maintain the PaCO2 between 35 and 45 mm Hg. When alveolar Secondary hyperaldosteronism ventilation is increased or decreased out of proportion to the Cushing syndrome PaCO2, a respiratory acid-base disorder exists. Liddle syndrome Bartter syndrome PATHOPHYSIOLOGY Exogenous corticoids Excessive licorice intake CO2 is produced by the body at a rate of 220 ml/min, which Ongoing diuretic use equates to production of 15 mol/L of carbonic acid each day.102 By way of comparison, total daily production of all the nonrespirato- Sodium salt administration (acetate, citrate) ry acids managed by the kidney and the gut amounts to less than Massive blood transfusions Exogenous sodium load Parenteral nutrition 500 mmol/L. Pulmonary ventilation is adjusted by the respiratory (Na+ > Cl–) Plasma volume expanders center in response to PaCO2, pH, and PO2, as well as in response to Sodium lactate (Ringer solution) exercise, anxiety, wakefulness, and other signals. Normal PaCO2 (40 mm Hg) is attained by precisely matching alveolar ventilation Other Severe deficiency of intracellular cations (Mg2+, K+) to metabolic CO2 production. PaCO2 changes in predictable ways as a compensatory ventilatory response to the altered arterial pH Chloride-Responsive Alkalosis produced by metabolic acidosis or alkalosis [see Table 1]. Chloride-responsive metabolic alkalosis usually occurs as a RESPIRATORY ACIDOSIS result of loss of Cl– from the stomach (e.g., through vomiting or gastric drainage). Treatment consists of replacing the lost Cl–, Mechanism either slowly (with NaCl) or relatively rapidly (with KCl or even When the rate of CO2 elimination is inadequate relative to the HCl). Because chloride-responsive alkalosis is usually accompa- rate of tissue CO2 production, the PaCO2 rises to a new steady nied by volume depletion, the most common therapeutic choice is state, determined by the new relation between alveolar ventilation to give saline along with KCl. Dehydration stimulates aldosterone and CO2 production. In the short term, this rise in the PaCO2 secretion, which results in reabsorption of Na+ and loss of K+. increases the concentrations of both H+ and HCO3– according to Saline is effective even though it contains Na+ because the admin- the carbonic acid equilibrium equation. Thus, the change in the istration of equal amounts of Na+ and Cl– yields a larger relative HCO3– concentration is mediated not by any systemic adaptation increase in the Cl– concentration than in the Na+ concentration but by chemical equilibrium. The higher HCO3– concentration (see above). In rare circumstances, when neither K+ loss nor vol- does not buffer the H+ concentration. The SID does not change, ume depletion is a problem, it may be desirable to replace Cl– by nor does the SBE.Tissue acidosis always occurs in respiratory aci- giving HCl. dosis because CO2 inevitably builds up in the tissue. Diuresis and other forms of volume contraction cause metabol- If the PaCO2 remains elevated, a compensatory response will ic alkalosis mainly by stimulating aldosterone secretion; however, occur, and the SID will increase to return the H+ concentration to diuretics also directly stimulate excretion of K+ and Cl–, further the normal range. The increase in the SID is accomplished pri- complicating the problem and inducing metabolic alkalosis more marily by removing Cl– from the plasma space. If Cl– moves into rapidly. tissues or red blood cells, it will result in intracellular acidosis (complicated by the elevated tissue PCO2); thus, to exert a lasting Chloride-Resistant Alkalosis effect on the SID, Cl– must be removed from the body. The kid- Chloride-resistant alkalosis [see Table 5] is characterized by an ney is designed to do this, whereas the GI tract is not (though the increased urine Cl– concentration (> 20 mmol/L) and ongoing Cl– adaptive capacity of the GI tract as a route of Cl– elimination has loss that cannot be abolished by Cl– replacement. Most common- not been fully explored). Accordingly, patients with renal disease ly, the proximate cause is increased mineralocorticoid activity. have a very difficult time adapting to chronic respiratory acidosis. Treatment involves identification and correction of the underlying Patients whose renal function is intact can eliminate Cl– in the disorder. urine; after a few days, the SID rises to the level required to restore the pH to a value of 7.35. It is unclear whether this amount of time Alkalosis from Other Causes is necessary because of the physiologic constraints of the system or In rare situations, an increased SID—and therefore metabolic because the body benefits from not being overly sensitive to tran- alkalosis—occurs secondary to cation administration rather than sient changes in alveolar ventilation. In any case, this response to anion depletion. Examples include milk-alkali syndrome and yields an increased pH for any degree of hypercapnia. According to
  11. 11. © 2006 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 8 ACID-BASE DISORDERS — 11 the Henderson-Hasselbalch equation, the increased pH results in is rapidly normalized in a patient with chronic respiratory acido- an increased HCO3– concentration for a given PCO2. Thus, the sis and an appropriately large SID, life-threatening alkalemia may “adaptive” increase in the HCO3– concentration is actually the ensue. Second, even if the PaCO2 is corrected slowly, the plasma consequence, not the cause, of the increased pH. Although the SID may decrease over time, making it impossible to wean the HCO3– concentration is a convenient and reliable marker of meta- patient from mechanical ventilation. bolic compensation, it is not the mechanism of the compensatory One option for treatment of hypercapnia is noninvasive ventila- response. This point is not merely a semantic one: as noted (see tion with a bilevel positive airway pressure (BiPAP) system. This above), only changes in the independent variables of acid-base bal- technique may be useful in the management of some patients, par- ance (PCO2, Atot, and SID) can affect the plasma H+ concentration, ticularly those whose sensorium is not impaired.103 Rapid infusion and HCO3– concentration is not an independent variable. of NaHCO3 in patients with respiratory acidosis may induce acute respiratory failure if alveolar ventilation is not increased to account Management for the increased CO2.Thus, if NaHCO3 is to be given, it must be Treatment of underlying ventilatory impairment As administered slowly, with alveolar ventilation adjusted appropri- with virtually all acid-base disorders, treatment begins by address- ately. Furthermore, it must be remembered that NaHCO3 works ing the underlying disorder. Acute respiratory acidosis may be by increasing the plasma Na+ concentration; if this effect is not caused by CNS suppression; neuromuscular diseases or condi- possible or not desirable, NaHCO3 should not be given. tions that impair neuromuscular functions (e.g., myasthenia Occasionally, it is useful to reduce CO2 production.This can be gravis, hypophosphatemia, and hypokalemia); or diseases affecting accomplished by reducing the amount of carbohydrates supplied the airway or the lung parenchyma (e.g., asthma and acute respi- in feedings (in patients requiring nutritional support), controlling ratory dysfunction syndrome [ARDS]). The last category of con- body temperature (in febrile patients), or providing sedation (in ditions produces not only alveolar hypoventilation but also prima- anxious or combative patients). In addition, treatment of shivering ry hypoxia.The two can be distinguished by means of the alveolar in the postoperative period can reduce CO2 production. Rarely, gas equation: however, can hypercapnia be controlled with these CO2-reducing PAO2 = PIO2 − PaCO2/R techniques alone. where R is the respiratory exchange coefficient (generally taken to Permissive hypercapnia. In the past few years, there has been be 0.8), and PIO2 is the inspired oxygen tension (approximately considerable interest in ventilator-associated lung injury. Overdis- 150 mm Hg in room air). Thus, as the PaCO2 increases, the PAO2 tention of alveoli can result in tissue injury and microvascular per- should also decrease in a predictable fashion. If the PAO2 falls by meability, which lead to interstitial and alveolar edema. In animal more than the predicted amount, there is a defect in gas exchange. studies, prolonged use of elevated airway pressures and increased In most cases, chronic respiratory acidosis is caused by either lung volumes resulted in increased pathologic pulmonary changes chronic lung disease (e.g., chronic obstructive pulmonary disease and decreased survival when compared with ventilatory strategies [COPD]) or chest wall disease (e.g., kyphoscoliosis). In rare cases, employing lower pressures and volumes.104,105 In a large multicen- it is caused by central hypoventilation or chronic neuromuscular ter clinical trial, simply lowering the tidal volume on the ventilator disease. from 12 ml/kg to 6 ml/kg in patients with acute lung injury resulted in a 9% absolute reduction in mortality risk.106 Although the proto- Control of hypoxemia Another aspect of respiratory acido- col followed in this trial did not advocate a reduced minute ventilation sis that is illustrated by the alveolar gas equation is that the pri- and hence an elevated PaCO2, this approach, often referred to as mary threat to life comes not from acidosis but from hypoxemia. permissive hypercapnia or controlled hypoventilation, has become In patients breathing room air, the PaCO2 cannot exceed 80 mm increasingly popular. Uncontrolled studies suggest that permissive Hg before life-threatening hypoxemia results. Accordingly, sup- hypercapnia may reduce mortality in patients with severe ARDS.20 plemental oxygen is required in the treatment of these patients. This strategy is not, however, without risks. Sedation is mandato- Unfortunately, oxygen administration is almost never sufficient ry, and neuromuscular blocking agents are frequently required. treatment by itself, and it generally proves necessary to address the Intracranial pressure rises, as does transpulmonary pressure; con- ventilatory defect. When the underlying cause can be addressed sequently, this technique is unusable in patients with brain injury quickly (as when the effects of narcotics are reversed with nalox- or right ventricular dysfunction. There is controversy regarding one), endotracheal intubation may be avoidable. In the majority of how low the pH can be allowed to fall. Some authors have report- patients, however, this is not the case, and mechanical ventilation ed good results with pH values of 7.0 or even lower,20 but most must be initiated. Mechanical support is indicated for patients have advocated more modest pH reductions (i.e., ≥ 7.25). who are unstable or at risk for instability and patients whose CNS function is deteriorating. Furthermore, in patients who exhibit RESPIRATORY ALKALOSIS signs of respiratory muscle fatigue, mechanical ventilation should Respiratory alkalosis may be the most frequently encountered be instituted before respiratory failure occurs. Thus, it is not the acid-base disorder. It occurs in residents of high-altitude locales absolute PaCO2 value that is the most important consideration in and in persons with any of a wide range of pathologic conditions, this situation but, rather, the clinical condition of the patient. the most important of which are salicylate intoxication, early sep- Chronic hypercapnia must be treated if the patient’s clinical sis, hepatic failure, and hypoxic respiratory disorders. Respiratory condition is deteriorating acutely. In this setting, it is important alkalosis also occurs in association with pregnancy and with pain or not to try to restore the PaCO2 to the normal range of 35 to 45 mm anxiety. Hypocapnia appears to be a particularly strong negative Hg. Instead, the patient’s baseline PaCO2, if known, should be the prognostic indicator in patients with critical illness.107 Like acute therapeutic target; if the baseline PaCO2 is not known, a target respiratory acidosis, acute respiratory alkalosis results in a small PaCO2 of 60 mm Hg is perhaps a reasonable choice. Overven- change in the HCO3– concentration, as dictated by the Henderson- tilation can have two undesirable consequences. First, if the PaCO2 Hasselbalch equation. If hypocapnia persists, the SID begins to