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CHAPTER 15:  Acid-Base Disorders      73 most drugs are small organic molecules, generally unable to stimulate an immune response alone, when a drug or metabolite becomes protein bound, either in serum or on cell surfaces, the drug–protein complex can become an allergen and stimulate immune system responses. Thus, the ability of a drug or its metabolites to sensitize the immune system depends largely on the ability to bind to tissue proteins. Many different drugs and treatments can cause allergic reactions and anaphylaxis. Penicillin is the drug most commonly implicated in eliciting true allergic reactions and accounts for approximately 90% of all reported allergic drug reactions and about 75% of fatal anaphylactic drug reactions. 64 Fatal reactions can occur without a prior allergic history; <25% of patients who die of penicillin-induced anaphylaxis exhibited allergic reactions during previous treatment with the drug. Paren teral penicillin administration is more than twice as likely to produce fatal allergic reactions as is oral administration. The cross-reactivity of penicillin allergy with cephalosporins is about 10%, so patients with a previous life-threatening or anaphylactic reaction to penicillin should not be given cephalosporins. The clinical manifestations of drug allergy vary widely. A generalized reaction similar to immune-complex or serum sickness reactions is very common, especially with trimethoprim-sulfamethoxazole and certain cephalosporins (cefaclor being the most frequent). While sulfa moieties are contained in many drugs, sulfa allergic reactions upon exposure to the nonantibiotic sulfas are uncommon. See Chapter 206, “ Antimicrobials, ” for more discussion of drug allergies. Serum sickness usually begins in the first or second week after initia tion of the drug and can take many weeks to subside after drug with drawal. Generalized malaise, arthralgias, arthritis, pruritus, urticarial eruptions, fever, adenopathy, and hepatosplenomegaly are common signs and symptoms. Drug fever may occur without other associated clinical findings and may also occur without an immunologic basis. Circulating immune complexes are probably responsible for the lupus-like reactions caused by some drugs. Other reactions are possible. Cytotoxic reactions include penicillininduced hemolytic anemia. Skin eruptions include erythema, pruri tus, urticaria, angioedema, erythema multiforme, and photosensitivity. Severe reactions, such as those seen in Stevens-Johnson syndrome and toxic epidermal necrolysis, may also occur. Delayed hypersensitivity reactions may manifest as contact dermatitis from drugs applied topically. Diagnosis is determined by a careful history. Treatment is supportive, with oral or parenteral antihistamines and corticosteroids. Drug ces sation is important, but reactions can continue. Referral to an allergy specialist is indicated for severe reactions. REFERENCES The complete reference list is available online at www.TintinalliEM.com. Acid-Base Disorders Gabor D. Kelen David M. Cline INTRODUCTION This chapter describes a practical approach to the clinical evaluation and treatment of acid-base disorders. We discuss the traditional approach recognizing that acid-base homeostasis is maintained by respiratory control of the partial pressure of carbon dioxide (Pco 2) through changes in alveolar ventilation and control of HCO3 – reabsorption and H+ excretion by the kidneys.

l evaluation and treatment of acid-base disorders. We discuss the traditional approach recognizing that acid-base homeostasis is maintained by respiratory control of the partial pressure of carbon dioxide (Pco 2) through changes in alveolar ventilation and control of HCO3 – reabsorption and H+ excretion by the kidneys. 1,2 The traditional bicarbonate-centered model con tinues to be the most commonly used at the bedside. 3 CHAPTER PATHOPHYSIOLOGY Plasma [H +]* is influenced by the rate of endogenous production, the rate of excretion, exogenous addition (e.g., acetylsalicylic acid inges tion), and the buffering capacity of the body. 1 Buffers mitigate the impact of large changes in available hydrogen ion on plasma pH. Buffer systems that are effective at physiologic pH include hemoglo bin, phosphate, proteins such as albumin, and bicarbonate (Figure 15-1). One can consider the [H+] to be the result of all physiologic buffers act ing on the common pool of hydrogen ions. The quantity of [HCO 3 –] in relation to carbonic acid buffer in the system is not fixed, but varies according to physiologic need. This flex ibility is largely provided by pulmonary exhalation of carbon dioxide (CO 2), which can vary significantly and change rapidly as required by alterations in the underlying acid-base status. The kidney regulates HCO 3 – excretion and the formation of new HCO3 –. The rate of these processes is dependent on the underlying acidbase status. The renal response to pulmonary acid-base disturbances begins within 30 minutes of onset, but requires hours to days to achieve equilibrium. Any condition that acts to increase [H +]—whether through endog enous production, decreased buffering capacity, decreased excretion, or exogenous addition—is known as acidosis. Similarly, any condition that acts to decrease [H +] is termed alkalosis. The terms acidemia and alkalemia refer to the net imbalance of [H+] in the blood. Acid-base disturbances are further classified as respiratory or meta bolic. Respiratory acid-base disorders are due to primary changes in Pco 2, and metabolic acid-base disorders reflect primary changes in [HCO3 –]. Compensatory mechanisms are, by definition, not “disorders, ” but rather normal physiologic responses to acid-base derangements. Failure of appropriate compensatory response implies the presence of another primary acid-base disturbance.  THE ANION GAP The principle of electrical neutrality requires that plasma have no net charge. The charge of the predominant plasma cation, Na +, must therefore be “balanced” by the charge of plasma anions.5 Although HCO3 – and Cl– constitute a significant fraction of plasma anions, the sum of their concentrations does not equal that of sodium. Therefore, there must be other anions present in the serum to maintain electrical neutrality. These Hemoglobin Protein Excretion *Carbonic anhydrase H2CO3 CO2 + H2O CA* H+ HCO – 3 Protein Hemoglobin MetabolismMetabolism Ingestion Excretion FIGURE 15-1. Schematic representation of hydrogen ion homeostasis. *Standard nomenclature is used in this chapter. The presence of brackets, [ ], surrounding an element or molecule implies the term concentration. Without the brackets, the chemical expressions simply refer to the element or molecule. Tintinalli_Sec03_p0053-0142.indd 73 8/2/19 2:57 PM

tation of hydrogen ion homeostasis. *Standard nomenclature is used in this chapter. The presence of brackets, [ ], surrounding an element or molecule implies the term concentration. Without the brackets, the chemical expressions simply refer to the element or molecule. Tintinalli_Sec03_p0053-0142.indd 73 8/2/19 2:57 PM 74 SECTION 3: Resuscitation TABLE 15-1 Unmeasured Anions Associated With an Elevated Anion Gap Metabolic Acidosis Diagnostic Category Anion Species Origin Diagnostic Adjuncts Renal failure (uremia) [PO4 2– ], [SO4 2– ] Protein metabolism BUN/creatinine Ketoacidosis Ketoacids, lactate Fatty acid metabolism Serum/urine ketones Diabetic β-hydroxybutyrate, lactate Fatty acid metabolism Specific test now available (older nitroprusside test yields false-negative result for β-hydroxybutyrate) Alcoholic Acetoacetate, lactate Fatty acid metabolism Starvation β-hydroxybutyrate   Consider coexistent volume depletion Lactic acidosis* Lactate Metabolism Lactate level for subtypes Sepsis Lactate Hypoperfusion, anaerobic metabolism Culture/organism-specific tests Cardiac arrest Lactate Hypoperfusion/reperfusion injury Consider other acidosis Liver failure Lactate Decreased lactate clearance Liver function tests Iron Lactate Disruption of cellular metabolism Serum iron level Metformin Lactate Inhibition of gluconeogenesis Cyanide Lactate Mitochondrial dysfunction, histotoxic hypoxia Carbon monoxide Lactate Hypoxia, anaerobic metabolism Carbon monoxide level Thiamine deficiency Lactate Aerobic metabolism interrupted, lactate accumulates Assess peripheral sensory and motor function for neuropathy Exogenous poisoning* Methanol Formate Methanol metabolism Osmolal gap Ethylene glycol (EG) Oxalate and organic anions EG metabolism favors pyruvate conversion to lactate Osmolal gap Oxalate crystals (urine) Salicylate Salicylate Salicylate, lactate, ketoacids Concomitant respiratory alkalosis and metabolic acidosis Isoniazid Lactate Anaerobic metabolism, lactate accumulation *This is not an exhaustive list; several other causes exist. anions are primarily albumin, phosphate, sulfate, organic anions such as lactate, and the conjugate bases of ketoacids. Because these substances are not commonly measured, they are termed unmeasured anions. Unmeasured cations also exist, largely in the form of Ca 2+ and Mg2+. The unmeasured anion concentration, the anion gap (AG), that is, the difference between the serum [Na+] and the sum of serum [Cl–] and [HCO3 –], equals the concentration of the unmeasured anions. There are other cations that could be considered in the equation, such as [Ca 2+], [Mg2+], and [K+]; however, typically they are not included. Most laboratories now provide a calculated AG in their reports of blood chemistries; readers should check with their own laboratories for information on their institutional methods. As with other acid-base concepts, the accepted “normal” range for the AG is less important than whether it has changed in relation to the patient’s steady-state baseline value. Thus, a relative change in the AG, referred to as the delta gap, may be more important than the actual AG value. Virtually all AG values above 15 mEq/L can be considered abnormal, even when there are no previous comparison values available. The common laboratory threshold is 12 mEq/L. Elevations of the AG are most commonly associated with metabolic acidosis (Table 15-1). Albumin is a major component of the AG. Critically ill patients are frequently hypoalbuminemic, which may decrease the AG into the normal range, effectively masking the presence of a wide AG acidosis. 6 If the albumin is significantly low, then the normal range for the AG should be lower. For every drop in the albumin level by 1 gram/dL, the normal AG range should be lowered by approximately 2.5.

hypoalbuminemic, which may decrease the AG into the normal range, effectively masking the presence of a wide AG acidosis. 6 If the albumin is significantly low, then the normal range for the AG should be lower. For every drop in the albumin level by 1 gram/dL, the normal AG range should be lowered by approximately 2.5. PARAMETERS REQUIRED FOR CLINICAL ACID-BASE EVALUATION When taking a medical history, ask about events that may result in the gain or loss of acid or base, such as vomiting, diarrhea, medications, or ingestions of toxins, and seek evidence of dysfunction of the organs of acid-base homeostasis—the liver, kidneys, and lungs. Obtain blood gases (pH, Pco 2, and [HCO3 –]), electrolytes ([Na+], [K+], [Cl–], and [HCO 3 –]), and other tests that affect the patient’s acid-base status (albumin, lactic acid, creatinine, BUN, drug levels of suspected ingestions such as salicylate). Based on current history and physical and past medical history, consider the need to obtain calcium, magnesium, phosphate, serum ketones, glucose, lactate, serum osmolality, and urine electrolytes and osmolality. Most clinical laboratories measure two of the parameters reported in blood gas results (most commonly the pH and Pco 2) and use the Henderson-Hasselbalch equation to calculate the third ([HCO3 –]). Venous or capillary blood gases, rather than arterial samples, may be satisfactory for many clinical situations. 7 Venous P co 2 may be a sensitive screen for hypercarbia (cutoff 45 mm Hg), but the venous and arterial Pco 2 values exhibit wide variation and are not interchangeable.8 Confirming an elevated venous lactate with an arterial sample 9 is not necessary.8,10 See the Box, “Clinical Approach to Acid-Base Disorders, ” for one method of assessing acid-base disorders. METABOLIC ACIDOSIS Metabolic acidosis may result from HCO 3 – loss, administration of acid (parenteral nutrition), or endogenous production and accumulation of acid. Loss of HCO – occurs by externalization of intestinal contents (e.g., vomiting, enterocutaneous fistulae) and renal wasting of bicarbonate (e.g., renal tubular acidosis, carbonic anhydrase inhibitor therapy). Endogenous acids accumulate in renal tubular acidosis, ketoacidosis, and lactic acidosis. Unopposed metabolic acidosis results in a decreased serum [HCO –] and an increase in serum [H +]. The increased [H+] stimulates the respiratory center, resulting in increased minute ventilation. The physiologically based “respiratory compensation” is an attempt to lower the [H +] by a reduction in Pco 2 through increased ventilation. With normal respiratory compensation, Pco 2 decreases by 1 mm Hg for every 1 mEq/L net decrease in [HCO 3 –]. Using these relationships Tintinalli_Sec03_p0053-0142.indd 74 8/2/19 2:57 PM

siologically based “respiratory compensation” is an attempt to lower the [H +] by a reduction in Pco 2 through increased ventilation. With normal respiratory compensation, Pco 2 decreases by 1 mm Hg for every 1 mEq/L net decrease in [HCO 3 –]. Using these relationships Tintinalli_Sec03_p0053-0142.indd 74 8/2/19 2:57 PM CHAPTER 15:  Acid-Base Disorders      75 allows the clinician to calculate the expected P co 2 from the measured [HCO3 –], assuming respiratory compensation is normal. If the expected Pco 2 value differs from the measured value in steady-state metabolic acidosis, then respiratory compensation is compromised, and a primary respiratory disorder exists in conjunction with the metabolic acidosis. There are limits to the adequacy of respiratory compensation for metabolic acidosis. Respiratory minute volume actually declines when pH decreases below 7.10. It is particularly important to appreciate any contribution to the acidosis from an inadequate respiratory response. Administration of HCO – in the presence of hypoventilation may exacerbate the respiratory acidosis, because the HCO3 – converts to CO2 and water (H2O). The development of metabolic acidosis that drives the pH below 7.10 is likely associated with a very high risk of inadequate ventilation response, since there is a limit to respiratory compensation. The lowest Pco 2 level achievable is approximately 12 mm Hg. This lower limit in obtainable Pco 2 is due to resistance in airflow and increased CO2 generated by the exertion required for rapid ventilation, both offsetting the ventilator exhalation of CO 2. The superimposition of respiratory acidosis on a patient in such a condition will result in a rapid decline of pH to levels at which organ function drops and pharmacotherapy will fail. Noninvasive or mechanical ventilation usually should be instituted in such situations to ensure the ventilatory rate and volume are sufficient to prevent an increase in Pco 2 at this critical time. Symptoms of metabolic acidosis can result from acidosis itself or the underlying disease itself. Patients may complain of abdominal pain, headache, nausea with or without vomiting, and generalized weakness, and because acidosis stimulates the respiratory center, the patient may complain of dyspnea. Acute metabolic acidosis depresses cardiovascular Clinical Approach to Acid-Base Disorders Following is one method that has work ed well for the authors. You will need results of a blood gas and serum sodium, chloride, and bicarbona te to apply this method. This method requires  methodical  int erpretation  of  labora tory  results  and  corr elation  with  clinical findings. 1. Look at the pH. If it is decreased below 7.35, the primary (or predominan t) disturbance is acidemia; go to step 2. If the pH is increased abov e 7.45, the predominan t disturbance is alkalemia; go to step 5. If the pH is in the normal range , but the [HCO3 – ] or the Pco 2 is abnormal, consider a mixed acid-base disorder. 2. Acidemia. If the pH indicates acidemia, the acidemia type can be ascer tained by examining the [HCO3 – ] and Pco 2. If the [HCO3 – ] decreased, go first to step 3; if the Pco 2 is elevated, but the [HCO3 – ] is normal, go to step 4. 3. Metabolic Acidosis a. If the [HCO3 – ] is lower than the labora tory normal range (implying a primary metabolic acidosis), then the anion gap (A G) should be examined and, if possible, compared with a known steady-state value.2 b.

first to step 3; if the Pco 2 is elevated, but the [HCO3 – ] is normal, go to step 4. 3. Metabolic Acidosis a. If the [HCO3 – ] is lower than the labora tory normal range (implying a primary metabolic acidosis), then the anion gap (A G) should be examined and, if possible, compared with a known steady-state value.2 b. Calculate the A G:  A G = [Na+] – ([HCO3 – ] + [Cl– ]) •   If the AG is increased compar ed with the kno wn steady -state value or is >12 (or above institutional threshold), then by definition, a wide AG metabolic acidosis is present, and the absolute change in the AG should be compar ed with the absolute change in the [HCO3 – ] from normal to detect other disturbances. •   If the AG is unchanged (or in the normal range), then the disturbance is nonwidened or normal AG metabolic acidosis, typically associated with hyperchloremia. •   If the change in the AG (increase) is equal to the change in the [HCO3 –] (decrease), then the wide AG acidosis is termed  pure.2  If the AG has risen more than the [HCO3 –] has decreased, then there is also likely to be a conc omitant metabolic alkalosis. If the change in the AG is less than the change in the [HCO3 –], then a normal AG acidosis is also presen t. (T his is a difficult conc ept, but tw o separa te physiologic mechanisms resulting in increased [H+] can occur simultaneously.) c. Next e xamine  whether the v entilatory r esponse is as e xpected. •   The expected respir atory compensa tion is 1:1, the Pco 2 decreases by 1 mm Hg for every 1 mEq/L decrease in [HCO3 – ]. (1)   If the measured Pco 2 from the blood gas equals the expec ted value based on the calculated Pco 2 (which is determined by the decrease in the [HCO3 – ]), there is appropriate respir atory compensa tion. Not e that the pH will not return to normal. (2)   If the measured Pco 2 from the blood gas is higher than the expec ted value based on the calculated Pco 2 (which is determined by the decrease in the [HCO3 –]),  there  is  a  concomitant  respir atory  acidosis. With  higher  than expected Pco 2, think respiratory acidosis. (3)   If  the  measured  Pco 2  from  the  blood  gas  is  low er  than  the  calc ulated Pco 2 (which is determined by the decrease in the [HCO3 –]), there is also a concomitant primary respiratory alkalosis. 4. Respiratory Acidosis a. If  the Pco 2 is elevated from normal (ra ther than the [HCO3 –] being decreased), the primary disturbance is respiratory acidosis. b. The  next step is to determine if the respir atory acidosis is acut e or chronic by examining the ratio of the down ward change in pH (from normal) to the upw ard change in Pco 2 (from normal). By determining  the drop in pH, you are examining the rise in [H+]. Subtract the measured pH on the blood gas from the institution’s lower limit of normal; use the number of hundredths (to the right of the decimal point). Divide this number by the eleva tion in Pco 2 in mm Hg (abov e normal range). •  If  the ratio is 0.8, it is considered acute.4 •  If  the ratio is 0.33, it is considered chronic. •   If the ratio is betw een 0.8 and 0.33, it is probably an acut e exac erbation of the chronic condition. An alterna te explana tion is that a metabolic acidosis is also present as evidenced by a decreased [HCO3 – ]. •   If the ratio is >0.8, there must be a metabolic acidosis as an explana tion for the excess [H+]. •  If  the ratio is <0.33, a metabolic alkalosis must also be present. 5. Alkalemia. If the pH is >7.45, the alkalemia type can be determined by examining the [HCO3 – ] and Pco 2. If the [HCO3 – ] is increased, go to step 6 first; if the Pco 2 is decreased, go to step 7. 6. Metabolic Alkalosis . If [HCO3 – ] is elevated, there is a primary metabolic alkalosis. a. There is an expected ventilatory response, although it is quite varied. b.

ype can be determined by examining the [HCO3 – ] and Pco 2. If the [HCO3 – ] is increased, go to step 6 first; if the Pco 2 is decreased, go to step 7. 6. Metabolic Alkalosis . If [HCO3 – ] is elevated, there is a primary metabolic alkalosis. a. There is an expected ventilatory response, although it is quite varied. b. The  ratio of the change upw ard in Pco 2 (mm Hg) to the change upw ard in [HCO3 – ] (mEq/L), each from the institutional  norms, can be examined . If the ra tio is much less than 0.7, there is also a respir atory alkalosis (in addition to the metabolic alkalosis). If the ra tio is close to 0.7, this is likely to be a compensa tory ven tilatory response. If the ra tio is well abov e 0.7, respir atory acidosis is conc omitantly present. 7. Respiratory Alkalosis. If the Pco 2 is lower than normal, there is a primary respir atory alkalosis. a. The ratio of the change in [H+] to the change in Pco 2 should be examined. Subtr act the institution’s upper limit of normal pH from the measured pH on the blood gas; use the number of hundredths (to the right of the decimal point). Divide this number by the decrease in Pco 2 in mm Hg (below normal range). •   Acute respiratory alkalosis has a ra tio of about 0.75. If the ra tio is well abov e 0.75,  there  is  probably  also  a  conc omitant  metabolic  alkalosis  to  explain  the greater  than  expected  decline  in  [H+]. If  the  ratio  is  smaller,  the  condition  is chronic or there may also be a metabolic acidosis component. 8. Mixed Acid-Base Disorder. Every arterial blood gas that shows no or minimal pH derangement should still call for examina tion of the Pco 2, [HCO3 – ], and AG, because there may well be a mixed acid-base disturbance . It is quite possible for the pH, [HCO3 – ], and Pco 2 to be normal and yet hav e significan t acid-base disturbances . The only evident abnormality  may be the AG. Tak e the example of an [Na+] of 145, [Cl– ] of 97, [K+] of 4.5, and [HCO3 – ] of 25 and a normal art erial blood gas. All the numbers look reasonably normal. Ho wever, the AG is 23, so by definition,  there must be a wide AG metabolic acidosis. The explana tion for the normal numbers is a conc omitant metabolic alkalosis. Tintinalli_Sec03_p0053-0142.indd 75 8/2/19 2:57 PM

] of 4.5, and [HCO3 – ] of 25 and a normal art erial blood gas. All the numbers look reasonably normal. Ho wever, the AG is 23, so by definition,  there must be a wide AG metabolic acidosis. The explana tion for the normal numbers is a conc omitant metabolic alkalosis. Tintinalli_Sec03_p0053-0142.indd 75 8/2/19 2:57 PM 76 SECTION 3: Resuscitation function, can facilitate cardiac dysrhythmias, stimulates inflammation, and suppresses the immune response.11  CAUSES OF METABOLIC ACIDOSIS The causes of elevated AG metabolic acidosis are listed in Table 15-1. A comparison with the patient’s steady-state AG should be made when ever possible. Measurement and detection of specific anions may be indicated. Differential Diagnosis of Wide AG Acidosis The differential diagnoses to be considered in emergency practice fall into four broad catego ries: renal failure (uremia), ketoacidosis (diabetic ketoacidosis, alcoholic ketoacidosis, starvation ketoacidosis), lactic acidosis, and ingestions (methanol, ethylene glycol, salicylates, and many others). Renal failure should be evident from the serum chemistries. Acidosis seen in initial stages of renal failure may be severe but tends to be stable, with [HCO –] approximately 15 mEq/L in cases of chronic renal failure. Positive serum ketones point to one of the ketoacidoses. In instances of known insulin-dependent diabetes mellitus, diabetic ketoacidosis is likely, although there is usually a component of lactic acidosis. In alco holics who have recently stopped heavy drinking, alcoholic ketoacidosis should be considered; ketoacids contribute far less to the acidosis in ketoacidosis than lactate. Starvation ketosis will be found in patients with recent oral intake that is inadequate, such as in cases of fasting, dieting, or protracted vomiting, although the magnitude of acid-base disturbance in starvation ketosis should be small. The major ketone present in the serum of a patient with untreated diabetic or alcoholic ketoacidosis may be β-hydroxybutyrate. See Chapter 223, “Type 1 Dia betes Mellitus, ” for a detailed discussion. Lactic acidosis occurs whenever lactate production exceeds lactate metabolism and is classified into two types. The first, in which tissue hypoxia is present and lactate production is elevated, is referred to as type A. Normal tissue oxygenation and impairment of lactate metabolism define the second, called type B. Severe acidosis that is resistant to treatment is seen in various type B lactic acidoses and ingestions. Lactic acidosis is not a diagnosis, but a syndrome with its own differential diagnosis. Causes of lactic acidosis are listed in Table 15-1. Lactate levels should be measured and accounted for in an adjustment of the AG. Ethanol is frequently cited as a cause of wide AG acidosis, but ethanol should never be considered the cause of any significant metabolic acidosis; look for other causes. Although ethyl alcohol metabolism may lead indirectly to very mild lactic acidosis, usually due to the same mechanism as alcoholic ketoacidosis, in which lactic acidosis is more substantial, neither the alcohol nor its metabolites directly contribute to the acidosis. The relation of [HCO –] to the AG and the [HCO3 –] to the expected Pco 2 compensation must be examined in every patient with wide AG acidosis to determine whether other acid-base disturbances, meta bolic or respiratory, exist. For example, the triple acid-base disturbance of wide AG metabolic acidosis, metabolic alkalosis, and respiratory alkalosis is seen with sepsis (lactic acidosis) and salicylate poisoning. Osmolal Gap Determination of the osmolal gap will help identify methanol and ethylene glycol from other etiologies. The interpretation of serum osmolality requires the measured (laboratory measurement) and calculated osmolality.

, and respiratory alkalosis is seen with sepsis (lactic acidosis) and salicylate poisoning. Osmolal Gap Determination of the osmolal gap will help identify methanol and ethylene glycol from other etiologies. The interpretation of serum osmolality requires the measured (laboratory measurement) and calculated osmolality. 12 The common formula is (2 × [NA +]) + [glucose] + [urea], but recently, a study of several methods determined that the most accurate equation to identify true osmolal gap is as follows: (2 × [NA +]) + (1.4 × [glucose]) + (1.2 × [urea]) + (1.2 × [ETOH]). 13 Increased osmolal gap can also be associated with an increased AG acidosis in the setting of acute kidney injury, lactic acidosis, and diabetic or alcoholic ketoacidosis. Differential Diagnosis of Unchanged (Normal) AG Acidosis The non-AG type of acidosis is often referred to as “normal” AG acidosis. 3 Some texts refer to this as hyperchloremic metabolic acidosis, but not all cases of normal AG acidosis are associated with hyperchloremia. If the patient has hyponatremia with a normal AG acidosis, the chloride may be in the normal range. Abnormal chloride levels alone usually signify a more serious underlying metabolic disorder, such as metabolic acidosis (elevated chloride) or metabolic alkalosis (low chloride). The causes of hyperkalemic and hypokalemic normal AG metabolic acidosis are listed in Table 15-2. One should be wary of traditional classification based on [K +], because serum [K+] itself is dependent on the actual pH. Thus, in severe acidosis, a normal range [K +] value may not represent true potassium levels. As acidosis is corrected and acidemia resolves, the [K +] will concordantly fall. Because all diuretics may cause a contraction alkalosis, the metabolic acidosis that occurs simultaneously with potassium-sparing diuret ics may not be evident, as the two may simply cancel each other out. Because the AG is unchanged, there is no indication that two distinct opposing processes may be occurring. As with wide AG–type acidosis, the expected P co 2 compensation must be examined in every patient with normal AG acidosis to determine whether other respiratory acidbase disturbances exist. Acidosis with Large-Volume Normal Saline Resuscitation It has been known for some time that large-volume fluid resuscitation with normal saline is associated with hyperchloremic acidosis (formerly called dilution acidosis). Two large, single-center, randomized con trolled trials compared normal saline to balanced salt solutions (lactated Ringer’s or Plasma-Lyte ®) in the resuscitation of patients in the ED prior to admission and found fewer major adverse events (persistent renal dysfunction, new renal replacement therapy, or mortality) in the bal anced salt group. 15,16 Since then, a meta-analysis including those two studies plus four prior randomized controlled trials, totaling 19,332 patients, found no significant differences in the outcome measures of intensive care unit mortality, acute kidney injury, and new renal replacement therapy when comparing 0.9 normal saline to balanced salt solutions. 17 Most consistent in all the cited trials is the frequent development of hyperchloremic metabolic acidosis associated with largevolume resuscitation using normal saline.  TREATMENT The treatment of acidosis reflects the treatment of the underlying dis order and the restoration of normal tissue perfusion and oxygenation. The most important step is to determine whether there is a respira tory component to the acidosis (i.e., a primary respiratory acidosis), because the treatment approach differs. If there is inadequate respiratory compensation, the most appropriate treatment will be to first correct the respiratory problem.

oxygenation. The most important step is to determine whether there is a respira tory component to the acidosis (i.e., a primary respiratory acidosis), because the treatment approach differs. If there is inadequate respiratory compensation, the most appropriate treatment will be to first correct the respiratory problem. Address electrolyte disturbances, administer antidotes for toxins as appropriate, and initiate treatment for underlying causes such as sepsis (see Chapter 151, “Sepsis”) or diabetic ketoacidosis (see Chapter 225, “Diabetic Ketoacidosis”). Bicarbonate Therapy in Acidosis Bicarbonate therapy results in the generation of significant quantities of CO 2, which diffuses readily into TABLE 15-2 Causes of Normal Anion Gap Metabolic Acidosis With a Tendency to Hyperkalemia With a Tendency to Hypokalemia Subsiding diabetic ketoacidosis Renal tubular acidosis, type I (classical distal acidosis) Early uremic acidosis Renal tubular acidosis, type II (proximal acidosis) Early obstructive uropathy Acetazolamide; carbonic anhydrase inhibitor, causing functional renal tubular acidosis Renal tubular acidosis, type IV Acute diarrhea with losses of HCO3 –  and K+ Hypoaldosteronism (Addison’s disease) Ureterosigmoidostomy with increased resorption of [H+] and [Cl– ] and losses of HCO3 –  and K+ Infusion or ingestion of HCl, NH4Cl, lysine- HCl, or arginine-HCl Obstruction of artificial ileal bladder Potassium-sparing diuretics Fluid resuscitation with unbalanced, high chloride content crystalloids (dilution acidosis) Tintinalli_Sec03_p0053-0142.indd 76 8/2/19 2:57 PM

H+] and [Cl– ] and losses of HCO3 –  and K+ Infusion or ingestion of HCl, NH4Cl, lysine- HCl, or arginine-HCl Obstruction of artificial ileal bladder Potassium-sparing diuretics Fluid resuscitation with unbalanced, high chloride content crystalloids (dilution acidosis) Tintinalli_Sec03_p0053-0142.indd 76 8/2/19 2:57 PM CHAPTER 15:  Acid-Base Disorders      77 TABLE 15-3 Potential Indications for Bicarbonate Therapy in Metabolic Acidosis Indication Rationale Severe hypobicarbonatemia (<4 mEq/L) Insufficient buffer concentrations may lead to extreme increases in acidemia with small increases in acidosis. Severe acidemia (pH <7.00 to 7.15)* in cases of wide anion gap acidosis, with signs of shock or myocardial irritability that has not responded to supportive measures including adequate ventilation and fluid resuscitation as indicated by the patient’s clinical characteristics Therapy for the underlying cause of acidosis depends on adequate organ perfusion. Severe hyperchloremic acidemia† Lost bicarbonate must be regenerated by kidneys and liver, which may require days. *Presented as a range because recommendations differ among authors; data do not support a specific threshold for treatment. †No specific threshold indication by pH exists. The presence of serious hemodynamic insufficiency despite supportive care should guide the use of bicarbonate therapy for this indication. cells, in particular those of the CNS, which may cause paradoxical worsening of intracellular acidosis.18 An abrupt CO2 increase may exceed the ventilatory capacity of a patient already at maximum minute ventilation, thereby producing abrupt and worsening respiratory acidosis. After successful treatment with bicarbonate, “overshoot” alkalosis may result. Bicarbonate therapy imposes an osmotic and sodium load (1000 mEq/L of typical 1 N solution). Bicarbonate therapy may be appropriate for limited indications (Table 15-3). 11,19-25 When given, HCO3 – can be dosed at 0.5 mEq/kg for each milliequivalent per liter rise in [HCO 3 –] desired.11 The goal is to restore adequate buffer capacity ([HCO3 –] >8 mEq/L) or to achieve clinical improvement in shock or dysrhythmias. Bicarbonate should be given as slowly as the clinical situation permits. Seventy-five milliliters of 8.4% sodium bicar bonate in 500 mL of dextrose 5% in water produces a nearly isotonic solution for infusion. Adequate time should be allowed for the desired effect to be achieved, with monitoring of acid-base balance. METABOLIC ALKALOSIS Metabolic alkalosis is typically classified as chloride sensitive or chloride insensitive, thus indicating the treatment approach. Metabolic alkalosis results from gain of bicarbonate or loss of acid. The physiologic effects of alkalemia are substantial. Neurologic abnormalities, especially tetany, neuromuscular instability, and seizures, are common. Reduction in [H +] results in reductions in ionized calcium, potassium, magnesium, and phosphate levels. Serum proteins, largely polyanionic, buffer H +; with rapid acid loss, such as that which occurs in respiratory alkalosis, the newly available buffer capacity of those proteins binds calcium and other cations instead. 26 Alkalemia may be of particular concern in patients with chronic obstructive pulmonary disease, because of the shift of the oxygen–hemoglobin dissociation curve to the left, which makes O 2 less available to the tissues. Alkalemia depresses respiration, a serious effect in patients with compromised ventilation. Many patients with chronic obstructive pulmonary disease also take diuretics, leading to a contrac tion alkalosis. Bicarbonate and chloride homeostasis is closely intertwined.

left, which makes O 2 less available to the tissues. Alkalemia depresses respiration, a serious effect in patients with compromised ventilation. Many patients with chronic obstructive pulmonary disease also take diuretics, leading to a contrac tion alkalosis. Bicarbonate and chloride homeostasis is closely intertwined. Condi tions that result in chloride loss, such as vomiting (which also causes acid loss), diarrhea, diuretic therapy, and chloride-wasting diseases (e.g., cystic fibrosis and chloride-wasting enteropathy), tend to reduce serum chloride concentration and extracellular volume. The reduc tion in extracellular volume increases mineralocorticoid activity, which enhances sodium reabsorption and potassium and hydrogen ion secre tion in the distal tubule, which in turn enhance bicarbonate generation. The resulting increase in serum [HCO –] eventually exceeds the tubule’s maximum ability to reabsorb filtered bicarbonate. The resulting urine is alkaline, and because its anionic content is mostly bicarbonate, it is largely free of chloride (<10 mEq/L). (Nevertheless, the urine chloride may be normal when diuretics are administered.) The result is hypoka lemic, hypochloremic alkalosis that responds to normal saline (chlorideresponsive alkalosis). Other diseases that cause metabolic alkalosis are usually associated with normovolemia or hypervolemia and often include hypertension. These diseases usually cause excess mineralocorticoid activity, resulting in the same pathophysiologic cascade described earlier. However, the excess mineralocorticoid activity is not associated with hypovolemia, so the urine chloride is generally normal or elevated (>10 mEq/L) and the alkalosis cannot be reversed with normal saline. Conditions producing “chloride-unresponsive alkalosis” and hypertension include renal artery stenosis, renin-secreting tumors, adrenal hyperplasia, hyperaldosteronism, Cushing’s syndrome, and exogenous mineralocorticoids (e.g., licorice, fludrocortisone). The compensation for metabolic alkalosis involves reduction in alveolar ventilation, but the exact relationship between P co 2 and [H+] is not well established. Most studies to date have been conducted in dialysis patients or patients with conditions that predispose to alveolar hyper ventilation (e.g., sepsis, pneumonia). As a guideline, Pco 2 in patients with significant metabolic alkalosis should rise by 0.7 mm Hg for each milliequivalent increase in [HCO –]. The P co 2 also rarely rises above 55 mm Hg in compensation for metabolic alkalosis.  TREATMENT In the emergency setting, metabolic alkalosis rarely requires active management. Treat the underlying cause. Hydrate, and replace volume with sodium chloride and potassium. Aggressive therapy, such as IV hydro chloric acid, requires intensive care unit admission and monitoring. RESPIRATORY ACIDOSIS Respiratory acidosis is defined by alveolar hypoventilation and is diag nosed when the P co 2 is greater than the expected value. Regardless of underlying cause, the final common path is inadequate ventilation. Inadequate minute ventilation most frequently results from head trauma, chest trauma, lung disease, or excess sedation. The chronic hypoventilation seen in extremely obese patients is often referred to as the Pickwickian syndrome or obesity hypoventilation syn drome. Patients with severe chronic obstructive pulmonary disease have increased dead space and frequently also have decreased minute ventilation. In general, a rise in the P co 2 stimulates the respiratory center to increase respiratory rate and minute ventilation. However, if the arterial Pco 2 chronically exceeds 60 to 70 mm Hg, as may occur in 5% to 10% of patients with severe emphysema, respiratory acidosis may depress the respiratory center.

te ventilation. In general, a rise in the P co 2 stimulates the respiratory center to increase respiratory rate and minute ventilation. However, if the arterial Pco 2 chronically exceeds 60 to 70 mm Hg, as may occur in 5% to 10% of patients with severe emphysema, respiratory acidosis may depress the respiratory center. Under such circumstances, the stimulus for ventila tion is provided primarily by hypoxemia acting on chemoreceptors in the carotid and aortic bodies. Giving oxygen could remove the main stimulus to breathe, causing the P co 2 to rise abruptly to extremely dangerous levels. Consequently, when administering oxygen to patients with chronic obstructive pulmonary disease, carefully monitor for apnea or hypoventilation; however, do not withhold oxygen in the case of severe hypoxemia. Evaluation of ventilation requires attention to several important clinical issues. First, the ventilation that would be expected based on assessment of the respiratory rate and depth should be com pared with the actual ventilation of the patient (i.e., P co 2). A “normal” Pco 2 of 40 mm Hg in a tachypneic, dyspneic patient likely reflects sig nificant ventilatory insufficiency. Second, the impact of respiratory aci dosis on partial pressure of oxygen in the alveoli (Pao2) in such a patient may be considerable. The alveolar gas equation suggests that if inspired oxygen concentration and respiratory quotient do not change, increases in Pco 2 will result in reductions in Pao2. Each 1-mm Hg increase in Pco 2 results in a 1-mmol increase in [H+]. Across the linear portion of the pH–hydrogen ion concentration rela tionship, each 1-mm Hg increase in P co 2 should theoretically produce a decrease in pH of 0.01. The actual relationship between changes in Pco 2 (up to values of 90 mm Hg) and changes in [H +] determined in normal humans is about 8 to 10. Thus, a 10-mm Hg increment in Pco 2 Tintinalli_Sec03_p0053-0142.indd 77 8/2/19 2:57 PM