Physiological Approach to Assessment of Acid-Base Disturbances
2014年10月09日
Physiological Approach to Assessment of Acid-Base Disturbances
Kenrick Berend, M.D., Ph.D., Aiko P.J. de Vries, M.D., Ph.D., and Rijk O.B. Gans, M.D., Ph.D. N Engl J Med 2014; 371:1434-1445October 9, 2014DOI: 10.1056/NEJMra1003327
Internal acid-base homeostasis is fundamental for maintaining life. Accurate and timely interpretation of an acid-base disorder can be lifesaving, but the establishment of a correct diagnosis may be challenging.1 The three major methods of quantifying acid-base disorders are the physiological approach, the base-excess approach, and the physicochemical approach (also called the Stewart method).2This article reviews a stepwise method for the physiological approach.
The physiological approach uses the carbonic acid-bicarbonate buffer system.Based on the isohydric principle, this system characterizes acids as hydrogen-ion donors and bases as hydrogenion acceptors. The carbonic acid-bicarbonate system is important in maintaining
homeostastic control .In the physiological approach, a primary change in the partial pressure of carbon dioxide (PCO2) causes a secondary “adaptive” response in the bicarbonate concentration and vice versa; further changes in carbon dioxide or bicarbonate reflect additional changes in acid-base status. The four recognized primary acid-base disorders comprise two metabolic disorders (acidosis and alkalosis ) and two respiratory disorders (acidosisi and alkalosis).
The hydrogen-ion concentration is tightly regulated because changes in hydrogen ions alter virtually all protein and membrance functions.2-6 Since the concentration of hydrogen ions in plasma is normally very low (approximately 40 nmol per liter ), the pH, which is the negative logarithm of the hydrogen-ion concentration, is generally used in clinical medicine to indicate acid-base status.3-5,7 The terms “acidemia” and “alkalemia” refer to states in which the blood pH is abnormally low (acidic) or abnormally high (alkaline). The process in which the hydrogen-ion concentration is increased is called acidosis, and the progress in which the hydrogen-ion
concentration is decreased is called alkalosis.3,4 The traditional determination of acid-base values is based on the Henderson-Hasselbalch equation (in which pK denotes the acid dissociation constant):
pH =Pk + log10 (bicarbonate [HCO3--]÷[0.03×partial pressure of arterial carbon dioxide (PaCO2)]),
where bicarbonate is in millimoles per liter and PaCO2 is in millimeters of mercury.6,7 An acid-base disorder is called “respiratory” when it is caused by a primary abnormality in
respiratory function (i.e.,a change in the PaCO2) and “metabolic” when the primary change is attributed to a variation in the bicarbonate concentration.
HISTORY AND PHYSICAL EXAMINATION
The first step in assessment of an acid-base disorder is a careful clinical evalution. Various signs and symptoms often provide clues regarding the underlying acid-base disorder; these include the patient’s vital signs (which may indicate shock or sepsis),neurologic state (consciousness vs.
unconsciousness),signs of infection (e.g., ferver), pulmonary status (respiratory rate and presence or absence of Kussmaul respiration, cyanosis, and clubbing of the fingers), and gastrointestinal symptoms (vomiting and diarrhea). Certain underlying medical conditions such as pregnancy, diabetes, and heart, lung,liver, and kidney disease may also hint at the cause. The clinician should
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Physiological Approach to Assessment of Acid-Base Disturbances
2014年10月09日
determine whether the patient has taken any medications that affect acid-base balance (e.g., laxatives, diuretics, topiramate, or metformin) and should consider signs of intoxication that may be associated with acid-base disturbances (e.g., acetone fetor as a sign of diabetic ketoacidosis or isopropyl alcohol intoxication, and visual disturbance as a symptom of methanol intoxication).
DETERMINATION OF THE PRIMARY ACID-BASE DISORDER AND THE SECONDARY RESPONSE
The second step is to determine the primary acid-base disorder and the secondary response. The
＋
range of pH that is compatible with life is 7.80 to 6.80 (a hydrogen-ion concentration [H] of 16 to 160 nmol per liter).3 For the purpose of this review, the reference value for pH is 7.40±0.02, for PaCO2, 38±2 mm Hg, and for [HCO3--],24±2 mmol per liter. The four major acid-base disturbances are defined as primary acid-base disorders (Table 1 and Figure 1).Empirical observations suggest that the homeostastic response to acid-base disorders is predictable and can be calculated.9-18 In response to metabolic acid-base disturbances, changes in the respiratory rate develop quickly, and a new steady-state PaCO2 is reached within hours. In cases of persistent respiratory
abnormalities, metabolic compensation develops slowly, and 2 to 5 days are required for the plasma bicarbonate concentration to reach a new steady-state level. A respiratory change is called “acute” or “chornoic” depending on whether a secondary change in the bicarbonate
concentration meets certain criteria (Table 1).Mixed acid-base disorders are diagnosed when the secondary response differs from that which would be expected.13,18-23
There are several caveats concerning compensatory changes. Blood gas values can always be explained by two or more coexisting acid-base disorders.12 The current prediction equations that are used to assess acid-base status are approximations based on nearly 40-year-old studies
involving humans and dogs.1 Experimental studies of severe chronic hypocapnia and hypercapnia in humans are not ethically feasible; thus, data are insufficient to construct confidence limits for severe chronic respiratory alkalosis and acidosis. It is generally accepted that compensatory process may normalize the pH only in chronic respiratory alkalosis. In contrast with older data, data from a more recent study13 indicate that the pH in chronic respiratory acidosis may be
normal and, in individual cases, higher than generally recognized (pH >7.40).13,17,24 Furthermore, the usual compensatory changes in the PaCO2 may be limited in cases of severe hypoxemia. Instruments used for the measurement of blood gas and electrolytes may differ, affecting
results.25-27 Indeed, studies involving the use of modern analyzers show pH reference values(7.40 to 7.44)28-30 and secondary responses that differ from those published in textbooks.12,21,31
Although these differences are small, a reappraisal of the prediction equations may be needed.
EVALUATION OF THE METABOLIC COMPONENT OF AN ACID-BASE DISORDER
The third step in an evaluation is to consider the metabolic component of the acid-base disorder.
METABOLIC ACIDOSIS
Calculation of the anion gap is useful in the initial evalution of metabolic acidosis.32-45 The sum of
＋＋＋＋
the positive and negative ion charges in plasma are equal in vivo: [Na]＋[K]＋[Ca]＋[Mg2]＋＋－－－－
[H]＋unmeasured cations = [Cl]＋[HCO3]＋[CO32]＋[OH]＋albumin＋phosphate＋sulfate＋lactate＋unmeasured anions (e.g., inorganic anions).35-44 Routine measurement of all the ions
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Physiological Approach to Assessment of Acid-Base Disturbances
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in plasma is generally unnecessary. A more practical approach takes advantage of the fact that most plasma ions are normally present at relatively low concentrations and that three ions with the highest plasma concentrations and largest variations in concentration are used to calculate the excess of “unmeasured anions” in metabolic acidosis that constitutes the “anion gap”, which
＋―－
is calculated as [Na]―[Cl]―[HCO3].
A ture ion gap, however, does not exist in vivo, because the sum of positive and negative ion charges in plasnma must be equal. Wide reference ranges of 3.0 to 12.0 mmol per liter up to 8.5 to 15.0 mmol per liter in the anion gap have been reported,33-36,43 owing to differences in
laboratory methods.23,45 Consequently, clinicians should know the reference range for their own laboratory.
High-Anion-Gap Metabolic Acidosis
There are many causes of high anion-gap metabolic acidosis (Table 2). A useful mnemonic for the most common causes is GOLD MARRK ( glycols [ethylene and propylene], 5-oxoproline
[pyroglutamic acid ]. L-lactate, D-lactate, methanol, aspirin, renal failure, rhabdomyolysis, and ketoacidosis).46 The anion gap increases when the concentration of bicarbonate decreases
relative to levels of sodium and chloride because of overproduction of acid (in ketoacidosis, lactic acidosis, and drug and alcohol-related intoxication), underexcretion of acid (in advanced renal failure), cell lysis (in massive rhabdomyolysis),or other circumstances (e.g., the use of penicillin-derived antibiotics).
Uses and Limitations of the Anion Gap
Lactic acidosis accounts for about half the cases of a high anion gap33-49 and is often due to shock or tissue hypoxia.44,47 However, the anion gap is a relatively insensitive reflection of lactic acidosis –roughly half the patients with serum lactate levels between 3.0 and 5.0 mmol per liter have an anion gap within the reference range.39,40 The anion gap which has a sensitivity and specificity below 80% in identifying elevated lactate levels, cannot replace a measurement of the serum lactate level.39,40,47-50 Nevertheless, lactate levels are not routinely measured or always rapidly available, and a high anion gap can alert the physician that further evaluation is necessary.34,39,43 Unfortunately, a baseline value of the anion gap is generally not available for an individual patient. In addition, the anion gap should always be adjusted for the albumin concentration, because this weak acid may account for up to 75% of the anion gap.36,39,40 Without correction for
hypoalbuminemia, the estimated anion gap does not reveal a clinically significant increase in anions (>5 mmol per liter) in more than 50% of cases. For every decrement of 1g per deciliter in the serum albumin concentration, the calculated anion gap should be increased by approximately 2.3 to 2.5 mmol per liter.9,36,39,40 Nevertheless, the albumin-corrected anion gap is merely an approximation, since it does not account for ions such as magnesium, calcium, and phosphate ions.
The anion gap can help to establish the diagnosis of diabetic ketoacidosis. In patients with this condition, the anion gap can be used to track the resolution of ketosis9,15,23,33 and diagnose a normal anion-gap acidosis if large volumes of isotonic saline are administered.50
A high anion gap with a normal lactate level in a patient with alcoholism may be a importangt clue for the diagnosis of alcoholic ketoacidosis. This diagnosis may be missed because the test widely used to assess ketonuria (the nitroprusside test ) reacts only with acetoacetate ,not with β-hydroxybutyrate, the primary keto acid seen in alcoholic ketoacidosis. The pH may also be
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misleadingly normal or elevated because of concomitant metabolic alkalosis from vomiting or respiratory alkalosis from liver disease, pregnancy, high temperature, or sepsis.18,51-53 The anion gap can also aid in the diagnosis of D-lactic acidosis in patients with the
short-bowel syndrome, because the standard lactate level (L-lactate ) remains normal while the anion gap increases.49
A low or negative anion gap is observed when hyperchloremia is caused by high levels of cations, as seen in lithium toxicity, monoclonal IgG gammopathy, or disorders characterized by high levels of calcium or magnesium. A negative anion gap is caused by pseudohyperchloremia in bromide or iodide intoxication.33,36,54
Normal Anion-Gap Acidosis
Chloride plays a central role in intracellular and extracellular acid-base regulation.55 A normal anion-gap acidosis occurs when the decrease in bicarbonate ions corresponds with an increase in chloride ions to retain electroneutrality, which is also called hyperchloremic metabolic acidosis. This type of acidosis occurs from renal loss of bicarbonate that may occur in defective urinary acidification by the renal tubules (renal tubular acidosis ), or in early renal failure when acid excretion is impaired.12,56,57 hospital-acquired hyperchloremic acidosis is usually caused by the the infusion of large volumes of normal saline (0.9%).58-67 Hyperchloremic acidosis should lead to included renal excretion of ammonium, and measurement of urinary ammonium can therefore be used to differentiate between renal and extrarenal causes of normal anion-gap acidosis. However, since urinary ammonium is seldom measured, the urinary anion gap and urinary osmolal gap are often used as surrogate measures of excretion of urinary ammonium.9,67
＋＋
The urinary anion gap ( [Na]＋[K] - [Cl-] ) is usually negative in normal anion-gap acidosis,
＋
but it will become positive when excretion of urinary ammonium (NH4) (as ammonium chloride [NH4Cl] is impaired, as in renal failure, distal renal tubular acidosis, or hypoaldosteronism.9,67 A negative urinary anion gap occurs in normal anion-gap acidosis because of diarrhea and proximal renal tubular acidosis, in which the distal acidification is intact.56 The urinary anion gap becomes unreliable when polyuria is present, when the urine pH exceeds 6.5,67 or when urinary
ammonium is excreted with an anion other than chloride (e.g., keto acids, acetylsalicylic acid, D-lactic acid, and large quantities of penicillin ).9 Furthermore, the acidification of the urine requires adequate distal delivery of sodium; thus, the usefulness of the urinary anion gap is questionable when the urinary sodium level is less than 20 mmol per liter.12 In such cases, the urinary osmolal gap is generally more reliable.
The urinary osmolal gap determines the difference between measured and calculated urinary osmolality. The urinary osmolality is calculated as follows:
＋＋
(2 [Na]＋2[K] ) ＋( blood urea nitrogen [in milligrams per deciliter ]/2.8＋(glucose [in milligrams per deciliter ] / 18) or (in millimoles per liter ):
＋＋
(2 [Na]＋2[K] ) ＋(blood urea nitrogen)＋( glucose ).
In patients without diabetes, the glucose concentration is often omitted from this calculation. A urinary osmolal gap below 40 mmol per liter in normal anion-gap acidosis indicates impairment in excretion of urinary ammonium, except in the presence of large quantities of a nondissociated acid, such as β-hydroxybutyric acid in ketoacidosis. The urinary osmolal gap, as compared with the urinary anion gap, has a better correlation with the urinary ammonium value.9,67
METABOLIC ALKALOSIS
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Physiological Approach to Assessment of Acid-Base Disturbances
2014年10月09日
The normal kidney is highly efficient at excreting large amounts of bicarbonate and,
accordingly, the generation of metabolic alkalosis (Figure 2 ) requires both an increase in alkali and impairment in renal excretion of bicarbonate.68-71 Loss of gastric fluid and the use of diuretics account for the majority of cases of metabolic alkalosis. By measureing chloride in urine, one can distinguish between chloride-responsive and chloride-resistant metabolic alkalosis. If the
effective circulating volume is reduced, the kidneys avidly reabsorb filtered sodium, bicarbonate, and chloride, largely through activation of the renin-angiotensin-aldosterone system, thus reducing the concentration of urinary chloride.
A (spot sample ) urinary chloride concentration of less than 25 mmol per liter suggests chloride-responsive metabolic alkalosis. Administration of fluids with sodium chloride (usually with potassium chloride ) restores effective arterial volume, replenishes potassium ions, or both with correction of metabolic alkalosis.
Metabolic alkalosis with a urinary chloride concentration of more than 40 mmol per liter is mainly caused by inappropriate renal excretion of sodium chloride, often reflecting
mineralocorticoid excess or severe hypokalemia ( potassium concentration <2 mmol per liter ). The administration of sodium chloride does not correct this type of metabolic alkalosis, which, for that reason, is called “chloride-resistant”. Diuretic-induced metabolic alkalosis is an exception because the concentration of chloride in urine may increase initially, until the diuretic effect wanes, after which the concentration will decrease to a level below 25 mmol per liter.68-70 Other important causes of chloride-resistant metabolic alkalosis are the Bartter syndrome, the Gitelman syndrome, extreme hypercalcemia, and severe magnesium deficiency. Incontrast to hyperaldosteronism, these causes are not associated with sodium retention (Figure 2).
EVALUATION FOR THE PRESENCE OF MIXED METABOLIC ACID-BASE DISTURBANCES
The fourth step in the evaluation of acid-base disturbances is to consider the possibility of a mixed metabolic acid-base disturbance. In high anion-gap metabolic acidosis, the magnitude of the increase in the anion gap ( the delta AG, or △AG ) is related to the decrease in the
bicarbonate ions ( △[HCO3-] ). To diagnose a high anion-gap acidosis with concomitant metabolic alkalosis or normal anion-gap acidosis, the so-called delta-delta (△-△) may be used.70,71 The delta gap is the comparison between the increase (delta ) in the anion gap above the upper reference value (e.g., 12 mmol per liter ) and the change (delta ) in the concentration of bicarbonate ions from the lower reference value of bicarbonate ions (e.g., 24 mmol per liter ).9 In ketoacidosis, there is a 1:1 correlation between the increase in the anion gap and the decrease in the
concentration of bicarbonate. In lactic acidosis, the decrease in the concentration of bicarbonate is 0.6 times the increase in the anion gap (e.g., if the anion gap increases by 10 mmol per liter, the concentration of bicarbonate should decrease by approximately 6.0 mmol per liter ). This difference is probably due to the lower renal clearance of lactate as compared with keto-anions.71 Hydrogen buffering in cells and bone takes time to reach completion. Accordingly, the ratio may be close to 1:1 with “very acute” lactic acidosis (e.g., shortly after seizures or in persons WHO exercise to the point of exhaustion ).71 If △AG -- △[HCO3-] = 0±5 mmol per liter in a patient with ketoacidosis or if 0.6 △AG -- △[HCO3-] = 0±5 mmol per liter in a patient with lactic acidosis, simple anion-gap metabolic acidosis is present. A difference greater than 5 mmol per liter
suggests a concomitant metabolic alkalosis, and if the difference is less than -5 mmol per liter, a concomitant normal anion-gap metabolic acidosis is diagnosed.
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