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NORMAL ACID-BASE HOMEOSTASIS
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Systemic arterial pH is maintained between 7.35 and 7.45 by extracellular and intracellular chemical buffering together with respiratory and renal regulatory mechanisms. The control of arterial CO2 tension (PaCO2) by the central nervous system (CNS) and respiratory system and the control of plasma bicarbonate by the kidneys stabilize the arterial pH by excretion or retention of acid or alkali. The metabolic and respiratory components that regulate systemic pH are described by the Henderson-Hasselbalch equation:
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Under most circumstances, CO2 production and excretion are matched, and the usual steady-state PaCO2 is maintained at 40 mmHg. Underexcretion of CO2 produces hypercapnia, and overexcretion causes hypocapnia. Nevertheless, production and excretion are again matched at a new steady-state PaCO2. Therefore, the PaCO2 is regulated primarily by neural respiratory factors and is not subject to regulation by the rate of CO2 production. Hypercapnia is usually the result of hypoventilation rather than of increased CO2 production. Increases or decreases in PaCO2 represent derangements of neural respiratory control or are due to compensatory changes in response to a primary alteration in the plasma [HCO3−].
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DIAGNOSIS OF GENERAL TYPES OF DISTURBANCES
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The most common clinical disturbances are simple acid-base disorders, that is, metabolic acidosis or alkalosis or respiratory acidosis or alkalosis.
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SIMPLE ACID-BASE DISORDERS
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Primary respiratory disturbances (primary changes in PaCO2) invoke compensatory metabolic responses (secondary changes in [HCO3−]), and primary metabolic disturbances elicit predictable compensatory respiratory responses (secondary changes in PaCO2). Physiologic compensation can be predicted from the relationships displayed in Table 51-1. In general, with one exception, compensatory responses return the pH toward, but not to, the normal value. Chronic respiratory alkalosis when prolonged is an exception to this rule and may return the pH to a normal value. Metabolic acidosis due to an increase in endogenous acid production (e.g., ketoacidosis) lowers extracellular fluid [HCO3−] and decreases extracellular pH. This stimulates the medullary chemoreceptors to increase ventilation and to return the ratio of [HCO3−] to PaCO2, and thus pH, toward, but not to, normal. The degree of respiratory compensation expected in a metabolic acidosis can be predicted from the relationship: PaCO2 = (1.5 × [HCO3−]) + 8 ± 2. Thus, a patient with metabolic acidosis and [HCO3−] of 12 mmol/L would be expected to have a PaCO2 of ∼26 mmHg. Values for PaCO2 <24 or >28 mmHg define a mixed disturbance (metabolic acidosis and respiratory alkalosis or metabolic acidosis and respiratory acidosis, respectively). Compensatory responses for primary metabolic disorders move the PaCO2 in the same direction as the change in [HCO3−], whereas, conversely, compensation for primary respiratory disorders moves the [HCO3−] in the same direction as the primary change in PaCO2 (Table 51-1). Therefore, changes in PaCO2 and [HCO3−] in opposite directions (i.e., PaCO2 or [HCO3−] is increased, whereas the other value is decreased) indicate a mixed acid-base disturbance. Another way to judge the appropriateness of the response in [HCO3−] or PaCO2 is to use an acid-base nomogram (Fig. 51-1). While the shaded areas of the nomogram show the 95% confidence limits for physiologic compensation in simple disturbances, finding acid-base values within the shaded area does not necessarily rule out a mixed disturbance. Imposition of one disorder over another may result in values lying within the area of a third. Thus, the nomogram, while convenient, is not a substitute for the equations in Table 51-1.
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MIXED ACID-BASE DISORDERS
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Mixed acid-base disorders—defined as independently coexisting disorders, not merely compensatory responses—are often seen in patients in critical care units and can lead to dangerous extremes of pH (Table 51-2). The diagnosis of mixed acid-base disorders requires consideration of the anion gap (AG), and requires the presence of or correction to a normal serum albumin of 4.5 g/dL. A patient with diabetic ketoacidosis (metabolic acidosis) may develop an independent respiratory problem (e.g., pneumonia) leading to a superimposed respiratory acidosis or alkalosis. Patients with underlying pulmonary disease (e.g., chronic obstructive pulmonary disease) may not respond to metabolic acidosis with an appropriate ventilatory response because of insufficient respiratory reserve. Such imposition of respiratory acidosis on metabolic acidosis can lead to severe acidemia. When metabolic acidosis and metabolic alkalosis coexist in the same patient, the pH may be in the normal range. In this circumstance, it is the presence of an elevated AG (see below) that denotes the presence of a metabolic acidosis. Assuming a normal value for the AG of 10 mmol/L, an incongruity in the ΔAG (prevailing minus normal AG) and the ΔHCO3− (normal value of 25 mmol/L minus abnormal HCO3− in the patient) indicates the presence of a mixed high-gap acidosis—metabolic alkalosis (see example below). A diabetic patient with ketoacidosis may have renal dysfunction resulting in simultaneous metabolic acidosis. Patients who have ingested an overdose of drug combinations such as sedatives and salicylates may have mixed disturbances as a result of the acid-base response to the individual drugs (metabolic acidosis mixed with respiratory acidosis or respiratory alkalosis, respectively). Triple acid-base disturbances are more complex. For example, patients with metabolic acidosis due to alcoholic ketoacidosis may develop metabolic alkalosis due to vomiting and superimposed respiratory alkalosis due to the hyperventilation of hepatic dysfunction or alcohol withdrawal.
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APPROACH TO THE PATIENT
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APPROACH TO THE PATIENT Acid-Base Disorders
A stepwise approach to the diagnosis of acid-base disorders follows (Table 51-3). Blood for electrolytes and arterial blood gases should be drawn simultaneously prior to therapy. An increase in [HCO3−] occurs with either metabolic alkalosis or respiratory acidosis. Conversely, a decrease in [HCO3−] occurs with either metabolic acidosis or respiratory alkalosis. In the determination of arterial blood gases by the clinical laboratory, both pH and PaCO2 are measured, and the [HCO3−] is calculated from the Henderson-Hasselbalch equation. This calculated value should be compared with the measured [HCO3−] (total CO2) on the electrolyte panel. These two values should agree within 2 mmol/L. If they do not, the values may not have been drawn simultaneously, or a laboratory error may be present. After verifying the blood acid-base values, the precise acid-base disorder can then be identified.
CALCULATE THE ANION GAP All evaluations of acid-base disorders should include a simple calculation of the AG. The AG is calculated as follows: AG = Na+ – (Cl− + HCO3−). In the United States, the value for plasma [K+] is typically omitted from the calculation of the AG. The “normal” value for the AG reported by clinical laboratories has declined with improved methodology for measuring plasma electrolytes, and ranges from 6 to 12 mmol/L, with an average of ∼10 mmol/L. The clinician is encouraged to be aware of the normal value for the AG in their clinical chemistry laboratory. The unmeasured anions normally present in plasma include anionic proteins (e.g., albumin), phosphate, sulfate, and organic anions. When acid anions, such as acetoacetate and lactate, accumulate in extracellular fluid, the AG increases, causing a high-AG acidosis. An increase in the AG is most often due to an increase in unmeasured anions and, less commonly, may be due to a decrease in unmeasured cations (calcium, magnesium, potassium). In addition, the AG may increase with an increase in anionic albumin. A decrease in the AG can be due to (1) an increase in unmeasured cations; (2) the addition to the blood of abnormal cations, such as lithium (lithium intoxication) or cationic immunoglobulins (plasma cell dyscrasias); (3) a reduction in the plasma anion albumin concentration (nephrotic syndrome, liver disease or malabsorption); or (4) hyperviscosity and severe hyperlipidemia, which can lead to an underestimation of sodium and chloride concentrations. Because the normal AG of 10 mmol/L assumes that the serum albumin is normal, if hypoalbuminemia is present, the value for the AG must be corrected. For example, for each g/dL of serum albumin below the normal value (4.5 g/dL), 2.5 mmol/L should be added to the reported (uncorrected) AG. Thus, in a patient with a serum albumin of 2.5 g/dL (2 g/dL below the normal value), and an uncorrected AG of 15, the corrected AG is calculated by adding 5 mmol/L (2.5 × 2 = 5; 5 + 15 = corrected AG of 20 mmol/L). The clinical disorders that cause a high-AG acidosis are displayed in Table 51-3.
A high AG is usually due to accumulation of non–chloride-containing acids that contain inorganic (phosphate, sulfate), organic (ketoacids, lactate, uremic organic anions), exogenous (salicylate or ingested toxins with organic acid production), or unidentified anions. The high AG is significant clinically even if the [HCO3−] or pH is normal. Simultaneous metabolic acidosis of the high-AG variety plus either chronic respiratory acidosis or metabolic alkalosis represents such a situation in which [HCO3−] may be normal or even high (Table 51-3). In cases of high-AG metabolic acidosis it is valuable to compare the decline in [HCO3−] (ΔHCO3−: 25 – patient’s [HCO3−]) with the increase in the AG (ΔAG: patient’s AG – 10).
Similarly, normal values for [HCO3−], PaCO2, and pH do not ensure the absence of an acid-base disturbance. For instance, an alcoholic who has been vomiting may develop a metabolic alkalosis with a pH of 7.55, PaCO2 of 47 mmHg, [HCO3−] of 40 mmol/L, [Na+] of 135, [Cl−] of 80, and [K+] of 2.8. If such a patient were then to develop a superimposed alcoholic ketoacidosis with a β-hydroxybutyrate concentration of 15 mmol/L, arterial pH would fall to 7.40, the [HCO3−] to 25 mmol/L, and the PaCO2 to 40 mmHg. Although these blood gases are normal, the AG is elevated at 30 mmol/L, indicating a mixed metabolic alkalosis and metabolic acidosis. A mixture of high-gap acidosis and metabolic alkalosis is recognized easily by comparing the differences (Δ values) in the normal to prevailing patient values. In this example, the ΔHCO3− is 0 (25 − 25 mmol/L), but the ΔAG is 20 (30 – 10 mmol/L). Therefore, 20 mmol/L is unaccounted for in the Δ/Δ value (ΔAG to ΔHCO3−).
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Metabolic acidosis can occur because of an increase in endogenous acid production (such as lactate and ketoacids), loss of bicarbonate (as in diarrhea), or accumulation of endogenous acids because of inappropriately low excretion of net acid by the kidney (as in chronic kidney disease [CKD]). Metabolic acidosis has profound effects on the respiratory, cardiac, and nervous systems. The fall in blood pH is accompanied by a characteristic increase in ventilation, especially the tidal volume (Kussmaul respiration). Intrinsic cardiac contractility may be depressed, but inotropic function can be normal because of catecholamine release. Both peripheral arterial vasodilation and central venoconstriction can be present; the decrease in central and pulmonary vascular compliance predisposes to pulmonary edema with even minimal volume overload. CNS function is depressed, with headache, lethargy, stupor, and, in some cases, even coma. Glucose intolerance may also occur.
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There are two major categories of clinical metabolic acidosis: high-AG and non-AG acidosis (Table 51-3 and Table 51-4). The presence of metabolic acidosis, a normal AG, and hyperchloremia denotes the presence of a normal AG metabolic acidosis.
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TREATMENT Metabolic Acidosis
Treatment of metabolic acidosis with alkali should be reserved for severe acidemia except when the patient has no “potential HCO3−” in plasma. The potential [HCO3−] can be estimated from the increment (Δ) in the AG (ΔAG = patient’s AG – 10), only if the acid anion that has accumulated in plasma is metabolizable (i.e., β-hydroxybutyrate, acetoacetate, and lactate). Conversely non-metabolizable anions that may accumulate in advanced stage CKD or after toxin ingestion are not metabolizable and do not represent “potential” HCO3−. With acute CKD improvement in kidney function to replenish the [HCO3−] deficit is a slow and often unpredictable process. Consequently, patients with a normal AG acidosis (hyperchloremic acidosis) or an AG attributable to a non-metabolizable anion due to advanced kidney failure should receive alkali therapy, either PO (NaHCO3 or Shohl’s solution) or IV (NaHCO3), in an amount necessary to slowly increase the plasma [HCO3−] to a target value of 22 mmol/L. Nevertheless, overcorrection should be avoided.
Controversy exists in regard to the use of alkali in patients with a pure AG acidosis owing to accumulation of a metabolizable organic acid anion (ketoacidosis or lactic acidosis). In general, severe acidemia (pH <7.10) in an adult patient (especially the elderly and patients with severe heart disease) warrants the IV administration of 50 meq of NaHCO3 diluted in 300 mL of sterile water over 30–45 min, during the initial 1–2 h of therapy. Provision of such modest quantities of alkali in this situation seems to provide an added measure of safety. Administration of alkali requires careful monitoring of plasma electrolytes, especially the plasma [K+], during the course of therapy. A reasonable initial goal is to increase the [HCO3−] to 10–12 mmol/L and the pH to ∼7.20, but clearly not to increase these values to normal. Estimation of the “bicarbonate deficit” by calculation of the volume of distribution of bicarbonate is often taught but is unnecessary and may result in administration of excessive amounts of alkali.
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HIGH-ANION GAP ACIDOSES
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APPROACH TO THE PATIENT
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APPROACH TO THE PATIENT
There are four principal causes of a high-AG acidosis: (1) lactic acidosis, (2) ketoacidosis, (3) ingested toxins, and (4) acute and chronic renal failure (Table 51-4). Initial screening to differentiate the high-AG acidoses should include (1) a probe of the history for evidence of drug and toxin ingestion and measurement of arterial blood gas to detect coexistent respiratory alkalosis (salicylates); (2) determination of whether diabetes mellitus is present (diabetic ketoacidosis); (3) a search for evidence of alcoholism or increased levels of β-hydroxybutyrate (alcoholic ketoacidosis); (4) observation for clinical signs of uremia and determination of the blood urea nitrogen (BUN) and creatinine (uremic acidosis); (5) inspection of the urine for oxalate crystals (ethylene glycol); and (6) recognition of the numerous clinical settings in which lactate levels may be increased (hypotension, shock, cardiac failure, leukemia, cancer, and drug or toxin ingestion).
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An increase in plasma l-lactate may be secondary to poor tissue perfusion (type A)—circulatory insufficiency (shock, cardiac failure), severe anemia, mitochondrial enzyme defects, and inhibitors (carbon monoxide, cyanide)—or to aerobic disorders (type B)—malignancies, nucleoside analogue reverse transcriptase inhibitors in HIV, diabetes mellitus, renal or hepatic failure, thiamine deficiency, severe infections (cholera, malaria), seizures, or drugs/toxins (biguanides, ethanol, and the toxic alcohols: ethylene glycol (EG), methanol, or propylene glycol). Unrecognized bowel ischemia or infarction in a patient with severe atherosclerosis or cardiac decompensation receiving vasopressors is a common cause of lactic acidosis in elderly patients. Pyroglutamic acidemia may occur in critically ill patients receiving acetaminophen, which causes depletion of glutathione and accumulation of 5-oxyprolene. D-Lactic acid acidosis, which may be associated with jejunoileal bypass, short bowel syndrome, or intestinal obstruction, is due to formation of D-lactate by gut bacteria.
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APPROACH TO THE PATIENT
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APPROACH TO THE PATIENT L-Lactic Acid Acidosis
The underlying condition that disrupts lactate metabolism should be corrected preemptively, if possible; tissue perfusion must be restored when inadequate, but vasoconstrictors should be avoided, if possible, because they may worsen tissue perfusion. Alkali therapy is generally advocated for acute, severe acidemia (pH <7.00) to improve cardiovascular function. However, NaHCO3 therapy may paradoxically depress cardiac performance and exacerbate acidosis by enhancing lactate production (HCO3− stimulates phosphofructokinase). While the use of alkali in moderate lactic acidosis is controversial, it is generally agreed that attempts to return the pH or [HCO3−] to normal by administration of exogenous NaHCO3 are deleterious. A reasonable approach is to infuse sufficient NaHCO3 to raise the arterial pH to no more than 7.2 or the [HCO3−] to no more than 12, over 30–40 min.
NaHCO3 therapy can cause fluid overload and hypertension because the amount required can be massive when accumulation of lactic acid is relentless. Fluid administration is poorly tolerated, especially in the oliguric patient, when central venoconstriction coexists. When the underlying cause of the lactic acidosis can be remedied, blood lactate will be converted to HCO3− and may result in an overshoot alkalosis if excess NaHCO3 has been administered excessively.
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DIABETIC KETOACIDOSIS (DKA)
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This condition is caused by increased fatty acid metabolism and the accumulation of ketoacids (acetoacetate and β-hydroxybutyrate). DKA usually occurs in insulin-dependent diabetes mellitus in association with cessation of insulin or an intercurrent illness such as an infection, gastroenteritis, pancreatitis, or myocardial infarction, which increases insulin requirements temporarily and acutely. The accumulation of ketoacids accounts for the increment in the AG and is accompanied most often by hyperglycemia (glucose >17 mmol/L [300 mg/dL]). The relationship between the ΔAG and ΔHCO3− is usually 1:1 in DKA. It should be noted that because insulin prevents production of ketones, bicarbonate therapy is rarely needed except with extreme acidemia (pH < 7.10), and then in only limited amounts. Patients with DKA are typically volume depleted and require fluid resuscitation with isotonic saline. Volume overexpansion with IV isotonic fluid administration is not uncommon, however, and contributes to the development of a hyperchloremic acidosis during treatment of DKA. The mainstay for treatment of this condition is IV regular insulin and is described in Chap. 396 in more detail.
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ALCOHOLIC KETOACIDOSIS (AKA)
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Chronic alcoholics can develop ketoacidosis when alcohol consumption is abruptly curtailed and nutrition is poor. AKA is usually associated with binge drinking, vomiting, abdominal pain, starvation, and volume depletion. The glucose concentration is variable, and acidosis may be severe because of elevated ketones, predominantly β-hydroxybutyrate. Hypoperfusion may enhance lactic acid production, chronic respiratory alkalosis may accompany liver disease, and metabolic alkalosis can result from vomiting (refer to the relationship between ΔAG and ΔHCO3−). Thus, mixed acid-base disorders are common in AKA. As the circulation is restored by administration of isotonic saline, the preferential accumulation of β-hydroxybutyrate is then shifted to acetoacetate. This explains the common clinical observation of an increasingly positive nitroprusside reaction (ketones) as the patient improves. The nitroprusside ketone reaction (Acetest) can detect acetoacetic acid but not β-hydroxybutyrate, so that the degree of ketosis and ketonuria can not only change with therapy, but can be underestimated initially. Patients with AKA usually present with relatively normal renal function, as opposed to DKA, where renal function is often compromised because of volume depletion (osmotic diuresis) or diabetic nephropathy. The AKA patient with normal renal function may excrete relatively large quantities of ketoacids in the urine and, therefore, may have a relatively normal AG and a discrepancy in the ΔAG/ΔHCO3− relationship.
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TREATMENT Alcoholic Ketoacidosis
Extracellular fluid deficits almost always accompany AKA and should be repleted by IV administration of saline and glucose (5% dextrose in 0.9% NaCl). Hypophosphatemia, hypokalemia, and hypomagnesemia may coexist and should be monitored carefully and corrected when indicated. Hypophosphatemia typically emerges 12–24 h after admission, may be exacerbated by glucose infusion, and, if severe, may induce rhabdomyolysis or even respiratory arrest. Upper gastrointestinal hemorrhage, pancreatitis, and pneumonia may accompany this disorder.
Drug- and Toxin-Induced Acidosis Salicylates Salicylate intoxication in adults usually causes respiratory alkalosis or a mixture of high-AG metabolic acidosis and respiratory alkalosis (See also Chap. 449). Only a portion of the AG is due to salicylates. Lactic acid production is also often increased.
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TREATMENT Salicylate-Induced Acidosis
Vigorous gastric lavage with isotonic saline (not NaHCO3) should be initiated immediately. All patients should receive at least one round of activated charcoal per nasogastric tube (1 g/kg up to 50 g). In the acidotic patient, to facilitate removal of salicylate, IV NaHCO3 is administered in amounts adequate to alkalinize the urine and to maintain urine output (urine pH >7.5), because raising the urine pH from 6.5 to 7.5 increases salicylate clearance fivefold. Patients with coexisting respiratory alkalosis should also receive NaHCO3, but with caution to avoid excessive alkalemia. Acetazolamide may be administered in the face of alkalemia, when an alkaline diuresis cannot be achieved, or to ameliorate volume overload associated with NaHCO3 administration, but this drug can cause systemic metabolic acidosis if the excreted HCO3− is not replaced, a circumstance that can markedly reduce salicylate clearance.
Hypokalemia should be anticipated with vigorous bicarbonate therapy and should be treated promptly and aggressively. Glucose-containing fluids should be administered because of the danger of hypoglycemia. Excessive insensible fluid losses may cause severe volume depletion and hypernatremia. If renal failure prevents rapid clearance of salicylate, hemodialysis can be performed against a bicarbonate–containing dialysate.
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Under most physiologic conditions, sodium, urea, and glucose generate the osmotic pressure of blood. Plasma osmolality is calculated according to the following expression: Posm = 2Na+ + Glu + BUN (all in mmol/L), or, using conventional laboratory values in which glucose and BUN are expressed in milligrams per deciliter: Posm = 2Na+ + Glu/18 + BUN/2.8. The calculated and determined osmolality should agree within 10–15 mmol/kg H2O. When the measured osmolality exceeds the calculated osmolality by >10–15 mmol/kg H2O, one of two circumstances prevails. Either the serum sodium is spuriously low, as with hyperlipidemia or hyperproteinemia (pseudohyponatremia), or osmolytes other than sodium salts, glucose, or urea have accumulated in plasma. Examples of such osmolytes include mannitol, radiocontrast media, ethanol, isopropyl alcohol, EG, propylene glycol, methanol, and acetone. In this situation, the difference between the calculated osmolality and the measured osmolality (osmolar gap) is proportional to the concentration of the unmeasured solute. With an appropriate clinical history and index of suspicion, identification of an osmolar gap is helpful in identifying the presence of toxic alcohol-associated AG acidosis. Three alcohols may cause fatal intoxications: EG, methanol, and isopropyl alcohol. All cause an elevated osmolal gap, but only the first two cause a high-AG acidosis. Isopropyl alcohol ingestion does not typically elevate the AG unless extreme overdose causes hypotension and lactic acid acidosis.
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Ingestion of EG (commonly used in antifreeze) leads to a metabolic acidosis and severe damage to the CNS, heart, lungs, and kidneys (See also Chap. 449). The combination of a high AG and high osmolar gap is highly suspicious for EG or methanol intoxication. The increased AG and osmolar gap in EG intoxication are attributable to EG and its metabolites, oxalic acid, glycolic acid, and other organic acids. Lactic acid production increases secondary to inhibition of the tricarboxylic acid cycle and altered intracellular redox state. In addition to the presence of elevated osmolar and AGs, the diagnosis is further enabled by recognition of oxalate crystals in the urine. Use of a Wood’s lamp to visualize the fluorescent additive to commercial antifreeze in the urine of patients with EG ingestion, has been reported, but is not reliable. The combination of a high AG and high osmolar gap in a patient suspected of EG ingestion should be taken as evidence of EG toxicity. Treatment should not be delayed while awaiting measurement of EG levels in this setting.
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TREATMENT Ethylene Glycol-Induced Acidosis
This includes the prompt institution of a saline or osmotic diuresis, thiamine and pyridoxine supplements, fomepizole, and usually, hemodialysis. The IV administration of the alcohol dehydrogenase inhibitor fomepizole (4-methylpyrazole; 15 mg/kg as a loading dose) is the agent of choice and offers the advantages of a predictable decline in EG levels without excessive obtundation as seen during ethyl alcohol infusion. If used, ethanol IV should be infused to achieve a blood level of 22 mmol/L (100 mg/dL). Both fomepizole and ethanol reduce toxicity because they compete with EG for metabolism by alcohol dehydrogenase. Hemodialysis is indicated when the arterial pH is <7.3 or the osmolar gap exceeds 20 mOsm/kg.
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The ingestion of methanol (wood alcohol) causes metabolic acidosis, and its metabolites formaldehyde and formic acid cause severe optic nerve and CNS damage (See also Chap. 449). Lactic acid, ketoacids, and other unidentified organic acids may contribute to the acidosis. Due to its low molecular mass (32 Da), an osmolar gap is usually present.
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TREATMENT Methanol-Induced Acidosis
This is similar to that for EG intoxication, including general supportive measures, fomepizole, and hemodialysis (as above).
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Propylene glycol is the vehicle used in IV administration of diazepam, lorazepam, phenobarbital, nitroglycerine, etomidate, enoximone, and phenytoin. Propylene glycol is generally safe for limited use in these IV preparations, but toxicity has been reported, most often in the setting of the intensive care unit in patients receiving frequent or continuous therapy. This form of high-gap acidosis should be considered in patients with unexplained high-gap acidosis, hyperosmolality, and clinical deterioration, especially in the setting of treatment for alcohol withdrawal. Propylene glycol, like EG and methanol, is metabolized by alcohol dehydrogenase. With intoxication by propylene glycol, the first response is to stop the offending infusion. Additionally, fomepizole should also be administered in acidotic patients.
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Ingested isopropanol is absorbed rapidly and may be fatal when as little as 150 mL of rubbing alcohol, solvent, or deicer is consumed. A plasma level >400 mg/dL is life-threatening. Isopropyl alcohol is metabolized by alcohol dehydrogenase to acetone. The characteristic features differ significantly from EG and methanol intoxication in that the parent compound, not the metabolites, causes toxicity, and a high AG acidosis is not present because acetone is rapidly excreted. Both isopropyl alcohol and acetone increase the osmolar gap, and hypoglycemia is common. Alternative diagnoses should be considered if the patient does not improve significantly within a few hours. Patients with hemodynamic instability with plasma levels above 400 mg/dL should be considered for hemodialysis.
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TREATMENT Isopropyl Alcohol Toxicity
Isopropanol alcohol toxicity is treated by supportive therapy, IV fluids, pressors, ventilatory support if needed, and occasionally hemodialysis for prolonged coma, hemodynamic instability, or levels >400 mg/dL.
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Acetaminophen-induced high-AG metabolic acidosis is uncommon but is being recognized more often in either patients with acetaminophen overdose or malnourished or critically ill patients receiving acetaminophen in typical dosage. 5-Oxoproline accumulation after acetaminophen should be suspected in the setting of an unexplained high-AG acidosis without elevation of the osmolar gap in patients receiving acetaminophen. The first step in treatment is to immediately discontinue the drug. Additionally, sodium bicarbonate IV should be given. Although N-acetylcysteine has been suggested, it is not known if it hastens the metabolism of 5-oxoproline by increasing intracellular glutathione concentrations in this setting.
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Chronic Kidney Disease
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The hyperchloremic acidosis of moderate CKD (Stage 3) is eventually converted to the high-AG acidosis of advanced renal failure (Stages 4 and 5 CKD) (See also Chap. 305). Poor filtration and reabsorption of organic anions contribute to the pathogenesis. As renal disease progresses, the number of functioning nephrons eventually becomes insufficient to keep pace with net acid production. Uremic acidosis in advanced CKD is characterized, therefore, by a reduced rate of NH4+ production and excretion. Alkaline salts from bone buffer the acid retained in chronic kidney disease. Despite significant retention of acid (up to 20 mmol/d), the serum [HCO3−] does not typically decrease further, indicating participation of buffers outside the extracellular compartment. Therefore, the trade-off in untreated chronic metabolic acidosis of CKD stages 3 and 4 is significant loss of bone mass due to reduction in bone calcium carbonate. Chronic acidosis also increases urinary calcium excretion, proportional to cumulative acid retention, and contributes significantly to muscle wasting.
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TREATMENT Metabolic Acidosis of Chronic Kidney Disease
Because of the association of metabolic acidosis in advanced CKD with muscle catabolism, bone disease and more rapid progression of CKD, both the “uremic acidosis” of ESRD and the non-AG metabolic acidosis of stages 3 and 4 CKD require oral alkali replacement to maintain the [HCO3−] to approximately the normal value (25 mmol/L). This can be accomplished with relatively modest amounts of alkali (1.0–1.5 mmol/kg body weight per day). Either NaHCO3 tablets (650-mg tablets contain 7.8 meq) or sodium citrate (Shohl’s solution) is effective.
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NON–ANION GAP METABOLIC ACIDOSES
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Alkali can be lost from the gastrointestinal tract as a result of diarrhea or from the kidneys due to renal tubular abnormalities (e.g., renal tubular acidosis [RTA]). In these disorders (Table 51-5), reciprocal changes in [Cl−] and [HCO3−] result in a normal AG. In pure non–AG acidosis, therefore, the increase in [Cl−] above the normal value approximates the decrease in [HCO3−]. The absence of such a relationship suggests a mixed disturbance.
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Stool contains a higher concentration of HCO3− and decomposed HCO3− than plasma so that metabolic acidosis develops in diarrhea. Instead of an acid urine pH (as anticipated with systemic acidosis), urine pH is usually >6 because metabolic acidosis and hypokalemia increase renal synthesis and excretion of NH4+, thus providing a urinary buffer that increases urine pH. Metabolic acidosis due to gastrointestinal losses with a high urine pH can be differentiated from RTA because urinary NH4+ excretion is typically low in RTA and high with diarrhea. Urinary NH4+ levels can be estimated by calculating the urine AG (UAG): UAG = [Na+ + K+]u – [Cl−]u. When [Cl−]u > [Na+ + K+]u, the UAG is negative by definition. This indicates that the urine ammonium level is appropriately increased, suggesting an extrarenal cause of the acidosis. Conversely, when the UAG is positive, the urine ammonium level is low, suggesting a renal cause of the acidosis.
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Proximal RTA (type 2 RTA) (Chap. 309) is most often due to generalized proximal tubular dysfunction manifested by glycosuria, generalized aminoaciduria, and phosphaturia (Fanconi syndrome). When the plasma [HCO3−] is low the urine pH is acid (pH <5.5), but exceeds 5.5 with alkali therapy. The fractional excretion of [HCO3−] may exceed 10–15% when the serum HCO3− is >20 mmol/L. Because HCO3− is not reabsorbed normally in the proximal tubule, therapy with NaHCO3 will enhance delivery of HCO3− to the distal nephron and enhance renal potassium secretion, thereby, causing hypokalemia.
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The typical findings in acquired or inherited forms of classic distal RTA (type 1 RTA) include hypokalemia, a non-AG metabolic acidosis, low urinary NH4+ excretion (positive UAG, low urine [NH4+]), and inappropriately high urine pH (pH > 5.5). Most patients have hypocitraturia and hypercalciuria, so nephrolithiasis, nephrocalcinosis, and bone disease are common. In generalized distal RTA (type 4 RTA), hyperkalemia is disproportionate to the reduction in glomerular filtration rate (GFR) because of coexisting dysfunction of potassium and acid secretion. Urinary ammonium excretion is invariably depressed, and kidney function may be compromised, for example, due to diabetic nephropathy, obstructive uropathy, or chronic tubulointerstitial disease.
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Hyporeninemic hypoaldosteronism typically causes non-AG metabolic acidosis, most commonly in older adults with diabetes mellitus or tubulointerstitial disease and CKD. Patients usually have mild to moderate CKD (GFR, 20–50 mL/min) and acidosis, with elevation in serum [K+] (5.2–6.0 mmol/L), concurrent hypertension, and congestive heart failure. Both the metabolic acidosis and the hyperkalemia are out of proportion to impairment in GFR. Nonsteroidal anti-inflammatory drugs, trimethoprim, pentamidine, angiotensin-converting enzyme (ACE) inhibitors, and aldosterone receptor blockers (ARBs), can also increase the risk for a hyperkalemia and a non-AG metabolic acidosis in patients with CKD (Table 51-5).
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TREATMENT Non–Anion Gap Metabolic Acidoses
For non-renal causes of non-AG acidosis due to gastrointestinal losses of bicarbonate, NaHCO3 may be administered intravenously or orally, as determined by the severity of both the acidosis and the accompanying volume depletion. Proximal RTA is the most challenging of the RTAs to treat if the goal is to restore the serum [HCO3–] to normal, because administration of oral alkali increases urinary excretion of potassium. In patients with proximal RTA (type 2), potassium administration is typically required. An oral solution of a combination of sodium and potassium citrate (citric acid 334 mg, sodium citrate 500 mg, and potassium citrate 550 mg per 5 mL) may be prescribed for this purpose and is available commercially as Virtrate-3. The syrup preparation is not recommended for chronic administration. In classical distal RTA (type 1), potassium should be administered in the acutely acidotic patient with hypokalemia. For chronic therapy, most patients respond to replacement with either sodium citrate (Shohl’s solution) or NaHCO3 tablets (650-mg tablets contain 7.8 meq) with the goal of correcting the serum [HCO3–] to normal. These patients typically respond to chronic alkali therapy readily and the benefits of adequate alkali therapy include a decrease in the frequency of nephrolithiasis, improvement in bone density, resumption of normal growth patterns in children, and preservation of kidney function in both adults and children. For type 4 RTA, attention must be paid to the dual goals of correction of the metabolic acidosis, using the same approach as for cDRTA, but in addition, effort toward correcting the plasma [K+] is necessary. This latter goal deserves emphasis because restoration of normokalemia increases urinary net acid excretion and in that way can greatly improve the metabolic acidosis. Chronic administration of oral sodium polystyrene solfonate (15 g of power prepared as an oral solution, and without sorbitol, once daily 2–3 times per week) is sometimes used. Additionally, the diet should be low in potassium-containing foods, all potassium-retaining medications should be discontinued, and a loop diuretic may be administered. The recent release of a new a non-absorbed, calcium-potassium cation exchange polymer, patiromer, may prove to be very useful for type 4 RTA patients with significant hyperkalemia. However, patiromer has not yet been investigated in this population of patients. Finally, patients with demonstrated adrenal insufficiency should also receive fludocortisone, but the dose varies with the cause of the hormone deficiency, and should be assiduously avoided in patients with hyporeninemic-hypoaldosteronism.
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Metabolic alkalosis is established by an elevated arterial pH, an increase in the serum [HCO3−], and an increase in PaCO2 as a result of compensatory alveolar hypoventilation (Table 51-1). It is often accompanied by hypochloremia and hypokalemia. The arterial pH establishes the diagnosis, because it is increased in metabolic alkalosis and decreased in respiratory acidosis. Metabolic alkalosis frequently occurs as a mixed acid base disorder in association with either respiratory acidosis, respiratory alkalosis, or metabolic acidosis.
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Metabolic alkalosis occurs as a result of net gain of [HCO3−] or loss of nonvolatile acid (usually HCl by vomiting) from the extracellular fluid. When vomiting causes loss of HCl from the stomach, HCO3− secretion cannot be initiated in the small bowel and thus HCO3 is added to the extracellular fluid. Thus, vomiting or nasogastric (NG) suction is an example of the generation stage, in which the loss of acid typically causes alkalosis. Upon cessation of vomiting, the maintenance stage, typically ensues because secondary factors prevent the kidneys from compensating by excreting HCO3−.
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Maintenance of metabolic alkalosis, therefore, represents a failure of the kidneys to eliminate excess HCO3− from the extracellular compartment. The kidneys will retain, rather than excrete, the excess alkali and maintain the alkalosis if (1) volume deficiency, chloride deficiency, and K+ deficiency exist in combination with a reduced GFR; or (2) hypokalemia exists because of autonomous hyperaldosteronism. In the first example, alkalosis is corrected by administration of NaCl and KCl, whereas, in the latter, it may be necessary to repair the alkalosis by pharmacologic or surgical intervention, not with saline administration.
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DIFFERENTIAL DIAGNOSIS
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To establish the cause of metabolic alkalosis (Table 51-6), it is necessary to assess the status of the extracellular fluid volume (ECFV), the recumbent and upright blood pressure (to determine if orthostasis is present), the serum [K+], and in some circumstances, an assessment of the renin-aldosterone system. For example, the presence of chronic hypertension and chronic hypokalemia in an alkalotic patient suggests either mineralocorticoid excess or that the hypertensive patient is receiving diuretics. Low plasma renin activity and normal values for both the urine [Na+] and [Cl−], in a patient who is not taking diuretics, suggest primary mineralocorticoid excess. The combination of hypokalemia and alkalosis in a normotensive, nonedematous patient can be due to Bartter’s or Gitelman’s syndrome, magnesium deficiency, vomiting, exogenous alkali, or diuretic ingestion. Measurement of urine electrolytes (especially the urine [Cl−]) and screening of the urine for diuretics is recommended. If the urine is alkaline, with an elevated [Na+]u and [K+]u but low [Cl−]u, the diagnosis is usually either vomiting (overt or surreptitious) or alkali ingestion. If the urine is relatively acid and has low concentrations of Na+, K+, and Cl−, the most likely possibilities are prior vomiting, the posthypercapnic state, or prior diuretic ingestion. If, on the other hand, neither the urine sodium, potassium, nor chloride concentrations are depressed, magnesium deficiency, Bartter’s or Gitelman’s syndrome, or current diuretic ingestion should be considered. Bartter’s syndrome is distinguished from Gitelman’s syndrome because of hypocalciuria in the latter disorder.
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Alkali Administration
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Chronic administration of alkali to individuals with normal renal function rarely causes alkalosis. However, in patients with coexistent hemodynamic disturbances associated with effective ECF volume depletion, alkalosis can develop because the normal capacity to excrete HCO3− is diminished or there may be enhanced reabsorption of HCO3−. Such patients include those who receive NaHCO3 (PO or IV), citrate loads (transfusions of whole blood, or therapeutic apheresis), or antacids plus cation-exchange resins (aluminum hydroxide and sodium polystyrene sulfonate). Nursing home patients receiving enteral tube feedings (an often overlooked source of alkali loads) have a higher incidence of metabolic alkalosis than nursing home patients receiving regular diets.
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METABOLIC ALKALOSIS ASSOCIATED WITH ECFV CONTRACTION, K+ DEPLETION, AND SECONDARY HYPERRENINEMIC HYPERALDOSTERONISM
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Gastrointestinal Origin
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Gastrointestinal loss of H+ from vomiting or gastric aspiration causes simultaneous addition of HCO3− into the extracellular fluid. During active vomiting, the filtered load of bicarbonate reaching the kidneys is acutely increased and will exceed the reabsorptive capacity of the proximal tubule for HCO3− absorption. Subsequently, enhanced delivery of HCO3 to the distal nephron will cause excretion of alkaline urine that is high in potassium. When vomiting ceases, the persistence of volume, potassium, and chloride depletion triggers maintenance of the alkalosis because these conditions promote HCO3− reabsorption. Correction of the contracted ECFV with NaCl and repair of K+ deficits with KCl corrects the acid-base disorder by restoring the ability of the kidney to excrete the excess bicarbonate.
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Diuretics such as thiazides and loop diuretics (furosemide, bumetanide, torsemide) increase excretion of salt and acutely diminish the ECFV without altering the total body bicarbonate content (See also Chap. 252). The serum [HCO3−] increases because the reduced ECFV “contracts” around the [HCO3−] in the plasma (contraction alkalosis). The chronic administration of diuretics tends to generate an alkalosis by increasing distal salt delivery, so that both K+ and H+ secretion are stimulated. The alkalosis is maintained by persistence of the contraction of the ECFV, secondary hyperaldosteronism, K+ deficiency, and the direct effect of the diuretic (as long as diuretic administration continues). Discontinuing the diuretic and providing isotonic saline to correct the ECFV deficit will repair the alkalosis.
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SOLUTE LOSING DISORDERS: BARTTER’S SYNDROME AND GITELMAN’S SYNDROME
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NONREABSORBABLE ANIONS AND MAGNESIUM DEFICIENCY
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Administration of large quantities of the penicillin derivatives carbenicillin or tricarcillin cause their nonreabsorbable anions to appear in the urine. This increases the transepithelial potential difference in the collecting tubule, and thereby enhances H+ and K+ secretion. Mg2+ deficiency, may occur with chronic administration of thiazide diuretics, alcoholism, and malnutrition, and in Gitelman’s syndrome potentiates the development of hypokalemic alkalosis by enhancing distal acidification through stimulation of renin and hence aldosterone secretion.
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Chronic K+ depletion may cause metabolic alkalosis by increasing urinary acid excretion. The renal generation of NH4+ (ammoniagenesis) is upregulated directly by hypokalemia. Chronic K+ deficiency also upregulates the renal H+, K+-ATPase to increase K+ absorption at the expense of enhanced H+ secretion. Alkalosis associated with severe K+ depletion is resistant to salt administration, but repair of the K+ deficiency corrects the alkalosis. Potassium depletion often occurs concomitant with magnesium deficiency in alcoholics with malnutrition.
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AFTER TREATMENT OF LACTIC ACIDOSIS OR KETOACIDOSIS
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When an underlying stimulus for the generation of lactic acid or ketoacid is corrected by treatment of the underlying disorder, such as correction shock or severe volume depletion by volume restoration, or with insulin therapy, respectively, the lactate or ketones are metabolized to yield an equivalent amount of HCO3−. Exogenous sources of HCO3− will be additive with that amount generated by organic anion metabolism to create a surfeit of HCO3−. Acidosis-induced contraction of the ECFV and K+ deficiency act in concert to sustain the alkalosis.
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Prolonged CO2 retention with chronic respiratory acidosis enhances renal HCO3− absorption and the generation of new HCO3− (increased net acid excretion). Metabolic alkalosis results from the effect of the persistently elevated [HCO3−] when the elevated PaCO2 is abruptly returned toward normal.
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METABOLIC ALKALOSIS ASSOCIATED WITH ECFV EXPANSION, HYPERTENSION, AND HYPERALDOSTERONISM
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Increased aldosterone levels may be the result of autonomous primary adrenal overproduction or of secondary aldosterone release due to renal overproduction of renin. Mineralocorticoid excess increases net acid excretion and may result in metabolic alkalosis, which is typically exacerbated by associated K+ deficiency. Salt retention is due to upregulation of the epithelial Na+ channels in the collecting tubule to aldosterone, as a result of the associated ECFV expansion, causes hypertension. The kaliuresis persists because of mineralocorticoid excess and distal Na+ absorption causing enhanced K+ excretion, continued K+ depletion with polydipsia, inability to concentrate the urine, and polyuria.
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Liddle’s syndrome (Chap. 309) results from an inherited gain of function mutation of genes that regulate the collecting duct Na+ channel (ENaC). Liddle’s is a rare monogenic form of hypertension due to volume expansion manifested as hypokalemic alkalosis and normal aldosterone levels.
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With metabolic alkalosis, changes in CNS and peripheral nervous system function are similar to those of hypocalcemia (Chap. 402); symptoms include mental confusion; obtundation; and a predisposition to seizures, paresthesia, muscular cramping, tetany, aggravation of arrhythmias, and hypoxemia in chronic obstructive pulmonary disease. Related electrolyte abnormalities include hypokalemia and hypophosphatemia.
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TREATMENT Metabolic Alkalosis
This is primarily directed at correcting the underlying stimulus for HCO3− generation. If primary aldosteronism or Cushing’s syndrome is present, correction of the underlying cause, when successful, will reverse the hypokalemia and alkalosis. [H+] loss by the stomach or kidneys can be mitigated by the use of proton pump inhibitors or the discontinuation of diuretics. The second aspect of treatment is to remove the factors that sustain the inappropriate increase in HCO3− reabsorption, such as ECFV contraction or K+ deficiency. K+ deficits should always be repaired. Isotonic saline is recommended to reverse the alkalosis when ECFV contraction is present. If associated conditions preclude infusion of saline, renal HCO3− loss can be accelerated by administration of acetazolamide, a carbonic anhydrase inhibitor (125–250 mg IV), which is usually effective in patients with adequate renal function but can worsen K+ losses. Dilute hydrochloric acid (0.1 N HCl) has been advocated historically in extreme cases, but can cause hemolysis, and must be delivered slowly in a central vein. This preparation is not available generally and must be mixed by the pharmacist. Because serious errors or harm may occur, its use is not recommended.
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Respiratory acidosis can be due to severe pulmonary disease, respiratory muscle fatigue, or abnormalities in ventilatory control and is recognized by an increase in PaCO2 and decrease in pH (Table 51-7). In acute respiratory acidosis, there is a compensatory elevation (due to cellular buffering mechanisms) in HCO3−, which increases 1 mmol/L for every 10-mmHg increase in PaCO2. In chronic respiratory acidosis (>24 h), renal adaptation increases the [HCO3−] by 4 mmol/L for every 10-mmHg increase in PaCO2. The serum HCO3− usually does not increase above 38 mmol/L.
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The clinical features vary according to the severity and duration of the respiratory acidosis, the underlying disease, and whether there is accompanying hypoxemia. A rapid increase in PaCO2 may cause anxiety, dyspnea, confusion, psychosis, and hallucinations and may progress to coma. Lesser degrees of dysfunction in chronic hypercapnia include sleep disturbances; loss of memory; daytime somnolence; personality changes; impairment of coordination; and motor disturbances such as tremor, myoclonic jerks, and asterixis. Headaches and other signs that mimic raised intracranial pressure, such as papilledema, abnormal reflexes, and focal muscle weakness, are due to vasoconstriction secondary to loss of the vasodilator effects of CO2.
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Depression of the respiratory center by a variety of drugs, injury, or disease can produce respiratory acidosis. This may occur acutely with general anesthetics, sedatives, and head trauma or chronically with sedatives, alcohol, intracranial tumors, and the syndromes of sleep-disordered breathing including the primary alveolar and obesity-hypoventilation syndromes (Chaps. 290 and 291). Abnormalities or disease in the motor neurons, neuromuscular junction, and skeletal muscle can cause hypoventilation via respiratory muscle fatigue. Mechanical ventilation, when not properly adjusted and supervised, may result in respiratory acidosis, particularly if CO2 production suddenly rises (because of fever, agitation, sepsis, or overfeeding) or alveolar ventilation falls because of worsening pulmonary function. High levels of positive end-expiratory pressure in the presence of reduced cardiac output may cause hypercapnia as a result of large increases in alveolar dead space (Chap. 279). Permissive hypercapnia may be used to minimize intrinsic positive end-expiratory pressure in acute lung injury/acute respiratory distress syndrome and severe obstructive lung disease. The respiratory acidosis associated with permissive hypercapnia may require administration of NaHCO3 to increase the arterial pH to ∼7.15–7.20, but correction of the acidemia to a normal arterial pH is deleterious.
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Acute hypercapnia follows sudden occlusion of the upper airway or generalized bronchospasm as in severe asthma, anaphylaxis, inhalational burn, or toxin injury. Chronic hypercapnia and respiratory acidosis occur in end-stage obstructive lung disease. Restrictive disorders involving both the chest wall and the lungs can cause respiratory acidosis because the high metabolic cost of respiration causes ventilatory muscle fatigue. Advanced stages of intrapulmonary and extrapulmonary restrictive defects present as chronic respiratory acidosis.
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The diagnosis of respiratory acidosis requires the measurement of PaCO2 and arterial pH. A detailed history and physical examination often indicate the cause. Pulmonary function studies (Chap. 279), including spirometry, diffusion capacity for carbon monoxide, lung volumes, and arterial PaCO2 and O2 saturation, usually make it possible to determine if respiratory acidosis is secondary to lung disease. The workup for nonpulmonary causes should include a detailed drug history, measurement of hematocrit, and assessment of upper airway, chest wall, pleura, and neuromuscular function.
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TREATMENT Respiratory Acidosis
The management of respiratory acidosis depends on its severity and rate of onset. Acute respiratory acidosis can be life-threatening, and measures to reverse the underlying cause should be undertaken simultaneously with restoration of adequate alveolar ventilation. This may necessitate tracheal intubation and assisted mechanical ventilation. Oxygen administration should be titrated carefully in patients with severe obstructive pulmonary disease and chronic CO2 retention who are breathing spontaneously (Chap. 286). When oxygen is used injudiciously, these patients may experience progression of the respiratory acidosis causing severe acidemia. Aggressive and rapid correction of hypercapnia should be avoided, because the falling PaCO2 may provoke the same complications noted with acute respiratory alkalosis (i.e., cardiac arrhythmias, reduced cerebral perfusion, and seizures). The PaCO2 should be lowered gradually in chronic respiratory acidosis, aiming to restore the PaCO2 to baseline levels and to provide sufficient Cl− and K+ to enhance the renal excretion of HCO3−.
Chronic respiratory acidosis is frequently difficult to correct, but measures aimed at improving lung function (Chap. 286) should be the primary focus of treatment.
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RESPIRATORY ALKALOSIS
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Alveolar hyperventilation decreases PaCO2 and increases the HCO3−/PaCO2 ratio, thus increasing pH (Table 51-7). Nonbicarbonate cellular buffers respond by consuming HCO3−. Hypocapnia develops when a sufficiently strong ventilatory stimulus causes CO2 output in the lungs to exceed its metabolic production by tissues. Plasma pH and [HCO3−] appear to vary proportionately with PaCO2 over a range from 40–15 mmHg. The relationship between arterial [H+] concentration and PaCO2 is ∼0.7 mmol/L per mmHg (or 0.01 pH unit/mmHg), and that for plasma [HCO3−] is 0.2 mmol/L per mmHg. Hypocapnia sustained for >2–6 h is further compensated by a decrease in renal ammonium and titratable acid excretion and a reduction in filtered HCO3− reabsorption. Full renal adaptation to respiratory alkalosis may take several days and requires normal volume status and renal function. The kidneys appear to respond directly to the lowered PaCO2 rather than to alkalosis per se. In chronic respiratory alkalosis a 1-mmHg decrease in PaCO2 causes a 0.4- to 0.5-mmol/L drop in [HCO3−] and a 0.3-mmol/L decrease (or 0.003 increase in pH) in [H+].
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The effects of respiratory alkalosis vary according to duration and severity but are primarily those of the underlying disease. Reduced cerebral blood flow as a consequence of a rapid decline in PaCO2 may cause dizziness, mental confusion, and seizures, even in the absence of hypoxemia. The cardiovascular effects of acute hypocapnia in the conscious human are generally minimal, but in the anesthetized or mechanically ventilated patient, cardiac output and blood pressure may fall because of the depressant effects of anesthesia and positive-pressure ventilation on heart rate, systemic resistance, and venous return. Cardiac arrhythmias may occur in patients with heart disease as a result of changes in oxygen unloading by blood from a left shift in the hemoglobin-oxygen dissociation curve (Bohr effect). Acute respiratory alkalosis causes intracellular shifts of Na+, K+, and PO42− and reduces free [Ca2+] by increasing the protein-bound fraction. Hypocapnia-induced hypokalemia is usually minor.
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Chronic respiratory alkalosis is the most common acid-base disturbance in critically ill patients and, when severe, portends a poor prognosis. Many cardiopulmonary disorders manifest respiratory alkalosis in their early to intermediate stages, and the finding of normocapnia and hypoxemia in a patient with hyperventilation may herald the onset of rapid respiratory failure and should prompt an assessment to determine if the patient is becoming fatigued. Respiratory alkalosis is common during mechanical ventilation.
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The hyperventilation syndrome may be disabling. Paresthesia; circumoral numbness; chest wall tightness or pain; dizziness; inability to take an adequate breath; and, rarely, tetany may be sufficiently stressful to perpetuate the disorder. Arterial blood-gas analysis demonstrates an acute or chronic respiratory alkalosis, often with hypocapnia in the range of 15–30 mmHg and no hypoxemia. CNS diseases or injury can produce several patterns of hyperventilation and sustained PaCO2 levels of 20–30 mmHg. Hyperthyroidism, high caloric loads, and exercise raise the basal metabolic rate, but ventilation usually rises in proportion so that arterial blood gases are unchanged and respiratory alkalosis does not develop. Salicylates are the most common cause of drug-induced respiratory alkalosis as a result of direct stimulation of the medullary chemoreceptor (Chap. 449). The methylxanthines, theophylline, and aminophylline stimulate ventilation and increase the ventilatory response to CO2. Progesterone increases ventilation and lowers arterial PaCO2 by as much as 5–10 mmHg. Therefore, chronic respiratory alkalosis is a common feature of pregnancy. Respiratory alkalosis is also prominent in liver failure, and the severity correlates with the degree of hepatic insufficiency. Respiratory alkalosis is often an early finding in gram-negative septicemia, before fever, hypoxemia, or hypotension develops.
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The diagnosis of respiratory alkalosis depends on measurement of arterial pH and PaCO2. The plasma [K+] is often reduced and the [Cl−] increased. In the acute phase, respiratory alkalosis is not associated with increased renal HCO3− excretion, but within hours net acid excretion is reduced. In general, the HCO3− concentration falls by 2.0 mmol/L for each 10-mmHg decrease in PaCO2. If the hypocapnia persists for >3–5 days, chronic respiratory alkalosis is present, and the decline in PaCO2 reduces the serum [HCO3−] by 4–5 mmol/L for each 10-mmHg decrease in PaCO2. It is unusual to observe a plasma HCO3− <12 mmol/L as a result of a pure respiratory alkalosis. Moreover, the compensatory reduction in the plasma HCO3– concentration is so effective in chronic respiratory alkalosis that the pH does not decline significantly from the normal value. In this regard, chronic respiratory alkalosis is the only acid-base disorder that may return the pH to the normal value.
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When a diagnosis of respiratory alkalosis is made, its cause should be investigated. The diagnosis of hyperventilation syndrome is made by exclusion. In difficult cases, it may be important to rule out other conditions such as pulmonary embolism, coronary artery disease, and hyperthyroidism.
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TREATMENT Respiratory Alkalosis
The management of respiratory alkalosis is directed toward alleviation of the underlying disorder. If respiratory alkalosis complicates ventilator management, changes in dead space, tidal volume, and frequency can minimize the hypocapnia. Patients with the hyperventilation syndrome may benefit from reassurance, rebreathing from a paper bag during symptomatic attacks, and attention to underlying psychological stress. Antidepressants and sedatives are not recommended. β-adrenergic blockers may ameliorate peripheral manifestations of the hyperadrenergic state.
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TD: Etiologic causes of metabolic acidosis I: The high anion gap acidosis, In Metabolic Acidosis. Wesson
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