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InternalMed_Harrison. FIGuRE 64e-2 11β-Hydroxysteroid dehydrogenase-2 (11βHSD-2) and syndromes of apparent mineralocorticoid excess. The enzyme 11βHSD-2 protects cells in the aldosterone-sensitive distal nephron (the distal convoluted tubule [DCT ], connecting tubule [CNT], and collecting duct) from the illicit activation of mineralocorticoid receptors (MLR) by cortisol. Binding of aldosterone to the MLR leads to activation of the thiazide-sensitive Na+-Cl− cotransporter in DCT cells and the amiloride-sensitive epithelial sodium channel (ENaC) in principal cells (CNT and collecting duct). Aldosterone also activates basolateral Na+/K+-ATPase and, to a lesser extent, the apical secretory K+ channel ROMK (renal outer medullary K+ channel). Cortisol has equivalent affinity for the MLR to that of aldosterone; metabolism of cortisol to cortisone, which has no affinity for the MLR, prevents these cells from activation by circulating cortisol. Genetic deficiency of 11βHSD-2 or inhibition of its activity causes the


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InternalMed_Harrison. of cortisol to cortisone, which has no affinity for the MLR, prevents these cells from activation by circulating cortisol. Genetic deficiency of 11βHSD-2 or inhibition of its activity causes the syndromes of apparent mineralocorticoid excess (see Case 8).


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InternalMed_Harrison. channels in principal cells of the CNT and collecting duct (Fig. 64e-2). Recessive loss-of-function mutations in the 11βHSD-2 gene lead to cortisol-dependent activation of the MLR and the syndrome of apparent mineralocorticoid excess (SAME), comprising hypertension, hypokalemia, hypercalciuria, and metabolic alkalosis, with suppressed plasma renin activity (PRA) and suppressed aldosterone. A similar syndrome is caused by biochemical inhibition of 11βHSD-2 by glycyrrhetinic/ glycyrrhizinic acid (found in licorice, for example) and/or carbenoxolone.


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InternalMed_Harrison. In Cushing’s syndrome caused by increases in pituitary ACTH, the incidence of hypokalemia is only 10%, whereas it is ~70% in patients with ectopic secretion of ACTH, despite a similar incidence of hypertension. The activity of renal 11βHSD-2 is reduced in patients with ectopic ACTH compared with Cushing’s syndrome, resulting in SAME; the prevailing theory is that the much greater cortisol production in ectopic ACTH syndromes overwhelms the renal 11βHSD-2 enzyme, resulting in activation of renal MLRs by unmetabolized cortisol (Fig. 64e-2).


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InternalMed_Harrison. Why was the patient so weak? The patient was profoundly weak due to the combined effect of hypokalemia and increased cortisol. Hypokalemia causes hyperpolarization of muscle, thereby impairing the capacity to depolarize and contract. Weakness and even ascending paralysis can frequently complicate severe hypokalemia. Hypokalemia also causes a myopathy and predisposes to rhabdomyolysis; notably, however, the patient had a normal creatine phosphokinase (CPK) level. Cushing’s syndrome is often accompanied by a proximal myopathy, due to the protein-wasting effects of cortisol excess.


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InternalMed_Harrison. The patient presented with a mixed acid-base disorder, with a significant metabolic alkalosis and a bicarbonate concentration of 44 meq/L. A venous blood gas was drawn soon after his presentation; venous and arterial blood gases demonstrate a high level of agreement in hemodynamically stable patients, allowing for the interpretation of acid-base disorders with venous blood gas results. In response to his metabolic alkalosis, the Pco2 should have increased by 0.75 mmHg for each 1-meq/L increase in bicarbonate; the expected Pco2 should have been ~55 mmHg. Given the Pco2 of 62 mmHg, he had an additional respiratory acidosis, likely caused by respiratory muscle weakness from his acute hypokalemia and subacute hypercortisolism.


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InternalMed_Harrison. The patient’s albumin-adjusted AG was 21 + ([4 – 2.8] × 2.5) = 24; this suggests a third acid-base disorder, AG acidosis. Notably, the measured AG can increase in alkalosis, due to both increases in plasma protein concentrations (in hypovolemic alkalosis) and to the alkalemiaassociated increase in net negative charge of plasma proteins, both causing an increase in unmeasured anions; however, this patient was neither volume-depleted nor particularly alkalemic, suggesting that these effects played a minimal role in his increased AG. Alkalosis also stimulates an increase in lactic acid production, due to activation of phosphofructokinase and accelerated glycolysis; unfortunately, however, a lactic acid level was not measured in this patient. It should be noted in this regard that alkalosis typically increases lactic acid levels by a mere 1.5–3 meq/L and that the patient was not significantly alkalemic. Regardless of the underlying pathophysiology, the increased AG was likely related to


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InternalMed_Harrison. typically increases lactic acid levels by a mere 1.5–3 meq/L and that the patient was not significantly alkalemic. Regardless of the underlying pathophysiology, the increased AG was likely related to the metabolic alkalosis, given that the AG had decreased to 18 by hospital day 2, coincident with a reduction in plasma bicarbonate.


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InternalMed_Harrison. Why did the patient have a metabolic alkalosis? The activation of MLRs in the distal nephron increases distal nephron acidification and net acid secretion. In consequence, mineralocorticoid excess causes a saline-resistant metabolic alkalosis, which is exacerbated significantly by the development of hypokalemia. Hypokalemia plays a key role in the generation of most forms of metabolic alkalosis, stimulating proximal tubular ammonium production, proximal tubular bicarbonate reabsorption, and distal tubular H+/K+-ATPase activity.


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InternalMed_Harrison. The first priority in the management of this patient was to increase his plasma K+ and magnesium concentrations rapidly; hypomagnesemic patients are refractory to K+ replacement alone, resulting in the need to correct hypomagnesemia immediately. This was accomplished via the administration of both oral and intravenous K+-Cl−, giving a total of 240 meq over the first 18 h; 5 g of intravenous magnesium sulfate was also administered. Multiple 100-mL “minibags” of saline containing 20 meq each were infused, with cardiac monitoring and frequent measurement of plasma electrolytes. Of note, intravenous K+-Cl− should always be given in saline solutions because dextrose-containing solutions can increase insulin levels and exacerbate hypokalemia.


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InternalMed_Harrison. This case illustrates the difficulty in predicting the whole-body deficit of K+ in hypokalemic patients. In the absence of abnormal K+ redistribution, the total deficit correlates with plasma K+ concentration, which drops by approximately 0.27 mM for every 100-mmol reduction in total-body stores; this would suggest a deficit of ~650 meq of K+ in this patient, at the admission plasma K+ concentration of 1.7 meq/L. Notably, however, alkalemia induces a modest intracellular shift of circulating K+ such that this patient’s initial plasma K+ concentration was not an ideal indicator of the total potassium deficit. Regardless of the underlying pathophysiology in this case, close monitoring of plasma K+ concentration is always essential during the correction of severe hypokalemia in order to gauge the adequacy of repletion and to avoid overcorrection.


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InternalMed_Harrison. Subsequent management of this patient’s Cushing’s syndrome and ectopic ACTH secretion was complicated by the respiratory issues. The prognosis in patients with ectopic ACTH secretion depends on the tumor histology and the presence or absence of distant metastases. This patient had an exceptionally poor prognosis, with widely metastatic small-cell lung cancer that had failed treatment; other patients with ectopic ACTH secretion caused by more benign, isolated tumors, most commonly bronchial carcinoid tumors, have a much better prognosis. In the absence of successful surgical resection of the causative tumor, management of this syndrome can include surgical adrenalectomy or medical therapy to block adrenal steroid production.


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InternalMed_Harrison. A stuporous 22-year-old man was admitted with a history of behaving strangely. His friends indicated he experienced recent emotional problems stemming from a failed relationship and had threatened suicide. There was a history of alcohol abuse, but his friends were unaware of recent alcohol consumption. The patient was obtunded on admission, with no evident focal neurologic deficits. The remainder of the physical examination was unremarkable. Na+ 140 meq/L K+ 5 meq/L Cl− 95 meq/L HCO3− 10 meq/L Glucose 125 mg/dL BUN 15 mg/dL Creatinine 0.9 mg/dL Ionized calcium 4.0 mg/dL Plasma osmolality 325 mOsm kg/H2O Urinalysis revealed crystalluria, with a mixture of envelope-shaped and needle-shaped crystals.


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InternalMed_Harrison. This patient presented with CNS manifestations and a history of suspicious behavior, suggesting ingestion of a toxin. The AG was strikingly elevated at 35 meq/L. The ΔAG of 25 significantly exceeded the ΔHCO3− of 15. The fact that the Δ values were significantly disparate indicates that the most likely acid-base diagnosis in this patient is a mixed high-AG metabolic acidosis and a metabolic alkalosis. The metabolic alkalosis in this case may have been the result of vomiting. Nevertheless, the most useful finding is that the osmolar gap is elevated. The osmolar gap of 33 (difference in measured and calculated osmolality or 325 – 292) in the face of a high-AG metabolic acidosis is diagnostic of an osmotically active metabolite in plasma; a difference of >10 mOsm/kg indicates a significant concentration of an unmeasured osmolyte. Examples of toxic osmolytes include ethylene glycol, diethylene glycol, methanol, and propylene glycol.


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InternalMed_Harrison. Several caveats apply to the interpretation of the osmolar gap and 64e-9 AG in the differential diagnosis of toxic alcohol ingestions. First, unmeasured, neutral osmolytes can also accumulate in lactic acidosis and alcoholic ketoacidosis; i.e., an elevated osmolar gap is not specific to AG acidoses associated with toxic alcohol ingestions. Second, patients can present having extensively metabolized the ingested toxin, with an insignificant osmolar gap but a large AG; i.e., the absence of an elevated osmolar gap does not rule out toxic alcohol ingestion. Third, the converse can also be seen in patients who present earlier after ingestion of the toxin, i.e., a large osmolar gap with minimal elevation of the AG. Finally, clinicians should be aware of the effect of co-ingested ethanol, which can itself elevate the osmolar gap and can reduce metabolism of the toxic alcohols via competitive inhibition of alcohol dehydrogenase (see below), thus attenuating the expected increase in the AG.


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InternalMed_Harrison. Ethylene glycol is commonly available as antifreeze or solvents and may be ingested accidently or as a suicide attempt. The metabolism of ethylene glycol by alcohol dehydrogenase generates acids such as glycoaldehyde, glycolic acid, and oxalic acid. The initial effects of intoxication are on the CNS and, in the earliest stages, mimic inebriation, but may quickly progress to full-blown coma. Delay in treatment is one of the most common causes of mortality with toxic alcohol poisoning. The kidney shows evidence of acute tubular injury with widespread deposition of calcium oxalate crystals within tubular epithelial cells. Cerebral edema is common, as is crystal deposition in the brain; the latter is irreversible.


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InternalMed_Harrison. The co-occurrent crystalluria is typical of ethylene glycol intoxication; both needle-shaped monohydrate and envelope-shaped dihydrate calcium oxalate crystals can be seen in the urine as the process evolves. Circulating oxalate can also complex with plasma calcium, reducing the ionized calcium as in this case. Although ethylene glycol intoxication should be verified by measuring ethylene glycol levels, therapy must be initiated immediately in this life-threatening situation. Although therapy can be initiated with confidence in cases with known or witnessed ingestions, such histories are rarely available. Therapy should thus be initiated in patients with severe metabolic acidosis and elevated anion and osmolar gaps. Other diagnostic features, such as hypocalcemia or acute renal failure with crystalluria, can provide important confirmation for urgent, empiric therapy.


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InternalMed_Harrison. Because all four osmotically active toxic alcohols—ethylene glycol, diethylene glycol, methanol, and propylene glycol—are metabolized by alcohol dehydrogenase to generate toxic products, competitive inhibition of this key enzyme is common to the treatment of all four intoxications. The most potent inhibitor of alcohol dehydrogenase, and the drug of choice in this circumstance, is fomepizole (4-methyl pyrazole). Fomepizole should be administered intravenously as a loading dose (15 mg/kg) followed by doses of 10 mg/kg every 12 h for four doses, and then 15 mg/kg every 12 h thereafter until ethylene glycol levels have been reduced to <20 mg/dL and the patient is asymptomatic with a normal pH. Additional important components of the treatment of toxic alcohol ingestion include fluid resuscitation, thiamine, pyridoxine, folate, sodium bicarbonate, and hemodialysis. Hemodialysis is used to remove both the parent compound and toxic metabolites, but it also removes administered fomepizole,


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InternalMed_Harrison. thiamine, pyridoxine, folate, sodium bicarbonate, and hemodialysis. Hemodialysis is used to remove both the parent compound and toxic metabolites, but it also removes administered fomepizole, necessitating adjustment of dosage frequency. Gastric aspiration, induced emesis, or the use of activated charcoal is only effective if initiated within 30–60 min after ingestion of the toxin. When fomepizole is not available, ethanol, which has more than 10-fold affinity for alcohol dehydrogenase compared to other alcohols, may be substituted and is quite effective. Ethanol must be administered IV to achieve a blood level of 22 meq/L (100 mg/dL). A disadvantage of ethanol is the obtundation that follows its administration, which is additive to the CNS effects of ethylene glycol. Furthermore, if hemodialysis is used, the infusion rate of ethanol must be increased because it is rapidly dialyzed. In general, hemodialysis is indicated for all patients with ethylene glycol intoxication when the


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InternalMed_Harrison. hemodialysis is used, the infusion rate of ethanol must be increased because it is rapidly dialyzed. In general, hemodialysis is indicated for all patients with ethylene glycol intoxication when the arterial pH is <7.3 or the osmolar gap exceeds 20 mOsm/kg H2O.


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InternalMed_Harrison. CHAPTER 64e Fluid and Electrolyte Imbalances and Acid-Base Disturbances: Case Examples TABLE 65-1 CAuSES of HyPERCALCEMiA Sundeep Khosla Primary hyperparathyroidism (adenoma, hyperplasia, rarely carcinoma)


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InternalMed_Harrison. Sundeep Khosla Primary hyperparathyroidism (adenoma, hyperplasia, rarely carcinoma) The calcium ion plays a critical role in normal cellular function and signaling, regulating diverse physiologic processes such as neuromuscular signaling, cardiac contractility, hormone secretion, and blood coagulation. Thus, extracellular calcium concentrations are maintained within an exquisitely narrow range through a series of feedback mechanisms that involve parathyroid hormone (PTH) and the active vitamin D metabolite 1,25-dihydroxyvitmin D [1,25(OH)2D]. These feedback mechanisms are orchestrated by integrating signals between the parathyroid glands, kidney, intestine, and bone (Fig. 65-1; Chap. 423). Disorders of serum calcium concentration are relatively common and often serve as a harbinger of underlying disease. This chapter provides a brief summary of the approach to patients with altered serum calcium levels. See Chap. 424 for a detailed discussion of this topic.


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InternalMed_Harrison. The causes of hypercalcemia can be understood and classified based on derangements in the normal feedback mechanisms that regulate serum calcium (Table 65-1). Excess PTH production, which is not appropriately suppressed by increased serum calcium concentrations, occurs in primary neoplastic disorders of the parathyroid glands (parathyroid adenomas; hyperplasia; or, rarely, carcinoma) that are associated with 1,25 (OH)2D


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InternalMed_Harrison. FIguRE 65-1 Feedback mechanisms maintaining extracellular calcium concentrations within a narrow, physiologic range (8.9–10.1 mg/dL [2.2–2.5 mM]). A decrease in extracellular (ECF) calcium (Ca2+) triggers an increase in parathyroid hormone (PTH) secretion (1) via the calcium sensor receptor on parathyroid cells. PTH, in turn, results in increased tubular reabsorption of calcium by the kidney (2) and resorption of calcium from bone (2) and also stimulates renal 1,25(OH)2D production (3). 1,25(OH)2D, in turn, acts principally on the intestine to increase calcium absorption (4). Collectively, these homeostatic mechanisms serve to restore serum calcium levels to normal.


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InternalMed_Harrison. Tertiary hyperparathyroidism (long-term stimulation of PTH secretion in renal insufficiency) Ectopic PTH secretion (very rare) Inactivating mutations in the CaSR or in G proteins (FHH) Alterations in CaSR function (lithium therapy) Hypercalcemia of malignancy Overproduction of PTHrP (many solid tumors) Lytic skeletal metastases (breast, myeloma) Excessive 1,25(OH)2D production Granulomatous diseases (sarcoidosis, tuberculosis, silicosis) Lymphomas Vitamin D intoxication Primary increase in bone resorption Hyperthyroidism Immobilization Excessive calcium intake Milk-alkali syndrome Total parenteral nutrition Other causes Endocrine disorders (adrenal insufficiency, pheochromocytoma, VIPoma) Medications (thiazides, vitamin A, antiestrogens) Abbreviations: CaSR, calcium sensor receptor; FHH, familial hypocalciuric hypercalcemia; PTH, parathyroid hormone; PTHrP, PTH-related peptide.


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InternalMed_Harrison. increased parathyroid cell mass and impaired feedback inhibition by calcium. Inappropriate PTH secretion for the ambient level of serum calcium also occurs with heterozygous inactivating calcium sensor receptor (CaSR) or G protein mutations, which impair extracellular calcium sensing by the parathyroid glands and the kidneys, resulting in familial hypocalciuric hypercalcemia (FHH). Although PTH secretion by tumors is extremely rare, many solid tumors produce PTH-related peptide (PTHrP), which shares homology with PTH in the first 13 amino acids and binds the PTH receptor, thus mimicking effects of PTH on bone and the kidney. In PTHrP-mediated hypercalcemia of malignancy, PTH levels are suppressed by the high serum calcium levels. Hypercalcemia associated with granulomatous disease (e.g., sarcoidosis) or lymphomas is caused by enhanced conversion of 25(OH) D to the potent 1,25(OH)2D. In these disorders, 1,25(OH)2D enhances intestinal calcium absorption, resulting in hypercalcemia and


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InternalMed_Harrison. sarcoidosis) or lymphomas is caused by enhanced conversion of 25(OH) D to the potent 1,25(OH)2D. In these disorders, 1,25(OH)2D enhances intestinal calcium absorption, resulting in hypercalcemia and suppressed PTH. Disorders that directly increase calcium mobilization from bone, such as hyperthyroidism or osteolytic metastases, also lead to hypercalcemia with suppressed PTH secretion as does exogenous calcium overload, as in milk-alkali syndrome, or total parenteral nutrition with excessive calcium supplementation.


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InternalMed_Harrison. Mild hypercalcemia (up to 11–11.5 mg/dL) is usually asymptomatic and recognized only on routine calcium measurements. Some patients may complain of vague neuropsychiatric symptoms, including trouble concentrating, personality changes, or depression. Other presenting symptoms may include peptic ulcer disease or nephrolithiasis, and fracture risk may be increased. More severe hypercalcemia (>12–13 mg/dL), particularly if it develops acutely, may result in lethargy, stupor, or coma, as well as gastrointestinal symptoms (nausea, anorexia, constipation, or pancreatitis). Hypercalcemia decreases renal concentrating ability, which may cause polyuria and polydipsia. With longstanding hyperparathyroidism, patients may present with bone pain or pathologic fractures. Finally, hypercalcemia can result in significant electrocardiographic changes, including bradycardia, AV block, and short QT interval; changes in serum calcium can be monitored by following the QT interval.


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InternalMed_Harrison. The first step in the diagnostic evaluation of hyperor hypocalcemia is to ensure that the alteration in serum calcium levels is not due to abnormal albumin concentrations. About 50% of total calcium is ionized, and the rest is bound principally to albumin. Although direct measurements of ionized calcium are possible, they are easily influenced by collection methods and other artifacts; thus, it is generally preferable to measure total calcium and albumin to “correct” the serum calcium. When serum albumin concentrations are reduced, a corrected calcium concentration is calculated by adding 0.2 mM (0.8 mg/dL) to the total calcium level for every decrement in serum albumin of 1.0 g/dL below the reference value of 4.1 g/dL for albumin, and, conversely, for elevations in serum albumin.


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InternalMed_Harrison. A detailed history may provide important clues regarding the etiology of the hypercalcemia (Table 65-1). Chronic hypercalcemia is most commonly caused by primary hyperparathyroidism, as opposed to the second most common etiology of hypercalcemia, an underlying malignancy. The history should include medication use, previous neck surgery, and systemic symptoms suggestive of sarcoidosis or lymphoma.


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InternalMed_Harrison. Once true hypercalcemia is established, the second most important laboratory test in the diagnostic evaluation is a PTH level using a two-site assay for the intact hormone. Increases in PTH are often accompanied by hypophosphatemia. In addition, serum creatinine should be measured to assess renal function; hypercalcemia may impair renal function, and renal clearance of PTH may be altered depending on the fragments detected by the assay. If the PTH level is increased (or “inappropriately normal”) in the setting of elevated calcium and low phosphorus, the diagnosis is almost always primary hyperparathyroidism. Because individuals with FHH may also present with mildly elevated PTH levels and hypercalcemia, this diagnosis should be considered and excluded because parathyroid surgery is ineffective in this condition. A calcium/creatinine clearance ratio (calculated as urine calcium/ serum calcium divided by urine creatinine/serum creatinine) of <0.01 is suggestive of FHH, particularly when


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InternalMed_Harrison. in this condition. A calcium/creatinine clearance ratio (calculated as urine calcium/ serum calcium divided by urine creatinine/serum creatinine) of <0.01 is suggestive of FHH, particularly when there is a family history of mild, asymptomatic hypercalcemia. In addition, sequence analysis of the CaSR gene is now commonly performed for the definitive diagnosis of FHH, although in some families, FHH may be caused by mutations in G proteins that mediate signaling by the CaSR. Ectopic PTH secretion is extremely rare.


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InternalMed_Harrison. A suppressed PTH level in the face of hypercalcemia is consistent with non-parathyroid-mediated hypercalcemia, most often due to underlying malignancy. Although a tumor that causes hypercalcemia is generally overt, a PTHrP level may be needed to establish the diagnosis of hypercalcemia of malignancy. Serum 1,25(OH)2D levels are increased in granulomatous disorders, and clinical evaluation in combination with laboratory testing will generally provide a diagnosis for the various disorders listed in Table 65-1. PART 2 Cardinal Manifestations and Presentation of Diseases


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InternalMed_Harrison. Mild, asymptomatic hypercalcemia does not require immediate therapy, and management should be dictated by the underlying diagnosis. By contrast, significant, symptomatic hypercalcemia usually requires therapeutic intervention independent of the etiology of hypercalcemia. Initial therapy of significant hypercalcemia begins with volume expansion because hypercalcemia invariably leads to dehydration; 4–6 L of intravenous saline may be required over the first 24 h, keeping in mind that underlying comorbidities (e.g., congestive heart failure) may require the use of loop diuretics to enhance sodium and calcium excretion. However, loop diuretics should not be initiated until the volume status has been restored to normal. If there is increased calcium mobilization from bone (as in malignancy or severe hyperparathyroidism), drugs that inhibit bone resorption should be considered. Zoledronic acid (e.g., 4 mg intravenously over ∼30 min), pamidronate (e.g., 60–90 mg intravenously over 2–4 h),


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InternalMed_Harrison. severe hyperparathyroidism), drugs that inhibit bone resorption should be considered. Zoledronic acid (e.g., 4 mg intravenously over ∼30 min), pamidronate (e.g., 60–90 mg intravenously over 2–4 h), and ibandronate (2 mg intravenously over 2 h) are bisphosphonates that are commonly used for the treatment of hypercalcemia of malignancy in adults. Onset of action is within 1–3 days, with normalization of serum calcium levels occurring in 60–90% of patients. Bisphosphonate infusions may need to be repeated if hypercalcemia relapses. An alternative to the bisphosphonates is gallium nitrate (200 mg/m2 intravenously daily for 5 days), which is also effective, but has potential nephrotoxicity. In rare instances, dialysis may be necessary. Finally, although intravenous phosphate chelates calcium and decreases serum calcium levels, this therapy can be toxic because calcium-phosphate complexes may deposit in tissues and cause extensive organ damage.


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InternalMed_Harrison. In patients with 1,25(OH)2D-mediated hypercalcemia, glucocorticoids are the preferred therapy, as they decrease 1,25(OH)2D production. Intravenous hydrocortisone (100–300 mg daily) or oral prednisone (40–60 mg daily) for 3–7 days is used most often. Other drugs, such as ketoconazole, chloroquine, and hydroxychloroquine, may also decrease 1,25(OH)2D production and are used occasionally.


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InternalMed_Harrison. The causes of hypocalcemia can be differentiated according to whether serum PTH levels are low (hypoparathyroidism) or high (secondary hyperparathyroidism). Although there are many potential causes of hypocalcemia, impaired PTH production and impaired vitamin D production are the most common etiologies (Table 65-2) (Chap. 424). Because PTH is the main defense against hypocalcemia, disorders associated with deficient PTH production or secretion may be associated with profound, life-threatening hypocalcemia. In adults, hypoparathyroidism most commonly results from inadvertent damage to all four glands during thyroid or parathyroid gland surgery. Hypoparathyroidism is a cardinal feature of autoimmune endocrinopathies (Chap. 408); rarely, it Vitamin D deficiency or impaired 1,25(OH)2D production/action Nutritional vitamin D deficiency (poor intake or absorption) Renal insufficiency with impaired 1,25(OH)2D production Vitamin D resistance, including receptor defects


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InternalMed_Harrison. Drugs Calcium chelators Inhibitors of bone resorption (bisphosphonates, plicamycin) Altered vitamin D metabolism (phenytoin, ketoconazole) Miscellaneous causes Acute pancreatitis Acute rhabdomyolysis Hungry bone syndrome after parathyroidectomy Osteoblastic metastases with marked stimulation of bone formation (prostate cancer) Abbreviations: CaSR, calcium sensor receptor; PTH, parathyroid hormone. may be associated with infiltrative diseases such as sarcoidosis. Impaired PTH secretion may be secondary to magnesium deficiency or to activating mutations in the CaSR or in the G proteins that mediate CaSR signaling, which suppress PTH, leading to effects that are opposite to those that occur in FHH.


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InternalMed_Harrison. Vitamin D deficiency, impaired 1,25(OH)2D production (primarily secondary to renal insufficiency), or vitamin D resistance also cause hypocalcemia. However, the degree of hypocalcemia in these disorders is generally not as severe as that seen with hypoparathyroidism because the parathyroids are capable of mounting a compensatory increase in PTH secretion. Hypocalcemia may also occur in conditions associated with severe tissue injury such as burns, rhabdomyolysis, tumor lysis, or pancreatitis. The cause of hypocalcemia in these settings may include a combination of low albumin, hyperphosphatemia, tissue deposition of calcium, and impaired PTH secretion.


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InternalMed_Harrison. Patients with hypocalcemia may be asymptomatic if the decreases in serum calcium are relatively mild and chronic, or they may present with life-threatening complications. Moderate to severe hypocalcemia is associated with paresthesias, usually of the fingers, toes, and circumoral regions, and is caused by increased neuromuscular irritability. On physical examination, a Chvostek’s sign (twitching of the circumoral muscles in response to gentle tapping of the facial nerve just anterior to the ear) may be elicited, although it is also present in ∼10% of normal individuals. Carpal spasm may be induced by inflation of a blood pressure cuff to 20 mmHg above the patient’s systolic blood pressure for 3 min (Trousseau’s sign). Severe hypocalcemia can induce seizures, carpopedal spasm, bronchospasm, laryngospasm, and prolongation of the QT interval.


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InternalMed_Harrison. In addition to measuring serum calcium, it is useful to determine albumin, phosphorus, and magnesium levels. As for the evaluation of hypercalcemia, determining the PTH level is central to the evaluation of hypocalcemia. A suppressed (or “inappropriately low”) PTH level in the setting of hypocalcemia establishes absent or reduced PTH secretion (hypoparathyroidism) as the cause of the hypocalcemia. Further history will often elicit the underlying cause (i.e., parathyroid agenesis vs. destruction). By contrast, an elevated PTH level (secondary hyperparathyroidism) should direct attention to the vitamin D axis as the cause of the hypocalcemia. Nutritional vitamin D deficiency is best assessed by obtaining serum 25-hydroxyvitamin D levels, which reflect vitamin D stores. In the setting of renal insufficiency or suspected vitamin D resistance, serum 1,25(OH)2D levels are informative.


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InternalMed_Harrison. The approach to treatment depends on the severity of the hypocalcemia, the rapidity with which it develops, and the accompanying complications (e.g., seizures, laryngospasm). Acute, symptomatic hypocalcemia is initially managed with calcium gluconate, 10 mL 10% wt/vol (90 mg or 2.2 mmol) intravenously, diluted in 50 mL of 5% dextrose or 0.9% sodium chloride, given intravenously over 5 min. Continuing hypocalcemia often requires a constant intravenous infusion (typically 10 ampules of calcium gluconate or 900 mg of calcium in 1 L of 5% dextrose or 0.9% sodium chloride administered over 24 h). Accompanying hypomagnesemia, if present, should be treated with appropriate magnesium supplementation.


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InternalMed_Harrison. Chronic hypocalcemia due to hypoparathyroidism is treated with calcium supplements (1000–1500 mg/d elemental calcium in divided doses) and either vitamin D2 or D3 (25,000–100,000 U daily) or calcitriol [1,25(OH)2D, 0.25–2 μg/d]. Other vitamin D metabolites (dihydrotachysterol, alfacalcidiol) are now used less frequently. Vitamin D deficiency, however, is best treated using vitamin D supplementation, with the dose depending on the severity of the deficit and the underlying cause. Thus, nutritional vitamin D deficiency generally responds to relatively low doses of vitamin D (50,000 U, 2–3 times per week for several months), whereas vitamin D deficiency due to malabsorption may require much higher doses 315 (100,000 U/d or more). The treatment goal is to bring serum calcium into the low normal range and to avoid hypercalciuria, which may lead to nephrolithiasis.


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InternalMed_Harrison. In countries with more limited access to health care or screening laboratory testing of serum calcium levels, primary hyperparathyroidism often presents in its severe form with skeletal complications (osteitis fibrosa cystica) in contrast to the asymptomatic form that is common in developed countries. In addition, vitamin D deficiency is paradoxically common in some countries despite extensive sunlight (e.g., India) due to avoidance of sun exposure and poor dietary vitamin D intake. Thomas D. DuBose, Jr.


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InternalMed_Harrison. Thomas D. DuBose, Jr. 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: P = 6.1+ logPaco2 × 0.0301


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InternalMed_Harrison. P = 6.1+ logPaco2 × 0.0301 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 -]. The most common clinical disturbances are simple acid-base disorders; i.e., metabolic acidosis or alkalosis or respiratory acidosis or alkalosis.


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InternalMed_Harrison. The most common clinical disturbances are simple acid-base disorders; i.e., metabolic acidosis or alkalosis or respiratory acidosis or alkalosis. 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 66-1. 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 often returns the pH to a normal value. Metabolic acidosis due to an increase in endogenous acids (e.g., ketoacidosis) lowers extracellular fluid [HCO3 -] and decreases extracellular pH. This stimulates the medullary chemoreceptors to increase ventilation and to return


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InternalMed_Harrison. PART 2 Cardinal Manifestations and Presentation of Diseases Range of Values


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InternalMed_Harrison. Prediction of the ratio of [HCO3 -] to Paco2, and thus pH, toward, but not to, normal. The degree of respiratory compensation expected in a simple form of 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 between 24 and 28 mmHg. Values for Paco2 <24 or >28 mmHg define a mixed disturbance (metabolic acidosis and respiratory alkalosis or metabolic alkalosis 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 66-1). 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 disturbance. Another way


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InternalMed_Harrison. (Table 66-1). 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 disturbance. Another way to judge the appropriateness of the response in [HCO3 -] or Paco2 is to use an acid-base nomogram (Fig. 66-1). While the shaded areas of the nomogram show the 95% confidence limits for normal 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 66-1.


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InternalMed_Harrison. 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 66-2). A patient with diabetic ketoacidosis (metabolic acidosis) may develop an independent respiratory problem (e.g., limits (range of values) of the normal respiratory and metabolic compensations for primary acid-base disturbances. (From TD DuBose Jr: Acid-base disorders, in Brenner and Rector’s The Kidney, 8th ed, BM Brenner [ed]. Philadelphia, Saunders, 2008, pp 505–546, with permission.) Key: Highor normal-AG metabolic acidosis; prevailing Paco2 below predicted value (Table 66-1) Example: Na+, 140; K+, 4.0; Cl-, 106; HCO3 -, 14; AG, 20; Paco2, 24; pH, 7.39 (lactic acidosis, sepsis in ICU) Metabolic acidosis—respiratory acidosis


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InternalMed_Harrison. Key: Highor normal-AG metabolic acidosis; prevailing Paco2 above predicted value (Table 66-1) Example: Na+, 140; K+, 4.0; Cl-, 102; HCO3 -, 18; AG, 20; Paco2, 38; pH, 7.30 (severe pneumonia, pulmonary edema) Metabolic alkalosis—respiratory alkalosis Key: Paco2 does not increase as predicted; pH higher than expected Example: Na+, 140; K+, 4.0; Cl-, 91; HCO3 -, 33; AG, 16; Paco2, 38; pH, 7.55 (liver Metabolic alkalosis—respiratory acidosis Key: Paco2 higher than predicted; pH normal Example: Na+, 140; K+, 3.5; Cl-, 88; HCO3 -, 42; AG, 10; Paco2, 67; pH, 7.42 Key: Only detectable with high-AG acidosis; ∆AG >> ∆HCO3 Example: Na+, 140; K+, 3.0; Cl-, 95; HCO3 -, 25; AG, 20; Paco2, 40; pH, 7.42 (uremia with vomiting) Key: Mixed high-AG—normal-AG acidosis; ∆HCO3 accounted for by combined change in ∆AG and ∆Cl- Example: Na+, 135; K+, 3.0; Cl-, 110; HCO3 -, 10; AG, 15; Paco2, 25; pH, 7.20 (diarrhea and lactic acidosis, toluene toxicity, treatment of diabetic ketoacidosis)


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InternalMed_Harrison. Example: Na+, 135; K+, 3.0; Cl-, 110; HCO3 -, 10; AG, 15; Paco2, 25; pH, 7.20 (diarrhea and lactic acidosis, toluene toxicity, treatment of diabetic ketoacidosis) Abbreviations: AG, anion gap; COPD, chronic obstructive pulmonary disease; ICU, intensive care unit.


InternalMed_Harrison

InternalMed_Harrison. pneumonia) leading to 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 normal or near normal. When the pH is normal, an elevated anion gap (AG; see below) reliably denotes the presence of an AG metabolic acidosis at a normal serum albumin of 4.5 g/dL. Assuming a normal AG of 10 mmol/L, a discrepancy in the ∆AG (prevailing minus normal AG) and the ∆HCO3 (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


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InternalMed_Harrison. 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:

InternalMed_Harrison. APPROACH TO THE PATIENT:


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InternalMed_Harrison. A stepwise approach to the diagnosis of acid-base disorders follows (Table 66-3). Care should be taken when measuring blood gases to obtain the arterial blood sample without using excessive heparin. Blood for electrolytes and arterial blood gases should be drawn simultaneously prior to therapy, because an increase in [HCO3 -] occurs with metabolic alkalosis and respiratory acidosis. Conversely, a decrease in [HCO3 -] occurs in metabolic acidosis and 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, a laboratory error may be present, or an error could have been made in calculating the [HCO3 -]. After verifying the blood


InternalMed_Harrison

InternalMed_Harrison. 2 mmol/L. If they do not, the values may not have been drawn simultaneously, a laboratory error may be present, or an error could have been made in calculating the [HCO3 -]. After verifying the blood acid-base values, the precise acid-base disorder can then be identified.


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InternalMed_Harrison. All evaluations of acid-base disorders should include a simple calculation of the AG; it represents those unmeasured anions in plasma (normally 8-10 mmol/L) and is calculated as follows: AG = Na+ – (Cl-+ HCO3 -). The unmeasured anions 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 1. Obtain arterial blood gas (ABG) and electrolytes simultaneously. 2. Compare [HCO3 -] on ABG and electrolytes to verify accuracy. 3. Calculate anion gap (AG). 4. Know four causes of high-AG acidosis (ketoacidosis, lactic acid acidosis, renal failure, and toxins). 5. Know two causes of hyperchloremic or nongap acidosis (bicarbonate loss from gastrointestinal tract, renal tubular acidosis). 6. Estimate compensatory response (Table 66-1). 7. Compare ∆AG and ∆HCO3 . 8. Compare change in [Cl-] with change in [Na+].


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InternalMed_Harrison. acidosis. An increase in the AG is most often due to an increase in unmeasured anions and, less commonly, is due to a decrease in unmeasured cations (calcium, magnesium, potassium). In addition, the AG may increase with an increase in anionic albumin, because of either increased albumin concentration or alkalosis, which alters albumin charge. 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 major plasma anion albumin concentration (nephrotic syndrome); (4) a decrease in the effective anionic charge on albumin by acidosis; or (5) hyperviscosity and severe hyperlipidemia, which can lead to an underestimation of sodium and chloride concentrations. A fall in serum albumin by 1 g/dL from the normal value (4.5 g/dL) decreases the AG by 2.5 meq/L. Know the common causes of a high-AG acidosis (Table


InternalMed_Harrison

InternalMed_Harrison. of sodium and chloride concentrations. A fall in serum albumin by 1 g/dL from the normal value (4.5 g/dL) decreases the AG by 2.5 meq/L. Know the common causes of a high-AG acidosis (Table 66-3).


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InternalMed_Harrison. In the face of a normal serum albumin, a high AG is usually due to 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 even if an additional acid-base disorder is superimposed to modify the [HCO3 -] independently. 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 66-3). Compare the change in [HCO3 -] (∆HCO3 -) and the change in the AG (∆AG).


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InternalMed_Harrison. 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 mM, arterial pH would fall to 7.40, [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 (∆ values) in the normal to prevailing patient values. In this example, the ∆HCO3 is 0 (25 25 mmol/L), but the ∆AG is 20 (30 – 10 mmol/L). Therefore, 20 mmol/L is unaccounted for in the ∆/∆ value (∆AG to ∆HCO3 -).


InternalMed_Harrison

InternalMed_Harrison. 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 (as in renal failure). Metabolic acidosis has profound effects on the respiratory, cardiac, and nervous systems. The fall in blood pH is accompanied by a char acteristic increase in ventilation, especially the tidal volume (Kussmaul respiration). Intrinsic cardiac contractility may be depressed, but ino tropic function can be normal because of catecholamine release. Both 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. There are two major categories of clinical metabolic acidosis: high-AG and non-AG, or hyperchloremic, acidosis (Table 66-3 and Table 66-4).


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InternalMed_Harrison. Table 66-4). Treatment of metabolic acidosis with alkali should be reserved for severe acidemia except when the patient has no “potential HCO3 -” in plasma. Potential [HCO3 -] can be estimated from the increment (∆) in the AG (∆AG = patient’s AG – 10). It must be determined if


InternalMed_Harrison

InternalMed_Harrison. CAuSES of HigH-Anion gAP METABoLiC ACiDoSiS the acid anion in plasma is metabolizable (i.e., β-hydroxybutyrate, acetoacetate, and lactate) or nonmetabolizable (anions that accumulate in chronic renal failure and after toxin ingestion). The latter requires return of renal function to replenish the [HCO3 -] deficit, a slow and often unpredictable process. Consequently, patients with a normal AG acidosis (hyperchloremic acidosis), a slightly elevated AG (mixed hyperchloremic and AG acidosis), or an AG attributable to a nonmetabolizable anion in the face of renal 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 -] into the 20–22 mmol/L range. Overcorrection must be avoided.


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InternalMed_Harrison. Controversy exists, however, 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 acidosis (pH <7.10) warrants the IV administration of 50–100 meq of NaHCO3, 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, but it is essential to monitor plasma electrolytes during the course of therapy, because the [K+] may decline as pH rises. The goal is to increase the [HCO3 -] to 10 meq/L and the pH to approximately 7.20, not to increase these values to normal. PART 2 Cardinal Manifestations and Presentation of Diseases APPROACH TO THE PATIENT:


InternalMed_Harrison

InternalMed_Harrison. 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 66-4). 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).


InternalMed_Harrison

InternalMed_Harrison. Lactic Acidosis 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, methanol, propylene glycol, isoniazid, and fructose). Unrecognized bowel ischemia or infarction in a patient with severe atherosclerosis or cardiac decompensation receiving vasopressors is a common cause of lactic acidosis. Pyroglutamic acidemia has been reported in critically ill patients receiving acetaminophen, which is associated with depletion of glutathione. d-Lactic acid acidosis, which may be associated with jejunoileal bypass, short bowel syndrome, or intestinal obstruction, is due to


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InternalMed_Harrison. acetaminophen, which is associated with depletion of glutathione. 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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InternalMed_Harrison. APPROACH TO THE PATIENT: The underlying condition that disrupts lactate metabolism must first be corrected; tissue perfusion must be restored when inadequate. Vasoconstrictors should be avoided, if possible, because they may worsen tissue perfusion. Alkali therapy is generally advocated for acute, severe acidemia (pH <7.15) to improve cardiac function and lactate use. However, NaHCO3 therapy may paradoxically depress cardiac performance and exacerbate acidosis by enhanc ing 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 over 30–40 min.


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InternalMed_Harrison. 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 because of central venoconstriction, especially in the oliguric patient. 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.


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InternalMed_Harrison. Ketoacidosis • dIABETIC kETOACIdOSIS (dkA) 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 ∆AG and ∆HCO3 is typically ∼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 < 7.1), and then in only limited amounts. Patients with DKA are typically volume depleted and require fluid resuscitation with isotonic saline. Volume overexpansion with IV fluid administration is


InternalMed_Harrison

InternalMed_Harrison. < 7.1), and then in only limited amounts. Patients with DKA are typically volume depleted and require fluid resuscitation with isotonic saline. Volume overexpansion with IV 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. 417 in more detail.


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InternalMed_Harrison. ALCOHOLIC kETOACIdOSIS (AkA) 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 ∆AG and ∆HCO3 -). 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 as the patient improves. The nitroprusside ketone reaction (Acetest) can detect acetoacetic acid but not


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InternalMed_Harrison. explains the common clinical observation of an increasingly positive nitroprusside reaction 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


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InternalMed_Harrison. AG and a discrepancy in the ∆AG/∆HCO3 relationship. 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 corrected. Hypophosphatemia usually 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. Drugand Toxin-Induced Acidosis • SALICYLATES (See also Chap. 472e) Salicylate intoxication in adults usually causes respiratory alkalosis or a mixture of high-AG metabolic acidosis and respiratory alkalosis. Only a portion of the AG is due to salicylates. Lactic acid production is also often increased.


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InternalMed_Harrison. Vigorous gastric lavage with isotonic saline (not NaHCO3) should be initiated immediately, followed by administration of activated charcoal per nasogastric tube. 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). While this form of therapy is straightforward in acidotic patients, a coexisting respiratory alkalosis may make this approach hazardous. Alkalemic patients should not receive NaHCO3. 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 HCO3 is not replaced. Hypokalemia should be anticipated with an alkaline diuresis and should be treated promptly and aggressively. Glucose-containing fluids should be administered because of the danger of hypoglycemia. Excessive insensible


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InternalMed_Harrison. be anticipated with an alkaline diuresis 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 dialysate.


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InternalMed_Harrison. ALCOHOLS 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, ethylene glycol, propylene glycol, methanol, and acetone. In this situation, the difference between the calculated osmolality and the measured


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InternalMed_Harrison. radiocontrast media, ethanol, isopropyl alcohol, ethylene glycol, 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 poison-associated AG acidosis. Three alcohols may cause fatal intoxications: ethylene glycol, methanol, and isopropyl alcohol. All cause an elevated osmolal gap, but only the first two cause a high-AG acidosis.


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InternalMed_Harrison. ETHYLENE gLYCOL (See also Chap. 472e) Ingestion of ethylene glycol (commonly used in antifreeze) leads to a metabolic acidosis and severe damage to the CNS, heart, lungs, and kidneys. The increased AG and osmolar gap are attributable to ethylene glycol 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. Diagnosis is facilitated by recognizing oxalate crystals in the urine, the presence of an osmolar gap in serum, and a high-AG acidosis. Although use of a Wood’s lamp to 319 visualize the fluorescent additive to commercial antifreeze in the urine of patients with ethylene glycol ingestion, this is rarely reproducible. The combination of a high AG and high osmolar gap in a patient suspected of ethylene glycol ingestion should be taken as evidence of ethylene glycol toxicity. Treatment should not be delayed while awaiting measurement of


InternalMed_Harrison

InternalMed_Harrison. high AG and high osmolar gap in a patient suspected of ethylene glycol ingestion should be taken as evidence of ethylene glycol toxicity. Treatment should not be delayed while awaiting measurement of ethylene glycol levels in this setting.


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InternalMed_Harrison. 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 ethylene glycol 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 ethylene glycol 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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InternalMed_Harrison. METHANOL (See also Chap. 472e) The ingestion of methanol (wood alcohol) causes metabolic acidosis, and its metabolites formaldehyde and formic acid cause severe optic nerve and CNS damage. 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. This is similar to that for ethylene glycol intoxication, including general supportive measures, fomepizole, and hemodialysis (as above).


InternalMed_Harrison

InternalMed_Harrison. This is similar to that for ethylene glycol intoxication, including general supportive measures, fomepizole, and hemodialysis (as above). PROPYLENE gLYCOL 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. Propylene glycol, like ethylene glycol 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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InternalMed_Harrison. ISOPROPYL ALCOHOL 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 from ethylene glycol and methanol in that the parent compound, not the metabolites, causes toxicity, and an AG acidosis is not present because acetone is rapidly excreted. Both isopropyl alcohol and acetone increase the osmolal 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.


InternalMed_Harrison

InternalMed_Harrison. Isopropanol alcohol toxicity is treated by watchful waiting and supportive therapy, IV fluids, pressors, ventilatory support if needed, and occasionally hemodialysis for prolonged coma, hemodynamic instability, or levels >400 mg/dL. 320 PYROgLUTAMIC ACId 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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InternalMed_Harrison. Renal Failure (See also Chap. 335) The hyperchloremic acidosis of moderate renal insufficiency is eventually converted to the high-AG acidosis of advanced renal failure. 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 is characterized, therefore, by a reduced rate of NH4+ production and excretion. The acid retained in chronic renal disease is buffered by alkaline salts from bone. Despite significant retention of acid (up to 20 mmol/d), the serum [HCO3 -] does not decrease further, indicating participation of buffers outside the extracellular compartment. Chronic metabolic acidosis results in significant loss of bone mass due to reduction in bone calcium carbonate. Chronic acidosis also increases urinary calcium excretion, proportional to cumulative acid retention.


InternalMed_Harrison

InternalMed_Harrison. Because of the association of renal failure acidosis with muscle catabolism and bone disease, both uremic acidosis and the hyperchloremic acidosis of renal failure require oral alkali replacement to maintain the [HCO3 -] >22 mmol/L. This can be accomplished with relatively modest amounts of alkali (1.0–1.5 mmol/kg body weight per day). Sodium citrate (Shohl’s solution) or NaHCO3 tablets (650-mg tablets contain 7.8 meq) are equally effective alkalinizing salts. Citrate enhances the absorption of aluminum from the gastrointestinal tract and should never be given together with aluminum-containing antacids because of the risk of aluminum intoxication. PART 2 Cardinal Manifestations and Presentation of Diseases


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InternalMed_Harrison. PART 2 Cardinal Manifestations and Presentation of Diseases Alkali can be lost from the gastrointestinal tract from diarrhea or from the kidneys (renal tubular acidosis, RTA). In these disorders (Table 66-5), 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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InternalMed_Harrison. In diarrhea, stools contain a higher [HCO3 -] and decomposed HCO3 than plasma so that metabolic acidosis develops along with volume depletion. 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 anion gap (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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InternalMed_Harrison. CAuSES of non–Anion gAP ACiDoSiS 1. Gastrointestinal bicarbonate loss A. Diarrhea B. External pancreatic or small-bowel drainage C. Ureterosigmoidostomy, jejunal loop, ileal loop D. Drugs 1. 2. 3. II. A. 1. Proximal RTA (type 2) Drug-induced: acetazolamide, topiramate 2. Distal (classic) RTA (type 1) Drug induced: amphotericin B, ifosfamide B. Hyperkalemia 1. Generalized distal nephron dysfunction (type 4 RTA) a. b. Mineralocorticoid resistance (PHA I, autosomal dominant) c. Voltage defect (PHA I, autosomal recessive, and PHA II) d. C. 1. Chronic progressive kidney disease III. A. Potassium-sparing diuretics (amiloride, triamterene, spironolactone, eplerenone) B. C. D. E. F. IV. A. Acid loads (ammonium chloride, hyperalimentation) B. Loss of potential bicarbonate: ketosis with ketone excretion C. D. E.


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InternalMed_Harrison. B. C. D. E. F. IV. A. Acid loads (ammonium chloride, hyperalimentation) B. Loss of potential bicarbonate: ketosis with ketone excretion C. D. E. Abbreviations: ACE-I, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; PHA, pseudohypoaldosteronism; RTA, renal tubular acidosis. Proximal RTA (type 2 RTA) (Chap. 339) is most often due to generalized proximal tubular dysfunction manifested by glycosuria, generalized aminoaciduria, and phosphaturia (Fanconi syndrome). With a low plasma [HCO3 -], the urine pH is acid (pH <5.5). The fractional excretion of [HCO3 -] may exceed 10–15% when the serum HCO3 - >20 mmol/L. Because HCO3 is not reabsorbed normally in the proximal tubule, therapy with NaHCO3 will enhance renal potassium wasting and hypokalemia.


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InternalMed_Harrison. The typical findings in acquired or inherited forms of classic distal RTA (type 1 RTA) include hypokalemia, 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 renal function may be compromised, for example, due to diabetic nephropathy, obstructive uropathy, or chronic tubulointerstitial disease.


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InternalMed_Harrison. Hyporeninemic hypoaldosteronism typically causes non-AG metabolic acidosis, most commonly in older adults with diabetes mellitus or tubulointerstitial disease and renal insufficiency. 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, and angiotensin-converting enzyme (ACE) inhibitors can also cause non-AG metabolic acidosis in patients with renal insufficiency (Table 66-5).


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InternalMed_Harrison. Metabolic alkalosis is manifested by an elevated arterial pH, an increase in the serum [HCO3 -], and an increase in Paco2 as a result of compensatory alveolar hypoventilation (Table 66-1). It is often accompanied by hypochloremia and hypokalemia. The arterial pH establishes the diagnosis, because it is increased in metabolic alkalosis and decreased or normal in respiratory acidosis. Metabolic alkalosis frequently occurs in association with other disorders such as respiratory acidosis or alkalosis or metabolic acidosis. Metabolic alkalosis occurs as a result of net gain of [HCO3 -] or loss of nonvolatile acid (usually HCl by vomiting) from the extracellular fluid.


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InternalMed_Harrison. For HCO3 to be added to the extracellular fluid, it must be administered exogenously or synthesized endogenously, in part or entirely by the kidneys. Because it is unusual for alkali to be added to the body, the disorder involves a generative stage, in which the loss of acid usually causes alkalosis, and a maintenance stage, in which the kidneys fail to compensate by excreting HCO3 . Maintenance of metabolic alkalosis represents a failure of the kid neys to eliminate HCO3 in the usual manner. 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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InternalMed_Harrison. To establish the cause of metabolic alkalosis (Table 66-6), it is necessary to assess the status of the extracellular fluid volume (ECFV), the recumbent and upright blood pressure, the serum [K+], and 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 urine [Na+] and [Cl-] in a patient who is not taking diuretics indicate a primary mineralocorticoid excess syndrome. 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. Determination of urine electrolytes (especially the urine [Cl-]) and screening of the urine for diuretics may be helpful. If the urine is alkaline, with an elevated [Na+] and [K+] but low [Cl-], the diagnosis is


InternalMed_Harrison

InternalMed_Harrison. of urine electrolytes (especially the urine [Cl-]) and screening of the urine for diuretics may be helpful. If the urine is alkaline, with an elevated [Na+] and [K+] but low [Cl-], 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 and hypomagnesemia in the latter disorder.


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InternalMed_Harrison. Alkali Administration Chronic administration of alkali to individuals with normal renal function rarely causes alkalosis. However, in patients with coexistent hemodynamic disturbances, alkalosis can develop because the normal capacity to excrete HCO3 may be exceeded or there may be enhanced reabsorption of HCO3 -. Such - patients include those who receive HCO3 (PO or IV), acetate loads CAuSES of METABoLiC ALKALoSiS I. Exogenous HCO3 -loads A. Acute alkali administration B. Milk-alkali syndrome II. Effective ECFV contraction, normotension, K+ deficiency, and secondary hyperreninemic hyperaldosteronism A. 1. 2. 3. 4. B. Renal origin 1. 2. 3. 4. 5. Nonreabsorbable anions including penicillin, carbenicillin 6. Mg2+ deficiency 7. 8. Bartter’s syndrome (loss of function mutations of transporters and ion channels in TALH) 9. Gitelman’s syndrome (loss of function mutation in Na+-Clcotransporter in DCT) III.


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InternalMed_Harrison. 8. Bartter’s syndrome (loss of function mutations of transporters and ion channels in TALH) 9. Gitelman’s syndrome (loss of function mutation in Na+-Clcotransporter in DCT) III. ECFV expansion, hypertension, K+ deficiency, and mineralocorticoid excess A. 1. 2. 3. 4. B. Low renin 1. Primary aldosteronism a. b. c. 2. Adrenal enzyme defects a. 11β-Hydroxylase deficiency b. 17α-Hydroxylase deficiency 3. 4. a. b. c. IV. Gain-of-function mutation of renal sodium channel with ECFV expansion, hypertension, K+ deficiency, and hyporeninemic-hypoaldosteronism A. Abbreviations: DCT, distal convoluted tubule; ECFV, extracellular fluid volume; TALH, thick ascending limb of Henle’s loop.


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InternalMed_Harrison. A. Abbreviations: DCT, distal convoluted tubule; ECFV, extracellular fluid volume; TALH, thick ascending limb of Henle’s loop. (parenteral hyperalimentation solutions), citrate loads (transfusions), or antacids plus cation-exchange resins (aluminum hydroxide and sodium polystyrene sulfonate). Nursing home patients receiving tube feedings have a higher incidence of metabolic alkalosis than nursing home patients receiving oral feedings. METABOLIC ALKALOSIS ASSOCIATED WITH ECFV CONTRACTION, K+ DEPLETION,


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InternalMed_Harrison. METABOLIC ALKALOSIS ASSOCIATED WITH ECFV CONTRACTION, K+ DEPLETION, AND SECONDARY HYPERRENINEMIC HYPERALDOSTERONISM gastrointestinal Origin Gastrointestinal loss of H+ from vomiting or gastric aspiration results in retention of HCO3 -. During active vomiting, the filtered load of bicarbonate is acutely increased to exceed the reabsorptive capacity of the proximal tubule for HCO3 so that the urine becomes alkaline and high in potassium. When vomiting ceases, the persistence of volume, potassium, and chloride depletion causes 322 maintenance of the alkalosis because of an enhanced capacity of the nephron to reabsorb HCO3 -. Correction of the contracted ECFV with NaCl and repair of K+ deficits corrects the acid-base disorder by restoring the ability of the kidney to excrete the excess bicarbonate.


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InternalMed_Harrison. Renal Origin • dIURETICS (See also Chap. 279) Drugs that induce chloruresis, such as thiazides and loop diuretics (furosemide, bumetanide, torsemide, and ethacrynic acid), acutely diminish the ECFV without altering the total body bicarbonate content. The serum [HCO3 -] increases because the reduced ECFV “contracts” the [HCO3 -] in the plasma (contraction alkalosis). The chronic administration of diuretics tends to generate an alkalosis by increasing distal salt delivery, so that 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). Repair of the alkalosis is achieved by providing isotonic saline to correct the ECFV deficit. SOLUTE LOSINg dISORdERS: BARTTER’S SYNdROME ANd gITELMAN’S SYNdROME See Chap. 339.


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InternalMed_Harrison. SOLUTE LOSINg dISORdERS: BARTTER’S SYNdROME ANd gITELMAN’S SYNdROME See Chap. 339. NONREABSORBABLE ANIONS ANd MAgNESIUM dEFICIENCY Administration of large quantities of nonreabsorbable anions, such as penicillin or carbenicillin, can enhance distal acidification and K+ secretion by increasing the transepithelial potential difference. Mg2+ deficiency results in hypokalemic alkalosis by enhancing distal acidification through stimulation of renin and hence aldosterone secretion. POTASSIUM dEPLETION Chronic K+ depletion may cause metabolic alkalosis by increasing urinary acid excretion. Both NH4+ production and absorption are enhanced and HCO3 reabsorption is stimulated. Chronic K+ deficiency 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.


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InternalMed_Harrison. AFTER TREATMENT OF LACTIC ACIdOSIS OR kETOACIdOSIS When an underlying stimulus for the generation of lactic acid or ketoacid is removed rapidly, as with repair of circulatory insufficiency or with insulin therapy, the lactate or ketones are metabolized to yield an equivalent amount of HCO3 -. Other sources of new HCO3 are additive with the original amount generated by organic anion metabolism to create a surfeit of HCO3 -. Such sources include (1) new HCO3 -added to the blood by the kidneys as a result of enhanced acid excretion during the preexisting period of acidosis, and (2) alkali therapy during the treatment phase of the acidosis. Acidosis-induced contraction of the ECFV and K+ deficiency act to sustain the alkalosis. POSTHYPERCAPNIA Prolonged CO2 retention with chronic respiratory acidosis enhances renal HCO3 absorption and the generation of new


InternalMed_Harrison

InternalMed_Harrison. POSTHYPERCAPNIA 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. METABOLIC ALKALOSIS ASSOCIATED WITH ECFV EXPANSION, HYPERTENSION, AND HYPERALDOSTERONISM 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 may be worsened by associated K+ deficiency. ECFV expansion from salt retention 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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InternalMed_Harrison. Liddle’s syndrome (Chap. 339) results from increased activity of the collecting duct Na+ channel (ENaC) and is a rare monogenic form of hypertension due to volume expansion manifested as hypokalemic alkalosis and normal aldosterone levels. Symptoms With metabolic alkalosis, changes in CNS and peripheral nervous system function are similar to those of hypocalcemia (Chap. 423); symptoms include mental confusion; obtundation; and PART 2 Cardinal Manifestations and Presentation of Diseases 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. This is primarily directed at correcting the underlying stimulus for


InternalMed_Harrison

InternalMed_Harrison. This is primarily directed at correcting the underlying stimulus for HCO3 generation. If primary aldosteronism, renal artery stenosis, or Cushing’s syndrome is present, correction of the underlying cause will reverse the 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 usually sufficient to reverse the alkalosis if ECFV contraction is present.


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InternalMed_Harrison. If associated conditions preclude infusion of saline, renal HCO3 loss can be accelerated by administration of acetazolamide, a carbonic anhydrase inhibitor, which is usually effective in patients with adequate renal function but can worsen K+ losses. Dilute hydrochloric acid (0.1 N HCl) is also effective but can cause hemolysis, and must be delivered slowly in a central vein. 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 66-7). In acute respiratory acidosis, there is an immediate 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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InternalMed_Harrison. 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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InternalMed_Harrison. 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 obesityhypoventilation syndromes (Chaps. 318 and 319). 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. 306e).


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InternalMed_Harrison. 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. 306e). Permissive hypercapnia is being used with increasing frequency because of studies suggesting lower mortality rates than with conventional mechanical ventilation, especially with severe CNS or heart disease. The respiratory acidosis associated with permissive hypercapnia may require administration of NaHCO3 to increase the arterial pH to 7.25, but overcorrection of the acidemia may be deleterious.


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InternalMed_Harrison. Acute hypercapnia follows sudden occlusion of the upper airway or generalized bronchospasm as in severe asthma, anaphylaxis, I. Alkalosis A. Central nervous system stimulation 1. 2. Anxiety, psychosis 3. 4. 5. Meningitis, encephalitis 6. 7. B. Hypoxemia or tissue hypoxia 1. 2. Pneumonia, pulmonary edema 3. 4. C. Drugs or hormones 1. Pregnancy, progesterone 2. 3. D. Stimulation of chest receptors 1. 2. 3. 4. E. Miscellaneous 1. 2. 3. 4. 5. II. A. 1. Drugs (anesthetics, morphine, sedatives) 2. 3. B. Airway 1. 2. C. Parenchyma 1. 2. 3. 4. 5. D. Neuromuscular 1. 2. 3. 4. E. Miscellaneous 1. 2. 3.


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InternalMed_Harrison. 2. 3. 4. 5. II. A. 1. Drugs (anesthetics, morphine, sedatives) 2. 3. B. Airway 1. 2. C. Parenchyma 1. 2. 3. 4. 5. D. Neuromuscular 1. 2. 3. 4. E. Miscellaneous 1. 2. 3. 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 extra-pulmonary restrictive defects present as chronic respiratory acidosis.


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InternalMed_Harrison. The diagnosis of respiratory acidosis requires the measurement of 323 Paco2 and arterial pH. A detailed history and physical examination often indicate the cause. Pulmonary function studies (Chap. 306e), 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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InternalMed_Harrison. 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. 314). When oxygen is used injudiciously, these patients may experience progression of the respiratory acidosis. 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


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InternalMed_Harrison. 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 Cland K+ to enhance the renal excretion of HCO3 .


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InternalMed_Harrison. Chronic respiratory acidosis is frequently difficult to correct, but measures aimed at improving lung function (Chap. 314) can help some patients and forestall further deterioration in most.


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InternalMed_Harrison. Alveolar hyperventilation decreases Paco2 and increases the HCO3 -/ Paco2 ratio, thus increasing pH (Table 66-7). 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


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InternalMed_Harrison. 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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InternalMed_Harrison. 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 PO42and reduces free [Ca2+] by increasing the protein-bound fraction. Hypocapnia-induced hypokalemia is usually


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InternalMed_Harrison. (Bohr effect). Acute respiratory alkalosis causes intracellular shifts of Na+, K+, and PO42and reduces free [Ca2+] by increasing the protein-bound fraction. Hypocapnia-induced hypokalemia is usually minor.


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InternalMed_Harrison. 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 324 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. 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


InternalMed_Harrison

InternalMed_Harrison. 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. 472e). 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


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InternalMed_Harrison. 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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InternalMed_Harrison. 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. Chronic hypocapnia reduces the serum [HCO3 -] by 4.0 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. 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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InternalMed_Harrison. 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. Kevin T. McVary