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901 | as important as the use of activated vitamin D. CALCIUM DEFICIENCY Pathophysiology Rickets secondary to inadequate dietary calcium is a significant problem in some countries in Africa, although there are cases in other regions of the world, including industrialized countries. Because breast milk and formula are excellent sources of calcium, this form of rickets develops after children have been weaned from breast milk or formula and is more likely to occur in children who are weaned early. Rickets develops because the diet has low calcium content, typically 200 mgday if 12 months old or 300 mgday if 12 months old. The child has minimal intake of dairy products or other sources of calcium. In addition, because of reliance on grains and green leafy vegetables, the diet may be high in phytate, oxalate, and phosphate, which decrease absorption of dietary calcium. In industrialized countries, rickets caused by calcium deficiency can occur in children who consume an unconventional diet. Examples include children with milk allergy who have low dietary calcium and children who transition from formula or breast milk to juice, soda, or a calcium poor soy drink, without an alternative source of dietary calcium. This type of rickets can develop in children who receive IV nutri tion without adequate calcium. Malabsorption of calcium can occur in celiac disease, intestinal abetalipoproteinemia, and after small bowel resection. There may be concurrent malabsorption of vitamin D. Clinical Manifestations Children with calcium deficiency have the classic signs and symp toms of rickets (see Table 69.3). Presentation can occur during infancy or early childhood, although some cases are diagnosed in teenagers. Because calcium deficiency occurs after the cessation of breastfeed ing, it tends to occur later than the nutritional vitamin D deficiency that is associated with breastfeeding. In Nigeria, nutritional vitamin D deficiency is most common at 4 15 months of age, whereas calcium deficiency rickets typically occurs at 15 25 months. Diagnosis Laboratory findings include increased levels of ALP, PTH, and 1,25 D (see Table 69.4). Calcium levels may be normal or low, although symp tomatic hypocalcemia is uncommon. There is decreased urinary excre tion of calcium, and serum phosphorus levels may be low as a result of renal wasting of phosphate from secondary hyperparathyroidism. In some children, there is coexisting nutritional vitamin D deficiency, with low 25 D levels. Treatment Treatment focuses on providing adequate calcium, typically as a dietary supplement (doses of 700 age 1 3 years, 1,000 4 8 years, Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 69 u Vitamin D Deficiency (Rickets) and Excess 477 and 1,300 9 18 years mgday of elemental calcium are effective). Vitamin D supplementation is necessary if there is concurrent vita min D deficiency (discussed earlier). Prevention strategies include discouraging early cessation of breastfeeding and increasing dietary sources of calcium. In countries such as Kenya, where many chil |
902 | dren have diets high in cereal with negligible intake of cows milk, school based milk programs have been effective in reducing the prevalence of rickets. PHOSPHORUS DEFICIENCY Inadequate Intake With the exception of starvation or severe anorexia, it is almost impossible to have a diet that is deficient in phosphorus, because phosphorus is present in most foods. Decreased phosphorus absorption can occur in diseases associated with malabsorption (celiac disease, cystic fibrosis, cholestatic liver disease), but if rick ets develops, the primary problem is usually malabsorption of vita min D andor calcium. Isolated malabsorption of phosphorus occurs in patients with long term use of aluminum containing antacids. These com pounds are very effective at chelating phosphate in the GI tract, leading to decreased absorption. This decreased absorption results in hypophosphatemia with secondary osteomalacia in adults and rickets in children. This entity responds to discontinuation of the antacid and short term phosphorus supplementation. Fibroblast Growth Factor 23 Fibroblast growth factor 23 (FGF 23) is a humoral mediator that decreases renal tubular reabsorption of phosphate and therefore decreases serum phosphorus. FGF 23, synthesized by osteocytes, also decreases the activity of renal 1 hydroxylase, resulting in a decrease in the production of 1,25 D. Increased levels of FGF 23 cause many of the renal phosphate wasting diseases (see Table 69.2). X Linked Hypophosphatemic Rickets Among the genetic disorders causing rickets because of hypophos phatemia, X linked hypophosphatemic rickets (XLH) is the most common, with a prevalence of 120,000. The defective gene is on the X chromosome, but female carriers are affected, so it is an X linked dominant disorder. Pathophysiology The pathologic variants are in a gene called PHEX because it is a phosphate regulating gene with homology to endopeptidases on the X chromosome. The product of this gene appears to have an indirect role in inactivating FGF 23. Thus pathologic variants in PHEX lead to increased levels of FGF 23. Because the actions of FGF 23 include inhi bition of phosphate reabsorption in the proximal tubule, phosphate excretion is increased. FGF 23 also inhibits renal 1 hydroxylase, lead ing to decreased production of 1,25 D. Clinical Manifestations These patients have rickets, but abnormalities of the lower extremities and poor growth are the dominant features. Delayed dentition and tooth abscesses are also common. Some patients have hypophosphate mia and short stature without clinically evident bone disease. Laboratory Findings Patients have high renal excretion of phosphate, hypophosphate mia, and increased ALP; PTH and serum calcium levels are normal (see Table 69.4). Hypophosphatemia normally upregulates renal 1 hydroxylase and should lead to an increase in 1,25 D, but these patients have low or inappropriately normal levels of 1,25 D. Treatment Burosumab is a monoclonal antibody to FGF 23 that is approved for treating XLH in children 1 year, although cost may limit its availabil ity in low resourced countries. Outcomes are better and side effects decreased when compared with conventional therapy. The dose of burosumab is titrated to normalize the serum phosphorus; it is contra indicated |
903 | in patients with severe renal impairment. Conventional treatment is a combination of oral phosphorus and 1,25 D (calcitriol). The daily need for phosphorus supplementation is 1 3 g of elemental phosphorus divided into four or five doses. Frequent dosing helps to prevent prolonged decrements in serum phosphorus because there is a rapid decline after each dose. In addi tion, frequent dosing decreases diarrhea, a complication of high dose oral phosphorus. Calcitriol is administered at 30 70 ngkgday in two doses. Complications of conventional treatment occur when there is not an adequate balance between phosphorus supplementation and cal citriol. Excess phosphorus, by decreasing enteral calcium absorption, leads to secondary hyperparathyroidism, with worsening of the bone lesions. In contrast, excess calcitriol causes hypercalciuria and neph rocalcinosis and can even cause hypercalcemia. Therefore laboratory monitoring of treatment includes serum calcium, phosphorus, ALP, PTH, and urinary calcium, as well as periodic renal ultrasound to evaluate patients for nephrocalcinosis. Because of variation in the serum phosphorus level and the importance of avoiding excessive phosphorus dosing, normalization of ALP levels is a more useful method of assessing the therapeutic response than measuring serum phosphorus. For children with significant short stature, growth hor mone is an effective option. Children with severe deformities might need osteotomies, but these procedures should be done only when treatment has led to resolution of the bone disease. Prognosis The response to therapy is usually good, although frequent dosing can lead to problems with compliance with conventional therapy. Girls generally have less severe disease than boys, probably because of the X linked inheritance. Short stature can persist despite healing of the rickets. Adults generally do well with less aggressive treatment, and options include burosumab, conventional treatment, and no treatment. Adults with bone pain, poorly healing fractures, or other symptoms improve with treatment. Autosomal Dominant Hypophosphatemic Rickets Autosomal dominant hypophosphatemic rickets (ADHR) is much less common than XLH. There is incomplete penetrance and vari able age of onset. Patients with ADHR have a pathologic variant in the gene encoding FGF 23 (FGF23). The pathologic variant prevents degradation of FGF 23 by proteases, leading its level to increase. The actions of FGF 23 include decreased reabsorption of phosphate in the renal proximal tubule, which results in hypophos phatemia, and inhibition of 1 hydroxylase in the kidney, causing a decrease in 1,25 D synthesis. In ADHR, as in XLH, abnormal laboratory findings are hypophospha temia, elevated ALP level, and a low or inappropriately normal 1,25 D level (see Table 69.4). Treatment is similar to the conventional approach with phosphate supplementation and calcitriol used in XLH. However, iron deficiency, which upregulates FGF 23 synthesis, should be corrected if present. Autosomal Recessive Hypophosphatemic Rickets Autosomal recessive hypophosphatemic rickets (ARHR) type 1 is an extremely rare disorder caused by pathologic variants in the DMP1 gene. ARHR type 2 occurs in patients with pathologic variants in ENPP1. Pathologic variants in ENPP1 also cause generalized arterial calcification of infancy. Raine syndrome, also called ARHR type 3, is an autosomal recessive disorder |
904 | caused by pathologic variants in FAM20C and is an osteosclerotic bone dysplasia that is often fatal in the neonatal period. However, patients who survive into childhood may develop rickets. The three types of ARHR are associated with elevated levels of FGF 23, leading to renal phosphate wasting, hypophosphatemia, and low or inappropriately normal levels of 1,25 D. Treatment is similar to the approach used in XLH, although monitoring for arterial calcification is prudent in patients with ENPP1 pathologic variants. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 478 Part V u Nutrition Hereditary Hypophosphatemic Rickets with Hypercalciuria Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare disorder that is mainly found in the Middle East. Pathophysiology This autosomal recessive disorder is caused by pathologic variants in the gene for a sodium phosphate co transporter in the proximal tubule (SLC34A3). The renal phosphate leak causes hypophospha temia, which then stimulates production of 1,25 D. The high level of 1,25 D increases intestinal absorption of calcium, suppressing PTH. Hypercalciuria ensues as a result of the high absorption of calcium and the low level of PTH, which normally decreases renal excretion of calcium. Clinical Manifestations The dominant symptoms of HHRH are rachitic leg abnormalities (see Table 69.3), muscle weakness, and bone pain. Patients can have short stature, with a disproportionate decrease in the length of the lower extremities. The severity of the disease varies, and some fam ily members have no evidence of rickets but have kidney stones sec ondary to hypercalciuria. Laboratory Findings Laboratory findings include hypophosphatemia, renal phosphate wast ing, elevated serum ALP levels, and elevated 1,25 D levels. PTH levels are low (see Table 69.4). Treatment Therapy for HHRH patients relies on oral phosphorus replacement (1 2.5 gday of elemental phosphorus in five divided doses). Treat ment of the hypophosphatemia decreases serum levels of 1,25 D and corrects the hypercalciuria. The response to therapy is usually excellent, with resolution of pain, weakness, and radiographic evi dence of rickets. Hypophosphatemic Rickets with Nephrolithiasis and Osteoporosis Types 1 and 2 Hypophosphatemic rickets with nephrolithiasis and osteoporosis type 1 is an autosomal recessive disorder caused by pathologic variants of SL34A1, which encodes a phosphate transporter in the proximal tubule. Pathologic variants in the same gene can also cause Fanconi syndrome and infantile hypercalcemia. Hypophosphatemic rickets with nephrolithiasis and osteoporosis type 2 is an autosomal dominant disorder resulting from pathologic variants in SLC9A3R1 that cause renal phosphate wasting. Laboratory findings and treatment for these disorders are similar to HHRH, with the exception of the features of Fanconi syndrome (see later and Chapter 569) in some patients with the type 1 disorder. Overproduction of FGF 23 Tumor induced osteomalacia is more common in adults; in children it can produce classic rachitic findings. Most tumors are mesenchymal in origin and are usually benign, small, and located in bone. These tumors |
905 | secrete FGF 23 and produce a biochemical phenotype similar to XLH, including urinary phosphate wasting, hypophosphatemia, ele vated ALP levels, and low or inappropriately normal 1,25 D levels (see Table 69.4). Curative treatment is excision of the tumor. If the tumor cannot be removed, treatment is identical to that for XLH, including use of burosumab. Renal phosphate wasting leading to hypophosphatemia and rickets (or osteomalacia in adults) is a potential complication in McCune Albright syndrome, an entity that includes the triad of polyostotic fibrous dysplasia, hyperpigmented macules, and poly endocrinopathy (see Chapter 600.06). Affected patients have inap propriately low levels of 1,25 D and elevated ALP levels. The renal phosphate wasting and inhibition of 1,25 D synthesis are related to the polyostotic fibrous dysplasia. Patients have elevated FGF 23, presumably caused by the dysplastic bone. Hypophosphatemic rickets can also occur in children with isolated polyostotic fibrous dysplasia. Although it is rarely possible, removal of the abnormal bone can cure this disorder in children with McCune Albright syn drome. Most patients receive the same conventional treatment as children with XLH, with case reports describing off label treatment with burosumab. Bisphosphonate treatment decreases the pain and fracture risk associated with the bone lesions. Rickets is an unusual complication of epidermal nevus syn drome, which is caused by somatic pathologic variants (Ras family of genes and others). It is called cutaneous skeletal hypophospha temia syndrome when associated with hypophosphatemic rickets or osteomalacia (see Chapter 692). Excessive production of FGF 23 causes renal phosphate wasting and an inappropriately normal or low level of 1,25 D. The timing of presentation with rickets var ies from infancy to early adolescence. Hypophosphatemia and rickets have resolved after excision of the epidermal nevi in some patients, but not in others. In most the skin lesions are too extensive to be removed, necessitating treatment with phosphorus supple mentation and 1,25 D. Rickets caused by phosphate wasting is an extremely rare complication in children with neurofibromatosis (see Chapter 636.1). Fanconi Syndrome Fanconi syndrome is secondary to generalized dysfunction of the renal proximal tubule (see Chapter 569.1). There are renal losses of phosphate, amino acids, bicarbonate, glucose, urate, and other mol ecules that are normally reabsorbed in the proximal tubule. Some patients have partial dysfunction, with less generalized losses. The most clinically relevant consequences are hypophosphatemia caused by phosphate losses and proximal renal tubular acidosis caused by bicarbonate losses. Patients have rickets as a result of hypophospha temia, with exacerbation from the chronic metabolic acidosis, which causes bone dissolution. Failure to thrive is a consequence of both rickets and renal tubular acidosis. Treatment is dictated by the etiol ogy (see Chapter 569). Dent Disease Dent disease is an X linked disorder usually caused by pathologic variants in the gene encoding a chloride channel expressed in the kidney (CLCN5). Some patients have pathologic variants in the OCRL1 gene, which can also cause Lowe syndrome (see Chapter 571.3). Affected males have variable manifestations, including hematuria, nephrolithiasis, nephrocalcinosis, rickets, and chronic kidney disease. Almost |
906 | all patients have low molecular weight pro teinuria and hypercalciuria. Other, less universal abnormalities are aminoaciduria, glycosuria, hypophosphatemia, and hypokalemia. Rickets occurs in approximately 25 of patients, and it responds to oral phosphorus supplements. Some patients also need 1,25 D, but this treatment should be used cautiously because it can worsen the hypercalciuria. RICKETS OF PREMATURITY Rickets in very low birthweight infants has become a significant prob lem as the survival rate for this group of infants has increased (see Chapter 119.2). Pathogenesis The transfer of calcium and phosphorus from mother to fetus occurs throughout pregnancy, but 80 occurs during the third tri mester. Premature birth interrupts this process, with rickets devel oping when the premature infant does not have an adequate supply of calcium and phosphorus to support mineralization of the grow ing skeleton. Most cases of rickets of prematurity occur in infants with a birth weight 1,000 g. It is more likely to develop in infants with lower Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 69 u Vitamin D Deficiency (Rickets) and Excess 479 birthweight and younger gestational age. Rickets occurs because unsupplemented breast milk and standard infant formula do not contain enough calcium and phosphorus to supply the needs of the premature infant. Other risk factors include cholestatic jaundice, a complicated neonatal course, prolonged use of parenteral nutri tion, the use of soy formula, and medications such as diuretics and corticosteroids. Clinical Manifestations Rickets of prematurity occurs 1 4 months after birth. Infants can have nontraumatic fractures, especially of the legs, arms, and ribs. Most fractures are not suspected clinically. Because fractures and softening of the ribs lead to decreased chest compliance, some infants have respiratory distress from atelectasis and poor ventila tion. This rachitic respiratory distress usually develops 5 weeks after birth, distinguishing it from the early onset respiratory dis ease of premature infants. These infants have poor linear growth, with negative effects on growth persisting beyond 1 year of age. An additional long term effect is enamel hypoplasia. Poor bone min eralization can contribute to dolichocephaly. There may be classic rachitic findings, such as frontal bossing, rachitic rosary (see Fig. 69.1), craniotabes, and widened wrists and ankles (see Table 69.3). Most infants with rickets of prematurity have no clinical manifesta tions, and the diagnosis is based on radiographic and laboratory findings. Laboratory Findings Because of inadequate intake, the serum phosphorus level is low or low normal in patients with rickets of prematurity. The renal response is appropriate, with conservation of phosphate leading to a low urine phosphate level; tubular reabsorption of phosphate is 95. Most patients have normal levels of 25 D unless there has been inadequate intake or poor absorption (discussed earlier). The hypophosphatemia stimulates renal 1 hydroxylase, so levels of 1,25 D are high or high normal. These high levels can contribute to bone demineralization |
907 | because 1,25 D stimulates bone resorp tion. Serum levels of calcium are low, normal, or high, and patients often have hypercalciuria. Elevated serum calcium levels and hyper calciuria are secondary to increased intestinal absorption and bone dissolution caused by elevated 1,25 D levels and inability to deposit calcium in bone because of an inadequate phosphorus supply. The hypercalciuria indicates that phosphorus is the limiting nutrient for bone mineralization, although increased provision of phospho rus alone often cannot correct the mineralization defect; increased calcium is also necessary. Thus there is an inadequate supply of cal cium and phosphorus, but the deficiency in phosphorus is greater. Alkaline phosphatase levels are often elevated, but some affected infants have normal levels. In some cases, normal ALP levels may be secondary to resolution of the bone demineralization because of an adequate mineral supply despite the continued presence of radiologic changes, which take longer to resolve. However, ALP lev els may be normal despite active disease. No single blood test is 100 sensitive for the diagnosis of rickets. The diagnosis should be suspected in infants with ALP 5 6 times the upper limit of nor mal (UL) for adults (unless there is concomitant liver disease) or phosphorus 5.6 mgdL. The diagnosis is confirmed by radiologic evidence of rickets, which is best seen on radiographs of the wrists and ankles. Films of the arms and legs might reveal fractures. The rachitic rosary may be visible on chest radiograph. Unfortunately, radiographs cannot show early demineralization of bone because changes are not evident until there is 2030 reduction in the bone mineral content. Diagnosis Because many premature infants have no overt clinical manifestations of rickets, screening tests are recommended. These tests should include weekly measurements of calcium, phosphorus, and ALP. Periodic mea surement of the serum bicarbonate concentration is also important because metabolic acidosis causes dissolution of bone. At least one screening radiograph for rickets at 6 8 weeks of age is appropriate in infants who are at high risk for it; additional films may be indicated in high risk infants. Prevention Provision of adequate amounts of calcium, phosphorus, and vita min D significantly decreases the risk of rickets of prematurity. Parenteral nutrition is often necessary initially in very premature infants. In the past, adequate parenteral calcium and phosphorus delivery was difficult because of limits secondary to insolubility of these ions when their concentrations were increased. Current amino acid preparations allow higher concentrations of calcium and phos phate, decreasing the risk of rickets. Early transition to enteral feed ings is also helpful. These infants should receive either human milk fortified with calcium and phosphorus or preterm infant formula, which has higher concentrations of calcium and phosphorus than standard formula. Soy formula should be avoided because there is decreased bioavailability of calcium and phosphorus. Increased mineral feedings should continue until the infant weighs 3 3.5 kg. These infants should also receive approximately 400 IUday of vita min D through formula and vitamin supplements. Treatment Therapy for rickets of prematurity focuses |
908 | on ensuring adequate deliv ery of calcium, phosphorus, and vitamin D. If mineral delivery has been good and there is no evidence of healing, it is important to screen for vitamin D deficiency by measuring serum 25 D. Measurement of PTH, 1,25 D, and urinary calcium and phosphorus may be helpful in some cases. DISTAL RENAL TUBULAR ACIDOSIS Distal renal tubular acidosis usually manifests with failure to thrive. Patients have a metabolic acidosis with an inability to acidify the urine appropriately. Hypercalciuria and nephrocalcinosis are typically pres ent. The many etiologies include autosomal recessive and autosomal dominant forms. Rickets is variable and responds to alkali therapy (see Fig. 69.5 and Chapter 569.2). HYPERVITAMINOSIS D Etiology Hypervitaminosis D is caused by excessive intake of vitamin D. It can occur with long term high intake or with a substantial, acute ingestion (see Table 69.1). Most cases are secondary to misuse of prescribed or nonprescription vitamin D supplements, but other cases have been secondary to accidental overfortification of milk, contamination of table sugar, and inadvertent use of vitamin D sup plements as cooking oil. The recommended upper limits for long term vitamin D intake are 1,000 IU for children 1 year old and 2,000 IU for older children and adults. Hypervitaminosis D can also result from excessive intake of syn thetic vitamin D analogs (25 D, 1,25 D). Vitamin D intoxication is never secondary to excessive exposure to sunlight, probably because ultraviolet irradiation can transform vitamin D3 and its precursor into inactive metabolites. Pathogenesis Although vitamin D increases intestinal absorption of calcium, the dominant mechanism of the hypercalcemia is excessive bone resorption. Clinical Manifestations The signs and symptoms of vitamin D intoxication are second ary to hypercalcemia. GI manifestations include nausea, vomit ing, poor feeding, constipation, abdominal pain, and pancreatitis. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 480 Part V u Nutrition Possible cardiac findings are hypertension, decreased QT interval, and arrhythmias. The central nervous system effects of hypercalce mia include lethargy, hypotonia, confusion, disorientation, depres sion, psychosis, hallucinations, and coma. Hypercalcemia impairs renal concentrating mechanisms, which can lead to polyuria, dehy dration, and hypernatremia. Hypercalcemia can also lead to acute kidney injury, nephrolithiasis, and nephrocalcinosis, which can result in chronic kidney disease. Deaths are usually associated with arrhythmias or dehydration. Laboratory Findings The classic findings in vitamin D intoxication are hypercalce mia, elevated levels of 25 D (100 ngmL), hypercalciuria, and suppressed PTH. Hyperphosphatemia is also common. Hyper calciuria can lead to nephrocalcinosis, which is visible on renal ultrasound. Hypercalcemia and nephrocalcinosis can lead to renal insufficiency. Surprisingly, levels of 1,25 D are usually normal. This may result from downregulation of renal 1 hydroxylase by the combination of low PTH, hyperphosphatemia, and a direct effect of 1,25 D. The level of free 1,25 D may be high because of displacement from vitamin Dbinding proteins by |
909 | 25 D. Anemia is sometimes present; the mechanism is unknown. Diagnosis and Differential Diagnosis The diagnosis is based on the presence of hypercalcemia and an ele vated serum 25 D level, although children with excess intake of 1,25 D or another synthetic vitamin D preparation have normal levels of 25 D. With careful sleuthing, there is usually a history of excess intake of vitamin D, although in some situations (overfortification of milk by a dairy), the patient and family may be unaware. The differential diagnosis of vitamin D intoxication focuses on other causes of hypercalcemia. Hyperparathyroidism produces hypophospha temia, whereas vitamin D intoxication usually causes hyperphosphate mia. Williams syndrome is often suggested by phenotypic features and accompanying cardiac disease. Idiopathic infantile hypercalcemia occurs in children taking appropriate doses of vitamin D. Subcutaneous fat necro sis is a common cause of hypercalcemia in young infants; skin findings are usually present. The hypercalcemia of familial benign hypocalciuric hypercalcemia is mild, asymptomatic, and associated with hypocalciuria. Hypercalcemia of malignancy is an important consideration. Hypercalce mia may occur on a ketogenic diet. High intake of calcium can also cause hypercalcemia, especially in the presence of renal insufficiency. Inquiring about calcium intake should be part of the history in a patient with hyper calcemia. Occasionally, patients are intentionally taking high doses of cal cium and vitamin D. Treatment The treatment of vitamin D intoxication focuses on control of hypercal cemia. Many patients with hypercalcemia are dehydrated as a result of polyuria from nephrogenic diabetes insipidus, poor oral intake, and vom iting. Rehydration lowers the serum calcium level by dilution and corrects prerenal azotemia. The resultant increased urine output increases urinary calcium excretion. Urinary calcium excretion is also increased by high urinary sodium excretion. The mainstay of the initial treatment is aggres sive therapy with normal saline, often in conjunction with a loop diuretic to further increase calcium excretion; this is often adequate for treating mild or moderate hypercalcemia. More significant hypercalcemia usually requires other therapies. Glucocorticoids decrease intestinal absorption of calcium by blocking the action of 1,25 D. There is also a decrease in the lev els of 25 D and 1,25 D. The usual dosage of prednisone is 1 2 mgkg24 hr. Calcitonin, which lowers calcium by inhibiting bone resorption, is a useful adjunct, but its effect is usually not dramatic. There is an excellent response to IV or oral bisphosphonates in vitamin D intoxication. Bisphosphonates inhibit bone resorption through their effects on osteoclasts. Hemodialysis using a low or zero dial ysate calcium can rapidly lower serum calcium in patients with severe hypercalcemia that is refractory to other measures. Vitamin E is a fat soluble vitamin and functions as an antioxidant, but its precise biochemical functions are not known. Vitamin E deficiency can cause hemolysis or neurologic manifestations and occurs in pre mature infants, in patients with malabsorption, and in an autosomal recessive disorder affecting vitamin E transport. Because of its role as an antioxidant, there is considerable research on vitamin E supplemen tation |
910 | in chronic illnesses. PATHOGENESIS The term vitamin E denotes a group of 8 compounds with simi lar structures and antioxidant activity. The most potent member of these compounds is tocopherol, which is also the main form in humans. The best dietary sources of vitamin E are vegetable oils, seeds, nuts, green leafy vegetables, and margarine (see Table 69.1). The majority of vitamin E is located within cell membranes, where it prevents lipid peroxidation and the formation of free radicals. Other antioxidants, such as ascorbic acid, enhance the antioxidant activity of vitamin E. The importance of other functions of vitamin E is still being delineated. Premature infants are particularly susceptible to vitamin E defi ciency because there is significant transfer of vitamin E during the last trimester of pregnancy. Vitamin E deficiency in premature infants causes thrombocytosis, edema, and hemolysis, potentially causing anemia. The risk of symptomatic vitamin E deficiency was increased by the use of formulas for premature infants that had a high content of polyunsaturated fatty acids (PUFAs). These formu las led to a high content of PUFAs in red blood cell membranes, making them more susceptible to oxidative stress, which could be ameliorated by vitamin E. Oxidative stress was augmented by aggressive use of iron supplementation; iron increases the produc tion of oxygen radicals. The incidence of hemolysis as a result of vitamin E deficiency in premature infants decreased secondary to the use of formulas with a lower content of PUFAs, less aggressive use of iron, and provision of adequate vitamin E. Because vitamin E is plentiful in common foods, primary dietary deficiency is rare except in premature infants and in severe, general ized malnutrition. Vitamin E deficiency does occur in children with fat malabsorption secondary to the bile acid needed for vitamin E absorption. Although symptomatic disease is most common in children with cholestatic liver disease, it can occur in patients with Chapter 70 Vitamin E Deficiency Larry A. Greenbaum Along with controlling hypercalcemia, it is imperative to eliminate the source of excess vitamin D. Additional sources of vitamin D such as multivitamins and fortified foods should be eliminated or reduced. Avoidance of sun exposure, including the use of sunscreen, is prudent. The patient should also restrict calcium intake. Prognosis Most children make a full recovery, but hypervitaminosis D may be fatal or can lead to chronic kidney disease. Because vitamin D is stored in fat, levels can remain elevated for months, necessitating regular monitoring of 25 D, serum calcium, and urine calcium. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 71 u Vitamin K Deficiency 481 cystic fibrosis, celiac disease, short bowel syndrome, and Crohn disease. The autosomal recessive disorder abetalipoproteinemia causes fat malabsorption, and vitamin E deficiency is a common complication (see Chapter 106). In ataxia with isolated vitamin E deficiency |
911 | (AVED), a rare auto somal recessive disorder, there are pathologic variants in TTPA, the gene for tocopherol transfer protein. Patients with this disorder are unable to incorporate vitamin E into lipoproteins before their release from the liver, leading to reduced serum levels of vitamin E. There is no associated fat malabsorption, and absorption of vitamin E from the intestine occurs normally. CLINICAL MANIFESTATIONS A severe, progressive neurologic disorder occurs in patients with prolonged vitamin E deficiency. Clinical manifestations do not appear until after 1 year of age, even in children with cholestasis since birth. Patients may have cerebellar disease, posterior col umn dysfunction, and retinal disease. Loss of deep tendon reflexes is usually the initial finding. Subsequent manifestations include limb ataxia (intention tremor, dysdiadochokinesia), truncal ataxia (wide based, unsteady gait), dysarthria, ophthalmoplegia (limited upward gaze), nystagmus, decreased proprioception (positive Rom berg test), decreased vibratory sensation, and dysarthria. Some patients have pigmentary retinopathy. Visual field constriction can progress to blindness. Cognition and behavior can also be affected. Myopathy and cardiac arrhythmias are less common findings. In premature infants, hemolysis as a result of vitamin E deficiency typically develops during the second month of life. Edema may also be present. LABORATORY FINDINGS Serum vitamin E levels increase in the presence of high serum lipid levels, even when vitamin E deficiency is present. Therefore vita min E status is best determined by measuring the ratio of vitamin E to serum lipids; a ratio 0.8 mgg is abnormal in older children and adults; 0.6 mgg is abnormal in infants 1 year. Premature infants with hemolysis caused by vitamin E deficiency also often have elevated platelet counts. Neurologic involvement can cause abnormal somatosensory evoked potentials and nerve conduction studies. Abnormalities on electroreti nography can precede physical examination findings in patients with retinal involvement. DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS Premature infants with unexplained hemolytic anemia after the first month of life, especially if thrombocytosis is present, either should be empirically treated with vitamin E or should have serum vitamin E and lipid levels measured. Children with neurologic findings and a disease that causes fat malabsorption should have their vitamin E sta tus evaluated. Because children with AVED do not have symptoms of malabsorp tion, a correct diagnosis requires a high index of suspicion. Friedreich ataxia has been misdiagnosed in some patients (see Chapter 637.1). Children with unexplained ataxia should be screened for vitamin E deficiency. TREATMENT For correction of deficiency in neonates, the dose of vitamin E is 25 50 unitsday for 1 week, followed by adequate dietary intake. Children with deficiency as a result of malabsorption should receive 1 unitkgday, with the dose adjusted based on levels; ongoing treat ment is necessary. Children with AVED normalize their serum vitamin E levels with high doses of vitamin E and require ongoing treatment. PROGNOSIS The hemolytic anemia in infants resolves with correction of the vitamin E deficiency. Some neurologic manifestations of vitamin E Vitamin K is necessary for the synthesis of clotting factors II, VII, IX, and X; |
912 | deficiency of vitamin K can result in clinically significant bleed ing. Vitamin K deficiency typically affects infants, who experience a transient deficiency related to inadequate intake, or patients of any age who have decreased vitamin K absorption. Mild vitamin K deficiency can affect long term bone and vascular health (see Chapters 142 and 529). PATHOGENESIS Vitamin K is a group of compounds that have a common naph thoquinone ring structure (see Table 69.1). Phylloquinone, called vitamin K1, is present in a variety of dietary sources, with green leafy vegetables, liver, and certain legumes and plant oils having the highest content. Vitamin K1 is the form used to fortify foods and as a medication in the United States. Vitamin K2 is a group of compounds called menaquinones, which are produced by intesti nal bacteria. There is uncertainty regarding the relative importance of intestinally produced vitamin K2. Menaquinones are also present in meat, especially liver, and cheese. A menaquinone is used phar macologically in some countries. Vitamin K is a cofactor for glutamyl carboxylase, an enzyme that performs posttranslational carboxylation, converting gluta mate residues in proteins to carboxyglutamate (Gla). The Gla residues, by facilitating calcium binding, are necessary for protein function. The classic Gla containing proteins involved in blood coagula tion that are decreased in vitamin K deficiency are factors II (pro thrombin), VII, IX, and X. Vitamin K deficiency causes a decrease in proteins C and S, which inhibit blood coagulation, and pro tein Z, which also has a role in coagulation. All these proteins are made only in the liver, except for protein S, a product of various tissues. Gla containing proteins are also involved in bone biology (osteo calcin and protein S) and vascular biology (matrix Gla protein and protein S). Based on the presence of reduced levels of Gla, these pro teins appear more sensitive than the coagulation proteins to subtle vitamin K deficiency. Evidence suggests that mild vitamin K defi ciency might have a deleterious effect on long term bone strength and vascular health. Because it is fat soluble, vitamin K requires the presence of bile salts for its absorption. Unlike other fat soluble vitamins, there are Chapter 71 Vitamin K Deficiency Larry A. Greenbaum deficiency may be reversible with early treatment, but many patients have little or no improvement. Importantly, treatment prevents progression. PREVENTION Premature infants should receive sufficient vitamin E through for mula or breast milk fortifier and formula without a high content of PUFAs. Children at risk for vitamin E deficiency as a result of mal absorption should be screened for deficiency and given adequate vitamin E supplementation. Vitamin preparations with high con tent of all the fat soluble vitamins are available. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 482 Part V u Nutrition limited body stores of vitamin K. |
913 | In addition, there is high turnover of vitamin K, and the vitamin Kdependent clotting factors have a short half life. Thus symptomatic vitamin K deficiency can develop within weeks when there is inadequate supply because of low intake or malabsorption. There are three forms of vitamin K deficiency bleeding (VKDB) of the newborn (see Chapter 142). Early VKDB was formerly called classic hemorrhagic disease of the newborn and occurs at 1 14 days of age. Early VKDB is secondary to low stores of vitamin K at birth as a result of the poor transfer of vitamin K across the placenta and inadequate intake during the first few days of life. In addition, there is no intestinal synthesis of vitamin K2 because the newborn gut is sterile. Early VKDB occurs mostly in breastfed infants as a con sequence of the low vitamin K content of breast milk (formula is fortified). Delayed feeding is an additional risk factor. Late VKDB most often occurs at 2 12 weeks of age, although cases can occur up to 6 months after birth. Almost all cases are in breastfed infants because of the low vitamin K content of breast milk. An additional risk factor is occult malabsorption of vitamin K, as occurs in children with undiagnosed cystic fibrosis or chole static liver disease (e.g., biliary atresia, 1 antitrypsin deficiency). Without vitamin K prophylaxis, the incidence is 4 10 per 100,000 newborns. The third form of VKDB of the newborn occurs at birth or shortly thereafter. It is secondary to maternal intake of medications (warfarin, phenobarbital, phenytoin) that cross the placenta and interfere with vitamin K function. VKDB as a result of fat malabsorption can occur in children of any age. Potential etiologies include cholestatic liver disease, pancreatic disease, and intestinal disorders (celiac sprue, inflammatory bowel dis ease, short bowel syndrome). Prolonged diarrhea can cause vitamin K deficiency, especially in breastfed infants. Children with cystic fibrosis are most likely to have vitamin K deficiency if they have pancreatic insufficiency and liver disease. Beyond infancy, low dietary intake by itself never causes vitamin K deficiency. However, the combination of poor intake and the use of broad spectrum antibiotics that eliminate the intestines vitamin K2producing bacteria can cause vitamin K deficiency. This sce nario is especially common in the intensive care unit. Vitamin K deficiency can also occur in patients who receive total parenteral nutrition (TPN) without vitamin K supplementation. CLINICAL MANIFESTATIONS In early VKDB, the most common sites of bleeding are the gas trointestinal (GI) tract, mucosal and cutaneous tissue, umbilical stump, and the postcircumcision site; intracranial bleeding is less common. GI blood loss can be severe enough to require a transfu sion. In contrast, the most common site of bleeding in late VKDB is intracranial, although cutaneous and GI bleeding may be the initial manifestation. Intracranial bleeding can cause convulsions, permanent neurologic sequelae, or death. In some patients with late VKDB, the presence of an underlying disorder may be suggested by jaundice or failure to thrive (malnutrition). |
914 | Older children with vitamin K deficiency can present with bruising, mucocutaneous bleeding, or more serious bleeding. Laboratory Findings In patients with bleeding as a result of vitamin K deficiency, the prothrombin time (PT) is prolonged. The PT must be interpreted based on the patients age because it is normally prolonged in new borns (see Chapters 142 and 524). The partial thromboplastin time (PTT) is usually prolonged, but may be normal in early deficiency. Factor VII has the shortest half life of the coagulation factors and is the first to be affected by vitamin K deficiency, but isolated factor VII deficiency does not affect PTT. The platelet count and fibrino gen level are normal. When there is mild vitamin K deficiency, the PT is normal, but there are elevated levels of the undercarboxylated forms of the proteins that are normally carboxylated in the presence of vitamin K. These undercarboxylated proteins are called proteins induced by vitamin K absence (PIVKA). Measurement of undercarboxyl ated factor II (PIVKA II) can be used to detect mild vitamin K deficiency. Determination of blood vitamin K levels is less useful because of significant variation based on recent dietary intake; lev els do not always reflect tissue stores. DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS The diagnosis is established by the presence of a prolonged PT that corrects rapidly after administration of vitamin K, which stops the active bleeding. Other possible causes of bleeding and a prolonged PT include disseminated intravascular coagulation (DIC), liver fail ure, and rare hereditary deficiencies of clotting factors. DIC, which is usually secondary to sepsis, is associated with thrombocytopenia, low fibrinogen, and elevated D dimers. Severe liver disease results in decreased production of clotting factors; the PT does not fully correct with administration of vitamin K. Children with a heredi tary disorder have a deficiency in a specific clotting factor (I, II, V, VII, X). Coumarin derivatives inhibit the action of vitamin K by prevent ing its recycling to an active form after it functions as a cofactor for glutamyl carboxylase. Bleeding can occur with overdosage of the common anticoagulant warfarin or with ingestion of rodent poison, which contains a coumarin derivative. High doses of salicylates also inhibit vitamin K regeneration, potentially leading to a prolonged PT and clinical bleeding. TREATMENT Infants with VKDB should receive 1 mg of parenteral vitamin K. The PT should decrease within 6 hours and normalize within 24 hours. For rapid correction in adolescents, the parenteral dose is 2.5 10 mg. In addition to vitamin K, a patient with severe, life threatening bleeding should receive an infusion of fresh frozen plasma (FFP), which corrects the coagulopathy rapidly. Children with vitamin K deficiency caused by malabsorption require chronic administration of high doses of oral vitamin K (2.5 mg twiceweek to 5 mgday). Parenteral vitamin K may be necessary if oral vitamin K is ineffective. PREVENTION Administration of either oral or parenteral vitamin K soon after birth prevents early VKDB of the newborn. In contrast, a single dose of oral vitamin K |
915 | does not prevent a substantial number of cases of late VKDB. However, a single intramuscular (IM) injection of vitamin K (1 mg), the current practice in the United States, is almost universally effective, except in children with severe malab sorption. This increased efficacy of the IM form is thought to be the result of a depot effect. Concerns about an association between par enteral vitamin K at birth and the later development of malignancy are unsubstantiated. Oral vitamin K is a less effective alternative for parents who refuse IM vitamin K, but multiple doses are necessary and rely on home administration. Discontinuing the offending medications before delivery can prevent VKDB attributable to maternal medications. If this is not possible, administration of vitamin K to the mother may be help ful. In addition, the neonate should receive parenteral vitamin K immediately after birth. If parenteral vitamin K does not correct the coagulopathy rapidly, the child should receive FFP. Children who are at high risk for malabsorption of vitamin K should receive supplemental vitamin K and periodic measurement of the PT. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 72 u Micronutrient Mineral Deficiencies 483 Micronutrients include vitamins (see Chapters 66 71) and trace ele ments. By definition, a trace element is 0.01 of the body weight. Trace elements have a variety of essential functions (Table 72.1), although the evidence is not always strong (chromium). With the exception of iron deficiency, trace element deficiency is uncommon in developed countries, but some deficiencies (iodine, zinc, selenium) are important public health problems in a number of developing countries. Because of low nutritional requirements and plentiful supply, deficien cies of some of the trace elements are extremely rare in humans and typically occur in patients receiving unusual diets or prolonged total parenteral nutrition without adequate delivery of a specific trace ele ment. Trace element deficiencies can also occur in children with short bowel syndrome or malabsorption. Excess intake of trace elements is uncommon, but can result from environmental exposure or overuse of supplements (see Table 72.1). For a number of reasons, children are especially susceptible to trace element deficiency. First, growth creates an increased demand for most trace elements. Second, some organs are more likely to sustain perma nent damage because of trace element deficiency during childhood. The developing brain is particularly vulnerable to the consequences of cer tain deficiency states (iron, iodide). Similarly, adequate fluoride is most critical for dental health during childhood. Third, children, especially in the developing world, are more prone to gastrointestinal disorders that can cause trace element deficiencies because of malabsorption. A normal diet provides adequate intake of most trace elements. How ever, the intake of certain trace elements varies significantly in different geographic locations. Iodide containing food is plentiful near the ocean, but inland areas |
916 | often have inadequate sources, leading to goiter and hypothyroidism. Iodine deficiency is not a problem in the United States because of the widespread use of iodized salt; however, symptomatic Chapter 72 Micronutrient Mineral Deficiencies Larry A. Greenbaum Table 72.1 Trace Elements ELEMENT PHYSIOLOGY EFFECTS OF DEFICIENCY EFFECTS OF EXCESS DIETARY SOURCES Chromium Potentiates the action of insulin Impaired glucose tolerance, peripheral neuropathy, and encephalopathy Unknown Meat, grains, fruits, and vegetables Copper Absorbed via specific intestinal transporter Circulates bound to ceruloplasmin Enzyme cofactor (superoxide dismutase, cytochrome oxidase, and enzymes involved in iron metabolism and connective tissue formation) Microcytic anemia, osteoporosis, neutropenia, neurologic symptoms, depigmentation of hair and skin Acute: nausea, emesis, abdominal pain, coma, and hepatic necrosis Chronic toxicity (liver and brain injury) occurs in Wilson disease (see Chapter 405.2) and secondary to excess intake (see Chapter 405.3) Vegetables, grains, nuts, liver, margarine, legumes, corn oil Fluoride Incorporated into bone Dental caries (see Chapter 358) Chronic: dental fluorosis (see Chapter 353) Toothpaste, fluoridated water Iodine Component of thyroid hormone (see Chapter 580) Hypothyroidism (see Chapters 601 and 603) Hypothyroidism and goiter (see Chapters 603 and 605); maternal excess can cause congenital hypothyroidism and goiter (see Chapter 603.1) Saltwater fish, iodized salt Iron Component of hemoglobin, myoglobin, cytochromes, and other enzymes Anemia (see Chapter 504), decreased alertness, impaired learning Acute (see Chapter 94): nausea, vomiting, diarrhea, abdominal pain, and hypotension Chronic excess usually secondary to hereditary disorders (see Chapter 511); causes organ dysfunction Meat, fortified foods Deficiency can also result from blood loss (hookworm infestation, menorrhagia) Manganese Enzyme cofactor Hypercholesterolemia, weight loss, decreased clotting proteins Neurologic manifestations, cholestatic jaundice Nuts, meat, grains, tea Molybdenum Enzyme cofactor (xanthine oxidase and others) Tachycardia, tachypnea, night blindness, irritability, coma Hyperuricemia and increased risk of gout Legumes, grains, liver Selenium Enzyme cofactor (prevents oxidative damage) Cardiomyopathy (Keshan disease), myopathy Nausea, diarrhea, neurologic manifestations, nail and hair changes, garlic odor Meat, seafood, whole grains, garlic Zinc Enzyme cofactor Constituent of zinc finger proteins, which regulate gene transcription Decreased growth, dermatitis of extremities and around orifices, impaired immunity, poor wound healing, hypo gonadism, diarrhea Supplements are beneficial in diarrhea and improve neuro developmental outcomes Abdominal pain, diarrhea, vomiting Can worsen copper deficiency Meat, shellfish, whole grains, legumes, cheese These deficiency states have been reported only in case reports associated with parenteral nutrition or highly unusual diets. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 484 Part V u Nutrition iodine deficiency (goiter, hypothyroidism) is common in many devel oping countries. Selenium content of the soil and consequently of food is also quite variable. Dietary selenium deficiency (associated with car diomyopathy) occurs in certain locations, such as some parts of China. The consequences of severe isolated trace mineral deficiency are illustrated in certain genetic disorders. The manifestations of Menkes disease are caused by pathologic variants in the gene coding for a pro tein |
917 | that facilitates intestinal copper absorption (see Chapters 639.5 and 703). These pathologic variants result in severe copper deficiency; subcutaneous copper is an effective treatment. Nutritional copper deficiency has been reported in children receiving unsupplemented parenteral nutrition and in children on a ketogenic diet (with associ ated neutropenia and anemia). The recessive disorder acrodermatitis enteropathica is secondary to malabsorption of zinc (see Chapter 712). These patients respond dramatically to zinc supplementation. Children can have apparently asymptomatic deficiencies of certain trace elements but still benefit from supplementation. As an example, zinc is highly effective in treating children before or during diarrheal illnesses in the developing world. Zinc deficiency is quite common in the developing world and is often associated with malnutrition or other micronutrient deficiencies (iron). Chronic zinc deficiency is associated with dwarfism, hypogo nadism, dermatitis, and T cell immunodeficiency. Diets rich in phy tates bind zinc, impairing its absorption. Zinc supplementation in at risk children reduces the incidence and severity of diarrhea, pneu monia, and possibly malaria. In developing countries, children who have diarrhea may benefit from zinc supplementation, especially if there is underlying malnutrition. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. PART VI Fluid and Electrolyte Disorders 485 73.1 Composition of Body Fluids Larry A. Greenbaum TOTAL BODY WATER Total body water (TBW) as a percentage of body weight varies with age (Fig. 73.1). The fetus has very high TBW, which gradually decreases to approximately 75 of birthweight for a term infant. Premature infants have higher TBW than term infants. During the first year of life, TBW decreases to approximately 60 of body weight and remains at this level until puberty. At puberty, the fat content of females increases more than that in males, who acquire more muscle mass than females. Because fat has very low water content and muscle has high water content, by the end of puberty TBW in males remains at 60, but TBW in females decreases to approximately 50 of body weight. The high fat content in over weight children causes a decrease in TBW as a percentage of body weight. During dehydration, TBW decreases and thus is a smaller percentage of body weight. FLUID COMPARTMENTS TBW is divided between two main compartments: intracellular fluid (ICF) and extracellular fluid (ECF). In the fetus and new born, the ECF volume is larger than the ICF volume (see Fig. 73.1). The normal postnatal diuresis causes an immediate decrease in the ECF volume. This is followed by continued expansion of the ICF volume, which results from cellular growth. By 1 year of age, the ratio of ICF volume to ECF volume approaches adult levels. The ECF volume is approximately 2025 of body weight, and the ICF volume is approximately 3040 of body weight, close to twice the ECF volume (Fig. 73.2). With puberty, the increased |
918 | muscle mass of males causes them to have a higher ICF volume than females. There is no significant difference in the ECF volume between postpubertal females and males. The ECF is further divided into the plasma water and the inter stitial fluid (see Fig. 73.2). The plasma water is 5 of body weight. The blood volume, given a hematocrit of 40, is usually 8 of body weight, although it is higher in newborns and young infants; in premature newborns it is approximately 10 of body weight. The volume of plasma water can be altered by pathologic conditions, including dehydration, anemia, polycythemia, heart failure, abnor mal plasma osmolality, and hypoalbuminemia. The interstitial fluid, normally 15 of body weight, can increase dramatically in diseases associated with edema, such as heart failure, protein losing enter opathy, liver failure, nephrotic syndrome, and sepsis. An increase in interstitial fluid also occurs in patients with ascites or pleural effusions. There is a delicate equilibrium between the intravascular fluid and the interstitial fluid. The balance between hydrostatic and Chapter 73 Electrolyte and Acid Base Disorders 100 B od y W ei gh t Total body water (TBW) Intracellular fluid (ICF) Extracellular fluid (ECF) 90 80 60 40 20 70 50 30 10 2 4 6 8 Birth Months Years Age 6 312 6 9 12 15 Adult 0 Fig. 73.1 Total body water, intracellular fluid, and extracellular fluid as a percentage of body weight as a function of age. (From Winters RW. Water and electrolyte regulation. In: Winters RW, ed. The Body Fluids in Pediatrics. Little, Brown; 1973.) Intracellular (3040) Extracellular (2025) Interstitial (15) Plasma (5) Fig. 73.2 Compartments of total body water, expressed as percent ages of body weight, in an older child or adult. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 486 Part VI u Fluid and Electrolyte Disorders oncotic forces regulates the intravascular volume, which is criti cal for proper tissue perfusion. The intravascular fluid has a higher concentration of albumin than the interstitial fluid, and the conse quent oncotic force draws water into the intravascular space. The maintenance of this gradient depends on the limited permeability of albumin across the capillaries. The hydrostatic pressure of the intravascular space, which is caused by the pumping action of the heart, drives fluid out of the intravascular space. These forces favor movement into the interstitial space at the arterial ends of the cap illaries. The decreased hydrostatic forces and increased oncotic forces, which result from the dilutional increase in albumin concen tration, cause movement of fluid into the venous ends of the capil laries. Overall, there is usually a net movement of fluid out of the intravascular space to the interstitial space, but this fluid is returned to the circulation via the lymphatics. An imbalance in these forces may cause expansion of the inter stitial volume at the expense |
919 | of the intravascular volume. In chil dren with hypoalbuminemia, the decreased oncotic pressure of the intravascular fluid contributes to the development of edema. Loss of fluid from the intravascular space may compromise the intravas cular volume, placing the child at risk for inadequate blood flow to vital organs. This is especially likely in diseases in which capil lary leak occurs because the loss of albumin from the intravascular space is associated with an increase in the albumin concentration in the interstitial space, further compromising the oncotic forces that normally maintain intravascular volume. In contrast, with heart failure, there is an increase in venous hydrostatic pressure from expansion of the intravascular volume, which is caused by impaired pumping by the heart, and the increase in venous pres sure causes fluid to move from the intravascular space to the inter stitial space. Expansion of the intravascular volume and increased intravascular pressure also cause the edema that occurs with acute glomerulonephritis. ELECTROLYTE COMPOSITION The composition of the solutes in the ICF and ECF are very differ ent (Fig. 73.3). Sodium (Na) and chloride (Cl) are the dominant cation and anion, respectively, in ECF. The sodium and chloride concentrations (Na, Cl) in the ICF are much lower. Potassium (K) is the most abundant cation in the ICF, and its concentration (K) within the cells is approximately 30 times higher than in the ECF. Proteins, organic anions, and phosphate are the most plenti ful anions in the ICF. The dissimilarity between the anions in the ICF and the ECF is largely determined by the presence of intra cellular molecules that do not cross the cell membrane, the bar rier separating the ECF and the ICF. In contrast, the difference in the distribution of cations (Na and K) relies on activity of the Na,K adenosine triphosphatase (ATPase) pump and membrane ion channels. The difference in the electrolyte compositions of the ECF and the ICF has important ramifications in the evaluation and treatment of electrolyte disorders. Serum concentrations of electrolytes (Na, K, and Cl) do not always reflect total body content. Intracellu lar K is much higher than the serum concentration. A shift of K from the intracellular space (ICS) can maintain a normal or even an elevated serum K despite massive losses of K from the ICS. This effect is seen in diabetic ketoacidosis, in which significant K depletion is masked by transmembrane shift of K from the ICF to the ECF. Therefore, for K and phosphorus, electrolytes with a high intracellular concentration, serum level may not reflect total body content. Similarly, the serum calcium concentration (Ca2) does not reflect total body content of Ca2, which is largely contained in bone (see Chapter 69). OSMOLALITY The ICF and the ECF are in osmotic equilibrium because the cell membrane is permeable to water. If the osmolality in one compart ment changes, then water movement leads to a rapid equalization of osmolality, with a shift of water between the ICS and extracellu lar space (ECS). Clinically, the primary |
920 | process is usually a change in the osmolality of the ECF, with resultant shift of water into the ICF if ECF osmolality decreases, or vice versa if ECF osmolality increases. The ECF osmolality can be determined and usually equals ICF osmolality. Plasma osmolality, normally 285 295 mOsmkg, is measured by the degree of freezing point depression. The plasma osmolality can also be estimated by a calculation based on the fol lowing formula: Osmolality 2 Na glucose 18 BUN 2.8 Glucose and blood urea nitrogen (BUN) are reported in mgdL. Division of these values by 18 and 2.8, respectively, converts the units into mmolL. Multiplication of the Na value by 2 accounts for its accompanying anions, principally Cl and bicarbonate. The calculated osmolality is usually slightly lower than measured osmolality. Urea is not confined to the ECS because it readily crosses the cell membrane, and its intracellular concentration approximately equals its extracellular concentration. Whereas an elevated Na causes a shift of water from the ICS, with uremia there is no osmo lar gradient between the two compartments and consequently no movement of water. The only exception is during hemodialysis, when the decrease in extracellular urea is so rapid that intracel lular urea does not have time to equilibrate. Disequilibrium syn drome during hemodialysis may result in a shift of water into brain cells and lead to severe symptoms. Ethanol, because it freely crosses cell membranes, is another ineffective osmole. Hence, the effective osmolality can be calculated as follows: Effective osmolality 2 Na glucose 18 The effective osmolality determines the osmotic force that is mediat ing the shift of water between the ECF and the ICF. PLASMA INTRACELLULAR Cations Anions Cations Anions K? (4) Na? (140) Ca? (2.5) Mg? (1.1) HCO3 ? (24) HCO3? (10) Cl? (104) Other (6) Phos? (2) Prot? (14) Na? (13) K? (140) Mg? (7) Prot? (40) Phos? (107) Cl? (3) Fig. 73.3 Concentrations of the major cations and anions in the intra cellular space and the plasma, expressed in mEqL. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 73 u Electrolyte and Acid Base Disorders 487 Hyperglycemia causes an increase in the plasma osmolality because it is not in equilibrium with the ICS. During hypergly cemia, there is shift of water from the ICS to the ECS. This shift causes dilution of the Na in the ECS, causing hyponatremia despite elevated plasma osmolality. The magnitude of this effect can be cal culated as follows: Nacorrected Nameasured 1.6 (glucose 100 mg dL) 100 where Nameasured Na concentration measured by the clinical laboratory and Nacorrected corrected Na concentration (the Na concentration if the glucose concentration were normal and its accom panying water moved back into the cells). The Nacorrected is the more reliable indicator of the ratio of total body Na to TBW, the usual deter minant of the Na. Normally, measured |
921 | osmolality and calculated osmolality are within 10 mOsmkg. However, there are some clinical situations in which this difference does not occur. The presence of unmeasured osmoles causes measured osmolality to be significantly elevated in comparison with the calculated osmolality. An osmolal gap is present when the difference between measured osmolality exceeds calculated osmolality by 10 mOsmkg. Examples of unmeasured osmoles include ethanol, ethylene glycol, methanol, sucrose, sorbitol, and mannitol. These sub stances increase measured osmolality but are not part of the equation for calculating osmolality. The presence of an osmolal gap is a clinical clue to the presence of unmeasured osmoles and may be diagnostically useful when there is clinical suspicion of poisoning with methanol or ethylene glycol. Pseudohyponatremia is a second situation in which there is dis cordance between measured osmolality and calculated osmolality. Lipids and proteins are the solids of the serum. In patients with elevated serum lipids or proteins, the water content of the serum decreases because water is displaced by the larger amounts of sol ids. Some instruments measure Na by determining the amount of Na per liter of serum, including the solid component. When the solid component increases, there is a decrease in Na per liter of serum, despite a normal concentration when based on the amount of Na per liter of serum water. It is the concentration of Na in serum water that is physiologically relevant. A similar prob lem occurs when using instruments that require dilution of the sample before measurement of Na (indirect potentiometry). In both situations, the plasma osmolality is normal despite the pres ence of pseudohyponatremia, because the method for measuring osmolality is not appreciably influenced by the percentage of serum that is composed of lipids and proteins. Pseudohyponatremia is diagnosed by the finding of a normal measured plasma osmolality despite hyponatremia. This laboratory artifact does not occur if the Na in water is measured directly with an ion specific electrode, as with arterial blood gas (ABG) analyzers. Pseudohypernatremia may occur in patients with very low levels of serum proteins by a similar mechanism. When there are no unmeasured osmoles and pseudohyponatre mia is not a concern, the calculated osmolality provides an accurate estimate of the plasma osmolality. Measurement of plasma osmo lality is useful for detecting or monitoring unmeasured osmoles and confirming the presence of true hyponatremia. Whereas many children with high plasma osmolality are dehydratedas seen with hypernatremic dehydration or diabetic ketoacidosishigh osmolal ity does not always equate with dehydration. A child with salt poison ing or uremia has an elevated plasma osmolality but may be volume overloaded. POINT OF CARE TESTING Point of care (POC) testing offers a number of advantages, includ ing rapid turnaround and usually smaller blood sample volume required. POC devices may provide more accurate results in certain situations, such as pseudohyponatremia (see earlier) and pseudo hyperkalemia (see Chapter 73.4). However, the agreement between POC and the laboratory is variable, and thus caution is needed when interpreting results. Because of bias, POC and laboratory |
922 | results should not be used on an alternating basis when following critical trends (e.g., during correction of hypernatremia or hypona tremia; see Chapter 73.3). Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. 73.2 Regulation of Osmolality and Volume Larry A. Greenbaum The regulation of plasma osmolality and the intravascular vol ume is controlled by independent systems for water balance, which determines osmolality, and sodium balance, which determines vol ume status. Maintenance of normal osmolality depends on control of water balance. Control of volume status depends on regulation of sodium balance. When present, volume depletion takes precedence over regulation of osmolality, and retention of water contributes to the maintenance of intravascular volume. REGULATION OF OSMOLALITY The plasma osmolality is tightly regulated and maintained at 285 295 mOsmkg. Modification of water intake and excretion maintains nor mal plasma osmolality. In the steady state, the combination of water intake and water produced by the body from oxidation balances water losses from the skin, lungs, urine, and gastrointestinal (GI) tract. Only water intake and urinary losses can be regulated. Osmoreceptors in the hypothalamus sense plasma osmolality (see Chapter 594). An elevated effective osmolality leads to secre tion of antidiuretic hormone (ADH) by neurons in the supra optic and paraventricular nuclei in the hypothalamus. The axons of these neurons terminate in the posterior pituitary. Circulating ADH binds to its V2 receptors in the collecting duct cells of the kidney and causes insertion of water channels (aquaporin 2) into the renal collecting duct cells. This produces increased perme ability to water, permitting resorption of water into the hypertonic renal medulla. Urine concentration increases and water excretion decreases. Urinary water losses cannot be eliminated because there is obligatory excretion of urinary solutes, such as urea and sodium. The regulation of ADH secretion is tightly linked to plasma osmo lality, responses being detectable with a 1 change in osmolality. ADH secretion virtually disappears when plasma osmolality is low, allowing excretion of maximally dilute urine. The resulting loss of free water (i.e., water without Na) corrects plasma osmolality. ADH secretion is not an all or nothing response; there is a graded adjustment as the osmolality changes. Water intake is regulated by hypothalamic osmoreceptors, which stimulate thirst when the serum osmolality increases. Thirst occurs with a small increase in the serum osmolality. Control of osmolality is subordinate to maintenance of an adequate intravascular volume. When volume depletion is present, both ADH secretion and thirst are stimulated, regardless of the plasma osmolality. The sensation of thirst requires moderate volume depletion but only a 12 change in the plasma osmolality. A number of conditions can limit the kidneys ability to excrete adequate water to correct low plasma osmolality. In the syndrome of inappropriate antidiuretic hormone (SIADH), ADH continues to be produced despite a low plasma osmolality (see Chapters 73.3 and 597). The glomerular filtration rate (GFR) affects the kidneys ability to eliminate water. With a decrease in the GFR, less water is delivered to Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern |
923 | California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 488 Part VI u Fluid and Electrolyte Disorders the collecting duct, limiting the amount of water that can be excreted. The impairment in the GFR must be quite significant to limit the kid neys ability to respond to an excess of water. The minimum urine osmolality is approximately 30 50 mOsm kg. This places an upper limit on the kidneys ability to excrete water; sufficient solute must be present to permit water loss. Massive water intoxication may exceed this limit, whereas a lesser amount of water is necessary in the child with a diet that has very little solute. This can produce severe hyponatremia in children who receive little salt and have minimal urea production as a result of inadequate pro tein intake. Volume depletion is an extremely important cause of decreased water loss by the kidney despite a low plasma osmolality. This appropriate secretion of ADH occurs because volume deple tion takes precedence over the osmolality in the regulation of ADH. The maximum urine osmolality is approximately 1,200 mOsm kg. The obligatory solute losses dictate the minimum volume of urine that must be produced, even when maximally concentrated. Obligatory water losses increase in patients with high salt intake or high urea losses, as may occur after relief of a urinary obstruction or during recovery from acute kidney injury. An increase in uri nary solute and thus water losses occurs with an osmotic diuresis, which results classically from glycosuria in diabetes mellitus as well as iatrogenically after mannitol administration. There are develop mental changes in the kidneys ability to concentrate the urine. The maximum urine osmolality in a newborn, especially a premature newborn, is less than that in an older infant or child. This limits the ability to conserve water and makes such a patient more vulnerable to hypernatremic dehydration. Very high fluid intake, as seen with psychogenic polydipsia, can dilute the high osmolality in the renal medulla, which is necessary for maximal urinary concentration. If fluid intake is restricted in patients with this condition, the kid neys ability to concentrate the urine may be somewhat impaired, although this defect corrects after a few days without polydipsia. This may also occur during the initial treatment of central diabetes insipidus with desmopressin acetate; the renal medulla takes time to achieve its normal maximum osmolality. REGULATION OF VOLUME An appropriate intravascular volume is critical for survival; both vol ume depletion and volume overload may cause significant morbidity and mortality. Because sodium is the principal extracellular cation and is restricted to the ECF, adequate body sodium is necessary for main tenance of intravascular volume. The principal extracellular anion, Cl, is also necessary, but for simplicity, Na balance is considered the main regulator of volume status because body content of sodium and that of chloride usually change proportionally, given the need for equal num bers of cations and anions. |
924 | In some situations, Cl depletion is consid ered the dominant derangement causing volume depletion (metabolic alkalosis with volume depletion). The kidney determines sodium balance because there is little homeostatic control of sodium intake, even though salt craving does occasionally occur, typically in children with chronic renal salt loss. The kidney regulates Na balance by altering the percent age of filtered Na that is resorbed along the nephron. Normally, the kidney excretes 1 of the Na filtered at the glomerulus. In the absence of disease, extrarenal losses and urinary output match intake, with the kidney having the capacity to adapt to large varia tions in sodium intake. When necessary, urinary sodium excre tion can be reduced to virtually undetectable levels or increased dramatically. The most important determinant of renal Na excretion is the vol ume status of the child; it is the effective intravascular volume that influences urinary Na excretion. The effective intravascular volume is the volume status that is sensed by the bodys regulatory mechanisms. Heart failure is a state of volume overload, but the effective intravas cular volume is low because poor cardiac function prevents adequate perfusion of the kidneys and other organs. This explains the avid renal Na retention often present in patients with heart failure. The renin angiotensin system is an important regulator of renal Na excretion. The juxtaglomerular apparatus produces renin in response to decreased effective intravascular volume. Specific stim uli for renin release are decreased perfusion pressure in the afferent arteriole of the glomerulus, decreased delivery of sodium to the dis tal nephron, and 1 adrenergic agonists, which increase in response to intravascular volume depletion. Renin, a proteolytic enzyme, cleaves angiotensinogen, producing angiotensin I. Angiotensin converting enzyme (ACE) converts angiotensin I into angiotensin II. The actions of angiotensin II include direct stimulation of the proximal tubule to increase sodium resorption and stimulation of the adrenal gland to increase aldosterone secretion. Through its actions in the distal nephronspecifically, the late distal convo luted tubule and the collecting ductaldosterone increases sodium resorption. Aldosterone also stimulates potassium excretion, increasing urinary losses. Along with decreasing urinary loss of sodium, angiotensin II acts as a vasoconstrictor, which helps main tain adequate blood pressure in the presence of volume depletion. Volume expansion stimulates the synthesis of atrial natriuretic pep tide (ANP), which is produced by the atria in response to atrial wall distention. Along with increasing the GFR, ANP inhibits Na resorp tion in the medullary portion of the collecting duct, facilitating an increase in urinary Na excretion. Volume overload occurs when Na intake exceeds output. Chil dren with kidney failure have impaired ability to excrete Na. The GFR is low at birth, limiting a newborns ability to excrete a Na load. In other situations, there is a loss of the appropriate regulation of renal Na excretion. This loss of regulation occurs in patients with excessive aldosterone, as seen in primary hyperaldosteron ism or renal artery stenosis, where excess renin production leads to high aldosterone levels. In acute glomerulonephritis, even without |
925 | significantly reduced GFR, the normal intrarenal mechanisms that regulate Na excretion malfunction, causing excessive renal reten tion of Na and volume overload. Renal retention of Na occurs during volume depletion, but this appropriate response causes the severe excess in total body Na that is present in heart failure, liver failure, nephrotic syndrome, and other causes of hypoalbuminemia. In these diseases, the effective intravas cular volume is decreased, causing the kidney and the various regu latory systems to respond, leading to renal Na retention and edema formation. Volume depletion usually occurs when Na losses exceed intake. The most common etiology in children is gastroenteritis. Exces sive losses of sodium may also occur from the skin in children with burns, in sweat from patients with cystic fibrosis, or after vigorous exercise. Inadequate intake of Na is uncommon except in neglect, in famine, or with an inappropriate choice of liquid diet in a child who cannot take solids. Urinary Na wasting may occur in a range of renal diseases, from renal dysplasia to tubular disorders, such as Bartter syndrome. The neonate, especially if premature, has a mild impairment in the ability to conserve Na. Iatrogenic renal Na wasting takes place during diuretic therapy. Renal Na loss occurs as a result of derangement in the normal regulatory systems. An absence of aldosterone, seen most frequently in children with con genital adrenal hyperplasia caused by 21 hydroxylase deficiency, causes sodium wasting (see Chapter 616). Isolated disorders of water balance can affect volume status and Na balance. Because the cell membrane is permeable to water, changes in TBW influence both the extracellular volume and the intracellular vol ume. In isolated water loss, as occurs in diabetes insipidus, the impact is greater on the ICS because it has a greater volume than the ECS. Thus, compared with other types of dehydration, hypernatremic dehy dration has less impact on plasma volume; most of the fluid loss comes from the ICS. Yet, significant water loss eventually affects intravascular volume and will stimulate renal Na retention, even if total body Na content is normal. Similarly, with acute water intoxication or SIADH, there is an excess of TBW, but most is in the ICS. However, there is some effect on the intravascular volume, which causes renal excretion Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 73 u Electrolyte and Acid Base Disorders 489 of Na. Children with SIADH or water intoxication have high urine Na concentration despite hyponatremia. This finding reinforces the concept of independent control systems for water and Na, but the 2 systems interact when pathophysiologic processes dictate, and control of effective intravascular volume always takes precedence over control of osmolality. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. 73.3 Sodium Larry A. Greenbaum SODIUM METABOLISM Body Content and Physiologic Function Sodium is the dominant cation of the ECF (see Fig. 73.3), and |
926 | it is the principal determinant of extracellular osmolality. Na is therefore necessary for the maintenance of intravascular volume. Less than 3 of Na is intracellular. More than 40 of total body Na is in bone; the remainder is in the interstitial and intravascular spaces. The low intracellular Na, approximately 10 mEqL, is maintained by Na,K ATPase, which exchanges intracellular Na for extracellular K. Sodium Intake A childs diet determines the amount of Na ingesteda predomi nantly cultural determination in older children. An occasional child has salt craving because of an underlying salt wasting renal disease or adrenal insufficiency. Children in the United States tend to have very high salt intakes because their diets include a large amount of junk food or fast food. Infants receive sodium from breast milk (approxi mately 7 mEqL) and formula (7 13 mEqL, for 20 calorieoz formula). Sodium is readily absorbed throughout the GI tract. Mineralocorti coids increase sodium transport into the body, although this effect has limited clinical significance. The presence of glucose enhances sodium absorption because of the presence of a co transport system. This is the rationale for including sodium and glucose in oral rehydration solu tions (see Chapter 387). Sodium Excretion Sodium excretion occurs in stool and sweat, but the kidney regulates Na balance and is the principal site of Na excretion. There is some Na loss in stool, but it is minimal unless diarrhea is present. Normally, sweat has 5 40 mEqL of sodium. Sweat Na is increased in children with cystic fibrosis, aldosterone deficiency, or pseudohypoaldosteron ism. The higher sweat losses in these conditions may cause or contrib ute to Na depletion. Sodium is unique among electrolytes because water balance, not Na balance, usually determines its concentration. When the Na increases, the resultant higher plasma osmolality causes increased thirst and increased secretion of ADH, which leads to renal conser vation of water. Both these mechanisms increase the water content of the body, and the Na returns to normal. During hyponatremia, the decrease in plasma osmolality stops ADH secretion, and consequent renal water excretion leads to an increase in the Na. Even though water balance is usually regulated by osmolality, volume depletion does stimulate thirst, ADH secretion, and renal conservation of water. Volume depletion takes precedence over osmolality; volume depletion stimulates ADH secretion, even if a patient has hyponatremia. The excretion of Na by the kidney is not regulated by the plasma osmolality. The patients effective plasma volume determines the amount of sodium in the urine. This is mediated by a variety of regulatory sys tems, including the renin angiotensin aldosterone system and intrarenal mechanisms. In hyponatremia or hypernatremia, the underlying patho physiology determines the amount of urinary Na, not the serum Na. HYPERNATREMIA Hypernatremia is a Na 145 mEqL, although it is sometimes defined as 150 mEqL. Mild hypernatremia is common in children, especially among infants with gastroenteritis. Hypernatremia in hospi talized patients may be iatrogenic, which is caused by inadequate water administration or, less often, by excessive Na |
927 | administration. Moder ate or severe hypernatremia has significant morbidity because of the underlying disease, the effects of hypernatremia on the brain, and the risks of overly rapid correction. Table 73.1 Causes of Hypernatremia EXCESSIVE SODIUM Improperly mixed formula Excess sodium bicarbonate Ingestion of seawater or sodium chloride Intentional salt poisoning (child abuse or fictitious disorder inflicted on another) Intravenous hypertonic saline Sodium phosphate enemas Hyperaldosteronism WATER DEFICIT Nephrogenic Diabetes Insipidus Acquired X linked (OMIM 304800) Autosomal recessive (OMIM 125800) Autosomal dominant (OMIM 125800) Central Diabetes Insipidus Acquired Autosomal recessive (OMIM 125700600955) Autosomal dominant (OMIM 125700) Wolfram syndrome (OMIM 222300604928598500) Hypothalamic neurogenic (essential) adipsic hypernatremia Increased Insensible Losses Premature infants Radiant warmers Phototherapy Inadequate Intake Ineffective breastfeeding Child neglect or abuse Adipsia (lack of thirst) WATER AND SODIUM DEFICITS Gastrointestinal Losses Diarrhea Emesisnasogastric suction Osmotic cathartics (lactulose) Cutaneous Losses Burns Excessive sweating Renal Losses Osmotic diuretics (mannitol) Diabetes mellitus Chronic kidney disease (dysplasia and obstructive uropathy) Polyuric phase of acute tubular necrosis Postobstructive diuresis Acquired: central diabetes insipidus from CNS malformations, trauma, meningitis, tumor, infiltration, unknown. OMIM, database number from the Online Mendelian Inheritance in Man (http:www.n cbi.nlm.nih.govomim). Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 490 Part VI u Fluid and Electrolyte Disorders Etiology and Pathophysiology There are three basic mechanisms of hypernatremia (Table 73.1). Sodium intoxication may be iatrogenic in a hospital setting because of correction of metabolic acidosis with sodium bicarbonate. Bak ing soda, a putative home remedy for upset stomach, is another source of sodium bicarbonate; the hypernatremia is accompanied by a profound metabolic alkalosis. Hypernatremia may develop fol lowing sodium phosphate emesis. In hyperaldosteronism, there is renal retention of sodium and resultant hypertension; hypernatre mia may not be present or is usually mild. The classic causes of hypernatremia from a water deficit are neph rogenic and central diabetes insipidus (see Chapters 570 and 596). Hypernatremia develops in diabetes insipidus only if the patient does not have access to water or cannot drink adequately because of immaturity, neurologic impairment, emesis, or anorexia. Infants are at high risk because of their inability to control their own water intake. Central diabetes insipidus and the genetic forms of nephro genic diabetes insipidus typically cause massive urinary water losses and very dilute urine. The water losses are less dramatic, and the urine often has the same osmolality as plasma when nephrogenic diabetes insipidus is secondary to intrinsic renal disease (obstruc tive uropathy, renal dysplasia, sickle cell disease). The other causes of a water deficit are also secondary to an imbal ance between losses and intake. Newborns, especially if premature, have high insensible water losses. Losses are further increased if the infant is placed under a radiant warmer or with the use of pho totherapy for hyperbilirubinemia. The renal concentrating mecha nisms are not optimal at birth, providing an additional source of water loss. Ineffective breastfeeding, |
928 | often in a primiparous mother, can cause severe hypernatremic dehydration. Adipsia, the absence of thirst, is usually secondary to damage to the hypothalamus, such as from trauma, tumor, hydrocephalus, or histiocytosis. Primary adipsia (essential hypernatremia) is rare but is seen in children with central nervous system (CNS) malformations (septo optic dysphasia, holoprosencephaly, optic nerve hypoplasia). When hypernatremia occurs in conditions with deficits of sodium and water, the water deficit exceeds the sodium deficit. This occurs only if the patient is unable to ingest adequate water. Diarrhea results in depletion of both Na and water. Because diarrhea is hypotonic typical Na concentration of 35 65 mEqLwater losses exceed Na losses, potentially leading to hypernatremia. Most children with gas troenteritis do not have hypernatremia because they drink enough hypotonic fluid to compensate for stool water losses (see Chapter 387). Fluids such as water, juice, and formula are more hypotonic than the stool losses, allowing correction of the water deficit and potentially even causing hyponatremia. Hypernatremia is most likely to occur in the child with diarrhea who has inadequate intake because of emesis, lack of access to water, or anorexia. Osmotic agents, including mannitol, and glucose in diabetes mel litus, cause excessive renal losses of water and Na. Because the urine is hypotonic (Na of approximately 50 mEqL) during an osmotic diuresis, water loss exceeds Na loss, and hypernatremia may occur if water intake is inadequate. Certain chronic kidney diseases, such as renal dysplasia and obstructive uropathy, are associated with tubular dysfunction, leading to excessive losses of water and Na. Many chil dren with such diseases have disproportionate water loss and are at risk for hypernatremic dehydration, especially if gastroenteritis supervenes. Similar mechanisms occur during the polyuric phase of acute kidney injury and after relief of urinary obstruction (postobstructive diuresis). Patients with either condition may have an osmotic diuresis from uri nary losses of urea and an inability to conserve water because of tubular dysfunction. Clinical Manifestations Most children with hypernatremia are dehydrated and show the typical clinical signs and symptoms (see Chapter 75). Children with hyperna tremic dehydration tend to have better preservation of intravascular volume because of the shift of water from the ICS to the ECS. This shift maintains blood pressure and urine output and allows hypernatremic infants to be less symptomatic initially and potentially to become more dehydrated before medical attention is sought. Breastfed infants with hypernatremia are often profoundly dehydrated, with failure to thrive (malnutrition). Probably because of intracellular water loss, the pinched abdominal skin of a dehydrated, hypernatremic infant has a doughy feel. Hypernatremia, even without dehydration, causes central nervous system (CNS) symptoms that tend to parallel the degree of Na elevation and the acuity of the increase. Patients are irritable, rest less, weak, and lethargic. Some infants have a high pitched cry and hyperpnea. Alert patients are very thirsty, even though nausea may be present. Hypernatremia may cause fever, although many patients have an underlying process that contributes to the fever. Hypernatremia is associated with hyperglycemia |
929 | and mild hypocalcemia; the mecha nisms are unknown. Beyond the sequelae of dehydration, there is no clear direct effect of hypernatremia on other organs or tissues, except the brain. Brain hemorrhage is the most devastating consequence of untreated hypernatremia. As the extracellular osmolality increases, water moves out of brain cells, leading to a decrease in brain volume. This decrease can result in tearing of intracerebral veins and bridging blood vessels as the brain moves away from the skull and the meninges. Patients may have subarachnoid, subdural, and parenchymal hemorrhages. Seizures and coma are possible sequelae of the hemorrhage, although seizures are more common during correction of hypernatremia. The cerebro spinal fluid protein is often elevated in infants with significant hyper natremia, probably because of leakage from damaged blood vessels. Neonates, especially if premature, seem especially vulnerable to hyper natremia and excessive sodium intake. There is an association between rapid or hyperosmolar sodium bicarbonate administration and the development of intraventricular hemorrhages in neonates. Even though osmotic demyelination syndrome (ODS), which includes central pontine myelinolysis and extrapontine myelinolysis, is classi cally associated with overly rapid correction of hyponatremia, it can occur in children with hypernatremia (see Treatment). Thrombotic complications occur in severe hypernatremic dehydration, including stroke, dural sinus thrombosis, peripheral thrombosis, and renal vein thrombosis. This is secondary to dehydration and possibly hyperco agulability associated with hypernatremia. Diagnosis The etiology of hypernatremia is usually apparent from the history. Hypernatremia resulting from water loss occurs only if the patient does not have access to water or is unable to drink. In the absence of dehydration, it is important to ask about sodium intake. Chil dren with excess salt intake do not have signs of dehydration, unless another process is present. Severe Na intoxication causes signs of volume overload, such as pulmonary edema and weight gain. Salt poisoning is associated with an elevated fractional excretion of Na, whereas hypernatremic dehydration causes a low fractional excretion of Na. Gastric sodium concentrations are often elevated in salt poisoning. In hyperaldosteronism, hypernatremia is usually mild or absent and is associated with edema, hypertension, hypoka lemia, and metabolic alkalosis. When there is isolated water loss, the signs of volume depletion are usually less severe initially because much of the loss is from the ICS. When pure water loss causes signs of dehydration, the hyper natremia and water deficit are usually severe. In the child with renal water loss, either central or nephrogenic diabetes insipidus, the urine is inappropriately dilute and urine volume is not low. The urine is maximally concentrated and urine volume is low if the losses are extrarenal or caused by inadequate intake. With extra renal causes of loss of water, the urine osmolality should be 1,000 mOsmkg. When diabetes insipidus is suspected, the evaluation may include measurement of ADH and a water deprivation test, including a trial of desmopressin acetate (synthetic ADH analog) to differentiate between nephrogenic diabetes insipidus and central Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier |
930 | on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 73 u Electrolyte and Acid Base Disorders 491 diabetes insipidus (see Chapters 570 and 596). A water deprivation test is unnecessary if the patient has simultaneous documentation of hypernatremia and poorly concentrated urine (osmolality lower than that of plasma). In children with central diabetes insipidus, administration of desmopressin acetate increases the urine osmo lality above the plasma osmolality, although maximum osmolality does not occur immediately because of the decreased osmolality of the renal medulla as a result of the chronic lack of ADH. In chil dren with nephrogenic diabetes insipidus, there is no response to desmopressin acetate. Hypercalcemia or hypokalemia may produce a nephrogenic diabetes insipiduslike syndrome. With combined Na and water deficits, analysis of the urine differen tiates between renal and nonrenal etiologies. When the losses are extra renal, the kidney responds to volume depletion with low urine volume, concentrated urine, and Na retention (urine Na 20 mEqL, frac tional excretion of Na 1). With renal causes, the urine volume is not appropriately low, the urine is not maximally concentrated, and the urine Na may be inappropriately elevated. Treatment As hypernatremia develops, the brain generates idiogenic osmoles to increase the intracellular osmolality and prevent the loss of brain water. This mechanism is not instantaneous and is most prominent when hypernatremia has developed gradually. If the serum Na is lowered rapidly, there is movement of water from the serum into the brain cells to equalize the osmolality in the two compartments. The resultant brain swelling may manifest as seizures or coma. Because of the associated dangers, chronic hypernatremia should not be corrected rapidly. The goal is to decrease the serum Na, but avoid a decrease of more than 10 mEqL every 24 hours. The most impor tant component of correcting moderate or severe hypernatremia is fre quent monitoring of the serum Na value so that fluid therapy can be adjusted to provide adequate correction, neither too slow nor too fast. If a child has seizures because of brain edema secondary to rapid correction, administration of hypotonic fluid should be stopped. An infusion of 3 saline can acutely increase the serum Na, reversing the cerebral edema. Chapter 75 outlines a detailed approach to the child with hyperna tremic dehydration. Acute, severe hypernatremia, usually secondary to sodium administration, can be corrected more rapidly with 5 dex trose in water (D5W) because idiogenic osmoles have not had time to accumulate. This fact balances the high morbidity and mortality rates associated with hypernatremia with the dangers of overly rapid correc tion. When hypernatremia is severe and is caused by sodium intoxi cation, it may be impossible to administer enough water to correct the hypernatremia rapidly without worsening the volume overload. In this situation, dialysis allows for removal of the excess Na, with the precise strategy dependent on the mode of dialysis. In less severe cases, the addition of a loop diuretic increases the |
931 | removal of excess Na and water, decreasing the risk of volume overload. With Na over load, hypernatremia is corrected with Na free intravenous (IV) fluid (D5W). Hyperglycemia from hypernatremia is not usually a problem and is not treated with insulin because the acute decrease in glucose may precipitate cerebral edema by lowering plasma osmolality. Rarely, the glucose concentration of IV fluids must be reduced (from 5 to 2.5 dextrose in water). The secondary hypocalcemia is treated as needed. It is important to address the underlying cause of the hyperna tremia, if possible. The child with central diabetes insipidus should receive desmopressin acetate. Because this treatment reduces renal excretion of water, excessive intake of water must be avoided to prevent both overly rapid correction of the hypernatremia and the development of hyponatremia. Over the long term, reduced sodium intake and the use of medications can somewhat amelio rate the water losses in nephrogenic diabetes insipidus (see Chapter 570). The daily water intake of a child receiving tube feeding may need to be increased to compensate for high losses. The patient with significant ongoing losses, such as through diarrhea, may need sup plemental water and electrolytes (see Chapter 74). Sodium intake is reduced if it contributed to the hypernatremia. HYPONATREMIA Hyponatremia, a very common electrolyte abnormality in hospitalized patients, is a serum sodium level 135 mEqL. Both total body sodium and TBW determine the serum sodium concentration. Hyponatremia exists when the ratio of water to Na is increased. This condition can occur with low, normal, or high levels of body Na. Similarly, body water can be low, normal, or high. Etiology and Pathophysiology Table 73.2 lists the causes of hyponatremia. Pseudohyponatremia is a laboratory artifact present when the plasma contains very high concentrations of protein (multiple myeloma, intravenous immune globulin IVIG infusion) or lipid (hypertriglyceridemia, hypercho lesterolemia). It does not occur when a direct ion selective elec trode determines the Na in undiluted plasma, a technique that is used by ABG analyzers or POC instruments (see Chapter 73.1). In true hyponatremia, the measured osmolality is low, whereas it is normal in pseudohyponatremia. Hyperosmolality, as may occur with hyperglycemia, causes a low Na because water moves down its osmotic gradient from the ICS into the ECS, diluting the Na. However, because the manifestations of hyponatremia are a result of the low plasma osmolality, patients with hyponatremia result ing from hyperosmolality do not have symptoms of hyponatremia. When the etiology of the hyperosmolality resolves, such as hyper glycemia in diabetes mellitus, water moves back into the cells, and the Na rises to its true value. Mannitol or sucrose, a compo nent of IVIG preparations, may cause hyponatremia because of hyperosmolality. Classification of hyponatremia is based on the patients volume status. In hypovolemic hyponatremia, the child has lost Na from the body. The water balance may be positive or negative, but Na loss has been higher than water loss. The pathogenesis of the hypo natremia is usually a combination of Na loss and water retention |
932 | to compensate for the volume depletion. The patient has a pathologic increase in fluid loss, and this fluid contains Na. Most fluid that is lost has a lower Na than that of plasma. Viral diarrhea fluid has an average Na of 50 mEqL. Replacing diarrhea fluid, which has Na of 50 mEqL, with formula, which has only approximately 7 10 mEqL of Na, reduces the serum Na. Intravascular volume depletion interferes with renal water excretion, the bodys usual mechanism for preventing hyponatremia. The volume depletion stimulates ADH synthesis, resulting in renal water retention. Vol ume depletion also decreases the GFR and enhances water resorp tion in the proximal tubule, thereby reducing water delivery to the collecting duct. Diarrhea as a result of gastroenteritis is the most common cause of hypovolemic hyponatremia in children. Emesis causes hypona tremia if the patient takes in hypotonic fluid, either IV or enterally, despite the emesis. Most patients with emesis have either a normal Na or hypernatremia. Burns may cause massive losses of isotonic fluid and resultant volume depletion. Hyponatremia develops if the patient receives hypotonic fluid. Losses of sodium from sweat are especially high in children with cystic fibrosis, aldosterone deficiency, or pseudohypoaldosteronism, although high losses can also occur in a hot climate. Third space losses are isotonic and can cause significant volume depletion, leading to ADH production and water retention, which can cause hyponatremia if the patient receives hypotonic fluid. In diseases that cause volume deple tion through extrarenal Na loss, the urine Na level should be low (10 mEqL) as part of the renal response to maintain the intravascular volume. The only exceptions are diseases that cause both extrarenal and renal Na losses: adrenal insufficiency and pseudohypoaldosteronism. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 492 Part VI u Fluid and Electrolyte Disorders Renal Na loss may occur in a variety of situations. In some situations the urine Na is 140 mEqL; thus hyponatremia may occur without any fluid intake. In many cases, the urine Na level is less than the serum Na; hence, the intake of hypotonic fluid is necessary for hyponatremia to develop. In diseases associated with urinary Na loss, the urine Na level is 20 mEqL despite volume depletion. This may not be true if the urinary Na loss is no longer occurring, as is frequently the case if diuretics are dis continued. Because loop diuretics prevent generation of a maxi mally hypertonic renal medulla, the patient can neither maximally dilute nor concentrate the urine. The inability to maximally retain water provides some protection against severe hyponatremia. The patient receiving thiazide diuretics can concentrate the urine and is at higher risk for severe hyponatremia. Osmotic agents, such as glucose during diabetic ketoacidosis, cause loss of both water and Na. Urea accumulates during kidney failure and then acts as an osmotic diuretic after relief |
933 | of urinary tract obstruction and dur ing the polyuric phase of acute tubular necrosis. Transient tubu lar damage in these conditions further impairs Na conservation. The serum Na in these conditions depends on Na of the fluid used to replace the losses. Hyponatremia develops when the fluid is hypotonic relative to the urinary losses. Renal salt wasting occurs in hereditary kidney diseases, such as juvenile nephronophthisis and autosomal recessive polycystic kidney disease. Obstructive uropathy, most often a result of pos terior urethral valves, produces salt wasting, but patients with the disease may also have hypernatremia as a result of impaired ability to concentrate urine and high water loss. Acquired tubulointersti tial nephritis, usually secondary to either medications or infections, may cause salt wasting, along with other evidence of tubular dys function. CNS injury may produce cerebral salt wasting, which is theoretically caused by the production of a natriuretic peptide that causes renal salt wasting. In type II renal tubular acidosis (RTA), usually associated with Fanconi syndrome (see Chapter 569.1), there is increased excretion of Na and bicarbonate in the urine. Patients with Fanconi syndrome also have glycosuria, aminoacid uria, and hypophosphatemia because of renal phosphate wasting. Aldosterone is necessary for renal Na retention and for the excretion of K and acid. In congenital adrenal hyperplasia caused by 21 hydroxylase deficiency, the block of aldosterone production results in hyponatremia, hyperkalemia, and metabolic acidosis. Decreased aldosterone secretion may be seen in Addison disease (adrenal insufficiency). In pseudohypoaldosteronism, aldosterone levels are elevated, but there is no response because of either a defective Na channel or a deficiency of aldosterone receptors. A lack of tubular response to aldosterone may occur in children with urinary tract obstruction, especially during an acute urinary tract infection. In hypervolemic hyponatremia, there is an excess of TBW and Na, although the increase in water is greater than the increase in Na. In most conditions that cause hypervolemic hyponatremia, there is a decrease in the effective blood volume, resulting from third space fluid loss, vasodilation, or poor cardiac output. The regula tory systems sense a decrease in effective blood volume and attempt to retain water and Na to correct the problem. ADH causes renal water retention, and the kidney, under the influence of aldosterone and other intrarenal mechanisms, retains sodium. The patients Table 73.3 Diagnostic Criteria for Syndrome of Inappropriate Antidiuretic Hormone Secretion Absence of: Renal, adrenal, or thyroid insufficiency Heart failure, nephrotic syndrome, or cirrhosis Diuretic ingestion Dehydration Urine osmolality 100 mOsmkg (usually plasma) Serum osmolality 280 mOsmkg and serum sodium 135 mEqL Urine sodium 30 mEqL Reversal of sodium wasting and correction of hyponatremia with water restriction Table 73.2 Causes of Hyponatremia PSEUDOHYPONATREMIA Hyperlipidemia Hyperproteinemia HYPEROSMOLALITY Hyperglycemia Iatrogenic (mannitol, sucrose, glycine) HYPOVOLEMIC HYPONATREMIA Extrarenal Losses Gastrointestinal (emesis, diarrhea) Skin (sweating or burns) Third space losses (bowel obstruction, peritonitis, sepsis) Renal Losses Thiazide or loop diuretics Osmotic diuresis Postobstructive diuresis Polyuric phase of acute tubular necrosis Juvenile nephronophthisis (OMIM 2561006069666020886043876 11498) Autosomal recessive polycystic kidney disease (OMIM 263200) Tubulointerstitial |
934 | nephritis Obstructive uropathy Cerebral salt wasting Proximal (type II) renal tubular acidosis (OMIM 604278) Lack of aldosterone effect (high serum potassium): Absence of aldosterone (e.g., 21 hydroxylase deficiency OMIM 201910) Pseudohypoaldosteronism type I (OMIM 264350177735) Urinary tract obstruction andor infection Addison disease EUVOLEMIC HYPONATREMIA Syndrome of inappropriate antidiuretic hormone secretion (SIADH) Nephrogenic syndrome of inappropriate antidiuresis (OMIM 304800) Desmopressin acetate Glucocorticoid deficiency Hypothyroidism Antidepressant medications Water intoxication Iatrogenic (excess hypotonic intravenous fluids) Feeding infants excessive water products Swimming lessons Tap water enema Child abuse Psychogenic polydipsia Diluted formula Beer potomania Exercise induced hyponatremia HYPERVOLEMIC HYPONATREMIA Heart failure Cirrhosis Nephrotic syndrome Acute, chronic kidney injury Capillary leak caused by sepsis Hypoalbuminemia caused by gastrointestinal disease (protein losing enteropathy) Most cases of proximal renal tubular acidosis are not caused by this primary genetic disorder. Proximal renal tubular acidosis is usually part of Fanconi syndrome, which has multiple etiologies. OMIM, database number from the Online Mendelian Inheritance in Man (http:www.n cbi.nlm.nih.govomim). Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 73 u Electrolyte and Acid Base Disorders 493 sodium concentration decreases because water intake exceeds sodium intake and ADH prevents the normal loss of excess water. In these disorders, there is low urine Na (10 mEqL) and an excess of both TBW and Na. The only exception is in patients with kidney failure and hyponatremia. These patients have an expanded intravascular volume, and hyponatremia can therefore appropriately suppress ADH production. Water cannot be excreted because very little urine is being made. Serum Na is diluted through ingestion of water. Because of renal dysfunction, the urine Na may be elevated, but urine volume is so low that urine Na excretion has not kept up with Na intake, leading to sodium overload. The urine Na in kid ney failure varies. In patients with acute glomerulonephritis, because it does not affect the tubules, the urine Na level is usually low, whereas in patients with acute tubular necrosis, it is elevated because of tubular dysfunction. Patients with hyponatremia and no evidence of volume overload or volume depletion have euvolemic hyponatremia. These patients typically have an excess of TBW and a slight decrease in total body Na. Some of these patients have an increase in weight, implying that they are volume overloaded. Nevertheless, from a clinical standpoint, they usually appear normal or have subtle signs of fluid overload. In SIADH the secretion of ADH is not inhibited by either low serum osmolality or expanded intravascular volume (see Chap ter 597). The result is that the child with SIADH is unable to excrete water. This results in dilution of the serum Na and hyponatremia. The expansion of the extracellular volume because of the retained water causes a mild increase in intravascular volume. The kidney increases Na excretion to decrease intravascular volume to normal; thus the patient has a mild decrease in body Na. |
935 | SIADH typically occurs with disorders of the CNS (infection, hemorrhage, trauma, tumor, thrombosis, Guillain Barr syndrome), but lung disease (infection, asthma, positive pressure ventilation) and malignant tumors (producing ADH) are other potential causes. A variety of medications may cause SIADH, including recreational use of 3,4 methylenedioxymethylamphetamine (MDMA, or Ecstasy), opi ates, antiepileptic drugs (carbamazepine, oxcarbazepine, valproate), tricyclic antidepressants, vincristine, cyclophosphamide, and selec tive serotonin reuptake inhibitors (SSRIs). The diagnosis of SIADH is one of exclusion, because other causes of hyponatremia must be eliminated (Table 73.3). Because SIADH is a state of intravascular volume expansion, low serum uric acid and BUN levels are sup portive of the diagnosis. A rare gain of function pathogenic variant in the renal ADH receptor causes nephrogenic syndrome of inap propriate antidiuresis. Patients with this X linked disorder appear to have SIADH but have undetectable levels of ADH. Hyponatremia in hospitalized patients is frequently caused by inappropriate production of ADH and administration of hypotonic IV fluids (see Chapter 74). Causes of inappropriate ADH produc tion include stress, medications such as narcotics or anesthetics, nausea, and respiratory illness. The synthetic analog of ADH, des mopressin acetate, causes water retention and may cause hypona tremia if fluid intake is not appropriately limited. The main uses of desmopressin acetate in children are for the management of central diabetes insipidus and nocturnal enuresis. Excess water ingestion can produce hyponatremia. In these cases, Na decreases as a result of dilution. This decrease sup presses ADH secretion, and there is a marked water diuresis by the kidney. Hyponatremia develops only because the intake of water exceeds the kidneys ability to eliminate water. This condition is more likely to occur in infants because their lower GFR limits their ability to excrete water. Hyponatremia may develop in infants 6 months of age when care givers offer water to their infant as a supplement, during hot weather, or when they run out of formula. Hyponatremia may result in transient seizures, hypothermia, and poor tone. With cessation of water intake, the hyponatremia rapidly corrects. Infants 6 months of age should not be given water to drink; infants 6 12 months of age should not receive 1 2 ounces. If the infant appears thirsty, the parent should offer formula or breastfeed the child. In some situations the water intoxication causes acute hypona tremia and is caused by a massive acute water load. Causes include infant swimming lessons, inappropriate use of hypotonic IV fluids, water enemas, and forced water intake as a form of child abuse. Chronic hyponatremia occurs in children who receive water but limited sodium and protein. The minimum urine osmolality is approximately 50 mOsmkg; the kidney can excrete 1 L of water only if there is enough solute ingested to produce 50 mOsm for urinary excretion. Because Na and urea (a breakdown product of protein) are the principal urinary solutes, a lack of intake of Na and protein prevents adequate water excretion. This occurs with the use of diluted formula or other inappropriate diets. Subsistence |
936 | on beer, a poor source of Na and protein, causes hyponatremia because of the inability to excrete the high water load (beer potomania). Exercise induced hyponatremia, reported frequently during mar athons, is caused by excessive water intake, salt losses from sweat, and secretion of ADH. The pathogenesis of the hyponatremia in glucocorticoid deficiency (adrenal insufficiency) is multifactorial and includes increased ADH secretion. In hypothyroidism there is an inappropriate retention of water by the kidney, but the precise mechanisms are not clearly elucidated. Cerebral salt wasting, an uncommon disorder in children, may be confused with SIADH and is often associated with CNS injury or lesions. Cerebral salt wasting produces renal salt losses and hypovole mia (orthostatic hypotension and elevated hematocrit, BUN, or creati nine). Hypovolemia is not seen in SIADH. Clinical Manifestations Hyponatremia causes a decrease in the osmolality of the ECS. Because the ICS then has a higher osmolality, water moves from the ECS to the ICS to maintain osmotic equilibrium. The increase in intracellu lar water causes cells to swell. Although cell swelling is not problem atic in most tissues, it is dangerous for the brain, which is confined by the skull. As brain cells swell, there is an increase in intracranial pressure (ICP), which impairs cerebral blood flow. Acute, severe hypo natremia can cause brainstem herniation and apnea; respiratory sup port is often necessary. Brain cell swelling is responsible for most of the symptoms of hyponatremia. Neurologic symptoms of hyponatremia include anorexia, nausea, emesis, malaise, lethargy, confusion, agita tion, headache, seizures, coma, and decreased reflexes. Patients may have hypothermia and Cheyne Stokes respirations. Hyponatremia can cause muscle cramps and weakness; rhabdomyolysis can occur with water intoxication. The symptoms of hyponatremia are mostly a result of the decrease in extracellular osmolality and the resulting movement of water down its osmotic gradient into the ICS. Brain swelling can be significantly obviated if the hyponatremia develops gradually, because brain cells adapt to the decreased extracellular osmolality by reducing intracel lular osmolality. This reduction is achieved by extrusion of the main intracellular ions (K, Cl) and a variety of small organic molecules. This process explains why the range of symptoms in hyponatremia is related to both the serum Na and its rate of decrease. A patient with chronic hyponatremia may have only subtle neurologic abnormali ties with a serum Na of 110 mEqL, but another patient may have seizures because of an acute decline in serum Na from 140 to 125 mEqL. Diagnosis The history usually points to a likely etiology of the hyponatremia. Most patients with hyponatremia have a history of volume depletion. Diarrhea and diuretic use are common causes of hyponatremia in chil dren. A history of polyuria, perhaps with enuresis, andor salt crav ing is present in children with primary kidney diseases or absence of aldosterone effect. Children may have signs or symptoms suggesting a diagnosis of hypothyroidism or adrenal insufficiency (see Chapters 603 and 615). Brain injury raises the possibility of SIADH or cerebral salt wasting, with the |
937 | caveat that SIADH is much more likely. Liver disease, nephrotic syndrome, kidney failure, or congestive heart failure may be Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 494 Part VI u Fluid and Electrolyte Disorders acute or chronic. The history should include a review of the patients intake, both IV and enteral, with careful attention to the amounts of water, Na, and protein. The traditional first step in the diagnostic process is determination of the plasma osmolality. This is done because some patients with a low serum Na do not have low osmolality. The clinical effects of hypona tremia are secondary to the associated low osmolality. Without a low osmolality, there is no movement of water into the ICS. A patient with hyponatremia can have a low, normal, or high osmo lality. A normal osmolality in combination with hyponatremia occurs in pseudohyponatremia. Children with elevation of serum glucose concentration or of another effective osmole (mannitol) have a high plasma osmolality and hyponatremia. The presence of a low osmolality indicates true hyponatremia. Patients with low osmolality are at risk for neurologic symptoms and require further evaluation to determine the etiology of the hyponatremia. In some situations, true hyponatremia is present despite a normal or elevated plasma osmolality. The presence of an ineffective osmole, usually urea, increases the plasma osmolality, but because urea has the same concentration in the ICS, it does not cause fluid to move into the ECS. There is no dilution of the serum Na by water, and the Na remains unchanged if the ineffective osmole is eliminated. Most importantly, the ineffective osmole does not protect the brain from edema caused by hyponatremia. Therefore a patient may have symp toms of hyponatremia despite having a normal or increased osmolality because of uremia. In patients with true hyponatremia, the next step in the diagnostic process is to clinically evaluate the volume status. Patients with hypo natremia can be hypovolemic, hypervolemic, or euvolemic. The diag nosis of volume depletion relies on the usual findings with dehydration (see Chapter 75), although subtle volume depletion may not be clini cally apparent. Children with hypervolemia are edematous on physical examination. They may have ascites, pulmonary edema, pleural effu sion, or hypertension. Hypovolemic hyponatremia can have renal or nonrenal causes. The urine Na is very useful in differentiating between renal and nonrenal causes. When the losses are nonrenal and the kidney is working properly, there is renal retention of Na, a normal homeo static response to volume depletion. Thus the urinary Na is low, typically 10 mEqL, although Na conservation in neonates is less avid. When the kidney is the cause of the Na loss, the urine Na is 20 mEqL, reflecting the defect in renal Na retention. The inter pretation of the urine Na level is challenging with diuretic therapy because it is high when diuretics are being |
938 | used but low after the diuretic effect is gone. This becomes an issue only when diuretic use is surreptitious. The urine Na is not useful if a metabolic alkalosis is present; the urine Cl must be used instead (see Chap ter 73.7). Differentiating among the nonrenal causes of hypovolemic hypona tremia is usually facilitated by the history. Although the renal causes are more challenging to distinguish, a high serum K is associated with disorders in which the Na wasting is caused by absence of or ineffectiveness of aldosterone. In the patient with hypervolemic hyponatremia, the urine Na is a helpful parameter. It is usually 10 mEqL, except in the patient with kidney failure. Treatment The management of hyponatremia is based on the pathophysiology of the specific etiology. The management of all causes requires judicious monitoring and avoidance of an overly quick normalization of the serum Na. A patient with severe symptoms (seizures), no matter the etiology, should be given a bolus of hypertonic saline to produce a small, rapid increase in serum sodium. Hypoxia worsens cerebral edema, and hyponatremia may exacerbate hypoxic cell swelling. There fore pulse oximetry should be monitored and hypoxia aggressively corrected. With all causes of hyponatremia, it is important to avoid overly rapid correction, which may cause osmotic demyelination syndrome (ODS), which includes central pontine myelinolysis and extrapontine myelinolysis. This syndrome, which occurs within several days of rapid correction of hyponatremia, produces neurologic symptoms, includ ing confusion, agitation, flaccid or spastic quadriparesis, and death. There are usually characteristic pathologic and radiologic changes in the brain. Despite severe symptoms, full recovery does occur in some patients. ODS is more common in patients who are treated for chronic hyponatremia than for acute hyponatremia. Presumably, this differ ence is based on the adaptation of brain cells to the hyponatremia. The reduced intracellular osmolality, an adaptive mechanism for chronic hyponatremia, makes brain cells susceptible to dehydra tion during rapid correction of the hyponatremia, which may be the mechanism of ODS. Even though ODS is rare in pediatric patients, it is advisable to avoid correcting the serum Na by 10 mEqL24 hr or 18 mEqL48 hr. Desmopressin is a potential option if the serum Na is increasing too rapidly. This guideline does not apply to acute hyponatremia, as may occur with water intoxica tion, because the hyponatremia is more often symptomatic, and the adaptive decrease in brain osmolality has not had time to occur. The consequences of brain edema in acute hyponatremia exceed the small risk of ODS. Patients with hyponatremia can have severe neurologic symptoms, such as seizures and coma. The seizures associated with hyponatre mia generally are poorly responsive to anticonvulsants. The child with hyponatremia and severe symptoms needs treatment that will quickly reduce cerebral edema. This goal is best accomplished by increasing the extracellular osmolality so that water moves down its osmolar gradient from the ICS to the ECS. Intravenous hypertonic saline rapidly increases serum Na, and the effect on serum osmolality leads to a decrease in brain |
939 | edema. Each mLkg of 3 NaCl increases the serum Na by approximately 1 mEqL. A child with active symptoms often improves after receiving 4 6 mLkg of 3 NaCl. The child with hypovolemic hyponatremia has a deficiency in Na and may have a deficiency in water. The cornerstone of therapy is to replace the Na deficit and any water deficit present. The first step in treating any dehydrated patient is to restore the intravascular volume with isotonic saline. Ultimately, complete restoration of intravascular volume suppresses ADH production, thereby permitting excretion of the excess water. Chapter 75 discusses the management of hypona tremic dehydration. The management of hypervolemic hyponatremia is difficult; patients have an excess of both water and Na. Administration of Na leads to worsening volume overload and edema. In addition, patients are retaining water and Na because of their ineffective intravascular volume or renal insufficiency. The cornerstone of therapy is water and Na restriction, because patients have volume overload. Diuretics may help by causing excretion of both Na and water. Vasopressin receptor antagonists (vaptans), by blocking the action of ADH and causing a water diuresis, are effective in correct ing the hypervolemic hyponatremia caused by heart failure. Vaptans are contraindicated if there are moderate to severe CNS symptoms. Hyponatremic patients with low albumin from nephrotic syn drome have a better response to diuretics after an infusion of 25 albumin; the Na often normalizes as a result of expansion of the intravascular volume. A child with heart failure may have an increase in renal water and Na excretion if there is an improvement in cardiac output. This improvement will turn off the regulatory hormones causing renal water (ADH) and Na (aldosterone) reten tion. The patient with kidney failure cannot respond to any of these therapies except fluid restriction. Insensible fluid losses eventually result in an increase in the Na as long as insensible and urinary losses are greater than intake. A more definitive approach in chil dren with kidney failure is to perform dialysis, which removes water and Na. In isovolumic hyponatremia there is usually an excess of water and a mild Na deficit. Therapy is directed at eliminating the excess water. The child with acute excessive water intake loses water in the urine Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 73 u Electrolyte and Acid Base Disorders 495 because ADH production is turned off as a result of the low plasma osmolality. Children may correct their hyponatremia spontaneously over 3 6 hours. For acute, symptomatic hyponatremia as a result of water intoxication, hypertonic saline may be needed to reverse cere bral edema. For chronic hyponatremia from poor solute intake, the child needs an appropriate formula, and excess water intake should be eliminated. Children with iatrogenic hyponatremia caused by the administra tion of hypotonic IV fluids should receive 3 saline if symptomatic. |
940 | Subsequent management is dictated by the patients volume status. The hypovolemic child should receive isotonic IV fluids. The child with nonphysiologic stimuli for ADH production should undergo fluid restriction. Prevention of this iatrogenic complication requires judi cious use of IV fluids (see Chapter 74). Specific hormone replacement is the cornerstone of therapy for the hyponatremia of hypothyroidism or cortisol deficiency. Correction of the underlying defect permits appropriate elimination of the excess water. SIADH is a condition of excess water, with limited ability of the kidney to excrete water. The mainstay of its therapy is fluid restric tion with normal sodium intake. Furosemide and NaCl supple mentation are effective in the patient with SIADH and severe hyponatremia. Even in a patient with SIADH, furosemide causes an increase in water and Na excretion. The loss of Na is somewhat counterproductive, but this Na can be replaced with hypertonic saline. Because the patient has a net loss of water and the urinary losses of Na have been replaced, there is an increase in the Na, but no significant increase in blood pressure. Vaptans, which block the action of ADH and cause a water diuresis, are effective at cor recting euvolemic hyponatremia, but overly rapid correction is a potential complication. Vaptans are not appropriate for treating symptomatic hyponatremia because it can take a few hours before the water diuresis occurs. Treatment of chronic SIADH is challenging. Fluid restriction in chil dren is difficult for nutritional and behavioral reasons. Other options are long term furosemide therapy with Na supplementation, an oral vaptan (tolvaptan), or oral urea. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. 73.4 Potassium Larry A. Greenbaum POTASSIUM METABOLISM Body Content and Physiologic Function The intracellular K, approximately 150 mEqL, is much higher than the plasma K (see Fig. 73.3). The majority of body K is contained in muscle. As muscle mass increases, there is an increase in body K. Thus an increase in body K occurs during puberty, and it is more significant in males. The majority of extracellular K is in bone; 1 of total body K is in plasma. Because most K is intracellular, the plasma concentration does not always reflect the total body K content. A variety of condi tions alter the distribution of K between the intracellular and extracellular compartments. Na,K ATPase maintains the high intracellular K by pumping Na out of the cell and K into the cell. This activity balances the normal leak of K out of cells via potassium channels that is driven by the favorable chemical gradient. Insulin increases K movement into cells by activat ing Na,K ATPase. Hyperkalemia stimulates insulin secretion, which helps mitigate the hyperkalemia. Acid base status affects K distribution, probably via K channels and the Na,K ATPase. A decrease in pH drives potassium extracellularly; an increase in pH has the opposite effect. Adrenergic agonists stimulate the Na,K ATPase, increasing cellular uptake of K. This increase is protective, in that hyperkalemia stimulates adrenal release of catecholamines. Adrenergic agonists and exercise cause a |
941 | net movement of K out of the ICS. An increase in plasma osmolality, as with mannitol infusion, leads to water movement out of the cells, and K follows as a result of solvent drag. The serum K increases by approximately 0.6 mEqL with each 10 mOsm rise in plasma osmolality. The high intracellular concentration of K, the principal intracel lular cation, is maintained through Na,K ATPase. The resulting chemical gradient is used to produce the resting membrane poten tial of cells. K is necessary for the electrical responsiveness of nerve and muscle cells and for the contractility of cardiac, skeletal, and smooth muscle. The changes in membrane polarization that occur during muscle contraction or nerve conduction make these cells susceptible to changes in serum K. The ratio of intracellular to extracellular K determines the threshold for a cell to generate an action potential and the rate of cellular repolarization. The intracel lular K affects cellular enzymes. K is necessary for maintaining cell volume because of its important contribution to intracellular osmolality. Potassium Intake Potassium is plentiful in food. Dietary consumption varies con siderably, even though 1 2 mEqkg is the recommended intake. The intestines normally absorb approximately 90 of ingested K. Most absorption occurs in the small intestine, whereas the colon exchanges body K for luminal Na. Regulation of intestinal losses normally has a minimal role in maintaining potassium homeostasis, although kidney failure, aldosterone, and glucocorticoids increase colonic secretion of K. The increase in intestinal losses in the set ting of kidney failure and hyperkalemia, which stimulates aldoste rone production, is clinically significant, helping to protect against hyperkalemia. Potassium Excretion Some loss of K occurs in sweat but is normally minimal. The colon has the ability to eliminate some K. In addition, after an acute K load, much of the K (40) moves intracellularly, through the actions of epinephrine and insulin, which are produced in response to hyperka lemia. This process provides transient protection from hyperkalemia, but most ingested K is eventually excreted in the urine. The kidneys principally regulate long term K balance, and they alter excretion in response to a variety of signals. K is freely filtered at the glomeru lus, but 90 is resorbed before reaching the distal tubule and collect ing duct, the principal sites of K regulation that have the ability to absorb and secrete K. The amount of tubular secretion regulates the amount of K that appears in the urine. The plasma K directly influ ences secretion in the distal nephron. As the K increases, secretion increases. The principal hormone regulating potassium secretion is aldo sterone, which is released by the adrenal cortex in response to increased plasma K. Its main site of action is the cortical collect ing duct, where aldosterone stimulates Na movement from the tubule into the cells. This movement creates a negative charge in the tubular lumen, facilitating K excretion. In addition, the increased intracellular Na stimulates the basolateral Na,K ATPase, causing more K to move into the cells lining |
942 | the cortical collecting duct. Glucocorticoids, ADH, a high urinary flow rate, and high Na deliv ery to the distal nephron also increase urinary K excretion. Insu lin, catecholamines, and urinary ammonia decrease K excretion. Whereas ADH increases K secretion, it also causes water resorp tion, decreasing urinary flow. The net effect is that ADH has little overall impact on K balance. Alkalosis causes potassium to move into cells, including the cells lining the collecting duct. This move ment increases K secretion, and because acidosis has the opposite effect; acidosis decreases K secretion. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 496 Part VI u Fluid and Electrolyte Disorders The kidney can dramatically vary K excretion in response to changes in intake. Normally, approximately 1015 of the filtered load is excreted. In an adult, excretion of K can vary from 5 1,000 mEqday. HYPERKALEMIA Hyperkalemiabecause of the potential for lethal arrhythmiasis one of the most alarming electrolyte abnormalities. Etiology and Pathophysiology Three basic mechanisms cause hyperkalemia including increased intake, cellular shifts, and decreased excretion; spurious lab values are also commonly seen (Table 73.4). In the individual patient, the etiology is sometimes multifactorial. Spurious hyperkalemia or pseudohyperkalemia is very common in children because of the difficulties in obtaining blood specimens. This laboratory result is usually caused by hemolysis during a heelstick or phlebotomy, but it can be the result of prolonged tourniquet applica tion or fist clenching, either of which causes local potassium release from muscle. The serum K is normally 0.4 mEqL higher than the plasma value, secondary to K release from cells during clot formation. This phenom enon is exaggerated with thrombocytosis because of K release from platelets. For every 100,000m3 increase in the platelet count, the serum K rises by approximately 0.15 mEqL. This phenomenon also occurs with the marked white blood cell (WBC) count elevations sometimes seen with leukemia. Elevated WBC counts, typically 200,000m3, can cause a dramatic elevation in the measured serum K. Analysis of a plasma sample usually provides an accurate result. It is important to analyze the sample promptly to avoid K release from cells, which occurs if the sample is stored in the cold, or cellular uptake of K and spurious hypokalemia, which occurs with storage at room tempera ture. Pneumatic tube transport can cause pseudohyperkalemia if cell membranes are fragile (leukemia). Occasionally, heparin causes lysis of leukemic cells and a false elevation of the plasma sample; a blood gas syringe has less heparin and may provide a more accurate reading than a standard tube. There are rare genetic disorders causing in vitro leak age of K from red blood cells (RBCs) that may causes familial pseudo hyperkalemia (autosomal dominant; ABCB6 gene). Because of the kidneys ability to excrete K, it is unusual for exces sive intake, by itself, to cause hyperkalemia. This condition can occur in a |
943 | patient who is receiving large quantities of IV or oral K for excessive losses that are no longer present. Frequent or rapid blood transfusions can acutely increase the K because of the K content of blood, which is variably elevated. Increased intake may precipitate hyperkalemia if there is an underlying defect in K excretion. The ICS has a very high K, so a shift of K from the ICS to the ECS can have a significant effect on the plasma K. This shift occurs with metabolic acidosis, but the effect is minimal with an organic acid (lac tic acidosis, ketoacidosis). A respiratory acidosis has less impact than a metabolic acidosis. Cell destruction, as seen with rhabdomyolysis, tumor lysis syndrome, tissue necrosis, or hemolysis, releases K into the extracellular milieu. The K released from RBCs in internal bleed ing, such as hematomas, is resorbed and enters the ECS. Normal doses of succinylcholine or blockers and fluoride or digi talis intoxication all cause a shift of K out of the intracellular compart ment. Succinylcholine should not be used during anesthesia in patients at risk for hyperkalemia. Blockers prevent the normal cellular uptake of K mediated by binding of agonists to the 2 adrenergic recep tors. K release from muscle cells occurs during exercise, and levels can increase by 1 2 mEqL with high activity. With an increased plasma osmolality, water moves from the ICS, and K follows. This process occurs with hyperglycemia, although in nondiabetic patients the resul tant increase in insulin causes K to move intracellularly. In diabetic ketoacidosis (DKA), the absence of insulin causes potassium to leave the ICS, and the problem is compounded by the hyperosmolality. The effect of hyperosmolality causes a transcellular shift of K into the ECS after mannitol or hypertonic saline infusions. Malignant hyperther mia, which is triggered by some inhaled anesthetics, causes muscle release of potassium (see Chapter 651.2). Hyperkalemic periodic paralysis is an autosomal dominant disorder caused by pathogenic variants in SCN4A, the gene for a Na channel. It results in episodic cellular release of K and attacks of paralysis (see Chapter 651.1). Table 73.4 Causes of Hyperkalemia SPURIOUS LABORATORY VALUE Hemolysis Tissue ischemia during blood drawing Thrombocytosis Leukocytosis Familial pseudohyperkalemia (OMIM 609153) INCREASED INTAKE Intravenous or oral Blood transfusions TRANSCELLULAR SHIFTS Acidosis Rhabdomyolysis Tumor lysis syndrome Tissue necrosis Hemolysishematomasgastrointestinal bleeding Succinylcholine Digitalis intoxication Fluoride intoxication Adrenergic blockers Exercise Hyperosmolality Insulin deficiency Malignant hyperthermia (OMIM 145600601887601888) Hyperkalemic periodic paralysis (OMIM 170500) DECREASED EXCRETION Kidney failure Primary adrenal disease Acquired Addison disease 21 Hydroxylase deficiency (OMIM 201910) 3 Hydroxysteroid dehydrogenase deficiency (OMIM 201810) Lipoid congenital adrenal hyperplasia (OMIM 201710) Adrenal hypoplasia congenita (OMIM 300200) Aldosterone synthase deficiency (OMIM 203400610600) Adrenoleukodystrophy (OMIM 300100) Hyporeninemic hypoaldosteronism Urinary tract obstruction Sickle cell disease (OMIM 603903) Kidney transplant Lupus nephritis Renal tubular disease Pseudohypoaldosteronism type I (OMIM 264350177735) Pseudohypoaldosteronism type II (OMIM 614491614492614495) Bartter syndrome, type 2 (OMIM 241200) Urinary tract obstruction Kidney transplant Medications Renin inhibitors Angiotensin converting enzyme inhibitors Angiotensin II blockers Potassium sparing diuretics Calcineurin inhibitors |
944 | Nonsteroidal antiinflammatory drugs Trimethoprim Heparin Drospirenone (in some oral contraceptives) OMIM, database number from the Online Mendelian Inheritance in Man (http:www.n cbi.nlm.nih.govomim). Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 73 u Electrolyte and Acid Base Disorders 497 The kidneys excrete most of the daily K intake, so a decrease in kid ney function can cause hyperkalemia. Newborn infants in general, and especially premature infants, have decreased kidney function at birth; thus they are at increased risk for hyperkalemia despite an absence of intrinsic renal disease. Neonates also have decreased expression of K channels, further limiting K excretion. A wide range of primary adrenal disorders, both hereditary and acquired, can cause decreased production of aldosterone, with secondary hyperkalemia (see Chapters 615 and 616). Patients with these disorders typically have metabolic acidosis and salt wasting with hyponatremia. Children with subtle adrenal insufficiency may have electrolyte problems only during acute illnesses. The most common form of congenital adrenal hyperplasia, 21 hydroxylase deficiency, typically manifests in male infants as hyperkalemia, metabolic acidosis, hyponatremia, and volume depletion. Females with this disorder usually are diagnosed as newborns because of their ambiguous genitals; treatment prevents the development of electrolyte problems. Renin, via angiotensin II, stimulates aldosterone production. A defi ciency in renin, a result of kidney damage, can lead to decreased aldoste rone production. Hyporeninemia occurs in many kidney diseases, with some of the more common pediatric causes listed in Table 73.4. These patients typically have hyperkalemia and a metabolic acidosis, without hyponatremia. Some of these patients have impaired renal function, par tially accounting for the hyperkalemia, but the impairment in K excre tion is more extreme than expected for the degree of renal insufficiency. A variety of renal tubular disorders impair renal excretion of K. Children with pseudohypoaldosteronism type 1 have hyper kalemia, metabolic acidosis, and salt wasting (kidney, colon, sweat) leading to hyponatremia and volume depletion; aldosterone values are elevated. In the autosomal recessive variant, there is a defect in the renal Na channel that is normally activated by aldosterone. Patients with this variant have severe symptoms (failure to thrive, diarrhea, recurrent respiratory infections, miliaria rubra like rash), beginning in infancy. Patients with the autosomal dominant form have a defect in the aldosterone receptor, and the disease is milder, often remitting in adulthood. Pseudohypoaldosteronism type 2 (familial hyperkalemic hypertension), also called Gordon syn drome, is an autosomal dominant disorder characterized by hyper tension caused by salt retention and impaired excretion of K and acid, leading to hyperkalemia and hyperchloremic metabolic aci dosis. Pathogenic variants in at least four genes (WNK4, WNK1, KLHL3, CUL3) may cause Gordon syndrome. Patients may respond well to thiazide diuretics. In Bartter syndrome, caused by patho genic variants in the potassium channel ROMK (type 2 Bartter syndrome), there can be transient hyperkalemia in neonates, but hypokalemia subsequently develops (see Chapter 571.1). Acquired renal |
945 | tubular dysfunction, with an impaired ability to excrete K, occurs in a number of conditions. These disorders, all characterized by tubulointerstitial disease, are often associated with impaired acid secretion and a secondary metabolic acidosis. In some affected children, the metabolic acidosis is the dominant feature, although a high K intake may unmask the defect in K handling. The tubular dysfunction can cause renal salt wasting, potentially leading to hyponatremia. Because of the tubulointerstitial damage, these conditions may also cause hyperka lemia as a result of hyporeninemic hypoaldosteronism. The risk of hyperkalemia resulting from medications is greatest in patients with underlying renal insufficiency. The predominant mechanism of medication induced hyperkalemia is impaired renal excretion, although ACE inhibitors may worsen hyperkalemia in anuric patients, probably by inhibiting GI potassium loss, which is normally upregulated in renal insufficiency. The hyperkalemia caused by trimethoprim is especially problematic at higher doses. Potassium sparing diuretics may easily cause hyperkalemia because they are often used in patients receiving oral K supplements. Oral contraceptives containing drospirenone, which blocks the action of aldosterone, may cause hyperkalemia and should not be used in patients with decreased renal function. Clinical Manifestations The most important effects of hyperkalemia result from the role of K in membrane polarization. The cardiac conduction system is usually the dominant concern. Changes in the electrocardiogram (ECG) begin with peaking of the T waves. This is followed, as K level increases, by ST segment depression, an increased PR interval, flattening of the P wave, and widening of the QRS complex (Fig. 73.4). However, the correlation between K level and ECG changes is poor. This process can eventually progress to ventricular fibrilla tion. Asystole may also occur. Some patients have paresthesias, fas ciculations, weakness, and even an ascending paralysis, but cardiac toxicity usually precedes these clinical symptoms, emphasizing the danger of assuming that an absence of symptoms implies an absence of danger. Chronic hyperkalemia is generally better tolerated than acute hyperkalemia. A B C Lead V3 Fig. 73.4 The effects of progressive hyperkalemia on the electrocar diogram. All of the ECGs are from lead V3. A, Serum potassium concen tration (K) 6.8 mEqL; note the peaked T waves together with nor mal sinus rhythm. B, Serum K 8.9 mEqL; note the peaked T waves and absent P waves. C, Serum K 8.9 mEqL; note the classic sine wave with absent P waves, marked prolongation of the QRS complex, and peaked T waves. (From Goldman L, Schafer AI, eds. Goldman Cecil Medicine. 26th ed. Elsevier; 2020. Fig. 109.2, p. 727.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 498 Part VI u Fluid and Electrolyte Disorders Diagnosis The etiology of hyperkalemia is often readily apparent. Spurious hyperkalemia is very common in children, so obtaining a second potassium measurement is often appropriate. If there is a signifi cant elevation of WBC or platelet count, the |
946 | second measurement should be performed on a plasma sample that is evaluated promptly. The history should initially focus on potassium intake, risk factors for transcellular shifts of K, medications that cause hyperkalemia, and signs of renal insufficiency, such as oliguria and edema. Initial laboratory evaluation should include creatinine, BUN, and assess ment of the acid base status. Many etiologies of hyperkalemia cause metabolic acidosis, which worsens hyperkalemia through the tran scellular shift of K out of cells. Decreased kidney function is a common cause of the combination of metabolic acidosis and hyper kalemia, also seen in diseases associated with aldosterone insuffi ciency or aldosterone resistance. Children with absent or ineffective aldosterone often have hyponatremia and volume depletion because of salt wasting. Genetic diseases, such as congenital adrenal hyper plasia and pseudohypoaldosteronism, usually manifest in infancy and should be strongly considered in the infant with hyperkalemia and metabolic acidosis, especially if hyponatremia is present. It is important to consider the various etiologies of a transcel lular K shift. In some of these disorders, the K level continues to increase, despite the elimination of all K intake, especially with concurrent renal insufficiency. This increase is potentially seen in tumor lysis syndrome, hemolysis, rhabdomyolysis, and other causes of cell death. All these entities can cause concomitant hyper phosphatemia and hyperuricemia. Rhabdomyolysis produces an elevated creatinine phosphokinase (CPK) value and hypocalce mia, whereas children with hemolysis have hemoglobinuria and a decreasing hematocrit. For the child with diabetes, elevated blood glucose and acidosis suggest a transcellular shift of K. Treatment The plasma K level, the ECG, and the risk of the problem worsening determine the aggressiveness of the therapeutic approach. High serum K and the presence of ECG changes require vigorous treatment. An additional source of concern is the patient in whom plasma K levels are rising despite minimal intake. This situation can happen if there is cellular release of K (tumor lysis syndrome), especially in the setting of diminished excretion (kidney failure). The first action in a child with a concerning elevation of plasma K is to stop all sources of additional K (oral, IV). Washed RBCs can be used for patients who require blood transfusions. If the K is 6.5 mEqL, an ECG should be obtained to help assess the urgency of the situation. Peaked T waves are the first sign of hyperkalemia, followed by a prolonged PR interval, and when most severe, pro longed QRS complex. Life threatening ventricular arrhythmias may also develop. The treatment of hyperkalemia has two basic goals: (1) to stabilize the heart to prevent life threatening arrhythmias and (2) to remove K from the body. The treatments that acutely prevent arrhythmias all have the advantage of working quickly (within minutes) but do not remove K from the body. Calcium stabilizes the cell membrane of heart cells, preventing arrhythmias; it is given IV over a few minutes, and its action is almost immedi ate. Calcium should be given over 30 minutes in a patient receiving digitalis because the calcium |
947 | may cause arrhythmias. Bicarbonate causes potassium to move intracellularly, lowering the plasma K; it is most efficacious in a patient with a metabolic acidosis. Insulin causes K to move intracellularly but must be given with glucose to avoid hypoglycemia. The combination of insulin and glucose works within 30 minutes. Nebulized albuterol, by stimulation of 1 adrenergic receptors, leads to rapid intracellular movement of K. This has the advantage of not requiring an IV route of administration, allowing it to be given concurrently with the other measures. It is critical to begin measures that remove K from the body. In patients who are not anuric, a loop diuretic increases renal excretion of K. A high dose may be required in a patient with significant renal insufficiency. Sodium polystyrene sulfonate (SPS; Kayexalate) is an exchange resin that is given either rectally or orally. Patiromer and sodium zirconium cyclosilicate are oral exchange resins for treating hyperkalemia. Some patients require dialysis for acute K removal. Dialysis is often necessary if the patient has either severe kidney failure or an especially high rate of endogenous K release, as is sometimes present with tumor lysis syndrome or rhabdomyolysis. Hemodialysis rapidly lowers plasma K. Peritoneal dialysis is not nearly as quick or reliable, but it is usually adequate as long as the acute problem can be managed with medications and the endogenous release of K is not high. Long term management of hyperkalemia includes reducing intake through dietary changes and eliminating or reducing medications that cause hyperkalemia (see Chapter 572). Some patients require medica tions to increase potassium excretion, such as SPS, patiromer, sodium zirconium cyclosilicate, and loop or thiazide diuretics. Some infants with chronic kidney disease may need to start dialysis to allow ade quate caloric intake without hyperkalemia. It is unusual for an older child to require dialysis principally to control chronic hyperkalemia. The disorders caused by aldosterone deficiency respond to replacement therapy with fludrocortisone. HYPOKALEMIA Hypokalemia is common in children, with most cases related to gastroenteritis. Etiology and Pathophysiology There are four basic mechanisms of hypokalemia (Table 73.5). Spuri ous hypokalemia occurs in patients with leukemia and very elevated WBC counts if plasma for analysis is left at room temperature, permit ting the WBCs to take up K from the plasma. With a transcellular shift, there is no change in total body K, although there may be con comitant potassium depletion resulting from other factors. Decreased intake, extrarenal losses, and renal losses are all associated with total body K depletion. In addition, seasonal pseudo hypokalemia is seen during warm summer months as a laboratory phenomenon when blood samples are exposed to a warm environment. On immediate retesting, the potassium level is normal. This should not be confused with a pseudo Bartter syndrome (hypokalemic, hypochloremic, alka losis) seen in children with cystic fibrosis in a very warm environment due to excessive sweating. Because the intracellular K is much higher than the plasma level, a significant amount of K can move into cells without greatly changing |
948 | the intracellular K. Alkalemia is one of the more com mon causes of a transcellular shift. The effect is much greater with a metabolic alkalosis than with a respiratory alkalosis. The impact of exogenous insulin on K movement into the cells is substantial in patients with DKA. Endogenous insulin may be the cause when a patient is given a bolus of glucose. Both endogenous (epinephrine in stress) and exogenous (albuterol) adrenergic agonists stimu late cellular uptake of K. Theophylline overdose, barium intoxi cation, administration of cesium chloride (a homeopathic cancer remedy), and toluene intoxication from paint or glue sniffing can cause a transcellular shift hypokalemia, often with severe clinical manifestations. Children with hypokalemic periodic paralysis, a rare autosomal dominant disorder, have acute cellular uptake of K (see Chapter 651). Thyrotoxic periodic paralysis, which is more common in Asians, is an unusual initial manifestation of hyperthy roidism. Affected patients have dramatic hypokalemia as a result of a transcellular shift of potassium. Hypokalemia can occur during refeeding syndrome (see Chapters 63 and 385.7). Inadequate K intake occurs in anorexia nervosa; accompanying bulimia and laxative or diuretic abuse exacerbates the K deficiency. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 73 u Electrolyte and Acid Base Disorders 499 Sweat losses of K can be significant during vigorous exercise in a hot climate. Associated volume depletion and hyperaldosteron ism increase renal losses of K (discussed later). Diarrheal fluid has a high concentration of K, and hypokalemia because of diarrhea is usually associated with metabolic acidosis resulting from stool losses of bicarbonate. In contrast, normal acid base balance or mild metabolic alkalosis is seen with laxative abuse. Intake of potassium binding resins (SPS) or ingestion of clay because of pica increases stool losses of potassium. Urinary potassium wasting may be accompanied by a metabolic acidosis (proximal or distal RTA). In DKA, although it is often associated with normal plasma K from transcellular shifts, there is significant total body K depletion from urinary losses because of the osmotic diuresis, and the K level may decrease dramatically with insulin therapy (see Chapter 629). Both the polyuric phase of acute tubular necrosis and postobstructive diuresis cause transient, highly variable K wasting and may be associated with metabolic acidosis. Tubular damage, which occurs either directly from medi cations or secondary to interstitial nephritis, is often accompanied by other tubular losses, including magnesium, Na, and water. Such tubular damage may cause a secondary RTA with metabolic acido sis. Isolated magnesium deficiency causes renal K wasting. Peni cillin is an anion excreted in the urine, resulting in increased K excretion because the penicillin anion must be accompanied by a cation. Hypokalemia from penicillin therapy occurs only with the sodium salt of penicillin, not with the potassium salt. Urinary K wasting is often accompanied by a metabolic alkalo sis. This condition is usually associated with |
949 | increased aldosterone, which increases urinary K and acid losses, contributing to the hypokalemia and the metabolic alkalosis. Other mechanisms often contribute to both the K losses and the metabolic alkalosis. With emesis or nasogastric suction, there is gastric loss of K, but this is minimal given the low K content of gastric fluid, approximately 10 mEqL. More important is the gastric loss of hydrochloric acid (HCl), leading to metabolic alkalosis and a state of volume deple tion. The kidney compensates for metabolic alkalosis by excreting bicarbonate in the urine, but there is obligate loss of K and Na with the bicarbonate. The volume depletion raises aldosterone lev els, further increasing urinary K losses and preventing correction of metabolic alkalosis and hypokalemia until the volume depletion is corrected. Urinary chloride (Cl) is low as a response to the volume depletion. Because the volume depletion is secondary to Cl loss, this is a state of Cl deficiency. There were cases of Cl deficiency resulting from infant formula deficient in Cl, which caused a metabolic alkalosis with hypo kalemia and low urine Cl. Current infant formula is not deficient in Cl. A similar mechanism occurs in cystic fibrosis because of Cl loss in sweat. In congenital chloride losing diarrhea, an autosomal recessive Table 73.5 Causes of Hypokalemia SPURIOUS LABORATORY VALUE High white blood cell count TRANSCELLULAR SHIFTS Alkalemia Insulin Adrenergic agonists Drugstoxins (theophylline, barium, toluene, cesium chloride, hydroxychloroquine) Hypokalemic periodic paralysis (OMIM 170400) Thyrotoxic period paralysis Refeeding syndrome DECREASED INTAKE Anorexia nervosa EXTRARENAL LOSSES Diarrhea Laxative abuse Sweating Sodium polystyrene sulfonate (Kayexalate) or clay ingestion RENAL LOSSES With Metabolic Acidosis Distal renal tubular acidosis (OMIM 179800602722267300611590) Proximal renal tubular acidosis (OMIM 604278) Ureterosigmoidostomy Diabetic ketoacidosis Without Specific Acid Base Disturbance Tubular toxins: amphotericin, cisplatin, aminoglycosides Interstitial nephritis Diuretic phase of acute tubular necrosis Postobstructive diuresis Hypomagnesemia High urine anions (e.g., penicillin or penicillin derivatives) With Metabolic Alkalosis Low urine chloride Emesis or nasogastric suction Chloride losing diarrhea (OMIM 214700) Cystic fibrosis (OMIM 219700) Low chloride formula Posthypercapnia Previous loop or thiazide diuretic use High urine chloride and normal blood pressure Gitelman syndrome (OMIM 263800) Bartter syndrome (OMIM 2412006073646025226016783009716 01198613090) Autosomal dominant hypoparathyroidism (OMIM 146200) EAST syndrome (OMIM 612780) Autosomal dominant kidney hypomagnesemia due to RRAGD variant (OMIM not assigned) Loop and thiazide diuretics (current) High urine chloride and high blood pressure Adrenal adenoma or hyperplasia Glucocorticoid remediable aldosteronism (OMIM 103900) Hyperaldosteronism type II (OMIM 605635) Familial hyperaldosteronism type III (OMIM 613677) Familial hyperaldosteronism type IV (OMIM 617027) Renovascular disease Renin secreting tumor 17 Hydroxylase deficiency (OMIM 202110) 11 Hydroxylase deficiency (OMIM 202010) Cushing syndrome 11 Hydroxysteroid dehydrogenase deficiency (OMIM 218030) Licorice ingestion Liddle syndrome (OMIM 177200) Early onset autosomal dominant hypertension with exacerbation in pregnancy (OMIM 605115) Most cases of proximal renal tubular acidosis are not caused by this primary genetic disorder. Proximal renal tubular acidosis is usually part of Fanconi syndrome, which has multiple etiologies. EAST, Epilepsy, ataxia, sensorineural hearing loss, and tubulopathy; OMIM, database number from the Online Mendelian Inheritance in |
950 | Man (http:www.ncbi.nlm.nih.govomim). Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 500 Part VI u Fluid and Electrolyte Disorders disorder, there is high stool loss of Cl, leading to metabolic alkalosis, an unusual sequela of diarrhea. Because of stool K losses, Cl defi ciency, and metabolic alkalosis, patients with congenital chloride losing diarrhea have hypokalemia. During respiratory acidosis, there is renal compensation, with retention of bicarbonate and excretion of Cl. After the respiratory acidosis is corrected, the patients have Cl deficiency and post hypercapnic alkalosis with secondary hypokalemia. Patients with Cl deficiency, metabolic alkalosis, and hypokalemia have a urinary Cl of 10 mEqL. Loop and thiazide diuretics lead to hypoka lemia, metabolic alkalosis, and Cl deficiency. During treatment, these patients have high urine chloride levels resulting from the effect of the diuretic. However, after the diuretics are discontinued, there is residual Cl deficiency, the urinary Cl is appropriately low, and neither the hypokalemia nor the alkalosis resolves until the Cl deficiency is corrected. The combination of metabolic alkalosis, hypokalemia, high urine Cl, and normal blood pressure is characteristic of Bartter syn drome, Gitelman syndrome, and current diuretic use. Patients with any of these conditions have high urinary losses of Cl despite a state of relative volume depletion with secondary hyperaldosteron ism with high plasma renin. Bartter and Gitelman syndromes are autosomal recessive disorders caused by defects in tubular trans porters (see Chapter 571). Bartter syndrome is usually associated with hypercalciuria, and often with nephrocalcinosis, whereas chil dren with Gitelman syndrome have low urinary calcium losses but hypomagnesemia because of urinary magnesium losses. Some patients with Bartter syndrome have hypomagnesemia. A transient antenatal form of Bartter syndrome is associated with severe poly hydramnios and pathogenic variants in MAGED2. Some patients with hypoparathyroidism and hypocalcemia caused by activating pathogenic variants of the calcium sensing receptor (autosomal dominant hypoparathyroidism) have hypo kalemia, hypomagnesemia, and metabolic alkalosis. The reason is that activation of the calcium sensing receptor in the loop of Henle impairs tubular resorption of sodium and chloride, causing volume depletion and secondary hyperaldosteronism. EAST syndrome, an autosomal recessive disorder caused by pathologic variants in the gene for a potassium channel in the kidney, inner ear, and brain, consists of epilepsy, ataxia, sensorineural hearing loss, and tubu lopathy (hypokalemia, metabolic alkalosis, hypomagnesemia, and hypocalciuria). In the presence of high aldosterone levels, there is urinary loss of K, hypokalemia, metabolic alkalosis, and elevated urinary Cl; renal retention of Na leads to hypertension. Primary hyper aldosteronism caused by adenoma or hyperplasia is much less common in children than in adults (see Chapters 619 and 620). Glucocorticoid remediable aldosteronism, an autosomal domi nant disorder that leads to high levels of aldosterone (but low renin levels), is often diagnosed in childhood, although hypokalemia is not always present. Familial hyperaldosteronism type II, an auto somal dominant disorder, is due to a gain of |
951 | function variant in CLCN2 that causes increased aldosterone synthesis. Familial hyper aldosteronism type III, an autosomal dominant disorder, is due to a gain of function variant in KCNJ5 that causes a dramatic increase in aldosterone synthesis and severe hypertension and hypokalemia. Familial hyperaldosteronism type IV, an autosomal dominant dis order, is due to a gain of function variant in CACNA1H that causes increased aldosterone synthesis. Increased aldosterone levels may also be secondary to increased renin production. Renal artery stenosis leads to hypertension from increased renin and secondary hyperaldosteronism. The increased aldosterone can cause hypokalemia and metabolic alka losis, although most patients have normal electrolyte levels. Renin producing tumors, which are extremely rare, can cause hypokalemia. A variety of disorders cause hypertension and hypokalemia with out increased aldosterone levels. Some are a result of increased levels of mineralocorticoids other than aldosterone. Such increases occur in two forms of congenital adrenal hyperplasia (see Chap ter 616). In 11 hydroxylase deficiency, which is associated with virilization, 11 deoxycorticosterone is elevated, causing variable hypertension and hypokalemia. A similar mechanism, increased 11 deoxycorticosterone, occurs in 17 hydroxylase deficiency, but patients with this disorder are more uniformly hypertensive and hypokalemic, and they have a defect in sex hormone production. Cushing syndrome, frequently associated with hypertension, less frequently causes metabolic alkalosis and hypokalemia, secondary to the mineralocorticoid activity of cortisol. In 11 hydroxysteroid dehydrogenase deficiency, an autosomal recessive disorder, the enzymatic defect prevents the conversion of cortisol to cortisone in the kidney. Because cortisol binds to and activates the aldosterone receptor, children with this deficiency have all the features of exces sive mineralocorticoids, including hypertension, hypokalemia, and metabolic alkalosis, but low levels of aldosterone and renin. Patients with this disorder, which is also called apparent mineralocorticoid excess, respond to spironolactone therapy, which blocks the min eralocorticoid receptor. An acquired form of 11 hydroxysteroid dehydrogenase deficiency occurs from the ingestion of substances that inhibit this enzyme. A classic example is glycyrrhizic acid, which is found in natural licorice. Liddle syndrome is an auto somal dominant disorder that results from activating pathogenic variants of the distal nephron sodium channel that is normally upregulated by aldosterone. Patients have the characteristics of hyperaldosteronismhypertension, hypokalemia, and alkalosis but low serum renin and aldosterone levels. These patients respond to the potassium sparing diuretics (triamterene and amiloride) that inhibit this sodium channel (see Chapter 571.3). A pathogenic vari ant in the mineralocorticoid receptor causes early onset autosomal dominant hypertension with exacerbation in pregnancy. Hypo kalemia is usually mild but worsens during pregnancy; renin and aldosterone levels are low. Clinical Manifestations The heart and skeletal muscle are especially vulnerable to hypokalemia. ECG changes include a flattened T wave, a depressed ST segment, and the appearance of a U wave, which is located between the T wave (if still visible) and the P wave (Fig. 73.5). Ventricular fibrillation and torsades de pointes may occur, although usually only in the context of underly ing heart disease. Hypokalemia makes the heart especially susceptible to digitalis induced arrhythmias, such |
952 | as supraventricular tachycardia, ventricular tachycardia, and heart block (see Chapter 484). The clinical consequences of hypokalemia in skeletal muscle include muscle weakness and cramps. Paralysis is a possible complication, gen erally only at K 2.5 mEqL. It usually starts in the legs and moves to the arms. Respiratory paralysis may require mechanical ventilation. Some patients have rhabdomyolysis; the risk increases with exercise. Hypokalemia slows GI motility. This effect manifests as constipation; with K levels 2.5 mEqL, an ileus may occur. Hypokalemia impairs bladder function, potentially leading to urinary retention. Hypokalemia causes polyuria and polydipsia by impairing urinary concentrating ability, which produces nephrogenic diabetes insipidus. Hypokalemia stimulates renal ammonia production, an effect that is clinically significant if hepatic failure is present, because the liver can not metabolize the ammonia. Consequently, hypokalemia may worsen hepatic encephalopathy. Chronic hypokalemia may cause kidney dam age, including interstitial nephritis and renal cysts. Diagnosis Most causes of hypokalemia are readily apparent from the history. It is important to review the childs diet, GI losses, and medications. Both emesis and diuretic use can be surreptitious. The presence of hyperten sion suggests excess mineralocorticoid effects or levels. Concomitant electrolyte abnormalities are useful clues. The combination of hypo kalemia and metabolic acidosis is characteristic of diarrhea and distal and proximal RTA. A concurrent metabolic alkalosis is characteristic of emesis or nasogastric losses, aldosterone excess, use of diuretics, and Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 73 u Electrolyte and Acid Base Disorders 501 Bartter and Gitelman syndromes. Figure 73.6 shows an approach to persistent hypokalemia. If a clear etiology is not apparent, the measurement of urinary K distinguishes between renal and extrarenal losses. The kidneys should conserve K in the presence of extrarenal losses. Urinary K losses can be assessed with a 24 hour urine collection, spot K:creatinine ratio, fractional excretion of K, or calculation of the transtubular K gradi ent (TTKG), which is the most widely used approach in children: TTKG KurineKplasma (plasma osmolality urine osmolality) where Kurine urine potassium concentration and Kplasma plasma potassium concentration. The urine osmolality must be greater than the serum osmolality for the result of this calculation to be valid. A TTKG 4 in the presence of hypokalemia suggests excessive urinary losses of K. The urinary K excretion value can be misleading if the stimulus for renal loss, such as a diuretic, is no longer present. Treatment Factors that influence the treatment of hypokalemia include the K level, clinical symptoms, kidney function, the presence of transcel lular shifts of K, ongoing losses, and the patients ability to toler ate oral K. Severe, symptomatic hypokalemia requires aggressive treatment. Supplementation is more cautious if renal function is decreased because of the kidneys limited ability to excrete excessive K. The plasma potassium level does not always provide an accurate estimation of the total body K deficit because there |
953 | may be shifts of K from the ICS to the plasma. Clinically, such shifts occur most often with metabolic acidosis and the insulin deficiency of DKA; the plasma K measurement underestimates the degree of total body K depletion. When these problems are corrected, K moves into the ICS, so more K supplementation is required to correct the hypokale mia. Likewise, the presence of a transcellular shift of K into the cells indicates that the total body K depletion is less severe. In an isolated transcellular shift, as in hypokalemic periodic paralysis, K supple mentation should be used cautiously, given the risk of hyperkale mia when the transcellular shift resolves. This caution is especially required in thyrotoxic periodic paralysis, which responds dramati cally to propranolol, with correction of weakness and hypokalemia. Patients who have ongoing losses of K need correction of the deficit and replacement of the ongoing losses. Because of the risk of hyperkalemia, IV K should be used very cau tiously. Oral K is safer, but not as rapid in urgent situations. Liquid preparations are bitter tasting; microencapsulated or wax matrix for mulations are less irritating than tablets to the gastric mucosa. Oral dosing is variable depending on the clinical situation. A typical starting dose is 1 2 mEqkgday, with a maximum of 60 mEqday in divided doses. The dose of IV potassium is 0.5 1.0 mEqkg, usually given over 1 hour. The adult maximum dose is 40 mEq. Conservative dosing is gen erally preferred. Potassium chloride is the usual choice for supplemen tation, although the presence of concurrent electrolyte abnormalities may dictate other options. Patients with acidosis and hypokalemia can receive potassium acetate or potassium citrate. If hypophosphatemia is present, some of the potassium deficit can be replaced with potassium phosphate. It is sometimes possible to decrease ongoing K losses. For patients with excessive urinary losses, potassium sparing diuretics are effective, but they need to be used cautiously in patients with decreased kidney function. If hypokalemia, metabolic alkalosis, and volume depletion are present (with gastric losses), restoration of intravascu lar volume with adequate NaCl will decrease urinary K losses. Cor rection of concurrent hypomagnesemia is important because it may cause hypokalemia. Disease specific therapy is effective in many of the genetic tubular disorders. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. 73.5 Magnesium Larry A. Greenbaum MAGNESIUM METABOLISM Body Content and Physiologic Function Magnesium is the fourth most common cation in the body and the third most common intracellular cation (see Fig. 73.3). From 5060 of body magnesium is in bone, where it serves as a reservoir because 30 is exchangeable, allowing movement to the ECS. Most intracel lular magnesium is bound to proteins; only approximately 25 is exchangeable. Because cells with higher metabolic rates have higher magnesium concentrations, most intracellular magnesium is present in muscle and liver. The normal plasma magnesium concentration is 1.5 2.3 mgdL (1.2 1.9 mEqL; 0.62 0.94 mmolL), with some variation among clinical laboratories. Infants have slightly higher plasma magnesium concen trations than older |
954 | children and adults. Only 1 of body magnesium is extracellular (60 ionized, 15 complexed, 25 protein bound). In the United States, serum magnesium is reported as mgdL (Table 73.6). Values in the left column unit are converted into the right column unit by multiplying the conversion factor (e.g., calcium of 10 mgdL 0.25 2.5 mmolL). Dividing the right column unit by the conversion fac tor converts to the units of the left column unit. V2 V3 V4 Fig. 73.5 The ECG manifestations of hypokalemia. The serum po tassium concentration was 2.2 mEqL. The ST segment is prolonged, primarily because of a U wave following the T wave, and the T wave is flattened. (From Goldman L, Schafer AI, eds. Goldman Cecil Medicine. 26th ed. Elsevier; 2020. Fig. 109.1, p 727.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 502 Part VI u Fluid and Electrolyte Disorders Hypokalemia Hypertension High aldosterone Low Normal DOC Variable aldosterone High DOC High 17OHP Low cortisol High ACTH High 17OHP High cortisol High ACTH Normal 17OHP Normal cortisol Normal ACTH Low normal 17OHP Low cortisol High ACTH Low aldosterone Low Normal DOC Acute alkalosis Insulin adrenergic stimulants Periodic paralysis Barium poisoning Acute increase in blood cells 11 hydroxylase deficiency 17 hydroxylase deficiency GR resistance DOCsecreting tumors Drugs (antibiotics, etc.) Polyuric disorders Saline diuresis (K? free) Magnesium depletion Congenital K? wasting Acquired K? wasting Leukemia Recent diuretic effect Bartter syndrome Gitelman syndrome Hypovolemia Renal parenchymal disease Renovascular disease Renal compression Renal tumors Pheochromocytoma Excess ACTH Glucocorticoids AME, licorice, Carbenoxolone Chronic grapefruit juice intake Liddle syndrome (PAI) MR activating mutation (PAII) Exogenous mineralocorticoid Excess ACTH Glucocorticoids Primary aldosteronism tumors, hyperplasia GRA (FHI), FHII Sweat loss Gi loss Pica geophagia K? binders, fistulas Diarrhea, laxatives Renal tubular acidosis (I and II) Carbonic anhydrase inhibitors Ureterosigmoid diversion Diabetic ketoacidosis Low normal BP Metabolic alkalosis Metabolic acidosis Variable acidbase status Reduced total body K? Cellular uptake of K? Excessive K? lossInsufficient K? intake Extrarenal loss (Urine K? ? 15 mEqL ; TTKG ? 4) Renal loss (Urine K? ? 15 mEqL ; TTKG ? 4) Urine Cl? ? 15Urine Cl? ? 15 Cl? Deficient diet GI Cl? loss (emesis NG drainage) Sweat Cl? loss Posthypercapnea Postdiuretic effect PRA ? 0.5 ngmLhr; DR ? 15 mUL PRA ? 0.5 ngmLhr; DR ? 15 mUL Fig. 73.6 Diagnostic algorithm to evaluate persistent hypokalemia. Spurious hypokalemia must be excluded. Hypokalemia is uncommon in uncomplicated edematous disorders and in conditions associated with excessive glucocorticosteroids. Conditions associated with high circulat ing levels of glucocorticosteroids often have normal renin activity. 17 OHP, 17 Hydroxyprogesterone; ACTH, adrenocorticotropic hormone; AME, apparent mineralocorticoid excess; BP, blood pressure; Cl, chloride; DOC, 11 deoxycorticosterone; DR, direct renin assay; GI, gastrointestinal; FH II, familial hyperaldosteronism type II; GR, glucocorticoid receptor; GRA (FH I), glucocorticoid remediable aldosteronism (familial hyperaldo steronism type I); K, potassium; MR, mineralocorticoid receptor; |
955 | PA I, pseudohyperaldosteronism type I; PA II, pseudohyperaldosteronism type II; PRA, plasma renin activity; TTKG, transtubular potassium gradient. (From Shoemaker LR, Eaton BV, Buchino JJ. A three year old with persistent hypokalemia. J Pediatr. 2007;1516:696699.) Magnesium is a necessary cofactor for hundreds of enzymes. It is important for membrane stabilization and nerve conduction. Adenos ine triphosphate (ATP) and guanosine triphosphate need associated magnesium when they are used by ATPases, cyclases, and kinases. Magnesium Intake Between 30 and 50 of dietary magnesium is absorbed. Good dietary sources include green vegetables, cereals, nuts, meats, and hard water, although many foods contain magnesium. Human milk contains approximately 35 mgL of magnesium; formula contains 40 70 mgL. The small intestine is the major site of magnesium absorption, but the regulation of magnesium absorption is poorly understood. There is passive absorption, which permits high absorption in the presence of excessive intake. It probably occurs by a paracellular mechanism. Absorption is diminished in the presence of substances that complex with magnesium (free fatty acids, fiber, phytate, phosphate, oxalate); increased intestinal motility and calcium also decrease magnesium absorption. Vitamin D and parathyroid hormone (PTH) may enhance absorption, although this effect is limited. Intestinal absorption does increase when intake is decreased, possibly by a saturable, active trans port system. If there is no oral intake of magnesium, obligatory secre tory losses prevent the complete elimination of intestinal losses. Magnesium Excretion Renal excretion is the principal regulator of magnesium balance. There is no defined hormonal regulatory system, although PTH may increase Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 73 u Electrolyte and Acid Base Disorders 503 tubular resorption. Approximately 15 of resorption occurs in the proximal tubule and 70 in the thick ascending limb (TAL) of the loop of Henle. Proximal resorption may be higher in neonates. High serum magnesium levels inhibit resorption in the TAL, suggesting that active transport is involved. Approximately 510 of filtered magnesium is resorbed in the distal tubule. Hypomagnesemia increases absorption in the TAL and the distal tubule. HYPOMAGNESEMIA Hypomagnesemia is relatively common in hospitalized patients, although most cases are asymptomatic. Detection requires a high index of suspicion because magnesium is not measured in most basic meta bolic panels. Etiology and Pathophysiology GI and renal losses are the major causes of hypomagnesemia (Table 73.7). Diarrheal fluid contains up to 200 mgL of magnesium; gastric contents have only approximately 15 mgL, but high losses can cause depletion. Steatorrhea causes magnesium loss because of the formation of magnesium lipid salts; restriction of dietary fat can decrease losses. The potassium lowering agent patiromer binds magnesium and may cause hypomagnesemia. Hypomagnesemia with secondary hypocalcemia, a rare autoso mal recessive disorder, is caused by decreased intestinal absorption of magnesium and renal magnesium wasting. Patients with this disorder have pathogenic variants in a gene expressed in intestine and kidney; TRPM6 codes for |
956 | a transient receptor potential cation channel. The patients have seizures, tetany, tremor, or restlessness at 2 8 weeks of life because of severe hypomagnesemia (0.2 0.8 mgdL) and secondary hypocalcemia. Renal losses may occur because of medications that are direct tubu lar toxins. Amphotericin frequently causes significant magnesium wasting and is typically associated with other tubular defects (espe cially potassium wasting). Cisplatin produces dramatic renal mag nesium losses. Diuretics affect tubular handling of magnesium. Loop diuretics cause a mild increase in magnesium excretion, and thiazide diuretics have even less effect. Chronic use of proton pump inhibi tors (PPIs) may cause hypomagnesemia. Potassium sparing diuretics reduce magnesium losses. Osmotic agents, such as mannitol, glucose in diabetes mellitus, and urea in the recovery phase of acute tubular necrosis, increase urinary magnesium losses. Epidermal growth fac tor (EGF) receptor inhibitors cause renal magnesium wasting. IV fluid, by expanding the intravascular volume, decreases renal resorption of Table 73.6 Conversion Factors for Calcium, Magnesium, and Phosphorus UNIT CONVERSION FACTOR UNIT Calcium mgdL 0.25 mmolL mEqL 0.5 mmolL mgdL 0.5 mEqL Magnesium mgdL 0.411 mmolL mEqL 0.5 mmolL mgdL 0.822 mEqL Phosphorus mgdL 0.32 mmolL Table 73.7 Causes of Hypomagnesemia GASTROINTESTINAL LOSSES Diarrhea Nasogastric suction or emesis Inflammatory bowel disease Celiac disease Cystic fibrosis Intestinal lymphangiectasia Small bowel resection or bypass Pancreatitis Protein calorie malnutrition Patiromer Hypomagnesemia with secondary hypocalcemia (OMIM 602014) RENAL DISORDERS Medications Amphotericin Cisplatin Cyclosporine, tacrolimus Loop and thiazide diuretics Mannitol Pentamidine Proton pump inhibitors Aminoglycosides Thiazide diuretics Epidermal growth factor receptor inhibitors Diabetes Acute tubular necrosis (recovery phase) Postobstructive nephropathy Chronic kidney diseases Interstitial nephritis Glomerulonephritis Postrenal transplantation Hypercalcemia Intravenous fluids Primary aldosteronism Genetic diseases Gitelman syndrome (OMIM 263800) Bartter syndrome (OMIM 2412006073646025226016783009716 01198613090) Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (OMIM 248250) Familial hypomagnesemia with hypercalciuria, nephrocalcinosis, and severe ocular involvement (OMIM 248190) Autosomal recessive renal magnesium wasting with normocalciuria (OMIM 611718) Renal cysts and diabetes syndrome due to HNF1 variants (OMIM 137920) Autosomal dominant hypomagnesemia (OMIM 160120613882154020) EAST syndrome (OMIM 612780) Autosomal dominant hypoparathyroidism (OMIM 146200) Mitochondrial disorders (OMIM 500005) Hyperuricemia, pulmonary hypertension, renal failure in infancy and alkalosis, HUPRA syndrome (OMIM 613845) Transient neonatal hyperphenylalaninemia followed by hypomagnesemia and maturity onset diabetes of the young (OMIM 264070) Hypomagnesemia, seizures and mental retardation due to CNNM2 pathogenic variants (OMIM 616418) Autosomal dominant kidney hypomagnesemia due to RRAGD pathogenic variants (OMIM not assigned) MISCELLANEOUS CAUSES Poor intake Hungry bone syndrome Insulin administration Pancreatitis Intrauterine growth restriction Infants of diabetic mothers Exchange transfusion This disorder is also associated with renal magnesium wasting. EAST, Epilepsy, ataxia, sensorineural hearing loss, and tubulopathy; OMIM, database number from the Online Mendelian Inheritance in Man (http:www.ncbi.nlm.nih.govomim). Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 504 Part VI u Fluid and Electrolyte Disorders sodium and water, thereby impairing magnesium resorption. Hyper calcemia inhibits magnesium resorption in the loop of Henle, although this inhibition |
957 | does not occur in hypercalcemia caused by familial hypercalcemic hypocalciuria or lithium. A number of rare genetic diseases cause renal magnesium loss. Gitelman and Bartter syndromes, both autosomal recessive disor ders, are the most common entities (see Chapter 571). Gitelman syndrome, caused by a defect in the thiazide sensitive Na Cl co transporter in the distal tubule, is usually associated with hypomag nesemia. Hypomagnesemia occurs in a minority of patients with Bartter syndrome, which can be caused by pathogenic variants in multiple genes necessary for Na and Cl reabsorption in the loop of Henle. In both disorders, there is hypokalemic metabolic alkalo sis. Typically, hypomagnesemia is not severe and is asymptomatic, although tetany as a result of hypomagnesemia occasionally occurs. Familial hypomagnesemia with hypercalciuria and nephro calcinosis (Michelis Castrillo syndrome), an autosomal recessive disorder, is caused by pathogenic variants in the gene for claudin 16 (paracellin 1), located in the tight junctions of the TAL of the loop of Henle. Patients with the disease have severe renal wasting of magnesium and calcium with secondary hypomagnesemia and nephrocalcinosis; serum calcium levels are normal. Chronic kidney failure frequently occurs during childhood. Other features include kidney stones, urinary tract infections, hematuria, increased PTH levels, tetany, seizures, incomplete distal RTA, hyperuricemia, poly uria, and polydipsia. Patients with familial hypomagnesemia with hypercalciuria, nephrocalcinosis, and severe ocular involvement have pathogenic variants in the gene for claudin 19. Autosomal recessive renal magnesium wasting with normocalci uria is caused by pathogenic variants in the EGF gene. Clinical mani festations include seizures, mild to moderate psychomotor retardation, and brisk tendon reflexes. Autosomal dominant renal magnesium wasting is caused by pathogenic variants in a number of different genes. A dominant negative pathogenic variant in the gene encoding the Na,K ATPase subunit is associated with hypomagnesemia, increased urinary magnesium losses, hypocalciuria, and normocalcemia. Patients may present with seizures; most are asymptomatic, despite serum magnesium levels of 0.8 1.5 mgdL. Pathogenic variants in CNNM2, which encodes a protein that mediates magnesium sensitive sodium currents, cause isolated hypomagnesemia. A pathogenic variant in KCNA1, a gene that encodes a K channel, also causes an autosomal dominant form of hypomagnesemia; symptoms may be severe. Renal cysts and diabetes syndrome, which is caused by patho genic variants in the gene for hepatocyte nuclear factor 1, is associated with hypomagnesemia, despite the frequent presence of decreased kidney function. The hypomagnesemia is usually mild but may cause symptomatic hypocalcemia. EAST syndrome is caused by pathogenic variants in a potassium channel, and patients with this autosomal recessive disorder have hypokalemia, metabolic alkalosis, and hypomagnesemia. Pathogenic variants of RRAGD cause autosomal dominant kidney hypomagnesemia, and affected patients may have hypokalemia, hypomagnesemia, metabolic alkalosis, hypercalciuria, nephrocalcinosis, and a severe cardiomyopathy. Autosomal dominant hypoparathyroidism is caused by an activating pathogenic variant in the calcium sensing receptor, which also senses magnesium levels in the kidney (see Chapter 611). The abnormal receptor inappropriately perceives that magnesium and calcium levels are elevated, leading to urinary wast ing of both cations. Hypomagnesemia, if present, is usually |
958 | mild. A pathogenic variant in a mitochondrially encoded transfer RNA is associated with hypomagnesemia, hypertension, and hypercho lesterolemia. Hypomagnesemia is occasionally present in children with other mitochondrial disorders. Poor intake is an unusual cause of hypomagnesemia, although it can be seen in children who are hospitalized and receive only IV fluids without magnesium. In hungry bone syndrome, which most frequently occurs after parathyroidectomy in patients with hyper parathyroidism, magnesium moves into bone as a result of acceler ated bone formation. These patients usually have hypocalcemia and hypophosphatemia through the same mechanism. A similar mecha nism can occur during the refeeding phase of protein calorie mal nutrition in children, with high magnesium use during cell growth depleting the patients limited reserves. Insulin therapy stimulates uptake of magnesium by cells, and in DKA, in which total body magnesium is low because of osmotic losses, hypomagnesemia fre quently occurs. In pancreatitis there is saponification of magne sium and calcium in necrotic fat, causing both hypomagnesemia and hypocalcemia. Transient hypomagnesemia in newborns, which is sometimes idio pathic, is more common in infants of diabetic mothers, presumably as a result of maternal depletion from osmotic losses. Other maternal dis eases that cause magnesium losses predispose infants to hypomagne semia. Hypomagnesemia is more common in infants with intrauterine growth restriction. Hypomagnesemia may develop in newborn infants who require exchange transfusions because of magnesium removal by the citrate in banked blood. Clinical Manifestations Hypomagnesemia causes secondary hypocalcemia by impairing the release of PTH by the parathyroid gland and through blunting of the tissue response to PTH. Thus hypomagnesemia is part of the differen tial diagnosis of hypocalcemia. It usually occurs only at magnesium levels 0.7 mgdL. The dominant manifestations of hypomagnesemia are caused by hypocalcemia: tetany, presence of Chvostek and Trous seau signs, and seizures. However, with severe hypomagnesemia, these same signs and symptoms may be present despite normocalcemia. Persistent hypocalcemia caused by hypomagnesemia is a rare cause of rickets. Many causes of hypomagnesemia also result in hypokalemia. Hypo magnesemia may produce renal potassium wasting and hypokalemia that corrects only with magnesium therapy. ECG changes with hypo magnesemia include flattening of the T wave and lengthening of the ST segment. Arrhythmias may occur, almost always in the setting of underlying heart disease. Diagnosis The etiology of hypomagnesemia is often readily apparent from the clinical situation. The child should be assessed for GI disease, adequate intake, and kidney disease, with close attention paid to medications that may cause renal magnesium wasting. When the diagnosis is uncertain, an evaluation of urinary magnesium losses distinguishes between renal and nonrenal causes. The fractional excretion of magnesium (FEMg) is calculated via the following formula: FEMg (UMg PCr) (0.7 PMg UCr) 100 where UMg urinary magnesium concentration, PCr plasma cre atinine concentration, PMg plasma magnesium concentration, and UCr urinary magnesium concentration. The plasma magnesium con centration is multiplied by 0.7 because approximately 30 is bound to albumin and not filtered at the glomerulus. The FEMg does not vary with age, but it does |
959 | change according to the serum magnesium concentration. The FEMg ranges from 18 in children with normal magnesium levels. In the patient with hypomag nesemia as a result of extrarenal causes, FEMg should be low because of renal conservation, typically 2. The FEMg is inappropriately elevated in the setting of renal magnesium wasting; values are usually 4 and frequently 10. The measurement should not be made during a magnesium infusion, because the acute increase in serum magnesium increases urinary magnesium. Other approaches for evaluating urinary magnesium losses include calculation of 24 hour urinary magnesium losses and the urine magnesiumcreatinine ratio, both of which vary with age. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 73 u Electrolyte and Acid Base Disorders 505 The genetic causes of renal magnesium loss are distinguished based on the measurement of other serum and urinary electrolytes. Children with Gitelman or Bartter syndrome have hypokalemia and metabolic alkalosis. Treatment Severe hypomagnesemia is treated with parenteral magnesium. Magnesium sulfate is given at a dose of 25 50 mgkg (0.05 0.1 mL kg of a 50 solution; 2.5 5.0 mgkg of elemental magnesium). It is administered as a slow IV infusion, although it may be given intra muscularly in neonates. The rate of IV infusion should be slowed if a patient experiences diaphoresis, flushing, or a warm sensa tion. The dose is often repeated every 6 hours (every 8 12 hours in neonates), for a total of 2 3 doses, before the plasma magnesium concentration is rechecked. Lower doses are used in children with decreased kidney function. Long term therapy is usually given orally. Preparations include magnesium gluconate (5.4 mg elemental magnesium100 mg), magnesium oxide (60 mg elemental magnesium100 mg), and magnesium sulfate (10 mg elemental magnesium100 mg). Sustained release preparations include Slow Mag (60 mg elemen tal magnesiumtablet) and Mag Tab SR (84 mg elemental magne siumtablet). Oral magnesium dosing should be divided to decrease cathartic side effects. Alternatives to oral magnesium are intramus cular injections and nighttime nasogastric infusion, both designed to minimize diarrhea. Magnesium supplementation must be used cautiously in the context of renal insufficiency. HYPERMAGNESEMIA Clinically significant hypermagnesemia is almost always secondary to excessive intake. It is unusual, except in neonates born to mothers who are receiving IV magnesium for preeclampsia or eclampsia (see Chap ter 121.5). Etiology and Pathophysiology There is no feedback mechanism to prevent magnesium absorption from the GI tract. Magnesium is present in high amounts in certain laxatives, enemas, cathartics used to treat drug overdoses, and ant acids. It is also usually present in total parenteral nutrition (TPN), and neonates may receive high amounts transplacentally if mater nal levels are elevated. Usually the kidneys excrete excessive magne sium, but this ability is diminished in patients with chronic kidney disease. In addition, neonates and young infants are vulnerable to excessive magnesium ingestion because of their |
960 | reduced GFR. Most pediatric cases not related to maternal hypermagnesemia occur in infants because of excessive use of antacids or laxatives. Mild hypermagnesemia may occur in chronic kidney disease, familial hypocalciuric hypercalcemia, DKA, lithium ingestion, milk alkali syndrome, and tumor lysis syndrome. The hypermagnesemia in DKA occurs despite significant intracellular magnesium depletion because of urinary losses; hypomagnesemia often occurs after insu lin treatment. Clinical Manifestations Symptoms usually do not appear until the plasma magnesium level is 4.5 mgdL. Hypermagnesemia inhibits acetylcholine release at the neuromuscular junction, producing hypotonia, hyporeflexia, and weakness; paralysis occurs at high concentrations. The neuro muscular effects may be exacerbated by aminoglycoside antibiot ics. Direct CNS depression causes lethargy and sleepiness; infants have a poor suck. Elevated magnesium values are associated with hypotension because of vascular dilation, which also causes flush ing. Hypotension can be profound at higher concentrations from a direct effect on cardiac function. ECG changes include prolonged PR interval, QRS complex, and QT interval. Severe hypermagne semia (15 mgdL) causes complete heart block and cardiac arrest. Other manifestations of hypermagnesemia include nausea, vomit ing, and hypocalcemia. Diagnosis Except for the case of the neonate with transplacental exposure, a high index of suspicion and a good history are necessary to determine the etiology of hypermagnesemia. Prevention is essential; magnesium containing compounds should be used judiciously in children with decreased kidney function. Treatment Most patients with normal kidney function rapidly clear excess mag nesium. Intravenous hydration and loop diuretics can accelerate this process. In severe cases, especially in patients with underlying renal insufficiency, dialysis may be necessary. Hemodialysis works faster than peritoneal dialysis. Exchange transfusion is another option in newborn infants. Supportive care includes monitoring of cardiorespi ratory status, provision of fluids, monitoring of electrolyte levels, and the use of pressors for hypotension. In acute emergencies, especially in the context of severe neurologic or cardiac manifestations, 100 mgkg of IV calcium gluconate is transiently effective. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. 73.6 Phosphorus Larry A. Greenbaum Approximately 65 of plasma phosphorus is in phospholipids, but these compounds are insoluble in acid and are not measured by clinical laboratories. It is the phosphorus content of plasma phosphate that is determined. The result is reported as either phosphate or phosphorus, although even when the term phosphate is used, it is actually the phos phorus concentration that is measured and reported. The result is that the terms phosphate and phosphorus are often used interchangeably. The term phosphorus is preferred when referring to the plasma concen tration. Conversion from the units used in the United States (mgdL) to mmolL is straightforward (see Table 73.6). PHOSPHORUS METABOLISM Body Content and Physiologic Function Most phosphorus is in bone or is intracellular, with 1 in plasma. At a physiologic pH, there are monovalent and divalent forms of phos phate because the pKa (ionization constant of acid) of these forms is 6.8. Approximately 80 is divalent, and the remainder is monovalent at a pH of 7.4. A small percentage of plasma phosphate, approximately |
961 | 15, is protein bound. The remainder can be filtered by the glomeru lus, with most existing as free phosphate and a small percentage com plexed with calcium, magnesium, or sodium. Phosphate is the most plentiful intracellular anion, although the majority is part of a larger compound (ATP). More than that of any other electrolyte, the phosphorus concentra tion varies with age (Table 73.8). The teleologic explanation for the high concentration during childhood is the need for phosphorus to facilitate growth. There is diurnal variation in the plasma phosphorus concentration, with the peak during sleep. Table 73.8 Serum Phosphorus Levels During Childhood AGE PHOSPHORUS LEVEL (mgdL) 0 5 day 4.8 8.2 1 3 yr 3.8 6.5 4 11 yr 3.7 5.6 12 15 yr 2.9 5.4 16 19 yr 2.7 4.7 Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 506 Part VI u Fluid and Electrolyte Disorders Phosphorus, as a component of adenosine triphosphate (ATP) and other trinucleotides, is critical for cellular energy metabolism. It is nec essary for cell signaling and nucleic acid synthesis, and it is a com ponent of cell membranes and other structures. Along with calcium, phosphorus is necessary for skeletal mineralization. A net positive phosphorus balance is required during growth, with the growing skel eton especially vulnerable to deficiency. Phosphorus Intake Phosphorus is readily available in food. Milk and milk products are the best sources of phosphorus; high concentrations are present in meat and fish. Vegetables have more phosphorus than fruits and grains. GI absorption of phosphorus is proportional to intake, with approxi mately 65 of intake being absorbed, including a small amount that is secreted. Absorption, almost exclusively in the small intestine, occurs via a paracellular diffusive process and a vitamin Dregulated trans cellular pathway. However, the impact of the change in phosphorus absorption caused by vitamin D is relatively small compared with the effect of variations in phosphorus intake. Phosphorus Excretion Despite the wide variation in phosphorus absorption dictated by oral intake, excretion matches intake, except for the needs for growth. The kidney regulates phosphorus balance, which is deter mined by intrarenal mechanisms and hormonal actions on the nephron. Approximately 90 of plasma phosphate is filtered at the glomeru lus, although there is some variation based on plasma phosphate and calcium concentrations. There is no significant secretion of phosphate along the nephron. Resorption of phosphate occurs mostly in the proximal tubule, although a small amount can be resorbed in the distal tubule. Normally, approximately 85 of the filtered load is resorbed. Sodium phosphate co transporters mediate the uptake of phosphate into the cells of the proximal tubule. Dietary phosphorus determines the amount of phosphate resorbed by the nephron. There are both acute and chronic changes in phos phate resorption that are based on intake. Many of these changes appear to be mediated by intrarenal mechanisms that are indepen |
962 | dent of regulatory hormones. Fibroblast growth factor 23 (FGF 23) inhibits renal resorption of phosphorus in the proximal tubule, and its level increases in the setting of hyperphosphatemia. FGF 23 also inhibits synthesis of 1,25 vitamin D in the kidney by decreasing 1 hydroxylase activity. Secreted in response to a low plasma calcium level, PTH decreases resorption of phosphate, increasing the urinary phosphate level. This process appears to have a minimal effect during normal physiologic variation in PTH levels. However, it does affect urinary phosphate in the setting of pathologic changes in PTH synthesis. Low plasma phosphorus stimulates the 1 hydroxylase in the kidney that converts 25 hydroxyvitamin D (25 D) to 1,25 dihydroxyvitamin D (1,25 D; calcitriol). Calcitriol increases intestinal absorption of phos phorus and is necessary for maximal renal resorption of phosphate. The effect of a change in calcitriol on urinary phosphate is significant only when the level of calcitriol was initially low, arguing against a role for calcitriol in nonpathologic conditions. HYPOPHOSPHATEMIA Because of the wide variation in normal plasma phosphorus levels, the definition of hypophosphatemia is age dependent (see Table 73.8). The normal range reported by a laboratory may be based on adult normal values and therefore may be misleading in children. A serum phos phorus level of 3 mgdL, a normal value in an adult, indicates clinically significant hypophosphatemia in an infant. The plasma phosphorus level does not always reflect the total body stores because only 1 of phosphorus is extracellular. Thus a child may have significant phosphorus deficiency despite a normal plasma phosphorus concentration when there is a shift of phosphorus from the ICS. Etiology and Pathophysiology A variety of mechanisms cause hypophosphatemia (Table 73.9). A transcellular shift of phosphorus into cells occurs with processes that stimulate cellular usage of phosphorus (glycolysis). Usually, this shift causes only a minor, transient decrease in plasma phosphorus, but if intracellular phosphorus deficiency is present, the plasma phosphorus level can decrease significantly, producing symptoms of acute hypo phosphatemia. Glucose infusion stimulates insulin release, leading to entry of glucose and phosphorus into the cells. Phosphorus is then used during glycolysis and other metabolic processes. A similar phenomenon can occur during the treatment of DKA, and patients with DKA are typi cally phosphorus depleted because of urinary phosphorus losses. Table 73.9 Causes of Hypophosphatemia TRANSCELLULAR SHIFTS Glucose infusion Insulin Refeeding Total parenteral nutrition Respiratory alkalosis Tumor growth Bone marrow transplantation Hungry bone syndrome DECREASED INTAKE Nutritional Premature infants Low phosphorus formula Antacids and other phosphate binders RENAL LOSSES Hyperparathyroidism Parathyroid hormonerelated peptide X linked hypophosphatemic rickets (OMIM 307800) Overproduction of fibroblast growth factor 23 Tumor induced rickets McCune Albright syndrome (OMIM 174800) Epidermal nevus syndrome Neurofibromatosis Autosomal dominant hypophosphatemic rickets (OMIM 193100) Autosomal recessive hypophosphatemic rickets, types 1, 2, and 3 (OMIM 241520613312) Ferric carboxymaltose Dent disease (OMIM 300009300555) Fanconi syndrome (OMIM 134600613388615605616026618913 612392) Hypophosphatemic rickets with hypercalciuria (OMIM 241530) Hypophosphatemic rickets with nephrolithiasis and osteoporosis types 1 and 2 (OMIM 612286612287) Volume expansion and intravenous fluids Metabolic acidosis Diuretics |
963 | Glycosuria Glucocorticoids Chemotherapy (cisplatin, ifosfamide) Kidney transplantation MULTIFACTORIAL Vitamin D deficiency Vitamin Ddependent rickets type 1 (OMIM 264700) Vitamin Ddependent rickets type 2 (OMIM 277440) Alcoholism Sepsis Dialysis These are primary genetic causes of Fanconi syndrome. Fanconi syndrome may also be secondary to medications, genetic disorders (cystinosis) or systemic disease (Sjgren syndrome). OMIM, database number from the Online Mendelian Inheritance in Man (http:www.n cbi.nlm.nih.govomim). Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 73 u Electrolyte and Acid Base Disorders 507 Refeeding of patients with protein calorie malnutrition causes anabolism, which leads to significant cellular demand for phospho rus (see Chapter 63). The increased phosphorus uptake for incorpo ration into newly synthesized compounds containing phosphorus leads to hypophosphatemia, which can be severe and symptomatic. Refeeding hypophosphatemia occurs frequently during treat ment of severe anorexia nervosa. It can occur during treatment of children with malnutrition from any cause, such as cystic fibrosis, Crohn disease, burns, neglect, chronic infection, or famine. Hypo phosphatemia usually occurs within the first 5 days of refeeding and is prevented by a gradual increase in nutrition with appropriate phosphorus supplementation. TPN without adequate phosphorus can cause hypophosphatemia. Phosphorus moves into the ICS during a respiratory alkalosis and during recovery from a respiratory acidosis. An acute decrease in the carbon dioxide concentration, by raising the intracellular pH, stimulates glycolysis, leading to intracellular use of phosphorus and hypophosphatemia. Because a metabolic alkalosis has less effect on the intracellular pH (CO2 diffuses across cell membranes much faster than bicarbonate), transcellular phosphorus movement is minimal with a metabolic alkalosis. Tumors that grow rapidly, such as those associated with leuke mia and lymphoma, may use large amounts of phosphorus, leading to hypophosphatemia. A similar phenomenon may occur during the hematopoietic reconstitution that follows bone marrow trans plantation. In hungry bone syndrome, there is avid bone uptake of phosphorus, along with calcium and magnesium, which can pro duce plasma deficiency of all three ions. Hungry bone syndrome is most common after parathyroidectomy for hyperparathyroidism because the stimulus for bone dissolution is acutely removed, but bone synthesis continues. Nutritional phosphorus deficiency is unusual because most foods contain phosphorus. However, infants are especially susceptible because of their high demand for phosphorus to support growth, especially of the skeleton. Very low birthweight infants have partic ularly rapid skeletal growth, and phosphorus deficiency and rickets may develop if they are fed human milk or formula for term infants. There is also a relative deficiency of calcium. The provision of addi tional calcium and phosphorus, using breast milk fortifier or special premature infant formula, prevents this complication. Phosphorus deficiency, sometimes with concomitant calcium and vitamin D deficiencies, occurs in infants who are not given enough milk or who receive a milk substitute that is nutritionally inadequate. Antacids containing aluminum hydroxide (e.g., Maalox, Mylanta) bind dietary phosphorus and secreted phosphorus, pre venting absorption. |
964 | This process can cause phosphorus deficiency and rickets in growing children. A similar mechanism causes hypo phosphatemia in patients who are overtreated for hyperphosphate mia with phosphorus binders. In children with kidney failure, the addition of dialysis to phosphorus binders increases the risk of iat rogenic hypophosphatemia in these normally hyperphosphatemic patients. This complication, which is more common in infants, can worsen kidney osteodystrophy. Excessive renal losses of phosphorus occur in a variety of inher ited and acquired disorders. Because PTH inhibits the resorption of phosphorus in the proximal tubule, hyperparathyroidism causes hypophosphatemia (see Chapter 613). The dominant clinical mani festation, however, is hypercalcemia, and the hypophosphatemia is usually asymptomatic. The phosphorus level in hyperparathyroid ism is not extremely low, and there is no continued loss of phos phorus because a new steady state is achieved at the lower plasma phosphorus level. Renal excretion therefore does not exceed intake over the long term. Occasional malignancies produce PTH related peptide, which has the same actions as PTH and causes hypophos phatemia and hypercalcemia. A variety of diseases cause renal phosphate wasting, hypophos phatemia, and rickets resulting from excess FGF 23 (see Chapter 69). These disorders include X linked hypophosphatemic rickets, tumor induced osteomalacia, autosomal dominant hypophospha temic rickets, and autosomal recessive hypophosphatemic rickets types 1 3. Ferric carboxymaltose, an IV iron preparation for cor recting iron deficiency, causes hypophosphatemia via increased levels of FGF 23. Fanconi syndrome is a generalized defect in the proximal tubule leading to urinary wasting of bicarbonate, phosphorus, amino acids, uric acid, and glucose (see Chapter 569.1). The clinical sequelae result from the metabolic acidosis and hypophosphatemia. In children, an underlying genetic disease, usually cystinosis, often causes Fanconi syndrome, but it can be secondary to a variety of toxins and acquired diseases. Some patients have incomplete Fanconi syndrome, and phosphorus wasting may be one of the manifestations. Dent disease, an X linked disorder, can cause renal phosphorus wasting and hypophosphatemia, although the latter is not pres ent in most cases. Other possible manifestations of Dent disease include tubular proteinuria, hypercalciuria, nephrolithiasis, rick ets, and decreased kidney function. Dent disease may be secondary to pathologic variants in a gene that encodes a chloride channel or the OCRL1 gene, which may also cause Lowe syndrome (see Chapter 569.1). Hypophosphatemic rickets with hypercalciuria is a rare autosomal recessive disorder, principally described in kin dreds from the Middle East (see Chapter 69). Pathologic variants in a sodium phosphate co transporter cause hypophosphatemia in this disorder, and complications may include nephrolithiasis and osteoporosis. Similar findings are seen in hypophosphatemic rick ets with nephrolithiasis and osteoporosis types 1 and 2 (see Chap ter 69). Metabolic acidosis inhibits resorption of phosphorus in the prox imal tubule. In addition, metabolic acidosis causes a transcellular shift of phosphorus out of cells because of intracellular catabolism. This released phosphorus is subsequently lost in the urine, lead ing to significant phosphorus depletion, even though the plasma phosphorus level may be normal. This classically occurs in DKA, in which |
965 | renal phosphorus loss is further increased by the osmotic diuresis. With correction of the metabolic acidosis and the adminis tration of insulin, both of which cause a transcellular movement of phosphorus into the cells, there is a marked decrease in the plasma phosphorus level. Volume expansion from any cause, such as hyperaldosteronism or SIADH, inhibits resorption of phosphorus in the proximal tubule. This effect also occurs with high rates of IV fluids. Thiazide and loop diuret ics can increase renal phosphorus excretion, but the increase is seldom clinically significant. Glycosuria and glucocorticoids inhibit renal conservation of phosphorus. Hypophosphatemia is common after kidney transplantation because of urinary phosphorus losses. Pos sible explanations include preexisting secondary hyperparathyroidism from chronic kidney disease, glucocorticoid therapy, and upregula tion of FGF 23 before transplantation. The hypophosphatemia usually resolves in a few months. Both acquired and genetic causes of vitamin D deficiency are associated with hypophosphatemia (see Chapter 69). The pathogen esis is multifactorial. By impairing intestinal calcium absorption, vita min D deficiency causes secondary hyperparathyroidism that leads to increased urinary phosphorus wasting. An absence of vitamin D decreases intestinal absorption of phosphorus and directly decreases renal resorption of phosphorus. The dominant clinical manifestation is rickets, although some patients have muscle weakness that may be related to phosphorus deficiency. Alcoholism is the most common cause of severe hypophosphate mia in adults. Fortunately, many of the risk factors that predispose alcoholic adults to hypophosphatemia are not usually present in adolescents (malnutrition, antacid abuse, recurrent DKA episodes). Hypophosphatemia often occurs in sepsis, but the mechanism is not clear. Aggressive, protracted hemodialysis, as might be used for Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 508 Part VI u Fluid and Electrolyte Disorders the treatment of methanol or ethylene glycol ingestion, can cause hypophosphatemia. Clinical Manifestations There are acute and chronic manifestations of hypophosphatemia. Rickets occurs in children with long term phosphorus deficiency. The clinical features of rickets are described in Chapter 69. Severe hypophosphatemia, typically at levels 1.0 1.5 mgdL, may affect every organ in the body because phosphorus has a critical role in maintaining adequate cellular energy. Phosphorus is a component of ATP and is necessary for glycolysis. With inadequate phosphorus, 2,3 diphosphoglycerate levels in RBCs decrease, impairing release of oxygen to the tissues. Severe hypophosphatemia can cause hemolysis and dysfunction of WBCs. Chronic hypophosphatemia causes proxi mal muscle weakness and atrophy. In the intensive care unit, phos phorus deficiency may slow weaning from mechanical ventilation or cause acute respiratory failure. Rhabdomyolysis is the most common complication of acute hypophosphatemia, usually in the setting of an acute transcellular shift of phosphorus into cells in a child with chronic phosphorus depletion (anorexia nervosa). The rhabdomyolysis is actu ally somewhat protective, in that cellular release of phosphorus occurs. Other manifestations of severe hypophosphatemia include cardiac dys function and neurologic symptoms, such as tremor, |
966 | paresthesia, ataxia, seizures, delirium, and coma. Diagnosis The history and basic laboratory evaluation often suggest the etiol ogy of hypophosphatemia. The history should investigate nutrition, medications, and familial disease. Hypophosphatemia and rickets in an otherwise healthy young child suggest a genetic defect in renal phosphorus conservation, Fanconi syndrome, inappropriate use of antacids, poor nutrition, vitamin D deficiency, or a genetic defect in vitamin D metabolism. The patient with Fanconi syndrome usually has metabolic acidosis, glycosuria, aminoaciduria, and a low plasma uric acid level. Measurement of 25 D and 1,25 D, calcium, and PTH differentiates among the various vitamin D deficiency disorders and primary renal phosphate wasting (see Chapter 69). Hyperparathy roidism is easily distinguished by the presence of elevated plasma PTH and calcium values. Treatment The plasma phosphorus level, the presence of symptoms, the like lihood of chronic depletion, and the presence of ongoing losses dictate the approach to therapy. Mild hypophosphatemia does not require treatment unless the clinical situation suggests that chronic phosphorus depletion is present or that losses are ongoing. Oral phosphorus can cause diarrhea, so the doses should be divided. IV therapy is effective in patients who have severe deficiency or who cannot tolerate oral medications. IV phosphorus is available as either sodium phosphate or potassium phosphate, with the choice usually based on the patients plasma potassium level. Starting doses are 0.08 0.16 mmolkg over 6 hours. The oral preparations of phos phorus are available with various ratios of sodium and potassium. This is an important consideration because some patients may not tolerate the potassium load, whereas supplemental potassium may be helpful in some diseases, such as Fanconi syndrome and malnu trition. Oral maintenance dosages are 2 3 mmolkgday in divided doses, although the maintenance dose varies considerably between patients. Increasing dietary phosphorus is the only intervention needed in infants with inadequate intake. Other patients may also benefit from increased dietary phosphorus, usually from dairy products. Phosphorus binding antacids should be discontinued in patients with hypophosphatemia. Certain diseases require specific ther apy (see Chapter 69). Specifically, X linked hypophosphatemia responds to burosumab, a monoclonal antibody targeting FGF 23. HYPERPHOSPHATEMIA Etiology and Pathophysiology Renal insufficiency is the most common cause of hyperphosphatemia, with the severity proportional to the degree of kidney impairment (see Chapter 572). This occurs because GI absorption of the large dietary intake of phosphorus is unregulated, and the kidneys normally excrete this phosphorus. As kidney function deteriorates, increased excretion of phosphorus is able to compensate. When kidney function is 30 of normal, hyperphosphatemia usually develops, although this varies considerably depending on dietary intake. Many of the other causes of hyperphosphatemia are more likely to develop in the setting of decreased kidney function (Table 73.10). Cellular content of phosphorus is high relative to plasma phos phorus, and cell lysis can release substantial phosphorus. This is the etiology of hyperphosphatemia in tumor lysis syndrome, rhabdo myolysis, and acute hemolysis. These disorders cause concomitant potassium release and the risk of hyperkalemia. Additional features of tumor lysis and rhabdomyolysis |
967 | are hyperuricemia and hypocalcemia, whereas indirect hyperbilirubinemia and elevated lactate dehydroge nase (LDH) values are often present with hemolysis. An elevated CPK level is suggestive of rhabdomyolysis. During lactic acidosis or DKA, use of phosphorus by cells decreases, and phosphorus shifts into the ECS. This problem reverses when the underlying problem is corrected, and especially with DKA, patients subsequently become hypophospha temic because of previous renal phosphorus loss. Excessive intake of phosphorus is especially dangerous in children with decreased kidney function. Neonates are at risk because kidney function is normally reduced during the first few months of life. In addition, they may erroneously be given doses of phosphorus that are meant for an older child or adult. In infants fed cows milk, which has higher phosphorus content than breast milk or formula, hyperphos phatemia may develop. Fleet Enema has a high amount of phosphorus that can be absorbed, especially in the patient with an ileus; infants and children with Hirschsprung disease are especially vulnerable. There is often associated hypernatremia from sodium absorption and water loss from diarrhea. Sodium phosphorus laxatives may cause hyperphospha temia if the dose is excessive or if renal insufficiency is present. Hyper phosphatemia occurs in children who receive overaggressive treatment for hypophosphatemia. Vitamin D intoxication causes excessive GI absorption of both calcium and phosphorus, and the suppression of PTH by hypercalcemia decreases renal phosphorus excretion. Table 73.10 Causes of Hyperphosphatemia TRANSCELLULAR SHIFTS Tumor lysis syndrome Rhabdomyolysis Acute hemolysis Diabetic ketoacidosis and lactic acidosis INCREASED INTAKE Enemas and laxatives Cows milk in infants Treatment of hypophosphatemia Vitamin D intoxication DECREASED EXCRETION Kidney failure Hypoparathyroidism or pseudohypoparathyroidism (OMIM 146200 603233103580241410203330) Acromegaly Hyperthyroidism Tumoral calcinosis with hyperphosphatemia: genetic (OMIM 211900617993617994) or autoimmune OMIM, database number from the Online Mendelian Inheritance in Man (http:www.n cbi.nlm.nih.govomim). Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 73 u Electrolyte and Acid Base Disorders 509 The absence of PTH in hypoparathyroidism or PTH responsive ness in pseudohypoparathyroidism causes hyperphosphatemia because of increased resorption of phosphorus in the proximal tubule of the kidney (see Chapters 611 and 612). The associated hypocalce mia is responsible for the clinical symptoms. The hyperphosphatemia in hyperthyroidism or acromegaly is usually mild. It is secondary to increased resorption of phosphorus in the proximal tubule from the actions of thyroxine or growth hormone. Excessive thyroxine can also cause bone resorption, which may contribute to the hyperphos phatemia and cause hypercalcemia. Patients with familial tumoral calcinosis (three types), a rare autosomal recessive disorder, have hyperphosphatemia because of decreased renal phosphate excre tion and heterotopic calcifications. The disease may be secondary to pathologic variants in the genes for a glycosyltransferase (most com mon etiology), FGF 23, or klotho, which encodes the co receptor for FGF 23. Autoimmune hyperphosphatemic tumoral calcinosis occurs with antibodies producing FGF 23 resistance. Clinical Manifestations The principal clinical consequences of hyperphosphatemia are |
968 | hypocalcemia and systemic calcification. The hypocalcemia is probably caused by tissue deposition of calcium phosphorus salt, inhibition of 1,25 D production, and decreased bone resorption. Symptomatic hypocalcemia is most likely to occur when the phos phorus level increases rapidly or when diseases predisposing to hypocalcemia are present (chronic kidney disease, rhabdomyolysis). Systemic calcification occurs because the solubility of phosphorus and calcium in the plasma is exceeded. Clinically, this condition is often apparent in the conjunctiva, where it manifests as a foreign body feeling, erythema, and injection. More ominous manifesta tions are hypoxia from pulmonary calcification and kidney failure from nephrocalcinosis. Diagnosis Plasma creatinine and BUN levels should be assessed in any patient with hyperphosphatemia. The history should focus on intake of phosphorus and the presence of chronic diseases that may cause hyperphosphatemia. Measurement of K, uric acid, calcium, LDH, bilirubin, hemoglobin, and CPK may be indicated if rhabdomy olysis, tumor lysis, or hemolysis is suspected. With mild hyper phosphatemia and significant hypocalcemia, measurement of the serum PTH level distinguishes between hypoparathyroidism and pseudohypoparathyroidism. Treatment The treatment of acute hyperphosphatemia depends on its severity and etiology. Mild hyperphosphatemia in a patient with reasonable renal function spontaneously resolves; the resolution can be accel erated by dietary phosphorus restriction. If kidney function is not impaired, IV fluids can enhance renal phosphorus excretion. For more significant hyperphosphatemia or a situation such as tumor lysis or rhabdomyolysis, in which endogenous phosphorus genera tion is likely to continue, addition of an oral phosphorus binder pre vents absorption of dietary phosphorus and can remove phosphorus from the body by binding what is normally secreted and absorbed by the GI tract. Phosphorus binders are most effective when given with food. Binders containing aluminum hydroxide are especially efficient, but calcium carbonate is an effective alternative and may be preferred if there is a need to treat concomitant hypocalcemia. Preservation of renal function, as with high urine flow in rhabdomy olysis or tumor lysis, is an important adjunct because it will permit continued excretion of phosphorus. If the hyperphosphatemia is not responding to conservative management, especially if acute kidney injury is supervening, dialysis may be necessary to increase phos phorus removal. Dietary phosphorus restriction is necessary for diseases causing chronic hyperphosphatemia. However, such diets are often difficult to follow, given the abundance of phosphorus in a variety of foods. Dietary restriction is often sufficient in conditions such as hypo parathyroidism and mild chronic kidney disease. For more prob lematic hyperphosphatemia, such as with moderate chronic kidney disease and end stage kidney disease, phosphorus binders are usu ally necessary. They include calcium carbonate, calcium acetate, sevelamer, ferric citrate, sucroferric oxyhydroxide, and lanthanum. Aluminum containing phosphorus binders are no longer used in patients with chronic kidney disease because of the risk of alumi num toxicity. Dialysis directly removes phosphorus from the blood in patients with end stage kidney disease, but it is only an adjunct to dietary restriction and phosphorus binders; removal by dialysis does not keep up with normal dietary intake. |
969 | Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. 73.7 Acid Base Balance Larry A. Greenbaum ACID BASE PHYSIOLOGY Terminology Chronic, mild derangements in acid base status may interfere with normal growth and development, whereas acute, severe changes in pH can be fatal. Control of acid base balance depends on the kidneys, the lungs, and intracellular and extracellular buffers. A normal pH is 7.35 7.45. There is an inverse relationship between the pH and the hydrogen ion concentration(H). At a pH of 7.40, H is 40 nmolL. A normal serum sodium concentration, 140 mEqL, is 1 million times higher. Maintaining a normal pH is necessary because hydrogen ions are highly reactive and are especially likely to combine with proteins, altering their function. An acid is a substance that releases (donates) a hydrogen ion (H). A base is a substance that accepts a hydrogen ion. An acid (HA) can dissociate into a hydrogen ion and a conjugate base (A), as follows: HAH A A strong acid is highly dissociated, so in this reaction, there is lit tle HA. A weak acid is poorly dissociated; not all the hydrogen ions are released from HA. A acts as a base when the reaction moves to the left. These reactions are in equilibrium. When HA is added to the system, there is dissociation of some HA until the concen trations of H and A increase enough that a new equilibrium is reached. Addition of hydrogen ions causes a decrease in A and an increase in HA. Addition of A causes a decrease in hydrogen ions and an increase in HA. Buffers are substances that attenuate the change in pH that occurs when acids or bases are added to the body. Given the extremely low H in the body at physiologic pH, without buffers a small amount of hydrogen ions could cause a dramatic decline in the pH. Buffers prevent the decrease in pH by binding the added hydrogen ions, as follows: A H HA The increase in H drives this reaction to the right. Similarly, when base is added to the body, buffers prevent the pH from increasing by releasing hydrogen ions, as follows: HAA H The best buffers are weak acids and bases. This is because a buffer works best when it is 50 dissociated (half HA and half A). The pH at which a buffer is 50 dissociated is its pKa (ionization constant Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 510 Part VI u Fluid and Electrolyte Disorders of acid). The best physiologic buffers have a pKa close to 7.40. The concentration of a buffer and its pKa determine the buffers effec tiveness (buffering capacity). When the pH is lower than the pKa of a buffer, there is more HA than A. When the pH is higher than the pKa, there is more A than HA. Physiologic |
970 | Buffers The bicarbonate and nonbicarbonate buffers protect the body against major changes in pH. The bicarbonate buffer system is routinely monitored clinically and is based on the relationship between carbon dioxide (CO2) and bicarbonate (HCO3 ): CO2 H2OH HCO3 CO2 acts as an acid in that, after combining with water, it releases an H; bicarbonate acts as its conjugate base in that it accepts an H. The pKa of this reaction is 6.1. The Henderson Hasselbalch equation expresses the relationship among pH, pKa, and the concentrations of an acid and its conjugate base. This relationship is valid for any buf fer. The Henderson Hasselbalch equation for bicarbonate and CO2 is as follows: pH 6.1 log HCO3 CO2 The Henderson Hasselbalch equation for the bicarbonate buf fer system has three variables: pH, bicarbonate concentration (HCO3 ), and carbon dioxide concentration (CO2). Thus, if any two of these variables are known, it is possible to calculate the third. When one is using the Henderson Hasselbalch equation, it is important that CO2 and bicarbonate have the same units. CO2 is reported clinically as mm Hg and must be multiplied by its solubil ity constant, 0.03 mmolLmm Hg, before the equation can be used. Mathematical manipulation of the Henderson Hasselbalch equa tion produces the following relationship: 2 3H 24 PCO HCO At a normal H of 40 nmol (pH 7.40), the partial pressure of carbon dioxide (Pco2), which is expressed as mm Hg in this equa tion, is 40 when the HCO3 is 24 mEqL. This equation emphasizes that H, and thus pH, can be determined by the ratio of Pco2 and HCO3 . The bicarbonate buffer system is very effective because of the high concentration of bicarbonate in the body (24 mEqL) and because it is an open system. The remaining body buffers are in a closed system. The bicarbonate buffer system is an open system because the lungs increase CO2 excretion when the blood CO2 con centration increases. When acid is added to the body, the following reaction occurs: H HCO3 CO2 H2O In a closed system, the CO2 would increase. The higher CO2 concen tration would lead to an increase in the reverse reaction: CO2 H2OH HCO3 This would increase H, limiting the buffering capacity of bicarbonate. However, because the lungs excrete the excess CO2, the reverse reaction does not increase; this fact enhances the buffering capacity of bicarbonate. The same principle holds with the addition of base, because the lungs decrease CO2 excretion and prevent the CO2 level from falling. The lack of change in CO2 dramatically increases the buffering capacity of bicarbonate. The nonbicarbonate buffers include proteins, phosphate, and bone. Protein buffers consist of extracellular proteins, mostly albumin and intracellular proteins, including hemoglobin. Proteins are effec tive buffers, largely because of the presence of the amino acid histi dine, which has a side chain that can bind or release H. The pKa of histidine varies slightly, depending on its position in the protein mol ecule, but its average pKa |
971 | is approximately 6.5. This is close enough to a normal pH (7.4) to make histidine an effective buffer. Hemoglobin and albumin have 34 and 16 histidine molecules, respectively. Phosphate can bind up to three hydrogen molecules, so it can exist as PO4 3, HPO4 2, H2PO4 1, or H3PO4. However, at a physiologic pH, most phosphate exists as either HPO4 2 or H2PO4 1. H2PO4 1 is an acid, and HPO4 2 is its conjugate base: H2PO4 1 H HPO4 2 The pKa of this reaction is 6.8, making phosphate an effective buffer. The concentration of phosphate in the ECS is relatively low, limiting the overall buffering capacity of phosphate; it is less important than albumin. However, phosphate is found at a much higher concentration in the urine, where it is an important buffer. In the ICS, most phosphate is covalently bound to organic molecules (ATP), but it still serves as an effective buffer. Bone is an important buffer. Bone is basicit is composed of com pounds such as sodium bicarbonate and calcium carbonateand thus dissolution of bone releases base. This release can buffer an acid load, although at the expense of bone density, if it occurs over an extended period. In contrast, bone formation, by consuming base, helps buffer excess base. Clinically, we measure the extracellular pH, but it is the intracellu lar pH that affects cell function. Measurement of the intracellular pH is unnecessary because changes in the intracellular pH parallel the changes in the extracellular pH. However, the change in the intracellu lar pH tends to be less than the change in the extracellular pH because of the greater buffering capacity in the ICS. NORMAL ACID BASE BALANCE The lungs and kidneys maintain a normal acid base balance. Car bon dioxide generated during normal metabolism is a weak acid. The lungs prevent an increase in the Pco2 in the blood by excret ing the CO2 that the body produces. CO2 production varies accord ing to the bodys metabolic needs, increasing with physical activity. The rapid pulmonary response to changes in the CO2 concentration occurs via central sensing of the Pco2 and a subsequent increase or decrease in ventilation to maintain a normal Pco2 (35 45 mm Hg). An increase in ventilation decreases the Pco2, and a decrease in ventilation increases the Pco2. The kidneys excrete endogenous acid. An adult normally pro duces approximately 1 2 mEqkg24 hr of H. Children normally produce 2 3 mEqkg24 hr of H. The three principal sources of H are dietary protein metabolism, incomplete metabolism of carbohy drates and fat, and stool losses of bicarbonate. Because metabolism of protein generates H, endogenous acid production varies with protein intake. The complete oxidation of carbohydrates or fats to CO2 and water does not generate H; the lungs remove the CO2. However, incomplete metabolism of carbohydrates or fats produces H. Incomplete glucose metabolism can produce lactic acid, and incomplete triglyceride metabolism can produce ketoacids, such as hydroxybutyric acid and acetoacetic acid. There is always some |
972 | baseline incomplete metabolism that contributes to endogenous acid production. This factor increases in pathologic conditions, such as lactic acidosis and diabetic ketoacidosis (DKA). Stool loss of bicarbonate is the third major source of endogenous acid produc tion. The stomach secretes H, but most of the remainder of the GI tract secretes bicarbonate, and the net effect is a loss of bicarbonate from the body. To secrete bicarbonate, the cells of the intestine pro duce hydrogen ions that are released into the bloodstream. For each bicarbonate molecule lost in the stool, the body gains one H. This source of endogenous acid production is normally minimal but may increase dramatically in a patient with diarrhea. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 73 u Electrolyte and Acid Base Disorders 511 The hydrogen ions formed from endogenous acid production are neutralized by bicarbonate, potentially causing the bicarbonate con centration to decrease. The kidneys regenerate this bicarbonate by secreting H. The lungs cannot regenerate bicarbonate, even though loss of CO2 lowers the H, as shown in the following reaction: H HCO3 CO2 H2O A decrease in CO2 causes the reaction to move to the right, which decreases H, but it also lowers HCO3 . During a metabolic acidosis, hyperventilation can lower CO2, decrease H, and thus increase pH. The underlying metabolic acidosis is still present. Similarly, the kidneys cannot correct an abnormally high CO2, as shown in the following reaction: H HCO3 CO2 H2O An increase in HCO3 also causes the reaction to move to the right, which increases CO2 while simultaneously decreasing H. During a respiratory acidosis, increased renal generation of bicarbon ate can decrease H and increase pH but cannot repair the respiratory acidosis. Both the lungs and the kidneys can affect H and thus pH. However, only the lungs can regulate CO2, and only the kidneys can regulate HCO3 . Renal Mechanisms The kidneys regulate the serum bicarbonate concentration by modify ing acid excretion in the urine. This requires a two step process. First, the renal tubules resorb the bicarbonate that is filtered at the glomeru lus. Second, there is tubular secretion of H. The urinary excretion of H generates bicarbonate that neutralizes endogenous acid production. The tubular actions necessary for renal acid excretion occur through out the nephron (Fig. 73.7). The resorption of filtered bicarbonate is a necessary first step in renal regulation of the acid base balance. A normal adult has a GFR of approximately 180 L24 hr. This fluid enters Bowmans space with HCO3 that is essentially identical to the plasma concentration, nor mally 24 mEqL. Multiplying 180 L by 24 mEqL indicates that 4,000 mEq of bicarbonate enters Bowmans space each day. This bicarbon ate, if not reclaimed along the nephron, would be lost in the urine and would cause a profound metabolic acidosis. The proximal tubule reclaims approximately |
973 | 85 of the fil tered bicarbonate (Fig. 73.8). The final 15 is reclaimed beyond the proximal tubule, mostly in the ascending limb of the loop of Henle. Bicarbonate molecules are not transported from the tubular fluid into the cells of the proximal tubule. Rather, hydrogen ions are secreted into the tubular fluid, leading to conversion of filtered bicarbonate into CO2 and water. The secretion of H by the cells of the proximal tubule is coupled to generation of intracellular bicarbonate, which is transported across the basolateral membrane of the proximal tubule cell and enters the capillaries. The bicar bonate produced in the cell replaces the bicarbonate filtered at the glomerulus. Increased bicarbonate resorption by the cells of the proximal tubulethe result of increased H secretionoccurs in a variety of clinical situations. Volume depletion increases bicarbonate resorption. This is partially mediated by activation of the renin angiotensin sys tem; angiotensin II increases bicarbonate resorption. Increased bicar bonate resorption in the proximal tubule is one of the mechanisms that accounts for the metabolic alkalosis that may occur in some patients with volume depletion. Other stimuli that increase bicarbonate resorption include hypokalemia and an increased Pco2. This partially explains the observations that hypokalemia causes a metabolic alkalo sis, and that a respiratory acidosis leads to a compensatory increase in serum HCO3 . Stimuli that decrease bicarbonate resorption in the proximal tubule may cause a decrease in the serum HCO3 . A decrease in the Pco2 (respiratory alkalosis) decreases proximal tubule bicarbonate resorp tion, partially mediating the decrease in serum HCO3 that com pensates for a respiratory alkalosis. PTH decreases proximal tubule bicarbonate resorption; hyperparathyroidism may cause a mild meta bolic acidosis. A variety of medications and diseases cause a metabolic acidosis by impairing bicarbonate resorption in the proximal tubule. Examples are the medication acetazolamide, which directly inhibits carbonic anhydrase, and the many disorders that cause proximal RTA (see Chapter 569.1). Proximal tubule Loop of Henle NH4? H? Collecting duct NH3 HCO3 ? HCO3 ? Fig. 73.7 Tubular sites involved in acid base balance. The proximal tubule is the site where most filtered bicarbonate is reclaimed, even though other sites along the nephron, especially the thick ascending limb of the loop of Henle, resorb some of the filtered bicarbonate. The collecting duct is the principal location for the hydrogen ion secretion that acidifies the urine. The proximal tubule generates the ammonia that serves as a urinary buffer in the collecting duct. Na? H? 3K? Na? Proximal tubule Peritubular fluid 2Na? Tubular lumen HCO3 ?CO2 ? OH?H2O ? CO2 Filtered HCO3 ? H2OH2CO3 3HCO3 ? 5 43 1 2 ? H? Fig. 73.8 Resorption of filtered bicarbonate in the proximal tubule. The Na,K ATPase (1) excretes sodium across the basolateral cell membrane, maintaining a low intracellular sodium concentration. The low intracellular sodium concentration provides the energy for the Na,H antiporter (2), which exchanges sodium from the tubular lumen for intracellular hydrogen ions. The hydrogen ions that are se creted into the tubular lumen then combine |
974 | with filtered bicarbonate to generate carbonic acid. CO2 and water are produced from carbonic acid (H2CO3). This reaction is catalyzed by luminal carbonic anhydrase (3). CO2 diffuses into the cell and combines with OH ions to gener ate bicarbonate. This reaction is catalyzed by an intracellular carbonic anhydrase (4). The dissociation of water generates an OH ion and an H ion. The Na,H antiporter (2) secretes the hydrogen ions. Bicar bonate ions cross the basolateral membrane and enter the blood via the 3HCO3 1Na co transporter (5). The energy for the 3HCO3 1Na co transporter comes from the negatively charged cell interior, which makes it electrically favorable to transport a net negative charge (i.e., 3 bicarbonates and only 1 sodium) out of the cell. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 512 Part VI u Fluid and Electrolyte Disorders After reclaiming filtered bicarbonate, the kidneys perform the sec ond step in renal acid base handling, the excretion of the acid created by endogenous acid production. Excretion of acid occurs mostly in the collecting duct, with a small role for the distal tubule. Along with secretion of H by the tubular cells lining the collect ing duct, adequate excretion of endogenous acid requires the pres ence of urinary buffers. The hydrogen pumps in the collecting duct cannot lower the urine pH below 4.5. The H at pH 4.5 is 0.04 mEqL; it would require 25 L of water with a pH of 4.5 to excrete one mEq of H. A 10 kg child, with an endogenous acid production of 20 mEq H each day, would need to have a daily urinary output of 500 L without the presence of urinary buffers. As in the blood, buf fers in the urine attenuate the decrease in pH that occurs with the addition of H. The two principal urinary buffers are phosphate and ammonia. Urinary phosphate is proportional to dietary intake. Whereas most of the phosphate filtered at the glomerulus is resorbed in the proximal tubule, the urinary phosphate concentration is usually much greater than the serum phosphate concentration. This arrange ment allows phosphate to serve as an effective buffer through the fol lowing reaction: H HPO4 2H2PO4 1 The pKa of this reaction is 6.8, making phosphate an effective buffer as the urinary pH decreases from 7.0 to 5.0 within the collecting duct. Although phosphate is an effective buffer, its buffering capacity is lim ited by its concentration; there is no mechanism for increasing urinary phosphate excretion in response to changes in acid base status. In contrast, ammonia production can be modified, allowing for regulation of acid excretion. The buffering capacity of ammonia (NH3) is based on the reaction of ammonia with hydrogen ions to form ammonium: NH3 H NH4 The cells of the proximal tubule are the source of the excreted ammonia, mostly through metabolism |
975 | of glutamine through the fol lowing reactions: GlutamineNH4 glutamate Glutamate NH4 ketoglutarate3 The metabolism of glutamine generates two ammonium ions. In addition, the metabolism of ketoglutarate generates two bicarbon ate molecules. The ammonium ions are secreted into the lumen of the proximal tubule, whereas the bicarbonate molecules exit the proximal tubule cells via the basolateral Na,3HCO3 co transporter (see Fig. 73.8). This arrangement would seem to accomplish the goal of excret ing H (as NH4 ) and regenerating bicarbonate molecules. However, the ammonium ions secreted in the proximal tubule do not remain within the tubular lumen. Cells of the TAL of the loop of Henle resorb the ammonium ions. The result is that there is a high medullary inter stitial concentration of ammonia, but the tubular fluid entering the collecting duct does not have significant amounts of ammonium ions. Moreover, the hydrogen ions that were secreted with ammonia (as ammonium ions) in the proximal tubule enter the bloodstream, can celing the effect of the bicarbonate generated in the proximal tubule. The excretion of ammonium ions, and thus of hydrogen ions, depends on the cells of the collecting duct. The cells of the collecting duct secrete H and regenerate bicarbon ate, which is returned to the bloodstream (Fig. 73.9). This bicarbonate neutralizes endogenous acid production. Phosphate and ammonia buffer the H secreted by the collecting duct. Ammonia is an effec tive buffer because of the high concentrations in the medullary inter stitium and because the cells of the collecting duct are permeable to ammonia but not to ammonium. As ammonia diffuses into the lumen of the collecting duct, the low urine pH causes almost all the ammonia to be converted into ammonium. This process maintains a low luminal ammonia concentration. Because the luminal pH is lower than the pH in the medullary interstitium, there is a higher concentration of ammonia within the medullary interstitium than in the tubular lumen, favoring movement of ammonia into the tubular lumen. Even though the concentration of ammonium in the tubular lumen is higher than in the interstitium, the cells of the collecting duct are impermeable to ammonium, preventing back diffusion of ammonium out of the tubular lumen and permitting ammonia to be an effective buffer. The kidneys adjust H excretion according to physiologic needs. There is variation in endogenous acid production, largely a result of diet and pathophysiologic stresses, such as diarrheal losses of bicar bonate, which increase the need for acid excretion. H excretion is increased by upregulation of H secretion in the collecting duct, caus ing the pH of the urine to decrease. This response is prompt, occurring within hours of an acid load, but it is limited by the buffering capacity of the urine; the hydrogen pumps in the collecting duct cannot lower the pH to 4.5. A more significant increase in acid excretion requires upregulation of ammonia production by the proximal tubule so that more ammonia is available to serve as a buffer in the tubular lumen of the collecting duct. |
976 | This response to a low serum pH reaches its maxi mum within 5 6 days; ammonia excretion can increase approximately 10 fold over the baseline value. Acid excretion by the collecting duct increases in a number of differ ent clinical situations. The extracellular pH is the most important regu lator of renal acid excretion. A decrease in the extracellular pH from either a respiratory or a metabolic acidosis causes an increase in renal acid excretion. Aldosterone stimulates H excretion in the collecting duct, causing an increase in the serum bicarbonate concentration. This explains the metabolic alkalosis that occurs with primary hyper aldosteronism or secondary hyperaldosteronism caused by volume depletion. Hypokalemia increases acid secretion, by both stimulating ammonia production in the proximal tubule and increasing H secre tion in the collecting duct. Hypokalemia therefore tends to produce a metabolic alkalosis. Hyperkalemia has the opposite effects, which may cause a metabolic acidosis. In patients with an increased pH, the kidney has two principal mech anisms for correcting the problem. First, less bicarbonate is resorbed in the proximal tubule, leading to an increase in urinary bicarbonate losses. Second, in a limited number of specialized cells, the process for Na? H? Cl? Collecting duct Peritubular fluid Tubular lumen HCO3 ?OH? ? CO2 HPO4 2? ? H? NH4 ? H2PO4 ? NH4 ? H2O NH3H? ? NH3 HCO3 ? 3 2 1 H? Fig. 73.9 Secretion of hydrogen ions in the collecting duct. The disso ciation of water generates an OH ion and an H ion. The H ATPase (1) secretes hydrogen ions into the tubular lumen. Bicarbonate is formed when an OH ion combines with CO2 in a reaction mediated by carbon ic anhydrase (2). Bicarbonate ions cross the basolateral membrane and enter the blood via the HCO3 Cl exchanger (3). The hydrogen ions in the tubular lumen are buffered by phosphate and ammonia (NH3). NH3 can diffuse from the peritubular fluid into the tubular lumen, but ammonium (NH4 ) cannot pass through the cells of the collecting duct. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 73 u Electrolyte and Acid Base Disorders 513 secretion of H by the collecting duct can be reversed (see Fig. 73.9), leading to secretion of bicarbonate into the tubular lumen and secre tion of hydrogen ions into the peritubular fluid, where they enter the bloodstream. CLINICAL ASSESSMENT OF ACID BASE DISORDERS The following rearrangement of the Henderson Hasselbalch equation emphasizes the relationship among Pco2, bicarbonate concentration, and hydrogen ion concentration: H 24 PCO2 HCO 3 An increase in the Pco2 or a decrease in HCO3 increases H; the pH decreases. A decrease in the Pco2 or an increase in HCO3 decreases H; the pH increases. Terminology Acidemia is a pH below normal (7.35), and alkalemia is a pH above normal (7.45). An acidosis is a pathologic process that causes an |
977 | increase in H, and an alkalosis is a pathologic process that causes a decrease in H. Whereas acidemia is always accompanied by an aci dosis, a patient can have an acidosis and a low, normal, or high pH. For example, a patient may have a mild metabolic acidosis but a simul taneous, severe respiratory alkalosis; the net result may be alkalemia. Acidemia and alkalemia indicate the pH abnormality; acidosis and alkalosis indicate the pathologic process that is taking place. A simple acid base disorder is a single primary disturbance. During a simple metabolic disorder, there is respiratory compensa tion. With a metabolic acidosis, the decrease in the pH increases the ventilatory drive, causing a decrease in Pco2. The decrease in the CO2 leads to an increase in the pH. This appropriate respira tory compensation is expected with a primary metabolic acidosis. Despite the decrease in CO2, appropriate respiratory compen sation is not a respiratory alkalosis, even though it is sometimes erroneously called a compensatory respiratory alkalosis. A low Pco2 can result either from a primary respiratory alkalosis or from appropriate respiratory compensation for a metabolic acidosis. Appropriate respiratory compensation also occurs with a primary metabolic alkalosis, although in this case CO2 increases to attenu ate the increase in the pH. The respiratory compensation for a met abolic process happens quickly and is complete within 12 24 hours; it cannot overcompensate for or normalize the pH. During a primary respiratory process, there is metabolic compensa tion, mediated by the kidneys. The kidneys respond to a respiratory acidosis by increasing H excretion, thereby increasing bicarbonate generation and raising the serum HCO3 . The kidneys increase bicar bonate excretion to compensate for a respiratory alkalosis; HCO3 decreases. Unlike respiratory compensation, which occurs rapidly, it takes 3 4 days for the kidneys to complete appropriate metabolic com pensation. There is, however, a small and rapid compensatory change in HCO3 during a primary respiratory process. The expected appro priate metabolic compensation for a respiratory disorder depends on whether the process is acute or chronic. A mixed acid base disorder is present when there is more than one primary acid base disturbance. An infant with bronchopulmo nary dysplasia may have a respiratory acidosis from chronic lung dis ease and a metabolic alkalosis from the furosemide used to treat the chronic lung disease. More dramatically, a child with pneumonia and sepsis may have severe acidemia because of a combined metabolic acidosis caused by lactic acid and respiratory acidosis caused by ven tilatory failure. There are formulas for calculating the appropriate metabolic or respiratory compensation for the six primary simple acid base dis orders (Table 73.11). The appropriate compensation is expected in a simple disorder; it is not optional. If a patient does not have the appropriate compensation, a mixed acid base disorder is present. For example, if a patient has a primary metabolic acidosis with a serum HCO3 of 10 mEqL, the expected respiratory compensa tion is CO2 of 23 mm Hg 2 (1.5 10 8 2 |
978 | 23 2; see Table 73.11). If the patients CO2 is 25 mm Hg, a concurrent respira tory acidosis is present; CO2 is higher than expected. A patient may have a respiratory acidosis despite a CO2 level below the nor mal value of 35 45 mm Hg. In this example, CO2 21 mm Hg indicates a concurrent respiratory alkalosis; CO2 is lower than exp ected. Diagnosis A systematic evaluation of an arterial blood gas (ABG) sample, com bined with the clinical history, can usually explain the patients acid base disturbance. Assessment of an ABG sample requires knowledge of normal values (Table 73.12). In most cases, this is accomplished through a three step process (Fig. 73.10): 1. Determine whether acidemia or alkalemia is present. 2. Determine a cause of the acidemia or alkalemia. 3. Determine whether a mixed disorder is present. Most patients with an acid base disturbance have an abnormal pH, although there are two exceptions. One exception is in the patient with a mixed disorder in which the two processes have opposite effects on pH (a metabolic acidosis and a respiratory alka losis) and cause changes in H that are comparable in magnitude, although opposite. The other exception is in the patient with a simple chronic respiratory alkalosis; in some cases, the appropriate metabolic compensation is enough to normalize the pH. In both situations, the presence of an acid base disturbance is deduced because of the abnormal CO2 and bicarbonate levels. Determining the acid base disturbance in these patients requires proceeding to the third step of the process. The second step requires inspection of the serum HCO3 and Pco2 to determine a cause of the abnormal pH (see Fig. 73.10). In most cases, there is only one obvious explanation for the abnormal pH. In some mixed disorders, however, there may be two possibilities (e.g., a high Pco2 and a low HCO3 in a patient with acidemia). In such cases, the patient has two causes for abnormal pHa metabolic acido sis and a respiratory acidosis, in this instanceand it is unnecessary to proceed to the third step. The third step requires determining whether the patients com pensation is appropriate. It is assumed that the primary disorder was Table 73.11 Appropriate Compensation During Simple Acid Base Disorders DISORDER EXPECTED COMPENSATION Metabolic acidosis Pco2 1.5 HCO3 8 2 Metabolic alkalosis Pco2 increases by 7 mm Hg for each 10 mEqL increase in serum HCO3 Respiratory Acidosis Acute HCO3 increases by 1 for each 10 mm Hg increase in Pco2 Chronic HCO3 increases by 3.5 for each 10 mm Hg increase in Pco2 Respiratory Alkalosis Acute HCO3 falls by 2 for each 10 mm Hg decrease in Pco2 Chronic HCO3 falls by 4 for each 10 mm Hg decrease in Pco2 Table 73.12 Normal Values of Arterial Blood Gases pH 7.35 7.45 HCO3 20 28 mEqL Pco2 35 45 mm Hg Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No |
979 | other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 514 Part VI u Fluid and Electrolyte Disorders diagnosed in the second step, and the expected compensation is cal culated (see Table 73.11). If the compensation is appropriate, a simple acid base disorder is present. If the compensation is not appropriate, a mixed disorder is present. The identity of the second disorder is deter mined by deciding whether the compensation is too little or too much compared with what was expected (see Fig. 73.10). The history is always useful in evaluating and diagnosing patients with acid base disturbances. It is especially helpful in a respiratory pro cess. The expected metabolic compensation for a respiratory process changes according to whether the process is acute or chronic, which can be deduced only from the history. The metabolic compensation for an acute respiratory acidosis is less than that for a chronic respiratory acidosis. In a patient with a respiratory acidosis, a small increase in HCO3 would be consistent with a simple acute respiratory acidosis or a mixed disorder (a chronic respiratory acidosis and a metabolic acidosis). Only the history can differentiate among the possibilities. Knowledge of the length of the respiratory process and the presence or absence of a risk factor for a metabolic acidosis (diarrhea) allows the correct conclusion to be reached. An alternative to the physiologic approach just described (which includes calculation of the anion gap; see later) is the physiochemical approach, often called the Stewart method. Some view this approach as superior to the physiologic approach, but it requires multiple calcu lations and additional laboratory values and is thus more challenging to use in the clinical setting. The physiochemical approach requires measurement of the blood pH and Pco2 and calculation of the appar ent strong ion difference (SIDa), the effective strong ion difference (SIDe), the strong ion gap (SIG), and the total concentration of weak acids (ATOT). METABOLIC ACIDOSIS Metabolic acidosis occurs frequently in hospitalized children; diarrhea is the most common etiology. For a patient with an unknown medical problem, the presence of a metabolic acidosis is often helpful diagnos tically, because it suggests a relatively narrow differential diagnosis. Patients with a metabolic acidosis have a low serum HCO3 , although not every patient with a low serum HCO3 has a metabolic acidosis. The exception is the patient with a respiratory alkalosis, which causes a decrease in the serum HCO3 as part of appropriate renal compensation. In a patient with an isolated metabolic acidosis, there is a predictable decrease in the blood CO2, as follows: PCO2 1.5 HCO 3 8 2 A mixed acid base disturbance is present if the respiratory com pensation is not appropriate. If the Pco2 is greater than predicted, the patient has a concurrent respiratory acidosis. A lower Pco2 than predicted indicates a concurrent respiratory alkalosis or, less fre quently, an isolated respiratory alkalosis. Because the appropriate respiratory compensation for a metabolic acidosis never normalizes the patients pH, the presence of a normal pH and |
980 | a low HCO3 occurs only if some degree of respiratory alkalosis is present. In this situation, distinguishing an isolated chronic respiratory alkalosis from a mixed metabolic acidosis and acute respiratory alkalosis may be possible only clinically. In contrast, the combination of a low serum pH and a low HCO3 occurs only if a metabolic aci dosis is present. Etiology and Pathophysiology There are many causes of a metabolic acidosis (Table 73.13), resulting from three basic mechanisms: 1. Loss of bicarbonate from the body 2. Impaired ability to excrete acid by the kidney 3. Addition of acid to the body (exogenous or endogenous) Diarrhea, the most common cause of metabolic acidosis in chil dren, causes a loss of bicarbonate from the body. The amount of bicarbonate lost in the stool depends on the volume of diarrhea and HCO3 of the stool, which tends to increase with more severe diarrhea. The kidneys attempt to balance the losses by increasing acid secretion, but metabolic acidosis occurs when this compensa tion is inadequate. Diarrhea often causes volume depletion because of losses of sodium and water, potentially exacerbating the acidosis by causing shock and a lactic acidosis. In addition, diarrheal losses of potassium lead to hypokalemia. Moreover, the volume depletion causes increased production of aldosterone. This increase stimu lates renal retention of sodium, helping to maintain intravascular volume, but also leads to increased urinary losses of potassium, exacerbating the hypokalemia. There are four forms of renal tubular acidosis (RTA): distal (type I), proximal (type II), mixed (type III), and hyperkalemic (type IV) (see Chapter 569). In distal RTA, children may have accompanying hypo kalemia, hypercalciuria, nephrolithiasis, and nephrocalcinosis. Failure Acidemia or Alkalemia Acidemia Decreased HCO3 ? Increased PCO2 Metabolic acidosis Step 3 Step 2 Step 1 Expected PCO2 Simple Met. Acid. Low PCO2 Mixed Met. Acid. and Resp. Alk. High PCO2 Mixed Met. Acid. and Resp. Acid. Expected HCO3 ? Simple Resp. Acid. Low HCO3 ? Mixed Resp. Acid. and Met. Acid. High HCO3 ? Mixed Resp. Acid. and Met. Alk. Expected PCO2 Simple Met. Alk. Low PCO2 Mixed Met. Alk. and Resp. Alk. High PCO2 Mixed Met. Alk. and Resp. Acid. Expected HCO3 ? Simple Resp. Alk. Low HCO3 ? Mixed Resp. Alk. and Met. Acid. High HCO3 ? Mixed Resp. Alk. and Met. Alk. Respiratory acidosis Alkalemia Increased HCO3 ? Decreased PCO2 Metabolic alkalosis Respiratory alkalosis Fig. 73.10 Three step process for interpreting acid base disturbances. In step 1, determine whether the pH is low (acidemia) or high (alkalemia). In step 2, establish an explanation for the acidemia or alkalemia. In step 3, calculate the expected compensation (see Table 73.11) and determine whether a mixed disturbance is present. Met. Acid., metabolic acidosis; Met. Alk., metabolic alkalosis; Resp. Acid., respiratory acidosis; Resp. Alk., respiratory alkalosis. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 73 u Electrolyte and |
981 | Acid Base Disorders 515 to thrive because of chronic metabolic acidosis is the most common presenting complaint. Patients with distal RTA cannot acidify their urine and thus have a urine pH 5.5 despite a metabolic acidosis. Proximal RTA is rarely present in isolation. In most patients, proximal RTA is part of Fanconi syndrome, a generalized dysfunc tion of the proximal tubule. The dysfunction leads to glycosuria, aminoaciduria, and excessive urinary losses of phosphate and uric acid. The presence of a low serum uric acid level, glycosuria, and aminoaciduria is helpful diagnostically. Chronic hypophosphatemia leads to rickets in children (see Chapter 69). Rickets andor failure to thrive may be the presenting complaint. The ability to acidify the urine is intact in proximal RTA; thus untreated patients have a urine pH 5.5. However, bicarbonate therapy increases bicarbon ate losses in the urine, and the urine pH increases. A mixed RTA (combined distal and proximal) occurs in patients with autosomal recessive osteopetrosis caused by pathologic variants in the gene for carbonic anhydrase II. In hyperkalemic RTA, renal excretion of acid and potassium is impaired. Hyperkalemic RTA is the result of hyperkalemia, absence of aldosterone, or inability of the kidney to respond to aldosterone. In severe aldosterone deficiency, as occurs with congenital adrenal hyperplasia because of 21 hydroxylase deficiency, the hyperkalemia and metabolic acidosis are accompanied by hyponatremia and volume depletion from renal salt wasting. Incomplete aldosterone deficiency causes less severe electrolyte disturbances; children may have isolated hyperkalemic RTA, hyperkalemia without acidosis, or isolated hypona tremia. Patients may have aldosterone deficiency caused by decreased renin production by the kidney; renin normally stimulates aldosterone synthesis. Children with hyporeninemic hypoaldosteronism usually have either isolated hyperkalemia or hyperkalemic RTA. The manifes tations of aldosterone resistance depend on the severity of the resis tance. In the autosomal recessive form of pseudohypoaldosteronism type I, which is the result of an absence of the sodium channel that normally responds to aldosterone, there is often severe salt wasting and hyponatremia. In contrast, the aldosterone resistance in kidney transplant recipients usually produces either isolated hyperkalemia or hyperkalemic RTA; hyponatremia is unusual. Similarly, the medica tions that cause hyperkalemic RTA do not cause hyponatremia. Pseu dohypoaldosteronism type II, an autosomal dominant disorder also known as Gordon syndrome, is a unique cause of hyperkalemic RTA because the genetic defect causes volume expansion and hypertension. Children with abnormal urinary tracts, usually secondary to con genital malformations, may require diversion of urine through intes tinal segments. Ureterosigmoidostomy, anastomosis of a ureter to the sigmoid colon, almost always produces a metabolic acidosis and hypo kalemia. Consequently, ileal conduits are the more commonly used procedure, although there is still a risk of a metabolic acidosis. The appropriate metabolic compensation for a chronic respira tory alkalosis is a decrease in renal acid excretion. The resultant decrease in the serum HCO3 lessens the alkalemia caused by the respiratory alkalosis. If the respiratory alkalosis resolves quickly, the patient continues to have a decreased serum HCO3 , causing acidemia as the result |
982 | of a metabolic acidosis. This resolves over 1 2 days through increased acid excretion by the kidneys. Lactic acidosis (l lactic) typically occurs when inadequate oxy gen delivery to the tissues leads to anaerobic metabolism and excess production of lactic acid. Lactic acidosis may be secondary to shock, severe anemia, or hypoxemia. When the underlying cause of the lactic acidosis is alleviated, the liver is able to metabolize the accu mulated lactate into bicarbonate, correcting the metabolic acidosis. There is normally some tissue production of lactate metabolized by the liver. In children with severe liver dysfunction, impair ment of lactate metabolism may produce a lactic acidosis. Rarely, a metabolically active malignancy grows so fast that its blood sup ply becomes inadequate, with resultant anaerobic metabolism and lactic acidosis. Patients who have short bowel syndrome resulting from small bowel resection can have bacterial overgrowth. In these patients, excessive intestinal bacterial metabolism of glucose into d lactic acid can cause a lactic acidosis. Lactic acidosis occurs in a variety of inborn errors of metabolism, especially those affect ing mitochondrial oxidation (see Chapters 107.4 and 108). Medica tions also can cause lactic acidosis. Nucleoside reverse transcriptase inhibitors that are used to treat HIV infection inhibit mitochondrial replication; lactic acidosis is a rare complication, although elevated serum lactate concentrations without acidosis are quite common. Metformin, used to treat type 2 diabetes mellitus, is most likely to cause a lactic acidosis in patients with chronic kidney disease. High dosages and prolonged use of propofol can cause lactic acidosis. Propylene glycol is a diluent in a variety of oral and IV medications; excessive intake causes a lactic acidosis, principally from accumula tion of d lactic acid. Linezolid is another medication that may cause a lactic acidosis Table 73.13 Causes of Metabolic Acidosis NORMAL ANION GAP Diarrhea RTA Distal (type I) RTA (OMIM 179800602722267300611590) Proximal (type II) RTA (OMIM 604278) Mixed (type III) RTA (OMIM 259730) Hyperkalemic (type IV) RTA (OMIM 201910264350177735145260) Urinary tract diversions Posthypocapnia Ammonium chloride intake INCREASED ANION GAP Lactic Acidosis Tissue hypoxia Shock Hypoxemia Severe anemia Liver failure Malignancy Intestinal bacterial overgrowth Inborn errors of metabolism Medications Nucleoside reverse transcriptase inhibitors Metformin Propofol Linezolid Ketoacidosis Diabetic ketoacidosis Starvation ketoacidosis Alcoholic ketoacidosis Kidney Failure Poisoning Ethylene glycol Methanol Salicylate Toluene Paraldehyde Along with these genetic disorders, distal RTA may be secondary to renal disease or medications. Most cases of proximal RTA are not caused by this primary genetic disorder. Proximal RTA is usually part of Fanconi syndrome, which has multiple etiologies. Hyperkalemic RTA can be secondary to a genetic disorder (some of the more common are listed) or other etiologies. OMIM, database number from the Online Mendelian Inheritance in Man (http:www.nc bi.nlm.nih.govomim); RTA, renal tubular acidosis. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 516 Part VI u Fluid and Electrolyte Disorders In insulin dependent diabetes mellitus, inadequate |
983 | insulin leads to hyperglycemia and DKA (see Chapter 629). Production of acetoacetic acid and hydroxybutyric acid causes the metabolic acidosis. Admin istration of insulin corrects the underlying metabolic problem and permits conversion of acetoacetate and hydroxybutyrate into bicar bonate, which helps correct the metabolic acidosis. However, in some patients, urinary losses of acetoacetate and hydroxybutyrate may be substantial, preventing rapid regeneration of bicarbonate. In these patients, full correction of the metabolic acidosis requires renal regen eration of bicarbonate, a slower process. The hyperglycemia causes an osmotic diuresis, usually producing volume depletion, along with sub stantial losses of potassium, sodium, and phosphate. In starvation ketoacidosis the lack of glucose leads to ketoacid pro duction, which in turn can produce a metabolic acidosis, although it is usually mild as a result of increased acid secretion by the kidney. In alcoholic ketoacidosis, which is much less common in children than in adults, the acidosis usually follows a combination of an alcoholic binge with vomiting and poor intake of food. The acidosis is potentially more severe than with isolated starvation, and the blood glucose level may be low, normal, or high. Hypoglycemia and acidosis also suggest an inborn error of metabolism. Kidney failure causes a metabolic acidosis because of the need for the kidneys to excrete the acid produced by normal metabolism. With mild or moderate chronic kidney disease, the remaining nephrons are usually able to compensate by increasing acid excretion. When the GFR is 2030 of normal, the compensation is inadequate, and a metabolic acidosis develops. In some children, especially those with chronic kidney disease because of tubular damage, the acidosis devel ops at a higher GFR because of a concurrent defect in acid secretion by the distal tubule (distal RTA). A variety of toxic ingestions can cause a metabolic acidosis (see Chapter 94). Salicylate intoxication is now much less common because aspirin is no longer recommended for fever control in children. Acute salicylate intoxication occurs after a large overdose. Chronic salicylate intoxication is possible with gradual buildup of the drug. Especially in adults, respiratory alkalosis may be the dominant acid base distur bance. In children, the metabolic acidosis is usually the more significant finding. Other symptoms of salicylate intoxication are fever, seizures, lethargy, and coma. Hyperventilation may be particularly marked. Tin nitus, vertigo, and hearing impairment are more likely with chronic salicylate intoxication. Ethylene glycol, a component of antifreeze, is converted in the liver to glyoxylic and oxalic acids, causing a severe metabolic acidosis. Excessive oxalate excretion causes calcium oxalate crystals to appear in the urine, and calcium oxalate precipitation in the kidney tubules can cause kidney failure. The toxicity of methanol ingestion also depends on liver metabolism; formic acid is the toxic end product that causes the metabolic acidosis and other sequelae, which include damage to the optic nerve and CNS. Symptoms may include nausea, emesis, visual impairment, and altered mental status. Toluene inhalation and par aldehyde ingestion are other potential causes of a metabolic acidosis. Many inborn errors of metabolism |
984 | cause a metabolic acidosis (see Chapters 104 107). The metabolic acidosis may be the result of exces sive production of ketoacids, lactic acid, and other organic anions. Some patients have accompanying hypoglycemia or hyperammone mia. In most patients, the acidosis occurs episodically during acute decompensations, which may be precipitated by ingestion of specific dietary substrates, the stress of a mild illness, or poor compliance with dietary or medical therapy. In a few inborn errors of metabolism, patients have a chronic metabolic acidosis. Clinical Manifestations The underlying disorder usually produces most of the signs and symp toms in children with a mild or moderate metabolic acidosis. The clini cal manifestations of the acidosis are related to the degree of acidemia; patients with appropriate respiratory compensation and less severe acidemia have fewer manifestations than those with a concomitant respiratory acidosis. At a serum pH 7.2, there may be impaired car diac contractility and an increased risk of arrhythmias, especially if underlying heart disease or other predisposing electrolyte disorders are present. With acidemia, there may be a decrease in the cardiovascular response to catecholamines, potentially exacerbating hypotension in children with volume depletion or shock. Acidemia causes vasocon striction of the pulmonary vasculature, which is especially problem atic in newborn infants with persistent pulmonary hypertension (see Chapter 130). The normal respiratory response to metabolic acidosiscompensa tory hyperventilation may be subtle with mild metabolic acidosis, but it causes discernible increased respiratory effort with worsen ing acidemia. The acute metabolic effects of acidemia include insulin resistance, increased protein degradation, and reduced ATP synthesis. Chronic metabolic acidosis causes failure to thrive in children. Aci demia causes potassium to move from the ICS to the ECS, thereby increasing the serum K. Severe acidemia impairs brain metabolism, eventually resulting in lethargy and coma. Diagnosis The etiology of a metabolic acidosis is often apparent from the history and physical examination. Acutely, diarrhea and shock are common causes of a metabolic acidosis. Shock, which causes a lactic acidosis, is usually apparent on physical examination and can be secondary to dehydration, acute blood loss, sepsis, or heart disease. Failure to thrive suggests a chronic metabolic acidosis, as with renal insufficiency or RTA. New onset of polyuria occurs in children with undiagnosed diabetes mellitus and DKA. Metabolic acidosis with seizures and or a depressed sensorium, especially in an infant, warrants consider ation of an inborn error of metabolism. Meningitis and sepsis with lactic acidosis are more common explanations for metabolic acidosis with neurologic signs and symptoms. Identification of a toxic inges tion (e.g., ethylene glycol, methanol) is especially important because of the potentially excellent response to specific therapy. A variety of medications can cause a metabolic acidosis, whether prescribed or accidentally ingested. Hepatomegaly and metabolic acidosis may occur in children with sepsis, congenital or acquired heart disease, hepatic failure, or inborn errors of metabolism. Basic laboratory tests in a child with a metabolic acidosis should include measurements of BUN, serum creatinine, serum glucose, uri nalysis, and serum electrolytes. Metabolic acidosis, hyperglycemia, gly cosuria, |
985 | and ketonuria support a diagnosis of DKA. Starvation causes ketosis, but the metabolic acidosis, if present, is usually mild (HCO3 18 mEqL). Most children with ketosis from poor intake and meta bolic acidosis have a concomitant disorder, such as gastroenteritis with diarrhea, that explains the metabolic acidosis. Alternatively, metabolic acidosis with or without ketosis occurs in inborn errors of metabolism; patients with these disorders may have hyperglycemia, normoglycemia, or hypoglycemia. Adrenal insufficiency may cause metabolic acidosis and hypoglycemia. Metabolic acidosis with hypoglycemia also occurs with liver failure. Metabolic acidosis, normoglycemia, and glycosuria occur in children when type II RTA is part of Fanconi syndrome; the defect in resorption of glucose by the proximal tubule of the kidney causes the glycosuria. The serum K is often abnormal in children with a metabolic aci dosis. Even though a metabolic acidosis causes potassium to move from the ICS to the ECS, many patients with a metabolic acidosis have a low serum K because of excessive body losses of K. With diar rhea, there are high stool losses of K and, often, secondary renal losses of K, whereas in type I or type II RTA, there are increased urinary losses of K. In DKA, urinary losses of K are high, but the shift of K out of cells because of a lack of insulin and metabolic acidosis is especially significant. Consequently, the initial serum K can be low, normal, or high, even though total body K is almost always decreased. The serum K is usually increased in patients with acidosis caused Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 73 u Electrolyte and Acid Base Disorders 517 by renal insufficiency; urinary K excretion is impaired. The combina tion of metabolic acidosis, hyperkalemia, and hyponatremia occurs in patients with severe aldosterone deficiency (adrenogenital syndrome) or aldosterone resistance. Patients with less severe, type IV RTA often have only hyperkalemia and metabolic acidosis. Very ill children with metabolic acidosis may have an elevated serum K because of a combi nation of renal insufficiency, tissue breakdown, and a shift of K from the ICS to the ECS secondary to the metabolic acidosis. The plasma anion gap is useful for evaluating patients with a meta bolic acidosis. It divides patients into two diagnostic groups, those with normal anion gap and those with increased anion gap. The following formula determines the anion gap: Anion gap Na (Cl HCO3 ) A normal anion gap is 4 11, although there is variation among labo ratories. Approximately 11 mEq of the anion gap is normally secondary to albumin. A 1 gdL decrease in the albumin concentration decreases the anion gap by approximately 2.5 mEqL. Thus, if the albumin is not close to 4 gdL, the anion gap should be corrected for the albumin concentration: Anion gap (corrected for albumin) Na (Cl HCO3 ) 2.5 x (4 |
986 | observed albumin) The number of serum anions must equal the number of serum cat ions to maintain electrical neutrality (Fig. 73.11). The anion gap is the difference between the measured cation (Na) and the measured anions (Cl bicarbonate). The anion gap is also the difference between the unmeasured cations (K, magnesium, calcium) and the unmeasured anions (albumin, phosphate, urate, sulfate). An increased anion gap occurs when there is an increase in unmeasured anions. With a lac tic acidosis, there is endogenous production of lactic acid, which is composed of positively charged hydrogen ions and negatively charged lactate anions. The hydrogen ions are largely buffered by serum bicar bonate, resulting in a decrease in HCO3 . The hydrogen ions that are not buffered by bicarbonate cause the serum pH to decrease. The lac tate anions remain, causing the increase in the anion gap. An increase in unmeasured anions, along with H generation, is present in all causes of an increased gap metabolic acidosis (see Table 73.13). In DKA, the ketoacids hydroxybutyrate and acetoacetate are the unmeasured anions. In kidney failure there is retention of unmea sured anions, including phosphate, urate, and sulfate. The increase in unmeasured anions in kidney failure is usually less than the decrease in HCO3 . Kidney failure is thus a mix of an increased gap and a normal gap metabolic acidosis. The normal gap metabolic acidosis is especially prominent in children with kidney failure because of tubular damage, as occurs with renal dysplasia or obstructive uropathy, because these patients have a concurrent RTA. The unmeasured anions in toxic ingestions vary: formate in methanol intoxication, glycolate in ethylene glycol intoxication, and lactate and ketoacids in salicylate intoxication. In inborn errors of metabolism, the unmeasured anions depend on the specific etiology and may include ketoacids, lactate, and other organic anions. In a few inborn errors of metabolism, the acidosis occurs with out generation of unmeasured anions; thus the anion gap is normal. A normalanion gap metabolic acidosis occurs when there is a decrease in HCO3 without an increase in the unmeasured anions. With diarrhea, there is a loss of bicarbonate in the stool, causing a decrease in the serum pH and HCO3 ; the serum Cl increases to maintain electrical neutrality (see Fig. 73.11). Hyperchloremic meta bolic acidosis is an alternative term for a normalanion gap metabolic acidosis. Calculation of the anion gap is more precise than using Cl to differentiate between a normal gap and an increased gap meta bolic acidosis, in that the anion gap directly determines the presence of unmeasured anions. Electrical neutrality dictates that the Cl increases or decreases according to the serum Na, making Cl a less reliable predictor of unmeasured anions than the more direct mea sure, calculation of the anion gap. An increase in unmeasured cations, such as calcium, potassium, and magnesium, decreases the anion gap. Conversely, a decrease in unmeasured cations is a very unusual cause of an increased anion gap. Because of these variables, the broad range of a normal |
987 | anion gap, and other variables, the presence of a normal or an increased anion gap is not always reliable in differentiating among the causes of a meta bolic acidosis, especially when the metabolic acidosis is mild. In some patients, there is more than one explanation for the metabolic acidosis, such as the child with diarrhea and lactic acidosis as a result of poor perfusion. The anion gap should not be interpreted in dogmatic isola tion; consideration of other laboratory abnormalities and the clinical history improves its diagnostic utility. Treatment The most effective therapeutic approach for patients with a metabolic acidosis is repair of the underlying disorder, if possible. The administra tion of insulin in DKA and the restoration of adequate perfusion with IV fluids in lactic acidosis because of hypovolemia or shock eventually result in normalization of the acid base balance. In other diseases, the use of bicarbonate therapy is indicated because the underlying disor der is irreparable. Children with metabolic acidosis caused by RTA or chronic kidney disease require long term base therapy. Patients with acute kidney injury and metabolic acidosis may need base therapy until their kidneys ability to excrete hydrogen normalizes. In other disorders the cause of the metabolic acidosis eventually resolves, but base therapy may be necessary during the acute illness. In salicylate poisoning, alkali administration increases renal clearance of salicylate and decreases the amount of salicylate in brain cells. Short term base therapy is often necessary in other poisonings (ethylene glycol, metha nol) and inborn errors of metabolism (pyruvate carboxylase deficiency, propionic acidemia). Some inborn errors of metabolism require long term base therapy. The use of base therapy in DKA with lactic acidosis is controver sial; there is little evidence that it improves patient outcome, and it has a variety of potential side effects. The risks of giving sodium bicarbonate Normal plasma Acidosis (no gap) Acidosis (gap) Na? UC Cl? UA Na? UC Cl? UA Na? UC Cl? UA HCO3 ? HCO3 ? HCO3 ? Fig. 73.11 Anion gap. The anion gap is the difference between the sodium concentration and the combined concentrations of chloride and bicarbonate (vertical black bars). In both a gap and a nongap meta bolic acidosis, there is a decrease in the bicarbonate concentration. There is an increase in unmeasured anions (UA) in patients with a gap metabolic acidosis. In a nongap metabolic acidosis, there is an increase in the serum chloride concentration. UC, Unmeasured cations. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 518 Part VI u Fluid and Electrolyte Disorders include the possibility of causing hypernatremia or volume overload. Furthermore, the patient may have overcorrection of the metabolic acidosis once the underlying disorder resolves, because metabolism of lactate or ketoacids generates bicarbonate. The rapid change from acidemia to alkalemia can cause a variety of problems, including hypo kalemia and hypophosphatemia. Bicarbonate therapy increases |
988 | the generation of CO2, which can accumulate in patients with respiratory failure. Because CO2 readily diffuses into cells, the administration of bicarbonate can lower the intracellular pH, potentially worsening cell function. Base therapy is usually reserved for children with severe acute lactic acidosis and severe DKA. Oral base therapy is given to children with chronic metabolic acido sis. Sodium bicarbonate tablets are available for older children. Younger children generally take citrate solutions; the liver generates bicarbonate from citrate. Citrate solutions are available as sodium citrate, potas sium citrate, and a 1:1 mix of sodium citrate and potassium citrate. The patients potassium needs dictate the choice. Children with type I or type II RTA may have hypokalemia and benefit from potassium supplements, but most children with chronic kidney failure cannot tol erate additional potassium. Oral or IV base can be used in acute metabolic acidosis; IV therapy is generally used when a rapid response is necessary. Sodium bicar bonate may be given as a bolus, usually at a dose of 1 mEqkg, in an emergency situation. Another approach is to add sodium bicarbonate or sodium acetate to the patients IV fluids, remembering to remove an equal amount of sodium chloride from the solution to avoid giv ing an excessive sodium load. Careful monitoring is mandatory so that the dose of base can be titrated appropriately. Tris(hydroxymethyl) aminomethane (tromethamine, THAM) is an option in patients with a metabolic acidosis and a respiratory acidosis, because it neutralizes acids without releasing CO2. THAM also diffuses into cells and there fore provides intracellular buffering. Hemodialysis is another option for correcting a metabolic acido sis, and it is an appropriate choice in patients with renal insufficiency, especially if significant uremia or hyperkalemia is also present. Hemo dialysis is advantageous for correcting the metabolic acidosis caused by methanol or ethylene glycol intoxication, because hemodialysis effi ciently removes the offending toxin. In addition, these patients often have a severe metabolic acidosis that does not respond easily to IV bicarbonate therapy. Peritoneal dialysis is another option for correct ing the metabolic acidosis due to chronic kidney disease. Many causes of metabolic acidosis require specific therapy. Admin istration of a glucocorticoid and a mineralocorticoid is necessary in patients with adrenal insufficiency. Patients with DKA require insu lin therapy, whereas patients with lactic acidosis respond to mea sures that alleviate tissue hypoxia. Along with correction of acidosis, patients with methanol or ethylene glycol ingestion should receive an agent that prevents the breakdown of the toxic substance to its toxic metabolites. Fomepizole has supplanted ethanol as the treatment of choice. These agents work by inhibiting alcohol dehydrogenase, the enzyme that performs the first step in the metabolism of ethylene glycol or methanol. There are a variety of disease specific therapies for patients with a metabolic acidosis resulting from an inborn error of metabolism. METABOLIC ALKALOSIS Metabolic alkalosis in children is most often secondary to emesis or diuretic use. The serum bicarbonate concentration is increased with a metabolic alkalosis, although a respiratory acidosis |
989 | also leads to a com pensatory elevation of the serum HCO3 . With a simple metabolic alkalosis, however, the pH is elevated; alkalemia is present. Patients with a respiratory acidosis are acidemic. Decreasing ventilation causes appropriate respiratory compensation for a metabolic alkalosis. Pco2 increases by 7 mm Hg for each 10 mEqL increase in the serum HCO3 . Appropriate respiratory compensation never exceeds a Pco2 of 55 60 mm Hg. The patient has a concurrent respiratory alkalosis if the Pco2 is lower than the expected compensation. A greater than expected Pco2 occurs with a concurrent respiratory acidosis. Etiology and Pathophysiology The kidneys normally respond promptly to a metabolic alkalosis by increasing base excretion. Two processes are therefore usually present to produce a metabolic alkalosis: (1) the generation of the metabolic alkalosis, which requires the addition of base to the body, and (2) the maintenance of the metabolic alkalosis, which requires impairment in the kidneys ability to excrete base. The etiologies of a metabolic alkalosis are divided into two catego ries based on the urinary chloride level (Table 73.14). The alkalosis in patients with a low urinary Cl is maintained by volume deple tion; thus volume repletion is necessary for correction of the alkalosis. The volume depletion in these patients is caused by losses of Na and K, but the loss of Cl is usually greater than the losses of Na and K combined. Because Cl losses are the dominant cause of the volume depletion, these patients require Cl to correct the volume depletion and metabolic alkalosis; they are said to have Cl responsive meta bolic alkalosis. In contrast, the alkalosis in a patient with an elevated urinary Cl does not respond to volume repletion and so is termed Cl resistant metabolic alkalosis. Table 73.14 Causes of Metabolic Alkalosis CHLORIDE RESPONSIVE (URINARY CHLORIDE 15 MEQL) Gastric losses Emesis Nasogastric suction Diuretics (loop or thiazide) Chloride losing diarrhea (OMIM 214700) Low chloride formula Cystic fibrosis (OMIM 219700) Posthypercapnia CHLORIDE RESISTANT (URINARY CHLORIDE 20 MEQL) High Blood Pressure Adrenal adenoma or hyperplasia Glucocorticoid remediable aldosteronismFamilial hyperaldosteronism type I (OMIM 103900) Familial hyperaldosteronism type II (OMIM 605635) Familial hyperaldosteronism type III (OMIM 613677) Familial hyperaldosteronism type IV (OMIM 617027) Renovascular disease Renin secreting tumor 17 Hydroxylase deficiency (OMIM 202110) 11 Hydroxylase deficiency (OMIM 202010) Cushing syndrome 11 Hydroxysteroid dehydrogenase deficiency (OMIM 218030) Licorice ingestion Liddle syndrome (OMIM 177200) Normal Blood Pressure Gitelman syndrome (OMIM 263800) Bartter syndrome (OMIM 24120060736460252260167830097160 1198613090) Autosomal dominant hypoparathyroidism (OMIM 146200) EAST syndrome (OMIM 612780) Hyperuricemia, Pulmonary Hypertension, Renal Failure in Infancy and Alkalosis, HUPRA Syndrome (OMIM 613845) Autosomal dominant kidney hypomagnesemia due to RRAGD variant (OMIM not assigned) Base administration EAST, Epilepsy, ataxia, sensorineural hearing loss, and tubulopathy; OMIM, database number from the Online Mendelian Inheritance in Man (http:www.ncbi.nlm.nih.go vomim). Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 73 u Electrolyte and |
990 | Acid Base Disorders 519 Emesis or nasogastric suction results in loss of gastric fluid, which has a high content of HCl. Generation of H by the gastric mucosa causes simultaneous release of bicarbonate into the bloodstream. Nor mally, the hydrogen ions in gastric fluid are reclaimed in the small intestine (by neutralizing secreted bicarbonate); thus there is no net loss of acid. With loss of gastric fluid, this does not occur, and a meta bolic alkalosis develops. This period is the generation phase of the met abolic alkalosis. The maintenance phase of the metabolic alkalosis from gastric losses is caused by the volume depletion (chloride depletion from gastric loss of HCl). Volume depletion interferes with urinary loss of bicarbonate, the normal renal response to a metabolic alkalosis. During volume depletion, several mechanisms prevent renal bicar bonate loss. First, there is a reduction in the GFR, so less bicar bonate is filtered. Second, volume depletion increases resorption of sodium and bicarbonate in the proximal tubule, limiting the amount of bicarbonate that can be excreted in the urine. This effect is mediated by angiotensin II and adrenergic stimulation of the kidney, both of which are increased in response to volume deple tion. Third, the increase in aldosterone during volume depletion increases bicarbonate resorption and H secretion in the collecting duct. In addition to volume depletion, gastric losses are usually associ ated with hypokalemia as a result of both gastric loss of K and, most importantly, increased urinary K losses. The increased urinary losses of K are mediated by aldosterone, through volume depletion, and by the increase in intracellular K secondary to the metabolic alkalosis, which causes K to move into the cells of the kidney, causing increased K excretion. Hypokalemia contributes to the maintenance of the met abolic alkalosis by decreasing bicarbonate loss. Hypokalemia increases H secretion in the distal nephron and stimulates ammonia production in the proximal tubule. Ammonia production enhances renal excretion of H. A metabolic alkalosis can develop in patients receiving loop or thiazide diuretics. Diuretic use leads to volume depletion, which increases angiotensin II, aldosterone, and adrenergic stimulation of the kidney. Diuretics increase the delivery of sodium to the distal nephron, further enhancing acid excretion. Moreover, these diuret ics cause hypokalemia, which increases acid excretion by the kid ney. The increase in renal acid excretion generates the metabolic alkalosis, and the decrease in bicarbonate loss maintains it. In addi tion, patients who are receiving diuretics have a contraction alka losis. Diuretic use causes fluid loss without bicarbonate; thus the remaining body bicarbonate is contained in a smaller total body fluid compartment. The HCO3 increases, helping to generate the metabolic alkalosis. Diuretics are often used in patients with edema, such as those with nephrotic syndrome, heart failure, or liver failure. In many of these patients, metabolic alkalosis resulting from diuretic use devel ops despite the continued presence of edema. This is because the effective intravascular volume is low, and it is the effective intra vascular volume that stimulates the |
991 | compensatory mechanisms that cause and maintain a metabolic alkalosis. Many of these patients have a decreased effective intravascular volume before they begin diuretic therapy, increasing the likelihood of diuretic induced met abolic alkalosis. Diuretic use increases chloride excretion in the urine. Conse quently, while a patient is receiving diuretics, the urine Cl is typically high (20 mEqL). After the diuretic effect has worn off, the urinary Cl is low (15 mEqL) because of appropriate renal Cl retention in response to volume depletion. Thus categorization of diuretics because of urinary Cl depends on the timing of the measurement. However, the metabolic alkalosis from diuretics is Cl responsive; it is corrected after adequate volume repletion. This is the rationale for including this process among the chloride responsive causes of a metabolic alkalosis. Most patients with diarrhea have a metabolic acidosis because of stool losses of bicarbonate. In chloride losing diarrhea, an auto somal recessive disorder, there is a defect in the normal intestinal exchange of bicarbonate for chloride, causing excessive stool losses of chloride (see Chapter 385). In addition, stool losses of H and K cause metabolic alkalosis and hypokalemia, both of which are exac erbated by increased renal H and K losses from volume depletion. Treatment is with oral supplements of K and NaCl. Use of a gastric proton pump inhibitor (PPI), by decreasing gastric HCl production, reduces both the volume of diarrhea and the need for electrolyte supplementation. Formulas with extremely low Cl content have led to Cl defi ciency and volume depletion. There is secondary metabolic alka losis and hypokalemia. Cystic fibrosis can rarely cause metabolic alkalosis, hypokalemia, and hyponatremia because of excessive NaCl losses in sweat (see Chapter 454). The volume depletion causes the metabolic alkalosis and hypokalemia through increased urinary losses, whereas the hyponatremia, a less common finding, is secondary to Na loss combined with renal water conservation in an effort to protect the intravascular volume (appropriate ADH production). A posthypercapnic metabolic alkalosis occurs after the cor rection of a chronic respiratory acidosis. This is typically seen in patients with chronic lung disease who are started on mechanical ventilation. During chronic respiratory acidosis, appropriate renal compensation leads to an increase in the serum HCO3 . Because it is still present after acute correction of the respiratory acidosis, the elevated HCO3 causes a metabolic alkalosis. The metabolic alka losis persists because the patient with a chronic respiratory acido sis is intravascularly depleted because of the Cl loss that occurred during the initial metabolic compensation for the primary respira tory acidosis. In addition, many children with a chronic respiratory acidosis receive diuretics, which further decrease the intravascular volume. The metabolic alkalosis responds to correction of the intra vascular volume deficit. The chloride resistant causes of metabolic alkalosis can be subdi vided according to blood pressure status. Patients with hypertension either have increased aldosterone levels or act as if they do. Aldosterone levels are elevated in children with adrenal adenomas or hyperplasia. Aldosterone causes renal retention of sodium, with resultant |
992 | hyper tension. Metabolic alkalosis and hypokalemia result from aldosterone mediated renal excretion of H and K. The urinary Cl level is not low because these patients are volume overloaded, not volume depleted. The volume expansion and hypertension allow normal excretion of Na and Cl despite the presence of aldosterone. This is known as the mineralocorticoid escape phenomenon. In glucocorticoid remediable aldosteronism, an autosomal dominant disorder, excess production of aldosterone results from the presence of an aldosterone synthase gene regulated by adreno corticotropic hormone (ACTH) (see Chapter 616.8). Glucocorticoids effectively treat this disorder by inhibiting ACTH production by the pituitary, downregulating the inappropriate aldosterone production. Familial hyperaldosteronism type II, which causes elevated aldoste rone levels, responds to spironolactone. Familial hyperaldosteronism type III typically requires bilateral adrenalectomy due to the severity of the hyperaldosteronism. Renovascular disease and renin secreting tumors both cause excessive renin, leading to an increase in aldo sterone, although hypokalemia and metabolic alkalosis are less com mon findings than hypertension. In two forms of congenital adrenal hyperplasia, 11 hydroxylase deficiency and 17 hydroxylase deficiency, there is excessive production of the mineralocorticoid 11 deoxycorticosterone (see Chapters 616.2 and 616.4). Hyperten sion, hypokalemia, and metabolic alkalosis are more likely in 17 hydroxylase deficiency than in 11 hydroxylase deficiency. These disorders respond to glucocorticoids because the excess production of 11 deoxycorticosterone is under the control of ACTH. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 520 Part VI u Fluid and Electrolyte Disorders Cushing syndrome frequently causes hypertension. Cortisol has some mineralocorticoid activity, and high levels can produce hypoka lemia and metabolic alkalosis in patients with Cushing syndrome. Cortisol can bind to the mineralocorticoid receptors in the kid ney and function as a mineralocorticoid. This binding normally does not occur because 11 hydroxysteroid dehydrogenase in the kidney converts cortisol to cortisone, which does not bind to the mineralocorticoid receptor. In the autosomal recessive disorder 11 hydroxysteroid dehydrogenase deficiency, also called apparent mineralocorticoid excess, cortisol is not converted in the kidney to cortisone. Cortisol is therefore available to bind to the miner alocorticoid receptor in the kidney and act as a mineralocorticoid. Patients with this deficiency, despite low levels of aldosterone, are hypertensive and hypokalemic, and they have a metabolic alkalosis. The same phenomenon can occur with excessive intake of natural licorice, a component of which, glycyrrhizic acid, inhibits 11 hydroxysteroid dehydrogenase. The autosomal dominant disorder Liddle syndrome is secondary to an activating variant in the gene for the sodium channel in the distal nephron (see Chapter 571.3). Upregulation of this sodium channel is one of the principal actions of aldosterone. Because this Na channel is continuously open, chil dren with Liddle syndrome have the features of hyperaldosteron ism, including hypertension, hypokalemia, and metabolic alkalosis, but low serum levels of aldosterone. Bartter and Gitelman syndromes are autosomal recessive disor ders associated with normal blood pressure, elevated urinary |
993 | Cl, metabolic alkalosis, and hypokalemia (see Chapter 571). In Bart ter syndrome, patients have a defect in Na and Cl resorption in the loop of Henle. This leads to excessive urinary losses of Na and Cl, and as in patients receiving loop diuretics, volume deple tion and secondary hyperaldosteronism occur, causing hypokale mia and metabolic alkalosis. Gitelman syndrome is usually milder than Bartter syndrome. Patients have renal Na and Cl wasting with volume depletion caused by variants in the gene encoding the thiazide sensitive Na Cl transporter in the distal tubule. As in patients receiving a thiazide diuretic, affected patients have volume depletion and secondary hyperaldosteronism with hypokalemia and metabolic alkalosis. Children with Gitelman syndrome have hypocalciuria and hypomagnesemia. Some patients with autoso mal dominant hypoparathyroidism have hypokalemia and meta bolic alkalosis from impaired Na and Cl resorption in the loop of Henle. EAST syndrome causes hypokalemia, metabolic alkalosis, and hypomagnesemia. Excessive base intake can cause a metabolic alkalosis. Affected patients do not have low urine Cl, unless there is associated vol ume depletion. In the absence of volume depletion, excess base is rapidly corrected via renal excretion of bicarbonate. Rarely, massive base intake can cause a metabolic alkalosis by overwhelming the kidneys ability to excrete bicarbonate. This may occur in infants who are given baking soda as a home remedy for colic or stom ach upset. Each teaspoon of baking soda has 42 mEq of sodium bicarbonate. Infants have increased vulnerability because of a lower GFR, limiting the rate of compensatory renal bicarbonate excretion. A metabolic alkalosis may also occur in patients who receive a large amount of sodium bicarbonate during cardiopulmonary resus citation. Blood products are anticoagulated with citrate, which is converted into bicarbonate by the liver. Patients who receive large amounts of blood products may have a metabolic alkalosis. Iat rogenic metabolic alkalosis can occur because of acetate in TPN. Aggressive use of bicarbonate therapy in a child with a lactic aci dosis or DKA may cause a metabolic alkalosis. This is especially likely in a patient in whom the underlying cause of the lactic aci dosis is successfully corrected (restoration of intravascular volume in a patient with severe dehydration). Once the cause of the lactic acidosis resolves, lactate can be converted by the liver into bicar bonate, which when combined with infused bicarbonate can create a metabolic alkalosis. A similar phenomenon can occur in a child with DKA because the administration of insulin allows ketoacids to be metabolized, producing bicarbonate. However, this phenome non rarely occurs because of judicious use of bicarbonate therapy in DKA and because there are usually significant pretreatment losses of ketoacids in the urine, preventing massive regeneration of bicar bonate. Base administration is most likely to cause a metabolic alka losis in patients who have an impaired ability to excrete bicarbonate in the urine. This impairment occurs in patients with concurrent volume depletion or renal insufficiency. Clinical Manifestations The symptoms in patients with a metabolic alkalosis are often related to the underlying |
994 | disease and associated electrolyte disturbances. Children with Cl responsive causes of metabolic alkalosis often have symptoms related to volume depletion, such as thirst and lethargy. In contrast, children with Cl unresponsive causes may have symptoms related to hypertension. Alkalemia causes potassium to shift into the ICS, producing a decrease in the extracellular K. Alkalemia leads to increased urinary losses of K. Increased K losses are present in many of the conditions that cause a metabolic alkalosis. Therefore most patients with a meta bolic alkalosis have hypokalemia, and their symptoms may be related to the hypokalemia (see Chapter 73.4). The symptoms of a metabolic alkalosis are caused by the associated alkalemia. The magnitude of the alkalemia is related to the severity of the metabolic alkalosis and the presence of concurrent respiratory acid base disturbances. During alkalemia, the ionized calcium concen tration decreases because of increased binding of calcium to albumin. The decrease in the ionized calcium concentration may cause symp toms of tetany (carpopedal spasm). Arrhythmias are a potential complication of a metabolic alkalosis, and the risk for arrhythmia increases if there is concomitant hypo kalemia. Alkalemia increases the risk of digoxin toxicity, and antiar rhythmic medications are less effective in the presence of alkalemia. In addition, alkalemia may decrease cardiac output. A metabolic alkalosis causes a compensatory increase in the Pco2 by decreasing ventilation. The decrease in ventilatory drive can cause hypoxia. Diagnosis Measurement of the urine Cl is the most helpful test in differen tiating among the causes of a metabolic alkalosis. The urine Cl is low in patients with a metabolic alkalosis resulting from volume depletion, unless there is a defect in renal handling of Cl. The urine Cl is superior to the urine Na in assessment of volume status in patients with a metabolic alkalosis because the normal renal response to a metabolic alkalosis is to excrete bicarbonate. Because bicarbonate is negatively charged, it can only be excreted with cations, usually Na and K. Therefore a patient with a meta bolic alkalosis may excrete Na in the urine despite the presence of volume depletion, which normally causes avid Na retention. The urine Cl is usually a good indicator of volume status, and it dif ferentiates Cl resistant and Cl responsive causes of a metabolic alkalosis. Diuretics and gastric losses are the most common causes of meta bolic alkalosis and are usually apparent from the patient history. Occasionally, metabolic alkalosis, usually with hypokalemia, may be a clue to the presence of bulimia or surreptitious diuretic use (see Chapter 41). Patients with bulimia have a low urine Cl level, indicating that they have volume depletion because of an extrarenal etiology, but there is no alternative explanation for their volume depletion. Surreptitious diuretic use may be diagnosed by obtaining a urine toxicology screen for diuretics. The urine Cl is increased while a patient is using diuretics but is low when the patient stops taking them. Rarely, children with mild Bartter or Gitelman syn drome are misdiagnosed as having bulimia or |
995 | abusing diuretics. The Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 73 u Electrolyte and Acid Base Disorders 521 urine Cl is always elevated in Bartter and Gitelman syndromes, and the urine toxicology screen for diuretics has a negative result. Metabolic alkalosis with hypokalemia is occasionally the initial manifestation of cystic fibrosis. An elevated sweat Cl finding is diagnostic. Patients with a metabolic alkalosis and a high urinary Cl are subdivided according to blood pressure status. Children with nor mal blood pressure may have Bartter or Gitelman syndrome. Excess base administration is another diagnostic possibility, but it is usu ally apparent from the history. In patients with sodium bicarbonate ingestion (baking soda), which may be unreported by the parent, the metabolic alkalosis usually occurs with significant hypernatremia. In addition, unless volume depletion is superimposed, the metabolic alkalosis from base ingestion resolves itself once the source of base is eliminated. Measuring serum concentrations of renin and aldosterone differ entiates children with a metabolic alkalosis, a high urinary Cl, and elevated blood pressure. Both renin and aldosterone are elevated in children with either renovascular disease or a renin secreting tumor. Aldosterone is high and renin is low in patients with adrenal adenomas or hyperplasia and glucocorticoid remediable aldosteronism. Renin and aldosterone are low in children with Cushing syndrome, Liddle syndrome, licorice ingestion, and 17 hydroxylase, 11 hydroxylase, and 11 hydroxysteroid dehydrogenase deficiencies. An elevated 24 hour urine cortisol value is diagnostic of Cushing syndrome, which is suspected from the presence of the other classic features of this dis ease (see Chapter 619). Elevations of 11 deoxycorticosterone values are seen in 17 hydroxylase and 11 hydroxylase deficiency. Treatment The approach to treatment of metabolic alkalosis depends on the sever ity of the alkalosis and the underlying etiology. In children with a mild metabolic alkalosis (HCO3 32 mEqL), intervention is often unnec essary, although this depends on the specific circumstances. In a child with congenital heart disease who is receiving a stable dose of a loop diuretic, a mild alkalosis does not require treatment. In contrast, inter vention may be appropriate in a child with a worsening mild metabolic alkalosis because of nasogastric suction. The presence of a concurrent respiratory acid base disturbance also influences therapeutic decision making. A patient with a concurrent respiratory acidosis should have some increase in bicarbonate from metabolic compensation; thus the severity of the pH elevation is more important than HCO3 . In con trast, a patient with respiratory alkalosis and a metabolic alkalosis is at risk for severe alkalemia; treatment may be indicated, even if the increase in bicarbonate value is only mild. Intervention is usually necessary in children with moderate or severe metabolic alkalosis. The most effective approach is to address the under lying etiology. In some children, nasogastric suction may be decreased or discontinued. Alternatively, the addition of a |
996 | gastric PPI reduces gastric secretion and losses of HCl. Diuretics are an important cause of meta bolic alkalosis, and if a change is tolerated, they should be eliminated or the dose reduced. Adequate potassium supplementation or the addition of a potassium sparing diuretic is also helpful in a child with a metabolic alkalosis from diuretics. Potassium sparing diuretics not only decrease renal K losses but, by blocking the action of aldosterone, also decrease H secretion in the distal nephron, increasing urinary bicarbonate excre tion. Many children cannot tolerate discontinuation of diuretic therapy; hence, potassium supplementation and potassium sparing diuretics are the principal therapeutic approach. Arginine HCl may also be used to treat chloride responsive metabolic acidosis if sodium or potassium salts are not appropriate. Arginine HCl may raise the serum K levels dur ing administration. Rarely, in cases of severe metabolic alkalosis, acet azolamide is an option. A carbonic anhydrase inhibitor, acetazolamide decreases resorption of bicarbonate in the proximal tubule, causing significant bicarbonate loss in the urine. The patient receiving this drug must be monitored closely, because acetazolamide produces major losses of potassium in the urine and increases fluid losses, potentially neces sitating a reduction in dosage of other diuretics. Most children with a metabolic alkalosis have one of the chloride responsive etiologies. In these situations, administration of sufficient sodium chloride and potassium chloride to correct the volume deficit and the potassium deficit is necessary to correct the metabolic alkalosis. This approach may not be an option in the child who has volume depletion due to diuretics, because volume repletion may be contraindicated. Adequate replacement of gastric losses of sodium and potassium in a child with a nasogastric tube can minimize or prevent the development of the meta bolic alkalosis. With adequate intravascular volume and a normal serum K, the kidney excretes the excess bicarbonate within 2 days. In children with the chloride resistant causes of a metabolic alkalosis that are associated with hypertension, volume repletion is contraindicated because it would exacerbate the hypertension and would not repair the metabolic alkalosis. Ideally, treatment focuses on eliminating the excess aldosterone effect. Adrenal adenomas can be resected, licorice intake can be eliminated, and renovascular dis ease can be repaired. Glucocorticoid remediable aldosteronism, 17 hydroxylase deficiency, and 11 hydroxylase deficiency respond to the administration of glucocorticoids. The mineralocorticoid effect of cortisol in 11 hydroxysteroid dehydrogenase deficiency can be decreased with the use of spironolactone, which blocks the miner alocorticoid receptor. In contrast, the metabolic alkalosis in children with Liddle syndrome does not respond to spironolactone; however, either triamterene or amiloride is effective therapy because both agents block the sodium channel that is constitutively active in Liddle syndrome. In children with Bartter or Gitelman syndrome, therapy includes oral potassium and sodium supplementation; potassium sparing diuretics may be helpful in select cases. Children with Gitelman syndrome often require magnesium supplementation, whereas children with severe Bartter syndrome often benefit from indomethacin. RESPIRATORY ACIDOSIS A respiratory acidosis is an inappropriate increase in blood carbon diox ide tension |
997 | (Pco2). CO2 is a by product of metabolism and is removed from the body by the lungs. During a respiratory acidosis, the effective ness of CO2 removal by the lungs is decreased. A respiratory acidosis is secondary to either pulmonary disease, such as severe bronchiolitis, or nonpulmonary disease, such as a narcotic overdose (see Chapter 86). Even though body production of CO2 can vary, normal lungs are able to accommodate this variation; excess production of CO2 is not an isolated cause of a respiratory acidosis. With impairment of alveolar ventilation, the rate of body production of CO2 may affect the severity of the respira tory acidosis, but this is usually not a significant factor. A respiratory acidosis causes a decrease in the blood pH, but there is normally a metabolic response that partially compensates, minimizing the severity of the acidemia. The acute metabolic response to a respira tory alkalosis occurs within minutes. The metabolic compensation for an acute respiratory acidosis is secondary to titration of acid by nonbi carbonate buffers. This buffering of H causes a predictable increase in the serum HCO3 : Plasma bicarbonate increases by 1 for each 10 mm Hg increase in the Pco2 (acute compensation). With a chronic respiratory acidosis, there is more significant met abolic compensation and thus less severe acidemia than in an acute respiratory acidosis with the same increase in Pco2. During a chronic respiratory acidosis, the kidneys increase acid excretion. This response occurs over 3 4 days and causes a predictable increase in the serum HCO3 : Plasma bicarbonate increases by 3.5 for each 10 mm Hg increase in the Pco2 (chronic compensation). The increase of serum HCO3 during a chronic respiratory acido sis is associated with a decrease in body chloride. After acute correction of a chronic respiratory acidosis, the plasma bicarbonate continues to Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 522 Part VI u Fluid and Electrolyte Disorders be increased, and the patient has a metabolic alkalosis. Because of the Cl deficit, this is a chloride responsive metabolic alkalosis; it corrects once the patients Cl deficit is replaced. A mixed disorder is present if the metabolic compensation is inap propriate. A higher than expected bicarbonate value occurs in the set ting of a concurrent metabolic alkalosis, and a lower than expected bicarbonate value occurs in the setting of a concurrent metabolic aci dosis. Evaluating whether compensation is appropriate during a respi ratory acidosis requires clinical knowledge of the acuity of the process, because the expected compensation is different, depending on whether the process is acute or chronic. The Pco2 cannot be interpreted in isolation to determine whether a patient has a respiratory acidosis. A respiratory acidosis is always present if a patient has acidemia and an elevated Pco2. However, an elevated Pco2 also occurs as appropriate respiratory compensation for a simple metabolic alkalosis. |
998 | The patient is alkalemic; this is not a respiratory acidosis. During a mixed disturbance, a patient can have a respiratory acidosis and a normal or even low Pco2. This condi tion may occur in a patient with a metabolic acidosis. A respiratory acidosis is present if the patient does not have appropriate respiratory compensation (the Pco2 is higher than expected from the severity of the metabolic acidosis). Etiology and Pathophysiology The causes of a respiratory acidosis are either pulmonary or nonpul monary (Table 73.15). CNS disorders can decrease the activity of the central respiratory center, reducing ventilatory drive. A variety of med ications and illicit drugs suppress the respiratory center. The signals from the respiratory center need to be transmitted to the respiratory muscles via the nervous system. Respiratory muscle failure can be sec ondary to disruption of the signal from the CNS in the spinal cord, the phrenic nerve, or the neuromuscular junction. Disorders directly affecting the muscles of respiration can prevent adequate ventilation, causing a respiratory acidosis. Mild or moderate lung disease often causes a respiratory alkalosis as a result of hyperventilation secondary to hypoxia or stimulation of lung mechanoreceptors or chemoreceptors. Only more severe lung disease causes a respiratory acidosis. Upper airway diseases, by impairing air entry into the lungs, may decrease ventilation, producing a respiratory acidosis. Table 73.15 Causes of Respiratory Acidosis CENTRAL NERVOUS SYSTEM DEPRESSION Encephalitis Head trauma Brain tumor Central sleep apnea Primary pulmonary hypoventilation (Ondine curse) Stroke Hypoxic brain damage Obesity hypoventilation (Pickwickian) syndrome Increased intracranial pressure Medications Narcotics Barbiturates Anesthesia Benzodiazepines Propofol Alcohols DISORDERS OF SPINAL CORD, PERIPHERAL NERVES, OR NEUROMUSCULAR JUNCTION Diaphragmatic paralysis Guillain Barr syndrome Poliomyelitis Acute flaccid myelitis Spinal muscular atrophies Tick paralysis Botulism Myasthenia Multiple sclerosis Spinal cord injury Medications Vecuronium Aminoglycosides Organophosphates (pesticides) RESPIRATORY MUSCLE WEAKNESS Muscular dystrophy Hypothyroidism Malnutrition Hypokalemia Hypophosphatemia Medications Succinylcholine Corticosteroids PULMONARY DISEASE Pneumonia Pneumothorax Asthma Bronchiolitis Pulmonary edema Pulmonary hemorrhage Acute respiratory distress syndrome Neonatal respiratory distress syndrome Cystic fibrosis Bronchopulmonary dysplasia Hypoplastic lungs Meconium aspiration Pulmonary thromboembolus Interstitial fibrosis UPPER AIRWAY DISEASE Aspiration Laryngospasm Angioedema Obstructive sleep apnea Tonsillar hypertrophy Vocal cord paralysis Extrinsic tumor Extrinsic or intrinsic hemangioma MISCELLANEOUS Flail chest Cardiac arrest Kyphoscoliosis Decreased diaphragmatic movement due to ascites or peritoneal dialysis Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 20, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 73 u Electrolyte and Acid Base Disorders 523 Increased production of CO2 is never the sole cause of a respiratory acidosis, but it can increase the severity of the disease in a patient with decreased ventilation of CO2. Increased production of CO2 occurs in patients with fever, hyperthyroidism, excess caloric intake, and high levels of physical activity. Increased respiratory muscle work also increases CO2 production. Clinical Manifestations Patients with a respiratory acidosis are often tachypneic in an effort to correct the inadequate ventilation. Exceptions include patients with a respiratory acidosis resulting from |
999 | CNS depression and patients who are on the verge of complete respiratory failure secondary to fatigue of the respiratory muscles. The symptoms of respiratory acidosis are related to the severity of the hypercarbia. Acute respiratory acidosis is usually more symptom atic than chronic respiratory acidosis. Symptoms are also increased by concurrent hypoxia or metabolic acidosis. In a patient breathing room air, hypoxia is always present if a respiratory acidosis is present. The potential CNS manifestations of respiratory acidosis include anxiety, dizziness, headache, confusion, asterixis, myoclonic jerks, hallucina tions, psychosis, coma, and seizures. Acidemia, no matter the etiology, affects the cardiovascular sys tem. An arterial pH 7.2 impairs cardiac contractility and the nor mal response to catecholamines in both the heart and the peripheral vasculature. Hypercapnia causes vasodilation, most dramatically in the cerebral vasculature, but hypercapnia produces vasoconstriction of the pulmonary circulation. Respiratory acidosis increases the risk of cardiac arrhythmias, especially in a child with underlying cardiac disease. Diagnosis The history and physical findings often point to a clear etiology. For the obtunded patient with poor respiratory effort, evaluation of the CNS is often indicated. This may include imaging studies (CT or MRI) and, potentially, a lumbar puncture for cerebrospinal fluid analysis. A toxicology screen for illicit drugs may also be appro priate. A response to naloxone is both diagnostic and therapeutic. In many of the diseases affecting the respiratory muscles, there is evidence of weakness in other muscles. Stridor is a clue that the child may have upper airway disease. Along with a physical exami nation, a chest radiograph is often helpful in diagnosing pulmonary disease. In many patients, respiratory acidosis may be multifactorial. A child with bronchopulmonary dysplasia, an intrinsic lung disease, may worsen because of respiratory muscle dysfunction caused by severe hypokalemia resulting from long term diuretic therapy. Conversely, a child with muscular dystrophy, a muscle disease, may worsen because of aspiration pneumonia. For a patient with respiratory acidosis, calculation of the gradient between the alveolar oxygen concentration and the arterial oxygen concentration, the A a O2 gradient, is useful for distinguishing between poor respiratory effort and intrinsic lung disease. The A a O2 gradient is increased if the hypoxemia is caused by intrinsic lung disease (see Chapter 421). Treatment Respiratory acidosis is best managed by treatment of the underly ing etiology. In some patients, the response is very rapid, such as after the administration of naloxone to a patient with a narcotic overdose. In contrast, in the child with pneumonia, a number of days of antibiotic therapy may be required before the respiratory status improves. In many children with a chronic respiratory aci dosis, there is no curative therapy, although an acute respiratory illness superimposed on a chronic respiratory condition is usually reversible. All patients with an acute respiratory acidosis are hypoxic and therefore need to receive supplemental oxygen. Mechanical ventila tion is necessary in some children with respiratory acidosis. Children with significant respiratory acidosis caused by CNS disease usually require mechanical ventilation because such a disorder |
1,000 | is unlikely to respond quickly to therapy. In addition, hypercarbia causes cerebral vasodilation, and the increase in ICP can be dangerous in a child with an underlying CNS disease. Readily reversible CNS depression, as from a narcotic overdose, may not require mechanical ventilation. Decisions on mechanical ventilation for other patients depend on a number of factors. Patients with severe hypercarbia (Pco2 75 mm Hg) usually require mechanical ventilation (see Chapter 86.1). The threshold for intubation is lower if there is concomitant metabolic acidosis, a slowly responsive underlying disease, or hypoxia that responds poorly to oxygen, or if the patient appears to be tiring and respiratory arrest seems likely. In patients with a chronic respiratory acidosis, the respiratory drive is often less responsive to hypercarbia and more responsive to hypoxia. Thus, with chronic respiratory acidosis, excessive use of oxygen can blunt the respiratory drive and therefore increase the Pco2. In these patients, oxygen must be used cautiously. When possible, it is best to avoid mechanical ventilation in a patient with chronic respiratory acidosis because extubation is often difficult. However, an acute illness may necessitate mechanical ventilation in a child with a chronic respiratory acidosis. When intubation is necessary, the Pco2 should be lowered only to the patients normal baseline, and this should be done gradually. These patients normally have an elevated serum HCO3 as a result of metabolic compensation for their respi ratory acidosis. A rapid lowering of the Pco2 can cause a severe meta bolic alkalosis, potentially leading to complications, including cardiac arrhythmias, decreased cardiac output, and decreased cerebral blood flow. In addition, prolonged mechanical ventilation at a normal Pco2 causes the metabolic compensation to resolve. When the patient is sub sequently extubated, the patient will no longer benefit from metabolic compensation, causing a more severe acidemia because of the respira tory acidosis. RESPIRATORY ALKALOSIS A respiratory alkalosis is an inappropriate reduction in the blood CO2 concentration. This is usually secondary to hyperventilation, initially causing removal of CO2 to surpass production. Eventually, a new steady state is achieved, with removal equaling production, although at a lower CO2 tension (Pco2). A respiratory alkalosis that is not the result of hyperventilation may occur in children receiving extracorpo real membrane oxygenation, with CO2 lost directly from the blood in the extracorporeal circuit. With a simple respiratory alkalosis, the pH increases, but there is a normal metabolic response that attenuates some of the change in the blood pH. A metabolic response to an acute respiratory alkalosis occurs within minutes, mediated by hydrogen ion release from nonbi carbonate buffers. The metabolic response to an acute respiratory alka losis is predictable: Plasma bicarbonate falls by 2 for each 10 mm Hg decrease in the Pco2 (acute compensation). A chronic respiratory alkalosis leads to more significant metabolic compensation because of the actions of the kidneys, which decrease acid secretion, producing a decrease in the serum HCO3 . Both the proximal and distal tubules decrease acid secretion. Metabolic com pensation for a respiratory alkalosis develops gradually and takes |
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