876 SECTION VII Pediatric Critical Care Renal Magnesium deficiency may be caused by decreased intake or increased losses Although slight falls in serum magnesium levels may occur after 1 week of a def[.]
876 S E C T I O N V I I Pediatric Critical Care: Renal Magnesium deficiency may be caused by decreased intake or increased losses Although slight falls in serum magnesium levels may occur after week of a deficient diet, a more sustained period of deprivation is generally necessary for significant hypomagnesemia to occur In children, magnesium deficiency has been particularly common in protein-energy malnutrition and in anorexia nervosa, where refeeding syndrome is a particular risk.200,201 Intestinal malabsorption is a major cause of magnesium deficiency Isolated familial primary hypomagnesemia occurs from selective malabsorption of magnesium with patients generally having symptoms in infancy These include tetany and convulsions as a result of severe hypomagnesemia with consequent hypocalcemia and respond well to supplemental magnesium Other causes associated with magnesium malabsorption include regional enteritis, ulcerative colitis, massive small bowel resection, generalized malabsorption syndromes, pancreatic insufficiency, and cystic fibrosis In some, the formation of insoluble soaps due to the complexing of magnesium with unabsorbed fat is the postulated mechanism for hypomagnesemia There are several other less common causes of hypomagnesemia Increasing use of induced hypothermia may increase hypomagnesemia occurrence.202 Epidermal growth factor blocking antibodies are associated with a small incidence of induced hypomagnesemia,203,204 and hypomagnesemia may be more common than appreciated in patients presenting with hematologic malignancies.205 Intrinsic renal tubular disorders associated with hypomagnesemia are rare in the ICU setting Drugs that induce renal magnesium wasting are more common causes of hypomagnesemia The list includes aminoglycosides,206 cisplatin,207 amphotericin B,208 diuretics,209 cyclosporin, tacrolimus,210 and proton pump inhibitors.211,212 Magnesium supplementation is often needed in transplant recipients who receive cyclosporine or tacrolimus Fractional excretion of magnesium and total excretion are elevated Patients with DKA may also have marked renal magnesium wasting during the acidotic period as well as in early treatment An increased urine calcium level, from whatever cause, is often associated with magnesium wasting from competitive inhibition of renal tubular reabsorption of magnesium in the ascending limb Causes of hypomagnesemia are listed in eBox 71.7 contractile proteins Similar effects in coronary and cerebral vessels have also been observed Seizures may be the first symptom noted in an ICU setting.215–217 Other neuromuscular changes may include tremors, fasciculations, spontaneous carpopedal spasm, muscle cramps, paresthesias, seizures, and coma.218–222 Personality changes, including apathetic behavior and depression, have also been associated with this condition Hypomagnesemia has been associated with greater risk of adverse events as well as mortality.198,223 Signs and Symptoms Cause In addition to biochemical derangements associated with hypomagnesemia, a wide spectrum of other clinical disorders has been attributed to its depletion, including cardiac arrhythmias, increased sensitivity to digoxin, coronary artery spasm, hypertension, seizures, and neuromuscular derangements Hypomagnesemic arrhythmias include ventricular premature beats, ventricular tachycardia, torsades de pointes, and ventricular fibrillation.213 Supraventricular arrhythmias are less common Following magnesium infusion, improvement in resistant ventricular arrhythmias, including torsades de pointes, has been reported,214 although other metabolic derangements often coexist in such patients Magnesium deficiency enhances myocardial cell uptake of digoxin and increases risk of toxicity Both inhibit Na1/K1-ATPase with resultant ICF potassium depletion Magnesium depletion is thought to contribute to the development or worsening of hypertension by increasing vascular smooth muscle tone and reactivity Increased cellular influx of calcium and decreased reuptake by sarcoplasmic reticula occur; the result is increased cytosolic calcium for activation of actin-myosin Hypermagnesemia occurs in patients with renal failure and is generally associated with iatrogenic administration of magnesium as antacids, cathartics, and enemas or through total parenteral nutrition (TPN) containing magnesium In the absence of renal failure, the administration of large quantities of magnesium cathartics in the management of constipation228 or overdoses229 and antacid use with increased peritoneal absorption of magnesium in the presence of a perforated viscus230 are documented causes Magnesium levels as high as 10 to 12 mEq/L have been reported Megadose vitamin-mineral supplementation, including magnesium oxide, has been fatal.231 Treatment Patients experiencing or at immediate risk of hypomagnesemic malignant ventricular arrhythmias (such as torsades de pointes) or seizures can be given magnesium sulfate intravenously with careful monitoring An IV infusion of 25 to 50 mg/kg per dose diluted to 10 mg/mL can be administered over 15 to 60 minutes The rate of infusion should not exceed 150 mg/min Doses may be repeated as needed depending on patient response Complications of parenteral magnesium therapy include neuromuscular and respiratory depression, rare arrhythmias, flushing, hypotension, and prolonged bleeding times.224 Other routes of therapy include intramuscular magnesium sulfate, injections of which are painful, and oral therapy with magnesium oxide or citrate In situations known to be associated with the development of hypomagnesemia, it seems particularly important to avoid deficiency by adequate magnesium intake before development of lifethreatening symptoms The use of supplemental magnesium infusions in perinatal asphyxia202 needs more rigorous testing prior to implementation or extension to other hypoxic-ischemic encephalopathies Hypermagnesemia Hypermagnesemia is less common than hypomagnesemia, but both can be life threatening when extreme.225 Intravenous magnesium boluses and, less often, continuous infusions are used as adjunctive therapy for pediatric status asthmaticus, although data from adult studies are conflicting.226 Large doses clearly produce elevated blood levels,227 but side effects are not common Signs and Symptoms Acute elevations of magnesium depress the CNS and peripheral neuromuscular junction Pseudocoma with fixed, dilated pupils has been reported Deep tendon reflexes are depressed at levels greater than mEq/L with total disappearance along with flaccid quadriplegia at levels greater than to 10 mEq/L Hypotension, 876.e1 • eBOX 71.7 Causes of Hypomagnesemia Decreased Intake Low Mg11 total parenteral nutrition Intravascular fluid Eating disorders Increased Losses Gastrointestinal Malabsorption Familial primary hypomagnesemia Small bowel disease Regional enteritis, ulcerative colitis, massive bowel resection Pancreatic insufficiency, pancreatitis Cystic fibrosis Renal Congenital renal magnesium wasting Diffuse tubular disorders Hypophosphatemia Drugs Aminoglycosides Cisplatin Amphotericin B Diuretics Cyclosporine Tacrolimus Pentamidine Foscarnet GM-CSF Hypercalciuria Diabetic ketoacidosis Barter syndrome Hyperaldosteronism Inappropriate antidiuretic hormone secretion Miscellaneous Epinephrine, b-agonists Thyrotoxicosis Citrated blood transfusion (massive) Burns Alcoholism CHAPTER 71 Fluid and Electrolyte Issues in Pediatric Critical Illness hypoventilation, and cardiac arrhythmias may also occur.232–235 Moderate hyperkalemia has occasionally resulted from prolonged magnesium infusions in patients Treatment Calcium acts as a direct antagonist to magnesium In life-threatening situations associated with severe magnesium intoxication, intravenous calcium should be used as the initial therapy An initial dose of calcium chloride at 10 to 20 mg/kg or an equivalent amount of calcium gluconate has been suggested for infants and children Magnesium-containing medications obviously should be discontinued If renal function is normal, IV furosemide may be administered to increase magnesium excretion while urine output is replaced with isotonic saline In patients with renal failure or severe toxicity, dialysis may be necessary for removal Calcium Hypocalcemia is a common issue in pediatric critical care.236,237 Hypercalcemia is an uncommon challenge in the PICU ECF calcium concentration is best estimated with measurement of ionized calcium (Ca11) concentration Total serum calcium includes physiologically accessible Ca11 plus that bound to protein or complexed with anions, such as citrate of phosphate The Ca11 concentration is under dual hormone control, with PTH mobilizing Ca11 and calcitonin acting in bone and cartilage to retain fixed calcium The concentration of Ca11 is particularly critical for cardiac, vasomotor, and neurologic function but is susceptible to disturbance by many factors, including drugs, sepsis, major surgery, enteric disease, malignancy, pancreatitis, endocrinopathy, genetic abnormalities, and many others Entry of Ca11 into cardiac and skeletal muscle cells mediates conversion of electrochemical energy into mechanical energy, with resultant muscle contraction Adenylate cyclase, phosphodiesterase, and protein kinases are regulated by the interaction of Ca11 with calmodulin A similar interaction stimulates myosin kinase in vascular smooth muscle so that Ca11 influx (enhanced by a-adrenergic and inhibited by b-adrenergic stimuli) causes vasoconstriction Ca11 also plays a critical role in the clotting system and various membrane transport systems Extracellular Ca11 is monitored by Ca11-sensing receptors238,239 on the surface of the chief cells of the parathyroid glands, juxtaglomerular apparatus, proximal tubule, cortical thick ascending limb of the loop of Henle, inner medullary collecting duct, intestine, parts of the brain, thyroid C cells, breast cells, and the adrenal glands Binding of Ca11 to these calcium sensors activates phospholipase C and the accumulation of inositol triphosphate, which leads to inhibition of the secretion and synthesis of PTH and inactivation of its proteolysis Regulation of Calcium In the ICU, changes in calcium concentration result from changes in protein binding and chelation, excessive or deficient hormonal action, or excessive losses or intake of calcium A majority of total serum calcium is bound to proteins, and the binding is pH dependent Acidic pH decreases calcium binding and increases Ca11, whereas alkalemia increases binding and reduces Ca11 Blood products, renal failure, or massive cell lysis may result in increased chelation Fortunately, direct measurement of Ca11 is now readily available in PICUs 877 Hormonal Regulation of Calcium Hormonal control of calcium homeostasis involves PTH, vitamin D, and calcitonin Secretion of PTH by the parathyroid chief cell varies inversely with the serum Ca11 and is inhibited by hypomagnesemia and 1,25-dihydroxyvitamin D [1,25(OH)2 D] Rapid proteolytic degradation of PTH yields a physiologically inactive C-terminal fragment and an active NH2-terminal fragment PTH binds to cell surface receptors in bone osteoblasts and kidney and exerts its effects through binding of a subunit of a membrane-associated heterotrimeric protein, which mediates increased formation of cyclic adenosine 3,5-monophosphate In the kidney, PTH inhibits proximal tubular phosphate reabsorption and promotes phosphaturia This loss of phosphate inhibits bone mineralization and tends to shift the flow of calcium from bone to the ECF PTH also increases distal tubular reabsorption of filtered calcium PTH stimulates 1a-hydroxylation of 25(OH)-vitamin D, resulting in production of metabolically active 1,25(OH)2 D that stimulates intestinal absorption of calcium and phosphate The overall effect of PTH is to raise serum calcium levels and lower serum phosphate levels This characteristic reciprocal relationship is helpful in distinguishing PTH disorders from those involving vitamin D alone.240 Hyperphosphatemia lowers Ca11 by chelation, by shifting the equilibrium in calcium flux from ECF toward bone, and by inhibiting 1a-hydroxylation activity Calcitonin is a 32-amino acid, calcium-lowering hormone elaborated by C cells of the thyroid in response to rising Ca11 levels.241 Although it rapidly reduces the bone resorptive function of osteoclasts and promotes calciuria and phosphaturia, its excess or absence causes no known disorder Hypocalcemia Clinical and Laboratory Concerns Hypocalcemia in pediatric critical illness may be associated with PTH deficiency, hypercalcitoninemia, or hypomagnesemia Vitamin D deficiency is also common in the critically ill population and parathyroid gland response secondary to hypocalcemia or vitamin D deficiency may be blunted.242 Multiple mechanisms may act simultaneously Children with severe burns may develop a combination of hypocalcemia, magnesium depletion, hypoparathyroidism, and renal resistance to PTH Cardiovascular manifestations are of particular concern in the ICU and may include hypotension, myocardial depression, CHF, and dysrhythmias Cardiac contractility may be compromised acutely, as in postoperative hypocalcemia However, subacute cardiac myopathy from vitamin D deficiency and hypocalcemia may also be life threatening and reversible.243–245 Hypocalcemia inhibits acetylcholine release in both sensory and motor nerves Accordingly, a variety of peripheral and CNS effects may manifest, including seizures, tetany, carpopedal spasms, muscle cramps and twitching, paresthesias, laryngeal stridor, and apnea in the newborn Somatic changes accompanying prolonged hypocalcemia include dry, coarse skin, eczematous dermatitis, brittle hair with areas of alopecia, brittle nails with smooth transverse grooves, and dental enamel hypoplasia Determination of the free ionized Ca11 level is diagnostic, although the rate of decline also contributes to the development of symptoms Estimations of Ca11 correcting for protein binding are 878 S E C T I O N V I I Pediatric Critical Care: Renal not appropriate for managing critical illness The causes of hypocalcemia are summarized in eBox 71.8 Reduced PTH effect can result from parathyroid gland failure (autoimmune or surgical or radiotherapy thyroidectomy),246–248 insensitivity to PTH (pseudohypoparathyroidism), or suppression of PTH release (hypomagnesemia, maternal hypocalcemia, burns) Hyperphosphatemia is frequently present Clinical features may be distinguishing, but measurement of immunoreactive PTH is diagnostic Reduced vitamin D effect results from vitamin D deficiency seen in malabsorption in enteric diseases248–251 or impaired conversion of 25(OH) to 1,25(OH)2 D seen in renal insufficiency Certain drugs, such as phenytoin, can increase vitamin D metabolic degradation and cause deficiency Obesity can alter the response to supplemental vitamin D in critically ill patients, which has been shown to be associated with poorer outcomes.252 Infusion of large amounts of citrate-preserved blood and acute phosphorus overload or retention can rapidly deplete ECF Ca11 Various drugs, particularly loop diuretics, also contribute to the development of hypocalcemia.253,254 Treatment Correction of hypocalcemia should be preceded by consideration of readily treated or confounding factors, such as respiratory alkalemia Rapid development of hyperphosphatemia suggests AKI, cell lysis, or excessive supply As appropriate, efforts should be made to reduce serum phosphate levels, because intravenous calcium therapy may cause metastatic deposition of calcium phosphate salts Hypomagnesemia impairs PTH release, response to PTH, and, consequently, correction of hypocalcemia Hypomagnesemia may develop in critically ill patients by several mechanisms previously discussed Urgency of therapy is determined by the child’s clinical status Asymptomatic hypocalcemia is appropriately treated with oral calcium salts and vitamin D if needed For the seriously ill patient with overt or evolving hypocalcemia, replacement therapy is accomplished with IV calcium chloride, to 20 mg/kg, or an equivalent calcium gluconate infusion Potential bradycardia and asystole with infusion of calcium should be anticipated, with cardiac monitoring and atropine readily available Care is required to prevent tissue damage by extravasation or precipitation with concomitantly administered bicarbonate In patients receiving digitalis, IV calcium is particularly dangerous, as the arrhythmia potential is significant Hyperkalemia in digitalis toxicity should be treated with antidigitalis Fab therapy and not IV calcium infusion Oral administration of calcium salts is efficient for control of most persistent hypocalcemia and is preferable to prolonged infusion (although some patients with DiGeorge hypocalcemia require aggressive multimodal treatment) Liberal amounts can be administered orally (e.g., calcium 50 mg/kg per day in 4–5 divided doses), with attention paid to the differing calcium content of various oral preparations For patients with fat malabsorption, supplementation of calcium therapy with magnesium or vitamin D may be needed In the setting of hypoparathyroidism secondary to magnesium depletion, magnesium replenishment must occur Hypercalcemia In contrast with dramatic manifestations of hypocalcemia, the effects of hypercalcemia may be subtle However, a serum total calcium greater than 15 mg/dL represents a medical emergency Renal, cardiovascular, and CNS disturbances predominate, reflecting both the degree and duration of calcium elevation Increased filtered load of calcium creates hypercalciuria and accompanying polyuria, reduced concentrating ability, dehydration, and eventual renal lithiasis Hypertension is common, mediated through increased renin production and vasoconstriction, which can also contribute to AKI Alterations in the cardiac conduction system include a shortened QT interval and a tendency to dysrhythmias Impaired nerve conduction creates hypotonia, hyporeflexia, and paresis in severe cases Changes in CNS function include lethargy, confusion, and even coma Constipation, anorexia, and abdominal pain resulting from reduced intestinal motility are frequent Promotion of gastrin release by calcium may account for an increased incidence of peptic ulcer disease Soft-tissue deposition of calcium phosphate can impair function of lungs, kidneys, cardiac conduction tissue, blood vessels, and joints In the absence of hyperproteinemia, determination of elevated serum total calcium levels reliably indicates increased Ca11 concentrations Because hyperparathyroidism and malignancies are less common in children, the pediatric intensivist encounters hypercalcemia less frequently Diagnostic possibilities may be approached by considering the underlying mechanisms of hypercalcemia Increased bone resorption reflects excess PTH effect, immobilization, or bone lysis by metastatic malignancy PTH-mediated hypercalcemia is distinguished by a depressed serum phosphate concentration, decreased renal tubular reabsorption of phosphate (TmPO4/GFR), and an intact PTH (iPTH) level inappropriately elevated for the simultaneous elevation in serum Ca11 In the child with hyperparathyroidism, evaluation for multiple endocrine neoplasias is warranted Heightened vitamin D effect is manifested by increased intestinal calcium absorption and can be related to vitamin D intoxication,255,256 increased sensitivity to vitamin D, or ectopically produced 1,25(OH)2 D, as seen in sarcoidosis Serum phosphate levels and TmPO4/GFR ratios are normal or increased, and iPTH levels are suppressed in these disorders Detection of an elevated 25(OH)-vitamin D level may be helpful High levels of vitamin A can also cause hypercalcemia and are particularly likely in patients with excessive intake or those with renal insufficiency.218,257 Decreased excretion of calcium occurs with dehydration or treatment with thiazide diuretics, aggravating the severity of hypercalcemia in hyperparathyroidism Much less commonly seen, familial hypocalciuric hypercalcemia is an autosomal-dominant disorder resulting from partially deactivating mutations in the Ca11-sensing receptor, characterized by normal to slightly elevated iPTH levels and decreased urinary calcium excretion.219 Thus, determination of serum Ca11, phosphate, iPTH, vitamin D levels, and urinary calcium and phosphate excretion allows differentiation of most hypercalcemic disorders Treatment A serum calcium level greater than 15 mg/dL may be life threatening and requires direct Ca-lowering therapy in addition to attention to the underlying disorder Hydration with isotonic saline (200–250 mL/kg/day) is necessary to correct the dehydration caused by increased renal calcium excretion Furosemide diuresis can augment calciuresis; however, its use must be balanced against the risk of hypovolemia and increased losses of sodium, potassium, magnesium, and phosphate 878.e1 • eBOX 71.8 Causes of Hypocalcemia Reduced PTH Effect Changes in Ca11 Binding or Chelation Parathyroid Gland Failure Alkalosis Hypoparathyroidism—idiopathic or autoimmune Trauma Postsurgery Infarction Infiltration (e.g., sarcoid hemosiderosis) Respiratory alkalosis Bicarbonate infusion Insensitivity to PTH Pseudohypoparathyroidism Hypomagnesemia Suppression of PTH Release Hypomagnesemia Neonatal, resulting from maternal hypercalcemia Burns Sepsis Drugs Aminoglycosides Cimetidine Cisplatin b-Adrenergic blockers Reduced Vitamin D Effect Vitamin D Deficiency Dietary insufficiency Increased losses related to: Malabsorption Nephrotic syndrome Phenytoin, phenobarbital Impaired Activation of Vitamin D Renal disease Hypoparathyroidism Liver failure Rhabdomyolysis Hyperphosphatemia Acute kidney injury or chronic kidney disease Phosphate administration (e.g., high-phosphate formulas, enemas) Chemotherapy Rhabdomyolysis Malignancy Pancreatitis Fat embolism Transfusion with citrate-preserved blood Drug/Toxins Glucagon Mithramycin Calcitonin Ethylenediamine tetraacetic acid Protamine Sodium fluoride Colchicine Theophylline Ethylene glycol ... the chief cells of the parathyroid glands, juxtaglomerular apparatus, proximal tubule, cortical thick ascending limb of the loop of Henle, inner medullary collecting duct, intestine, parts of... 3,5-monophosphate In the kidney, PTH inhibits proximal tubular phosphate reabsorption and promotes phosphaturia This loss of phosphate inhibits bone mineralization and tends to shift the flow of calcium from... phosphate The overall effect of PTH is to raise serum calcium levels and lower serum phosphate levels This characteristic reciprocal relationship is helpful in distinguishing PTH disorders from those