879CHAPTER 71 Fluid and Electrolyte Issues in Pediatric Critical Illness Adjunct therapy is directed at the specific cause of hypercalce mia Drugs that inhibit bone resorption include calcitonin (10 U[.]
CHAPTER 71 Fluid and Electrolyte Issues in Pediatric Critical Illness Adjunct therapy is directed at the specific cause of hypercalcemia Drugs that inhibit bone resorption include calcitonin (10 U/ kg IV every 4–6 hours), mithramycin (25 mg/kg IV over hours), and indomethacin (1 mg/kg per day) Recombinant calcitonin blocks PTH-induced bone resorption, facilitates calciuria, is relatively nontoxic, and has peak effect by hour Mithramycin is a toxic antibiotic that inhibits osteoclastic activity but has potential adverse effects, including thrombocytopenia, hepatotoxicity, and renal injury Thus, it should be used with caution Indomethacin is useful when excessive prostaglandin E2 production is suspected, as in some cases of malignancy hypercalcemia Bisphosphonates have been used successfully in pediatrics for treatment of various disorders, including hypercalcemia.220–222 Corticosteroids are useful for treatment of vitamin D–related hypercalcemia, although the onset of action is not rapid Phosphorus Virtually all of plasma phosphorus is in the inorganic form, with a small organic component composed entirely of phospholipids bound to protein Serum levels vary with age; approximate normal values (specific to the analytic instrument) are 4.8 to 8.2 mg/ dL for neonates, 3.8 to 6.5 mg/dL for children aged week to years, 3.7 to 5.5 mg/dL for children aged to 12 years, and 2.9 to mg/dL for adolescents aged 12 to 19 years.258 Differences are thought to be related to more rapid rates of skeletal growth in the pediatric population Most total body phosphorus resides in bone As much as 60% to 80% of ingested phosphorus is absorbed, primarily in the jejunum Absorption occurs by two pathways, one passive and one active Passive paracellular transport is nonsaturable; thus, the greater the dietary intake, the higher the net absorption Active transport accounts for only 20% of total absorption via a vitamin D–dependent transporter, the Na1-dependent phosphorus transporter 2b (NPT2b) Increased excretion of phosphorus from the kidneys after increased dietary intake is dependent on inhibition of the Na1-phosphorus cotransporters 2a and 2c (NPT2a and NPT2c) in the luminal membrane of the proximal tubule These transporters are inhibited by increased secretion of fibroblast growth factor 23 (FGF23) FGF23 is secreted by osteocytes and osteoblasts in response to oral phosphorus loading or an increase in serum 1,25(OH)2 D levels FGF23 induces an increase in the fractional excretion of phosphorus in the proximal tubule and decreases the efficiency of phosphorus absorption in the gut by lowering 1,25(OH)2 D levels PTH is also stimulated by increased intake of phosphorus secondary to the fall in ionized calcium induced by transient hyperphosphatemia Increased PTH causes a decrease in the expression of NPT2a and NPT2c in proximal tubules, resulting in increased renal excretion of phosphorus.259 Intestinal absorption may also be decreased by high calcium intake or by ingestion of antacids such as calcium carbonate or acetate, which bind phosphorus in the bowel Glucose competitively inhibits phosphorus reabsorption Glucocorticoids produce phosphaturia by a decrease in sodium-dependent transport in the proximal tubule Phosphorus plays an important role in cellular structure and function, bone mineralization, and urinary acid excretion The development of severe phosphorus depletion affects the availability of intracellular ATP, depletes the erythrocyte of 2,3diphosphoglycerate (2,3-DPG), with resultant tissue hypoxia, and impairs urinary acid excretion The major acute effect of hyperphosphatemia is hypocalcemia; the long-term consequence is soft-tissue calcification.260 879 Hypophosphatemia Hypophosphatemia is common in pediatric critically ill children and has been shown to be associated with prolonged mechanical ventilation and ICU LOS.261,262 Hypophosphatemia as measured by serum or plasma levels may or may not indicate true phosphorus deficiency Severely depressed levels of serum-measurable phosphorus may occur in the absence of true deficiency after transcellular shifts from the ECF to the ICF, whereas a moderate phosphorus deficiency may be indicated only by slightly decreased serum levels.263 Other processes that lead to true hypophosphatemia include increased excretion from the kidneys and decreased intestinal absorption Hypophosphatemia may also result from a combination of these three mechanisms Moderate hypophosphatemia has been defined as levels between 1.5 and 2.5 mg/dL and severe hypophosphatemia as levels less than 1.5 mg/ dL on serum determination In general, only with severe deficiency of phosphorus multiple symptoms occur as well as overt cell dysfunction or necrosis Risk is greatest when superimposed additional cellular injury exists Causes of Severe Hypophosphatemia Although numerous abnormalities may result in moderate decreases in phosphorus levels, severe hypophosphatemia has been associated with only a handful of clinical syndromes These syndromes include significant respiratory alkalosis, prolonged use of phosphate-deficient TPN, the nutritional refeeding syndrome, thermal burns, DKA, pharmacologic binding of phosphorus in the gut, alcohol withdrawal, and several medications.263–266 An association with CRRT and bone recovery after renal transplant are also possible etiologies.267–270 The increase in ICF pH associated with acute respiratory alkalosis stimulates the enzymes of glycolysis, with subsequent depletion of ICF phosphorus, which is replaced by an influx from the ECF space Although carbon dioxide diffuses across membranes much more readily than bicarbonate does, metabolic alkalosis rarely produces a decrease in phosphorus levels, whereas very low levels may be seen with respiratory alkalosis.271 An absolute deficiency from malnutrition and transcellular shifts from the ECF to the ICF with an anabolic response to increasing caloric intake are the causes associated with TPN use.272 In the pediatric population, the preterm infant is particularly susceptible Nearly 80% of calcium-phosphorus assimilation in the fetus occurs in the last trimester of pregnancy Therefore, the preterm infant is born deficient in total body phosphorus When reasonable nutrition has been absent for even short periods or when phosphorus has not been provided in TPN, severe hypophosphatemia occurs, associated in several cases with the development of hypercalcemia.273 A similar situation may occur with the refeeding of patients who have significant protein calorie malnutrition, including anorexia patients.274 As previously noted, an absolute phosphorus deficiency and transcellular shifts from the ECF to the ICF in the face of an anabolic response are responsible Significant hypophosphatemia in burn patients during their recovery phase has been associated with the presence of respiratory alkalosis, diuresis of initially retained sodium and water, and acceleration of glycolysis.259,263 As previously described, ECF phosphorus shifts to the ICF compartment when intracellularfree phosphorus has been used in phosphorylation of organic compounds such as occurs during glycolysis, oxidative phosphorylation, glycogenolysis, and synthesis of glycogen, protein, 880 S E C T I O N V I I Pediatric Critical Care: Renal and phosphocreatine Acidosis decomposes organic compounds within the cell with subsequent movement of inorganic phosphorus from ICF to ECF and excretion in the urine Osmotic diuresis augments these losses Decreased intake also commonly occurs During treatment of DKA, renal phosphorus clearance generally increases with fluid administration In addition, insulin therapy results in stimulation of glycolysis and anabolism, with a shift of phosphorus back to the ICF If the acidosis has been present for only a few days, then rarely is there a severe phosphorus deficiency Although levels may decrease, they generally return to normal without extra phosphorus therapy In the patient whose symptoms have been present for a number of days to weeks, however, severe deficiency may exist at the time of admission These patients may have life-threatening complications of hypophosphatemia if they are not treated In general, this subset of patients has low phosphorus levels on admission, whereas phosphorus levels are normal or increased at admission in less severely affected patients Patients undergoing CRRT who become hypophosphatemic may be at higher risk for mortality.275 In burn patients with more than 19% total body surface area burns, patients receiving preemptive infusions of IV phosphorus beginning at 24 hours after injury had less hypophosphatemia and fewer complications versus those treated once hypophosphatemia developed.276 Signs and Symptoms Multiple organ systems may be affected by severe hypophosphatemia, including CNS, cardiac, respiratory, musculoskeletal, hematologic, renal, and hepatic abnormalities.277–284 Decreased diaphragmatic contractility in patients with hypophosphatemia with acute respiratory failure significantly improved as measured by transdiaphragmatic pressures during phrenic stimulation with treatment of hypophosphatemia.285 Respiratory muscle weakness in patients with hypophosphatemia with or without respiratory failure also has been documented and shown to normalize with phosphorus repletion.281,283,284,286 Hypophosphatemia during acute renal replacement therapy has been associated with muscle weakness, prolonged respiratory failure, and myocardial dysfunction, leading to longer need for mechanical ventilation and pressor support.269,270 Neurologic symptoms may initially include irritability and apprehension followed by weakness, peripheral neuropathy with numbness, and paresthesias Dysarthria, confusion, obtundation, seizures, and coma may occur in more profound cases.279,281,287 Reports in the literature include Guillain-Barré–like syndrome,288 diffuse slowing on electroencephalogram, and congestive cardiomyopathy,289 which significantly improved with correction of phosphorus depletion In dogs, decreased cardiac output, decreased ventricular ejection velocity, and increased left ventricular end-diastolic pressure reversed with phosphorus repletion In humans, rhabdomyolysis has been predominantly seen in alcoholic patients, in whom subtle myopathy was likely present, and rarely in patients with DKA or after TPN therapy Decreased levels of 2,3-DPG in red blood cells (RBCs) may depress P-50 (oxygen half-saturation pressure) values so that the release of molecular oxygen to peripheral tissues is decreased, with resultant tissue hypoxia.277 Structural defects of RBCs associated with hypophosphatemia have included rigidity and, rarely, hemolysis These defects have generally occurred when additional metabolic stresses, such as metabolic acidosis or infection, were placed on the RBCs Decreased levels of ATP in neutrophils may result in decreased chemotaxis, phagocytosis, and bacterial killing.290 The mechanisms underlying the development of metabolic acidosis include decreased phosphorus excretion that thereby limits titratable acid excretion and decreased ammonia levels Treatment As with other minerals and electrolytes, oral therapy is the preferable route for administration when it is potentially possible In patients with severe hypophosphatemia, IV therapy is often indicated, though there remain no evidence-based recommendations for IV replacement.291–293 Few data exist in the pediatric literature regarding dosage Therefore, most data are extrapolated from adult literature.293–295 Reasonable recommendations in children with severe phosphorus depletion are to use 0.15 to 0.33 mmol/ kg per dose, given as a continuous infusion over to hours Subsequent doses are generally calculated on the basis of response to this initial dosage Either potassium or sodium phosphate may be administered, with the attendant potential complications of hypernatremia or hyperkalemia A common recommendation is to use potassium phosphate if potassium (K) is less than meq/L and sodium phosphate if it is greater than meq/L Other potential complications of therapy include hyperphosphatemia, metastatic deposition of calcium phosphate, hypocalcemia, potential nephrocalcinosis with AKI, and hypotension Both sodium and potassium phosphate contain phosphate mmol/mL and or 4.5 mEq of sodium or potassium, respectively For oral administration, a combination product of sodium with potassium phosphate (Neutra-Phos) has been used commonly in children One capsule supplies mmol of phosphorus along with 7.1 mEq of sodium and potassium Capsules can be reconstituted in water as well In infants, the IV preparations may be used enterally, with smaller volumes needed Hypophosphatemia associated with CRRT provides a special case IV replacement is required in many such patients and depends on the prescription of dialysis as well as the phosphorus content of the dialysate.267,269 Hyperphosphatemia Causes of Hyperphosphatemia AKI and chronic kidney disease with decreased phosphorus excretion are the most common causes of hyperphosphatemia, with elevation in serum phosphorus occurring when the GFR is less than 30 mL/min per 1.73 m2 Extreme hyperphosphatemia associated with several deaths in infants and children has been reported from the use of either oral sodium phosphate or enemas containing sodium phosphate.296,297 Abnormalities of intestinal anatomy or motility predisposing to retention of enemas or renal insufficiency represent risk factors; however, in 30% of patients, no risk factors were identified Previous treatment does not guarantee safety with these agents, as 30% of affected patients had previously received enemas or oral therapy without complications Average time to recognition has ranged from 12 minutes to 24 hours, with a mean of 6.53 hours Mean phosphorus levels were 27.9 mg/dL, with a plasma total calcium mean of 4.95 mg/ dL But for kidney disease in older children and adolescents, all reported patients have been younger than years.296 The administration of IV boluses of sodium or potassium phosphate rather than slow infusion may result in symptomatic hyperphosphatemia An error in parenteral nutrition resulted in hyperphosphatemia in multiple infants,298 and severe hyperphosphatemia has been reported related to use of liposomal amphotericin B.299 CHAPTER 71 Fluid and Electrolyte Issues in Pediatric Critical Illness Tumor lysis syndrome is an additional cause of hyperphosphatemia, along with hyperkalemia, acidosis, hypocalcemia, and AKI It results from induced lysis of tumor cells and is always a concern in a child with a lymphoid malignancy and substantial cellular mass, but it can occur in a variety of settings (see also Chapter 92) Initial chemotherapy or radiation of B-cell lymphoma is particularly likely to produce cell lysis and hyperphosphatemia, along with hyperuricemia, AKI, hyperkalemia, metabolic acidosis, and hypocalcemia Aggressive hydration and careful initiation of chemotherapy usually will result in a manageable degree of electrolyte abnormality Urinary alkalinization to increase urate solubility has historically been used but more recent evidence recommends avoiding alkaline urine given the increased risk of calcium phosphate deposition Rasburicase can be used to acutely lower uric acid levels, whereas allopurinol can be used to prevent a rise in uric acid level but not to lower existing hyperuricemia.300 Hemodialysis or CRRT is an essential resource to have available if managing such a patient (see Table 71.3) Signs and Symptoms The major clinical consequences of severe hyperphosphatemia are its associated hypocalcemia and soft-tissue deposition of calcium phosphate salts Seizures, coma, and cardiac arrest have been reported, generally in the presence of both hypocalcemia and hyperphosphatemia In one case report, however, seizures, malignant ventricular arrhythmias, and cardiac arrest with acute hyperphosphatemia alone were described.301 Hyperphosphatemia has been associated with increased mortality in multiple studies.302,303 Hyperphosphatemia may be a proximate cause of AKI via precipitation in renal tissue.304,305 Treatment In patients with life-threatening complications or multiple additional electrolyte disturbances or in the presence of renal failure, dialysis may be required Intravenous fluid loading to increase renal phosphorus losses and intravenous calcium may increase 881 excretion Mannitol diuresis will inhibit proximal phosphorus reabsorption and theoretically should expedite phosphaturia When oral administration was possible, sevelamer has been used in patients with TLS to bind enteral phosphorus and perhaps decrease the need for more invasive therapy.306 Key References Alobaidi R, Morgan C, Basu RK, et al Association between fluid balance and outcomes in critically ill children: a systematic review and metaanalysis JAMA Pediatr 2018;172(3):257-268 Caironi P, Tognoni G, Masson S, et al Albumin replacement in patients with severe sepsis or septic shock N Engl J Med 2014;370(15):14121421 Chauhan K, Pattharanitima P, Patel N, et al Rate of correction of hypernatremia and health outcomes in critically ill patients Clin J Am Soc Nephrol 2019;14(5):656-663 de Baaij JH, Hoenderop JG, Bindels RJ Magnesium in man: implications for health and disease Physiol Rev 2015;95(1):1-46 Gaudry S, Hajage D, Schortgen F, et al Initiation strategies for renalreplacement therapy in the intensive care unit N Engl J Med 2016; 375:122-133 Lehnhardt A, Kemper MJ Pathogenesis, diagnosis and management of hyperkalemia Pediatr Nephrol 2011;26(3):377-384 Moritz ML, Ayus JC Maintenance intravenous fluids in acutely ill patients N Engl J Med 2015;373(14):1350-1360 Semler MW, Self WH, Wanderer JP, et al.; SMART Investigators and the Pragmatic Critical Care Research Group Balanced crystalloids versus saline in critically ill adults N Engl J Med 2018;378:829-839 Steele T, Kolamunnage-Dona R, Downey C, Toh CH, Welters I Assessment and clinical course of hypocalcemia in critical illness Crit Care 2013;17(3):R106 Zarbock A, Kellum JA, Schmidt C, et al Effect of early vs delayed initiation of renal replacement therapy on mortality in critically ill patients with acute kidney injury: the ELAIN Randomized Clinical Trial JAMA 2016;315:2190-2199 The full reference list for this chapter is available at ExpertConsult.com e1 References Yunos NM, Bellomo R, Story D, Kellum J Bench-to-bedside review: chloride in critical illness Crit Care 2010;14(4):226 Kaplan LJ, Kellum JA Fluids, pH, ions and electrolytes Curr Opin Crit Care 2010;16(4):323-331 Myburgh JA, Mythen MG Resuscitation fluids N Engl J Med 2013;369(25):2462-2463 Krajewski ML, Raghunathan K, Paluszkiewicz SM, Schermer CR, Shaw AD Meta-analysis of high- versus low-chloride content in perioperative and critical care fluid resuscitation Br J Surg 2015;102: 24-36 Yunos NM, Bellomo R, Hegarty C, Story D, Ho L, Bailey M Association between a chloride-liberal vs chloride-restrictive intravenous fluid administration strategy and kidney injury in critically ill adults JAMA 2012;308(15):1566-1572 Semler MW, Self WH, Wanderer JP, et al.; SMART Investigators and the Pragmatic Critical Care Research Group Balanced crystalloids versus saline in critically ill adults N Engl J Med 2018;378:829-839 Self WH, Semler MW, Wanderer JP, et al.; SALT-ED Investigators Balanced crystalloids versus saline in noncritically ill adults N Engl J Med 2018;378:819-828 Peng ZY, Kellum JA Perioperative fluids: a clear road ahead? 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I Pediatric Critical Care: Renal and phosphocreatine Acidosis decomposes organic compounds within the cell with subsequent movement of inorganic phosphorus from ICF to ECF and excretion in... may have life-threatening complications of hypophosphatemia if they are not treated In general, this subset of patients has low phosphorus levels on admission, whereas phosphorus levels are normal... continuous infusion over to hours Subsequent doses are generally calculated on the basis of response to this initial dosage Either potassium or sodium phosphate may be administered, with the attendant