Chapter 73 1009

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73 Fluid and Electrolyte Issues in Pediatric Critical Illness Robert Lynch, Ellen Glenn Wood, and Tara M. Neumayr

intraoperative fluids influence acid-base and electrolyte status, PEARLS particularly of vulnerable patients.4 The choice of Na+ content • Hypotonic maintenance IV fluids are associated with mild to and balancing ions of IVF for postoperative or critical care moderate hyponatremia in postoperative patients. maintenance may be important for some patients thus justify- Anesthesia, stress, and inflammatory mediators probably ing additional expense. Clearly 0.18 and 0.225 mM saline is 5,6 contribute. Electrolyte monitoring in patients at risk is associated with a higher incidence of mild hyponatremia, essential for detection and management of the occasional although controlled trials do not show this effect for 0.46 mM 7,8 patient who develops severe hyponatremia. This critical saline. Severe hyponatremia has been associated with pul- effect of the syndrome of inappropriate antidiuretic hormone monary or CNS illness in pediatrics and is infrequent even may occur even in patients on isotonic IV fluids. within those categories, with the exception of children with • Medical patients with high levels of inflammatory mediators traumatic brain injury (TBI). Among patients with those and appear to be at increased risk of significant hyponatremia. other illnesses, the evolving study of the influence of inflam- Interleukin effects on antidiuretic hormone release may matory mediators directly on the hypothalamus and indirectly contribute. on vasopressin secretion may further clarify which patients are 9,10 • Albumin infusions have been generally safe but may at most risk of clinically significant hyponatremia. introduce increased mortality risk in patients with traumatic Evidence for and against the use of colloids in specific brain injury. Those given albumin had increased intracranial groups of critical patients is accumulating. Intriguing but less 11-14 pressure, which may contribute to the apparent risk. than definitive studies suggest benefit in severe sepsis and • After septic patients achieve hemodynamic stabilization, possible harm in patients with TBI, perhaps associated with 15 avoiding or correcting excessive fluid volume overload will increased intracranial pressure. Consideration of albumin 16,17 assist in liberating patients from ventilators and the intensive use in selected patients remains appropriate. Albumin does care unit. appear useful in stabilizing patients with severe hepatic failure 18-20 • Proton pump inhibitors may cause hypomagnesemia, and in prevention of hepatorenal syndrome. particularly in patients on concurrent diuretics. Although Evidence for albumin use with or without diuresis among usually mild, this may be of significance in critically those with acute respiratory distress syndrome (ARDS) sug- 21 vulnerable patients. gests improved oxygenation but minimal effect on outcomes. In general, in patients with relatively intact vascular endothe- lium, 10 to 15 mL/kg of 4% or 5% albumin may be used for intravascular volume expansion with slower leakage into the ECF space compared to crystalloids. Albumin concentrate at Overview 25% may be useful in temporarily redistributing ECF volume Traditional fluid and electrolyte management in critical illness from the extravascular to the intravascular space to facilitate is being refined by science, observations of clinical experience, organ perfusion and spontaneous or drug-assisted diuresis and expert opinion. Particular attention is drawn to intrave- with minimal additional infused fluid volume. There are cur- nous fluid (IVF) composition, appropriate uses and choices rently no formulations of hydroxyethyl starch that can be of colloids, extracellular fluid (ECF) volume targets from recommended for use in critically ill patients.22,23 resuscitation to maintenance, and approaches to removal of Adult and pediatric studies have raised concern regarding excessive ECF volume using diuresis, continuous renal replace- damaging effects of fluid volume overload particularly in ment therapy (CRRT), and intermittent hemodialysis (IHD). patients with sepsis or ARDS.24,25 Patients with less fluid gain Fluid and electrolyte management often begins at resuscita- early in their illness have more ventilator-free days and shorter tion, but important choices are also made at anesthesia induc- ICU stays than those with greater than 10% to 15% early posi- tion and at initial postoperative maintenance. Resuscitative tive fluid balance. It remains unclear if mortality rates are normal saline imposes an acid load, largely related to the affected.26-29 chloride content.1 Although physiologically effective and This effect of fluid volume on morbidity and perhaps mor- cost effective in almost all circumstances,2 concerns regarding tality has led to proposals of a phased approach to fluid man- chloride toxicity warrant further clarification.3 Similarly, agement including aggressive resuscitation using appropriate

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Downloaded for Anonymous User (n/a) at Walter Reed National Military Medical Center from ClinicalKey.com by Elsevier on December 26, 2018. For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved. 1008 Section V Renal, Fluids, Electrolytes fluids guided by careful clinical measurement and evaluation, severe hyponatremia, although gross feeding or iatrogenic prompt reduction of resuscitation fluid rates when hemody- misadventures also should be considered. Severe hyponatre- namically tolerated, gradual correction of volume excesses mia, which is variably defined as a serum sodium concentra- using fluid restriction, colloid dosing to adjust fluid space tion of either <125 mEq/L or <120 mEq/L, is uncommon distribution, continuous infusion diuresis, and CRRT or IHD and is usually associated with known risk factors such as pul- when needed.30-33 monary or CNS disease or injury or the use of certain drugs. As ICU patients progress from stabilization to maintenance, Mild hyponatremia is common among hospitalized pediatric ECF volume overload may spontaneously resolve, or it may patients and occurs predictably in postoperative patients. warrant active intervention due to the association of persisting Patients with renal, hepatic, or cardiac disease and those major overload with increased morbidity. Loop diuretics do exposed to prolonged general anesthesia are particularly at not prevent or ameliorate acute kidney injury34 but may be risk. Accurate identification of patients at risk will inform useful in mobilizing excess ECF volume.35 Studies of this decisions on frequency of laboratory monitoring and will measure are variable as to dosages, patient diagnoses, and allow an early evaluation of and response to evolving hypo- renal conditions. Carefully titrated continuous infusion of natremia, whether related to water retention or sodium loop diuretics may be superior to bolus dosing.36-39 In ARDS, excretion. continuous infusion plus albumin have enhanced fluid mobilization.40-42 Careful studies of approaches to fluid Pathophysiology and Etiology removal are needed. Accompanying loss of K+, Ca++, and Hyponatremia may occur in the presence of decreased, Mg++ should be anticipated and replaced appropriately. For increased, or normal amounts of total body sodium. patients unresponsive to diuresis, either CRRT or IHD can provide electrolyte management and gradual ECF fluid Decreased Total Body Sodium correction43-45 (see also Chapter 78). Loss of total body sodium results in hyponatremia if total body water is retained in relative excess of the sodium loss. Hypovolemic stimulation of antidiuretic hormone (ADH) Sodium release may overwhelm osmotic ADH control, maintaining Sodium distribution is 90% extracellular and, with its associ- water retention despite hyponatremia and hypoosmolality. A ated anions, largely determines the osmotic condition of the decrease of as little as 5% in circulating volume may be suf- extracellular fluid (ECF). Disturbance of ECF osmolality ficient to trigger this response.54 Sodium deficit and volume affects cell volume with critical clinical significance in the loss may occur through extrarenal or renal losses. In children, central nervous system (CNS). Neurologic symptoms, there- extrarenal losses most often occur from vomiting and diar- fore, dominate the clinical picture in both hyponatremia and rhea. In critically ill patients, large extrarenal losses may result hypernatremia. In pediatric patients in the intensive care unit from fluid sequestration that occurs with septicemia, perito- (ICU), young age, underlying neurologic conditions, develop- nitis, pancreatitis, ileus, rhabdomyolysis, ventriculostomy mental delay, cerebral hypoperfusion, and medication effects drains, and burns. Renal losses include diuretic use, osmotic may obscure subtle neurologic findings, and judicious labora- diuresis, various salt-losing renal diseases, CSW, and adrenal tory monitoring along with careful clinical assessment is insufficiency.55 essential. Emerging evidence in both adult and pediatric patients sug- Renal Sodium Losses gests an association between disturbances in sodium balance Renal salt-wasting states are generally identified by a urinary and adverse outcomes, including mortality, ICU length of stay sodium excretion in excess of 20 mEq/L and a fractional (LOS), use of both noninvasive and invasive mechanical ven- excretion (FENa) of more than 1%. The use of thiazide diuret- tilation, and long-term neurologic sequelae.46-52 It is unclear ics can exacerbate hyponatremia and hypovolemia and lead to at this time whether these adverse effects are a direct conse- a characteristic hypokalemic metabolic alkalosis (ie, “contrac- quence of the sodium imbalance, are a reflection of a greater tion alkalosis”). In normally functioning kidneys, concen- severity of illness, or are related to other underlying pathologic trated urine is produced by the equilibration of fluid in the processes. Mild disturbances of sodium may serve as a warning collecting tubules with the hyperosmotic medullary intersti- of an ongoing process of greater significance. More severe tium, which in turn is generated by sodium chloride (NaCl) hyponatremia or hypernatremia may be life threatening.53 reabsorption without water in the ascending limb of the loop These disturbances may result from the disproportionate gain of Henle. Thiazides act in the cortical distal tubule and do not or loss of either sodium or water. Pathologic sodium retention impair the ability of ADH to increase water reabsorption in may occur in disorders such as congestive heart failure (CHF), the collecting tubules and collecting duct,56 resulting in cirrhosis, and nephrotic syndrome without causing a signifi- thiazide-associated hyponatremia. Osmotic sodium and water cant change in ECF concentration, but the concomitant losses occur in a child with uncontrolled hyperglycemia with expansion of the ECF volume may be damaging. glucosuria, with mannitol use, and during urea diuresis following relief of urinary tract obstruction. Hyperglycemia and mannitol, in addition to inducing urinary sodium and water Hyponatremia losses, produce osmotic water movement from the intracel- Sudden, severe hyponatremia is life threatening, and its man- lular fluid (ICF) to the extracellular fluid (ECF), further low- agement demands prompt, measured action with ongoing ering serum sodium. Sodium levels drop about 1.5 mEq/L for monitoring and therapeutic adjustment. The syndrome of every 100 mg/dL rise in blood glucose level. Significant salt inappropriate antidiuretic hormone secretion (SIADH) and wasting may occur with several intrinsic renal diseases (Box cerebral salt wasting (CSW) are the most common causes of 73.1). Adrenal insufficiency is distinguished by hyponatremia

BOX 73.1 Causes of Hyponatremia TABLE 73.1 Cerebral-Renal Salt-Wasting Syndrome

Decreased Total Body Sodium Cerebral Salt Wasting Syndrome Extrarenal Vomiting/diarrhea Trigger Acute intracranial injury or illness Sequestration: sepsis, peritonitis, pancreatitis, rhabdomyolysis, (subarachnoid hemorrhage, trauma, etc.) ileus Onset Typically a few days after the injury Cutaneous: burns, cystic fibrosis occurs Ventriculostomy drainage Signs Falling serum Na+, high urine output, Renal high urine Na+ Cerebral-renal salt wasting (CRSW) Course Without treatment, proceeds to Diuretics intravascular volume depletion, Thiazides, loop diuretics (listed in order of severity of salt wasting) hypotension, and hypoperfusion Osmotic diuretic agents: mannitol, glucose, urea Tubulointerstitial diseases Treatment Replace salt and water losses; may Medullary cystic disease, obstructive uropathy, tubulointerstitial require 3% NaCl +/− loop diuretics; nephritis, chronic pyelonephritis, renal tubular acidosis, fludrocortisone in refractory cases Kearns-Sayre syndrome Adrenal insufficiency Resolution Days to weeks Congenital adrenal hyperplasia, Addison disease Differential diagnosis Syndrome of inappropriate antidiuretic Adrenal insufficiency hormone (SIADH), adrenal insufficiency, Congenital adrenal hyperplasia, Addison disease osmotic diuresis Increased Total Body Sodium Congestive heart failure Cirrhosis Nephrotic syndrome Cerebral Salt Wasting (CSW) Versus Syndrome of Advanced renal failure TABLE 73.2 Inappropriate Antidiuretic Hormone (SIADH) Normal Total Body Sodium Syndrome of inappropriate antidiuretic hormone secretion (SIADH) CSW SIADH Glucocorticoid deficiency + Hypothyroidism Urine Na Very high, often Variable, but usually Infantile water intoxication >100 mEq/L >30 mEq/L Abusive water intoxication Urine output Inappropriately high, Variable; may be leading to volume normal or decreased depletion in association with hyperkalemia and decreased urinary Response to Improvement in No improvement potassium excretion. saline challenge volume deficit and serum Na+ Cerebral Salt Wasting Response to fluid No improvement; Improvement in Cerebral salt wasting (CSW) is a clinical entity that continues and salt restriction volume deficit and serum Na+ to generate controversy. First described by Peters and cowork- hyponatremia may ers in 1950, it was superseded by the description of SIADH worsen by Schwartz and coworkers in 1957 and then rediscovered in 1981 when Nelson and associates studied hyponatremia in a series of neurosurgical patients with isotopically measured kidneys is another postulated mechanism.61 Distinguishing low blood volumes.57 Despite lingering skepticism, its distinct CSW from SIADH may be difficult in many complex clinical clinical identity continues to be supported (Table 73.1).58-61 scenarios. In cases of severe or symptomatic hyponatremia, Patients typically have an acute neurologic injury with hemor- however, this may be temporarily unnecessary because the rhage, trauma, infection, or a mass and may have undergone initial therapy is the same.57 Administration of enough con- neurosurgical procedures. CSW differs from SIADH in that centrated sodium to result in a small increase in osmolality is large urine volumes contain very high sodium concentrations, appropriate, and support of intravascular volume is required. leading to rapid depletion of both sodium and ECF volume A reasonable approach might begin with the administration (Table 73.2). An otherwise unexplained intravascular volume of 5 mL/kg of hypertonic (3%) NaCl followed by isotonic contraction is central to the diagnosis and may cause a sec- repletion of the remaining volume deficit. Once this is ondary boost in ADH release. Left untreated, CSW results in achieved, sufficient sodium and fluid administration to intravascular volume depletion, hypotension, and hypoperfu- account for daily maintenance requirements as well as ongoing sion or hypovolemic shock as well as hyponatremia. Untreated losses is necessary. Administration of fludrocortisone, a min- SIADH, in contrast, leads to progressive hyponatremia and the eralocorticoid, has been reported to aid in CSW management clinical consequences thereof with maintenance or mild in severe or prolonged cases that are refractory to initial expansion of fluid balance. The pathophysiologic link between therapy.61 In less severe cases, infusion of isotonic saline rep- intracranial injury and renal salt wasting has yet to be eluci- resents a reasonable first step in management, and the observed dated, contributing in no small part to the controversy. Both response may help to differentiate between CSW and SIADH. brain natriuretic peptide (BNP) and atrial natriuretic peptide In CSW, saline administration addresses volume depletion (ANP) are attractive as potential mediators, but neither has a and hyponatremia. It is of limited or no benefit in patients proved etiologic role.62,63 Decreased sympathetic input to the with SIADH, who are more effectively managed with fluid

Downloaded for Anonymous User (n/a) at Walter Reed National Military Medical Center from ClinicalKey.com by Elsevier on December 26, 2018. For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved. 1010 Section V Renal, Fluids, Electrolytes restriction.59 Throughout, the absolutely essential part of efforts to maintain sodium balance. Edema develops when therapy is the frequent reassessment of sodium levels and larger quantities of sodium are ingested than can be excreted. volume status with treatment adjustments as indicated. The ability to excrete water is also impaired, primarily because of the progressive decrease in GFR. Hyponatremia occurs Increased Total Body Sodium when water intake exceeds insensible losses plus the maximum Hyponatremia with increased total body sodium occurs when volume that can be excreted. the increase in total body water exceeds the sodium retention. Four clinical situations are commonly seen: congestive heart Normal Total Body Sodium failure, cirrhosis, nephrotic syndrome, and advanced renal Hyponatremia without evidence of hypovolemia or edema in failure. In all four conditions, hyponatremia tends to be mild the pediatric population is usually associated with SIADH. or moderate, asymptomatic, and nonprogressive or slowly Renal concentrating and diluting ability ultimately depends progressive. These patients typically present to the ICU pri- on the presence or absence of ADH to modulate water perme- marily for care related to these underlying conditions rather ability in the collecting duct. Osmoreceptors for ADH reside than for symptoms related to hyponatremia. in the anterior hypothalamus, responding to changes of as little as 1% in plasma osmolality. The nonosmotic stimuli that Congestive Heart Failure induce release of ADH are associated with changes in auto- Hyponatremia in heart failure is associated with a worse prog- nomic neural tone due to physical pain or trauma, emotional nosis.64,65 Low cardiac output states are characterized by a stress, hypoxia, cardiac failure, nausea and vomiting, adrenal decrease in effective circulating volume that is detected by insufficiency, volume depletion, and exposure to general anes- vasoreceptors in the carotid sinus, the aortic arch, and the thesia (Box 73.2). Nonosmotic stimuli, as the name implies, renal juxtaglomerular apparatus. Activation of various neuro- are active even in the face of normal plasma osmolality, and a hormonal modulators promotes vasoconstriction along with decrease in plasma volume of as little as 5% is sufficient to sodium and water retention. Increased sympathetic activity trigger a strong ADH response.54 Vasopressin (ADH) synthe- and stimulation of the renin-angiotensin-aldosterone system sized in the hypothalamus is transported in neurosecretory (RAAS) produce increased afferent and efferent arteriolar vas- granules to the axonal bulbs in the median eminence and cular resistance and decreased glomerular filtration rate (GFR) posterior pituitary gland and is released by exocytosis in the with a resultant decrease in urinary sodium excretion. Non- presence of appropriate stimuli. Increasing evidence indicates osmotic ADH release is stimulated, further impairing water that inflammatory mediators facilitate release and contribute excretion. In addition, decreased aldosterone degradation, to the high incidence of hyponatremia in Rocky Mountain along with altered levels of other vasoactive and nonvasoactive spotted fever, Kawasaki, and other inflammatory illnesses.10 substances, leads to a primary increase in tubular sodium After release, ADH binds to V2 receptors in the basolateral reabsorption. A deleterious positive feedback loop is created, membrane of the renal collecting duct, increasing cyclic in which the vasoconstrictive and fluid retentive effects of adenosine 3′,5′-monophosphate formation and facilitating these neurohormonal systems promote further vasoconstric- phosphorylation of aquaporin-2. Incorporation of aquaporin- tion and worsening renal perfusion.66 The complex interac- 2-containing vesicles in the apical (luminal) membrane tions between renal and cardiovascular pathophysiology have increases cell permeability to water and provides a pathway been described as the “cardiorenal syndromes” with five sub- for water reabsorption.69 types based on the primary organ affected and the acuity of Clinically, SIADH is characterized by (1) hyponatremia, (2) the physiologic derangement.67 euvolemia or mild hypervolemia, (3) hypoosmolality, (4) inappropriately elevated urine osmolality, and (5) elevated Cirrhosis urine sodium concentration. It has been associated with Early in cirrhosis, increased intrahepatic pressure may initiate several categories of clinical disease, including CNS and pul- renal sodium retention before ascites formation. The develop- monary disorders, malignancies, and as an adverse effect of ment of portal hypertension leads to nitric oxide–mediated numerous drugs (Box 73.2).70 Underlying renal function is peripheral vasodilation and to the formation of arteriovenous normal. Under normal physiologic conditions, a decrease in fistulae. The result is a decrease in effective circulating volume. serum sodium of 4 to 5 mEq/L below normal (with a serum These decompensated patients have higher levels of renin, osmolality of less than 270 mOsm) should maximally inhibit aldosterone, ADH, and norepinephrine than do compensated ADH secretion with a resultant urine osmolality of less than patients with cirrhosis. Hyponatremia arises in the setting of 100 mOsm. It is frequently difficult to determine, however, persistent renal sodium and water retention.68 whether urine osmolality and urine sodium are inappropriately elevated, particularly in critically ill patients receiving IV Nephrotic Syndrome fluids. Variable sodium and water administration rates,- iso Hyponatremia is an occasional finding in patients with tonic or hypertonic fluid boluses, fluctuations in hemody- nephrotic syndrome. It may be present, however, in patients namic status and urine output, and a history of diuretic use with apparently normal or decreased central volume. The can all confound laboratory interpretation. The key consider- humoral factors involved in patients with decreased central ation is the relative relationship between the degree of hypo- volume appear to be similar to those with decompensated natremia and hypoosmolality and the robustness of the cirrhosis. dilutional response in the urine. Failure to maximally dilute urine in the face of hypoosmolality represents inappropriate Renal Failure ADH response so that a urine osmolality of 200 to 250 mOsm As a diseased kidney loses nephrons, the remaining nephrons may reflect SIADH in hyponatremic patients. The urinary exhibit a dramatically elevated fractional sodium excretion in sodium level is generally more than 30 mEq/L but may be

Nonosmotic Stimuli Associated With Syndrome of BOX 73.2 Signs and Symptoms Inappropriate Antidiuretic Hormone The severity of signs and symptoms depends on the rapidity CNS Disorders of the development of hyponatremia. Neurologic symptoms Infection predominate as plasma hypoosmolality causes a shift in fluid Meningitis from the ECF to the ICF compartment, leading to generalized Encephalitis, including HIV/AIDS encephalitis cellular swelling. The rigidity of the intracranial space leaves Brain abscess Rocky Mountain spotted fever little room for cellular expansion, resulting in increasing intra- Mass lesions cranial pressure. Brain cells prevent massive swelling in the Subarachnoid or subdural hemorrhage early phases of hyponatremia by extrusion of electrolytes and Cerebral thrombosis or hemorrhage other cellular osmolytes. Acute decreases in sodium concen- Brain tumors tration are associated with lethargy, apathy, and disorienta- Head trauma with cerebral edema Hydrocephalus tion, often accompanied by nausea, vomiting, and muscle Cavernous sinus thrombosis cramps. No predictable correlation exists between the degree Other of hyponatremia and its resultant symptoms, as severe hypo- Guillain-Barré syndrome natremia that develops gradually may present with minimal Multiple sclerosis Hypoxic encephalopathy, including neonatal hypoxic-ischemic symptoms. Acute decreases in sodium to less than 120 mEq/L, encephalopathy (HIE) however, generally produce severe symptoms such as seizures Pituitary disease or coma. Other findings may include decreased deep tendon Acute psychosis reflexes, pathologic reflexes, pseudobulbar palsy, and a Cheyne- Pulmonary Disease Stokes respiratory pattern. Cerebral edema and intracranial Infection hypertension may be severe enough to result in herniation, Bacterial and viral pneumonias permanent neurologic injury, and death.72 Pulmonary abscess Tuberculosis Treatment Aspergillosis Asthma Prevention Respiratory failure with positive pressure ventilation Stimuli for ADH release are frequently present in both surgical and nonsurgical ICU patients, putting them at risk for hypo- Tumors natremia. Use of hypotonic intravenous (IV) maintenance Carcinomas of the lung, oropharynx, gastrointestinal tract (including the pancreas), and genitourinary tract fluids increases the risk for development of hyponatremia. Lymphoma, thymoma The appropriate administration of isotonic IV fluids in these Ewing sarcoma, mesothelioma patients will decrease the incidence of hyponatremia.73-78 For patients with severe SIADH or CSW, however, the use of Drugs Antidiuretic hormone analogs (vasopressin, desmopressin/1- isotonic fluids alone may not be adequate to prevent life- deamino-8-D-arginine vasopressin [DDAVP], oxytocin) threatening disturbances in sodium and water balance. Vincristine Thoughtful monitoring of sodium levels along with avoidance Salicylates of large volumes of hypotonic fluids is mandatory. Chlorpropamide Cyclophosphamide Therapy Carbamazepine Barbiturates The time course over which hyponatremia develops is a key Colchicine determinant of the therapeutic approach. Severe hyponatre- Haloperidol mia is associated with significant morbidity and mortality Fluphenazine Tricyclic antidepressants and selective serotonin reuptake inhibitors and requires urgent attention. As described previously, acute (SSRIs) hyponatremia produces significant cerebral edema when Clofibrate initial compensation mechanisms are overwhelmed and more Indomethacin and nonsteroidal antiinflammatory drugs (NSAIDs) chronic adaptive mechanisms are not yet fully developed. Interferon Ecstasy (3,4-methylenedioxy-methamphetamine [MDMA]) Hyponatremia that has been present less than 4 hours can safely be corrected promptly. When the evolution of hypona- Miscellaneous tremia is gradual, however, brain cells respond adaptively to High levels of inflammatory mediators general anesthesia prevent cerebral edema. Nausea/vomiting Pain or emotional stress Thus there are two essential questions in constructing a General anesthesia therapeutic plan: (1) Did hyponatremia evolve rapidly or Marathon running or endurance exercise slowly, and (2) does the patient have CNS symptoms or Hereditary (gain-of-function mutations in the vasopressin V2 imaging suggestive of cerebral edema? CNS cellular swelling receptor) and its symptoms are more likely with acute hyponatremia or with severe chronic hyponatremia.79,80 Symptomatic hypona- much less in patients who are provided a low sodium intake.71 tremia that develops suddenly—that is, in fewer than 4 When the urinary sodium concentration is very high, it is the hours—can be rapidly reversed without incurring risk. If net balance between intake and output that differentiates asymptomatic hyponatremia has developed over many hours, between SIADH and a renal salt-wasting syndrome. Renal salt days, or weeks (ie, chronic hyponatremia), a gradual, conser- wasting is favored when the urinary sodium excretion grossly vative approach is likely to be uncomplicated. Symptomatic exceeds sodium intake. chronic hyponatremia, on the other hand, requires a small but

Downloaded for Anonymous User (n/a) at Walter Reed National Military Medical Center from ClinicalKey.com by Elsevier on December 26, 2018. For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved. 1012 Section V Renal, Fluids, Electrolytes rapid increase in serum sodium to stabilize or begin to reverse mortality or ICU length of stay, however, is currently lacking. cerebral swelling and to avoid impending herniation, followed Conivaptan is an intravenous ADH V1 and V2 receptor antag- by a more gradual correction to normalize sodium balance. onist that is approved for the treatment of euvolemic and An increase of 5 mEq/L is usually sufficient to halt the prog- hypervolemic hyponatremia in adults.100 Tolvaptan, an oral ress of symptomatic cerebral edema and can be achieved with ADH V2 receptor antagonist, was approved in 2009 as therapy an initial bolus of 5 to 6 mL/kg of 3% saline. The subsequent for euvolemic or hypervolemic hyponatremia in adult patients correction rate for patients with either acute symptomatic with heart failure, cirrhosis, or SIADH.99 Pediatric usage of the hyponatremia or any chronic hyponatremia should not exceed ADH receptor blockers has been reported in the settings of 0.5 mEq/L/h. In acute hyponatremia without CNS symptoms, SIADH and cardiac disease,99-103 but further study of kinetics, rates of 0.7 to 1 mEq/L/h have been reported without patient safety, and efficacy will be needed to clarify the clinical role in morbidity or mortality. A regimen of hypertonic 3% saline pediatrics. infused at 1 to 2 mL/kg/h with intermittent administration of a loop diuretic results in an appropriate correction for those Hypernatremia patients for whom “rapid” correction is safe. Further correc- As with hyponatremia, hypernatremia can develop with low, tion may require isotonic fluids or a mixture of isotonic and normal, or high levels of total body sodium. History and hypertonic fluids, particularly in patients with CSW. In resis- weights are particularly important in evaluating the hydration tant, severe CSW, mineralocorticoid (fludrocortisone) treat- state of patients with hypernatremia because a shift in the ICF ment has been helpful in several reports.61,81,82 Other protocol to the ECF tends to obscure the physical findings of dehydra- approaches are available.83 tion. Accurate assessment of total body sodium and water aids Prolonged hyponatremia in animal studies is notable for a considerably in planning management, although the most striking decrease in total brain amino acid content as well as important management principle is the frequent monitoring lower brain water content.84 When this brain cell adaptation of the patient’s progress with treatment adjustments as needed. has occurred, a rapid rise in serum sodium concentration may induce a shift of water from the ICF to the ECF compartment, Pathophysiology and Etiology resulting in brain dehydration, brain injury, and the osmotic Low Total Body Sodium demyelination syndrome (ODS).85 Both central pontine and Patients with a low total body sodium level have a loss of water extrapontine myelinolysis have been reported in children.86-89 in relative excess of sodium losses. Because the ECF space is Extrapontine sites include the cerebellum, thalamus, basal hyperosmolar, water movement from the ICF occurs with nuclei, hippocampus, midbrain, and subcortical white resulting cellular dehydration. The ECF space, therefore, is matter.41 Traditional risk factors for ODS include chronic alco- somewhat preserved until an extreme degree of hypovolemia holism, malnutrition, and rapid correction of hyponatremia.90 is present. Losses of sodium and water may be extrarenal or Osmotic demyelination can occur, however, without hypona- renal (see Box 73.3). tremia as a starting point.88,89,91 Large bolus doses of hyper- In the pediatric patient, extrarenal losses are commonly tonic saline may place the patient at risk regardless of starting seen from vomiting and diarrhea, although hospital-acquired sodium concentration. Electrolyte fluctuations around the hypernatremia from insufficient free water administration is time of liver transplantation may account for the risk of myelinolysis noted in these patients.92 Rarely, ODS has been reported in patients with diabetic ketoacidosis but without BOX 73.3 Causes of Hypernatremia hyponatremia on admission, including one case in an 18-month-old child.87,89 Even rapid correction of hypernatre- Decreased Total Body Sodium mia is a possible cause of myelinolysis and suggests that pres- Extrarenal sure effects may be capable of causing damage to myelinated Vomiting/diarrhea, excessive sweating structures. Symptoms of osmotic demyelination may include Administration of 70% sorbitol obtundation, quadriplegia, pseudobulbar palsy, tremor, Renal 93,94 amnesia, seizures, and coma. Classically, the clinical pre- Osmotic diuresis: mannitol, glucose, urea sentation is that of a brief period of recovery from encephalopathy followed by emergence of a “locked in” state or various Inadequate Intake movement disorders.90 When CNS symptoms concerning for Insufficient lactation ODS emerge during therapy, long-term neurologic sequelae Normal Total Body Sodium may be avoided by decreasing serum sodium to its nadir fol- Extrarenal lowed by a slower rate of correction.95-97 Respiratory insensible water losses In cases of SIADH where fluid restriction is a feasible Cutaneous insensible water losses Fever, burns, phototherapy option, a decrease in fluid intake, occasionally with the use of Radiant warmers, especially with premature infants oral sodium supplements, may be all that is required to normalize serum sodium gradually and safely. In a patient with Renal hypovolemia, volume status clearly must be corrected in Diabetes insipidus (DI) addition to the hyponatremia. Patients with SIADH or fluid- Central DI Nephrogenic DI retaining states may respond to treatment with an ADH recep- Hypodipsia (reset osmostat) tor antagonist. This receptor blocker group increases urine volume and reduces urine osmolality, creating a water diuresis Increased Total Body Sodium that leads to an increase in serum sodium concentration.98,99 Administration or ingestion of large sodium loads Improperly diluted formula Evidence for improvement in other clinical outcomes such as

Downloaded for Anonymous User (n/a) at Walter Reed National Military Medical Center from ClinicalKey.com by Elsevier on December 26, 2018. For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved. Fluid and Electrolyte Issues in Pediatric Critical Illness Chapter 73 1013 a major concern.104,105 Renal causes include osmotic diuresis BOX 73.4 Causes of Diabetes Insipidus from mannitol, hyperglycemia, or increased urea excretion. Infants are particularly susceptible to hypernatremic dehydra- Central tion due to their high surface area/weight ratio and their rela- Congenital tive renal immaturity, which necessitates greater water losses Arginine vasopressin (AVP) antidiuretic hormone (ADH) gene for excretion of a solute load compared with older children mutations, autosomal dominant or (rarely) autosomal recessive 106 inheritance and adults. Insufficient maternal lactation places young Idiopathic (30% to 50% of cases) infants at risk of hypernatremic dehydration. Acquired Normal Total Body Sodium Head trauma, orbital trauma Loss of water occurs without excessive sodium losses in some Tumors, suprasellar and intrasellar Encephalitis conditions. Extrarenal losses include (1) increased respiratory Meningitis losses as may occur with tachypnea, hyperventilation, or Guillain-Barré syndrome mechanical ventilation with inadequate humidification and Hypoxic injury, including neonatal hypoxic-ischemic (2) transcutaneous losses associated with fever, burns, extreme encephalopathy (HIE) Postneurosurgical procedures prematurity, or use of phototherapy or radiant warmers in Cerebral aneurysms, thrombosis, hemorrhage the neonate without adequate water replacement. Renal losses Histiocytosis result from congenital or acquired diabetes insipidus (DI), Granulomas either central or nephrogenic. Acquired forms of DI are more Nontraumatic brain death commonly seen in the ICU. Major insults resulting in central Nephrogenic DI include head trauma, tumors, infections, hypoxic brain Congenital injury, neurosurgical procedures, and nontraumatic brain VR2 mutation, X-linked death. Classically, in experimental animals and in humans, AQP-2 mutation three stages occur: (1) an initial polyuric phase (hours to Acquired several days), (2) a period of antidiuresis probably due to ADH Chronic renal failure release from injured axons (hours to days), and (3) a second Renal tubulointerstitial diseases 107,108 period of polyuria that may or may not resolve. Sudden Hypercalcemia onset of polyuria is characteristic, and the conscious patient K+ depletion will often experience a concomitant polydipsia. In the critically Drugs Alcohol, lithium, diuretics, amphotericin B, methoxyflurane, ill patient, the inability to access increased water intake— demeclocycline whether from altered mental status, impaired thirst regulation, Sickle cell disease or other causes—may result in life-threatening hypernatre- Dietary abnormalities mia.109 Patients with the rare congenital forms of nephrogenic Primary polydipsia DI, resulting from X-linked alteration of the ADH V2 receptor Decreased sodium chloride intake Severe protein restriction or depletion or from autosomal recessive changes in the aquaporin II water channel itself, may have repeated bouts of hypernatremic dehydration.110 Causes of DI are shown in Box 73.4. lethargy to coma, increased muscle tone, and overt seizure Increased Total Body Sodium activity may occur in children with the development of severe Hypernatremia with an increased total body sodium level is hypernatremia over 48 hours or more. Hyperglycemia and most often an iatrogenic problem. In the ICU, hypertonic hypocalcemia also may occur. In infants with acute hyperna- solutions of sodium bicarbonate are administered during tremia, vomiting, fever, respiratory distress, spasticity, tonic- resuscitation efforts or as therapy for intractable metabolic clonic seizures, and coma are common. Death from respiratory acidosis, excessive hypertonic saline administration, ingestion failure occurred in experimental animals when serum osmo- by infants of improperly diluted formula, and dialysis against lality approached 430 mOsm/kg.113 Mortality in children a high sodium concentration. Normonatremic patients with with severe hypernatremia has ranged from 10% to 45% with massive edema who undergo a forced diuresis frequently chronic and acute hypernatremia, respectively. become mildly hypernatremic because the induced urine may Anatomic changes seen with the hyperosmolar state include be hypotonic, with water loss exceeding sodium loss. loss of volume of brain cells with resultant tearing of cerebral Hypernatremia is intentionally induced in patients with vessels, capillary and venous congestion, subcortical or sub- traumatic brain injury as a form of osmotherapy for control arachnoid bleeding, and venous sinus thrombosis. During of intracranial hypertension associated with cerebral the first 4 hours of experimental acute hypernatremia, brain edema.111,112 Such patients have tolerated serum sodium as water significantly decreases, while the concentration of high as 175 mEq/L when carefully managed. When the ECF solutes (electrolytes and glucose) increases.114 This leads to a osmolality of these patients is manipulated, the risks involved partial restitution of brain volume within a few hours’ time. with rapid changes in either direction must be kept in mind Over several days, brain volume normalizes as a result of intra- (see also Chapter 119). cellular accumulation of organic osmolytes consisting of polyols, amino acids, and methylamines.108,115 Signs and Symptoms Clinical manifestations of hypernatremia, as is the case with Treatment hyponatremia, relate predominantly to the CNS. Marked irri- Whenever possible, therapy of hypernatremia should address tability, a high-pitched cry, altered sensorium varying from correction of the underlying disease process as a primary goal.

Correction of dehydration with slow hypernatremia correc- Changes in extracellular or intracellular K+ concentration tion is the target. When sodium exceeds 165 mEq/L, isotonic may alter the critical transmembrane potential of cardiac, fluid or colloid may be used for correction of shock or circula- skeletal, or smooth muscle cells with serious results. tory collapse and initial reversal of hypernatremia. When Hypokalemia is relatively common in pediatric intensive hypernatremia has been present for more than a few hours, care unit (PICU) patients but generally is detectable and man- the presence of intracellular organic osmolytes dictates a slow ageable.121 Severe hyperkalemia is much less frequent but rate of correction. Numerous fatal cases of cerebral edema much more likely to be life threatening with minimal warning. and herniation have occurred with correction over a 24-hour Factors involved in total body distribution include period, leading to recommendations for correction over no acid-base status, insulin, catecholamines, magnesium, and less than 48 hours.116,117 There is general agreement that aldosterone.122-125 Acidemia tends to increase the serum plasma osmolality should not be decreased more rapidly than potassium, and alkalemia lowers it. The type of acid-base 2 mOsm/h, correlating with a rate of sodium decline that does disturbance (metabolic or respiratory), the duration of the not exceed 1 mEq/h. In cases of very severe or long-standing disturbance, and the nature of the anion accompanying the hypernatremia, a more conservative correction rate of hydrogen ion in metabolic acidosis are important in deter- 1 mOsm/h (0.5 mEq/hr of sodium) may be appropriate. Thus, mining what effect a particular acid-base disorder may have normalization from extreme hypernatremia may take several on potassium concentration. days. This slower rate of correction appears to allow time for Diabetic ketoacidosis (DKA) may occasionally present dissipation of the organic osmolytes without development of with severe hypokalemia126 due to losses. Hyperosmolality cerebral edema. Estimated deficits, ongoing maintenance and decreased circulating insulin will preserve or even elevate requirements, and additional excessive losses must be serum K+ in most cases.127,128 Epinephrine, albuterol,129 and accounted for in calculations of the amount of fluid replace- other beta-agonists decrease serum potassium, moving it into ment required. cells. β-adrenergic blocking drugs abolish this effect. Change Central DI is a likely cause of hypernatremia in an ICU in intracellular magnesium (Mg++) may affect the sodium- patient with high urine volume and low urine osmolality, potassium adenosine triphosphatase (ATPase) pump and alter particularly in patients who have head trauma or who have the transcellular distribution. All of these mechanisms, undergone a recent intracranial operation. In these patients, a however, are generally representative of fine-tuning in potas- trial of vasopressin is in order. Either aqueous vasopressin sium homeostasis. Ultimately, potassium balance is regulated given subcutaneously or intravenously (0.5 to 10 milliunits/ through excretion by the kidney and to a lesser extent the kg/h) or 1-deamino-8-D-arginine vasopressin (DDAVP) given gastrointestinal (GI) tract. Massive cell lysis may overwhelm orally or intranasally may be used. Oral dosing is limited to these and require aggressive management of the sudden shift tablet form at this time with a recommended dosing range of of intracellular K into the ECF, particularly in the presence of 0.05 to 0.4 mg administered twice daily. Intranasal DDAVP is compromised renal function. generally begun in a dosage ranging from 0.05 to 0.1 mL once Most of the filtered potassium is absorbed before the distal or twice daily. An increase in urine osmolality to values exceed- nephron in normal kidneys. The potassium excreted in the ing that in serum after vasopressin administration supports urine then is mainly due to secretion in the distal convoluted the diagnosis of central DI. Hyponatremia has been reported tubule and cortical collecting duct. As with sodium, the kid- after vasopressin administration in patients with central DI as ney’s capacity to vary potassium excretion is profound, ranging well as in patients receiving vasopressin for hemodynamic from a low of approximately 5 mEq/L to amounts exceeding support and for bleeding disorders in the perioperative 100 mEq/L of urine. Factors influencing renal potassium period.118,119 In the outpatient setting, symptomatic hypona- excretion include mineralocorticoid and glucocorticoid hor- tremia, including seizures and altered mental status, has been mones, acid-base balance, anion effects, tubular fluid flow reported in patients receiving DDAVP for enuresis, particu- rate, sodium intake, potassium intake, ICF and plasma potas- larly in periods of intercurrent illness or with excess fluid sium concentrations, and diuretics.130 Aldosterone is a major intake.120 Careful attention to the IV fluid prescription, serial kaliuretic hormone. Metabolic acidosis decreases and meta- monitoring of sodium levels, and timely adjustment in therapy bolic alkalosis increases intracellular potassium activity in are necessary to avoid severe complications in patients receiv- cells of the distal tubule, causing enhanced potassium secre- ing any type of vasopressin therapy. tion during alkalosis and reabsorption during acidosis. Fluid In patients with an increased total body sodium level and, delivery to the distal tubule probably enhances potassium often, hypervolemia, the goal is sodium removal. In patients secretion by two mechanisms: (1) the faster fluid moves past with intact renal function, sodium removal may be accom- the secretory site, and a greater amount of potassium can be plished with diuretics and a decrease in sodium administra- secreted, and (2) because tubular fluid potassium concentration. If renal failure is present, dialysis may be required. tion decreases as flow rate increases, a favorable gradient for potassium movement is maintained at high flow rates. Potassium The total body K+ of about 50 mEq/kg is divided with about Hypokalemia 98% being intracellular. The transmembrane concentration gradient is large with the intracellular concentration of Causes of Hypokalemia 150 mEq/L being maintained by sodium-potassium adenos- Hypokalemia Without Potassium Deficit ine triphosphatase (Na+/K+-ATPase) pumps. The resultant The detection of a low serum potassium level may reflect a transmembrane potential is normally tightly regulated but true deficit in total body stores or an apparent deficit from the physiologically dynamic in contractile or conductive cells. shift of this ion from the ECF to the ICF pool. A shift to the

ICF pool may occur in alkalemia,131 administered or endoge- Concomitant volume depletion and metabolic alkalosis asso- nous release of beta-agonist,129,132 familial or thyrotoxic peri- ciated with NaCl and hydrogen ion losses often result in sec- odic paralysis,133,134 barium poisoning,135 and excess insulin. In ondary aldosteronism, however, and an increased filtered load the case of alkalemia, potassium moves into the cell in exchange of bicarbonate with resultant renal potassium losses. Diarrhea, for H+ in an attempt to maintain extracellular pH. The pedi- regardless of cause, may result in large potassium losses, the atric patient with alkalemia may have a true potassium deficit amount lost being related to the volume of fluid lost. Other in addition due to decreased potassium intake or increased GI causes are listed in Box 73.5. losses. Periodic paralysis is a rare autosomal dominant disorder Signs and Symptoms presenting with intermittent episodes of profound muscle For the intensivist, cardiovascular and neuromuscular effects weakness associated with a sudden fall in serum potassium of potassium deficiency are of particular concern, although concentration precipitated high-carbohydrate/low-potassium metabolic, hormonal, and renal effects may also occur. diet, exercise, infection, stress, or alcohol ingestion. Barium Electrocardiographic (ECG) changes include T-wave flat- poisoning can produce hypokalemic weakness and paralysis, tening or inversion, ST depression, and the appearance of a U probably by competitive blockade of inward rectifying K+ wave. Resting membrane potential is increased, as are both the channels. Insulin shifts potassium into muscle and liver cells duration of the action potential and the refractory period. in association with glycogen formation. The decreased conductivity predisposes to arrhythmias, as do increased threshold potential and automaticity.143 Hypokalemia With Potassium Deficit Hypokalemia diminishes skeletal muscular excitability. This A deficit in total body potassium may occur from decreased can present as a dynamic ileus or a skeletal muscle weakness intake, from renal losses, or from GI losses. GI loss occurs with resembling Guillain-Barré syndrome. It can eventually affect pyloric stenosis or other persistent vomiting, diarrhea, or the trunk and upper extremities, becoming severe enough to binding of enteric K+ by ingested clay in patients with pica.136 result in quadriplegia and respiratory failure.144 Hypokalemia Renal Losses can lead to severe rhabdomyolysis in a variety of underlying Major categories seen in the ICU include loop, thiazide, and conditions,145-148 and may progress to ARF and hyperkale- osmotic diuretics, renal tubular acidosis, hyperaldosteronism, mia.149 Autonomic insufficiency may also occur, generally magnesium deficiency, and recovery from acute renal failure manifested as orthostatic hypotension. In patients with (ARF). Osmotic diuresis from glucosuria can cause severe severe liver disease, hypokalemia may precipitate or exacerbate renal potassium wasting in prolonged DKA predisposing to encephalopathy. Glucose intolerance in the presence of ventricular arrhythmia. The severity of K+ loss may be masked primary hyperaldosteronism and in certain patients receiving by the shift of potassium from the ICF to the ECF space related to insulin deficiency, metabolic acidosis, and hypertonicity. Primary aldosteronism, congenital adrenal hyperplasia, adrenal adenoma, and familial idiopathic hyperaldosteron- BOX 73.5 Causes of Hypokalemia 137,138 ism are rare in children and even rarer in the pediatric Hypokalemia without potassium deficit ICU setting. Secondary hyperaldosteronism is common, Alkalosis however, either from volume depletion or from CHF, cirrho- β-agonist, exogenous or endogenous sis, or nephrotic syndrome. Patients with the latter conditions, Familial periodic paralysis Thyrotoxic periodic paralysis however, rarely have severe hypokalemia unless they are addi- Barium poisoning tionally treated with diuretics. Infants with Bartter or Gitel- Excessive insulin man syndrome139 may initially come to the ICU because of Hypokalemia with potassium deficit multiple metabolic derangements including hypokalemia, Decrease intake metabolic alkalosis, hypomagnesemia, and hyperuricemia. Renal losses Hyperaldosteronism Other findings include weakness, polyuria, and failure to Primary or secondary thrive, with elevated renin and aldosterone levels in the Barter, Liddle, Gitelman syndrome absence of hypertension. Additional conditions associated Laxative or diuretic abuse with elevated renin secretion, secondary hyperaldosteronism, Licorice ingestion Osmotic agents and hypokalemia include renal artery stenosis, malignant Drugs hypertension, renin-producing tumor, or Wilms tumor. Addi- Caffeine tional mechanisms include secondary hyperaldosteronism Diuretics and increased distal tubular fluid delivery. Amphotericin B Other agents that induce excessive renal losses include Aminoglycosides High-dose penicillin, carbenicillin amphotericin B (kaliuresis with reduced renal function and Miscellaneous tubular injury); aminoglycosides, particularly gentamicin; Hypomagnesemia and high-dose penicillin and carbenicillin, which produce an Renal tubular acidosis osmotic load in addition to acting as non-reabsorbable anions. Toluene toxicity Renal tubular acidosis, hypomagnesemia, and caffeine toxicity Extrarenal losses 140-142 Gastrointestinal may cause renal potassium wasting. Vomiting, nasogastric suction Gastrointestinal Losses Diarrhea Upper GI losses from vomiting or from nasogastric (NG) Laxative abuse suction are frequently associated with hypokalemia. The Ureteral sigmoidostomy Obstructed or long ileal loop gastric concentration of potassium ranges from 5 to 10 mEq/L.

Redistribution Hyperkalemia In general, when extracellular pH falls, potassium exits from cells; the result is an increase in serum potassium. As men- Causes tioned earlier, metabolic acidosis from mineral acids has a Hyperkalemia may result from artifactual elevation; from more pronounced effect than that of organic acids. Respira- redistribution of potassium from ICF to ECF space; or from tory acidosis does not usually cause a marked change in potas- increased intake, decreased losses, or both (Box 73.6). sium concentration. Hypertonicity per se produces a shift of potassium from Artifactual ICF to ECF. Studies of anephric animals show potassium Tight, prolonged tourniquet use produces spurious potassium increasing by 0.1 to 0.6 mEq/L for each increment of elevation due to potassium release from ischemic muscle. 10 mOsm/kg H2O in tonicity. Hypertonicity causes cellular Even more common is hemolysis of red cells with potassium dehydration and therefore an increase in ICF potassium that release associated with capillary sampling or aspiration or favors increased passive diffusion out of cells. A very small delivery under pressure through a small needle. The lab may percentage shift of IC potassium delivers a significant potas- note hemolysis, but artifactual normality or actual elevation sium load to the ECF. In the hyperkalemic patient in the ICU should always be considered.150 Less commonly, in vitro release who has acute oliguria, mannitol should not be used for diure- of potassium occurs from white blood cells (WBCs) (>100,000/ sis as further K+ elevation may result. In the patient with uL) or platelets (>1,000,000/uL) and may result in increased hyperglycemia, hypertonicity is likely only one of several levels. mechanisms resulting in elevated serum levels.

Several commonly used drugs result in net movement of progression may occur over a matter of minutes is extremely potassium from ICF to ECF. Digoxin inhibits the net uptake important. of K by cells by inhibiting Na/K-ATPase, with hyperkalemia commonly occurring in severe digitalis poisoning.151 Other Treatment drugs include beta-blockers with β2 activity and the muscle Treatment of hyperkalemia depends on the level of plasma relaxant succinylcholine. This drug induces a prolonged dose- potassium and the state of cardiac irritability.47 If the potas- related increase in the ionic permeability of muscle, with sub- sium concentration is more than 6.5 mEq/L with associated sequent efflux of potassium from muscle cells. Normal serum ECG changes, additional measures are indicated. In the potassium concentration rises about 0.5 mEq/L. Succinylcho- absence of digitalis toxicity, hyperkalemia with ECG changes line should be avoided in patients with burns, muscle trauma, should be treated with a secure and rapid IV infusion of spinal injuries, certain neuromuscular diseases, near drown- calcium chloride or calcium gluconate. Hand injection with ing, and closed head trauma, as up-regulated and new forms ECG monitoring is reasonable beginning with the administra- of acetylcholine receptors may respond with life-threatening tion of 10 mg/kg of calcium chloride (or gluconate equiva- hyperkalemia.152 New examples of patients at risk will con- lent) over 1 to 5 minutes. Infusion may be stopped if the tinue to be reported.153,154 Hyperkalemia may result in nonsus- electrocardiogram has normalized or if deterioration of the pect patients via rhabdomyolysis or malignant hyperthermia electrocardiogram seems to be precipitated by the potassium, following succinylcholine. Rhabdomyolysis has many causes suggesting a clinical scenario more complex than simple including influenza, severe exercise, drugs, ischemia, and hyperkalemia. If the electrocardiogram improves but is not many more.155-157 Familial hyperkalemic periodic paralysis normalized by this calcium dose, additional calcium chloride appears to be related to potassium redistribution related to may be given at a lower rate. It should be anticipated that ECG changes in ion channel function. Rebound hyperkalemia may changes will recur in 15 to 30 minutes unless additional mea- be life threatening after coma-inducing barbiturate is stopped sures are taken immediately to treat the hyperkalemia. The or surgical insulinoma removal. effective calcium dose may be repeated as necessary to preserve cardiac function while additional treatments are in prog- Increased Load ress. Additional, rapidly effective treatments include nebulized Hyperkalemia due to an increased potassium load is unusual albuterol (rapid neb or continuous neb of 0.3 to 0.5 mg/kg) as long as renal function is normal. Serious elevations may or salbutamol (IV dose of 4 to 5 µg/kg over 20 minutes and be seen with inappropriate IV infusion, large volume blood repeated after 2 hours).168,169 transfusions,158 bypass circuit initiation,159 oral potassium Insulin and glucose are also rapidly helpful in redistributing supplements, salt substitutes containing potassium, or large potassium to the ICF. Glucose (1 g/kg) and insulin (0.2 U/g doses of potassium penicillin. Strict measures to guard against of glucose) may be given over 15 to 30 minutes and then accidental K overdoses are mandatory.160 Large endogenous infused continuously with a similar amount per hour. A pre- loads of potassium are more likely in the patient who is in the mixed combination glucose and insulin solution has been suc- ICU. The release of cellular potassium associated with tissue cessfully demonstrated in a 21 patient series.170 Blood glucose necrosis from burns, trauma, rhabdomyolysis including that monitoring is essential because the relative glucose and insulin from spider bites161 or the propofol syndrome,162,163 massive amounts may need adjustment. intravascular coagulopathy, rapid hemolysis, or GI bleeding Sodium bicarbonate (1–2 mEq/kg given intravenously) has may lead to hyperkalemia. been a part of the classic treatment of hyperkalemia. Its Tumor lysis syndrome (TLS) is classically associated with benefit, however, is more difficult to predict and slower in drug or radiation treatment of sensitive lymphoid malignan- onset than that of the measures mentioned earlier. cies and results in hyperkalemia often accompanied by hypo- Sodium polystyrene sulfonate removes potassium and may calcemia, hyperphosphatemia, acidosis, and compromised be administered while dialysis arrangements are made. Sodium renal function.164 Many fatalities have been reported. The list polystyrene sulfonate administered rectally must be retained of TLS-producing events or therapies includes transcatheter for 15 to 30 minutes to be effective. If the oral route is avail- chemical and embolic tumor necrosis, monoclonal antibody able, it is generally more efficient. treatment with rituximab, and enzyme-inhibiting agents bort- Hemodialysis is the treatment of choice for removal of K+ ezomib, imatinib, and sorafinib. Cases have occurred in tumor in emergent conditions. In the patient with severely compro- patients with surgical stress or dexamethasone given for mised renal function, the measures above generally allow sta- potential airway edema (see also Chapter 94). bilization of potassium long enough to institute dialysis. Although hemodialysis is much more efficient for potassium Manifestations of Hyperkalemia removal than peritoneal dialysis, the latter may be more Life-threatening complications are most likely to result quickly instituted in many centers, particularly in the small from the cardiac changes caused by hyperkalemia. ECG infant in whom vascular access to support reasonable blood signs include tall, peaked T waves in the precordial leads, flow may be difficult to accomplish. In the absence of renal followed by a decrease in amplitude of the R wave, bradycar- failure, loop diuretics or thiazide diuretics or both are useful dia, widened QRS complexes, prolonged PR intervals, and for the increase of renal excretion. If mineralocorticoid activ- decreased amplitude and disappearance of the P wave.165 ity is deficient, the administration of fludrocortisone may Finally, the classic sine wave of hyperkalemia from the blend- be indicated. In patients with severe hyperglycemia and mod- ing of the QRS complex with the P wave may appear. ECG erate hyperkalemia, early steps to improve glucose control changes do not necessarily correlate with specific levels of should decrease ECF potassium shifts from hyperosmolality serum K+.166 Realizing that ventricular arrhythmias or cardiac and decrease ECF potassium shifts from hyperosmolality and arrest may occur at any point in this progression and that decreased insulin.

If the potassium is less than 6.5 mEq/L without ECG the Na/K pump, allowing potassium loss from the ICF to the changes, discontinuation of exogenous potassium and drugs ECF and urinary excretion. Magnesium repletion is important that decrease its excretion with close follow-up of potassium to resolution of these secondary disturbances. levels may be all that is necessary. In the patient with renal compromise, extra potassium may be eliminated with use of Causes the potassium-binding agent sodium polystyrene sulfonate Intensivists deal with hypomagnesemia most often in patients (Kayexalate, resonium) (oral, NG, or rectal doses of 1 to 2 g/ receiving loop diuretics or transplant immunosuppressives.174 kg in a sorbitol or dextrose solution). When administered Other causes must be considered. rectally, sorbitol may not be necessary, and it should certainly Magnesium deficiency may be caused by decreased intake not be given rectally in concentration greater than 20%. or increased losses. Although slight falls in serum magnesium Highly concentrated sorbitol may cause severe proctitis and levels may occur after 1 week of a deficient diet, a more sus- colonic injury. Increasing reports of colonic injury particu- tained period of deprivation is generally necessary for signifi- larly in hemodynamically compromised or premature patients cant hypomagnesemia to occur. In children, magnesium suggest caution be exercised in using this preparation. deficiency has been particularly common in protein-energy However, when needed, having the pharmacy stock a pre- malnutrition and in anorexia nervosa, where refeeding mixed 10% to 20% suspension of sodium polystyrene sulfo- syndrome is a particular risk.175,176 Intestinal malabsorption nate and sorbitol allows either oral or rectal administration is a major cause of magnesium deficiency. Isolated familial on short notice. primary hypomagnesemia occurs from selective malabsorption of magnesium with patients generally having symptoms in infancy. These include tetany and convulsions as a result of Magnesium severe hypomagnesemia with consequent hypocalcemia and Magnesium plays a key role in numerous metabolic processes, respond well to supplemental magnesium. Other causes asso- including cellular energy production, storage, and utilization ciated with magnesium malabsorption include regional enter- involving adenosine triphosphate (ATP); the metabolism of itis, ulcerative colitis, massive small bowel resection, generalized protein, fat, and nucleic acids; and the maintenance of normal malabsorption syndromes, pancreatic insufficiency, and cystic cell membrane function. It is also involved in neuromuscular fibrosis. In some, the formation of insoluble soaps due to the transmission, cardiac excitability, and cardiovascular tone.171 complexing of magnesium with unabsorbed fat is the postu- Magnesium balance is maintained through intestinal lated mechanism for hypomagnesemia. absorption and renal excretion; 25% to 65% of ingested Mg Increasing use of induced hypothermia may increase hypo- is absorbed in the ileum. Absorption varies inversely with magnesemia occurrence.177 Epidermal growth factor blocking intake and is also affected by paracellular water reabsorption. antibodies are associated with a small incidence of induced Increased bowel water from any cause results in decreased hypomagnesemia.178,179 Hypomagnesemia may be more com- magnesium absorption. Regulation of renal excretion occurs mon than appreciated in patients presenting with hematologic by glomerular filtration and reabsorption. The majority of malignancies.180 filtered magnesium is reabsorbed in the ascending limb of the Intrinsic renal tubular disorders associated with hypomag- loop of Henle, resulting from active NaCl reabsorption and nesemia are rare in the ICU setting (Box 73.7). susceptible to loop diuretic inhibition. The threshold value for Drugs that induce renal magnesium wasting are more magnesium excretion varies between 1.5 and 2 mg/dL in dif- common causes and include aminoglycosides,181 cisplatin,182 ferent species. Thus if serum magnesium levels fall even amphotericin B,183 diuretics,184 cyclosporin A,185 tacrolimus,185 slightly, renal excretion dramatically decreases under normal and proton pump inhibitors.186,187 Magnesium supplementa- circumstances. Primary factors that increase renal magnesium tion is often needed in transplant recipients who receive cyclo- excretion include ECF volume expansion; hypermagnesemia; sporine or tacrolimus. Fractional excretion of magnesium and hypercalcemia; metabolic acidosis; phosphate depletion; and total excretion are elevated. Patients with DKA may also have various drugs including loop and osmotic diuretics, cisplatin, marked renal magnesium wasting during the acidotic period, aminoglycosides, cyclosporin, and digoxin. Decreased excre- as well as in early treatment. An increased urine calcium level, tion occurs with ECF volume depletion, hypomagnesemia, from whatever cause, is often associated with magnesium hypocalcemia, hypothyroidism, and metabolic alkalosis to a wasting from competitive inhibition of renal tubular reab- lesser extent. Parathyroid hormone (PTH) may decrease mag- sorption of magnesium in the ascending limb. nesium excretion but that effect may be offset by the opposite effect of causing hypercalcemia. Signs and Symptoms In addition to biochemical derangements associated with hypomagnesemia, a wide spectrum of other clinical disor- Hypomagnesemia ders has been attributed to its depletion, including cardiac Free, ionized magnesium and intracellular magnesium may be arrhythmias, increased sensitivity to digoxin, coronary spasm, the critical concentrations, but determination of total magne- hypertension, seizures, and neuromuscular derangements. sium is still clinically effective. Critically ill children have been Hypomagnesemic arrhythmias include ventricular premature reported to frequently have low ionized magnesium despite beats, ventricular tachycardia, torsades de pointes, and ven- normal total magnesium levels.172 Evidence supporting oblig- tricular fibrillation.188 Supraventricular arrhythmias are less atory ionized magnesium measurement remains elusive.173 common. Following magnesium infusion, improvement Magnesium depletion may result in hypocalcemia, via sup- in resistant ventricular arrhythmias including torsades has pression of PTH secretion. Hypokalemia also occurs in pa- been reported,189 although other metabolic derangements tients with hypomagnesemia. Magnesium deficiency impairs often coexist in such patients. Magnesium deficiency enhances

by adequate magnesium intake before development of life- BOX 73.7 Causes of Hypomagnesemia threatening symptoms. The use of supplemental magnesium Decreased intake infusions in perinatal asphyxia177 remains to be fully tested or Low Mg++ TPN, IVF, eating disorders extended to other hypoxic-ischemic encephalopathies. Increased losses Gastrointestinal Malabsorption Familial primary hypomagnesemia Hypermagnesemia Small bowel disease Hypermagnesemia is less common than hypomagnesemia, Regional enteritis, ulcerative colitis, massive bowel resection but they can be life threatening when extreme.194 Magnesium Pancreatic insufficiency, pancreatitis Cystic fibrosis infusions in pediatric status asthmaticus have become Renal common, despite remaining controversial in adult pulmonol- Congenital renal magnesium wasting ogy.195 Large doses clearly produce elevated blood levels,196 but Diffuse tubular disorders side effects are not common. Hypophosphatemia Drugs: aminoglycosides, cisplatin, amphotericin B, diuretics, Cause cyclosporine, tacrolimus, pentamidine, foscarnet, GM-CSF Hypercalciuria Hypermagnesemia occurs in patients with renal failure and is Diabetic ketoacidosis generally associated with iatrogenic administration of magne- Barter syndrome sium as antacids, cathartics, or enemas or through total par- Hyperaldosteronism Inappropriate ADH secretion enteral nutrition (TPN) containing magnesium. In the absence Miscellaneous of renal failure, the administration of large quantities of mag- 197 Epinephrine, β-agonists nesium cathartics in the management of constipation or Thyrotoxicosis overdoses198 and antacid use with increased peritoneal absorp- Citrated blood transfusion (massive) tion of magnesium in the presence of a perforated viscus199 Burns Alcoholism are causes. Magnesium levels as high as 10 to 12 mEq/L have been reported. Megadose vitamin-mineral supplementation, ADH, antidiuretic hormone; GM-CSF, granulocyte-macrophage colony- including magnesium oxide, has been fatal.200 stimulating factor; IVF, intravascular fluid; TPN, total parenteral nutrition. Signs and Symptoms Acute elevations of magnesium depress the CNS and the peripheral neuromuscular junction. Pseudocoma with fixed, myocardial cell uptake of digoxin and toxicity. Both inhibit dilated pupils has been reported. Deep tendon reflexes are Na/K-ATPase with resultant ICF potassium depletion. depressed at levels greater than 4 mEq/L with total disappear- Depletion is thought to contribute to the development or ance along with flaccid quadriplegia at levels greater than worsening of hypertension by increasing vascular smooth 8 to 10 mEq/L. Hypotension, hypoventilation, and cardiac muscle tone and reactivity. Increased cellular influx of calcium arrhythmias may also occur.201-204 Moderate hyperkalemia has and decreased reuptake by sarcoplasmic reticula occur; the resulted from prolonged magnesium infusions in occasional result is increased cytosolic calcium for activation of actin- patients. myosin contractile proteins. Similar effects in coronary and cerebral vessels have also been observed. Treatment Seizures may be the first symptom noted in an ICU setting. Calcium acts as a direct antagonist to magnesium. In life- Other neuromuscular changes may include tremors, fascicula- threatening situations associated with severe magnesium tions, spontaneous carpopedal spasm, muscle cramps, pares- intoxication, intravenous calcium should be used as the initial thesias, seizures, and coma.190,191,192 Personality changes, therapy. An initial dose of calcium chloride at 10 mg/kg or an including apathetic behavior and depression, have also been equivalent amount of calcium gluconate has been suggested associated. for infants and children. Magnesium-containing medications obviously should be discontinued. If renal function is normal, Treatment IV furosemide may be administered to increase magnesium Patients undergoing or at immediate risk of hypomagnesemic excretion while urine output is replaced with half-normal malignant ventricular arrhythmias (such as torsades) or sei- saline. In patients with renal failure or severe toxicity, dialysis zures can be given magnesium sulfate intravenously with may be necessary for removal. 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. Calcium Doses may be repeated as needed depending on patient Hypocalcemia is a common issue in pediatric critical response. Complications of parenteral magnesium therapy care.205,206 Hypercalcemia is an uncommon challenge in the include neuromuscular and respiratory depression, rare PICU. Extracellular fluid (ECF) calcium concentration is arrhythmias, flushing, hypotension, and prolonged bleeding best estimated with measurement of ionized calcium (Ca++) times.193 Other routes of therapy include intramuscular mag- concentration. Total serum calcium includes physiologically nesium sulfate, injections of which are painful, and oral accessible Ca++ plus that bound to protein or complexed with therapy with magnesium oxide or citrate. In situations known anions such as citrate of phosphate. The Ca++ concentration to be associated with the development of hypomagnesemia, it is under dual hormone control with PTH mobilizing Ca++ seems particularly important to attempt to avoid deficiency and calcitonin acting in bone and cartilage to retain fixed

Downloaded for Anonymous User (n/a) at Walter Reed National Military Medical Center from ClinicalKey.com by Elsevier on December 26, 2018. For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved. 1020 Section V Renal, Fluids, Electrolytes calcium. The concentration of Ca++ is particularly critical for Hyperphosphatemia lowers Ca++ by chelation, by shifting cardiac, vasomotor, and neurologic function but is susceptible the equilibrium in calcium flux from ECF toward bone to disturbance by many factors including drugs, sepsis, major and by inhibiting 1α–hydroxylation activity. Calcitonin is a surgery, enteric disease, malignancy, pancreatitis, endocrinop- 32-amino acid, calcium-lowering hormone elaborated by C athy, genetic misfortune, and many others. cells of the thyroid in response to rising Ca++ levels.210 Entry of Ca++ into cardiac and skeletal muscle cell mediates Although it rapidly reduces the bone resorptive function of conversion of electrochemical into mechanical energy with osteoclasts and promotes calciuria and phosphaturia, its excess resultant muscle contraction. Adenylate cyclase, phosphodies- or absence causes no known disorder. terase and protein kinases are regulated by the interaction of Ca++ with calmodulin. A similar interaction stimulates myosin kinase in vascular smooth muscle so that Ca++ influx Hypocalcemia (enhanced by α-adrenergic and inhibited by β-adrenergic stimuli) causes vasoconstriction. Ca++ also plays a critical role Clinical and Laboratory Concerns in the clotting system and various membrane transport Hypocalcemia in pediatric critical illness may be associated systems. with PTH deficiency, hypercalcitoninemia, or hypomagnese- Extracellular Ca++ is monitored by Ca++-sensing recep- mia. Multiple mechanisms may act simultaneously. In chil- tors207,208 on the surface of the chief cells of the parathyroid dren with severe burns, hypocalcemia, magnesium depletion, glands, the juxtaglomerular apparatus, the proximal tubule, hypoparathyroidism, and renal resistance to PTH may all the cortical thick ascending limb of the loop of Henle, the develop. inner medullary collecting duct, the intestine, parts of the Cardiovascular manifestations are of particular ICU brain, thyroid C cells, breast cells, and the adrenal glands. concern and may include hypotension, myocardial depression, Binding of Ca++ to this calcium sensor activates phospholi- CHF, and dysrhythmias. Cardiac contractility may be compro- pase C and the accumulation of inositol triphosphate, which mised acutely as in postoperative hypocalcemia. However, leads to inhibition of the secretion and synthesis of PTH and subacute cardiac myopathy from vitamin D deficiency and inactivation of its proteolysis. hypocalcemia may also be life threatening and reversible.211-213 Hypocalcemia inhibits acetylcholine release in both sensory Regulation of Calcium and motor nerves. Accordingly, a variety of peripheral and In the ICU, many changes in calcium activity result from CNS effects may result, including seizures, tetany, carpopedal changes in protein binding and chelation, excessive or defi- spasms, muscle cramps and twitching, paresthesias, laryngeal cient hormonal action, or excessive losses or intake of calcium. stridor, and apnea in the newborn. A majority of total serum calcium is bound to proteins, and Somatic changes accompanying prolonged hypocalcemia this binding is pH dependent. Acidic pH decreases calcium include dry coarse skin, eczematous dermatitis, brittle hair binding and increases Ca++, whereas alkalemia increases with areas of alopecia, brittle nails with smooth transverse binding and reduces Ca++. Blood products, renal failure, or grooves, and dental enamel hypoplasia. massive cell lysis may result in increased chelation. Fortu- Determination of the free ionized Ca++ level is diagnostic, nately, direct measurement of Ca++ is now readily available in although the rate of decline also contributes to the develop- PICUs. ment of symptoms. Estimations of Ca++ correcting for protein binding are not appropriate for managing critical illness. Hormonal Regulation of Calcium The causes of hypocalcemia are summarized in Box 73.8. Hormonal control of calcium homeostasis involves PTH, Reduced PTH effect can result from parathyroid gland vitamin D, and calcitonin. Secretion of PTH by the parathy- failure (autoimmune or surgical or radiotherapy thyroidec- roid chief cell varies inversely with the serum Ca++ and is tomy),214-216 insensitivity to PTH (pseudohypoparathyroid- inhibited by hypomagnesemia and 1,25(OH)2-vitamin D. ism), or suppression of PTH release (hypomagnesemia, Rapid proteolytic degradation of PTH yields a physiologically maternal hypocalcemia, burns). Hyperphosphatemia is fre- inactive C-terminal fragment and an active NH2-terminal quently present. Clinical features may be distinguishing, but fragment. PTH binds to cell surface receptors in bone osteo- measurement of immunoreactive PTH is diagnostic. blasts and kidney and exerts its effects through binding of a Reduced vitamin D effect results from vitamin D deficiency subunit of a membrane-associated heterotrimeric protein, seen in malabsorption in enteric diseases217-219 or impaired which mediates increased formation of cyclic adenosine conversion of 25(OH) to 1,25 (diOH) vitamin D seen in renal 3′,5′-monophosphate. insufficiency. Certain drugs such as phenytoin can increase In the kidney, PTH inhibits proximal tubular phosphate vitamin D metabolic degradation and cause deficiency. reabsorption and promotes phosphaturia. This loss of phos- Infusion of large amounts of citrate-preserved blood and phate inhibits bone mineralization and tends to shift the flow acute phosphorus overload or retention can rapidly deplete of calcium from bone to the ECF. PTH also increases distal ECF Ca++. Various drugs, particularly loop diuretics, also tubular reabsorption of filtered calcium. PTH stimulates contribute to the development of hypocalcemia (see Box 1α-hydroxylation of 25(OH)-vitamin D, resulting in produc- 73.8).220-221 tion of metabolically active 1,25(diOH)-vitamin D that stimulates intestinal absorption of calcium and phosphate. The Treatment overall effect of PTH is to raise serum calcium levels and lower Correction of hypocalcemia should be preceded by consider- serum phosphate levels. This characteristic reciprocal rela- ation of readily treated or confounding factors such as respira- tionship is helpful in distinguishing PTH disorders from those tory alkalemia. Rapid development of hyperphosphatemia involving vitamin D alone.209 suggests acute renal failure, cell lysis, or excessive supply. As

appropriate, efforts should be made to reduce serum phos- BOX 73–8 Causes of Hypocalcemia phate levels, because intravenous calcium therapy may cause Reduced PTH Effect metastatic deposition of calcium phosphate salts. Hypomag- Parathyroid Gland Failure nesemia impairs PTH release, response to PTH, and, conse- Hypoparathyroidism—idiopathic or autoimmune quently, correction of hypocalcemia. Hypomagnesemia may Trauma develop in critically ill patients by several mechanisms previ- Postsurgery Post–131I therapy ously discussed. Infarction Urgency of therapy is determined by the child’s clinical Infiltration (eg, sarcoid hemosiderosis) status. Asymptomatic hypocalcemia is appropriately treated with oral calcium salts and vitamin D if needed. For the seri- Insensitivity to PTH ously ill patient with overt or evolving hypocalcemia, replace- Pseudohypoparathyroidism Hypomagnesemia ment therapy is accomplished with IV calcium chloride, 5 to 20 mg/kg, or an equivalent calcium gluconate infusion. Poten- Suppression of PTH Release tial bradycardia and asystole with infusion of calcium should Hypomagnesemia be anticipated with cardiac monitoring and atropine readily Neonatal, resulting from maternal hypercalcemia Burns available. Care is required to prevent tissue damage by extrava- Sepsis sation or precipitation with concomitantly administered Drugs bicarbonate. In patients receiving digitalis, IV calcium is • Aminoglycosides particularly dangerous as the arrhythmia potential is great. • Cimetidine Hyperkalemia in digitalis toxicity should be treated with anti- • Cisplatin • β-Adrenergic blockers digitalis FAB therapy and not IV calcium infusion. Oral administration of calcium salts is efficient for control of Reduced Vitamin D Effect most persistent hypocalcemia and is preferable to prolonged Vitamin D Deficiency infusion (although some patients with DiGeorge hypocalcemia Dietary insufficiency require aggressive multi-modal treatment). Liberal amounts Increased losses related to: Malabsorption can be administered orally (eg, calcium 50 mg/kg/day in 4–5 Nephrotic syndrome divided doses), with attention paid to the differing calcium Phenytoin, phenobarbital content of various oral preparations. For patients with fat Impaired Activation of Vitamin D malabsorption, supplementation of calcium therapy with Renal disease magnesium or vitamin D may be needed. In the setting of Hypoparathyroidism hypoparathyroidism secondary to magnesium depletion, mag- Liver failure nesium replenishment must occur. Rhabdomyolysis Changes in Ca++ Binding or Chelation Hypercalcemia Alkalosis Respiratory alkalosis In contrast to dramatic manifestations of hypocalcemia, the Bicarbonate infusion effects of hypercalcemia may be subtle. However, a serum total calcium greater than 15 mg/dL represents a medical emer- Hyperphosphatemia Renal failure gency. Renal, cardiovascular, and CNS disturbances predomi- Phosphate administration (eg, high-phosphate formulas, enemas) nate and reflect both the degree and duration of calcium Chemotherapy elevation. Increased filtered load of calcium creates hypercal- Rhabdomyolysis ciuria and accompanying polyuria, reduced concentrating Malignancy ability, dehydration, and eventual renal lithiasis. Hypertension Pancreatitis Fat embolism is common, mediated through increased renin production Transfusion with citrate-preserved blood and peripheral vasoconstriction. Alterations in the cardiac conduction system include a shortened QT interval and a Drug/Toxins tendency to dysrhythmias. Impaired nerve conduction creates Glucagon Mithramycin hypotonia, hyporeflexia, and paresis in severe cases. Changes Calcitonin in CNS function include lethargy, confusion, and even coma. EDTA Constipation, anorexia, and abdominal pain resulting from Protamine reduced intestinal motility are frequent. Promotion of gastrin Sodium fluoride Colchicine release by calcium may account for an increased incidence of Theophylline peptic ulcer disease. Soft tissue deposition of calcium phos- Ethylene glycol phate can impair function of lungs, kidneys, cardiac conduction tissue, blood vessels, and joints. EDTA, ethylenediamine tetraacetic acid. In the absence of hyperproteinemia, determination of elevated serum total calcium levels reliably indicates increased Ca++ concentrations. Because hyperparathyroidism and malignancies are less common in children, the pediatric intensivist encounters hypercalcemia less frequently. Diagnos- tic possibilities may be approached by considering the underlying mechanisms of hypercalcemia as outlined in Table 73.3.

nin (10 U/kg IV every 4–6 hours), mithramycin (25 mg/kg IV TABLE 73.3 Tumor Lysis Syndrome over 4 hours), and indomethacin (1 mg/kg/day). Recombi- High risk Lymphoid malignancies, large tumor nant calcitonin blocks PTH-induced bone resorption, facili- mass, B-cell lymphoma concurrent tates calciuria, is relatively nontoxic, and has peak effect by 1 renal compromise hour. Mithramycin is a toxic antibiotic that inhibits osteoclas- Initiating event Cytolytic chemotherapy tic activity but has potential adverse effects including throm- bocytopenia, hepatotoxicity, and renal injury. Indomethacin is Radiation therapy useful when excessive prostaglandin E2 production is sus- Embolic tumor infarction pected as in some cases of malignancy hypercalcemia. Prophylaxis Hydration, urinary alkalinization, Bisphosphonates have been used successfully in pediatrics allopurinol for treatment of various disorders including hypercalce- 227-229 Gradual chemotherapy initiation, mia. Corticosteroids are useful for treatment of vitamin rasburicase D–related hypercalcemia, although the onset of action is not Serious disturbances Hyperkalemia, hypocalcemia, acidosis, rapid. renal failure, hyperuricemia, hyperphosphatemia Phosphorus Management Obsessive electrolyte monitoring, Virtually all of plasma phosphorus is in the inorganic form, Hemodialysis available stat, CVVHD with a small organic component composed entirely of phos- helpful, may not be adequate pholipids bound to protein. Serum levels vary with age; approximate normal values (specific to the analytical instru- CVVHD, continuous venovenous hemodialysis; stat, immediately. ment) are 4.8 to 8.2 mg/dL for neonates, 3.8 to 6.5 mg/dL for children aged 1 week to 3 years, 3.7 to 5.5 mg/dL for children aged 3 years to 12 years, and 2.9 to 5 mg/dL for adolescents Increased bone resorption reflects excess PTH effect, immo- aged 12 to 19 years.230 Differences are thought to be related to bilization, or bone lysis by metastatic malignancy. PTH- more rapid rates of skeletal growth in the pediatric popula- mediated hypercalcemia is distinguished by a depressed serum tion. Most total body phosphorus resides in bone. As much as phosphate concentration, decreased renal tubular reabsorp- 60% to 80% of ingested phosphorus is absorbed, primarily in tion of phosphate (TmPO4/GFR), and an iPTH level inap- the jejunum. Absorption occurs by two pathways, one passive propriately elevated for the simultaneous serum Ca++. In and one active. Passive paracellular transport is nonsaturable, the child with hyperparathyroidism, evaluation for multiple so the greater the dietary intake, the higher is the net absorp- endocrine neoplasias is warranted. Heightened vitamin D tion. Active transport accounts for only 20% of total absorp- effect is manifested by increased intestinal calcium absorption tion via a vitamin D–dependent transporter, the Na-dependent and can be related to vitamin D intoxication,222,223 increased phosphorus transporter 2b (NPT2b). Increased excretion of sensitivity to vitamin D, or ectopically produced 1,25(diOH)- phosphorus from the kidneys after increased dietary intake vitamin D, as seen in sarcoidosis. Serum phosphate levels is dependent on inhibition of the Na-phosphorus cotrans- and TmPO4/GFR ratios are normal or increased, and iPTH porters 2a and 2c (NPT2a and NPT2c) in the luminal levels are suppressed in these disorders. Detection of an ele- membrane of the proximal tubule. These transporters are vated 25(OH)-vitamin D level may be helpful. High levels of inhibited from increased secretion of fibroblast growth factor vitamin A can also cause hypercalcemia and are particularly 23 (FGF23). FGF23 is secreted by osteocytes and osteoblasts likely in patients with excessive intake or those with renal in response to oral phosphorus loading or an increase in insufficiency.224,225 serum 1,25 dihydroxy vitamin D levels. FGF23 induces an Decreased excretion of calcium occurs with dehydration or increase in the fractional excretion of phosphorus in the treatment with thiazide diuretics, aggravating the severity of proximal tubule and decreases the efficiency of phosphorus hypercalcemia in hyperparathyroidism. Familial hypocalciu- absorption in the gut by lowering 1,25 vitamin D levels. PTH ric hypercalcemia, an autosomal dominant disorder resulting is also stimulated by increased intake of phosphorus by the from partially deactivating mutations in the Ca++-sensing fall in ionized calcium induced by transient hyperphosphate- receptor, is characterized by normal to slightly elevated iPTH mia. Increased PTH causes a decrease in the expression of levels and decreased urinary calcium excretion.226 Thus deter- NPT2a and NPT2c in proximal tubules.231 Absorption may mination of serum Ca++, phosphate, iPTH, vitamin D levels, also be decreased by a high calcium intake or by ingestion of and urinary calcium and phosphate excretion allows differen- antacids such as calcium carbonate or acetate, which bind tiation of most hypercalcemic disorders. phosphorus in the bowel. Glucose competitively inhibits phosphorus reabsorption. Glucocorticoids produce phospha- Treatment turia by a decrease in sodium-dependent transport in the A serum calcium level greater than 15 mg/dLc may be life proximal tubule. threatening and requires direct Ca-lowering therapy in addi- Phosphorus plays an important role in cellular structure tion to attention to the underlying disorder. Hydration with and function, bone mineralization, and urinary acid excretion. isotonic saline (200 to 250 mL/kg/day) and furosemide diure- The development of severe phosphorus depletion affects sis results in calciuresis and amelioration of hypercalcemia in the availability of intracellular ATP, depletes the erythrocyte the majority of cases. Excessive losses of sodium, potassium, of 2,3-diphosphoglycerate (2,3-DPG), with resultant tissue magnesium, and phosphate may require replacement. hypoxia, and impairs urinary acid excretion. The major acute Adjunct therapy is directed at the specific cause of hyper- effect of hyperphosphatemia is hypocalcemia; the long-term calcemia. Drugs that inhibit bone resorption include calcito- consequence is soft tissue calcification.232

decomposes organic compounds within the cell with Hypophosphatemia subsequent movement of inorganic phosphorus from ICF to Hypophosphatemia as measured by serum or plasma levels ECF and excretion in the urine. Osmotic diuresis augments may or may not indicate true phosphorus deficiency. Severely these losses. Decreased intake also commonly occurs. During depressed levels of serum-measurable phosphorus may occur treatment of DKA, renal phosphorus clearance generally in the absence of true deficiency after transcellular shifts from increases with fluid administration. In addition, insulin the ECF to the ICF, whereas a moderate phosphorus deficiency therapy results in stimulation of glycolysis and anabolism may be indicated only by slightly decreased serum levels.233 with a shift of phosphorus back to the ICF. If the acidosis has Other processes that lead to true hypophosphatemia include been present for only a few days, then rarely is there a severe increased excretion from the kidneys and decreased intestinal phosphorus deficiency. Although levels may decrease, they absorption. Hypophosphatemia may also result from a com- generally return to normal without extra phosphorus therapy. bination of these three mechanisms. Moderate hypophospha- In the patient whose symptoms have been present for a temia has been defined as levels between 1.5 and 2.5 mg/dL number of days to weeks, however, severe deficiency may and severe hypophosphatemia as levels less than 1.5 mg/dL on exist at the time of admission. These patients may have serum determination. In general, only with severe deficiency life-threatening complications of hypophosphatemia if they of phosphorus do multiple symptoms occur, as well as overt are not treated. In general, this subset of patients has low cell dysfunction or necrosis. Risk is greatest when superim- phosphorus levels on admission, whereas phosphorus levels posed additional cellular injury exists. are normal or increased at admission in less severely affected patients. Patients undergoing continuous renal replacement Cause of Severe Hypophosphatemia therapy (CRRT) who become hypophosphatemic may be Although numerous abnormalities may result in moderate at higher risk for mortality.242 In burn patients with >19% decreases in phosphorus levels, severe hypophosphatemia has total body surface area burns, patients receiving preemptive been associated with only a handful of clinical syndromes. infusions of intravenous (IV) phosphorus beginning at These syndromes include significant respiratory alkalosis, 24 hours after injury had less hypophosphatemia and fewer prolonged use of phosphate-deficient TPN, the nutritional complications versus those treated once hypophosphatemia refeeding syndrome, thermal burns, DKA, pharmacologic developed.243 binding of phosphorus in the gut, alcohol withdrawal, and several medications.233-235 An association with continuous Signs and Symptoms renal replacement therapy and bone recovery after renal trans- Multiple organ systems may be affected by severe hypophos- plant also has been reported.236,237 The increase in the ICF pH phatemia, including CNS, cardiac, respiratory, musculoskele- associated with acute respiratory alkalosis stimulates the tal, hematologic, renal, and hepatic abnormalities.244-251 enzymes of glycolysis, with subsequent depletion of ICF phos- Decreased diaphragmatic contractility in patients with hypo- phorus, which is replaced by an influx from the ECF space. phosphatemia with acute respiratory failure significantly Although carbon dioxide diffuses across membranes much improved as measured by transdiaphragmatic pressures more readily than bicarbonate does, metabolic alkalosis rarely during phrenic stimulation with treatment of hypophospha- produces a decrease in phosphorus levels, whereas very low temia.252 Respiratory muscle weakness in patients with hypo- levels may be seen with respiratory alkalosis.238 An absolute phosphatemia but with or without respiratory failure also has deficiency from malnutrition and transcellular shifts from the been documented and shown to normalize with phosphorus ECF to the ICF with an anabolic response to increasing caloric repletion.248,250,251,253 intake are the causes associated with TPN use.239 In the pedi- Neurologic symptoms may initially include irritability and atric population, the preterm infant is particularly susceptible. apprehension followed by weakness, peripheral neuropathy Nearly 80% of calcium-phosphorus assimilation in the fetus with numbness, and paresthesias. Dysarthria, confusion, occurs in the last trimester of pregnancy. The preterm infant obtundation, seizures, and coma may occur in more profound is therefore born deficient in total body phosphorus. When cases.246,249,254 Reports in the literature include Guillain-Barré– reasonable nutrition has been absent for even short periods like syndrome,255 diffuse slowing on electroencephalogram, or when phosphorus has not been provided in TPN, severe and congestive cardiomyopathy256 that significantly improved hypophosphatemia has occurred, associated in several cases with correction of phosphorus depletion. In dogs, decreased with the development of hypercalcemia.240 A similar situation cardiac output, decreased ventricular ejection velocity, and may occur with the refeeding of patients who have significant increased left ventricular end-diastolic pressure reversed with protein calorie malnutrition including anorexia patients.241 As phosphorus repletion. In humans, rhabdomyolysis has been previously noted, an absolute phosphorus deficiency and tran- predominantly seen in alcoholic patients, in whom subtle scellular shifts from the ECF to the ICF in the face of an myopathy was likely present, and rarely in patients with DKA anabolic response are responsible. or after TPN therapy. Decreased levels of 2,3-DPG in red Significant hypophosphatemia in burn patients during blood cells (RBCs) may depress P-50 (oxygen half-saturation their recovery phase has been associated with the presence of pressure) values so that the release of molecular oxygen to respiratory alkalosis, diuresis of initially retained sodium peripheral tissues is decreased, with resultant tissue hypoxia.244 and water, and acceleration of glycolysis.231,233 As previously Structural defects of RBCs associated with hypophosphatemia described, ECF phosphorus shifts to the ICF compartment have included rigidity and rarely hemolysis and have generally when intracellular-free phosphorus has been used in phos- occurred when additional metabolic stresses such as metabolic phorylation of organic compounds such as occurs during acidosis or infection were placed on the RBC. Decreased glycolysis, oxidative phosphorylation, glycogenolysis, and syn- levels of ATP in neutrophils may result in decreased chemo- thesis of glycogen, protein, and phosphocreatine. Acidosis taxis, phagocytosis, and bacterial killing.257 The mechanisms

Downloaded for Anonymous User (n/a) at Walter Reed National Military Medical Center from ClinicalKey.com by Elsevier on December 26, 2018. For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved. 1024 Section V Renal, Fluids, Electrolytes underlying the development of metabolic acidosis include in hyperphosphatemia in multiple infants,266 and severe decreased phosphorus excretion that thereby limits titratable hyperphosphatemia has been reported related to use of lipo- acid excretion and decreased ammonia levels. somal amphotericin B.267 Tumor lysis syndrome represents an additional cause of Treatment hyperphosphatemia along with hyperkalemia, acidosis, hypo- As with other minerals and electrolytes, when oral therapy is calcemia, and renal failure. It results from induced lysis of potentially possible it is the preferable route for administra- tumor cells and is always a concern in a child with a lymphoid tion. In patients with severe hypophosphatemia, IV therapy is malignancy and substantial cellular mass, but it can occur in often indicated, though there remain no evidence-based rec- a variety of settings (see also Chapter 94). Initial chemother- ommendations for IV replacement.258-260 Few data exist in the apy or radiation of B-cell lymphoma is particularly likely to pediatric literature regarding dosage. Therefore most data are produce cell lysis and hyperphosphatemia along with hyper- extrapolated from adult literature.260-263 Reasonable recom- uricemia, acute renal failure (ARF), hyperkalemia, metabolic mendations in children with severe phosphorus depletion are acidosis, and hypocalcemia. Aggressive hydration and careful to use 0.15 to 0.33 mmol/kg per dose, given as a continuous initiation of chemotherapy usually will result in a manageable infusion over 4 to 6 hours. Subsequent doses are generally degree of electrolyte abnormality. Urinary alkalinization to calculated on the basis of response to this initial dosage. Either increase urate solubility is usually recommended but is being potassium or sodium phosphate may be administered with the reexamined. Rasburicase is replacing allopurinol in the control attendant potential complications of hypernatremia or hyper- of urate levels. Hemodialysis or CRRT is an essential resource kalemia. A common recommendation is to use potassium to have available if managing such a patient (see Table 73.2). phosphate if potassium (K) is <4 meq/L and sodium phosphate if the K is >4 meq/L. Other potential complications of Signs and Symptoms therapy include hyperphosphatemia, metastatic deposition of The major clinical consequence of severe hyperphosphatemia calcium phosphate, hypocalcemia, potential nephrocalcinosis is its associated hypocalcemia, as well as soft tissue deposition with renal failure, and hypotension. Both sodium and potas- of calcium phosphate salts. Seizures, coma, and cardiac arrest sium phosphate contain 3 mmol of phosphate per mL and 4 have been reported, generally in the presence of both hypo- or 4.5 mEq of sodium or potassium, respectively. For oral calcemia and hyperphosphatemia. In one case report, however, administration, a combination product of sodium with potas- seizures, malignant ventricular arrhythmias, and cardiac sium phosphate (Neutra-Phos) has been used commonly in arrest with acute hyperphosphatemia alone were described.268 children. One capsule supplies 8 mmol of phosphorus along Hyperphosphatemia may be a proximate cause of ARF via with 7.1 mEq of sodium and potassium. Capsules can be precipitation in renal tissue.269,270 reconstituted in water as well. In infants the IV preparations may be used enterally with smaller volumes needed. Hypo- Treatment phosphatemia associated with continuous renal replacement In patients with life-threatening complications or multiple therapy provides a special case. IV replacement is required in additional electrolyte disturbances or in the presence of renal many such patients.236 failure, dialysis may be required. Intravenous fluid loading to increase renal phosphorus losses and intravenous calcium may increase excretion. Mannitol diuresis will inhibit proxi- Hyperphosphatemia mal phosphorus reabsorption and theoretically should expe- dite phosphaturia. If oral administration is possible, Sevelamer Causes of Hyperphosphatemia has been used in patients with TLS to bind phosphorus and Acute and chronic renal failure with decreased phosphorus perhaps decrease the need for more invasive therapy.271 excretion are the most common causes of hyperphosphatemia, with elevation in serum phosphorus occurring when the GFR is less than 30 mL/min/1.73 m2. Extreme hyperphospha- K e y R eferences temia associated with several deaths has been reported from 1. Kaplan L, Kellum J, et al. Fluids, pH, ions and electrolytes. Curr Opin the use of either oral sodium phosphate or enemas containing Crit Care. 2010;16:323-331. 264,265 sodium phosphate in infants and children. Abnormalities 5. Kannan L, Lodha R, Vivekanandhan S, et al. Intravenous fluid regimen of intestinal anatomy or motility predisposing to retention of and hyponatraemia among children: a randomized controlled trial. enemas or renal insufficiency represent risk factors, but no risk Peidatr Nephrol. 2010;25:2303-2309. 8. Friedman JN, Beck CE, DeGroot J, et al. Comparison of isotonic and factors are identified in 30% of reported patients. Previous hypotonic intravenous maintenance fluids: a randomized clinical trial. treatment does not guarantee safety with these agents, as 30% JAMA Pediatr. 2015;10:1001. of reported patients had previously received enemas or oral 9. Mastorakos G, Weber JS, Magiakou MA, et al. Hypothalamic-pituitary- therapy without complications. Average time to recognition adrenal axis activation and stimulation of systemic vasopressin secretion has ranged from 12 minutes to 24 hours, with mean of 6.53 by recombinant interleukin-6 in humans: potential implications for the syndrome of inappropriate vasopressin secretion. J Clin Endocrinol hours. Mean phosphorus levels were 27.9 mg/dL with plasma Metab. 1994;79:934-939. total calcium mean of 4.95 mg/dL. Unless there was kidney 10. Park SJ, Shin JI, et al. Inflammation and hyponatremia: an underrecog- disease when older children and adolescents have also been nized condition? Korean J Pediatr. 2013;56:519-522. affected, all reported patients have been <5 years of age.264 The 13. Caironi P, Tognoni G, Masson S, et al. Albumin replacement in patients with severe sepsis or septic shock. N Engl J Med. 2014;370:1412-1421. administration of IV boluses of sodium or potassium phos- 25. Arikan AA, Zappitelli M, Goldstein SL, et al. 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