chapter 73 - fluid and electrolyte issues in pediatric

1007

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

C h a p t e r

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intraoperative fluids influence acid-base and electrolyte status, particularly of vulnerable patients.4 The choice of Na+ content and balancing ions of IVF for postoperative or critical care maintenance may be important for some patients thus justify-ing additional expense. Clearly 0.18 and 0.225 mM saline is associated with a higher incidence of mild hyponatremia,5,6 although controlled trials do not show this effect for 0.46 mM saline.7,8 Severe hyponatremia has been associated with pul-monary or CNS illness in pediatrics and is infrequent even within those categories, with the exception of children with traumatic brain injury (TBI). Among patients with those and other illnesses, the evolving study of the influence of inflam-matory mediators directly on the hypothalamus and indirectly on vasopressin secretion may further clarify which patients are at most risk of clinically significant hyponatremia.9,10

Evidence for and against the use of colloids in specific groups of critical patients is accumulating. Intriguing but less than definitive studies suggest benefit in severe sepsis11-14 and possible harm in patients with TBI, perhaps associated with increased intracranial pressure.15 Consideration of albumin use in selected patients remains appropriate.16,17 Albumin does appear useful in stabilizing patients with severe hepatic failure and in prevention of hepatorenal syndrome.18-20

Evidence for albumin use with or without diuresis among those with acute respiratory distress syndrome (ARDS) sug-gests improved oxygenation but minimal effect on outcomes.21 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 25% may be useful in temporarily redistributing ECF volume from the extravascular to the intravascular space to facilitate organ perfusion and spontaneous or drug-assisted diuresis with minimal additional infused fluid volume. There are cur-rently no formulations of hydroxyethyl starch that can be recommended for use in critically ill patients.22,23

Adult and pediatric studies have raised concern regarding damaging effects of fluid volume overload particularly in patients with sepsis or ARDS.24,25 Patients with less fluid gain early in their illness have more ventilator-free days and shorter ICU stays than those with greater than 10% to 15% early posi-tive fluid balance. It remains unclear if mortality rates are affected.26-29

This effect of fluid volume on morbidity and perhaps mor-tality has led to proposals of a phased approach to fluid man-agement including aggressive resuscitation using appropriate

PEAR LS• HypotonicmaintenanceIVfluidsareassociatedwithmildto

moderatehyponatremiainpostoperativepatients.Anesthesia,stress,andinflammatorymediatorsprobablycontribute.Electrolytemonitoringinpatientsatriskisessentialfordetectionandmanagementoftheoccasionalpatientwhodevelopsseverehyponatremia.ThiscriticaleffectofthesyndromeofinappropriateantidiuretichormonemayoccureveninpatientsonisotonicIVfluids.

• Medicalpatientswithhighlevelsofinflammatorymediatorsappeartobeatincreasedriskofsignificanthyponatremia.Interleukineffectsonantidiuretichormonereleasemaycontribute.

• Albumininfusionshavebeengenerallysafebutmayintroduceincreasedmortalityriskinpatientswithtraumaticbraininjury.Thosegivenalbuminhadincreasedintracranialpressure,whichmaycontributetotheapparentrisk.

• Aftersepticpatientsachievehemodynamicstabilization,avoidingorcorrectingexcessivefluidvolumeoverloadwillassistinliberatingpatientsfromventilatorsandtheintensivecareunit.

• Protonpumpinhibitorsmaycausehypomagnesemia,particularlyinpatientsonconcurrentdiuretics.Althoughusuallymild,thismaybeofsignificanceincriticallyvulnerablepatients.

OverviewTraditional fluid and electrolyte management in critical illness is being refined by science, observations of clinical experience, and expert opinion. Particular attention is drawn to intrave-nous fluid (IVF) composition, appropriate uses and choices of colloids, extracellular fluid (ECF) volume targets from resuscitation to maintenance, and approaches to removal of excessive ECF volume using diuresis, continuous renal replace-ment therapy (CRRT), and intermittent hemodialysis (IHD).

Fluid and electrolyte management often begins at resuscita-tion, but important choices are also made at anesthesia induc-tion and at initial postoperative maintenance. Resuscitative normal saline imposes an acid load, largely related to the chloride content.1 Although physiologically effective and cost effective in almost all circumstances,2 concerns regarding chloride toxicity warrant further clarification.3 Similarly,

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1008 Section V Renal, Fluids, Electrolytes

fluids guided by careful clinical measurement and evaluation, prompt reduction of resuscitation fluid rates when hemody-namically tolerated, gradual correction of volume excesses using fluid restriction, colloid dosing to adjust fluid space distribution, continuous infusion diuresis, and CRRT or IHD when needed.30-33

As ICU patients progress from stabilization to maintenance, ECF volume overload may spontaneously resolve, or it may warrant active intervention due to the association of persisting major overload with increased morbidity. Loop diuretics do not prevent or ameliorate acute kidney injury34 but may be useful in mobilizing excess ECF volume.35 Studies of this measure are variable as to dosages, patient diagnoses, and renal conditions. Carefully titrated continuous infusion of loop diuretics may be superior to bolus dosing.36-39 In ARDS, continuous infusion plus albumin have enhanced fluid mobilization.40-42 Careful studies of approaches to fluid removal are needed. Accompanying loss of K+, Ca++, and Mg++ should be anticipated and replaced appropriately. For patients unresponsive to diuresis, either CRRT or IHD can provide electrolyte management and gradual ECF fluid correction43-45 (see also Chapter 78).

SodiumSodium distribution is 90% extracellular and, with its associ-ated anions, largely determines the osmotic condition of the extracellular fluid (ECF). Disturbance of ECF osmolality affects cell volume with critical clinical significance in the central nervous system (CNS). Neurologic symptoms, there-fore, dominate the clinical picture in both hyponatremia and hypernatremia. In pediatric patients in the intensive care unit (ICU), young age, underlying neurologic conditions, develop-mental delay, cerebral hypoperfusion, and medication effects may obscure subtle neurologic findings, and judicious labora-tory monitoring along with careful clinical assessment is essential.

Emerging evidence in both adult and pediatric patients sug-gests an association between disturbances in sodium balance and adverse outcomes, including mortality, ICU length of stay (LOS), use of both noninvasive and invasive mechanical ven-tilation, and long-term neurologic sequelae.46-52 It is unclear at this time whether these adverse effects are a direct conse-quence of the sodium imbalance, are a reflection of a greater severity of illness, or are related to other underlying pathologic processes. Mild disturbances of sodium may serve as a warning of an ongoing process of greater significance. More severe hyponatremia or hypernatremia may be life threatening.53 These disturbances may result from the disproportionate gain or loss of either sodium or water. Pathologic sodium retention may occur in disorders such as congestive heart failure (CHF), cirrhosis, and nephrotic syndrome without causing a signifi-cant change in ECF concentration, but the concomitant expansion of the ECF volume may be damaging.

HyponatremiaSudden, severe hyponatremia is life threatening, and its man-agement demands prompt, measured action with ongoing monitoring and therapeutic adjustment. The syndrome of inappropriate antidiuretic hormone secretion (SIADH) and cerebral salt wasting (CSW) are the most common causes of

severe hyponatremia, although gross feeding or iatrogenic misadventures also should be considered. Severe hyponatre-mia, which is variably defined as a serum sodium concentra-tion of either <125 mEq/L or <120 mEq/L, is uncommon and is usually associated with known risk factors such as pul-monary or CNS disease or injury or the use of certain drugs. Mild hyponatremia is common among hospitalized pediatric patients and occurs predictably in postoperative patients. Patients with renal, hepatic, or cardiac disease and those exposed to prolonged general anesthesia are particularly at risk. Accurate identification of patients at risk will inform decisions on frequency of laboratory monitoring and will allow an early evaluation of and response to evolving hypo-natremia, whether related to water retention or sodium excretion.

Pathophysiology and EtiologyHyponatremia may occur in the presence of decreased, increased, or normal amounts of total body sodium.

Decreased Total Body SodiumLoss 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) release may overwhelm osmotic ADH control, maintaining water retention despite hyponatremia and hypoosmolality. A decrease of as little as 5% in circulating volume may be suf-ficient to trigger this response.54 Sodium deficit and volume loss may occur through extrarenal or renal losses. In children, extrarenal losses most often occur from vomiting and diar-rhea. In critically ill patients, large extrarenal losses may result from fluid sequestration that occurs with septicemia, perito-nitis, pancreatitis, ileus, rhabdomyolysis, ventriculostomy drains, and burns. Renal losses include diuretic use, osmotic diuresis, various salt-losing renal diseases, CSW, and adrenal insufficiency.55

Renal Sodium LossesRenal salt-wasting states are generally identified by a urinary sodium excretion in excess of 20 mEq/L and a fractional excretion (FENa) of more than 1%. The use of thiazide diuret-ics can exacerbate hyponatremia and hypovolemia and lead to a characteristic hypokalemic metabolic alkalosis (ie, “contrac-tion alkalosis”). In normally functioning kidneys, concen-trated urine is produced by the equilibration of fluid in the collecting tubules with the hyperosmotic medullary intersti-tium, which in turn is generated by sodium chloride (NaCl) reabsorption without water in the ascending limb of the loop of Henle. Thiazides act in the cortical distal tubule and do not impair the ability of ADH to increase water reabsorption in the collecting tubules and collecting duct,56 resulting in thiazide-associated hyponatremia. Osmotic sodium and water losses occur in a child with uncontrolled hyperglycemia with glucosuria, with mannitol use, and during urea diuresis fol-lowing relief of urinary tract obstruction. Hyperglycemia and mannitol, in addition to inducing urinary sodium and water losses, produce osmotic water movement from the intracel-lular fluid (ICF) to the extracellular fluid (ECF), further low-ering serum sodium. Sodium levels drop about 1.5 mEq/L for every 100 mg/dL rise in blood glucose level. Significant salt wasting may occur with several intrinsic renal diseases (Box 73.1). Adrenal insufficiency is distinguished by hyponatremia


Chapter 73 1009Fluid and Electrolyte Issues in Pediatric Critical Illness

kidneys is another postulated mechanism.61 Distinguishing CSW from SIADH may be difficult in many complex clinical scenarios. In cases of severe or symptomatic hyponatremia, however, this may be temporarily unnecessary because the initial therapy is the same.57 Administration of enough con-centrated sodium to result in a small increase in osmolality is appropriate, and support of intravascular volume is required. A reasonable approach might begin with the administration of 5 mL/kg of hypertonic (3%) NaCl followed by isotonic repletion of the remaining volume deficit. Once this is achieved, sufficient sodium and fluid administration to account for daily maintenance requirements as well as ongoing losses is necessary. Administration of fludrocortisone, a min-eralocorticoid, has been reported to aid in CSW management in severe or prolonged cases that are refractory to initial therapy.61 In less severe cases, infusion of isotonic saline rep-resents a reasonable first step in management, and the observed response may help to differentiate between CSW and SIADH. In CSW, saline administration addresses volume depletion and hyponatremia. It is of limited or no benefit in patients with SIADH, who are more effectively managed with fluid

in association with hyperkalemia and decreased urinary potassium excretion.

Cerebral Salt WastingCerebral salt wasting (CSW) is a clinical entity that continues to generate controversy. First described by Peters and cowork-ers in 1950, it was superseded by the description of SIADH 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 low blood volumes.57 Despite lingering skepticism, its distinct clinical identity continues to be supported (Table 73.1).58-61 Patients typically have an acute neurologic injury with hemor-rhage, trauma, infection, or a mass and may have undergone neurosurgical procedures. CSW differs from SIADH in that large urine volumes contain very high sodium concentrations, leading to rapid depletion of both sodium and ECF volume (Table 73.2). An otherwise unexplained intravascular volume contraction is central to the diagnosis and may cause a sec-ondary boost in ADH release. Left untreated, CSW results in intravascular volume depletion, hypotension, and hypoperfu-sion or hypovolemic shock as well as hyponatremia. Untreated SIADH, in contrast, leads to progressive hyponatremia and the clinical consequences thereof with maintenance or mild expansion of fluid balance. The pathophysiologic link between intracranial injury and renal salt wasting has yet to be eluci-dated, contributing in no small part to the controversy. Both brain natriuretic peptide (BNP) and atrial natriuretic peptide (ANP) are attractive as potential mediators, but neither has a proved etiologic role.62,63 Decreased sympathetic input to the

BOX 73.1 CausesofHyponatremia

Decreased Total Body SodiumExtrarenalVomiting/diarrheaSequestration:sepsis,peritonitis,pancreatitis,rhabdomyolysis,

ileusCutaneous:burns,cysticfibrosisVentriculostomydrainage

RenalCerebral-renalsaltwasting(CRSW)DiureticsThiazides,loopdiuretics(listedinorderofseverityofsaltwasting)Osmoticdiureticagents:mannitol,glucose,ureaTubulointerstitialdiseasesMedullarycysticdisease,obstructiveuropathy,tubulointerstitial

nephritis,chronicpyelonephritis,renaltubularacidosis,Kearns-Sayresyndrome

AdrenalinsufficiencyCongenitaladrenalhyperplasia,AddisondiseaseAdrenalinsufficiencyCongenitaladrenalhyperplasia,Addisondisease

Increased Total Body SodiumCongestiveheartfailureCirrhosisNephroticsyndromeAdvancedrenalfailure

Normal Total Body SodiumSyndromeofinappropriateantidiuretichormonesecretion(SIADH)GlucocorticoiddeficiencyHypothyroidismInfantilewaterintoxicationAbusivewaterintoxication

TABLE 73.1 Cerebral-RenalSalt-WastingSyndrome

Cerebral Salt Wasting Syndrome

Trigger Acuteintracranialinjuryorillness(subarachnoidhemorrhage,trauma,etc.)

Onset Typicallyafewdaysaftertheinjuryoccurs

Signs FallingserumNa+,highurineoutput,highurineNa+

Course Withouttreatment,proceedstointravascularvolumedepletion,hypotension,andhypoperfusion

Treatment Replacesaltandwaterlosses;mayrequire3%NaCl+/−loopdiuretics;fludrocortisoneinrefractorycases

Resolution Daystoweeks

Differentialdiagnosis Syndromeofinappropriateantidiuretichormone(SIADH),adrenalinsufficiency,osmoticdiuresis

TABLE 73.2 CerebralSaltWasting(CSW)VersusSyndromeof

InappropriateAntidiureticHormone(SIADH)

CSW SIADH

UrineNa+ Veryhigh,often>100mEq/L

Variable,butusually>30mEq/L

Urineoutput Inappropriatelyhigh,leadingtovolumedepletion

Variable;maybenormalordecreased

Responsetosalinechallenge

ImprovementinvolumedeficitandserumNa+

Noimprovement

Responsetofluidandsaltrestriction

Noimprovement;volumedeficitandhyponatremiamayworsen

ImprovementinserumNa+



efforts to maintain sodium balance. Edema develops when larger quantities of sodium are ingested than can be excreted. The ability to excrete water is also impaired, primarily because of the progressive decrease in GFR. Hyponatremia occurs when water intake exceeds insensible losses plus the maximum volume that can be excreted.

Normal Total Body SodiumHyponatremia without evidence of hypovolemia or edema in the pediatric population is usually associated with SIADH. Renal concentrating and diluting ability ultimately depends on the presence or absence of ADH to modulate water perme-ability in the collecting duct. Osmoreceptors for ADH reside in the anterior hypothalamus, responding to changes of as little as 1% in plasma osmolality. The nonosmotic stimuli that induce release of ADH are associated with changes in auto-nomic neural tone due to physical pain or trauma, emotional stress, hypoxia, cardiac failure, nausea and vomiting, adrenal insufficiency, volume depletion, and exposure to general anes-thesia (Box 73.2). Nonosmotic stimuli, as the name implies, are active even in the face of normal plasma osmolality, and a decrease in plasma volume of as little as 5% is sufficient to trigger a strong ADH response.54 Vasopressin (ADH) synthe-sized in the hypothalamus is transported in neurosecretory granules to the axonal bulbs in the median eminence and posterior pituitary gland and is released by exocytosis in the presence of appropriate stimuli. Increasing evidence indicates that inflammatory mediators facilitate release and contribute to the high incidence of hyponatremia in Rocky Mountain spotted fever, Kawasaki, and other inflammatory illnesses.10 After release, ADH binds to V2 receptors in the basolateral membrane of the renal collecting duct, increasing cyclic adenosine 3′,5′-monophosphate formation and facilitating phosphorylation of aquaporin-2. Incorporation of aquaporin-2-containing vesicles in the apical (luminal) membrane increases cell permeability to water and provides a pathway for water reabsorption.69

Clinically, SIADH is characterized by (1) hyponatremia, (2) euvolemia or mild hypervolemia, (3) hypoosmolality, (4) inappropriately elevated urine osmolality, and (5) elevated urine sodium concentration. It has been associated with several categories of clinical disease, including CNS and pul-monary disorders, malignancies, and as an adverse effect of numerous drugs (Box 73.2).70 Underlying renal function is normal. Under normal physiologic conditions, a decrease in serum sodium of 4 to 5 mEq/L below normal (with a serum osmolality of less than 270 mOsm) should maximally inhibit ADH secretion with a resultant urine osmolality of less than 100 mOsm. It is frequently difficult to determine, however, whether urine osmolality and urine sodium are inappropri-ately elevated, particularly in critically ill patients receiving IV fluids. Variable sodium and water administration rates, iso-tonic or hypertonic fluid boluses, fluctuations in hemody-namic status and urine output, and a history of diuretic use can all confound laboratory interpretation. The key consider-ation is the relative relationship between the degree of hypo-natremia and hypoosmolality and the robustness of the dilutional response in the urine. Failure to maximally dilute urine in the face of hypoosmolality represents inappropriate ADH response so that a urine osmolality of 200 to 250 mOsm may reflect SIADH in hyponatremic patients. The urinary sodium level is generally more than 30 mEq/L but may be

restriction.59 Throughout, the absolutely essential part of therapy is the frequent reassessment of sodium levels and volume status with treatment adjustments as indicated.

Increased Total Body SodiumHyponatremia with increased total body sodium occurs when the increase in total body water exceeds the sodium retention. Four clinical situations are commonly seen: congestive heart failure, cirrhosis, nephrotic syndrome, and advanced renal failure. In all four conditions, hyponatremia tends to be mild or moderate, asymptomatic, and nonprogressive or slowly progressive. These patients typically present to the ICU pri-marily for care related to these underlying conditions rather than for symptoms related to hyponatremia.

Congestive Heart FailureHyponatremia in heart failure is associated with a worse prog-nosis.64,65 Low cardiac output states are characterized by a decrease in effective circulating volume that is detected by vasoreceptors in the carotid sinus, the aortic arch, and the renal juxtaglomerular apparatus. Activation of various neuro-hormonal modulators promotes vasoconstriction along with sodium and water retention. Increased sympathetic activity and stimulation of the renin-angiotensin-aldosterone system (RAAS) produce increased afferent and efferent arteriolar vas-cular resistance and decreased glomerular filtration rate (GFR) with a resultant decrease in urinary sodium excretion. Non-osmotic ADH release is stimulated, further impairing water excretion. In addition, decreased aldosterone degradation, along with altered levels of other vasoactive and nonvasoactive substances, leads to a primary increase in tubular sodium reabsorption. A deleterious positive feedback loop is created, in which the vasoconstrictive and fluid retentive effects of these neurohormonal systems promote further vasoconstric-tion and worsening renal perfusion.66 The complex interac-tions between renal and cardiovascular pathophysiology have been described as the “cardiorenal syndromes” with five sub-types based on the primary organ affected and the acuity of the physiologic derangement.67

CirrhosisEarly in cirrhosis, increased intrahepatic pressure may initiate renal sodium retention before ascites formation. The develop-ment of portal hypertension leads to nitric oxide–mediated peripheral vasodilation and to the formation of arteriovenous fistulae. The result is a decrease in effective circulating volume. These decompensated patients have higher levels of renin, aldosterone, ADH, and norepinephrine than do compensated patients with cirrhosis. Hyponatremia arises in the setting of persistent renal sodium and water retention.68

Nephrotic SyndromeHyponatremia is an occasional finding in patients with nephrotic syndrome. It may be present, however, in patients with apparently normal or decreased central volume. The humoral factors involved in patients with decreased central volume appear to be similar to those with decompensated cirrhosis.

Renal FailureAs a diseased kidney loses nephrons, the remaining nephrons exhibit a dramatically elevated fractional sodium excretion in



Signs and SymptomsThe severity of signs and symptoms depends on the rapidity of the development of hyponatremia. Neurologic symptoms predominate as plasma hypoosmolality causes a shift in fluid from the ECF to the ICF compartment, leading to generalized cellular swelling. The rigidity of the intracranial space leaves little room for cellular expansion, resulting in increasing intra-cranial pressure. Brain cells prevent massive swelling in the early phases of hyponatremia by extrusion of electrolytes and other cellular osmolytes. Acute decreases in sodium concen-tration are associated with lethargy, apathy, and disorienta-tion, often accompanied by nausea, vomiting, and muscle cramps. No predictable correlation exists between the degree of hyponatremia and its resultant symptoms, as severe hypo-natremia that develops gradually may present with minimal symptoms. Acute decreases in sodium to less than 120 mEq/L, however, generally produce severe symptoms such as seizures or coma. Other findings may include decreased deep tendon reflexes, pathologic reflexes, pseudobulbar palsy, and a Cheyne-Stokes respiratory pattern. Cerebral edema and intracranial hypertension may be severe enough to result in herniation, permanent neurologic injury, and death.72

TreatmentPreventionStimuli for ADH release are frequently present in both surgical and nonsurgical ICU patients, putting them at risk for hypo-natremia. Use of hypotonic intravenous (IV) maintenance fluids increases the risk for development of hyponatremia. The appropriate administration of isotonic IV fluids in these patients will decrease the incidence of hyponatremia.73-78 For patients with severe SIADH or CSW, however, the use of isotonic fluids alone may not be adequate to prevent life-threatening disturbances in sodium and water balance. Thoughtful monitoring of sodium levels along with avoidance of large volumes of hypotonic fluids is mandatory.

TherapyThe time course over which hyponatremia develops is a key determinant of the therapeutic approach. Severe hyponatre-mia is associated with significant morbidity and mortality and requires urgent attention. As described previously, acute hyponatremia produces significant cerebral edema when initial compensation mechanisms are overwhelmed and more chronic adaptive mechanisms are not yet fully developed. Hyponatremia that has been present less than 4 hours can safely be corrected promptly. When the evolution of hypona-tremia is gradual, however, brain cells respond adaptively to prevent cerebral edema.

Thus there are two essential questions in constructing a therapeutic plan: (1) Did hyponatremia evolve rapidly or slowly, and (2) does the patient have CNS symptoms or imaging suggestive of cerebral edema? CNS cellular swelling and its symptoms are more likely with acute hyponatremia or with severe chronic hyponatremia.79,80 Symptomatic hypona-tremia that develops suddenly—that is, in fewer than 4 hours—can be rapidly reversed without incurring risk. If asymptomatic hyponatremia has developed over many hours, days, or weeks (ie, chronic hyponatremia), a gradual, conser-vative approach is likely to be uncomplicated. Symptomatic chronic hyponatremia, on the other hand, requires a small but

BOX 73.2 NonosmoticStimuliAssociatedWithSyndromeof

InappropriateAntidiureticHormone

CNS DisordersInfectionMeningitisEncephalitis,includingHIV/AIDSencephalitisBrainabscessRockyMountainspottedfeverMasslesionsSubarachnoidorsubduralhemorrhageCerebralthrombosisorhemorrhageBraintumorsHeadtraumawithcerebraledemaHydrocephalusCavernoussinusthrombosisOtherGuillain-BarrésyndromeMultiplesclerosisHypoxicencephalopathy,includingneonatalhypoxic-ischemic

encephalopathy(HIE)PituitarydiseaseAcutepsychosis

Pulmonary DiseaseInfectionBacterialandviralpneumoniasPulmonaryabscessTuberculosisAspergillosisAsthmaRespiratoryfailurewithpositivepressureventilation

TumorsCarcinomasofthelung,oropharynx,gastrointestinaltract

(includingthepancreas),andgenitourinarytractLymphoma,thymomaEwingsarcoma,mesothelioma

DrugsAntidiuretichormoneanalogs(vasopressin,desmopressin/1-

deamino-8-D-argininevasopressin[DDAVP],oxytocin)VincristineSalicylatesChlorpropamideCyclophosphamideCarbamazepineBarbituratesColchicineHaloperidolFluphenazineTricyclicantidepressantsandselectiveserotoninreuptakeinhibitors

(SSRIs)ClofibrateIndomethacinandnonsteroidalantiinflammatorydrugs(NSAIDs)InterferonEcstasy(3,4-methylenedioxy-methamphetamine[MDMA])

MiscellaneousHighlevelsofinflammatorymediatorsgeneralanesthesiaNausea/vomitingPainoremotionalstressGeneralanesthesiaMarathonrunningorenduranceexerciseHereditary(gain-of-functionmutationsinthevasopressinV2

receptor)

much less in patients who are provided a low sodium intake.71 When the urinary sodium concentration is very high, it is the net balance between intake and output that differentiates between SIADH and a renal salt-wasting syndrome. Renal salt wasting is favored when the urinary sodium excretion grossly exceeds sodium intake.



mortality or ICU length of stay, however, is currently lacking. Conivaptan is an intravenous ADH V1 and V2 receptor antag-onist that is approved for the treatment of euvolemic and hypervolemic hyponatremia in adults.100 Tolvaptan, an oral ADH V2 receptor antagonist, was approved in 2009 as therapy for euvolemic or hypervolemic hyponatremia in adult patients with heart failure, cirrhosis, or SIADH.99 Pediatric usage of the ADH receptor blockers has been reported in the settings of SIADH and cardiac disease,99-103 but further study of kinetics, safety, and efficacy will be needed to clarify the clinical role in pediatrics.

HypernatremiaAs with hyponatremia, hypernatremia can develop with low, normal, or high levels of total body sodium. History and weights are particularly important in evaluating the hydration state of patients with hypernatremia because a shift in the ICF to the ECF tends to obscure the physical findings of dehydra-tion. Accurate assessment of total body sodium and water aids considerably in planning management, although the most important management principle is the frequent monitoring of the patient’s progress with treatment adjustments as needed.

Pathophysiology and EtiologyLow Total Body SodiumPatients with a low total body sodium level have a loss of water in relative excess of sodium losses. Because the ECF space is hyperosmolar, water movement from the ICF occurs with resulting cellular dehydration. The ECF space, therefore, is somewhat preserved until an extreme degree of hypovolemia is present. Losses of sodium and water may be extrarenal or renal (see Box 73.3).

In the pediatric patient, extrarenal losses are commonly seen from vomiting and diarrhea, although hospital-acquired hypernatremia from insufficient free water administration is

rapid increase in serum sodium to stabilize or begin to reverse cerebral swelling and to avoid impending herniation, followed by a more gradual correction to normalize sodium balance. An increase of 5 mEq/L is usually sufficient to halt the prog-ress of symptomatic cerebral edema and can be achieved with an initial bolus of 5 to 6 mL/kg of 3% saline. The subsequent correction rate for patients with either acute symptomatic hyponatremia or any chronic hyponatremia should not exceed 0.5 mEq/L/h. In acute hyponatremia without CNS symptoms, rates of 0.7 to 1 mEq/L/h have been reported without patient morbidity or mortality. A regimen of hypertonic 3% saline infused at 1 to 2 mL/kg/h with intermittent administration of a loop diuretic results in an appropriate correction for those patients for whom “rapid” correction is safe. Further correc-tion may require isotonic fluids or a mixture of isotonic and hypertonic fluids, particularly in patients with CSW. In resis-tant, severe CSW, mineralocorticoid (fludrocortisone) treat-ment has been helpful in several reports.61,81,82 Other protocol approaches are available.83

Prolonged hyponatremia in animal studies is notable for a striking decrease in total brain amino acid content as well as lower brain water content.84 When this brain cell adaptation has occurred, a rapid rise in serum sodium concentration may induce a shift of water from the ICF to the ECF compartment, resulting in brain dehydration, brain injury, and the osmotic demyelination syndrome (ODS).85 Both central pontine and extrapontine myelinolysis have been reported in children.86-89 Extrapontine sites include the cerebellum, thalamus, basal nuclei, hippocampus, midbrain, and subcortical white matter.41 Traditional risk factors for ODS include chronic alco-holism, malnutrition, and rapid correction of hyponatremia.90 Osmotic demyelination can occur, however, without hypona-tremia as a starting point.88,89,91 Large bolus doses of hyper-tonic saline may place the patient at risk regardless of starting sodium concentration. Electrolyte fluctuations around the 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 hyponatremia on admission, including one case in an 18-month-old child.87,89 Even rapid correction of hypernatre-mia is a possible cause of myelinolysis and suggests that pres-sure effects may be capable of causing damage to myelinated structures. Symptoms of osmotic demyelination may include obtundation, quadriplegia, pseudobulbar palsy, tremor, amnesia, seizures, and coma.93,94 Classically, the clinical pre-sentation is that of a brief period of recovery from encepha-lopathy followed by emergence of a “locked in” state or various movement disorders.90 When CNS symptoms concerning for ODS emerge during therapy, long-term neurologic sequelae may be avoided by decreasing serum sodium to its nadir fol-lowed by a slower rate of correction.95-97

In cases of SIADH where fluid restriction is a feasible option, a decrease in fluid intake, occasionally with the use of oral sodium supplements, may be all that is required to nor-malize serum sodium gradually and safely. In a patient with hypovolemia, volume status clearly must be corrected in addition to the hyponatremia. Patients with SIADH or fluid-retaining states may respond to treatment with an ADH recep-tor antagonist. This receptor blocker group increases urine volume and reduces urine osmolality, creating a water diuresis that leads to an increase in serum sodium concentration.98,99 Evidence for improvement in other clinical outcomes such as

BOX 73.3 CausesofHypernatremia

Decreased Total Body SodiumExtrarenalVomiting/diarrhea,excessivesweatingAdministrationof70%sorbitol

RenalOsmoticdiuresis:mannitol,glucose,urea

InadequateIntakeInsufficientlactation

Normal Total Body SodiumExtrarenalRespiratoryinsensiblewaterlossesCutaneousinsensiblewaterlossesFever,burns,phototherapyRadiantwarmers,especiallywithprematureinfants

RenalDiabetesinsipidus(DI)CentralDINephrogenicDIHypodipsia(resetosmostat)

Increased Total Body SodiumAdministrationoringestionoflargesodiumloadsImproperlydilutedformula



a major concern.104,105 Renal causes include osmotic diuresis from mannitol, hyperglycemia, or increased urea excretion. Infants are particularly susceptible to hypernatremic dehydra-tion due to their high surface area/weight ratio and their rela-tive renal immaturity, which necessitates greater water losses for excretion of a solute load compared with older children and adults.106 Insufficient maternal lactation places young infants at risk of hypernatremic dehydration.

Normal Total Body SodiumLoss of water occurs without excessive sodium losses in some conditions. Extrarenal losses include (1) increased respiratory losses as may occur with tachypnea, hyperventilation, or mechanical ventilation with inadequate humidification and (2) transcutaneous losses associated with fever, burns, extreme prematurity, or use of phototherapy or radiant warmers in the neonate without adequate water replacement. Renal losses result from congenital or acquired diabetes insipidus (DI), either central or nephrogenic. Acquired forms of DI are more commonly seen in the ICU. Major insults resulting in central DI include head trauma, tumors, infections, hypoxic brain injury, neurosurgical procedures, and nontraumatic brain death. Classically, in experimental animals and in humans, three stages occur: (1) an initial polyuric phase (hours to several days), (2) a period of antidiuresis probably due to ADH release from injured axons (hours to days), and (3) a second period of polyuria that may or may not resolve.107,108 Sudden onset of polyuria is characteristic, and the conscious patient will often experience a concomitant polydipsia. In the critically ill patient, the inability to access increased water intake—whether from altered mental status, impaired thirst regulation, or other causes—may result in life-threatening hypernatre-mia.109 Patients with the rare congenital forms of nephrogenic DI, resulting from X-linked alteration of the ADH V2 receptor 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.

Increased Total Body SodiumHypernatremia with an increased total body sodium level is most often an iatrogenic problem. In the ICU, hypertonic solutions of sodium bicarbonate are administered during resuscitation efforts or as therapy for intractable metabolic acidosis, excessive hypertonic saline administration, ingestion by infants of improperly diluted formula, and dialysis against a high sodium concentration. Normonatremic patients with massive edema who undergo a forced diuresis frequently become mildly hypernatremic because the induced urine may be hypotonic, with water loss exceeding sodium loss.

Hypernatremia is intentionally induced in patients with traumatic brain injury as a form of osmotherapy for control of intracranial hypertension associated with cerebral edema.111,112 Such patients have tolerated serum sodium as high as 175 mEq/L when carefully managed. When the ECF osmolality of these patients is manipulated, the risks involved with rapid changes in either direction must be kept in mind (see also Chapter 119).

Signs and SymptomsClinical manifestations of hypernatremia, as is the case with hyponatremia, relate predominantly to the CNS. Marked irri-tability, a high-pitched cry, altered sensorium varying from

BOX 73.4 CausesofDiabetesInsipidus

CentralCongenitalArgininevasopressin(AVP)antidiuretichormone(ADH)gene

mutations,autosomaldominantor(rarely)autosomalrecessiveinheritance

Idiopathic(30%to50%ofcases)

AcquiredHeadtrauma,orbitaltraumaTumors,suprasellarandintrasellarEncephalitisMeningitisGuillain-BarrésyndromeHypoxicinjury,includingneonatalhypoxic-ischemic

encephalopathy(HIE)PostneurosurgicalproceduresCerebralaneurysms,thrombosis,hemorrhageHistiocytosisGranulomasNontraumaticbraindeath

NephrogenicCongenitalVR2mutation,X-linkedAQP-2mutation

AcquiredChronicrenalfailureRenaltubulointerstitialdiseasesHypercalcemiaK+depletionDrugsAlcohol,lithium,diuretics,amphotericinB,methoxyflurane,

demeclocyclineSicklecelldiseaseDietaryabnormalitiesPrimarypolydipsiaDecreasedsodiumchlorideintakeSevereproteinrestrictionordepletion

lethargy to coma, increased muscle tone, and overt seizure activity may occur in children with the development of severe hypernatremia over 48 hours or more. Hyperglycemia and hypocalcemia also may occur. In infants with acute hyperna-tremia, vomiting, fever, respiratory distress, spasticity, tonic-clonic seizures, and coma are common. Death from respiratory failure occurred in experimental animals when serum osmo-lality approached 430 mOsm/kg.113 Mortality in children with severe hypernatremia has ranged from 10% to 45% with chronic and acute hypernatremia, respectively.

Anatomic changes seen with the hyperosmolar state include loss of volume of brain cells with resultant tearing of cerebral vessels, capillary and venous congestion, subcortical or sub-arachnoid bleeding, and venous sinus thrombosis. During the first 4 hours of experimental acute hypernatremia, brain water significantly decreases, while the concentration of solutes (electrolytes and glucose) increases.114 This leads to a partial restitution of brain volume within a few hours’ time. Over several days, brain volume normalizes as a result of intra-cellular accumulation of organic osmolytes consisting of polyols, amino acids, and methylamines.108,115

TreatmentWhenever possible, therapy of hypernatremia should address correction of the underlying disease process as a primary goal.



Changes in extracellular or intracellular K+ concentration may alter the critical transmembrane potential of cardiac, skeletal, or smooth muscle cells with serious results.

Hypokalemia is relatively common in pediatric intensive care unit (PICU) patients but generally is detectable and man-ageable.121 Severe hyperkalemia is much less frequent but much more likely to be life threatening with minimal warning.

Factors involved in total body distribution include acid-base status, insulin, catecholamines, magnesium, and aldosterone.122-125 Acidemia tends to increase the serum potassium, and alkalemia lowers it. The type of acid-base disturbance (metabolic or respiratory), the duration of the disturbance, and the nature of the anion accompanying the hydrogen ion in metabolic acidosis are important in deter-mining what effect a particular acid-base disorder may have on potassium concentration.

Diabetic ketoacidosis (DKA) may occasionally present with severe hypokalemia126 due to losses. Hyperosmolality and decreased circulating insulin will preserve or even elevate serum K+ in most cases.127,128 Epinephrine, albuterol,129 and other beta-agonists decrease serum potassium, moving it into cells. β-adrenergic blocking drugs abolish this effect. Change in intracellular magnesium (Mg++) may affect the sodium-potassium adenosine triphosphatase (ATPase) pump and alter the transcellular distribution. All of these mechanisms, however, are generally representative of fine-tuning in potas-sium homeostasis. Ultimately, potassium balance is regulated through excretion by the kidney and to a lesser extent the gastrointestinal (GI) tract. Massive cell lysis may overwhelm these and require aggressive management of the sudden shift of intracellular K into the ECF, particularly in the presence of compromised renal function.

Most of the filtered potassium is absorbed before the distal nephron in normal kidneys. The potassium excreted in the urine then is mainly due to secretion in the distal convoluted tubule and cortical collecting duct. As with sodium, the kid-ney’s capacity to vary potassium excretion is profound, ranging from a low of approximately 5 mEq/L to amounts exceeding 100 mEq/L of urine. Factors influencing renal potassium excretion include mineralocorticoid and glucocorticoid hor-mones, acid-base balance, anion effects, tubular fluid flow rate, sodium intake, potassium intake, ICF and plasma potas-sium concentrations, and diuretics.130 Aldosterone is a major kaliuretic hormone. Metabolic acidosis decreases and meta-bolic alkalosis increases intracellular potassium activity in cells of the distal tubule, causing enhanced potassium secre-tion during alkalosis and reabsorption during acidosis. Fluid delivery to the distal tubule probably enhances potassium secretion by two mechanisms: (1) the faster fluid moves past the secretory site, and a greater amount of potassium can be secreted, and (2) because tubular fluid potassium concentra-tion decreases as flow rate increases, a favorable gradient for potassium movement is maintained at high flow rates.

Hypokalemia

Causes of HypokalemiaHypokalemia Without Potassium DeficitThe detection of a low serum potassium level may reflect a true deficit in total body stores or an apparent deficit from the shift of this ion from the ECF to the ICF pool. A shift to the

Correction of dehydration with slow hypernatremia correc-tion is the target. When sodium exceeds 165 mEq/L, isotonic fluid or colloid may be used for correction of shock or circula-tory collapse and initial reversal of hypernatremia. When hypernatremia has been present for more than a few hours, the presence of intracellular organic osmolytes dictates a slow rate of correction. Numerous fatal cases of cerebral edema and herniation have occurred with correction over a 24-hour period, leading to recommendations for correction over no less than 48 hours.116,117 There is general agreement that plasma osmolality should not be decreased more rapidly than 2 mOsm/h, correlating with a rate of sodium decline that does not exceed 1 mEq/h. In cases of very severe or long-standing hypernatremia, a more conservative correction rate of 1 mOsm/h (0.5 mEq/hr of sodium) may be appropriate. Thus, normalization from extreme hypernatremia may take several days. This slower rate of correction appears to allow time for dissipation of the organic osmolytes without development of cerebral edema. Estimated deficits, ongoing maintenance requirements, and additional excessive losses must be accounted for in calculations of the amount of fluid replace-ment required.

Central DI is a likely cause of hypernatremia in an ICU patient with high urine volume and low urine osmolality, particularly in patients who have head trauma or who have undergone a recent intracranial operation. In these patients, a trial of vasopressin is in order. Either aqueous vasopressin given subcutaneously or intravenously (0.5 to 10 milliunits/kg/h) or 1-deamino-8-D-arginine vasopressin (DDAVP) given orally or intranasally may be used. Oral dosing is limited to tablet form at this time with a recommended dosing range of 0.05 to 0.4 mg administered twice daily. Intranasal DDAVP is generally begun in a dosage ranging from 0.05 to 0.1 mL once or twice daily. An increase in urine osmolality to values exceed-ing that in serum after vasopressin administration supports the diagnosis of central DI. Hyponatremia has been reported after vasopressin administration in patients with central DI as well as in patients receiving vasopressin for hemodynamic support and for bleeding disorders in the perioperative period.118,119 In the outpatient setting, symptomatic hypona-tremia, including seizures and altered mental status, has been reported in patients receiving DDAVP for enuresis, particu-larly in periods of intercurrent illness or with excess fluid intake.120 Careful attention to the IV fluid prescription, serial monitoring of sodium levels, and timely adjustment in therapy are necessary to avoid severe complications in patients receiv-ing any type of vasopressin therapy.

In patients with an increased total body sodium level and, often, hypervolemia, the goal is sodium removal. In patients with intact renal function, sodium removal may be accom-plished with diuretics and a decrease in sodium administra-tion. If renal failure is present, dialysis may be required.

PotassiumThe total body K+ of about 50 mEq/kg is divided with about 98% being intracellular. The transmembrane concentration gradient is large with the intracellular concentration of 150 mEq/L being maintained by sodium-potassium adenos-ine triphosphatase (Na+/K+-ATPase) pumps. The resultant transmembrane potential is normally tightly regulated but physiologically dynamic in contractile or conductive cells.



Concomitant volume depletion and metabolic alkalosis asso-ciated with NaCl and hydrogen ion losses often result in sec-ondary aldosteronism, however, and an increased filtered load of bicarbonate with resultant renal potassium losses. Diarrhea, regardless of cause, may result in large potassium losses, the amount lost being related to the volume of fluid lost. Other GI causes are listed in Box 73.5.

Signs and SymptomsFor the intensivist, cardiovascular and neuromuscular effects of potassium deficiency are of particular concern, although metabolic, hormonal, and renal effects may also occur.

Electrocardiographic (ECG) changes include T-wave flat-tening or inversion, ST depression, and the appearance of a U wave. Resting membrane potential is increased, as are both the duration of the action potential and the refractory period. The decreased conductivity predisposes to arrhythmias, as do increased threshold potential and automaticity.143

Hypokalemia diminishes skeletal muscular excitability. This can present as a dynamic ileus or a skeletal muscle weakness resembling Guillain-Barré syndrome. It can eventually affect the trunk and upper extremities, becoming severe enough to result in quadriplegia and respiratory failure.144 Hypokalemia can lead to severe rhabdomyolysis in a variety of underlying conditions,145-148 and may progress to ARF and hyperkale-mia.149 Autonomic insufficiency may also occur, generally manifested as orthostatic hypotension. In patients with severe liver disease, hypokalemia may precipitate or exacerbate encephalopathy. Glucose intolerance in the presence of primary hyperaldosteronism and in certain patients receiving

ICF pool may occur in alkalemia,131 administered or endoge-nous release of beta-agonist,129,132 familial or thyrotoxic peri-odic paralysis,133,134 barium poisoning,135 and excess insulin. In the case of alkalemia, potassium moves into the cell in exchange for H+ in an attempt to maintain extracellular pH. The pedi-atric patient with alkalemia may have a true potassium deficit in addition due to decreased potassium intake or increased losses.

Periodic paralysis is a rare autosomal dominant disorder presenting with intermittent episodes of profound muscle weakness associated with a sudden fall in serum potassium concentration precipitated high-carbohydrate/low-potassium diet, exercise, infection, stress, or alcohol ingestion. Barium poisoning can produce hypokalemic weakness and paralysis, probably by competitive blockade of inward rectifying K+ channels. Insulin shifts potassium into muscle and liver cells in association with glycogen formation.

Hypokalemia With Potassium DeficitA deficit in total body potassium may occur from decreased intake, from renal losses, or from GI losses. GI loss occurs with pyloric stenosis or other persistent vomiting, diarrhea, or binding of enteric K+ by ingested clay in patients with pica.136

RenalLossesMajor categories seen in the ICU include loop, thiazide, and osmotic diuretics, renal tubular acidosis, hyperaldosteronism, magnesium deficiency, and recovery from acute renal failure (ARF). Osmotic diuresis from glucosuria can cause severe renal potassium wasting in prolonged DKA predisposing to ventricular arrhythmia. The severity of K+ loss may be masked 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-ism137,138 are rare in children and even rarer in the pediatric ICU setting. Secondary hyperaldosteronism is common, however, either from volume depletion or from CHF, cirrho-sis, or nephrotic syndrome. Patients with the latter conditions, however, rarely have severe hypokalemia unless they are addi-tionally treated with diuretics. Infants with Bartter or Gitel-man syndrome139 may initially come to the ICU because of multiple metabolic derangements including hypokalemia, metabolic alkalosis, hypomagnesemia, and hyperuricemia. Other findings include weakness, polyuria, and failure to thrive, with elevated renin and aldosterone levels in the absence of hypertension. Additional conditions associated with elevated renin secretion, secondary hyperaldosteronism, and hypokalemia include renal artery stenosis, malignant hypertension, renin-producing tumor, or Wilms tumor. Addi-tional mechanisms include secondary hyperaldosteronism and increased distal tubular fluid delivery.

Other agents that induce excessive renal losses include amphotericin B (kaliuresis with reduced renal function and tubular injury); aminoglycosides, particularly gentamicin; and high-dose penicillin and carbenicillin, which produce an osmotic load in addition to acting as non-reabsorbable anions. Renal tubular acidosis, hypomagnesemia, and caffeine toxicity may cause renal potassium wasting.140-142

GastrointestinalLossesUpper GI losses from vomiting or from nasogastric (NG) suction are frequently associated with hypokalemia. The gastric concentration of potassium ranges from 5 to 10 mEq/L.

BOX 73.5 CausesofHypokalemia

HypokalemiawithoutpotassiumdeficitAlkalosisβ-agonist,exogenousorendogenousFamilialperiodicparalysisThyrotoxicperiodicparalysisBariumpoisoningExcessiveinsulin

HypokalemiawithpotassiumdeficitDecreaseintakeRenallossesHyperaldosteronismPrimaryorsecondaryBarter,Liddle,GitelmansyndromeLaxativeordiureticabuseLicoriceingestionOsmoticagents

DrugsCaffeineDiureticsAmphotericinBAminoglycosidesHigh-dosepenicillin,carbenicillin

MiscellaneousHypomagnesemiaRenaltubularacidosisToluenetoxicity

ExtrarenallossesGastrointestinal

Vomiting,nasogastricsuctionDiarrheaLaxativeabuseUreteralsigmoidostomyObstructedorlongilealloop



RedistributionIn general, when extracellular pH falls, potassium exits from cells; the result is an increase in serum potassium. As men-tioned earlier, metabolic acidosis from mineral acids has a more pronounced effect than that of organic acids. Respira-tory acidosis does not usually cause a marked change in potas-sium concentration.

Hypertonicity per se produces a shift of potassium from ICF to ECF. Studies of anephric animals show potassium increasing by 0.1 to 0.6 mEq/L for each increment of 10 mOsm/kg H2O in tonicity. Hypertonicity causes cellular dehydration and therefore an increase in ICF potassium that favors increased passive diffusion out of cells. A very small percentage shift of IC potassium delivers a significant potas-sium load to the ECF. In the hyperkalemic patient in the ICU who has acute oliguria, mannitol should not be used for diure-sis as further K+ elevation may result. In the patient with hyperglycemia, hypertonicity is likely only one of several mechanisms resulting in elevated serum levels.

thiazide diuretics has been corrected with potassium reple-tion. Renal effects of hypokalemia include polyuria and poly-dipsia, renal structural changes and functional deterioration with cellular vacuolization in the proximal tubule, and occa-sional interstitial fibrosis.

TreatmentBecause of the wide spectrum of abnormalities resulting from marked potassium depletion, judicious correction is generally in order. In most pediatric ICUs, patients with cardiovascular disease are given NG or IV supplements at serum levels of 3 to 3.5 mEq/L. In the patient without life-threatening compli-cations, the oral route is generally preferred for treatment, if possible, because this route is rarely associated with “over-shoot” hyperkalemia if normal renal function exists. Oral dosage is frequently 1 mEq/kg up to a maximum of 20 mEq per dose, repeated if necessary. If, however, depletion is associated with digoxin use or with life-threatening complica-tions, including cardiac arrhythmias, rhabdomyolysis, extreme weakness with quadriplegia, or respiratory distress, then urgent IV therapy is generally needed. Recommendations for IV dosage in the pediatric patient have ranged from infusions of 0.25 mEq/kg/hr to those as high as 1 to 2 mEq/kg/hr in the face of severe hypokalemia associated with DKA, arrhythmias, or quadriparesis and respiratory insufficiency. Ventricular tachycardia clearly associated with hypokalemia may initially require more rapid administration. Continuous ECG moni-toring is essential, as well as frequent physical examination and determination of serum potassium levels to avoid hyper-kalemic complications. Highly concentrated K solutions given IV should only be administered centrally. Patients who receive albuterol continuously are frequently mildly hypokalemic, but they rarely warrant potassium chloride replacement.

The potential for catastrophic drug error in replacing potas-sium is real. In most pediatric ICUs, patients with cardiovas-cular disease frequently require NG or IV supplements. Steps to decrease the chance of error include satellite pharmacy dosing, use of a mandatory drug request form, NG replace-ment when possible, use of a single solution concentration for all doses, and small aliquot solution containers. Continuing education regarding this risk for the pediatric ICU staff is essential.

Hyperkalemia

CausesHyperkalemia may result from artifactual elevation; from redistribution of potassium from ICF to ECF space; or from increased intake, decreased losses, or both (Box 73.6).

ArtifactualTight, prolonged tourniquet use produces spurious potassium elevation due to potassium release from ischemic muscle. Even more common is hemolysis of red cells with potassium release associated with capillary sampling or aspiration or delivery under pressure through a small needle. The lab may note hemolysis, but artifactual normality or actual elevation should always be considered.150 Less commonly, in vitro release of potassium occurs from white blood cells (WBCs) (>100,000/uL) or platelets (>1,000,000/uL) and may result in increased levels.

BOX 73.6 CausesofHyperkalemia

ArtifactualIschemicpotassiumlossfrommuscleduetotourniquetuseInvitrohemolysis,profoundleukocytosis,thrombocytosis

DrugsDigoxintoxicity,β-blockers(b2-inhibitoryactivity),succinylcholine,

arginine,orlysinehydrochloride,chemotherapeuticagents,sodiumfluoride,epsilon-aminocaproicacid

True Potassium ExcessIncreasedLoadIVinfusion,POsupplements,potassium-containingsaltsubstitutes,

potassiumpenicillin,bloodtransfusion

Redistribution and Tissue NecrosisInvivoredcellinjuryChangeinpHHypertonicityBurns,trauma,rhabdomyolysis,intravascularcoagulationGastrointestinalbleedingTumorcelllysisReabsorptionofhematomaDiabetesmellitus,diabeticketoacidosis(DKA)

Decreased ExcretionAcuterenalfailureChronicrenalfailureMineralocorticoiddeficiency

Addisondisease21-HydroxylasedeficiencyDesmolasedeficiency3-b-OH-dehydrogenasedeficiency

Renaltubulointerstitialdisease

Renal Tubular Secretory DeficitPseudohypoaldosteronismSicklecelldiseaseSystemiclupuserythematosusRenalallograftrejectionUrinarytractobstructionVery-low-birth-weightinfants

Inhibition of Tubular SecretionDrugs

Spironolactone,triamterene,amilorideIndomethacin,convertingenzymeinhibitors,heparin,

cyclosporine,tacrolimustrimethoprim,pentamidine,amphotericinB



Several commonly used drugs result in net movement of potassium from ICF to ECF. Digoxin inhibits the net uptake of K by cells by inhibiting Na/K-ATPase, with hyperkalemia commonly occurring in severe digitalis poisoning.151 Other drugs include beta-blockers with β2 activity and the muscle relaxant succinylcholine. This drug induces a prolonged dose-related increase in the ionic permeability of muscle, with sub-sequent efflux of potassium from muscle cells. Normal serum potassium concentration rises about 0.5 mEq/L. Succinylcho-line should be avoided in patients with burns, muscle trauma, spinal injuries, certain neuromuscular diseases, near drown-ing, and closed head trauma, as up-regulated and new forms of acetylcholine receptors may respond with life-threatening hyperkalemia.152 New examples of patients at risk will con-tinue to be reported.153,154 Hyperkalemia may result in nonsus-pect patients via rhabdomyolysis or malignant hyperthermia following succinylcholine. Rhabdomyolysis has many causes including influenza, severe exercise, drugs, ischemia, and many more.155-157 Familial hyperkalemic periodic paralysis appears to be related to potassium redistribution related to changes in ion channel function. Rebound hyperkalemia may be life threatening after coma-inducing barbiturate is stopped or surgical insulinoma removal.

Increased LoadHyperkalemia due to an increased potassium load is unusual as long as renal function is normal. Serious elevations may be seen with inappropriate IV infusion, large volume blood transfusions,158 bypass circuit initiation,159 oral potassium supplements, salt substitutes containing potassium, or large doses of potassium penicillin. Strict measures to guard against accidental K overdoses are mandatory.160 Large endogenous loads of potassium are more likely in the patient who is in the ICU. The release of cellular potassium associated with tissue necrosis from burns, trauma, rhabdomyolysis including that from spider bites161 or the propofol syndrome,162,163 massive intravascular coagulopathy, rapid hemolysis, or GI bleeding may lead to hyperkalemia.

Tumor lysis syndrome (TLS) is classically associated with drug or radiation treatment of sensitive lymphoid malignan-cies and results in hyperkalemia often accompanied by hypo-calcemia, hyperphosphatemia, acidosis, and compromised renal function.164 Many fatalities have been reported. The list of TLS-producing events or therapies includes transcatheter chemical and embolic tumor necrosis, monoclonal antibody treatment with rituximab, and enzyme-inhibiting agents bort-ezomib, imatinib, and sorafinib. Cases have occurred in tumor patients with surgical stress or dexamethasone given for potential airway edema (see also Chapter 94).

Manifestations of HyperkalemiaLife-threatening complications are most likely to result from the cardiac changes caused by hyperkalemia. ECG signs include tall, peaked T waves in the precordial leads, followed by a decrease in amplitude of the R wave, bradycar-dia, widened QRS complexes, prolonged PR intervals, and decreased amplitude and disappearance of the P wave.165 Finally, the classic sine wave of hyperkalemia from the blend-ing of the QRS complex with the P wave may appear. ECG changes do not necessarily correlate with specific levels of serum K+.166 Realizing that ventricular arrhythmias or cardiac arrest may occur at any point in this progression and that

progression may occur over a matter of minutes is extremely important.

TreatmentTreatment of hyperkalemia depends on the level of plasma potassium and the state of cardiac irritability.47 If the potas-sium concentration is more than 6.5 mEq/L with associated ECG changes, additional measures are indicated. In the absence of digitalis toxicity, hyperkalemia with ECG changes should be treated with a secure and rapid IV infusion of calcium chloride or calcium gluconate. Hand injection with ECG monitoring is reasonable beginning with the administra-tion of 10 mg/kg of calcium chloride (or gluconate equiva-lent) over 1 to 5 minutes. Infusion may be stopped if the electrocardiogram has normalized or if deterioration of the electrocardiogram seems to be precipitated by the potassium, suggesting a clinical scenario more complex than simple hyperkalemia. If the electrocardiogram improves but is not normalized by this calcium dose, additional calcium chloride may be given at a lower rate. It should be anticipated that ECG changes will recur in 15 to 30 minutes unless additional mea-sures are taken immediately to treat the hyperkalemia. The effective calcium dose may be repeated as necessary to pre-serve cardiac function while additional treatments are in prog-ress. Additional, rapidly effective treatments include nebulized albuterol (rapid neb or continuous neb of 0.3 to 0.5 mg/kg) or salbutamol (IV dose of 4 to 5 µg/kg over 20 minutes and repeated after 2 hours).168,169

Insulin and glucose are also rapidly helpful in redistributing potassium to the ICF. Glucose (1 g/kg) and insulin (0.2 U/g of glucose) may be given over 15 to 30 minutes and then infused continuously with a similar amount per hour. A pre-mixed combination glucose and insulin solution has been suc-cessfully demonstrated in a 21 patient series.170 Blood glucose monitoring is essential because the relative glucose and insulin amounts may need adjustment.

Sodium bicarbonate (1–2 mEq/kg given intravenously) has been a part of the classic treatment of hyperkalemia. Its benefit, however, is more difficult to predict and slower in onset than that of the measures mentioned earlier.

Sodium polystyrene sulfonate removes potassium and may be administered while dialysis arrangements are made. Sodium polystyrene sulfonate administered rectally must be retained for 15 to 30 minutes to be effective. If the oral route is avail-able, it is generally more efficient.

Hemodialysis is the treatment of choice for removal of K+ in emergent conditions. In the patient with severely compro-mised renal function, the measures above generally allow sta-bilization of potassium long enough to institute dialysis. Although hemodialysis is much more efficient for potassium removal than peritoneal dialysis, the latter may be more quickly instituted in many centers, particularly in the small infant in whom vascular access to support reasonable blood flow may be difficult to accomplish. In the absence of renal failure, loop diuretics or thiazide diuretics or both are useful for the increase of renal excretion. If mineralocorticoid activ-ity is deficient, the administration of fludrocortisone may be indicated. In patients with severe hyperglycemia and mod-erate hyperkalemia, early steps to improve glucose control should decrease ECF potassium shifts from hyperosmolality and decrease ECF potassium shifts from hyperosmolality and decreased insulin.



the Na/K pump, allowing potassium loss from the ICF to the ECF and urinary excretion. Magnesium repletion is important to resolution of these secondary disturbances.

CausesIntensivists deal with hypomagnesemia most often in patients receiving loop diuretics or transplant immunosuppressives.174 Other causes must be considered.

Magnesium deficiency may be caused by decreased intake or increased losses. Although slight falls in serum magnesium levels may occur after 1 week of a deficient diet, a more sus-tained period of deprivation is generally necessary for signifi-cant hypomagnesemia to occur. In children, magnesium deficiency has been particularly common in protein-energy malnutrition and in anorexia nervosa, where refeeding syndrome is a particular risk.175,176 Intestinal malabsorption is a major cause of magnesium deficiency. Isolated familial primary hypomagnesemia occurs from selective malabsorp-tion of magnesium with patients generally having symptoms in infancy. These include tetany and convulsions as a result of severe hypomagnesemia with consequent hypocalcemia and respond well to supplemental magnesium. Other causes asso-ciated with magnesium malabsorption include regional enter-itis, ulcerative colitis, massive small bowel resection, generalized malabsorption syndromes, pancreatic insufficiency, and cystic fibrosis. In some, the formation of insoluble soaps due to the complexing of magnesium with unabsorbed fat is the postu-lated mechanism for hypomagnesemia.

Increasing use of induced hypothermia may increase hypo-magnesemia occurrence.177 Epidermal growth factor blocking antibodies are associated with a small incidence of induced hypomagnesemia.178,179 Hypomagnesemia may be more com-mon than appreciated in patients presenting with hematologic malignancies.180

Intrinsic renal tubular disorders associated with hypomag-nesemia are rare in the ICU setting (Box 73.7).

Drugs that induce renal magnesium wasting are more common causes and include aminoglycosides,181 cisplatin,182 amphotericin B,183 diuretics,184 cyclosporin A,185 tacrolimus,185 and proton pump inhibitors.186,187 Magnesium supplementa-tion is often needed in transplant recipients who receive cyclo-sporine or tacrolimus. Fractional excretion of magnesium and total excretion are elevated. Patients with DKA may also have marked renal magnesium wasting during the acidotic period, as well as in early treatment. An increased urine calcium level, from whatever cause, is often associated with magnesium wasting from competitive inhibition of renal tubular reab-sorption of magnesium in the ascending limb.

Signs and SymptomsIn addition to biochemical derangements associated with hypomagnesemia, a wide spectrum of other clinical disor-ders has been attributed to its depletion, including cardiac arrhythmias, increased sensitivity to digoxin, coronary spasm, hypertension, seizures, and neuromuscular derangements. Hypomagnesemic arrhythmias include ventricular premature beats, ventricular tachycardia, torsades de pointes, and ven-tricular fibrillation.188 Supraventricular arrhythmias are less common. Following magnesium infusion, improvement in resistant ventricular arrhythmias including torsades has been reported,189 although other metabolic derangements often coexist in such patients. Magnesium deficiency enhances

If the potassium is less than 6.5 mEq/L without ECG changes, discontinuation of exogenous potassium and drugs that decrease its excretion with close follow-up of potassium levels may be all that is necessary. In the patient with renal compromise, extra potassium may be eliminated with use of the potassium-binding agent sodium polystyrene sulfonate (Kayexalate, resonium) (oral, NG, or rectal doses of 1 to 2 g/kg in a sorbitol or dextrose solution). When administered rectally, sorbitol may not be necessary, and it should certainly not be given rectally in concentration greater than 20%. Highly concentrated sorbitol may cause severe proctitis and colonic injury. Increasing reports of colonic injury particu-larly in hemodynamically compromised or premature patients suggest caution be exercised in using this preparation. However, when needed, having the pharmacy stock a pre-mixed 10% to 20% suspension of sodium polystyrene sulfo-nate and sorbitol allows either oral or rectal administration on short notice.

MagnesiumMagnesium plays a key role in numerous metabolic processes, including cellular energy production, storage, and utilization involving adenosine triphosphate (ATP); the metabolism of protein, fat, and nucleic acids; and the maintenance of normal cell membrane function. It is also involved in neuromuscular transmission, cardiac excitability, and cardiovascular tone.171

Magnesium balance is maintained through intestinal absorption and renal excretion; 25% to 65% of ingested Mg is absorbed in the ileum. Absorption varies inversely with intake and is also affected by paracellular water reabsorption. Increased bowel water from any cause results in decreased magnesium absorption. Regulation of renal excretion occurs by glomerular filtration and reabsorption. The majority of filtered magnesium is reabsorbed in the ascending limb of the loop of Henle, resulting from active NaCl reabsorption and susceptible to loop diuretic inhibition. The threshold value for magnesium excretion varies between 1.5 and 2 mg/dL in dif-ferent species. Thus if serum magnesium levels fall even slightly, renal excretion dramatically decreases under normal circumstances. Primary factors that increase renal magnesium excretion include ECF volume expansion; hypermagnesemia; hypercalcemia; metabolic acidosis; phosphate depletion; and various drugs including loop and osmotic diuretics, cisplatin, aminoglycosides, cyclosporin, and digoxin. Decreased excre-tion occurs with ECF volume depletion, hypomagnesemia, hypocalcemia, hypothyroidism, and metabolic alkalosis to a lesser extent. Parathyroid hormone (PTH) may decrease mag-nesium excretion but that effect may be offset by the opposite effect of causing hypercalcemia.

HypomagnesemiaFree, ionized magnesium and intracellular magnesium may be the critical concentrations, but determination of total magne-sium is still clinically effective. Critically ill children have been reported to frequently have low ionized magnesium despite normal total magnesium levels.172 Evidence supporting oblig-atory ionized magnesium measurement remains elusive.173

Magnesium depletion may result in hypocalcemia, via sup-pression of PTH secretion. Hypokalemia also occurs in pa-tients with hypomagnesemia. Magnesium deficiency impairs



by adequate magnesium intake before development of life-threatening symptoms. The use of supplemental magnesium infusions in perinatal asphyxia177 remains to be fully tested or extended to other hypoxic-ischemic encephalopathies.

HypermagnesemiaHypermagnesemia is less common than hypomagnesemia, but they can be life threatening when extreme.194 Magnesium infusions in pediatric status asthmaticus have become common, despite remaining controversial in adult pulmonol-ogy.195 Large doses clearly produce elevated blood levels,196 but side effects are not common.

CauseHypermagnesemia occurs in patients with renal failure and is generally associated with iatrogenic administration of magne-sium as antacids, cathartics, or enemas or through total par-enteral nutrition (TPN) containing magnesium. In the absence of renal failure, the administration of large quantities of mag-nesium cathartics in the management of constipation197 or overdoses198 and antacid use with increased peritoneal absorp-tion of magnesium in the presence of a perforated viscus199 are causes. Magnesium levels as high as 10 to 12 mEq/L have been reported. Megadose vitamin-mineral supplementation, including magnesium oxide, has been fatal.200

Signs and SymptomsAcute elevations of magnesium depress the CNS and the peripheral neuromuscular junction. Pseudocoma with fixed, dilated pupils has been reported. Deep tendon reflexes are depressed at levels greater than 4 mEq/L with total disappear-ance along with flaccid quadriplegia at levels greater than 8 to 10 mEq/L. Hypotension, hypoventilation, and cardiac arrhythmias may also occur.201-204 Moderate hyperkalemia has resulted from prolonged magnesium infusions in occasional patients.

TreatmentCalcium acts as a direct antagonist to magnesium. In life-threatening situations associated with severe magnesium intoxication, intravenous calcium should be used as the initial therapy. An initial dose of calcium chloride at 10 mg/kg or an equivalent amount of calcium gluconate has been suggested for infants and children. Magnesium-containing medications obviously should be discontinued. If renal function is normal, IV furosemide may be administered to increase magnesium excretion while urine output is replaced with half-normal saline. In patients with renal failure or severe toxicity, dialysis may be necessary for removal.

CalciumHypocalcemia is a common issue in pediatric critical care.205,206 Hypercalcemia is an uncommon challenge in the PICU. Extracellular fluid (ECF) calcium concentration is best estimated with measurement of ionized calcium (Ca++) concentration. Total serum calcium includes physiologically accessible Ca++ plus that bound to protein or complexed with anions such as citrate of phosphate. The Ca++ concentration is under dual hormone control with PTH mobilizing Ca++ and calcitonin acting in bone and cartilage to retain fixed

ADH,antidiuretichormone;GM-CSF,granulocyte-macrophagecolony-stimulatingfactor;IVF,intravascularfluid;TPN,totalparenteralnutrition.

BOX 73.7 CausesofHypomagnesemia

DecreasedintakeLowMg++TPN,IVF,eatingdisorders

IncreasedlossesGastrointestinalMalabsorptionFamilialprimaryhypomagnesemiaSmallboweldiseaseRegionalenteritis,ulcerativecolitis,massivebowelresectionPancreaticinsufficiency,pancreatitisCysticfibrosis

RenalCongenitalrenalmagnesiumwastingDiffusetubulardisordersHypophosphatemiaDrugs:aminoglycosides,cisplatin,amphotericinB,diuretics,

cyclosporine,tacrolimus,pentamidine,foscarnet,GM-CSFHypercalciuriaDiabeticketoacidosisBartersyndromeHyperaldosteronismInappropriateADHsecretion

MiscellaneousEpinephrine,β-agonistsThyrotoxicosisCitratedbloodtransfusion(massive)BurnsAlcoholism

myocardial cell uptake of digoxin and toxicity. Both inhibit Na/K-ATPase with resultant ICF potassium depletion.

Depletion is thought to contribute to the development or worsening of hypertension by increasing vascular smooth muscle tone and reactivity. Increased cellular influx of calcium and decreased reuptake by sarcoplasmic reticula occur; the result is increased cytosolic calcium for activation of actin-myosin contractile proteins. Similar effects in coronary and cerebral vessels have also been observed.

Seizures may be the first symptom noted in an ICU setting. Other neuromuscular changes may include tremors, fascicula-tions, spontaneous carpopedal spasm, muscle cramps, pares-thesias, seizures, and coma.190,191,192 Personality changes, including apathetic behavior and depression, have also been associated.

TreatmentPatients undergoing or at immediate risk of hypomagnesemic malignant ventricular arrhythmias (such as torsades) or sei-zures can be given magnesium sulfate intravenously with careful monitoring. An IV infusion of 25 to 50 mg/kg per dose diluted to 10 mg/mL can be administered over 15 to 60 minutes. The rate of infusion should not exceed 150 mg/min. Doses may be repeated as needed depending on patient response. Complications of parenteral magnesium therapy include neuromuscular and respiratory depression, rare arrhythmias, flushing, hypotension, and prolonged bleeding times.193 Other routes of therapy include intramuscular mag-nesium sulfate, injections of which are painful, and oral therapy with magnesium oxide or citrate. In situations known to be associated with the development of hypomagnesemia, it seems particularly important to attempt to avoid deficiency



Hyperphosphatemia lowers Ca++ by chelation, by shifting the equilibrium in calcium flux from ECF toward bone and by inhibiting 1α–hydroxylation activity. Calcitonin is a 32-amino acid, calcium-lowering hormone elaborated by C cells of the thyroid in response to rising Ca++ levels.210 Although it rapidly reduces the bone resorptive function of osteoclasts and promotes calciuria and phosphaturia, its excess or absence causes no known disorder.

Hypocalcemia

Clinical and Laboratory ConcernsHypocalcemia in pediatric critical illness may be associated with PTH deficiency, hypercalcitoninemia, or hypomagnese-mia. Multiple mechanisms may act simultaneously. In chil-dren with severe burns, hypocalcemia, magnesium depletion, hypoparathyroidism, and renal resistance to PTH may all develop.

Cardiovascular manifestations are of particular ICU concern and may include hypotension, myocardial depression, CHF, and dysrhythmias. Cardiac contractility may be compro-mised acutely as in postoperative hypocalcemia. However, subacute cardiac myopathy from vitamin D deficiency and hypocalcemia may also be life threatening and reversible.211-213

Hypocalcemia inhibits acetylcholine release in both sensory and motor nerves. Accordingly, a variety of peripheral and CNS effects may result, including seizures, tetany, carpopedal spasms, muscle cramps and twitching, paresthesias, laryngeal stridor, and apnea in the newborn.

Somatic changes accompanying prolonged hypocalcemia include dry coarse skin, eczematous dermatitis, brittle hair with areas of alopecia, brittle nails with smooth transverse grooves, and dental enamel hypoplasia.

Determination of the free ionized Ca++ level is diagnostic, although the rate of decline also contributes to the develop-ment of symptoms. Estimations of Ca++ correcting for protein binding are not appropriate for managing critical illness.

The causes of hypocalcemia are summarized in Box 73.8.Reduced PTH effect can result from parathyroid gland

failure (autoimmune or surgical or radiotherapy thyroidec-tomy),214-216 insensitivity to PTH (pseudohypoparathyroid-ism), or suppression of PTH release (hypomagnesemia, maternal hypocalcemia, burns). Hyperphosphatemia is fre-quently present. Clinical features may be distinguishing, but measurement of immunoreactive PTH is diagnostic.

Reduced vitamin D effect results from vitamin D deficiency seen in malabsorption in enteric diseases217-219 or impaired conversion of 25(OH) to 1,25 (diOH) vitamin D seen in renal insufficiency. Certain drugs such as phenytoin can increase vitamin D metabolic degradation and cause deficiency.

Infusion of large amounts of citrate-preserved blood and acute phosphorus overload or retention can rapidly deplete ECF Ca++. Various drugs, particularly loop diuretics, also contribute to the development of hypocalcemia (see Box 73.8).220-221

TreatmentCorrection of hypocalcemia should be preceded by consider-ation of readily treated or confounding factors such as respira-tory alkalemia. Rapid development of hyperphosphatemia suggests acute renal failure, cell lysis, or excessive supply. As

calcium. The concentration of Ca++ is particularly critical for cardiac, vasomotor, and neurologic function but is susceptible to disturbance by many factors including drugs, sepsis, major surgery, enteric disease, malignancy, pancreatitis, endocrinop-athy, genetic misfortune, and many others.

Entry of Ca++ into cardiac and skeletal muscle cell mediates conversion of electrochemical into mechanical energy with resultant muscle contraction. Adenylate cyclase, phosphodies-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 (enhanced by α-adrenergic and inhibited by β-adrenergic stimuli) causes vasoconstriction. Ca++ also plays a critical role in the clotting system and various membrane transport systems.

Extracellular Ca++ is monitored by Ca++-sensing recep-tors207,208 on the surface of the chief cells of the parathyroid glands, the juxtaglomerular apparatus, the proximal tubule, the cortical thick ascending limb of the loop of Henle, the inner medullary collecting duct, the intestine, parts of the brain, thyroid C cells, breast cells, and the adrenal glands. Binding of Ca++ to this calcium sensor activates phospholi-pase C and the accumulation of inositol triphosphate, which leads to inhibition of the secretion and synthesis of PTH and inactivation of its proteolysis.

Regulation of CalciumIn the ICU, many changes in calcium activity result from changes in protein binding and chelation, excessive or defi-cient hormonal action, or excessive losses or intake of calcium. A majority of total serum calcium is bound to proteins, and this binding is pH dependent. Acidic pH decreases calcium binding and increases Ca++, whereas alkalemia increases binding and reduces Ca++. Blood products, renal failure, or massive cell lysis may result in increased chelation. Fortu-nately, direct measurement of Ca++ is now readily available in PICUs.

Hormonal Regulation of CalciumHormonal control of calcium homeostasis involves PTH, vitamin D, and calcitonin. Secretion of PTH by the parathy-roid chief cell varies inversely with the serum Ca++ and is inhibited by hypomagnesemia and 1,25(OH)2-vitamin D. Rapid proteolytic degradation of PTH yields a physiologically inactive C-terminal fragment and an active NH2-terminal fragment. PTH binds to cell surface receptors in bone osteo-blasts and kidney and exerts its effects through binding of a subunit of a membrane-associated heterotrimeric protein, which mediates increased formation of cyclic adenosine 3′,5′-monophosphate.

In the kidney, PTH inhibits proximal tubular phosphate reabsorption and promotes phosphaturia. This loss of phos-phate inhibits bone mineralization and tends to shift the flow of calcium from bone to the ECF. PTH also increases distal tubular reabsorption of filtered calcium. PTH stimulates 1α-hydroxylation of 25(OH)-vitamin D, resulting in produc-tion of metabolically active 1,25(diOH)-vitamin D that stimu-lates intestinal absorption of calcium and phosphate. The overall effect of PTH is to raise serum calcium levels and lower serum phosphate levels. This characteristic reciprocal rela-tionship is helpful in distinguishing PTH disorders from those involving vitamin D alone.209



appropriate, efforts should be made to reduce serum phos-phate levels, because intravenous calcium therapy may cause metastatic deposition of calcium phosphate salts. Hypomag-nesemia impairs PTH release, response to PTH, and, conse-quently, correction of hypocalcemia. Hypomagnesemia may develop in critically ill patients by several mechanisms previ-ously discussed.

Urgency of therapy is determined by the child’s clinical status. Asymptomatic hypocalcemia is appropriately treated with oral calcium salts and vitamin D if needed. For the seri-ously ill patient with overt or evolving hypocalcemia, replace-ment therapy is accomplished with IV calcium chloride, 5 to 20 mg/kg, or an equivalent calcium gluconate infusion. Poten-tial bradycardia and asystole with infusion of calcium should be anticipated with cardiac monitoring and atropine readily available. Care is required to prevent tissue damage by extrava-sation or precipitation with concomitantly administered bicarbonate. In patients receiving digitalis, IV calcium is particularly dangerous as the arrhythmia potential is great. Hyperkalemia in digitalis toxicity should be treated with anti-digitalis FAB therapy and not IV calcium infusion.

Oral administration of calcium salts is efficient for control of most persistent hypocalcemia and is preferable to prolonged infusion (although some patients with DiGeorge hypocalcemia require aggressive multi-modal treatment). Liberal amounts can be administered orally (eg, calcium 50 mg/kg/day in 4–5 divided doses), with attention paid to the differing calcium content of various oral preparations. For patients with fat malabsorption, supplementation of calcium therapy with magnesium or vitamin D may be needed. In the setting of hypoparathyroidism secondary to magnesium depletion, mag-nesium replenishment must occur.

HypercalcemiaIn contrast to dramatic manifestations of hypocalcemia, the effects of hypercalcemia may be subtle. However, a serum total calcium greater than 15 mg/dL represents a medical emer-gency. Renal, cardiovascular, and CNS disturbances predomi-nate and reflect both the degree and duration of calcium elevation. Increased filtered load of calcium creates hypercal-ciuria and accompanying polyuria, reduced concentrating ability, dehydration, and eventual renal lithiasis. Hypertension is common, mediated through increased renin production and peripheral vasoconstriction. Alterations in the cardiac conduction system include a shortened QT interval and a tendency to dysrhythmias. Impaired nerve conduction creates hypotonia, hyporeflexia, and paresis in severe cases. Changes in CNS function include lethargy, confusion, and even coma. Constipation, anorexia, and abdominal pain resulting from reduced intestinal motility are frequent. Promotion of gastrin release by calcium may account for an increased incidence of peptic ulcer disease. Soft tissue deposition of calcium phos-phate can impair function of lungs, kidneys, cardiac conduc-tion tissue, blood vessels, and joints.

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 under-lying mechanisms of hypercalcemia as outlined in Table 73.3.

EDTA,ethylenediaminetetraaceticacid.

BOX 73–8 CausesofHypocalcemia

Reduced PTH EffectParathyroidGlandFailureHypoparathyroidism—idiopathicorautoimmuneTraumaPostsurgeryPost–131ItherapyInfarctionInfiltration(eg,sarcoidhemosiderosis)

InsensitivitytoPTHPseudohypoparathyroidismHypomagnesemia

SuppressionofPTHReleaseHypomagnesemiaNeonatal,resultingfrommaternalhypercalcemiaBurnsSepsisDrugs

• Aminoglycosides• Cimetidine• Cisplatin• β-Adrenergicblockers

Reduced Vitamin D EffectVitaminDDeficiencyDietaryinsufficiencyIncreasedlossesrelatedto:

MalabsorptionNephroticsyndromePhenytoin,phenobarbital

ImpairedActivationofVitaminDRenaldiseaseHypoparathyroidismLiverfailureRhabdomyolysis

Changes in Ca++ Binding or ChelationAlkalosisRespiratoryalkalosisBicarbonateinfusion

HyperphosphatemiaRenalfailurePhosphateadministration(eg,high-phosphateformulas,enemas)ChemotherapyRhabdomyolysisMalignancyPancreatitisFatembolismTransfusionwithcitrate-preservedblood

Drug/ToxinsGlucagonMithramycinCalcitoninEDTAProtamineSodiumfluorideColchicineTheophyllineEthyleneglycol



nin (10 U/kg IV every 4–6 hours), mithramycin (25 mg/kg IV over 4 hours), and indomethacin (1 mg/kg/day). Recombi-nant calcitonin blocks PTH-induced bone resorption, facili-tates calciuria, is relatively nontoxic, and has peak effect by 1 hour. Mithramycin is a toxic antibiotic that inhibits osteoclas-tic activity but has potential adverse effects including throm-bocytopenia, hepatotoxicity, and renal injury. Indomethacin is useful when excessive prostaglandin E2 production is sus-pected as in some cases of malignancy hypercalcemia.

Bisphosphonates have been used successfully in pediatrics for treatment of various disorders including hypercalce-mia.227-229 Corticosteroids are useful for treatment of vitamin D–related hypercalcemia, although the onset of action is not rapid.

PhosphorusVirtually all of plasma phosphorus is in the inorganic form, with a small organic component composed entirely of phos-pholipids bound to protein. Serum levels vary with age; approximate normal values (specific to the analytical instru-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 aged 12 to 19 years.230 Differences are thought to be related to more rapid rates of skeletal growth in the pediatric popula-tion. Most total body phosphorus resides in bone. As much as 60% to 80% of ingested phosphorus is absorbed, primarily in the jejunum. Absorption occurs by two pathways, one passive and one active. Passive paracellular transport is nonsaturable, so the greater the dietary intake, the higher is the net absorp-tion. Active transport accounts for only 20% of total absorp-tion via a vitamin D–dependent transporter, the Na-dependent phosphorus transporter 2b (NPT2b). Increased excretion of phosphorus from the kidneys after increased dietary intake is dependent on inhibition of the Na-phosphorus cotrans-porters 2a and 2c (NPT2a and NPT2c) in the luminal membrane of the proximal tubule. These transporters are inhibited from increased secretion of fibroblast growth factor 23 (FGF23). FGF23 is secreted by osteocytes and osteoblasts in response to oral phosphorus loading or an increase in serum 1,25 dihydroxy vitamin D levels. FGF23 induces an increase in the fractional excretion of phosphorus in the proximal tubule and decreases the efficiency of phosphorus absorption in the gut by lowering 1,25 vitamin D levels. PTH is also stimulated by increased intake of phosphorus by the fall in ionized calcium induced by transient hyperphosphate-mia. Increased PTH causes a decrease in the expression of NPT2a and NPT2c in proximal tubules.231 Absorption may also be decreased by a high calcium intake or by ingestion of antacids such as calcium carbonate or acetate, which bind phosphorus in the bowel. Glucose competitively inhibits phosphorus reabsorption. Glucocorticoids produce phospha-turia by a decrease in sodium-dependent transport in the proximal tubule.

Phosphorus plays an important role in cellular structure and function, bone mineralization, and urinary acid excretion. The development of severe phosphorus depletion affects the availability of intracellular ATP, depletes the erythrocyte of 2,3-diphosphoglycerate (2,3-DPG), with resultant tissue hypoxia, and impairs urinary acid excretion. The major acute effect of hyperphosphatemia is hypocalcemia; the long-term consequence is soft tissue calcification.232

Increased bone resorption reflects excess PTH effect, immo-bilization, or bone lysis by metastatic malignancy. PTH-mediated hypercalcemia is distinguished by a depressed serum phosphate concentration, decreased renal tubular reabsorp-tion of phosphate (TmPO4/GFR), and an iPTH level inap-propriately elevated for the simultaneous serum Ca++. In the child with hyperparathyroidism, evaluation for multiple endocrine neoplasias is warranted. Heightened vitamin D effect is manifested by increased intestinal calcium absorption and can be related to vitamin D intoxication,222,223 increased sensitivity to vitamin D, or ectopically produced 1,25(diOH)-vitamin D, as seen in sarcoidosis. Serum phosphate levels and TmPO4/GFR ratios are normal or increased, and iPTH levels are suppressed in these disorders. Detection of an ele-vated 25(OH)-vitamin D level may be helpful. High levels of vitamin A can also cause hypercalcemia and are particularly likely in patients with excessive intake or those with renal insufficiency.224,225

Decreased excretion of calcium occurs with dehydration or treatment with thiazide diuretics, aggravating the severity of hypercalcemia in hyperparathyroidism. Familial hypocalciu-ric hypercalcemia, an autosomal dominant disorder resulting from partially deactivating mutations in the Ca++-sensing receptor, is characterized by normal to slightly elevated iPTH levels and decreased urinary calcium excretion.226 Thus deter-mination of serum Ca++, phosphate, iPTH, vitamin D levels, and urinary calcium and phosphate excretion allows differen-tiation of most hypercalcemic disorders.

TreatmentA serum calcium level greater than 15 mg/dLc may be life threatening and requires direct Ca-lowering therapy in addi-tion to attention to the underlying disorder. Hydration with isotonic saline (200 to 250 mL/kg/day) and furosemide diure-sis results in calciuresis and amelioration of hypercalcemia in the majority of cases. Excessive losses of sodium, potassium, magnesium, and phosphate may require replacement.

Adjunct therapy is directed at the specific cause of hyper-calcemia. Drugs that inhibit bone resorption include calcito-

TABLE 73.3 TumorLysisSyndrome

Highrisk Lymphoidmalignancies,largetumormass,B-celllymphomaconcurrentrenalcompromise

Initiatingevent Cytolyticchemotherapy

Radiationtherapy

Embolictumorinfarction

Prophylaxis Hydration,urinaryalkalinization,allopurinol

Gradualchemotherapyinitiation,rasburicase

Seriousdisturbances Hyperkalemia,hypocalcemia,acidosis,renalfailure,hyperuricemia,hyperphosphatemia

Management Obsessiveelectrolytemonitoring,Hemodialysisavailablestat,CVVHDhelpful,maynotbeadequate

CVVHD, continuous venovenous hemodialysis; stat, immediately.



decomposes organic compounds within the cell with subsequent movement of inorganic phosphorus from ICF to ECF and excretion in the urine. Osmotic diuresis augments these losses. Decreased intake also commonly occurs. During treatment of DKA, renal phosphorus clearance generally increases with fluid administration. In addition, insulin therapy results in stimulation of glycolysis and anabolism with a shift of phosphorus back to the ICF. If the acidosis has been present for only a few days, then rarely is there a severe phosphorus deficiency. Although levels may decrease, they generally return to normal without extra phosphorus therapy. In the patient whose symptoms have been present for a number of days to weeks, however, severe deficiency may exist at the time of admission. These patients may have life-threatening complications of hypophosphatemia if they are not treated. In general, this subset of patients has low phosphorus levels on admission, whereas phosphorus levels are normal or increased at admission in less severely affected patients. Patients undergoing continuous renal replacement therapy (CRRT) who become hypophosphatemic may be at higher risk for mortality.242 In burn patients with >19% total body surface area burns, patients receiving preemptive infusions of intravenous (IV) phosphorus beginning at 24 hours after injury had less hypophosphatemia and fewer complications versus those treated once hypophosphatemia developed.243

Signs and SymptomsMultiple organ systems may be affected by severe hypophos-phatemia, including CNS, cardiac, respiratory, musculoskele-tal, hematologic, renal, and hepatic abnormalities.244-251 Decreased diaphragmatic contractility in patients with hypo-phosphatemia with acute respiratory failure significantly improved as measured by transdiaphragmatic pressures during phrenic stimulation with treatment of hypophospha-temia.252 Respiratory muscle weakness in patients with hypo-phosphatemia but with or without respiratory failure also has been documented and shown to normalize with phosphorus repletion.248,250,251,253

Neurologic symptoms may initially include irritability and apprehension followed by weakness, peripheral neuropathy with numbness, and paresthesias. Dysarthria, confusion, obtundation, seizures, and coma may occur in more profound cases.246,249,254 Reports in the literature include Guillain-Barré–like syndrome,255 diffuse slowing on electroencephalogram, and congestive cardiomyopathy256 that significantly improved with correction of phosphorus depletion. In dogs, decreased cardiac output, decreased ventricular ejection velocity, and increased left ventricular end-diastolic pressure reversed with phosphorus repletion. In humans, rhabdomyolysis has been predominantly seen in alcoholic patients, in whom subtle myopathy was likely present, and rarely in patients with DKA or after TPN therapy. Decreased levels of 2,3-DPG in red blood cells (RBCs) may depress P-50 (oxygen half-saturation pressure) values so that the release of molecular oxygen to peripheral tissues is decreased, with resultant tissue hypoxia.244 Structural defects of RBCs associated with hypophosphatemia have included rigidity and rarely hemolysis and have generally occurred when additional metabolic stresses such as metabolic acidosis or infection were placed on the RBC. Decreased levels of ATP in neutrophils may result in decreased chemo-taxis, phagocytosis, and bacterial killing.257 The mechanisms

HypophosphatemiaHypophosphatemia as measured by serum or plasma levels may or may not indicate true phosphorus deficiency. Severely depressed levels of serum-measurable phosphorus may occur in the absence of true deficiency after transcellular shifts from the ECF to the ICF, whereas a moderate phosphorus deficiency may be indicated only by slightly decreased serum levels.233 Other processes that lead to true hypophosphatemia include increased excretion from the kidneys and decreased intestinal absorption. Hypophosphatemia may also result from a com-bination of these three mechanisms. Moderate hypophospha-temia has been defined as levels between 1.5 and 2.5 mg/dL and severe hypophosphatemia as levels less than 1.5 mg/dL on serum determination. In general, only with severe deficiency of phosphorus do multiple symptoms occur, as well as overt cell dysfunction or necrosis. Risk is greatest when superim-posed additional cellular injury exists.

Cause of Severe HypophosphatemiaAlthough numerous abnormalities may result in moderate decreases in phosphorus levels, severe hypophosphatemia has been associated with only a handful of clinical syndromes. These syndromes include significant respiratory alkalosis, prolonged use of phosphate-deficient TPN, the nutritional refeeding syndrome, thermal burns, DKA, pharmacologic binding of phosphorus in the gut, alcohol withdrawal, and several medications.233-235 An association with continuous renal replacement therapy and bone recovery after renal trans-plant also has been reported.236,237 The increase in the ICF pH associated with acute respiratory alkalosis stimulates the enzymes of glycolysis, with subsequent depletion of ICF phos-phorus, which is replaced by an influx from the ECF space. Although carbon dioxide diffuses across membranes much more readily than bicarbonate does, metabolic alkalosis rarely produces a decrease in phosphorus levels, whereas very low levels may be seen with respiratory alkalosis.238 An absolute deficiency from malnutrition and transcellular shifts from the ECF to the ICF with an anabolic response to increasing caloric intake are the causes associated with TPN use.239 In the pedi-atric population, the preterm infant is particularly susceptible. Nearly 80% of calcium-phosphorus assimilation in the fetus occurs in the last trimester of pregnancy. The preterm infant is therefore born deficient in total body phosphorus. When reasonable nutrition has been absent for even short periods or when phosphorus has not been provided in TPN, severe hypophosphatemia has occurred, associated in several cases with the development of hypercalcemia.240 A similar situation may occur with the refeeding of patients who have significant protein calorie malnutrition including anorexia patients.241 As previously noted, an absolute phosphorus deficiency and tran-scellular shifts from the ECF to the ICF in the face of an anabolic response are responsible.

Significant hypophosphatemia in burn patients during their recovery phase has been associated with the presence of respiratory alkalosis, diuresis of initially retained sodium and water, and acceleration of glycolysis.231,233 As previously described, ECF phosphorus shifts to the ICF compartment when intracellular-free phosphorus has been used in phos-phorylation of organic compounds such as occurs during glycolysis, oxidative phosphorylation, glycogenolysis, and syn-thesis of glycogen, protein, and phosphocreatine. Acidosis



in hyperphosphatemia in multiple infants,266 and severe hyperphosphatemia has been reported related to use of lipo-somal amphotericin B.267

Tumor lysis syndrome represents an additional cause of hyperphosphatemia along with hyperkalemia, acidosis, hypo-calcemia, and renal failure. It results from induced lysis of tumor cells and is always a concern in a child with a lymphoid malignancy and substantial cellular mass, but it can occur in a variety of settings (see also Chapter 94). Initial chemother-apy or radiation of B-cell lymphoma is particularly likely to produce cell lysis and hyperphosphatemia along with hyper-uricemia, acute renal failure (ARF), hyperkalemia, metabolic acidosis, and hypocalcemia. Aggressive hydration and careful initiation of chemotherapy usually will result in a manageable degree of electrolyte abnormality. Urinary alkalinization to increase urate solubility is usually recommended but is being reexamined. Rasburicase is replacing allopurinol in the control of urate levels. Hemodialysis or CRRT is an essential resource to have available if managing such a patient (see Table 73.2).

Signs and SymptomsThe major clinical consequence of severe hyperphosphatemia is its associated hypocalcemia, as well as soft tissue deposition of calcium phosphate salts. Seizures, coma, and cardiac arrest have been reported, generally in the presence of both hypo-calcemia and hyperphosphatemia. In one case report, however, seizures, malignant ventricular arrhythmias, and cardiac arrest with acute hyperphosphatemia alone were described.268 Hyperphosphatemia may be a proximate cause of ARF via precipitation in renal tissue.269,270

TreatmentIn patients with life-threatening complications or multiple additional electrolyte disturbances or in the presence of renal failure, dialysis may be required. Intravenous fluid loading to increase renal phosphorus losses and intravenous calcium may increase excretion. Mannitol diuresis will inhibit proxi-mal phosphorus reabsorption and theoretically should expe-dite phosphaturia. If oral administration is possible, Sevelamer has been used in patients with TLS to bind phosphorus and perhaps decrease the need for more invasive therapy.271

K e y R e f e r e n c e s1. Kaplan L, Kellum J, et al. Fluids, pH, ions and electrolytes. Curr Opin

Crit Care. 2010;16:323-331.5. Kannan L, Lodha R, Vivekanandhan S, et al. Intravenous fluid regimen

and hyponatraemia among children: a randomized controlled trial. Peidatr Nephrol. 2010;25:2303-2309.

8. Friedman JN, Beck CE, DeGroot J, et al. Comparison of isotonic and hypotonic intravenous maintenance fluids: a randomized clinical trial. JAMA Pediatr. 2015;10:1001.

9. Mastorakos G, Weber JS, Magiakou MA, et al. Hypothalamic-pituitary-adrenal axis activation and stimulation of systemic vasopressin secretion by recombinant interleukin-6 in humans: potential implications for the syndrome of inappropriate vasopressin secretion. J Clin Endocrinol Metab. 1994;79:934-939.

10. Park SJ, Shin JI, et al. Inflammation and hyponatremia: an underrecog-nized condition? Korean J Pediatr. 2013;56:519-522.

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.

25. Arikan AA, Zappitelli M, Goldstein SL, et al. Fluid overload is associ-ated with impaired oxygenation and morbidity in critically ill children. Pediatr Crit Care Med. 2012;13:253-258.

underlying the development of metabolic acidosis include decreased phosphorus excretion that thereby limits titratable acid excretion and decreased ammonia levels.

TreatmentAs with other minerals and electrolytes, when oral therapy is potentially possible it is the preferable route for administra-tion. In patients with severe hypophosphatemia, IV therapy is often indicated, though there remain no evidence-based rec-ommendations for IV replacement.258-260 Few data exist in the pediatric literature regarding dosage. Therefore most data are extrapolated from adult literature.260-263 Reasonable recom-mendations in children with severe phosphorus depletion are to use 0.15 to 0.33 mmol/kg per dose, given as a continuous infusion over 4 to 6 hours. Subsequent doses are generally calculated on the basis of response to this initial dosage. Either potassium or sodium phosphate may be administered with the attendant potential complications of hypernatremia or hyper-kalemia. A common recommendation is to use potassium phosphate if potassium (K) is <4 meq/L and sodium phos-phate if the K is >4 meq/L. Other potential complications of therapy include hyperphosphatemia, metastatic deposition of calcium phosphate, hypocalcemia, potential nephrocalcinosis with renal failure, and hypotension. Both sodium and potas-sium phosphate contain 3 mmol of phosphate per mL and 4 or 4.5 mEq of sodium or potassium, respectively. For oral administration, a combination product of sodium with potas-sium phosphate (Neutra-Phos) has been used commonly in children. One capsule supplies 8 mmol of phosphorus along with 7.1 mEq of sodium and potassium. Capsules can be reconstituted in water as well. In infants the IV preparations may be used enterally with smaller volumes needed. Hypo-phosphatemia associated with continuous renal replacement therapy provides a special case. IV replacement is required in many such patients.236

Hyperphosphatemia

Causes of HyperphosphatemiaAcute and chronic renal failure with decreased phosphorus excretion are the most common causes of hyperphosphate-mia, with elevation in serum phosphorus occurring when the GFR is less than 30 mL/min/1.73 m2. Extreme hyperphospha-temia associated with several deaths has been reported from the use of either oral sodium phosphate or enemas containing sodium phosphate in infants and children.264,265 Abnormalities of intestinal anatomy or motility predisposing to retention of enemas or renal insufficiency represent risk factors, but no risk factors are identified in 30% of reported patients. Previous treatment does not guarantee safety with these agents, as 30% of reported patients had previously received enemas or oral therapy without complications. Average time to recognition has ranged from 12 minutes to 24 hours, with mean of 6.53 hours. Mean phosphorus levels were 27.9 mg/dL with plasma total calcium mean of 4.95 mg/dL. Unless there was kidney disease when older children and adolescents have also been affected, all reported patients have been <5 years of age.264 The administration of IV boluses of sodium or potassium phos-phate rather than slow infusion may result in symptomatic hyperphosphatemia. An error in parenteral nutrition resulted



177. Horn A, Thompson C, Woods D, et al. Induced hypothermia for infants with hypoxic-ischemic encephalopathy using a servo-controlled fan: an exploratory pilot study. Pediatrics. 2009;123:e1090-e1098.

196. Egelund TA, Wassil SK, Edwards EM, et al. High-dose magnesium sulfate infusion protocol for status asthmaticus: a safety and pharmaco-kinetics cohort study. Intensive Care Med. 2013;39:117-122.

205. Cias CR, Leite HP, Nogueira PC, et al. Ionized hypocalcemia is an early event and is associated with organ dysfunction in children admitted to the intensive care unit. J Crit Care. 2013;28:810-815.

207. Ward BK, Magno AL, Walsh JP, et al. The role of the calcium-sensing receptor in human disease. Clin Biochem. 2012;45:943-953.

213. Yilmaz O, Olgun H, Ciftel M, et al. Dilated cardiomyopathy secondary to rickets-related hypocalcaemia: eight case reports and a review of the literature. Cardiol Young. 2015;25:261-266.

225. Manickavasagar B, McArdle AJ, Yadav P, et al. Hypervitaminosis A is prevalent in children with CKD and contributes to hypercalcemia. Pediatr Nephrol. 2015;30:317-325.

234. Amanzadeh J, Reilly RF Jr. Hypophosphatemia: an evidence-based approach to its clinical consequences and management. Nat Clin Pract Nephrol. 2006;2:136.

236. Santiago MJ, Lopez-Herce J, Urbano J, et al. Hypophosphatemia and phosphate supplementation during continuous renal replacement therapy in children. Kidney Int. 2009;75:312.

241. de Meneses JF, Leite HP, de Carvalho WB, et al. Hypophosphatemia in critically ill children: prevalence and associated risk factors. Pediatr Crit Care Med. 2009;10:234.

251. Sprung J, Weingarten TN. Severe hypophosphatemia: a rare cause of postoperative muscle weakness. J Clin Anesth. 2014;26:584.

265. Mendoza J, Legido J, Rubio S, et al. Systematic review: the adverse effects of sodium phosphate enema. Aliment Pharmacol Ther. 2007;26:9.

271. Abdullah S, Diezi M, Sung L, et al. Sevelamer hydrochloride: a novel treatment of hyperphosphatemia associated with tumor lysis syndrome in children. Pediatr Blood Cancer. 2008;51:59.

26. Sinitsky L, Walls D, Nadel S, et al. Fluid overload at 48 hours is associated with respiratory morbidity but not mortality in a general PICU: retro-spective cohort study. Pediatr Crit Care Med. 2015;16:205-209.

27. Wiedemann HP, Wheeler AP, Bernard GR, et al. Comparison of two fluid-management strategies in acute lung injury. N Engl J Med. 2006;354:2564-2575.

57. Stern RH, Silver SM. Cerebral salt wasting versus SIADH: what differ-ence? J Am Soc Nephrol. 2008;19:194.

61. Celik T, Orkun T, Ilknur T, et al. Cerebral salt wasting in status epilep-ticus: two cases and review of the literature. Pediatr Neurol. 2014;50:397.

69. Schrier RW. Vasopressin and Aquaporin 2 (AQP2) in clinical disorders of water homeostasis. Semin Nephrol. 2008;28:289.

85. Kallakatta RN, Radhakrishnan A, Fayaz RK, et al. Clinical and functional outcome and factors predicting prognosis in osmotic demyelination syndrome (central pontine and/or extrapontine myelinolysis) in 25 patients. J Neurol Neurosurg Psychiatry. 2011;82:326.

103. Jones RC, Rajasekaran S, Rayburn M, et al. Initial experience with conivaptan use in critically ill infants with cardiac disease. J Pediatr Pharmacol Ther. 2012;17:78.

121. Cummings BM, Macklin EA, Yager PH, et al. Potassium abnormalities in a pediatric intensive care unit: frequency and severity. J Intensive Care Med. 2014;29:269-274.

151. Woof AD, Wenger T, Smith TW, et al. The use of digoxin-specific fab fragments for severe digitalis intoxication in children. N Engl J Med. 1992;326:1739-1744.

152. Racca F, Mongini T, Wolfler A, et al. Recommendations for anesthesia and perioperative management of patients with neuromuscular disor-ders. Minerva Anestesiol. 2013;79:419-433.

164. Rajendran A, Bansal D, Marwaha RK, et al. Tumor lysis syndrome. Indian J Pediatr. 2013;80:50-54.

170. Janjua HS, Mahan JD, Patel HP, et al. Continuous infusion of a standard combination solution in the management of hyperkalemia. Nephrol Dial Transplant. 2011;26:2503-2508.

171. De Baaij JH, Hoenderop JG, Bendels RJ, et al. Magnesium in man: impli-cations for health and disease. Physiol Rev. 2015;95:1-46.


Chapter 73 1025.e1Fluid and Electrolyte Issues in Pediatric Critical Illness

R e f e r e n c e s1. Kaplan L, Kellum J, et al. Fluids, pH, ions and electrolytes. Curr Opin

Crit Care. 2010;16:323-331.2. Yunos’ N, Bellomo R, Story D, et al. Bench-to-bedside review: chloride

in critical illness. Crit Care. 2010;14:226.3. Myburgh J, Mythen M, et al. Resuscitation fluids. N Engl J Med. 2013;

369:1243-1251.4. Peng Z, Kellum J, et al. Perioperative fluids: a clear road ahead? Crit Care.

2013;19:353-358.5. Kannan L, Lodha R, Vivekanandhan S, et al. Intravenous fluid regimen

and hyponatraemia among children: a randomized controlled trial. Peidatr Nephrol. 2010;25:2303-2309.

6. Foster BA, Tom D, Hill V, et al. Hypotonic verses isotonic fluids in hos-pitalized children: a systematic review and meta-analysis. J Pediatr. 2014;165:163-169.

7. Saba TG, Fairbairn J, Houghton F, et al. A randomized controlled trial of isotonic versus hypotonic maintenance intravenous fluids in hospital-ized children. BMC Pediatr. 2011;11:82.

8. Friedman JN, Beck CE, DeGroot J, et al. Comparison of isotonic and hypotonic intravenous maintenance fluids: a randomized clinical trial. JAMA Pediatr. 2015;10:1001.

9. Mastorakos G, Weber JS, Magiakou MA, et al. Hypothalamic-pituitary-adrenal axis activation and stimulation of systemic vasopressin secretion by recombinant interleukin-6 in humans: potential implications for the syndrome of inappropriate vasopressin secretion. J Clin Endocrinol Metab. 1994;79:934-939.

10. Park SJ, Shin JI, et al. Inflammation and hyponatremia: an underrecog-nized condition? Korean J Pediatr. 2013;56:519-522.

11. Dubois MJ, Orellana-Jimenez C, Melot C, et al. Albumin administration improves organ function in critically ill hypoalbuminemic patients: a prospective, randomized, controlled, pilot study. Crit Care Med. 2006;34:2536-2540.

12. SAFE Study Investigators, et al. Impact of albumin compared to saline on organ function and mortality of patients with severe sepsis. Intensive Care Med. 2011;37:86-96.

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.

14. Patel A, Laffan MA, Waheed U, et al. Randomised trials of human albumin for adults with sepsis: systematic review and meta-analysis with trial sequential analysis of all-cause mortality. BMJ. 2014;349:g4850.

15. Cooper DJ, Myburgh J, Heritier S, et al. Albumin resuscitation for trau-matic brain injury: is intracranial hypertension the cause of increased mortality? J Neurotrauma. 2013;30:512-518.

16. Dellinger RP, Levy M, Rhodes A, et al. Surviving sepsis campaign: inter-national guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med. 2013;39:165-228.

17. Karakala N, Raghunathan K, Shaw AD, et al. Intravenous fluids in sepsis: what to use and what to avoid. Curr Opin Crit Care. 2013;19:537-543.

18. Fabrizi F, Aghemo A, Messa P, et al. Hepatorenal syndrome and novel advances in its management. Kidney Blood Press Res. 2013;37:588-601.

19. Bernardi M, Ricci CS, Zaccherini G, et al. Role of human albumin in the management of complications of liver cirrhosis. J Clin Exp Hepatol. 2014;4:302-311.

20. Cavallin M, Kamath PS, Merli M, et al. Terlipressin plus albumin versus midodrine and octreotide plus albumin in the treatment of hepatorenal syndrome: a randomized trial. Hepatology. 2015;62:567-574.

21. Uhlig C, Silva PL, Deckert S, et al. Albumin versus crystalloid solutions in patients with the acute respiratory distress syndrome: a systematic review and meta-analysis. Crit Care. 2014;18:R10.

22. Mutter TC, Ruth CA, Dart AB, et al. Hydroxyethyl starch (HES) versus other fluid therapies: effects on kidney function (review). Cochrane Database Syst Rev. 2013;(7):CD007594.

23. Ghijselings I, Rex S, et al. Hydroxyethyl starches in the perioperative period: a review on the efficacy and safety of starch solutions. Acta Anaesthesiol Belg. 2014;65:9-22.

24. Gattinoni L, Cressoni M, Brazzi L, et al. Fluids in ARDS: from onset through recovery. Curr Opin Crit Care. 2014;20:373-377.

25. Arikan AA, Zappitelli M, Goldstein SL, et al. Fluid overload is associated with impaired oxygenation and morbidity in critically ill children. Pediatr Crit Care Med. 2012;13:253-258.

26. Sinitsky L, Walls D, Nadel S, et al. Fluid overload at 48 hours is associated with respiratory morbidity but not mortality in a general PICU: retro-spective cohort study. Pediatr Crit Care Med. 2015;16:205-209.

27. Wiedemann HP, Wheeler AP, Bernard GR, et al. Comparison of two fluid-management strategies in acute lung injury. N Engl J Med. 2006;354:2564-2575.

28. Schrier RW, et al. Fluid administration in critically ill patients with acute kidney injury. Clin J Am Soc Nephrol. 2010;5:733-739.

29. Karvellas CJ, Farhat MR, Sajjak I, et al. A comparison of early versus late initiation of renal replacement therapy in critically ill patients with acute kidney injury: a systematic review and meta-analysis. Crit Care. 2011;15:R72.

30. Chang DW, Huynh R, Sandoval E, et al. Volume of fluids administered during resuscitation for severe sepsis and septic shock and the develop-ment of the acute respiratory distress syndrome. J Crit Care. 2014;29:1011-1015.

31. Hoste EA, Maitland K, Brudney CS, et al. Four phases of intravenous fluid therapy: a conceptual model. Br J Anaesth. 2014;113:740-747.

32. Roch A, Hraiech S, Dizier S, et al. Pharmacological interventions in acute respiratory distress syndrome. Ann Intensive Care. 2013;3:20.

33. Rosner MH, Ostermann M, Murugan R, et al. Indications and manage-ment of mechanical fluid removal in critical illness. Br J Anaesth. 2014;113:764-771.

34. Ejaz AA, Mohandas R, et al. Are diuretics harmful in the management of acute kidney injury? Curr Opin Nephrol Hypertens. 2014;23:155-160.

35. Bagshaw SM, Delaney A, Haase M, et al. Loop diuretics in the manage-ment of acute renal failure: a systematic review and meta-analysis. Crit Care Resusc. 2007;9:60-68.

36. Pacifici GM, et al. Clinical pharmacology of furosemide in neonates: a review. Pharmaceuticals (Basel). 2013;6:1094-1129.

37. Caetano F, Mota P, Almeida I, et al. Continuous infusion or bolus injec-tion of loop diuretics for patients admitted for severe acute heart failure: is one strategy better than the other? Rev Port Cardiol. 2015;34:95-102.

38. Reddy KRBK, Basavaraja GV, Shivananda, et al. Furosemide infusion in children with dengue fever and hypoxia. Indian Pediatr. 2014;5:303-305.

39. Amer M, Adomaityte J, Qayyum R, et al. Continuous infusion versus intermittent bonus furosemide in ADHF: an updated meta-analysis of randomized control trials. J Hosp Med. 2012;7:270-275.

40. Calfee CS, Matthay MA, et al. Nonventilatory treatments for acute lung injury and ARDS. Chest. 2007;131:913-920.

41. Martin GS, et al. Fluid balance and colloid osmotic pressure in acute respiratory failure: emerging clinical evidence. Crit Care. 2000;4(suppl 2):S21-S25.

42. Martin GS, Moss M, Wheeler AP, et al. A randomized, controlled trial of furosemide with or without albumin in hypoproteinemic patients with acute lung injury. Crit Care Med. 2005;33:1681-1687.

43. Wang X, Jie Yuan W, et al. Timing of initiation of renal replacement therapy in acute kidney injury: a systematic review and meta-analysis. Ren Fail. 2012;34:396-402.

44. Smith OM, Wald R, Adhikari NK, et al. Standard versus accelerated initiation of renal replacement therapy in acute kidney injury (STARRT-AKI): study protocol for a randomized controlled trial. Trials. 2013;14:320.

45. Goldstein SL, et al. Fluid management in acute kidney injury. J Intensive Care Med. 2014;29:183-189.

46. Kim WR, Biggins SW, Kremers WK, et al. Hyponatremia and mortality among patients on the liver-transplant waiting list. N Engl J Med. 2008;359:1018.

47. Funk G-C, Lindner G, Druml W, et al. Incidence and prognosis of dys-natremias present on ICU admission. Intensive Care Med. 2010;36:304.

48. Carey RG, Bucuvalas JC, Balistreri WF, et al. Hyponatremia increases mortality in pediatric patients listed for liver transplantation. Pediatr Transplant. 2010;14:115.

49. Guarner J, Hochman J, Kurbatova E, et al. Study of outcomes associated with hyponatremia and hypernatremia in children. Pediatr Dev Pathol. 2011;14:117.

50. Ohuchi H, Negishi J, Ono S, et al. Hyponatremia and its association with the neurohormonal activity and adverse clinical events in children and young adult patients after the Fontan operation. Congenit Heart Dis. 2011;6:304.

51. Moini M, Hoseini-Asl MK, Taghavi SA, et al. Hyponatremia a valuable predictor of early mortality in patients with cirrhosis listed for liver transplantation. Clin Transplant. 2011;25:638.

52. Luu R, DeWitt PE, Reiter PD, et al. Hyponatremia in children with bronchiolitis admitted to the pediatric intensive care unit is associated with worse outcomes. J Pediatr. 2013;163:1652.


Renal, Fluids, Electrolytes1025.e2 Section V

53. Topjian AA, Stuart A, Pabalan AA, et al. Greater fluctuations in serum sodium levels are associated with increased mortality in children with externalized ventriculostomy drains in a PICU. Pediatr Crit Care Med. 2014;15:846.

54. Trachtman H. Sodium and water homeostasis. Pediatr Clin North Am. 1995;42:1343.

55. Schrier RW, Bansal S. Diagnosis and management of hyponatremia in acute illness. Curr Opin Crit Care. 2008;14:627.

56. Szatalowicz VL, Miller PD, Lacher JW, et al. Comparative effect of diuretics on renal H2O excretion in hyponatremic oedematous disor-ders. Clin Sci. 1982;62:235.

57. Stern RH, Silver SM. Cerebral salt wasting versus SIADH: what differ-ence? J Am Soc Nephrol. 2008;19:194.

58. Kojima J, Katayama Y, Moro N, et al. Cerebral salt wasting in subarach-noid hemorrhagic rats: model, mechanism, and tool. Life Sci. 2005;76:2361.

59. Jimenez R, Casado-Flores J, Nieto M, et al. Cerebral salt wasting syn-drome in children with acute central nervous system injury. Pediatr Neurol. 2006;35:261.

60. Palmer B. Hyponatremia in patients with central nervous system disease: SIADH versus CSW. Trends Endocrinol Metab. 2003;14:182.

61. Celik T, Orkun T, Ilknur T, et al. Cerebral salt wasting in status epilep-ticus: two cases and review of the literature. Pediatr Neurol. 2014;50:397.

62. Berger TM, Kestler W, Berendes E, et al. Hyponatremia in a pediatric stroke patient: syndrome of inappropriate antidiuretic hormone secre-tion or cerebral salt wasting? Crit Care Med. 2002;30:792.

63. Bismarck PV, Ankermann T, Eggert P, et al. Diagnosis and management of cerebral salt wasting (CSW) in children: the role of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). Childs Nerv Syst. 2006;22:1275.

64. Gheorghiade M, Abraham WT, Albert NM, et al. Relationship between admission serum sodium concentration and clinical outcomes in patients hospitalized for heart failure: an analysis from the OPTIMIZE-HF registry. Eur Heart J. 2007;28:920.

65. Farmakis D, Filippatos G, Parissis J, et al. Hyponatremia in heart failure. Heart Fail Rev. 2009;14:59.

66. Rea ME, Dunlap ME. Renal hemodynamics in heart failure: implications for treatment. Curr Opin Nephrol Hypertens. 2008;17:87.

67. Ronco C, Haapio M, House AA, et al. Cardiorenal syndrome. J Am Coll Cardiol. 2008;52:1527.

68. Kashani A, Landaverde C, Medici V, et al. Fluid retention in cirrhosis: pathophysiology and management. Q J Med. 2008;101:71.

69. Schrier RW. Vasopressin and Aquaporin 2 (AQP2) in clinical disorders of water homeostasis. Semin Nephrol. 2008;28:289.

70. Palmer BF. Hyponatremia in the intensive care unit. Semin Nephrol. 2009;29:257.

71. Decaux G, Musch W. Clinical laboratory evaluation of the syndrome of inappropriate secretion of antidiuretic hormone. Clin J Am Soc Nephrol. 2008;3:1175.

72. Arieff AI. Hyponatremia, convulsions, respiratory arrest, and permanent brain damage after elective surgery in healthy women. N Engl J Med. 1986;314:1529.

73. Foster BA, Tom D, Hill V. Hypotonic versus isotonic fluids in hospital-ized children: a systematic review and meta-analysis. J Pediatr. 2014;165:163.

74. Kannan L, Lodha R, Vivekanandhan S, et al. Intravenous fluid regimen and hyponatraemia among children: a randomized controlled trial. Pediatr Nephrol. 2010;25:2303.

75. Choong K, Arora S, Cheng J, et al. Hypotonic versus isotonic mainte-nance fluids after surgery for children: a randomized controlled trial. Pediatrics. 2011;128:857.

76. McNab S, Duke T, South M, et al. 140 mmol/L of sodium versus 77 mmol/L of sodium in maintenance intravenous fluid therapy for children in hospital (PIMS): a randomised controlled double-blind trial. Lancet. 2015;385:1190.

77. Yung M, Keeley S. Randomized, controlled trial of intravenous mainte-nance fluids. J Paediatr Child Health. 2007;45:9.

78. Montanana PA, Alapont MI, Ocon AP. The use of isotonic fluid as maintenance therapy prevents iatrogenic hyponatremia in pediatrics: a randomized, controlled open study. Pediatr Crit Care Med. 2008;9:589.

79. Smith DM, McKenna K, Thompson CJ. Hyponatremia. Clin Endocrinol (Oxf). 2000;52:667.

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82. Bonkowsky JL, Filloux FM. Extrapontine myelinolysis in a pediatric case of diabetic ketoacidosis and cerebral edema. J Child Neurol. 2003;18:144.

83. Brown WD, Caruso JM. Extrapontine myelinolysis with involvement of the hippocampus in three children with severe hypernatremia. J Child Neurol. 1999;14:428.

84. Gencpinar P, Tekguc H, Senol AU, et al. Extrapontine myelinolysis in an 18-month-old boy with diabetic ketoacidosis: case report and literature review. J Child Neurol. 2014;29:1548.

85. Kallakatta RN, Radhakrishnan A, Fayaz RK, et al. Clinical and functional outcome and factors predicting prognosis in osmotic demyelination syndrome (central pontine and/or extrapontine myelinolysis) in 25 patients. J Neurol Neurosurg Psychiatry. 2011;82:326.

86. Dobato JL, Barriga FJ, Pareja JA, et al. Extrapontine myelinolysis caused by iatrogenic hypernatremia following rupture of a hydatid cyst of the liver with an amnesic syndrome as sequelae. (Sp). Rev Neurol. 2000;31:1033.

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89. Tanasescu R, Ticmeanu M, Cojocaru IM, et al. Central pontine and extrapontine myelinolysis. Rom J Intern Med. 2008;46:199.

90. Sterns RH, Nigwekar SU, Hix JK. The treatment of hyponatremia. Semin Nephrol. 2009;29:282.

91. Berkenbosch JW, Lentz CW, Jimenez DF, et al. Cerebral salt wasting syndrome following brain injury in three pediatric patients: suggestions for rapid diagnosis and therapy. Pediatr Neurosurg. 2002;36:75.

92. Taplin CE, Cowell CT, Silink M, et al. Fludrocortisone therapy in cere-bral salt wasting. Pediatrics. 2006;118:e1904.

93. Papadimitriou DT, Spiteri A, Pagnier A, et al. Mineralocorticoid defi-ciency in post-operative cerebral salt wasting. J Pediatr Endocrinol Metab. 2007;20:1145.

94. Woo CH, Rao VA, Sheridan W, et al. Performance characteristics of a sliding-scale hypertonic saline infusion protocol for the treatment of acute neurologic hyponatremia. Neurocrit Care. 2009;11:228.

95. Soupart A, Ngassa M, Decaux G. Therapeutic relowering of serum sodium in a patient after excessive correction of hyponatremia. Clin Nephrol. 1999;51:383.

96. Oya S, Tsutsumi K, Ueki K, et al. Reinduction of hyponatremia to treat central pontine myelinolysis. Neurology. 2001;57:1931.

97. Soupart A, Penninckx R, Stenuit A, et al. Reinduction of hyponatremia improves survival in rats with myelinolysis-related neurologic syn-drome. J Neuropathol Exp Neurol. 1996;55:594.

98. Kumar S, Berl T. Vasopressin antagonists in the treatment of water-retaining disorders. Semin Nephrol. 2008;28:279.

99. Regen RB, Gonzalez A, Zawodniak K, et al. Tolvaptan increases serum sodium in pediatric patients with heart failure. Pediatr Cardiol. 2013;34:1463.

100. Sahu R, Balaguru D, Thapar V, et al. Conivaptan therapy in an infant with severe hyponatremia and congestive heart failure. Tex Heart Inst J. 2012;39:724.

101. Rianthavorn P, Cain JP, Turman MA. Use of conivaptan to allow aggres-sive hydration to prevent tumor lysis syndrome in a pediatric patient with large-cell lymphoma and SIADH. Pediatr Nephrol. 2008;23:1367.

102. Peters S, Kuhn R, Gardner B, et al. Use of conivaptan for refractory syndrome of inappropriate secretion of antidiuretic hormone in a pedi-atric patient. Pediatr Emerg Care. 2013;29:230.

103. Jones RC, Rajasekaran S, Rayburn M, et al. Initial experience with conivaptan use in critically ill infants with cardiac disease. J Pediatr Pharmacol Ther. 2012;17:78.

104. Moritz ML, Ayus JC. The changing pattern of hypernatremia in hospi-talized children. Pediatrics. 1999;104:435.

105. Lindner G, Kneidinger N, Holzinger U, et al. Tonicity balance in patients with hypernatremia acquired in the intensive care unit. Am J Kidney Dis. 2009;54:674.

106. Finberg L. Hypernatremia (hypertonic) dehydration in infants. N Engl J Med. 1973;289:196.

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108. Adrogue HJ, Madias NE. Hypernatremia. N Engl J Med. 2000;342:1493.109. O’Donoghue SD, Kulhunty JM, Brandeshe HK, et al. Acquired hyperna-

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110. Birnbaumer M. The V2 vasopressin receptor mutations and fluid homeostasis. Cardiovasc Res. 2001;51:409.

111. Peterson B, Khanna S, Fisher B, et al. Prolonged hypernatremia controls elevated intracranial pressure in head-injured pediatric patients. Crit Care Med. 2000;28:1136.

112. Froelich M, Ni Q, Wess C, et al. Continuous hypertonic saline therapy and the occurrence of complications in neurocritically ill patients. Crit Care Med. 2009;37:1433.

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115. Ropper AH. Hyperosmolar therapy for raised intracranial pressure. N Engl J Med. 2012;367:746.

116. Kumar S, Berl T. Sodium. Lancet. 1998;352:220.117. Robertson G, Carrihill M, Hatherill M, et al. Relationship between fluid

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118. Davalos MC, Barrett R, Seshadri S, et al. Hyponatremia during arginine vasopressin therapy in children following cardiac surgery. Pediatr Crit Care Med. 2013;14:290.

119. Sharma R, Stein D. Hyponatremia after desmopressin (DDAVP) use in pediatric patients with bleeding disorders undergoing surgeries. J Pediatr Hematol Oncol. 2014;36:e371.

120. Lucchini B, Simonetti GD, Ceschi A, et al. Severe signs of hyponatremia secondary to desmopressin treatment for enuresis: a systematic review. J Pediatr Urol. 2013;9:1049.

121. Cummings BM, Macklin EA, Yager PH, et al. Potassium abnormalities in a pediatric intensive care unit: frequency and severity. J Intensive Care Med. 2014;29:269-274.

122. Greenlee M, Wingo CS, McDonough AA, et al. Narrative review: evolv-ing concepts in potassium homeostasis and hypokalemia. Ann Intern Med. 2009;151:143-144.

123. Hernandez RJ, et al. Na+/K(+)-ATPase regulation by neurotransmitters. Neurochem Int. 1992;20:1-10.

124. Ferre S, Hoenderop JJ, Bindels RJ, et al. Role of the distal convoluted tubule in renal Mg2+ handling: molecular lessons from inherited hypo-magnesemia. Magnes Res. 2011;24:S101-S108.

125. Banki NF, Ver A, Wagner LJ, et al. Aldosterone antagonists in mono-therapy are protective against streptozotocin-induced diabetic nephrop-athy in rats. PLoS ONE. 2012;7:e39938.

126. Davis SM, Maddux AB, Alonso GT, et al. Profound hypokalemia associated with severe diabetic ketoacidosis. Pediatr Diabetes. 2016;17:61-65.

127. Naeem MA, Al-Alem HA, Al-Dubayee MS, et al. Characteristics of pedi-atric diabetic ketoacidosis patients in Saudi Arabia. Saudi Med J. 2015;36:20-25.

128. Uribarri J, Oh MS, Carroll HJ, et al. Hyperkalemia in diabetes mellitus. J Diabet Complications. 1990;4:3-7.

129. Phumeetham S, Bahk TJ, Abd-Allah S, et al. Effect of high-dose continu-ous albuterol nebulization on clinical variables in children with status asthmaticus. Pediatr Crit Care Med. 2015;16:e41-e46.

130. Welling PA, et al. Regulation of renal potassium secretion: molecular mechanisms. Semin Nephrol. 2013;33:215-228.

131. Lee Hamm L, Hering-Smith KS, Nakhoul NL, et al. Acid-based and potassium homeostasis. Semin Nephrol. 2013;33:257-264.

132. Frank BS, et al. Hypokalemia following fresh-water submersion injuries. Pediatr Emerg Care. 1987;3:158-159.

133. Cheng CJ, Kuo E, Huang CL, et al. Extracellular potassium homeostasis: insights from hypokalemic periodic paralysis. Semin Nephrol. 2013;33:237-247.

134. Gomez-Torres JY, Bravo-Llerena WE, Reyes-Ortiz LM, et al. Thyrotoxic hypokalemic periodic paralysis is a rare but potentially fatal emergency: case report and literature review. Bol Asoc Med P R. 2011;103:67-74.

135. Ananda S, Shaohua Z, Liang L, et al. Fatal barium chloride poisoning: four cases report and literature review. Am J Forensic Med Pathol. 2013;34:115-118.

136. Setime MA, Sesay S, Cainelli F, et al. A case of severe hypokalemic myopathy due to clay ingestion. Isr Med Assoc J. 2013;15:524-525.

137. Choi KB, et al. Hypertensive hypokalemic disorders. Electrolyte Blood Press. 2007;5:34-41.

138. Jain G, Ong S, Warnock DG, et al. Genetic disorders of potassium homeostasis. Semin Nephrol. 2013;33:300-309.

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Renal, Fluids, Electrolytes1025.e4 Section V

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chapter 73 - fluid and electrolyte issues in pediatric

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