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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_2804_Библиотеки_им_академика_М_И_Перельмана
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diabetesinsipidus;↓K+,hypokalemia;(+),conditionswithincrease inurine osmolalityinresponsetodesmopressinacetate; (−),
conditionswithlittleincreaseinurineosmolalityinresponsetodesmopressinacetate.
The appropriate renal response to hypernatremia is a small volume of concentrated urine (urine
osmolality >800 mOsm/L). Urine osmolality <800 mOsm/L suggests a defect in renal water
conservation.
Aurineosmolality<300mOsm/LinthesettingofhypernatremiasuggestscompleteformsofCDIand
NDI.
Urine osmolality between 300 and 800 mOsm/L can occur from partial forms of DI as well as
osmoticdiuresis.Thetwocanbedifferentiatedbyquantifyingthedailysoluteexcretion(estimated
by the urine osmolality multiplied by urine volume in 24 hours). A daily solute excretion >900
mOsm/Ldefinesanosmoticdiuresis.
Response to DDAVP. Complete forms of CDI and NDI can be distinguished by administering the
vasopressinanalog DDAVP(10 μg intranasally)after careful waterrestriction.Theurineosmolality
should increase by at least 50% in complete CDI and does not change in NDI. The diagnosis is
sometimesdifficultwhenpartialdefectsarepresent.
TREATMENT
Rateofcorrection
Aggressivecorrectionofsymptomatichypernatremiaispotentiallydangerous,althoughtheriskis
notas welldefinedasovercorrectioninhyponatremia. Outof anabundanceofcaution,thewater
deficitshouldbereducedgraduallyandplasma[Na+]levelsshouldbereducedbynomorethan10–
12mEq/L/d.
Inchronichypernatremia,theriskoftreatment-relatedcomplicationsmaybeincreasedbecauseof
thecerebraladaptationtothechronichyperosmolarstate.Theplasma[Na+]shouldbeloweredata
moremoderaterate(between5and8mEq/L/d).
Intervention
Themainstayofmanagementistheadministrationofwater,preferablybymouthornasogastrictube.
Alternatively,5%dextroseinwater(D5W)orquarterNScanbegivenviaIV.
Theextentofthefreewaterdeficitcanbecalculatedbytheequation:
This free waterdeficitprovidesa targetamountofwaterthatshouldbe replaced tocorrectthe
hypernatremia.
Therateofwateradministrationcanbeestimatedbydividingthisamountbythetimeframeover
whichhypernatremiashouldbenormalizedtoachievethetargetrateofcorrectionoutlinedabove.
□ Example:Fora3-Lfreewaterdeficitthatyouwishtocorrectover24hours,theD5Wcanbe
runat3L/24h=125mL/h.
□ ItshouldbenotedthatthisequationdoesNOTaccountforongoingfreewaterlosses.Usingthis
equationalonewithoutconsideringongoinglossesthroughGIor renalexcretion mayresultin
anunderestimationoftheamountofwaterrequiredtocorrectapatient’shypernatremia.
Nosingleequationadequatelycaptures thedynamic input andoutput offree water ina patient.
Becauseofthis,itiscriticallyimportanttorechecklaboratorydatatoensurethatanappropriate
rateofcorrectionisbeingachieved.
Specifictherapiesfortheunderlyingcause
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Hypovolemichypernatremia. Inpatients withmild volume depletion, Na+-containingsolutions
suchas0.45%NScanbeusedtoreplenishtheECFaswellasthewaterdeficit.Ifpatientshave
severe orsymptomatic volume depletion,correctionofvolume status withisotonic fluidshould
take precedenceover correctionofthe hyperosmolar state.Oncethe patientishemodynamically
stable,hypotonicfluidcanbegiventoreplacethefreewaterdeficit.
Hypernatremia from primary Na+gain is unusual. Cessation of iatrogenic Na+ is typically
sufficient.
DIwithouthypernatremia.DIisbesttreatedbyremovingtheunderlyingcause.Despitetherenal
waterloss,DIshouldnotresultinhypernatremiaifthethirstmechanismremainsintact.However,
treatmentissometimesrequiredtoalleviatesymptomaticpolyuria.
□ CDI.Becausethepolyuriaistheresultofimpairedsecretionofvasopressin,treatmentisbest
accomplishedwiththeadministrationofDDAVP,avasopressinanalog.
□ NDI.Alow-Na+dietcombinedwiththiazidediureticswilldecreasepolyuriabyinducingmild
volume depletion. This enhances proximal reabsorption of salt and water, thus decreasing
urinary free water loss. Decreasing protein intake will further decrease urine output by
minimizingthesoluteloadthatmustbeexcreted.
Potassium
Potassiumisthemajorintracellularcation.
TheK+intakeofindividualsonanaverageWesterndietisapproximately1mEq/kg/d,90%ofwhichis
absorbed by the GI tract. Maintenance of the steady state necessitates matching K+ excretion with
ingestion.
Theeliminationofpotassiumoccurspredominatelythroughrenalexcretion.Itishighlydependenton
thedistalurineflowrateandaldosterone,bothofwhichenhanceNareabsorptioninexchangeforK+
secretioninthedistalnephron.
Hypokalemia
GENERALPRINCIPLES
Hypokalemiaisdefinedasaplasma[K+]<3.5mEq/L.
Truehypokalemiamayresultfromoneormoreofthe following:(1)decreasednetintake,(2) shift
intocells,or(3)increasednetloss.
Diminished intake is seldom the sole cause of K+ depletion because urinary excretion can be
effectively decreased to <15 mEq/d. However, dietary K+ restriction may exacerbate the
hypokalemiafromGIorrenalloss.
Transcellularshift. Movement of K+ into cells may transientlydecrease theplasma[K+] without
altering total body K+ content.These shifts canresult from alkalemia, insulin, and catecholamine
release.Hypokalemicperiodicparalysisisararedisorderthatpredisposespatientstotranscellular
K+ shifts that resultinepisodic muscle weakness. Thehypokalemic form can be triggered after a
carbohydrate-richmeal.
NonrenalK+loss.Hypokalemiamayresultfromthelossofpotassium-richfluidsfromthelowerGI
tract. Hypokalemia from the loss of upper GI contents is typically more attributable to renal K
+
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secretionfromsecondaryhyperaldosteronism.
RenalK+lossaccountsformostcases ofchronichypokalemia. Thismay be caused byany ofthe
followingfactors:
Augmented distal urine flow occurs commonly with diuretic use and osmotic diuresis (e.g.,
glycosuria).BartterandGitelmansyndromesmimicdiureticuseandpromoterenalK+lossbythe
samemechanism.
Hyperaldosteronism canresultin increased renal K+ loss because aldosteroneplays a central
roleincouplingthereabsorptionofsodiumwiththeexcretionofpotassium.
□ Primarymineralocorticoidexcesscanbetheresultofanadrenaladenomaoradrenocortical
hyperplasia.
□ Cortisolalsohasanaffinityformineralocorticoidreceptorsbutistypicallyconvertedquickly
tocortisone,whichhasmarkedlylessmineralocorticoidactivity.Still,ifcortisolispresentin
abundance (Cushing syndrome) or fails to be converted to cortisone (syndrome of
mineralocorticoidexcess),itmaymimichyperaldosteronism.
□ Secondary hyperaldosteronism can be seen in any situation with a decreased effective
circulatingvolume.
□ ConstitutiveactivationofthedistalrenalepithelialNa+channelcanmimichyperaldosteronism.
This occurs in a number of monogenic disorders, including Liddle syndrome, and leads to
hypertension andhypokalemia. Unlikeprimaryor secondaryhyperaldosteronism,aldosterone
levelsareoftensuppressedindisordersoftheepithelialNa+channel.
DIAGNOSIS
ClinicalPresentation
Theclinical features ofK+depletionvarygreatlyandtheirseverity dependsinpartonthedegree of
hypokalemia.Symptomsseldomoccurunlesstheplasma[K+]is<3.0mEq/L.
Fatigue, myalgias, and muscular weakness or cramps of the lower extremities are common.Smooth
muscle function may also be affected and may manifest with complaints of constipation or frank
paralytic ileus. Severe hypokalemia may lead to complete paralysis, hypoventilation, or
rhabdomyolysis.
DiagnosticTesting
Whentheetiologyisnotimmediatelyapparent,renalK+excretionandtheacid–basestatuscanhelp
identifythecause.
Urine K+. The appropriate response to hypokalemia is to excrete <25 mEq/d of K+ in the urine.
UrinaryK+excretioncanbemeasuredwitha24-hoururinecollectionorestimatedbymultiplyingthe
spoturine[K+]bythetotaldailyurineoutput.Aspoturine[K+]maybehelpful(urine[K+]<15mEq/L
suggestsappropriateK+conservation),buttheresultscanbeconfoundedbyavarietyoffactors.
Acid–base status. Intracellular shifting and renal excretion of K+ are often closely linked with the
acid–basestatus.Hypokalemiaisgenerallyassociatedwithmetabolicalkalosisandcanplayacritical
role in the maintenance of metabolic alkalosis. The finding of metabolic acidosis ina patient with
hypokalemia thus narrows the differential significantly, implying lower GIloss, distal renal tubular
acidosis (RTA), or the excretion of a nonreabsorbable anion from an organic acid (diabetic
ketoacidosis[DKA],hippuratefromtolueneintoxication).
ECGchangesassociatedwithhypokalemiaincludeflatteningorinversionoftheTwave,aprominent
U wave, ST-segmentdepression,and a prolongedQU interval. Severe K+ depletionmay resultin a
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prolongedPRinterval,decreasedvoltage,andwideningoftheQRScomplex.
TREATMENT
The therapeutic goals are to safely correct the K+ deficit and to minimize ongoing losses through
treatmentoftheunderlyingcause.Hypomagnesemiashouldalsobesoughtinallhypokalemicpatients
andcorrectedtoalloweffectiveK+repletion.
CorrectionoftheK+deficitcanbeaccomplishedwitheitheroralorIVtherapy.
Oraltherapy.ItisgenerallysafertocorrecttheK+deficitviatheoralroutewhenhypokalemiaismild
andthepatientcantolerateoraladministration.Oraldosesof40mEqaregenerallywelltoleratedand
canbegivenasoftenasevery4hours.Traditionally,10mEqofpotassiumsaltsaregivenforeach0.10
mEq/L decrement in serum [K+]. However, with increasing severity of hypokalemia, this grossly
underestimatestheK+necessarytonormalizetotalK+content.Furthermore,astheK+shiftsbacktothe
intracellular space, it mayappear as thoughK+ supplementation is doing verylittle to correct ECF
[K+].In suchcases,potassiumsupplementationshouldbeincreased andcontinueduntilserum levels
rise.
IVtherapy.Patientswithimminentlylife-threatening hypokalemia andthosewhoare unable to take
anything by mouth require IV replacement therapy with KCl. The maximum concentration of
administeredK+shouldbe nomorethan40 mEq/L viaa peripheral veinor100mEq/L viaacentral
vein. The rate of infusion should not exceed 20 mEq/h unless paralysis or malignant ventricular
arrhythmiasarepresent.RapidIVadministrationofK+shouldbeusedjudiciouslyandrequiresclose
observation.
Hyperkalemia
GENERALPRINCIPLES
Hyperkalemiaisdefinedasaplasma[K+]>5.0mEq/L.
Pseudohyperkalemiarepresentsanartificiallyelevatedplasma[K+]duetoK+movementoutofcells
immediately before or following venipuncture. Contributing factors include repeated fist clenching,
hemolysis,andmarkedleukocytosisorthrombocytosis.
Truehyperkalemiaoccursasaresultofoneofthefollowing:
Transcellular shift. Insulin deficiency, hyperosmolality, nonselective β-blockers, digitalis,
metabolicacidosis(excludingthosefromorganicacids),anddepolarizingmusclerelaxants,suchas
succinylcholine,releaseK+fromICFstoresintotheECFcompartment.Thereleaseofintracellular
K+canalsobeseenaftersevereexercise,rhabdomyolysis,andtumorlysissyndrome.
IncreasedexposuretoK+israrelythesolecauseofhyperkalemiaunlessthereisanimpairmentin
renalexcretion.FoodswithahighcontentofK+includesaltsubstitutes,driedfruits,nuts,tomatoes,
potatoes, spinach, bananas, andoranges. Juices derived from these foods may be especially rich
sources.
DecreasedrenalK+excretion.Inthesettingofhyperkalemia,thekidneyiscapableofgeneratinga
significant urinary excretion of K+. This process can be impaired by a number of processes,
including volume depletion, renal injury, adrenal insufficiency, and hyporeninemic
hypoaldosteronism(type4RTA).
Drugs may also be implicated in the genesis of hyperkalemia through a variety of mechanisms.
Common culprits include angiotensin-converting enzyme inhibitors, angiotensin receptor blockers,
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potassium-sparingdiuretics,NSAIDs,andcyclosporine.Heparinandketoconazolecanalsocontribute
to hyperkalemia through the decreased production of aldosterone, although these agents alone are
typicallyinsufficienttosustainaclinicallysignificanthyperkalemia.
DIAGNOSIS
ClinicalPresentation
Themostseriouseffectofhyperkalemiaiscardiacarrhythmogenesissecondarytopotassium’spivotal
role inmembranepotentials.Patientsmaypresentwithpalpitations,syncope,orevensuddencardiac
death.
Severe hyperkalemia causes partial depolarization of the skeletal muscle cell membrane and may
manifestasweakness,potentiallyprogressingtoflaccidparalysisandhypoventilationiftherespiratory
musclesareinvolved.
DiagnosticTesting
Iftheetiologyisnotreadilyapparentandthepatientisasymptomatic,pseudohyperkalemiashouldbe
excludedbyrecheckinglaboratorydata.
Anassessmentofrenal[K+]excretionandtherenin–angiotensin–aldosteroneaxiscanhelpnarrow
thedifferentialdiagnosiswhentheetiologyisnotimmediatelyapparent.
Low aldosterone levels suggest either adrenal disease (renin levels elevated) or hyporeninemic
hypoaldosteronism(reninlevelslow;occurswithtype4RTA).
Highaldosteronelevels,typicallyaccompaniedbyhighreninlevels,suggestaldosteroneresistance
(pseudohypoaldosteronism)butcanalsobeseeninK+-sparingdiuretics.
ECG changes include increased T-wave amplitude or peaked T waves. More severe degrees of
hyperkalemia resultinaprolongedPRinterval andQRSduration,atrioventricularconductiondelay,
and loss of P waves. Progressive widening of the QRS complex and its merging with the T wave
produceasinewavepattern.Theterminaleventisusuallyventricularfibrillationorasystole.
TREATMENT
SeverehyperkalemiawithECGchangesisamedicalemergencyandrequiresimmediatetreatment
directedatminimizingmembranedepolarizationandacutelyreducingtheECF[K+].Acutetherapymay
consistofsomeorallofthefollowing(thehypokalemiceffectisadditive):
Calciumgluconatedecreasesmembraneexcitabilitybutdoesnotlower[K+].Theusualdoseis10mL
ofa10%solutioninfusedover2–3minutes.Theeffectbeginswithinminutesbutisshortlived(30–60
minutes),andthedosecanberepeatedifnoimprovementintheECGisseenafter5–10minutes.
Insulin causes K+ to shift into cells and temporarily lowers the plasma [K+]. A commonly used
combinationis10–20unitsofregularinsulinand25–50gofglucoseadministeredIV.Hyperglycemic
patientsshouldbegiventheinsulinalone.
NaHCO3iseffectiveforseverehyperkalemiaassociatedwithmetabolicacidosis.Intheacutesetting,
itcanbegivenasanIVisotonicsolution(threeampulesofNaHCO3in1Lof5%dextrose).
β2-AdrenergicagonistspromotecellularuptakeofK+.Theonsetofactionis30minutes,loweringthe
plasma[K+]by0.5–1.5mEq/L,andtheeffectlastsfor2–4hours.Albuterolcanbeadministeredina
doseof10–20mgasacontinuousnebulizedtreatmentover30–60minutes.
Longertermmeansfor[K+]removal.
IncreasingdistalNa+deliveryinthekidneyenhancesrenalK+clearance.Thiscanbeachievedwith
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the administration of salineinpatients whoappear volume depleted. Otherwise, diuretics can be
usedifrenalfunctionisadequate.
Cation exchange resins, such as sodium zirconium cyclosilicate and patiromer, promote the
excretion of K+ in the GI tract and can be used in the management of chronic or resistant
hyperkalemia. Both agents appear to be effective, well tolerated, and safe. The usual dose of
patiromer is 8.4 gmixedwith 100 mL of water, given daily. Sodium zirconium cyclosilicate may
haveafasteronsetofactionandisusuallyinitiatedat10guptothreetimes/day.
Dialysis should be reserved for patients with renal failure and those with severe life-threatening
hyperkalemiawhoareunresponsivetomoreconservativemeasures.
Chronic therapymayinvolvedietarymodificationstoavoid highK+foods,correction ofmetabolic
acidosiswithoralalkali,thepromotionofkaliuresiswithdiuretics,and/oradministrationofexogenous
mineralocorticoidinstatesofhypoaldosteronism.
Calcium
Approximately99%ofbodycalciumisinbone;mostoftheremaining1%isintheECF.Nearly50%
ofserumcalciumisionized(free),whereastheremainderiscomplexedtoalbumin(40%)andanions
suchasphosphate(10%).
Calciumbalanceisregulatedbyparathyroidhormone(PTH)andcalcitriol.
PTHincreasesserumcalciumbystimulatingboneresorption,increasingcalciumreclamationinthe
kidney, and promoting renal conversionof vitamin D to calcitriol. Serum calcium regulates PTH
secretion by a negative feedback mechanism: Hypocalcemia stimulates and hypercalcemia
suppressesPTHrelease.
Calcitriol[1,25-dihydroxycholecalciferol,1,25-dihydroxyvitaminD3,or1,25(OH)2D3]istheactive
form of vitamin D. It stimulates intestinal absorption of calcium and is one of many factors that
providefeedbacktotheparathyroidgland.
Hypercalcemia
GENERALPRINCIPLES
Aserumcalcium>10.3mg/dLwithanormalserumalbuminoranionizedcalcium>5.2mg/dLdefines
hypercalcemia.
ClinicallysignificanthypercalcemiatypicallyrequiresbothanincreaseinECFcalciumandadecrease
inrenal calcium clearance.Underlyingdisturbances tocalcium metabolism are thus often maskedby
compensatorymechanismsuntil thepatient develops a concomitantdisorder,such as decreased renal
clearancefromvolumedepletion.Morethan90%ofcasesareduetoprimaryhyperparathyroidismor
malignancy.
Primaryhyperparathyroidismcausesmostcasesofhypercalcemiainambulatorypatients.
Malignancy is responsible for most cases of hypercalcemia among hospitalized patients. Patients
usuallyhaveadvanced,clinicallyobviousdisease.Inthesepatients,hypercalcemiamaydevelopfrom
stimulation of osteoclast bone resorption from tumor cell products, tumor-derived PTH-related
peptide(PTHrP),andtumorcalcitriolproduction.
Lesscommoncausesaccountforabout10%ofcasesofhypercalcemiaandincludeincreasedvitamin
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D activity (exogenous exposure to vitamin D or increased generation of calcitriol in chronic
granulomatous diseases),themilk-alkalisyndrome(acuteorchronicdevelopment ofhypercalcemia,
alkalosis, and renal failure from the ingestion of large quantities of calcium-containing antacids),
adrenalinsufficiency,prolongedimmobilization,Pagetdisease,andacromegaly.
DIAGNOSIS
ClinicalPresentation
Clinicalmanifestationsgenerallyarepresentonlyifserumcalciumexceeds12mg/dLandtendtobemore
severeifhypercalcemiadevelopsrapidly.Mostpatientswithprimaryhyperparathyroidismhave
asymptomatichypercalcemiathatisfoundincidentally.Symptomsincluderenalmanifestations(polyuria
andnephrolithiasisandriskofrenalfailurewithnephrocalcinosiswhencalciumlevelrisesabove13
mg/dL),GIsymptoms(anorexia,vomiting,constipation),andneurologicsymptoms(weakness,fatigue,
confusion,stupor,andcoma).
DiagnosticTesting
Serum calciumshould be interpreted withknowledge of the serum albumin, or an ionized calcium
should be measured. Corrected [Ca
2+
] = [Ca2+] + {0.8 × (4.0 − [albumin])}. Many patients with
primary hyperparathyroidism will have a calcium level that is chronically within the high-normal
range.
IntactserumPTHmaybethemostimportantfirststepintheevaluationofhypercalcemia.
ElevationsinECFcalciumtypicallyresultinsuppressionofPTH.Thus,thefindingofanormalor
elevatedintactPTHinthesettingofhypercalcemiaissuggestiveofprimaryhyperparathyroidism.
Whenthe intactPTHisappropriatelysuppressed,PTHrP canbemeasuredtoinvestigatepossible
humoralhypercalcemiaofmalignancy.
1,25(OH)2D3levelsareelevatedingranulomatous disorders,primaryhyperparathyroidism,calcitriol
overdose,andacromegaly.
Serumphosphorusisoftendecreasedinhyperparathyroidismbecauseofstimulationofphosphaturia,
whereasPagetdiseaseandvitaminDintoxicationbothtendtohaveincreasedphosphoruslevels.
Urinecalciummaybeelevatedinprimaryhyperparathyroidismbecauseofafilteredloadofcalcium
that exceeds the capacity for renal reabsorption. If the family history and clinical picture are
suggestive,patientswithfamilialhypocalciurichypercalcemiacanbedistinguishedfrompatientswith
primary hyperparathyroidism by documenting a low calcium clearance by 24-hour urine collection
(<200mgcalciumperday)orfractionalexcretionofcalcium(<1%).
ECGmay reveala shortenedQTinterval and,withverysevere hypercalcemia, variable degrees of
atrioventricularblock.
TREATMENT
Acute management of hypercalcemia is warranted if severe symptoms are present or with serum
calcium>12mg/dL.Thefollowingregimenispresentedintheorderthattherapyshouldbegiven.
Correction of hypovolemia with 0.9% saline fluid is mandatory in patients who demonstrate
volume depletion,because hypovolemia prevents effective calciuresis. Maintenance fluids can be
continuedafterachievingeuvolemiatosustainaurineoutputof100–150mL/h.Thepatientshouldbe
monitoredcloselyforsignsofvolumeoverload.
IV bisphosphonates can be used to decrease the liberation of calcium from bone in persistent
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hypercalcemia. Pamidronate 60 mg is infused over 2–4 hours; for severe hypercalcemia (>13.5
mg/dL), 90 mg can be given over the same duration. A hypocalcemic response is typically seen
within2 days and may persist for 2 weeks or longer. Treatment can be repeated after 7 days if
hypercalcemia recurs. Zoledronate is a more potent bisphosphonate that is given as a 4-mg dose
infusedoveratleast15minutes.Hydrationshouldprecedebisphosphonateuse.Renalinsufficiency
isarelativecontraindication.
Otheroptions
Calcitonin inhibitsboneresorptionandincreases renalcalciumexcretion. Salmon calcitonin,4–8
IU/kgIMorSCevery6–12hours,lowersserumcalcium1–2mg/dLwithinseveralhoursin60%–
70%ofpatients.Althoughitislesspotentthanotherinhibitorsofboneresorption,ithasnoserious
toxicity,issafeinrenalfailure,andmayhaveananalgesiceffectinpatientswithskeletalmetastases.
Glucocorticoidsareeffectiveinhypercalcemiaduetohematologicmalignanciesandgranulomatous
productionofcalcitriol.Theinitialdoseis20–60mg/dofprednisoneoritsequivalent.Afterserum
calciumstabilizes,thedoseshouldbegraduallyreducedtotheminimumneededtocontrolsymptoms
ofhypercalcemia.
Denosumab is a receptoractivator of nuclear factorkappa-B ligandinhibitor that canbe used in
patients with hypercalcemia that is refractory to bisphosphonates or in patients with a
contraindicationtobisphosphonatetherapy,suchaspatientswithchronickidneydisease.Itisgiven
atadoseof120mgSCweeklyfor4weeksandthenmonthly.
Dialysis.Hemodialysisandperitonealdialysisusinglowcalciumdialysateareeffectiveforpatients
withveryseverehypercalcemia(>16mg/dL)andCHForrenalinsufficiency.
Chronicmanagementofhypercalcemia
Primaryhyperparathyroidism. In manypatients,this disorder hasa benign course, with minimal
fluctuationinserum calcium concentration andnoobviousclinicalsequelae.Parathyroidectomyis
indicatedinpatientswith(1)correctedserumcalcium>1.0mg/dLabovetheupperlimitofnormal,
(2)creatinineclearance<60mL/min,(3)age<50years,and(4)bonedensityathip,lumbarspine,
or distal radius>2.5 standarddeviationsbelow peakbonemass (Tscore <−2.5)and/orprevious
fragilityfracture.3Surgicalinterventiontypicallyhasahighsuccessrate(95%)withlowmorbidity
andmortality.
Medical therapy may be a reasonable option in asymptomatic patients who are not surgical
candidates. Management consists of liberal oral hydration with a high-salt diet, daily physical
activity tolessenboneresorption, and avoidance of thiazide diuretics. Oral bisphosphonates and
estrogen replacement therapy or raloxifene in postmenopausal women can be considered in the
appropriateclinicalcontext.Cinacalcet,anactivatorofthecalcium-sensingreceptor,hasalsobeen
showntoreducePTHsecretionandserumcalciumlevels.
Malignant hypercalcemia. Bisphosphonate and glucocorticoid therapy with a calcium-restricted
diet(<400mg/d) canbe tried, although these maneuvers rarelyyield long-termsuccess unless the
malignancy responds to treatment. Denosumab may be used in patients with persistent
hypercalcemia of malignancy in whom bisphosphonates may be contraindicated because of renal
failure.
Hypocalcemia
GENERALPRINCIPLES
Aserumcalcium<8.4mg/dLwithanormalserumalbuminoranionizedcalcium<4.2mg/dLdefines
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hypocalcemia.
Effective hypoparathyroidism. ReducedPTHactivity can resultfrom decreased PTH release from
autoimmune, infiltrative, or iatrogenic (e.g., post-thyroidectomy) destruction of parathyroid tissue.
ReleaseofPTHisalsoimpairedwithbothhypomagnesemia(<1mg/dL)andseverehypermagnesemia
(>6mg/dL).
Vitamin D deficiency lowers total body calcium but does not usually affect serum calcium levels
unless the deficiency is severe because the resultant secondary hyperparathyroidism often corrects
serumcalciumlevels. SignificantvitaminDdeficiency canoccurintheelderlyorthosewithlimited
sun exposure, advanced liver disease (due to decreased synthesis of precursors), and nephrotic
syndrome. Reduced activity in vitamin D activation via 1-α-hydroxylase activity can be seen with
vitaminD–dependentricketsandchronicrenalinsufficiency.
Serum calcium levels may also be reducedbyprofoundelevations inserum phosphorus or oxalate,
which bind with the calcium and deposit in various tissues. Calcium can also be bound by citrate
(during transfusion of citrate-containing blood products or with continual renal replacement using
citrateanticoagulation)aswellasbydrugssuchasfoscarnetandfluoroquinolones.Increasedbinding
toalbumincanalso be seen in the context of alkalemia, whichincreases theexposureofnegatively
chargedbindingsitesonalbumin.
DIAGNOSIS
ClinicalPresentation
Clinicalmanifestationsvarywiththedegreeofhypocalcemiaandrateofonset.
Acute, severe hypocalcemiamaycauselaryngospasm,confusion,seizures, orvascular collapse with
bradycardiaanddecompensatedheartfailure.
Acute, moderate hypocalcemia may cause increased excitability of nerves and muscles, leading to
circumoralordistalparesthesiasandtetany.
Trousseau sign is the development of carpal spasm when a blood pressure cuff is inflated above
systolicpressurefor3minutes.Chvosteksignreferstotwitchingofthefacialmuscleswhenthefacial
nerveistappedanteriortotheear.Thepresenceofthesesignsisknownaslatenttetany.
DiagnosticTesting
Laboratory data should be used to evaluate the calcium–PTH axis as well as concurrent mineral
abnormalities.
Albumin should be measured when there is an abnormality in serum calcium levels to rule out
pseudohypocalcemia.
Serum PTH that is low or inappropriately normal in the setting of hypocalcemia is indicative of
hypoparathyroidism. A high PTH is often found with vitamin D deficiency, PTH resistance, and
hyperphosphatemia.
SerumphosphorusisoftenhelpfulinidentifyingvitaminDdeficiency(lowcalcium,lowphosphorus)
orintravascularchelationofcalcium(lowcalcium,highphosphorus).
VitaminDstoresareusuallyassessedbymeasuringonly25(OH)D3becausecalcitriol[1,25(OH)2D3]
levelscanbenormalizedthroughthecompensatoryincreaseof1-α-hydroxylaseactivity.
Magnesiumdeficiencyshouldalwaysberuledoutduringmanagementofhypocalcemia.
ECGmayshowaprolongedQTintervalandbradycardia.
TREATMENT
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Acutemanagementofsymptomatichypocalcemiarequirespromptandaggressivetherapy.
Phosphorus must first be checked. In severe hyperphosphatemia (>6.5 mg/dL), administration of
calcium will increase the calcium–phosphorusproduct and may exacerbatethe formation of ectopic
calcifications.In acute,symptomatic hypocalcemia with severe hyperphosphatemia, dialysis maybe
neededtoacutelymanagethemineralabnormalities.Ifthehypocalcemiaisasymptomatic,areduction
ofphosphorusshouldprecedeaggressivecalciumsupplementation.
Hypomagnesemia,ifpresent,mustbetreatedfirsttoeffectivelycorrectthehypocalcemia.
Calciumsupplementation. IV calcium should be reserved for severe or symptomatic hypocalcemia
and can be administered as calcium chloride or calcium gluconate. Calcium gluconate is typically
favored because of reduced risk of tissue toxicity with extravasation. Calcium gluconate is often
preparedasa10% solution(100 mgofcalciumgluconateper mL). Oneampule (10 mL) ofcalcium
gluconatethuscontains1000mgofcalciumgluconateandapproximately90mgofelementalcalcium.
Chronicmanagement.TreatmentrequirescalciumsupplementsandvitaminDoritsactivemetabolite
toincreaseintestinalcalciumabsorption.
Oralcalciumsupplements. Calciumcarbonate(40%elemental calcium) orcalciumacetate(25%
elementalcalcium)canbegivenwiththegoaladministrationof1–2gofelementalcalciumPOtid.
Calciumsupplementationshouldbegivenapartfrommealstominimizebindingwithphosphorusand
maximizeentericabsorption.
VitaminD.Simpledietarydeficiencycanbecorrectedbytheuseofergocalciferol400–1000IU/d.
A6-to8-weekregimenof50,000IUshouldbedosedweeklyinthosewithunderlyingimpairments
invitaminDmetabolism(i.e.,renalinsufficiency)anddailyinpatientswithseveremalnutritionor
malabsorption.
Incomparison,calcitriolhasamuchmorerapidonsetofaction.Theinitialdosageis0.25μgdaily,
andmostpatientsare maintainedon 0.5–2.0 μgdaily. Thedose canbe increased at2- to 4-week
intervals. Because calcitriol increases enteric absorption of phosphorus as well as calcium,
phosphoruslevelsshouldbemonitored andoralphosphatebindersinitiatedifphosphorusexceeds
thenormalrange.
Phosphorus
Approximately85%oftotalbodyphosphorus isinbone,andmostofthe remainderiswithincells.
Thus,serumphosphoruslevelsmaynotreflecttotalbodyphosphorusstores.
Phosphorusbalanceisdeterminedprimarilybyfourfactors:
PTHregulatestheincorporationandreleaseofmineralsfrombonestoresanddecreasesproximal
tubularreabsorptionofphosphate,causingurinarywasting.
Thephosphateconcentrationitselfregulatesrenalproximalreabsorption.
Insulinlowersserumlevelsbyshiftingphosphateintocells.
Calcitriol[1,25(OH)2D3]increasesserumphosphatebyenhancingintestinalphosphorusabsorption.
Hyperphosphatemia
GENERALPRINCIPLES
Aserumphosphate>4.5mg/dLdefineshyperphosphatemia.
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