Ebook Decision making in emergency critical care: Part 2

26
Pancreatitis
SusanY.QuanandWalterG.ParkBACKGROUND

Thepancreasisapproximately6to10incheslong,islocateddirectlybehindthe
stomach, and has distinct endocrine and exocrine functions. The endocrine
portionofthepancreasiscomposedofisletsofLangerhanscellsthatconstitute
about 2% of the organ. These cells produce and secrete hormones including
insulin, glucagon, and somatostatin. The exocrine portion of the pancreas is
composedofacinarcells(80%oftheorgan)andductalcells(18%oftheorgan).
Acinar cells produce digestive enzymes that are sequestered until physiologic
impulsesstimulatetheirreleaseintothepancreaticductalsystemwheretheyare
transportedtothesmallintestine.Thedigestiveenzymesareenzymaticallyinert
until activated in the small intestine by various peptides. Disruption of this
physiologicprocess,byanyofavarietyofetiologies,isthebasisforourcurrent
understanding ofacuteandchronicpancreatitis.Thischapterprimarilyfocuses
on acute pancreatitis, which is more commonly seen in emergency care.
Pertinentaspectsofchronicpancreatitisarealsoaddressed.

ACUTEPANCREATITIS
Theincidenceofacutepancreatitisisestimatedtobeashighas38per100,000
patients and accounts for more than 220,000 hospital admissions in the United
States annually.1 Most cases are clinically mild and self-limited; a minority of
cases are severe and are associated with critical illness, prolonged
hospitalization,infection,organfailure,anddeath.
Acute pancreatitis occurs from premature activation of digestive enzymes
withinthepancreaticparenchymaleadingtoanautodigestiveandinflammatory
process. Evolution into a life-threatening systemic process begins when acinar
cell injury leads to expression of endothelial adhesion molecules that further
potentiates the inflammatory response. Local microcirculatory failure and
ischemia–reperfusion injury ensue, with some patients developing systemic

complicationssuchassystemicinflammatoryresponsesyndrome(SIRS),acute
respiratorydistresssyndrome,andmultiorganfailure.
The most common causes of acute pancreatitis are gallstones and excess
alcohol ingestion. These account for about 45% and 35% of cases,
respectively.2,3 Hypertriglyceridemia accounts for up to 5% of cases. Other
causes include hypercalcemia, autoimmune diseases, infections, medications,
trauma,
and
complications
after
endoscopic
retrograde
cholangiopancreatography(ERCP)(Table26.1).Controversialetiologiesinclude
pancreatic divisum and sphincter of Oddi dysfunction. Idiopathic pancreatitis
occursinupto20%ofpatients,andbydefinition,thecauseisnotestablishedby
history,physicalexam,routinelaboratorytests,orimaging.
TABLE

26.1

Causes

of

Acute

Pancreatitis

HistoryandPhysicalExam
Thetypicalpresentationincludesaconstant(asopposedtowaxingandwaning)
upper abdominal pain located primarily in the epigastric area with radiation to
the back. The onset of pain is rapid and typically reaches maximum intensity
within 10 to 20 minutes. Pain that lasts only a few hours is unlikely to be
pancreatitis.About90%ofpatientswillalsocomplainofnauseaandvomiting.
Mild pancreatitis may involve minimal abdominal tenderness without
guarding. In severe disease, abdominal tenderness can be elicited with
superficialpalpation.Abdominaldistentionandreducedbowelsoundscanoccur


secondarytoileus.Extravasationofhemorrhagicpancreaticexudatecanleadto
ecchymosis in one or both flanks (Turner sign) or the periumbilical regions
(Cullensign).Severediseaseshouldbesuspectedwithabnormalvitalsignsthat
can include fever, tachycardia, tachypnea, and hypotension. These signs
represent a transition from localized retroperitoneal inflammation to one of
systemic inflammation. Pleural effusions and mental status changes are also
hallmarksofseveredisease.Thepresenceofjaundicemaysuggestanunderlying
alcoholismorcholedocholithiasis.

DiagnosticEvaluation
Acutepancreatitisisdiagnosedwhentwoofthefollowingthreecriteriaaremet:
(1)characteristicabdominalpain,(2)serumamylaseorlipasegreaterthanthree
timestheupperlimitofnormal,and,ifneeded,(3)radiologicimagingconsistent
with the diagnosis.4 Amylase and lipase are the most frequently used serumbased tests for pancreatitis. The most common source of amylase is not the
pancreas, but salivary glands. In contrast, 90% of lipase is made from the
pancreas,makingitamorespecificmarker.Amylaseriseswithin6to24hours
ofacutepancreatitisandpeaksin48hours,normalizingin3to7days.Lipase
has a longer half-life than amylase, with levels increasing within 4 to 8 hours,
peakingat24hours,andfallingover8to14days.5Thedegreeofelevationis

not a marker of disease severity, and mild elevation of these serum markers—
lessthanthreetimestheupperlimitofnormal—isnotspecificforpancreatitis.
The use of computed tomography (CT) or magnetic resonance imaging
(MRI) should only be considered when the first two diagnostic criteria are not
metand(1)thepretestprobabilityforpancreatitisremainshighor(2)thereisa
highpretestprobabilityforanotherabdominalprocess.Otherwise,CTandMRI
havenoroleandmayexacerbaterenalinjuryfromuseofintravenouscontrast.6
Such imaging can be considered 7 days later should the diagnosis remain
uncertain or to assess disease severity and identify complications related to
severe pancreatitis. Following clinical and laboratory parameters allows
adequateinitialassessmentofdiseaseseverity.Forpatientswithanestablished
history of chronic pancreatitis or recent acute pancreatitis, imaging may be
considered as part of the initial emergency department assessment for specific
treatable complications of pancreatitis including, but not limited to, enlarging
pseudocysts,arterialpseudoaneurysms,and/ornewcommonbilestones.

DifferentialDiagnosis
The differential diagnosis includes biliary colic, acute cholecystitis, acute


cholangitis,biliarydyskinesia,pepticulcerdisease,dyspepsia,acutemesenteric
ischemic,andbowelobstruction.Nongastrointestinaldisorders,includingacute
myocardial infarction, aortic dissection, pulmonary embolism, acute spinal
disorders,andrenalcalculi,shouldalsobeconsidered.

Complications
The majority of cases (80% to 90%) of pancreatitis are mild and self-limiting;
10% of cases, however, develop severe disease, defined as the presence of
significant fluid collections, infectious complications including abscess
formation,infectednecrosis,and/orextrapancreaticorganfailure.Thesepatients

typicallyexhibitSIRSorsepsisphysiology.
Fluidcollectionsaroundthepancreasaffectoverhalfofpatients.Mostwill
resolve, but for those that persist, a fibrogenic anti-inflammatory response will
lead to containment of these fluid collections, resulting in the formation of a
pseudocyst.Apancreaticpseudocystisafluidcollectionthatpersistsbeyond4
weeks.Othercomplicationsincludeinfections(arisingfrompancreaticnecrosis
or within pseudocysts), thrombosis (splenic, superior mesenteric, and/or portal
vein),arterialpseudoaneurysms,andgastrointestinalbleeding.Themortalityrate
forpatientswithseverepancreatitisisapproximately30%.Deathwithinthefirst
2 weeks of illness is usually due to multiorgan failure. Death after 2 weeks
typicallystemsfrominfection.

ManagementGuidelines
Once a diagnosis of acute pancreatitis is made, a risk stratification calculation
should be performed. Clinical risk scoring systems, such as Ranson's and
APACHEII,havetraditionallybeen used. However,botharecumbersome and
require 48 hours before a meaningful interpretation can be made. The Bedside
Index for Severity in Acute Pancreatitis (BISAP) score is a newer validated
scoring system that requires five data points of collection in the emergency
room.7,8Thisincludesabloodureanitrogen(BUN)>25mg/dL,impairedmental
status,SIRS,age>60,andthepresenceofapleuraleffusion(Table26.2).The
presenceofthreeormorefeaturesatadmissionisassociatedwitha7-to12-fold
increaseinorganfailure.Suchpatientsshouldbemanagedintheintensivecare
unit.
TABLE 26.2 Risk Stratification Scoring System for Severity of Acute
Pancreatitis


Initial treatment is primarily supportive and includes adequate fluid
resuscitation, pain control, and bowel rest.6 Fluid resuscitation is necessary to

replaceintravascularvolumedepletionthatoccursfromthird-spacelosses.The
amount of fluid should be calibrated to a urine output of 0.5 mL/kg/h. Initial
resuscitation may begin with 1 to 2 L of normal saline within the first several
hours of presentation. Early resuscitation appears to be clinically important in
reducing downstream complications. In a large retrospective analysis of 434
patients with acute pancreatitis, early compared to late resuscitation was
associated with less organ failure at 72 hours (5% vs. 10%), a lower rate of
admission to the intensive care unit (6% vs. 17%), and a reduced length of
hospitalstay(8vs.11days).9Afterearlyinitialbolustreatmentofintravenous
fluids, maintenance fluids should be titrated (up or down) to urine output. In
severe disease, aggressive fluid resuscitation is important to maintain adequate
vascular volume in the setting of SIRS or sepsis physiology.9 Pain can be
controlledwithintravenousshort-actingnarcoticpainmedications.Nauseaand
vomitingcanbecontrolledwithantiemeticmedicationsasneeded.
Acute pancreatitis is a hypercatabolic state, and initiating nutrition at 48
hoursfromonsetisimportant.Inmilddisease,patientscanbestartedonanoral
diet. For those with severe disease, enteral nutrition by nasojejunal feeding
shouldbestarted.Thecurrentrationalefornasojejunalfeedingisthatbypassing
theduodenumminimizespancreaticstimulation.Enteralnutritionissuperiorto
parenteral nutrition because it carries a lower risk for infectious complications
andmortality.10
Documentedinfectionsassociatedwithpancreatitisrequireprompttreatment
with carbapenem-based antibiotics to ensure optimal penetration. Antibiotic
prophylaxis,however,isnotindicated.11,12Endoscopyisindicatedforremoving
commonbileductstonesandsecondarycholangitis,andcholecystectomyshould
be planned during hospitalization for those with gallstone-related pancreatitis
identifiedbyrightupperquadrantultrasound.
For some patients who have no clinical or laboratory evidence to suggest

severe disease (i.e., a BISAP score of 0, no other laboratory abnormalities),
discharge from the emergency room can be considered. These patients should
alsohavemildenoughpaintobemanagedwithPOpainmedications,havethe
ability to consume liquids without vomiting, and be considered adequately
competentandcomplianttofollowinstructionstoreturntotheemergencyroom
forworseningsignsand/orsymptoms.

CHRONICPANCREATITIS
Chronicpancreatitisischaracterizedbychronicinflammationandfibrosiswith
destructionofexocrineandendocrinecells.Theincidenceisestimatedtobe6
cases per 100,000 people, and it affects about 0.04% of the US population.13
Although relatively uncommon, chronic pancreatitis is associated with a high
level of morbidity and use of health care resources.14 In the United States, the
mostcommoncauseischronicalcoholuse,accountingfornearly70%ofcases.
Itshouldbenotedthatonlyapproximately10%ofheavydrinkerseverdevelop
pancreatitis, suggesting an underlying genetic predisposition. In up to 20% of
patients, the etiology is idiopathic. The remaining 10% are due to obstructive
causes, metabolic derangements, autoimmune diseases, and hereditary
disorders.15

HistoryandPhysicalExam
Themostcommoncomplaintischronicabdominalpainthatisoftenassociated
with nausea and vomiting. In advanced disease, maldigestion develops from
pancreatic exocrine insufficiency and presents as chronic diarrhea with
unintentional weight loss. The stool is particularly odorous as most is
maldigested fat (also known as steatorrhea). Other late findings include
symptomsandsignsofdiabetes.
Mild abdominal tenderness with palpation may be elicited. An abdominal
massmayrepresentapseudocystorsplenomegaly.Splenomegalyoccursinthe
setting of splenic vein thrombosis—the result of chronic (or recurrent acute)

pancreaticinflammationinproximitytothesplenicvein—andcancompromise
venous return from the spleen with subsequent splenic engorgement and
splenomegaly. As alcohol is the most common precipitating cause of
pancreatitis,findingsofliverdiseaseincludinghepatomegaly,jaundice,ascites,
and hepatic encephalopathy may also be observed. Because of chronic
maldigestionoffat,thesepatientscanbefat-solublevitamindeficient(vitamins
A, D, E, and K), and this can lead to related examination findings including


peripheralneuropathy,fatigue,andsignsofeasybruisingandbleeding.

DiagnosticEvaluation
Diagnosis begins with an assessment of clinical symptoms, signs, and risk
factorsforchronicpancreatitis.CTcanbeusedfordiagnosingstructuralfeatures
associated with advanced disease including calcifications, atrophy, pancreatic
duct dilation, and/or strictures. CT may also show common complications
including pseudocysts, splenic vein thromboses, and inflammatory masses.
Magnetic resonance cholangiopancreatography may be used to evaluate the
pancreatic and biliary ducts without requiring ERCP. Endoscopic ultrasound
currentlyoffersthemostsensitiveimagingfordiagnosisofchronicpancreatitis.
Functional diagnostic tests for chronic pancreatitis include stool elastase, 72hourfecalfat,andsecretinstimulationtest.

DifferentialDiagnosis
The differential diagnosis for chronic pancreatitis includes gastritis, dyspepsia,
smallbowelbacterialovergrowth,intestinalobstruction,neoplasms,mesenteric
ischemia, biliary obstruction, celiac disease, inflammatory bowel disease,
Zollinger-Ellisonsyndrome,andfunctionalgutdisorderssuchasirritablebowel
syndrome.

Complications

Chronicpancreatitisisassociatedwithanearlyfourfoldincreaseinstandardized
mortalityrate,whichstemsmostlyfromcontinuedalcoholandtobaccoabuse.16
Commoncomplicationsincludepseudocysts,gastrointestinalbleeding,bileduct
obstruction,duodenalobstruction,andpancreaticfistulaformation.

ManagementGuidelines
Management of suspected chronic pancreatitis with increased abdominal pain
should include prompt and adequate analgesia (often requiring narcotic pain
medications) and assessment of hydration and nutrition status.17 Evaluation of
acute complications of chronic pancreatitis and nonpancreatic abdominal
emergencies should also occur though with judicious use of imaging. When
imaging suggests a main duct stricture, pancreatic ductal stones, and/or
pseudocysts,anendoscopicinterventionmaybeappropriate.Duringevaluation,
patientsshouldbecounseledonsmokingandalcoholcessationwhenapplicable.
Management of chronic pain and nutritional deficiencies from long-standing


pancreatitisisprimarilyanoutpatientissue,andareferraltogastroenterologyis
indicated.

CONCLUSION
Pancreatitisisacommonpresentingillnessintheemergencydepartment.Initial
management centers on early aggressive fluid resuscitation, pain control, and
bowelrest.Allpatientsshouldberisk-stratifiedusingavalidatedscoringsystem
suchastheBISAPtohelpdirectappropriatedisposition,includingintensivecare
services. Advanced imaging, although generally not required, should be used
whenthereisdiagnosticuncertaintyorwhenthereisconcernforthepresenceof
associated complications including pseudocysts, arterial pseudoaneurysms, or
commonbilestones.
LITERATURETABLE

REFERENCES
1.DeFrancesCJ,HallMJ.2005Nationalhospitaldischargesurvey.AdvData.2007;385:1–19.
2.SandersG,KingsnorthAN.Gallstones.BMJ.2007;335:295–299.
3.SteinbergW,TennerS.Acutepancreatitis.NEnglJMed.1994;330:1198–1210.
4.BanksPA,FreemanML,PracticeParametersCommitteeoftheAmericanCollegeofGastroenterology.
PracticeGuidelinesinAcutePancreatitis.AmJGastroenterol.2006;101:2379–2400.
5.YadavD,AgarwalN,PitchumoniCS.Acriticalevaluationoflaboratorytestsinacutepancreatitis.Am
JGastroenterol.2002;97:1309–1318.
6. Forsmark CE, Baillie J. AGA institute technical review on acute pancreatitis. Gastroenterology.
2007:132;2022–2044.
7. Wu BU, Johannes RS, Sun X, et al. The early prediction of mortality in acute pancreatitis: a large
population-basedstudy.Gut.2008;57:1698–1703.
8.PapachristouGI,MuddanaV,YadavD,etal.ComparisonofBISAP,Ranson's,APACHE-II,andCTSI
scores in predicting organ failure, complications, and mortality in acute pancreatitis. Am J
Gastroenterol.2010;105:435–441.
9. Warndorf MD, Kurtzman JT, Bartel MJ, et al. Early fluid resuscitation reduces morbidity among
patientswithacutepancreatic.ClinGastroenterolHepatol.2011;9:705–709.
10. Petrov MS, van Santvoort HC, Besselink MG, et al. Enteral nutrition and the risk of mortality and
infectious complications in patients with severe acute pancreatitis: a meta-analysis of randomized
trials.ArchSurg.2008;143:1111–1117.


11.BaiY,GaoJ,ZouDW,etal.Prophylacticantibioticscannotreduceinfectedpancreaticnecrosisand
mortality in acute necrotizing pancreatitis: evidence from a meta-analysis of randomized controlled
trials.AmJGastroenterol.2008;103:104–110.
12. Jafri NS, Mahid SS, Idstein SR, et al. Antibiotic prophylaxis is not protective in severe acute
pancreatitis:asystematicreviewandmeta-analysis.AmJSurg.2009;197:806–813.
13.JuppJ,FineD,JohnsonCD.Theepidemiologyandsocioeconomicimpactofchronicpancreatitis.Best

PractResClinGastroenterol.2010;24:219–231.
14.GardnerTB,KennedyAT,GelrudA.Chronicpancreatitisanditseffectonemploymentandhealthcare
experience:resultsofaprospectiveAmericamulticenterstudy.Pancreas.2010;39:498–501.
15.BraganzaJM,LeeSH,McCloyRF,etal.Chronicpancreatitis.Lancet2011;377:1184–1197.
16. Lowenfels AB, Maisonneuve P, Cavallini G. Prognosis of chronic pancreatitis: an international
multicenterstudy.InternationalPancreatitisStudyGroup.AmJGastroenterol.1994;89:1467–1471.
17.WarshawAL,BanksPA,Fernández-DelCastilloC.AGAtechnicalreview:treatmentofpaininchronic
pancreatitis.Gastroenterology.1998;115:765–776.


27
AcuteLeukemia
MartinaTrinkausACUTELEUKEMIAAcuteleukemia
isaneoplasmofthestemcellthatresultsinrapid
accumulationofimmaturemyeloidorlymphoid
precursors(functionallyinertblasts)inthebonemarrow.
Thisaccumulation—termedclonalproliferation—takes
upspacenecessaryfornormalhematopoiesisandcauses
secondarycytopenias.Leukemiaaffectsdifferentcell
lineagesinhematopoietictissues,includingerythrocytes,
lymphocytes,granulocytes,andmegakaryocytes.
Individualleukemiccellsdonotdividemorerapidlythan
donormalcells;however,atanygivenmoment,alarger
proportionofleukemiccellsaredividing.Chemotherapy
exploitsthisincreaseinmitoticactivity.1Whenacute
leukemiaisleftuntreated,theaccumulationof1012cells
isfatal.1

TheWorldHealthOrganizationofTumorsofHematopoieticandLymphoid
Tissues2definesleukemiaasthepresenceof>20%blastsinthebonemarrowor

peripheralblood.Leukemiaissubdividedbylineageintomyeloidandlymphoid
disease. Acute myeloid leukemia (AML) is further subdivided into seven
subgroups based on cytology, cytogenetics, and molecular analysis. In some
instances, a diagnosis of AML is made regardless of the percentage of bone
marrow blasts—specifically, in patients with translocations between
chromosome8and21or15and17,inversionsinchromosome16,ormyeloid


sarcomas. Acute lymphoblastic leukemia (ALL) is divided into three major
subgroupsbasedondifferencesintreatmentandprognosis:(1)precursorB-or
T-cell ALL, with further subdivision made based on recurring molecular–
cytogeneticabnormalities;(2)Burkittleukemia/lymphoma;and(3)biphenotypic
acuteleukemia.Approximately90%ofleukemiaisofmyeloidorigin,with10%
oflymphoidorigin.2
The annual incidence of AML is 3.5 per 100,000; an estimated 13,780
patientswerediagnosedintheUnitedStatesin2012.3AMLincidenceincreases
withage,withamedianageatdiagnosisof67accordingtotheNationalCancer
Institute'sSurveillance,Epidemiology,andEndResultsdata.4Ifuntreated,AML
is fatal and confers an average overall survival of <20 weeks from time of
diagnosis.5 Six thousand and fifty total adult and pediatric cases of ALL were
reportedintheUnitedStatesin2012.3ALLisfivetimesmorelikelytooccurin
the pediatric population than in the adult population; it represents 30% of all
childhood neoplasms, with the average age at diagnosis of 13 years.6 With
improved treatment strategies, the 5-year overall cure rate for ALL in the
pediatric population is over 80%; the lower adult cure rate of 30% to 40% is
largelyduetoage-relatedadversemolecularfeaturesandresistancetotherapy.7

RISKFACTORS
Most cases of acute leukemia are idiopathic. Known risks include exposure to
cytotoxicchemotherapy (particularly topoisomeraseIIinhibitorsand alkylating

agents8),pesticides,benzene,orradiation.9Geneticdisorders,includingtrisomy
21andinheritedbonemarrowfailuresyndromes,havealsobeenassociatedwith
AML.2
InAML,specificprognosticfeaturesguidepatientsurvivalprediction.These
include, but are not limited to, advanced age10; previous exposure to
chemotherapy11; cytogenetic features that stratify disease prognosis into
favorable, intermediate, and poor12; and evolution of a patient's AML from a
previous myelodysplasia or myeloproliferative neoplasms.13 Molecular
screening investigations can further delineate prognosis, with poor outcomes
conferredbythepresenceoftheFMS-liketyrosinekinase3(FLT-3)14andc-kit
mutation,15 and favorable outcomes conferred by nucleophosmin-1 and
CEBPA16mutations.InALL,aswell,severalprognosticfactors—includingage,
leukocytecount,andmoleculargenotypessuchasBCR-ABL1positivity—guide
selectionoftreatment.17


PATIENTHISTORY
Patientsymptomsvaryaccordingtoclinicalstageofacuteleukemia.Symptoms
oninitialpresentationareduetoincreasedtumorcellmass,factorsreleasedby
leukemic cells, pancytopenia, and immunologic reactions. Later symptoms are
usually secondary to either the sequelae of pancytopenia or complications of
chemotherapy. Table 27.1 reviews pertinent clinical history and physical exam
findingsofpatientsontheirinitialpresentation.
TABLE 27.1 Pertinent Findings on Patient History and Physical Exam with
First
Presentation

From Miller KB, Daoust PR. Clinical manifestations of acute myeloid leukemia. In: Hoffman R, ed.
Hematology Basic Principles and Practice. 4th ed. Philadelphia, PA: Elsevier Inc.; 2005:1071–1095;
Zuckerman T, Ganzel C, Tallman M, et al. How I treat hematologic emergencies in adults with acute

leukemia.Blood.2012;120(10):1993–2002.18


DIAGNOSTICEVALUATION
Thefollowingstudiesarerecommendedforanypatientinwhomacuteleukemia
issuspected:
CBC with peripheral blood film, ideally read by an experienced
hematologist or pathologist. In cases of elevated blast counts, a manual
plateletcountshouldbemade,asautomatedcellcountersmayerroneously
countfragmentsofblastcellsasplatelets.
Coagulation studies: PT, PTT, fibrinogen, D-dimer. Consider fibrinogen
assaysforthebleedingpatient.
Complete biochemical profile to assess for tumor lysis syndrome (TLS)
(electrolytes,creatinine,calcium,magnesium,phosphate,uricacid,LDH).
Liverenzymesandliverfunctiontests.
Viralserologies:HSV,VZV,CMV,hepatitisBandC.
Screeningforsyphilis.
In the case of fever: blood cultures, urine cultures, imaging guided by
physicalexam,andacompleteevaluationoforalhygiene,asthemouthisa
commonsiteofbacterialseeding.
InthecaseofsignificantCNSsignsorsymptoms:CTheadorMRIimaging
to rule out intracerebral hemorrhage, leptomeningeal disease, or
extramedullarydisease.
Hematology should be consulted and will typically coordinate the following
studies:
CTchesttoruleoutoccultfungalinfection
Bonemarrowaspirateandbiopsy
Cardiac function test: if anthracyclines are to be administered, MUGA
nuclear imaging is preferred over echocardiography because of
cardiotoxicityrisk

Lumbar puncture: provided the patient is not coagulopathic and
neuroimagingisnormal
HLAtypingofthepatientandsiblingsifconsideringatransplant
Acuteleukemiaisdiagnosedwhentheperipheralbloodorbonemarrowcontains
>20% blasts. Typically, a bone marrow aspirate and biopsy are performed to
distinguish AML from ALL and high-grade myelodysplasia. Alternative
diagnoses to consider in the setting of severe pancytopenia include aplastic


anemia,severeB12deficiency,ordrug-inducedaplasia.Inpatientswithblastson
peripheral blood film, myeloproliferative neoplasms, including myelofibrosis
andchronicmyelogenousleukemia,shouldalsobeconsidered.

EMERGENCIES
LEUKEMIA

IN

ACUTE

Hyperleukocytosis
Hyperleukocytosisisamedicalemergencythattypicallyoccurswhentheblast
count exceeds >100,000/μL. It is seen in 5% to 18% of acute leukemia,
predominantly in disease of monocytic origin.19 Increased blood viscosity in
hyperleukocytosisisduetotherigidityofthemyeloblastmembraneandanupregulation of blast adhesion molecules; this results in blasts occluding
circulatory flow, with subsequent tissue hypoxia, tissue infiltration, and
secondaryhemorrhage.Hyperviscositydoesnotoccurwithsimilarelevationsof
neutrophils (as seen in severe infections) or lymphocytes (as seen in chronic
lymphocyticleukemia).Presentingsymptomsofhyperleukocytosisarevariable
and include respiratory distress and hypoxia, as well as seizure, confusion,

abdominalpain,angina,priapism,andvisualcomplaints.Funduscopyshouldbe
performed to rule out papilledema, dilated vessels, or hemorrhage. In
circumstances of respiratory decline, it is important to consider alternative
explanations, including pneumonia, volume overload, or transfusion
complications,includingtransfusion-relatedacutelunginjury(TRALI).18Pulse
oximetryprovidesamorereliablemeasureofoxygensaturationforthehypoxic
patient than does PaO2, which can be misleadingly low because of blast
consumption of oxygen in the collection medium.20 If untreated,
hyperleukocytosisconfersamortalityof20%;itsmostseriouscomplicationsare
pulmonaryfailureandintracerebralhemorrhage.21
Treatment of symptomatic hyperleukocytosis (aka leukostasis) varies by
institution;astandardapproachincludesthepromptinitiationofhydroxyureafor
cytoreduction, with 2 to 5 g/day administered in divided doses.22 The role of
leukapheresis is controversial; most studies that support its impact on survival
are retrospective in design.23–25 Finally, caution should be used in transfusing
patientswithhyperleukocytosisbecauseoftheriskofworseningbloodviscosity
andaggravatingsymptoms.


AnemiaandTransfusions
No clinical trials have evaluated a specific transfusion trigger in patients with
acuteleukemia.Incriticallyillpatientswithoutcardiacdisease,theTRICCtrial
demonstrated that a restrictive transfusion strategy in the ICU (maintaining
hemoglobinvaluesbetween7and9g/dL)resultedinareducedmortalityrateat
30days.26Fortheleukemicpatient,thisapproachhasunclearbenefit;thus,the
threshold for transfusion is often practice dependent, with most providers
transfusing for hemoglobin levels below 8 g/dL or as warranted given clinical
symptoms.27 Caution must be exercised when transfusing patients with high
blast counts in order to avoid inciting hyperviscosity. There is no role for
erythropoietin-stimulatingagents.

Alltransfusedbloodproductsshouldbeirradiatedandleukocytedepletedto
minimizeriskoftransfusion-associatedgraftversushostdisease(TA-GvHD).If
a patient's cytomegalovirus (CMV) status is unknown, exclusively CMVnegative blood products should be used. TA-GvHD is seen in
immunocompromised hosts, particularly those undergoing AML therapy, post–
allogeneic stem cell transplantation, or post–purine analogue therapy. One to
four weeks post-transfusion patients with TA-GvHD can present with severe
cytopenias and with associated fever, hepatitis, rash, and/or diarrhea. A bone
marrow biopsy will reveal complete bone marrow aplasia. No treatment is
effective, and the mortality rate of TA-GvHD exceeds 95%; it is therefore
imperative to provide these patients with blood products that are leukoreduced
andirradiated.18

CoagulopathyandThrombocytopenia
Allpatientswithleukemiashouldbetransfused tomaintainaplateletcountof
>10,000/μL in cases of nonactive bleeding or >50,000/μL in cases of active
bleeding.28–31Allcoagulopathicderangementsshouldbepromptlyreversedwith
frozenplasmaorcryoprecipitate.NotethatpatientswithAPL,acutemonocytic,
or myelomonocytic leukemias are at highest risk of disseminated intravascular
coagulation (DIC); in these populations, coagulation screening should be
performed at least twice daily to ensure proper replacement of platelets,
coagulation factors, and fibrinogen.32 As with red blood cell support, all
products should be irradiated and CMV negative if a patient's CMV status is
unknown.

AcutePromyelocyticLeukemia


APLisasubsetofAMLdefinedbythetranslocationoftheretinoicacidreceptor
t(15;17);“PML;RAR-alpha”in95%ofpatients.APLconstitutes10%ofAML
casesintheUnitedStateswithmostpatientsbeingdiagnosedbetweenages30

and40.APLhasanoverallcurerateof80%to90%.33Unlikeotherleukemias,
APL poses an increased risk of fatal hemorrhage from DIC or primary
hyperfibrinolysisandhasapretreatmentmortalityratereportedtobeashighas
10%to17%.34Becauseofthis,anypatientsuspectedofhavingleukemia(i.e.,
blasts reported on their CBC differential) and a concurrent unexplained
coagulopathy should be evaluated promptly for APL. A pathologist or
hematologist should assess blast morphology; if APL is confirmed, treatment
with all-trans retinoic acid (ATRA), which allows for differentiation of APL
promyelocytes and restoration of coagulation, should begin immediately.35
Dosesinchildrenmaybemodifiedbecauseofthepotentialriskofpseudotumor
cerebri.36 Concurrent anthracycline chemotherapy is typically reserved for the
patient with high-risk disease (i.e., WBC > 10,000/μL) to minimize the risk of
leukocytosis, differentiation syndrome (previously ATRA syndrome), and
provocation of coagulopathy—all potential risks when ATRA is administered
alone.37 Because of the risk of fatal coagulopathy and hyperfibrinolysis, the
plateletcount,PT,PTT,andfibrinogenshouldbecloselymonitored.Thereare
scant data on the optimal trigger for platelet and plasma product infusion, but
consensus opinion targets a platelet count of 30,000 to 50,000/μL and a
fibrinogen level of >150 mg/dL.32 Coagulopathy of APL can last for up to 20
daysdespiteATRAtherapy.38Placementofacentralvenouscatheter,orinvasive
proceduressuchaslumbarpunctures,shouldbeavoideduntilthecoagulopathy
has been corrected. The hypogranular variant, a subset of APL, is conversely
associated with thrombosis in up to 5% of patients39 and is typically managed
withintravenousheparinandreplacementoffactorproductasneeded.

TumorLysisSyndrome
TLSoccurssecondarytorapidcelldeath,ascellularproductsareexcretedinto
thecirculation.Thiscanbeobservedatthetimeofleukemiadiagnosisorafter
initiationofchemotherapy.TLSmanifestsbiochemicallyeitherasincreaseduric
acid that may result in concomitant renal failure or as marked

hyperphosphatemia that leads to hypocalcemia and its attendant complications.
Patients at highest risk of TLS include those with a high tumor burden,
preexisting renal failure, chemotherapy-sensitive tumors with rapid lysis, and
inadequate TLS prophylaxis (i.e., allopurinol).40 Uncontrolled TLS places


patientsatriskofrenalfailure,cardiacdysrhythmias,seizure,anddeath.41

TLS-AssociatedUricAcidNephropathy
TreatmentofTLSfocusesonintravenoushydrationtoattainaurineoutputof80
to100mL/m.2,18Patientsoftenrequiremorethan4Lofdailyintravenousfluid
supporttoachievethisgoal.40Alkalinizationoftheurineisnolongeraroutine
treatment, as it has the potential to cause calcium phosphate or xanthine
precipitationinrenaltubules.42Reductioninuricacidistypicallyachievedwith
renal-dosed allopurinol, a xanthine oxidase inhibitor, which generally lowers
uricacidwithin1to3days.Rasburicase,arecombinantversionofurateoxidase,
has proven effective in cases of renal failure or allopurinol intolerance.43
Allopurinolaffectsonlyfurtherproductionofuricacid;rasburicase,bycontrast,
canconvertexistinguricacidtoallantoin,whichis5to10timesmoresoluble
thanisuricacid.Thestandardrasburicasedoseis0.2mg/kgIVinfusionover30
minutes. The use of rasburicase is contraindicated in patients with G6PD
deficiency because of the increased risk of oxidative hemolysis and
methemoglobinemia.44

TLS-AssociatedMetabolicDerangements
Hyperphosphatemia results in a secondary hypocalcemia. Because calcium
phosphate crystals can precipitate in the renal parenchyma and lead to renal
failure,calciumcorrectionshouldoccuronlyinthecontextofclinicallysevere
hypocalcemia(e.g.,tetany,seizures)oraftercorrectionofhyperphosphatemia.37
If hypercalcemia is seen in the context of acute leukemia, the diagnoses of

plasma cell leukemia or adult T-cell leukemia/lymphoma should be considered
asalternateexplanations.
Hyperkalemia should be monitored closely in the first 24 to 48 hours after
initiation of chemotherapy (including hydroxyurea), when the risk of TLS is
greatest. Potassium levels, however, should be interpreted with caution.
Monocytic leukemias may present with significant hypokalemia due to renal
tubular damage from high levels of muramidase (the lysozyme released by
monoblasts), with subsequent renal potassium wasting.1 In addition,
measurement of potassium in samples can be factitious: when blast counts are
significantly high, metabolically active blasts up-take residual potassium from
the serum if a blood specimen is left standing too long, resulting in
pseudohypokalemia.Conversely,pseudohyperkalemiamaybecausedbyinvitro
blast lysis in the sample. Treatment of hyperkalemia should, therefore, be


pursuedonlyafterobtainingaheparinized—andmoretrulydiagnostic—plasma
potassiumlevel.45

Infection
Becausechemotherapydestroysdividingcells,itdisproportionatelyaffectsthose
cells with increased mitotic potential—in the bone marrow, oral cavity, GI
endothelium,nails,andhair.Chemotherapypatientsthuscarryahighriskoforal
mucositis and ulcers, as well as enteric ulcers, resulting in multiple potential
portalsofentryforgram-negativebacteria.
Inpatientswithfebrileneutropenia,treatmentshouldincludebroad-spectrum
antibioticsincludingcoverageforPseudomonasaeruginosa.Antifungaltherapy
isrecommendedintheeventofpersistentfeversdespite4to7daysofantibiotic
coverage or in the event of persistent neutropenia. Treatment should continue
throughoutthedurationofneutropeniauntiltheANCexceeds500cells/mm3.46
The use of granulocyte colony–stimulating factor varies by institution; most

literature specific to AML shows no impact or mixed results on duration of
neutropenia,infection,antibioticusage,hospitalization,orsurvival.47,48
Theselectionofantiviral,antifungal,andantibioticprophylaxisisdependent
onlocallevelsofinvasivefungalinfectionsandisofteninstitutionspecific.The
Infectious Disease Society of America recommends acyclovir prophylaxis for
HSV seropositive patients.46 Posaconazole has been shown to significantly
reducefungalinfectionswhencomparedtofluconazoleandisincreasinglybeing
usedintheleukemiapopulation.49

NeutropenicColitis/Typhylitis
Neutropeniccolitis—termedtyphlitiswhenonlytheileocecalregionisinvolved
—typically occurs 10 to 14 days after initiation of chemotherapy and presents
withneutropenia,rightlowerquadrantpain,andfever.50Patientsmayalsohave
nausea, vomiting, and watery or bloody diarrhea. The pathogenesis of
neutropenic colitis is likely related to chemotherapy-induced mucosal injury
with bowel wall edema, ulceration, and secondary intestinal microbial
infiltration.Thececumisparticularlyvulnerablebecauseofitslowbloodsupply.
Patients will typically demonstrate gram-negative bacteremia; up to 15% of
patients will have fungus isolated in blood or bowel specimens.51 Along with
testing and empirical treatment for Clostridiumdifficile, patients must undergo
immediate CT imaging. Bowel wall thickening of >4 mm on imaging is
consistent with the diagnosis.52 Despite aggressive treatment with broad-


spectrumantibiotics,bowelrest,volumeresuscitation,andsurgicalconsultation,
themortalityrateoftyphlitisisashighas30%to50%.53

DifferentiationSyndromeofAPL
Differentiationsyndromeoccursin15%to25%ofpatientsreceivingATRAor
arsenictrioxide(ATO)andcanoccurbetween2and47daysafterexposureto

ATRAorATO.54,55Patientswillpresentwithcough,fever,ordyspneaandoften
withawhitebloodcellcountof>10,000/μL.Thiscardiopulmonarysyndromeis
oftenmistakenforpulmonaryedemaorpneumonia.Patientsmustbemonitored
closelyforhypoxia,pulmonaryinfiltrates,andpleuralorpericardialeffusions.In
cases of APL with a WBC > 10,000/μL, or suspicion for differentiation
syndrome,patientsshouldreceivedexamethasone10mgbidfor3to5dayswith
a taper over 2 weeks.35 Treatment should commence immediately, rather than
after abnormalities appear on chest radiograph. If differentiation syndrome is
suspected, ATRA and/or ATO should be discontinued and not resumed until
resolution of all signs and symptoms; steroid therapy should be given
concurrently.37

CytoreductiveTherapyinAMLandALL
AMLtreatmentisdividedintotwostages:inductionchemotherapytoinducea
remission and subsequent consolidation (postremission) therapy. The goal of
therapy is to achieve a complete response (CR)—defined as having <5% of
blastsinarepeatbonemarrowaspiratewithacountof200nucleatedcells.To
date,thecureratesforAMLexcludingAPLarelow;only40%ofyoungadults
and10%ofelderlypatientswillbecured.37Treatmentvariesbyinstitution;in
patients who are transplant eligible (age <60 with good performance status),
everyeffortshouldbemadetoenrollthepatientintoaclinicaltrial.
Induction chemotherapy has not changed considerably for over 30 years: it
consistsofanthracyclinessuchasdaunorubicin(60to90mg/m2×3days)and
cytarabine (100 to 200 mg/m2 continuous infusion × 7 days),56 known as the
“3+7”strategy.Studieshaveshownthatvaryingthedosesofchemotherapycan
improve CR rates but can also precipitate considerable toxicity. Patients who
achieve remission proceed to consolidation (postremission therapy), typically
with high-dose cytarabine. Treatment regimens, including subsequent
hematopoieticstemcelltransplant,aredependentonprognosticfactorsandtype
ofleukemia.

Treatment of ALL includes multiagent chemotherapies divided into


induction,consolidation,andmaintenancephasesoftreatment,withallpatients
receiving CNS prophylaxis. Treatment will always include anthracyclines,
vincristine, L-asparaginase, cyclophosphamide, methotrexate, cytrarabine,
mercaptopurine, and corticosteroids, all of which can result in significant
toxicity. Imatinib is added in those patients who are Philadelphia chromosome
positive.Duetotheirsignificantexposuretosteroids,patientsmustalsoreceive
prophylaxisfor Pneumocystisjiroveci and are often placed on viral and fungal
prophylaxis as well. Impressively, with this regimen, most children with ALL
includedinclinicaltrialshave5-yearsurvivalratesthatapproach85%;inadults,
only a 30% 5-year survival rate is achieved.57 Table 27.2 highlights the major
toxicitiesassociatedwiththestandardchemotherapiesusedforAML,APL,and
ALL.
TABLE

27.2

Selected

Chemotherapy

Drug

Complications

FromCancerDrugManual.BritishColumbiaCancerAgency.Availableat:www.bccancer.bc.ca.Accessed
January29,2013.58

CONCLUSION
Acute leukemia is a medical emergency. It should be suspected in any patient
who presents with blasts on white cell differential or peripheral blood film or
with undiagnosed pancytopenia. Patients should be referred promptly to the
hematology service and screened for life-threatening complications (see Table
27.1). In patients with high blast counts (>100,000 μL) or symptoms of
hyperleukostasis, a monitored setting should be considered, as these cases
require aggressive cytoreduction with chemotherapy. Electrolytes must be also
monitored with any leukemic diagnosis to rule out TLS and secondary renal
failure. Coagulopathies should be aggressively reversed to avoid secondary
hemorrhage, and platelet counts >10,000/μL should be maintained. Transfused
bloodproductsshouldbeirradiatedand,ifpossible,CMVnegative.Itshouldbe
emphasized that patients with acute leukemia are immunocompromised, and a
full pan-culture with initiation of broad-spectrum antibiotics must be started in
theeventoffeverorinfection.
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