Expert Consensus Guidelines for Stocking of Antidotes in Hospitals That Provide Emergency Care

13 Pages·2017·0.25 MB·English

TOXICOLOGY/CONCEPTS
Expert Consensus Guidelines for Stocking of
Antidotes in Hospitals That Provide Emergency Care
Richard C. Dart, MD, PhD; Lewis R. Goldfrank, MD; Brian L. Erstad, PharmD; David T. Huang, MD, MPH;
Knox H. Todd, MD, MPH; Jeffrey Weitz, MD; Vikhyat S. Bebarta, MD; E. Martin Caravati, MD, MPH; Fred M. Henretig, MD;
Theodore R. Delbridge, MD, MPH; William Banner, MD, PhD; Sandra M. Schneider, MD; Victoria E. Anderson, MPH*
*CorrespondingAuthor.E-mail:[email protected].
Weproviderecommendationsforstockingofantidotesusedinemergencydepartments(EDs).Anexpertpanelrepresenting
diverseperspectives(clinical pharmacology,medicaltoxicology,criticalcaremedicine, hematology/oncology,hospital
pharmacy,emergency medicine,emergencymedicalservices,pediatricemergency medicine,pediatriccriticalcare
medicine,poisoncenters,hospitaladministration,andpublichealth)wasformedtocreaterecommendationsforantidote
stocking. Usingastandardizedsummaryof themedicalliterature,theprimaryreviewer foreachantidoteproposed
guidelinesforantidotestockingtothefullpanel.Thepanelusedaformaliterativeprocesstoreachtheirrecommendation
forboththequantityofantidotethatshouldbestockedand theacceptable timeframeforitsdelivery.Thepanel
recommendedconsiderationof45antidotes; 44wererecommendedforstocking,ofwhich23shouldbeimmediately
available. Inmosthospitals,thistimeframerequires thattheantidotebestockedinalocation thatallowsimmediate
availability.Another14antidoteswererecommendedforavailabilitywithin1hourofthedecisiontoadminister,allowingthe
antidotetobestockedinthehospitalpharmacyifthehospitalhasamechanismforpromptdeliveryofantidotes.Thepanel
recommendedthateachhospitalperformaformalantidotehazardvulnerabilityassessmenttodetermineitsspecificneed
forantidotestocking.Antidoteadministrationisanimportantpartofemergencycare. Theseexpertrecommendations
provideatoolforhospitalsthatofferemergencycaretoprovideappropriatecareofpoisonedpatients.[AnnEmergMed.
2017;-:1-12.]
0196-0644/$-seefrontmatter
Copyright©2017bytheAmericanCollegeofEmergencyPhysicians.ThisisanopenaccessarticleundertheCCBY-NC-NDlicense(http://creativecommons.
org/licenses/by-nc-nd/4.0/).
http://dx.doi.org/10.1016/j.annemergmed.2017.05.021
INTRODUCTION agents, and rescue agents are readily available,” as well as
Antidotesareimportantinthecareofpoisonedpatients. “[i]dentify which antidotes, reversal agents, and rescue
When used in a timely and appropriate manner, they limit agents should be administered immediately in emergency
morbidity and mortality.1 Conversely, when unavailable or situations to prevent patient harm.”11
used inappropriately, the patient may not benefit or may Although the effectiveness of antidotes is often studied
experienceharmfromthepoisonorantidote.Forexample, rigorously,otherfactorsinvolvedintheuseandstockingof
drugs such as cyanide antidotes can be lifesaving, but only antidotes are not often addressed in published studies. For
if available in a timely manner and administered before example, the time to antidote delivery is crucial but few
irreversible injury occurs. If they are not immediately studies have been adequately designed and powered to
available, the patient may succumb to cyanide poisoning, investigate the effect of delay to antidote administration.
and if used incorrectly, the antidotes can be harmful. Researchers may comment on the need for early use of an
In2015,USpoisoncentersreportedthatantidoteswere antidote, but there are rarely rigorous data available to
used 184,742 times.2 Unfortunately, important antidotes evaluate such a claim.
often are not stocked or are stocked in insufficient Therecommendationsofanexpertpanelonthestocking
quantities. Insufficient stocking of a diverse group of of emergency antidotes were published.12,13 We have
antidotes has been documented repeatedly in more than a repeated that process in this study for 2 reasons. First, the
dozen countries, including the United States, the United antidotes available for use have changed substantially since
Kingdom, and Canada.3-10 The Institute for Safe 2009. For example, ethanol USP and the Lilly cyanide
Medication Practice issues Targeted Medication Safety antidote kit are no longer commercially available and new
Best Practices for Hospitals. Best Practice 9 states that a antidotes such as idarucizumab have been introduced.
hospital should “[e]nsure all appropriate antidotes, reversal Second, recent evidence indicates persistent deficiencies in
Volume-,no.- : -2017 Annalsof Emergency Medicine 1
Expert Consensus Guidelines for Antidote Stocking Dart et al
antidote stocking worldwide.3,4,14,15 The causes of this includeinformationonstudydesign, numberofpatients,
serious problem are unknown, but are likely related in part clinicalcourse,antidotedose, time ofantidote
tolimitededucation,inadequateawareness,infrequentuse, administration,patient outcomes,adverseevents, and
interruptions in supply, and limited hospital pharmacy effectivenessofthe antidote.Eachcomprehensive antidote
resources. Previous studies have found that larger hospitals evaluationwasthenindependentlyreviewedandrevisedbya
are more likely to have adequate stocks of antidotes than primaryreviewerfromthe expertpanel.Inphase2,the
smaller or rural hospitals.6,16 Perceived cost of antidotes reviewerpresentedthe evaluationand hisorher
basedonpurchaseprice,aswellaspharmacistandphysician recommendationtothe fullpanel,andaniterativeprocess
unfamiliarity with poisons and their antidotes, may wasusedtoachieveconsensus.The panelwas instructedto
contribute.6,9,17 Changes in the types and complexity of specificallyaddressthe needsofhospitalsthatprovide
antidotesavailableandtoxicologicproblemsalsoplayarole. emergencycareintheUnitedStates.Stockingofantidotesfor
The Joint Commission (TJC) oversees hospital mass casualtyeventsandthespecificclinical considerations
accreditation in the United States, but does not explicitly foradministration ofeachantidotewerenotincluded.
address antidote stocking. TJC standard MM 02.01.01
reads that medications available for dispensing or Phase 1
administration are selected, listed, and procured according The expert panel was provided with an initial list of
to hospital-defined criteria. Standard MM 2.30 states that antidotes developed by the principal investigator, which
emergency medications or supplies, if any, must be was based on the antidotes in the previous consensus
consistently available, controlled, and secured.18 Individual recommendations, along with revisions based on current
state governments also regulate antidotes in some cases. market availability of several drugs and discussion with
The state of California sanctioned a hospital for violating a panel members. The panel deliberated additions and
regulation requiring “.availability of prescribed revisions until consensus on the final list to be evaluated
medications 24 hours a day.”19 In that case, digoxin Fab was reached.
was not immediately available for a patient with cardiac Usingthesamesearchapproachasourpreviousreports,
glycoside toxicity. we expanded the literature database since 2008. Relevant
Given the approval of new antidotes, the changes in published studies were obtained by nonmedical staff with
availability of antidotes, an evolving regulatory extensive experience in searching and retrieving medical
environment, and the persistent lack of and chaotic literature. Evidence-based summaries of the medical
approach to antidote stocking, we performed an evidence- literature for each antidote were created by a group of
based consensus process to develop recommendations for researchers, emergency physicians, and clinical
the stocking of antidotes at hospitals that provide toxicologists not involved in the consensus voting process.
emergency care. For each antidote, a standardized evaluation of 5 to 115
pages was created for subsequent assessment by the
primary reviewer.
MATERIALS AND METHODS
Publications used to create the evaluations were
Overview identified with 3 methods: (1) searches for each antidote
Toproduceusefulandclinically relevant and its indications, using the US National Library of
recommendationsdespiteanevidencebasethatis Medicine’s PubMed database (http://www.pubmed.gov),
incomplete,weusedthe sameapproachasinourprevious MEDLINE (through Ovid), EMBASE, and the Cochrane
recommendations:astructuredanalysisoftheexisting Library, limited to “human” and “English” publications
literaturebyanexpertconsensuspanel.13Wepurposefully withinthelast10years;(2)reviewofchapterbibliographies
includedawiderangeofclinicianswithextensiveexperience for each antidote in one textbook of toxicology20; and (3)
intheuse and stockingofantidotes,aswellashospital review of bibliographies of selected articles from the
administrationofclinicalactivities(TableE1,availableonline previous 2 methods for additional citations. Each article
athttp://www.annemergmed.com).Recommendationsfor was classified according to its methodology, using the
antidotestockingwerecreatedin2phases,similartothe clinical guideline model of the American College of
development ofAmericanCollege ofEmergency Physicians Emergency Physicians by trained researchers (class I, good-
clinicalpolicies.Inphase1,a standardizedevidence-based quality randomized clinical trials and good-quality
summaryofeachpublicationwas generatedandall systematic reviews of good-quality randomized trials; class
summarieswerecompiledintoacomprehensiveevaluation II, prospective nonrandomized clinical trials, cohort, or
foreachantidote.Specifically,eacharticlewassummarizedto well-designed case-control studies, good-quality
2 Annals of Emergency Medicine Volume-,no.- : -2017
Dart et al Expert Consensus Guidelines for Antidote Stocking
observational or volunteer studies; class III, retrospective If theconsensuswasaffirmativeforthefirst 2questions,
case series or case studies), and then summarized with a the panel addressed 2 additional questions:
standardized form.21 3. Is time an important factor in antidote use?
a. Doestheantidoteneedtobeimmediatelyavailable
(ie, available for immediate administration)?
Phase 2
b. Does the antidote need to be available for
Each comprehensive literature evaluation developed in
administration within 60 minutes of the decision
phase 1 was provided to one expert panel member serving
to use?
as the primary reviewer for that antidote. The expert panel
4. What amount of the antidote is needed to treat one
wasadiversegroupof12professionalsrepresentingvarious
patient weighing 100 kg?
perspectives (Table 1 and Table E1, available online at
An iterative process was used to reach consensus on
http://www.annemergmed.com).Theprincipalinvestigator
stocking of each antidote. After presentation of an antidote
served as the nonvoting chairperson and selected
bytheprimaryreviewer anddiscussion bythe entirepanel,
individuals for the panel according to evidence of previous
a vote was taken to determine consensus. Each member
antidoteresearchorprofessionalexperienceinregardtothe
could vote in 1 of 3 ways: agreement, disagreement, or
acquisition and use of antidotes. This approach was
strong disagreement. If one or more panel members
necessary because there is no formal body or compendium
expressed strong disagreement, discussion was continued
that evaluates candidate antidotes or their appropriate
and another vote was taken. For all questions, consensus
stocking.
was defined as agreement by at least 75% of eligible panel
Theprimaryreviewersassessed andrevisedtheliterature
members, provided there was no vote of strong
evaluation produced in phase 1 for each assigned antidote,
disagreement. An antidote was recommended for stocking
using their knowledge and experience. The primary
if the panel consensus was affirmative for the first 2
reviewer could alter the evaluation according to their
questions. If agreement could not be reached, the decision
analysis of the published studies. Each primary reviewer
was listed as “consensus not reached.”
thenformedaprovisionalrecommendationinregardtothe
The additional 2 questions were addressed to assist
antidoteandpresented therevisedliteratureevaluationand
hospitals in determining when an antidote should be
hisorherrecommendationtotheentirepanel.Thepanel’s
available and in what quantity. The term immediately
deliberations occurred on November 29 to 30, 2016. The
available was defined as available for immediate
evidence-based analysis was formulated to provide
administration.Thepanelunderstoodthistomeanthatthe
information to the panel in regard to the fundamental
physical location where the drug is stored may vary by
questions involved in the selection of each antidote:
institution and by drug preparation requirements and
1. Is the antidote effective?
focusedonthetimingofagentavailability,notthelocation
2. Do the medical benefits of the antidote outweigh its
of stocking. The panel’s estimate of the antidote amount
risks?
needed per patient was based on clinical considerations:
dose, duration of therapy (8 or 24 hours), use of
Table1. Profileofantidotepanelmembers. extracorporeal elimination such as hemodialysis, and other
DisciplineorSpecialty No.ofParticipants factors. The panel chose to consider one 100-kg patient as
Clinicalpharmacology 1 the basis for calculating the amount of antidote to stock.
Clinicalpharmacy 1 This weight was chosen because, according to recent data
Criticalcaremedicine 2
from National Health and Nutrition Examination Survey,
Emergencymedicine 7
this weight corresponds to the 75thpercentile formen and
Emergencymedicalservices 1
Hematology/oncology 2 between the 90th and 95th percentiles for women.22
Hospitaladministration 2 Competing interests were managed proactively and
Hospitalpharmacy 1
transparently. Each panel member completed a competing
Medicaltoxicology 6
Pediatriccriticalcaremedicine 1 interest form for each antidote, disclosing any financial
Pediatricemergencymedicine 1 interest or stock ownership or financial support (eg,
Poisoncenteradministration 2
research grants, consulting agreements) from each antidote
Publichealth 2
manufacturer or marketer for the preceding 10 years. Any
Categorieswereself-selectedbypanelmembers.Thetotalisgreaterthan12because
ofmultipledesignationsbysomeindividuals.Additionalinformationonthepanel’s relationship (ie, funding for a clinical trial, a single
experienceisprovidedinTableE1,availableonlineathttp://www.annemergmed. consultation with the company, or any level of equity
com.
holding in the company) was considered a competing
Volume-,no.- : -2017 Annalsof Emergency Medicine 3
Expert Consensus Guidelines for Antidote Stocking Dart et al
interest. No participant reported equity holdings in a cyanide may be lifesaving if administered before
company. One participant reported funding for clinical irreversible injury occurs. In most hospitals, this
research and 5 reported previous consulting agreements timeframe requires that the antidote be stocked in a
with an antidote manufacturer during the preceding 10 location that allows immediate availability. Another 14
years.Thepanelwasinformedofallcompetinginterestsfor antidotes were recommended for availability within 1
each antidote as it was considered. Each panel member hour of the decision to use the antidote (Table 2),
with a competing interest was allowed to participate in allowing the antidote to be stocked in the pharmacy,
discussion, but was excluded from serving as the primary providing the hospital has an efficient mechanism for
reviewer and voting for the antidote involved. prompt delivery of medications from the pharmacy to the
emergency department. The panel recommended that an
additional 8 antidotes be stocked but not necessarily
RESULTS
available within 1 hour of ordering. Among the 45
A total of 3,804 articles were retrieved and reviewed;
provisional recommendations made by the primary
2,447 articles were used to develop the literature
reviewers, 11 (24.4%) were changed substantially in the
evaluations and provisional recommendations (Figure). final recommendations as a result of panel discussion.
Class I evidence was infrequently available, typically to
Consensus was reached for all antidotes evaluated. Seven
assess the efficacy of the drug. Class II evidence was more
drugs were not recommended for consideration by the
commonly available, but again usually focused on
panel because they were either not approved by the Food
effectiveness.ClassIIIevidencewasplentiful,butextremely
and Drug Administration (FDA) or were no longer
variable. Few articles explicitly addressed the questions of
commercially available. Activated charcoal was not
the appropriate time for availability.
included because it acts by reducing absorption rather
Overall, the panel considered 45 antidotes for stocking
than as an antidote and is already widely available.
in hospitals that accept emergency patients. The panel
For some conditions, more than one antidote can
recommended stocking of 44 of these antidotes, with 23
effectively treat a poisoning or overdose. The panel
immediately available (Table 2). Antidotes for conditions identified 3 instances in which more than one effective
such as poisoning by an opioid, cardiac glycoside, or
antidote was available: ethanol or fomepizole for treatment
of toxic alcohol exposure, sodium nitrite and sodium
thiosulfate or hydroxocobalamin for cyanide toxicity, and
3- or 4-factor prothrombin complex concentrate for
Abstracts Reviewed reversal of acquired deficiency of the vitamin K–dependent
15,632 coagulation factors. In these cases, the panel designated a
Excluded: preferred agent, although either agent was recognized as
No antidote administered acceptable in meeting the need for stocking. Each
Review article or editorial
preference was determined in the same manner as the
Full text article not available
Animal study decisiontorecommendstockingofanantidote:byiterative
group debate reaching consensus without a vote of strong
11,828
disagreement. Fomepizole was preferred over ethanol for
Full Text Articles
several reasons: simplicity of use, lack of need for
Retrieved
compoundinginpharmacy,reductioninmedicationerrors,
3,804
potential to avoid hemodialysis, and anticipated safety in
Excluded: children. The use of ethanol is further complicated by the
No antidote administered lack of a commercially available solution in the United
No outcome data reported
States. Hydroxocobalamin was preferred over sodium
Duplicate
nitrite and sodium thiosulfate because of its wider
1,357 indications, ease of use, and anticipated safety in
widespread use. The use of 4-factor prothrombin complex
Articles Summarized concentrate was preferred over 3-factor prothrombin
complex concentrate because of a higher level of available
2,447
evidenceforsafetyandeffectiveness,aswellasitshavingan
FDA-approved labeling indication for management of
Figure. Article selection. vitamin K antagonist-associated bleeding.
4 Annals of Emergency Medicine Volume-,no.- : -2017
V D
o a
lum Table2. Antidotestockingrecommendationsfor facilitiesthatacceptemergency patients. rt
e et
- StrengthofEvidence* PanelRecommendation a
, l
n
o Isthe DoMedical IsTimean ShouldBe ShouldBe
.- Drug Benefits Important Stockedby ShouldBeAvailable Immediately
Antidote PoisoningIndication(s) Effective? OutweighRisks? Factor? theHospital Within60Minutes Available
:
- Acetylcysteine(IV) Acetaminophentoxicity I I I Yes Yes No
20 Acetylcysteine(PO) II I I Yes Yes No
17 Antivenin(Latrodectusmactans) Blackwidowspiderenvenomation II II III Yes No No
Antivenin(Micrurusfulvius) EasternandTexascoralsnakeenvenomation II II III Yes Yes No
Atropinesulfate Organophosphatepesticideornerveagent II II III Yes Yes Yes
poisoning,carbamatetoxicity
Calciumchloride†‡ Fluoride,calciumchannelblockingagent III III III Yes Yes Yes
Calciumgluconate†‡ toxicity III III III Yes Yes Yes
CalciumdisodiumEDTA Leadpoisoning II II III Yes No No
Calciumtrisodiumpentetate(calcium Internalcontaminationwithplutonium, III III III Yes No No
DTPA) americium,orcurium
Centruroides(scorpion)F(ab0) Scorpionenvenomationinpediatrics(A)and I(A) I(A) II Yes Yes No
2
adults(B) III(B) III(B)
CrotalidaepolyvalentimmuneFab(ovine) NorthAmericancrotalinesnakeenvenomation II I III Yes Yes No
(CroFab;FabAV)
Cyproheptadine‡ Serotonintoxicity III III III Yes No No
Dantrolene‡ Malignanthyperthermia II II II Yes Yes Yes
Deferoxaminemesylate Ironpoisoning I I III Yes Yes No
Dextrose(D50) Hypoglycemia I II II Yes Yes Yes
DigoxinimmuneFab Cardiacglycosidestoxicity(A)orcardiacsteroid II(A) II(A) II Yes Yes Yes
toxicity(B) I(B) I(B)
Dimercaprol(BAL) Heavymetaltoxicity(arsenic[A],lead[B], II(A,B) II II Yes Yes No
mercury[C]) III(C)
DMSA(succimer) Heavymetaltoxicity(arsenic[A],lead[B], III(A) III(A,C) III Yes No No
E
mercury[C]) I(B) I(B) x
p
II(C) e
r
Ethanol(PO)‡or Methanolorethyleneglycolpoisoning II II III Yes Yes No tC
fomepizole§ II II III Yes Yes No o
n
Flumazenil Benzodiazepinetoxicity I I II Yes Yes Yes se
Glucagonhydrochloride‡ b-Blocker,calciumchannelblockertoxicity III II III Yes Yes Yes ns
u
Glucarpidase Methotrexatetoxicity II II II Yes No No s
Hydroxocobalamin§or Cyanidepoisoning II II II Yes Yes Yes G
A u
nnals Isdoadriuucmizunmitraitbeandsodiumthiosulfate† Reversalofanticoagulanteffectsofdabigatran IIIII IIII IIIII YYeess YYeess YYeess idelin
o Leucovorin Methotrexateormethanoltoxicity II II II Yes Yes No e
fEm LLeipviodceamrnuitlisnieo‡n‡ VLoaclparloaicneasctidhettoicxicsiytsytemictoxicity IIIII IIIII IIIIII YYeess YYeess YNeos sfor
ergenc MNaeltohxyolenneehbydlureochloride OMpeitohidemtooxgicloitbyinemia III III IIII YYeess YYeess YYeess Antid
yM Octreotide‡ Sulfonylurea-inducedhypoglycemia I I II Yes Yes No ote
edic Physostigmine Anticholinergicsyndrome I II III Yes Yes Yes Sto
ine ckin
5 g
6 Table2. Continued. E
x
A p
n StrengthofEvidence* PanelRecommendation e
n rt
a
ls Isthe DoMedical IsTimean ShouldBe ShouldBe C
of Drug Benefits Important Stockedby ShouldBeAvailable Immediately on
Em Antidote PoisoningIndication(s) Effective? OutweighRisks? Factor? theHospital Within60Minutes Available sen
ergen PPohtyatosnsiaudmionioedi(dveitaminK1) TRheyvreorisdarlaodfiociooudminaeripnr-ointedcutcioendcoagulopathy III III IIII YYeess YYeess YNeos susG
cyM Pralidoximechloride Organophosphoruspoisoning I I II Yes Yes No uid
ed Protaminesulfate Reversalofcoagulopathyinducedby I(A) I II(A) Yes Yes Yes elin
ic unfractionated(A)orlow-molecular-weight III(B) III(B) e
ine 3-factorprothrombincomplexconcentrate‡ Re(vBe)rshaelpoafriancquiredcoagulationfactor II II II Yes Yes Yes sfor
or deficiencyinducedbyvitaminKantagonists An
4-factorprothrombincomplexconcentrate§ I I II Yes Yes Yes tid
Activatedprothrombincomplex II II II No N/A N/A o
t
concentrate‡ e
S
Prussianblue Thallium(A)orradiocesium(B)toxicity III(A) III(A) III(A) Yes No No to
c
II(B) II(B) II(B) k
Pyridoxinehydrochloride Isoniazid,hydrazinetoxicity III III III Yes Yes Yes ing
Sodiumbicarbonate‡ Tricyclicantidepressanttoxicity(A),urine III(A,C) III(A,C) III Yes Yes Yes
alkalizationforsalicylatetoxicity(B),or II(B) II(B)
cocainetoxicity(C)
Thiamine Ethyleneglycoltoxicity(A),thiaminedeficiency III(A) III(A) III(A) Yes Yes Yes
associatedwithchronicalcoholism(B) I(B) II(B) III(B)
Uridinetriacetate Fluorouracilorcapecitabineoverdose III III III Yes No No
regardlessofsymptomsorearly-onset
toxicity
IV,Intravenous;PO,oral;EDTA,ethylenediaminetetra-acetate;DTPA,diethylenetriaminepenta-aceticacid;FabAv,Fabantivenom;BAL,Britishantilewisite;DMSA,dimercaptosuccinicacid.
*Strengthofevidence:classI:good-qualityrandomizedcontrolledtrialsandgood-qualitysystematicreviewsofgood-qualityrandomizedcontrolledtrials;classII:prospectivenonrandomizedclinicaltrials,cohortorwell-designed
case-controlstudies,good-qualityobservationalorvolunteerstudies;classIII:retrospectivecaseseries,casereports.
†Bothagentsshouldbestocked.
‡Indicationlistedonpackageinsertdoesnotincludeitsantidotaluse.
§Preferredagent.
V
o
lu
m
e
-
,
n
o
.
-
D
:
a
- rt
20 et
17 al
Dart et al Expert Consensus Guidelines for Antidote Stocking
In 2 instances, the panel recommended the stocking of approach helped to constrain undocumented or
an antidote for a particular indication, but not for more unsubstantiatedopinionofpanelmembersin2ways.First,
general usage. Intravenous lipid emulsion was the published medical evidence was reviewed, and this
recommended by the panel for use in the setting of local supported the expectation that the reviewer’s conclusions
anesthetic systemic toxicity, but not for a broader would be evidence based within the limits of available
spectrum of intoxicants because of the panel’s consensus information. Second, the other panel members (who
that evidence for the latter was currently inconclusive. reviewed the evidence simultaneously) acted as a
Additionally, there are no FDA-approved products counterbalanceagainstunsubstantiatedindividualpositions
indicated for the reversal of direct oral anticoagulants, of the reviewer.
other than idarucizumab for the reversal of dabigatran. The panel was chosen by the nonvoting chairman
Although reversal agents for rivaroxaban, apixaban, and (R.C.D.) according to documented clinical and
edoxaban are currently under investigation, none has been research expertise, which may have resulted in an
licensed. In light of the rapidly evolving research in this unintended bias toward academia. This possibility was
area and the lack of sufficient evidence to support the counterbalanced by the voting rules that allowed rejection
effectiveness of 3- or 4-factor prothrombin complex of a recommendation by a single vote of strong
concentrate for this indication, the panel elected not to disagreement. Several exotic antidotes and antidotes not
include prothrombin complex concentrate stocking readily available in North America were not considered.
recommendations for reversal of rivaroxaban, apixaban, or The panel was specifically asked not to anticipate singular
edoxaban or for dabigatran reversal if idarucizumab is or rare events, such as terrorist acts or mass casualty
unavailable. incidents, although individual hospitals may take regional
Thepanelrecommendedtheamountofantidoteneeded risk factors for such events into account when making
totreata100-kgpatientforaperiodofeither8or24hours stocking decisions according to their own hazard
(Table 3). In most cases, the amount of antidote vulnerability assessment. The cost-benefit relationship of
recommended for stocking did not precisely match the antidotes was not assessed because major changes in the
package label because of changes in clinical practice since marketingofpharmaceuticalsmeansthatthepricepaidby
the label content was approved by the FDA and because hospitals may vary severalfold and may differ month to
someantidotes,suchasoctreotide,arenotlabeledforuseas month. The intended audienceofthe recommendationsis
antidotes. the group of personnel responsible for providing
Thepanelnotedthatmanyconsiderationscanaffectthe emergency care in an individual hospital, rather than
decision to stock an antidote, as well as the amount of larger regions, states, or national organizations, given the
antidote that should be stocked. A rigid recommendation different needs and resources of such entities.
forallhospitalsisdifficulttojustifyandmayleadtounder-
oroverstocking.Forexample,ahospitalinanareaendemic
DISCUSSION
for crotaline snakes (Crotalus, Agkistrodon, and Sistrurus)
The panel recommended 44 antidotes for emergency
shouldstockantivenom,buttheamountrecommendedfor
one patient may be insufficient if 2 envenomed patients stocking by facilities that provide emergency care in the
United States. The recommendations are intended to be
require simultaneous treatment. To address these
interpreted in the context of the potential clinical uses
situations,thepanelrecommendedthathospitalsperforma
created by the catchment area served by a hospital; special
hazard vulnerability assessment for each antidote, which
needs for mass casualty events are not addressed in these
allows a customized application of the recommendations
recommendations.
according to institutional antidote needs (Tables 4 and 5).
The major changes from previous recommendations
include the addition of 17 antidotes, removal of stocking
LIMITATIONS
recommendations for drugs that are not currently
Limited class I and II evidence was available for most commercially available (antivenin [Crotalidae] polyvalent,
antidotes; therefore, many of the panel’s recommendations ethanol solution for injection, botulism antitoxin, and
are based on expert analysis and experience. The process botulismimmuneglobulin[BabyBIG]),andremovalofthe
attempted to compensate for individual bias by using a recommendation to stock amyl nitrite, previously
diverse and experienced panel, by presenting structured recommendedasacomponentoftheLillycyanideantidote
evaluations of medical information, and by prohibiting kit, which is no longer available. Sodium nitrite and
voting by members with a competing interest. This sodium thiosulfate are still recommended but are available
Volume-,no.- : -2017 Annalsof Emergency Medicine 7
Expert Consensus Guidelines for Antidote Stocking Dart et al
Table3. Amountofantidoteneededtotreatonepatientweighing100kg.
StockingRecommendation,Hours
Antidote 8 24 Notes
Acetylcysteine(IV),g 22 30 Administerintravenouslyforhepaticfailure.
Acetylcysteine(PO),g 28 56
Antivenin(Lmactans),vial 1 1 Producthasbeendiscontinuedbymanufacturer;somesupplies
remain.
Antivenin(Mfulvius),vial 5 10 Producthasbeendiscontinuedbymanufacturer;somesupplies
remain.
Atropinesulfate,mg 45 165
Calciumchloride,g 10 10 Donotadministercalciumchloridesubcutaneously;shouldbe
Calciumgluconate,g 30 30 administeredbycentralvenousroute,ifpossible.Calcium
gluconatemaybegivenbyIV,subcutaneousroutes.
CalciumdisodiumEDTA,g 0.75 2.25
Calciumtrisodiumpentetate(calciumDTPA),g 1 1
Centruroides(scorpion)F(ab0) ,vial 3 3
2
FabAV,vial 12 18
Cyproheptadine,mg 20 36
Dantrolene,mg 800 2,000 Shouldbeavailableanywheregeneralanesthesiaisperformed.
Deferoxaminemesylate,g 12 36
Dextrose(D50),g 250 250 D50asinitialtreatmentmaybefollowedbyadditionaldextrose
atlowerconcentrations.
DigoxinimmuneFab,vial 15 15
Dimercaprol(BAL) 800mg 2.4g
DMSA(succimer),g 1 3
Ethanol(PO),g 180 360 IVethanolsolutionforinjectionmaybeadministered,ifavailable.
Fomepizole,g 1.5 4.5
Flumazenil,mg 6 12
Glucagonhydrochloride,mg 90 250
Glucarpidase,U 5,000 5,000 Glucarpidaseshouldnotbeadministereduntil(cid:2)2hafter
leucovorin.
Hydroxocobalamin,g 10 10 Canbeusedsafelyinpatientswithsmokeinhalation.Redcolor
ofdrugcauseslaboratorytestinterference,technologic
dysfunctionofdialyzers,andreddiscolorationofskinand
urine.
Sodiumnitrite,mg,and 600 600 Nitritescausemethemoglobinemiaandcanimpairoxygen
sodiumthiosulfate,g 25 25 delivery;shouldnotbeusedinsmokeinhalationpatientswith
carbonmonoxidepoisoning.
Idarucizumab,g 5 5
Leucovorin 300mg 1g
Levocarnitine,g 9 15 AdministerIVforacutetoxicity
Lipidemulsion(IV),mL 1,250 1,250 Recommendationsbasedonproductscontaininganemulsionof
soybeanoil,eggphospholipids,andglycerin.
Methyleneblue,mg 400 600
Naloxonehydrochloride,mg 20 40
Octreotide,mg 75 225
Physostigmine,mg 4 4
Phytonadione(vitaminK ),mg 50 100 InitialdoseshouldbeadministeredIV(nottoexceed10mg),with
1
subsequentdosesadministeredPO.Patientspresentingwith
elevatedinternationalnormalizedratioandbleedingshould
alsobetreatedwithprothrombincomplexconcentrate.
Potassiumiodide,mg 130 130
Pralidoximechloride,g 7 18
Protaminesulfate 400mg 1.2g
3-factorprothrombincomplexconcentrate,IU 5,000 5,000 VitaminK 10mgIVshouldbeadministeredconcurrentlyto
1
4-factorprothrombincomplexconcentrate,IU 5,000 5,000 maintainclottingfactorlevelsafterprothrombincomplex
concentratelevelshavediminished.
Activatedprothrombincomplexconcentrate N/A N/A
Prussianblue,g 12.5 25
Pyridoxinehydrochloride,g 8 24
Sodiumbicarbonate,g 63 84
Thiamine 500mg 1.5g
Uridinetriacetate,g 20 40
8 Annals of Emergency Medicine Volume-,no.- : -2017
Dart et al Expert Consensus Guidelines for Antidote Stocking
Table4. Considerationsforhazardvulnerability assessment.
Antidote Consideration
Acetylcysteine(IV) Antidoteforwidelyavailabletherapeuticagents
Acetylcysteine(PO)
Antivenin(Lmactans) Geographic/endemicareas
Antivenin(Mfulvius) Geographic/endemicareas
Atropinesulfate Industry,referralpatternsfromagriculturalareas
Calciumchloride Industry,antidoteforwidelyavailabletherapeuticagents
Calciumgluconate
CalciumdisodiumEDTA Prevalenceofleadriskfactorssuchasoldhousing,industryusingleadproducts
Calciumtrisodiumpentetate(calciumDTPA) Receivinghospitalforresearchlaboratory
Centruroides(scorpion)F(ab0) Geographic/endemicareas
2
FabAV Geographic/endemicareas,history/experiencewithexoticbites,considersimultaneousbitevictims
Cyproheptadine Allhospitals:serotonintoxicityoccursthroughouttheUnitedStates
Dantrolene Allhospitals:malignanthyperthermiaoccursthroughouttheUnitedStates
Deferoxaminemesylate Allhospitals:acuteironingestionoccursthroughouttheUnitedStates
Dextrose(D50) Allhospitals:acutehypoglycemiaoccurscommonlythroughouttheUnitedStates
DigoxinimmuneFab Antidoteforwidelyavailabletherapeuticagents
Dimercaprol(BAL) Industry,prevalenceofheavymetalriskfactors
DMSA(succimer) Historicalrateofpediatricleadpoisoninginhospitalservicearea
Ethanol(PO) Allhospitals:ethyleneglycolandmethanolarecommonthroughouttheUnitedStates
Fomepizole Allhospitals:ethyleneglycolandmethanolarecommonthroughouttheUnitedStates
Flumazenil Antidoteforwidelyavailabletherapeuticagents
Glucagonhydrochloride Antidoteforwidelyavailabletherapeuticagents
Glucarpidase Hospitalcatchmentarea
Hydroxocobalamin Industry,history,localconditions,communityplanning,facilityservicearea
Sodiumnitriteand Industry,history,localconditions,communityplanning,facilityservicearea
sodiumthiosulfate
Idarucizumab Onlyapprovedantidoteforreversalofanticoagulanteffectsofdabigatran
Leucovorin Antidoteforwidelyavailabletherapeuticagent
Levocarnitine Antidoteforwidelyavailabletherapeuticagents
Lipidemulsion(IV) Allhospitals:localanestheticsystemictoxicityoccursthroughouttheUnitedStates
Methyleneblue Allhospitals:methemoglobinemiaoccursthroughouttheUnitedStates;highnumberofcausativeagents
Naloxonehydrochloride Antidoteforwidelyavailableandcommonlyabusedagents
Octreotide Antidoteforwidelyavailabletherapeuticagent
Physostigmine Antidoteforwidelyavailabletherapeuticagent
Phytonadione(vitaminK ) Antidoteforwidelyavailabletherapeuticagents
1
Potassiumiodide Industry,localconditions
Pralidoximechloride Industry,referralpatternsfromagriculturalareas
Protaminesulfate Antidoteforwidelyavailabletherapeuticagent
3-factorprothrombincomplexconcentrate Antidoteforwidelyavailabletherapeuticagents
4-factorprothrombincomplexconcentrate
Prussianblue Industry
Pyridoxinehydrochloride Industry,history,endemicconditions,communityplanning,facilityservicearea
Sodiumbicarbonate Antidoteforwidelyavailabletherapeuticagents
Thiamine Allhospitals:ethyleneglycoltoxicityandthiaminedeficiencyassociatedwithchronicalcoholismoccur
throughouttheUnitedStates
Uridinetriacetate Prevalenceoffluorouracilorcapecitabinetoxicityriskfactors
individually or in a 2-component kit without amyl nitrite. United States and other countries. However, it is difficult
Additionally, the recommendations for intravenous for hospitals to address this situation because widely
acetylcysteine and dimercaprol were updated to more acceptedguidelinesforantidotestockinghavenotemerged,
accurately reflect labeled dosing. Finally, the panel reached although certain regional guidelines have been
consensus on stocking recommendations for Prussian blue promulgated.10,23 National guidelines are difficult to
and for the lack of need for immediate availability of produce because of the heterogeneity of hospital
pralidoxime, for which consensus was not previously organization and management, as well as the diversity of
established. service area. The expert panel therefore concluded that a
Insufficient stocking of antidotes needed on an mechanism allowing customization of stocking for each
emergency basis has been documented repeatedly in the hospital should be used.
Volume-,no.- : -2017 Annalsof Emergency Medicine 9
Expert Consensus Guidelines for Antidote Stocking Dart et al
Table5. Hazardvulnerability assessment foremergencyantidotes.
Factor Principle Example
Pharmaceuticalproducts Agentsthatarewidelyavailableshould Acetaminophen
usedastherapeuticagents generallyhavetheantidotestockedbecause Anticholinergicagents
importantgeographicdifferencesarenot Benzodiazepines
anticipated. Dapsone
Digoxin
Iron
Isoniazid
Localanesthetics
Neworalanticoagulants
Opioidanalgesics
Serotonergicagents
Sulfonylureahypoglycemicagents
Warfarin
Characteristicsofhospital Industries,practices,activities,andindigenous Industriesgeneratingorusingcyanide,heavymetals,hydrogenfluoride,
catchmentarea faunaindicatepotentialneedforantidote organophosphoruschemicals,radionuclides,thallium
Chemicaltransportationroutes
Indigenousfaunaandflora(snakes,spiders,scorpions,plants)
Agriculturalpractices(organophosphorusinsecticides,cyanidebaits,
mining)
Prevalenceofoncologypatients
Referralpatterns Manyhospitalsacceptreferralsfromremote Transferstourbanhospitalfromagriculturalareas
areas.Theseshouldbeincludedinrisk Referralfromminingarea
assessment.
Historyorexperienceofuse Somemodesofsuicideorabusebecome Popularityofcyanideorotherspecificagentsasasuicideagent
locallyprevalentwithoutaspecificindustry’s Amateursnakekeepersinthearea
beingpresent
Anticipatedvolumeofuse Dependingonthecharacteristicsofthearea, Multiplecasualtyincidents(eg,smokeinhalationinvolvingtreatment
morethanonevictimofapoisoningmaybe withcyanideantidotes,large-scaleindustrialortransportation
anticipated. incidents,chemicalterrorismevents)
Indigenouscrotalinesnakebiteinareaswithfrequentoccurrencessuch
asthesoutheasternorsouthwesternUnitedStates
Anticipatedtimeto Timetorestockingvariesgreatlyamong Hospitalsthatstabilizeandreferpatientstootherinstitutionsshould
restockingorresupplyof hospitals stockfortheanticipatedperiod.
antidote Hospitalsthatprovidetertiaryordefinitivetreatmentshouldstockfor
anticipateddurationofillnessoruntilrestockingfromanother
hospitalordistributorcanoccur.
Timetorestockingvariesbyantidote.Somemayhaveprolongedperiods
beforerestockingcanoccur
To allow customized application of these guidelines, the (hospital services and use, demographic information, local
panel developed the concept of an antidote hazard industrial uses, availability of antidote at neighboring
vulnerability assessment, an adaptation of the hazard facilities, and chemical transportation routes, among other
vulnerability assessment required in the United States for factors)thatrequireinteractionwithappropriatebusinesses
accreditation of hospitals by TJC. As defined by TJC, a and manufacturers, as well as local, state, and federal
hazard vulnerability assessment is the identification of agencies.Table5providespotentialvariablesthatshouldbe
potential emergencies and the direct and indirect effects considered in this hazard assessment. A hospital should use
theymayhaveonthehospital’soperationsandthedemand the hazard assessment process to determine the treatment
for its services.24 This assessment is already required of period for which antidote stocking should occur. Some
hospitals that are accredited by TJC and provides a useful hospitals may exist in an environment making stabilization
framework to assess contingencies presented by poisoned and referral of a patient simple and rapid. Other hospitals
patients. may be subject to serious transportation difficulties and
The hazard assessment concept requires a hospital to extreme weather conditions. The process of hazard
formallyanalyzethetypesofpoisonedpatientswhomaybe assessment should include all stakeholders; for example,
admitted to their facility, the number of patients who may pharmacy, emergency medicine, clinical toxicology, ICU,
be admitted, and the amount of each antidote needed. risk management, nursing, pharmacy and therapeutic
Prioritization of risks is based on available objective data committee, hospital preparedness committee, and hospital
10 Annalsof Emergency Medicine Volume-,no.- : -2017