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                                                                                                             Review      Articles


Yellow Oleander Poisoning                                            most common in significant poisonings, which may appear
                                                                     within   a few    hours     of poisoning.(3;8;9)       Cardiac

DarrenRoberts (1,2),                                                 dysrhythmias such as bradycardia or an irregular pulse are

KusalWijayaweera          (1) and                                    the most common [mdings on examination. Blood pressure

Michael Eddleston (1,2)                                              is generally preserved until the patient is pre-arrest.(8)
                                                                     Weakness and dizziness has been reported by some
  (I) South Asian Clinical Toxicology              Research          patients.(3 ;9)

      Collaboration(SACTRC) Clinical Units, North
      CentralProvince, Sri Lanka                                     Electrocardiogr,.aphic changes are the most obvious marker

                                                                     of yellow     oleander    toxicity.   Not   all patients   with
  (2) Department of Clinical Medicine, Faculty of
      Medicine, niversityof Colombo, Sri Lanka
              U
                                                                     intentional self poisoning will develop cardiotoxicity. In a
                                                                     study of 162 patients with intentional self poisoning, only
                                                                                                                                              .
                                                                     56% developed dysrhythmias requiring treatment.(1 0)
Introduction

           he yellow oleander tree is found commonly             ,   Patients with mild poisoning have flattening or inversion of


T          through much of the tropics and subtropics
           around houses       and gardens.(1)
cardenolideshave been identified in the yellow oleander
                                                       Many
                                                                     the Twave and depression of the ST segment. Patients with
                                                                     moderate poisoning show a prolonged PR interval (first
                                                                     degree heart block) or sick sinus syndrome, which may
that are structurally similar to the digitalis cardenolides          progress to conduction defects at the atrioventricular (AV)
                      ;2)
derivedfrom foxglove.(1 Because of this structural                   node (second or third degree heart block) consistent with
          i
similarity,nvestigationsand treatments developed for                 severe poisoning. These cardiac effects are similar to those
digitalismay be useful in the management of yellow                   noted in digoxin poisoning, except that atrial fibrillation,
oleanderpoisoning.                                                   ventricular ectopics and tachycardias are uncommon from
                                                                     yellow oleander.(3;8;1O)But these effects are also rare in
Inpartsof India and Sri Lanka it has become a popular                otherwise healthy subjects with digoxin poisoning.( 11;12)
means
    ofselfharm.(3-6)There are now tens of thousands                  This difference might be related to co-existent cardiac
ofyellow       poisoningcases in SouthAsia each year
        oleander                                                     disease or pre-existing electrolyte' disturbances from
and probably thousands of deaths. Management       of patients       diuretic therapy in patients who are being treated with
with severe poisoning may be difficult    and costly, placing        digoxin.(8; 13)
 eat stress on the health system due to requirements for
I~xpensive
        treatments and transfers to secondary or tertiary            The most common ECG abnormality is bradycardia, which
 ospitals for temporary cardiac pacing.                              may be sinus bradycardia, sinus arrest or exit block, or AV
                                                                     nodal dissociation (third degree heart block).(3; 10) Deaths
  linical Features                                                   from ventricular fibrillation (VF) or asystolic arrests have

  e clinicalfeatures of yellow oleander poisoning are,               been reported to occur suddenly in patients in sinus rhythm

      t
limilaro those of poisoning with digitalis and other                 or first degree heart block, without the development           of

  denolides.(7)                                                      other heart blocks, but other factors may have been
                                                                     important here, including hyperthermia and metabolic
 ausea,   vomiting,abdominalpain and diarrhoea are the               disturbances from atropine toxicity. Severely poisoned

           M      J
  uradhapura edical ournal. Volume4.December 2005                                                                                12
                                                                                                        Review    Article!


patients may die of VF resistant            to electrical      Hyperkalaemia is associated with increased toxicity, withafacilities are available.
cardioversion.(14)                                             higher mean admission serum K+ in patients with severeReversing               brady(
The time course for progression and resolution of              cardiotoxicity       (5.4mmol/L)      than those with mildBradycardia has been trl

cardiotoxicity is variable. For example, lOne patient          cardiotoxicity (4.3mmol/L). However, because there i!0.6 mg in uncontrolled

remained in sinus rhythm for 72 hours before developing                                                              atropine bolus followe(
                                                               significant variability between patients within each 01

second degree heart block, while another had a serious         these groups, it is does not appear to be a reliable marker 0:pulse above 80 beats/m
dysrhythmia at 92hrs.(3;9) Others have redeveloped             toxicity.(8) Other factors may alter serum potassiun only used for bradyca
                                                               concentrations and complicate their interpretation in thi         .
dysrhythmias after treatment with anti-digoxin Fab                                                                       accompame d by hypot             I

                                                               context of yellow oleander poisoning, such as acid-basi. d            .      "   .
antitoxin.(9)A 5 year old child was asymptomatic for 24                                                                 m uce an antlc h 0 Imergu
                                                               disturbances from the use of sodium bicarbonate in forcel
hours post-ingestion before developing severe vomiting                                                                       close nursing care, or hn
                                                               emesis solutions.
and bradycardia,which persisted for four days.(l5) Up to                                                                     in hot, non-air conditiont
40% of patients with severe cardiotoxicity may revert to                                                              outcomes has not been
                                                               Other biochemical abnormalities ha~e not been shown If
sinus rhythm after a number of hours without specific                                                                 experience suggests bem
                                                               be associated with cardiac toxicity, including liver aD!
treatment,(8) but there is insufficient information to
                                                               renal function tests, creatine kinase, magnesium and bloo!
determinewhichpatients will revert and which will require                                                                Isoprenaline infusions hi
                                                               glucose levels.(8)
specifictreatment.
                                                                                                                             of bradycardia in yell

OUTCOMES                                                       Digoxin assay                                                 Because    of isoprenal

Case fatality from yellow oleander poisoning varies                                                                     v
                                                               Because of the structural similarities between digoxin aD! entricular ectopy, it i:

betweeninstitutions and studies, with an overall mortality     other cardiac glycosides, digoxin assays can be used Ifdigitalis poisoning.(12)

of 3-10%.(3;6;10;16) This' wide variability in mortality       measure      the      concentration       of   digoxin-likl   suggested, but informati

may reflect the availability of temporary cardiac pacing       immunofluorescence substances (DLIS) in oleandGtreatment are not availabl

facilities,intermittentsupply of anti-digoxin Fab antitoxin,   poisoning.(7 ;8;15)Although higher plasma concentration!

the higher proportion of severely poisoned patients at         ofDLIS are associated with increased toxicity,(8; 15)thesfDECONTAMINATI

referral hospitals, inadequate cardiac monitoring, or          concentrations do not appear to provide prognostilThere is debate regardin

complicationsassociatedwith high doses of atropine.            information, or guide therapy.(7;9) Further, the digoxirdecontamination, if any,
                                                               assay is not widely available in Sri Lankan Hospitals.        long been considered e
RANGE OF TOXICITY                                                                                                            yellow oleander poisonn
                                                               Management                                                    more definitive treatment
Thenumberof seeds ingested does not correlate well with
the severity of cardiotoxicity that develops. Death has        Standard management of yellow oleander poisonin!not available. Clinical tr

occurred after ingestion of one or two seeds despite           involves resuscitation, prompt cardiac monitoring, gastrotreatment of this poiso
admission to a referral hospital experienced in the                                                              (
                                                               intestinal decontamination, treatment of nausea aD!Table 1).
management of oleander poisoning.(9;17) In contrast,           bradycardia, and for severe dysrhythmias administration 0
patientshavebeen discharged from hospital in good health       anti-digoxin Fab anti-toxin or temporary cardiac pacingThe American              and H
withoutrequiring pacing or antitoxin after consuming ten       Unfortunately, some of these treatments are not widel)toxicology published po:
ormoreseeds.(3)                                                available and, while the evidence base for their use ligastrointestinal decontam
                                                                                                               These reviews conclude(
                                                               oleander poisoning is now slowly increasing, goo<
INVESTIGATIONS                                                                                                            c
                                                               evidence is still lacking for some interventions. Because 01linical benefit from th
Biochemistry                                                   the unpredictable course of clinical toxicity, all patientlperformed beyond one h(
Overall,   the importance       of hyperkalaemia         on
                                                                                                                     g
                                                               with acute poisoning will probably benefit frOIl astric lavage and sir
cardiotoxicityfrom yellow oleander is not well dermed.         continuous cardiac monitoring for at least 72 hours i
AnuradhapuraMedicalJournal. Volume4.December 2005                                                                    Anuradhapura MedicalJo
                                                                                                                  1]
                                                                                                                                         r

                                                                                                               Review Articles

    facilities are available.                                           (SDAC).(18-22) It should be highlighted that these
    Reversing radycardia
            b                                                           conclusions were drawn mostly from data on poisonings
    Bradycardiahas been treated with bolus doses of atropine            with pharmaceuticals, not yellow oleander.

    0.6 mg in uncontrolledstudies.(10;17) We use such an
F          b             by
    atropine olusfollowed an infusionto maintainthe                     Forced emesis is commonly performed in some regions for
., pulseabove80 beats/minute.Larger doses of 2-3mg are                  initial decontamination. This usually involves the forceful
    only used for bradycardias less than 40 beats/minute                ingestion oflarge volumes offluid, such as water or sodium

              by
    accompanied hypotension. Large doses of atropine                    bicarbonate    solution. This practice may cause harm by

    inducean anticholinergic delirium, requiring sedatives and          speeding gastric emptying through the pylorus, disturbing
    closenursingcare, or hyperthermia which can be hazardous            serum electrolytes, delaying administration of oral
    inhot,non-air conditioned wards. The effect of atropine on          treatments     including activated charcoal, aspiration
    outcomes has not been formally assessed, but clinical               pneumonia or increased vagal tone which may exacerbate
    experience suggests benefit.                                        bradycardia or induce vasovagal cardiac arrests.


    Isoprenalineinfusions have been suggested as a treatment        .   Gastric lavage involves the placement of an orogastric or
    of bradycardia in yellow       oleander   poisoning. (10; 17)       nasogastric tube, aspiration of the stomach contents, and

    Because of isoprenaline's potential         to precipitate          repeated      washouts    with water, saline or sodium
    ventricularectopy, it is not recommended for use in                 bicarbonate. It has been recommended for use in patients
    digitalispoisoning.(12)Oral salbutamol has also been                who present within 24 hours of ingesting oleander seeds by
    suggested, informationregarding outcomes from this
             but                                                        some clinicians based on the observation that seed
    treatment are not available.                                        fragments may be retained in the stomach for a prolonged
                                                                        period of time.(10;17) If a clinician chooses to perform
    DECONTAMINATION                                                     gastric lavage, it must be performed carefully, without
    There is debate regarding which form of gastrointestinal            interfering      with    cardiac   monitoring   or patient
    decontamination, if any, is effective. Decontamination    has       resuscitation. Aspiration and local trauma are particular
    long been considered essential in the management of                 concerns when performing on unwilling patients. Since
    yellowoleanderpoisoning, particularly in regions where              seed fragments may be large in size, a'large bore orogastric
    moredefmitive treatments such as antitoxin and pacing are           tube is probably required for aspiration of these fragments,
    not available. Clinical trials of activated charcoal in the         a procedure that is poorly tolerated by patients who are not

    treatmentof this poison have recently been reported             .   intubated and sedated, and may precipitate a vagal event.
         I).
    (Table
                                                                        Because       cardenolides    may undergo enterohepatic
    The American and European societies of clinical                     recirculation, it is possible that delayed administration
    toxicologypublishedposition papers on the efficacy of               (beyond one hour) of activated charcoal may be effective,
    gastrointestinaldecontamiI1.ation between 1997 and 1999..           and that MDAC may be more effective than SDAC. Two
    These reviews concluded that there was no evidence of               RCTs have addressed whether SDAC or MDAC are

    clinicalbenefit from these techniques, particularly if              effective for yellow oleander poisoning         -   both are
            beyondone hour in the case of forced emesis,
    performed                                                           described in Table 1. The first study by de Silva et a1.(17)
    gastric lavage and single dose activated charcoal                   reported that MDAC was safe and highly effective at

    Anuradhapura Medical Journal. Volume 4.December          2005                                                                   14
                                                                                                    Review Article
                                                                                                                             Table 1.
reducing deaths, but this conclusion was subsequently          in rural South Asia, so patients will probably requll
                                                               transfer. The delays in reaching these facilities may b          Outcomes of CO
debated.(23) The second study was conducted by the
                                                                                                                                pOIsonmg;
authors and did not demonstrate clinical benefits from         considerable and some patients will die during transfer.A
                                                               RCT is urgently required to determine the efficacy I           Study
MDAC. It does not appear unreasonable to administer
MDAC, although it should not be used in preference to          temporary cardiac pacing in yellow oleander poisoning.         Study type

othertreatments.                                                                                                              Number of participal
                                                               Electrical cardioversion
                                                               We find that electrical cardioversion        is generalt       Types of patients
Hypokalaemia (eg. due to excessive diarrhoea or vomiting)
should be corrected since it increases cardiotoxicity   with   ineffective for patients with malignant ventricul~             Intervention

therapeutic dosing and digitalis poisoning, and deaths have    dysrhythmias from yellow oleander poisoning. Experielll
                                                               with digitalis poisonings is similar, where it has bef          Setting
been reported    in hypokalaemic    patients   with yellow
                                                               recommended that electrical cardipversion should t             Results
0Ieanderpoisoning.(8;   11)
                                                               reserved for cases refractory to other treatments using IOf

SPECIFIC THERAPY                                               energy levels.(li ;25)

Anti-digoxin Fab antitoxin
                                                               Future therapy
An RCT was conducted (Table 1), but improvements in
                                                               A recent animal study suggested that an intermediate (II
mortalitywere not evaluated in this study at the time it was
not known whether the Fab would cross-react with the           metabolism, fructose-I,6-diphosphate (FDP; CAS regisUl
                                                               number 488-69-7), may be effective in dogs poisoned wia
cardenolides sufficiently to have any effect. With the clear
                                                               the common 0Ieander.(26) It is relatively cheap and hi
improvements in cardiac rhythm from the antitoxin shown
                                                               been used as a treatment for patients with coronary he~
in this RCT, it would now probably be considered unethical
                                                               disease and heart failure, in addition to being used f(]l
to conduct a larger :R.CTto assess changes in mortality with                                                                   Other comments
                                                               parenteral nutrition and in sports medicine. IfFDP canhi
the use of antitoxin. Recent experiences suggest that doses
                                                               shown to reverse oleander-induced cardiotoxicity II
of 800mg IV (compared         to 1200mg in the RCT) are
                                                               humans, then it would be an affordable option for oleande
effective in the management of severe cardiotoxicity.
                                                               poisoning in SouthAsia.

Temporary cardiac pacing
                                                               Acknowledgements
The efficacy of temporary cardiac pacing in the treatment
                                                               We thank the medical and nursing staff of thi
of cardenolidepoisoning is unknown. French retrospective
                                                               Anuradhapura, PolonnaJVwaand Kurunegala Hospitals fo
studies have compared outcomes between anti-toxin and
                                                               their support of our clinical research in Sri Lanka. DR
pacing. These have suggested increased complications
                                                               acknowledges the National Health and Medical Researcl
with temporary pacing (including cardiac or arterial
                                                               Council (Australia) for provision of a scholarship. ME isi
perforation, precipitation of malignant dysrhythmia,
                                                               Wellcome Trust Career Development Fellow, funded b)
thrombosis and infection, contributing to death in 13% of
                                                               grant GRO63560MAfrom the Wellcome Trust's Tropic~                         SDAC.
patients receiving this treatment), failure of pacing to                                                                                 MDAC
                                                               Interest Group. The South Asian Clinical Toxicology
prevent life threatening dysrhythmia more often than Fab                                                                                 GL-g:
                                                               Research Collaboration (SACTRC) is funded by the
(23%vs 8% failure). Pacing is also ineffective at reversing                                                                              RCT-
                                                               Wellcome TrustlNational Health and Medical Researcl                       NG-n
hyperkalaemia (13;24) and facilities and expertise. to
                                                               Council International Collaborative Research Granl
performtemporary cardiac pacing are not widely available
                                                               GRO71669MA

Anuradhapura Medical Journal. Volume 4.December         2005                                                            15 Anuradhapura MediI
:iclel                                                                                                                         Review Articles
              Table1.
equ~
Lay~             Outcomesof controlled studies assessing the efficacy of interventions in the management of yellow oleander
                 pOlsonmg.
ler..M
lCY 01         Study                    Eddleston et al(9)          de Silva et al(17)          Eddleston et al(27)         Eddleston et al
                                                                                                                            (ISRCTN02920054)
Ig.            Studytype                RCT                         RCT                         Observational study         RCT
                                                                                                using historical controls
               Number of participants   66                          401                         N/A                         1515 patients with
                                                                                                                            yellow oleander
                                                                                                                            poisoning
eral1~         Types of patients        Severe yellow oleander      Symptomatic yellow          History of yellow           History of yellow
                                        cardiotoxicity              oleander poisoning          oleander poisoning          oleander poisoning
 iculari       Intervention             1200mg anti-digoxin         50g MDAC every six          Availability of anti-       50g SDAC vs 50g
 iencel                                 Fab antitoxin vs saline     hours for 12 doses vs       digoxin Fab antitoxin       MDAC q4h for six
                                        placebo                     SDAC                                                    doses vs no charcoal
  beenj        Setting                  Tertiary referral           Tertiary referral           Secondary and tertiary      Secondary referral
                                        hospital                    hospital                    referral hospitals          hospitals
 rd bel        Results                  2 hours post treatment:     5/201 deaths (2.5%)         Tertiary hospital: 4.4%     No significant
                                        resolution of toxicity in   with MDAC vs 16/200         ARR in death (95% CI        differences in death
 g loVl!
                                        15/34 patients treated      (8.4%) control; ARR         1.5-6.8) and 8.8% ARR       between MDAC,
                                        with antitoxin vs 2/32      5.5% (95% CI 0.6-10.3)      for pacing (95% CI 6.2-     SD1\C, and NoAC.
                                        controls (p<O.OOl).         Fewer patients required     11.0).                      No significant adverse
                                        8 hours post-treatment:     antitoxm or pacmg in        Secondary hospitals:        effects from AC.
                                        24/33 patients treated      the MDAC arm.               6.2% ARI in death
                                        with antitoxin vs 5/32      No significant adverse      (95% CI 1.7-10.5) and
 Ite on                                 controls (p<O.OOI).         effects from AC.            17.3% ARI for pacing
                                        Time to 50% reversal: 3                                 (95% CI 12'1-22'5).
 ~istry/                                hours for treatment and                                 Treatment given on 49
                                        30 hours for control.                                   occasions for 194
  withl                                 Normokalaemia within                                    patients, so 4 courses of
                                        2 hours in treatment                                    antitoxin needed to
  1 hasl                                arm.                                                    save one life (95% CI
  heartl                                No deaths in either arm.                                2.4-14'7).

  1 for
               Othercomments            Admission criteria: 2na     GL givento all patients     Conducted to measure        These are preliminary
  mbel                                  or 3'd degree AV block,     on admIssion.               the effect of shortages     results. This study was
                                        sinus bradycardia <40       May have included a         m supply since              stopped under the
  ~ inl                                 beats/min, sinus arrest     higher number of            introduction in 2001.       direction of an
  nder                                  or exit block, or atrial    patients with severe        Supply exhausted due        independent Data
                                        tachyarrhythmias.           toxicity.                   to high cost of             Monitoring and Ethics
                                        Many patients included      Small number of deaths      antitoxin.                  Committee in October
                                        in this study had been      within six hours which                                  2004.
                                        transferred from            is more likely to relate                                90% of deaths occurred
                                        peripheral units, with a    to the cohort rather than                               within 24h of poisoning
                                        mean transit time of 16-    the intervention.                                       while AC was being
      thel                               18 hours, which may         11/21 deaths (52%)                                     adinistered,
                                        represent a survival        occurred in patients                                    suggesting that longer
  sfor'                                 cohort.                     from atypical                                           treatment regimens will
                                        Anaphylactoid               dysrhythmias.                                           not be more effective.
      DR                                reactions noted in some     Atypical features were
                                        patients, but without       noted in this series
   ITch
                                        complications.              which has !,:atised these
      is a                                                          outcomes to be
                                                                    questioned. (23)
      Ibyl
      icali               SDAC- single dose activated charcoal                                   ARR - absolute risk reduction
      ogyl                MDAC- Multi-dose activated charcoal                                    CI - confidence interval
      theI                GL- gastriclavage                                                      AV - atrioventricular
                          RCI - randomised controlled trial                                      ARI - absolute risk increase
      rch
                          NG- nasogastric
      ant



      15                MedicalJournal. Volume4.December 2005
              Anuradhapura
                                                                                                                                                      16
                                                                                               Reviewt

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                                                                                                           ,'Management
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                                                                                                II
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                                                           21. Anonymous.      Position statement ano    .11.6% Sport..



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       2000;83(3):301-6.                                       charcoal in the treatment of acute' Unfortunately Sri Lank:
   9. Eddleston M, Rajapakse S, Jayalath S, Sjostrom                                                    incidence of spinal trau:
                                                               American Academy         of Clinical To'
       L, Santharaj W, Thenabadu PN et al.Anti-digoxin
       Fab fragments in cardiotoxicity induced by
                                                               European Association of PoisonsC           ~
                                                                                                        collected last 4 month
                                                                                                                 "




                                                               Clinical      Toxicologists.        [W 2005) 26 Cases have h
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   10. Fonseka MM, Seneviratne SL, de Silva CE,                                                       ~
                                                           22. Vale JA. Position statement: gastric patients had thoracic S1
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                                                               European Association of PoisonsC~
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                                                           23. Juurlink DN, Sivilotti MLA. Multidoseq
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   12. Smith TW, Antman EM, Friedman PL,                       digitalis intoxication--is pacing stillap~~
                                                               J. Toxicol.Clin. Toxicol. 1993 ;31(2):261-1J.                     Amz4
                                                                                                                                8%
       Blatt    CM, Marsh          JD. Digitalis                                                                              12%Object Fal!!D-'
                                                           25. Antman EM, Smith TW. DigitalisI~
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                                                               Annu.Rev.Med.1985;36:357-67.
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       495.                                                    diphosphate                              The incidence of spi
                                                                            in the treatment of oleandertIDI
  13. Taboulet P, Baud FJ, Bismuth C. Clinical                 dogs. Vet.Hum.Toxicoi.                   of Sri Lanka is 7 pe'
                                                                                         1999;41(1):9-15.
                                                           27. Eddleston M, Senarathna L, Mohamrni' cordinjury without'
       features and management of digitalis                    Buckley N, Juszczak E, SheriffMHRetal. missedCSI is very 1
       poisoning--rationale for immunotherapy                                                        f~
                                                               due to a lack of an affordable antitoxin identified angiogr:
       J. Toxicol. Clin. Toxicol.1993 ;31 (2):247-             poisoning. Lancet2003;362: 1041-4.       Occlusion of the VI
       60.                                                                                              level of the spinal
                                                                                                        patients. Commoru
                                                                                                         vertebrae.
Anuradhapura MedicalJournal. Volume4.December 2005                                                                           Anuradhapura   Mec

								
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