Summon Chomchai, MD, MPH
         Department of Preventive and Social Medicine
Faculty of Medicine Siriraj Hospital, Mahid...
   A 55 year-old-man
   Found unconscious at home 1 hour PTA
   1-2 hours PTA: He was seen eating Kratom and
    drank ...
   0.4 mg of Naloxone was given with no
    response
   He was treated with supportive (IV fluid,
    oxygen by canular ...
 Mithragyna  Speciosa Korth
 A plant used in Thailand and
  Malaysia
 Scheduled to be illegal in
  Thailand, Malaysia, ...
   Mithragynine and 7-hydroxymithragynine
   Unknown human pharmacokinetics
   Agonists of delta and delta opioid recep...
   Rat pharmacokinetic study:
    ◦ Peak plasma level:1.2-1.8 hour
    ◦ Elimination half-life: 3.86-9.43 hours
    ◦ Vol...
   Dose-dependent neuropsychiatric symptoms
   Onset 10-15 minutes; duration 1 hour
    ◦ Low dose: Stimulation: hyperte...
   It is used in workers in Thailand
   In 2003, at least 221600 people were
    estimated to use Kratom in Thailand
   ...
   Age of first uses: 20-40 years
   Regular users: use because of condonation
    by family and peers as opposed to oth...
   61% of regular uses believe that they are
    addicted to Kratom
   Withdrawal symptoms
    ◦ Inability to work
    ◦...
   Rarely reported
   2 case in Pubmed
   1 case with unconsciousness and seizures
   1 case of seizures
   AMS for 3...
   Supportive and symptomatic care
   Naloxine may be considered in cases with
    respiratory depression

   J Med Tox...
   A 12-year-old girl was brought to the
    emergency room due to alteration of
    consciousness.
   Her parents gave ...
   Six hours prior to hospitalization, the patient took 26 tablets
    of dextromethorphan (Romilar).
   She reported of...
   Non-opioid synthetic analog of codeine
    ◦ dextro-isomer of levorphanol
   Actions are modulated by central sigma r...
   Metablozied by CYP 2D6 to dextrophan
    ◦ noncompetitively antagonize the N-methyl-D-aspartate
     (NMDA) receptor a...
J Am Pharm Assoc. 2009;49:e20–e27
   Minimal: 80-100 mg
   Common: 200-400 mg
   Heavy: 600-1500 mg
   It may be ingested or snorted
   Vivid visual ha...
   Clinical diagnosis
   Urine test: false positive for PCP

        J Emerg Med. 2000;18:379-381.
   Gastric decontamination
   Naloxone therapy: shown to be effective
    when used in children and for the specific
   ...
   A 18 y/o woman was brought in because of
    alteration of consciousness with a container of
    abamestin 1.8% W/V be...
   Abamectin is a potent
    antihelmintic, insecticide,
    and miticide
   Derived from Strepto-myces
    avermitilis ...
   Toxic effects of abamectin are usually seen
    after oral ingestions
   May be absorbed dermally
   Following their...
   CNS symptoms such as incoordination,
    tremor, lethargy, excitation, and mydriasis via
    GABA agonistic effect
  ...
   Only one study in the literature by Chung et al
   a significant correlation between the ingested
    abamectin dose ...
   Airway protection
   Hypotension: intravenous fluid and
    vasopressor

      Clin Toxicol (Phila). 2007;45(3):299-...
   Inhibitor of AchE
   Bind to AchE and form a stable compound
   Inactivate AchE molecule inactive
   Once AchE mole...
   Signs and Symptoms
     I. Muscarinic or parasympathetic symptoms
       SLUDGE + 3 KILLER Bs
     II. Nicotinic/ga...
   Clinical diagnosis
   Cholinesterase level
     Wide normal range
     RBC cholinesterase
       Specific
       ...
   Pupils
   Sweating
   Lung sounds: air entry, bronchospasm,
    secretion
   Heart rate
   Blood pressure




    ...
   Antagonizing muscarininc effects
   Reactivating blocked cholinesterase
   Treatment of muscle hyperstimulation/
   ...
   If the clinical presentation is not clear
    ◦ administer atropine 0.6– 1 mg
   A marked increase in heart rate (mor...
   Atropine 1.8–3 mg (three to five 0.6 mg vials)
   3-5 minutes after giving atropine, check the
    five markers of ch...
   Clear chest on auscultation         Pupils
    with no wheeze                      Lung sounds
   Heart rate >80 be...
   With no improvement in 3-5 minutes: double dose the
    atropine until the goal is achieved
   Continue doubling the ...
   Infusion of atropine
   Rate per hour = 10-20% loading dose

   Atropine intoxication: agitation, confusion, urinary...
   Oximes reactivate acetylcholinesterase
    inhibited by oganophosphorus
   Despite the beneficial effects of pralidox...
   Meta-analysis of 7 studies of severe OP
    poisoning
   382 patients
   No significant risk or harm in terms of
   ...
Crit Care Med. 2006 Feb;34(2):502-10.
Crit Care Med. 2006 Feb;34(2):502-10.
   A randomized controlled trial studied the effect of
    very-high-dose pralidoxime
   Pralidoxime iodide (2 g loading...
   A prospective study on 802 patients self-
    poisoned with chlorpyrifos, dimethoate, or
    fenthion
   Mortality: c...
   Dimethoate-poisoned patients
    ◦ Died sooner than other pesticides
    ◦ Often died from hypotensive shock
   Fenth...
Lancet. 2005 Oct 22-28;366(9495):1452-9.
   Acephate             Chlorpyriphos Dialifos
   Dicrotophos          Diazinon
                         Dichlofenthi...
   A double-blind randomised placebo-controlled
    trial of pralidoxime chloride (2 g loading dose over
    20 min, foll...
PLoS Med. 2009 Jun 30;6(6):e1000104.
PLoS Med. 2009 Jun 30;6(6):e1000104.
   Pralidoximes be given to all symptomatic
    patients who need atropine or manifesting
    neuromuscular manifestation...
   In the cholinergic nervous system, diazepam
    appears to decrease the synaptic release of
    Ach
   In CNS diazepa...
   Overall effects of benzodiazepine: reducing
    anxiety and restlessness, reducing muscle
    fasciculation and seizur...
   A bipyridium herbicide
   Toxicokinetics
    ◦   Rapid absorption: peak plasma level within 1-2 hours
    ◦   Incompl...
 Ingestion of paraquat leads to
    ◦ Generation of free oxygen radicals
    ◦ Lipid peroxidation
    ◦ Damaging cell mem...
   Mild poisoning:
    ◦ Local irritation: vomiting and diarhea
    ◦ Ingestion of less than 20 mg/kg of paraquat ion
   ...
   Fulminant poisoning:
    ◦ Ingestion of more than 40 mg/kg of paraquat ion Usually die within 1-5 days
    ◦ GI ulcera...
   Hart’s Nomogram
   Plasma paraquat level drawn within 28
    hours
   Those with level 3 mg/L at anytime:
    100% m...
Method           Sensivitity   Specificity   Positive     Negative
                                             predictive...
   In a study with 53 cases of paraquat
    poisoning
   All patients with urinary paraquat
    concentrations less than...
   A study using sodium dithionite test for plasma paraquat
    as a qualitative test in 233 paraquat poisoning patients
...
   Urine should be tested serially for 24 h after
    ingestion
   An early urinary semiquantitative testing may
    und...
   Although quantitative plasma paraquat
    concentrations have a greater predictive
    value, qualitative urine and pl...
   Activated charcoal/ Fuller’s earth/ bentonite
   Improve survival in animal studies
   Equivocal efficacy in animal ...
   Significant clearance and improved survival shown in canine models
    loaded with LD50 and LD100 dose.
   No systema...
   The most widely investigated and applied aspect of
    specific management is immunosuppressive therapy,
    especiall...
 Regimen: cyclophosphamide 5
  mg/kg/day and dexamethasone 24
  mg/day for 14 days
 Total cases = 72
 Mortality: treate...
 A single-blinded randomized clinical trial in
  142 paraquat-poisoned patients, pulse
  therapy reduced mortality in mod...
   N = 23 cases of paraquat poisoned patients with
    predictive mortality > 50% but < 90% by plasma
    level
   Initi...
 A retrospective study in 54 cases
 Significantly higher survival with
  suppression of leucocyte or neutrophil
  counts...
   12 studies using immunosuppressive therapy in
    the management of paraquat poisoning
    ◦ Four non-randomized
    ◦...
   Systematic review
   3 RCT
   Total cases : 164 moderate to severe cases
   Inclusion criteria: Urine navy blue or ...
Cochrane Database Syst Rev. 2010 Jun 16;6:CD008084.
toxbuster@hotmail.com
Toxicology updates
Toxicology updates
Toxicology updates
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Toxicology updates
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Toxicology updates

  1. 1. Summon Chomchai, MD, MPH Department of Preventive and Social Medicine Faculty of Medicine Siriraj Hospital, Mahidol University
  2. 2.  A 55 year-old-man  Found unconscious at home 1 hour PTA  1-2 hours PTA: He was seen eating Kratom and drank ethanol  At the ED:  P 96/min, R 12/min, BP 100/70 mmHg, O2 Sat 95% at room air  GCS: E1V1M1, pupils 2 mm  CVS and Chest: WNL, no secretion sound  Normal skin and mucosa  NS: Comatose, reflexes: 2+, plantar reflexes: fleoxor responses
  3. 3.  0.4 mg of Naloxone was given with no response  He was treated with supportive (IV fluid, oxygen by canular and monitoring)  He woke up 10 hours after presentation  Admitted to ingested one handful of Kratom and one bottle of whiskey
  4. 4.  Mithragyna Speciosa Korth  A plant used in Thailand and Malaysia  Scheduled to be illegal in Thailand, Malaysia, Myanmar and Australia  Increasing popularity as a drug of abuse  Clinical Toxicology (2008) 46, 146–152
  5. 5.  Mithragynine and 7-hydroxymithragynine  Unknown human pharmacokinetics  Agonists of delta and delta opioid receptors: Analgesia, euphoria and respiratory depression  Agonist to presynaptic alpha-2 adrenergic ,adenosine and serotonin receptors  Clinical Toxicology (2008) 46, 146–152
  6. 6.  Rat pharmacokinetic study: ◦ Peak plasma level:1.2-1.8 hour ◦ Elimination half-life: 3.86-9.43 hours ◦ Volume of distribution: 37.9-89.5 L/kg ◦ Clinical Toxicology (2008) 46, 146–152
  7. 7.  Dose-dependent neuropsychiatric symptoms  Onset 10-15 minutes; duration 1 hour ◦ Low dose: Stimulation: hypertension, tachycardia, tremor at low dose ◦ High dose: Opioid effects in high doses  Nausea, vomiting and diarrhea are commonly reported  Clinical Toxicology (2008) 46, 146–152
  8. 8.  It is used in workers in Thailand  In 2003, at least 221600 people were estimated to use Kratom in Thailand ◦ ~2% of Southern Thailand population  Purposes: ◦ Abuse: increase work endurance ◦ Medicinal use: treatment of chronic pain, cough, weight control ◦ Reports of using kratom for treating opioid withdrawal  Substance Use & Misuse (2006), 42:2145–2157
  9. 9.  Age of first uses: 20-40 years  Regular users: use because of condonation by family and peers as opposed to other ‘hard drugs’  Chewing leaves, drinking tea, smoking dry leaves  Very bitter taste; usually wash the taste with water, energizing beverages and palm juice  Adverse effects perceived by users: constipation, tremor and headahce  Substance Use & Misuse (2006), 42:2145–2157
  10. 10.  61% of regular uses believe that they are addicted to Kratom  Withdrawal symptoms ◦ Inability to work ◦ Pain the the back, legs and muscles ◦ Crave  Other reported withdrawal symptoms: Yawn, rhinorrhea, myalgia, arthralgia and diarrhea  Substance Use & Misuse (2006), 42:2145–2157
  11. 11.  Rarely reported  2 case in Pubmed  1 case with unconsciousness and seizures  1 case of seizures  AMS for 30 hours  Confirmed mithragynine detection in urine by HPLC-ESI/MS/MS  No known long-term effects  J Med Toxicol. 2010 Apr 22.  Addiction. 2008 Jun;103(6):1048-50.
  12. 12.  Supportive and symptomatic care  Naloxine may be considered in cases with respiratory depression  J Med Toxicol. 2010 Apr 22.
  13. 13.  A 12-year-old girl was brought to the emergency room due to alteration of consciousness.  Her parents gave the history of using an over-the-counter antitussive drug, a small yellow coated tablet, for illicit purposes.  Her habit changed from gradual to progressive increase in the dosage of drug use, and from occasional with a few tablets at a time to daily doses in order to gain the desired effect of euphoria
  14. 14.  Six hours prior to hospitalization, the patient took 26 tablets of dextromethorphan (Romilar).  She reported of feeling sleepy, with nausea and abdominal discomfort.  Her father noted that she became increasingly confused and brought her to the emergency department (ED).  At the ED, vital signs BP117/70 mmHg, P 122 / min, R 20/ min, T38.2o C.  The patient appeared drowsy with Glascow coma scale of 15 (E4V5M6)  She was responsive and verbalized with notably slow speech.  Nystagmus was seen, Fundoscopic examination was normal  J Med Assoc Thai 2005; 88(Suppl 8): S242-5
  15. 15.  Non-opioid synthetic analog of codeine ◦ dextro-isomer of levorphanol  Actions are modulated by central sigma receptor binding sigma receptors  Unlike most opioids, the drug is devoid of activity at mu and delta receptors  Typical adult and pediatric doses (>12 years of age) of DM range from 60 to 120 mg/day in divided doses  At clinical doses, the drug produces no euphoriant, analgesic, or dependence-producing effects J Am Pharm Assoc. 2009;49:e20–e27
  16. 16.  Metablozied by CYP 2D6 to dextrophan ◦ noncompetitively antagonize the N-methyl-D-aspartate (NMDA) receptor and serotonin release ◦ Euphoria, hyperactivity and hallucination  In general, acute overdose of dextromethorphan causes nausea, vomiting, hyperexcitability, restlessness, hallucination, dizziness, drowsiness, ,lethargy, slurred speech, mydriasis, euphoria, tachycardia, hypertension and urinary retention.  The classical opioid effects such as respiratory depression and miosis are not commonly seen J Am Pharm Assoc. 2009;49:e20–e27
  17. 17. J Am Pharm Assoc. 2009;49:e20–e27
  18. 18.  Minimal: 80-100 mg  Common: 200-400 mg  Heavy: 600-1500 mg  It may be ingested or snorted  Vivid visual hallucinations and complete body analgesia  Mild withdrawal symptoms that are similar to those of opiate withdrawal  http//:www.erowid.org/chemicals/dxm.
  19. 19.  Clinical diagnosis  Urine test: false positive for PCP  J Emerg Med. 2000;18:379-381.
  20. 20.  Gastric decontamination  Naloxone therapy: shown to be effective when used in children and for the specific indications of hyperexcitability, altered mental status or respiratory depression  Am J Emerg Med. 1991;9:237-238.
  21. 21.  A 18 y/o woman was brought in because of alteration of consciousness with a container of abamestin 1.8% W/V beside her  BP 102/60 mmHg, P 64/min, R 26/min, O2sat 90% @ room air  E1V1M2, pupils 3mm not reactive to light, normal skin and mucosa  CVS & Chest: WNL  Abdomen: Soft normal bowel sound  NS: Flaccid tone, reflexes: 1+ upper extremities, absent: lower extremities
  22. 22.  Abamectin is a potent antihelmintic, insecticide, and miticide  Derived from Strepto-myces avermitilis (species of Actinomyces)  Abamectin: a mixture of avermectins containing >80% avermectin B1a and <20% avermectin B1b ◦ Similar biological and toxicological properties
  23. 23.  Toxic effects of abamectin are usually seen after oral ingestions  May be absorbed dermally  Following their absorption, maximum  Serum concentrations peak 2.7 to 5 hours after oral dosing  Elimination half-life was 2.8 to10 hours among healthy volunteers ◦ Largely excreted into the bile and feces  Clin Toxicol (Phila). 2007;45(3):299-300.
  24. 24.  CNS symptoms such as incoordination, tremor, lethargy, excitation, and mydriasis via GABA agonistic effect  Deaths related to Abamectin ingestion are commonly a result of respiratory failure  From our experience: shock and status epilepticus  Clin Toxicol (Phila). 2007;45(3):299-300.
  25. 25.  Only one study in the literature by Chung et al  a significant correlation between the ingested abamectin dose and clinical severity ◦ For asymptomatic and mild poisoning, the average ingested dose was 23.0 mg/kg ◦ Average dose for severely poisoned patients was 100.7 mg/kg ~ 280 mL ◦ CNS and gastrointestinal effects:diarrhea, nausea, vomiting, AMS, dizziness and weakness  Ann Emerg Med. 1999 Jul;34(1):51-7.
  26. 26.  Airway protection  Hypotension: intravenous fluid and vasopressor  Clin Toxicol (Phila). 2007;45(3):299-300.
  27. 27.  Inhibitor of AchE  Bind to AchE and form a stable compound  Inactivate AchE molecule inactive  Once AchE molecules are unavailable, continued stimulation  cholinergic overstimulation  paralysis
  28. 28.  Signs and Symptoms  I. Muscarinic or parasympathetic symptoms  SLUDGE + 3 KILLER Bs  II. Nicotinic/ganglionic/NM symptoms  Muscle fasciculations, progressive paralysis and respiratory failure.  Hypertension, tachycardia, pupillary dilatation and pallor  III. CNS symptoms  Restlessness, tremor, confusion, ataxia, slurred speech and seizure.
  29. 29.  Clinical diagnosis  Cholinesterase level  Wide normal range  RBC cholinesterase  Specific  Hardly available  Plasma cholinesterase  More available  Non-specific
  30. 30.  Pupils  Sweating  Lung sounds: air entry, bronchospasm, secretion  Heart rate  Blood pressure Lancet. 2008 Feb 16;371(9612):597-607.
  31. 31.  Antagonizing muscarininc effects  Reactivating blocked cholinesterase  Treatment of muscle hyperstimulation/ seizures Lancet. 2008 Feb 16;371(9612):597-607.
  32. 32.  If the clinical presentation is not clear ◦ administer atropine 0.6– 1 mg  A marked increase in heart rate (more than 20–25 beats/min) and flushing of the skin suggest that the patient does not have significant cholinergic poisoning and further atropine is not required Lancet. 2008 Feb 16;371(9612):597-607.
  33. 33.  Atropine 1.8–3 mg (three to five 0.6 mg vials)  3-5 minutes after giving atropine, check the five markers of cholinergic poisoning(  A uniform improvement in most of the five parameters is required  The most important parameters are air entry on chest auscultation, heart rate, and blood pressure Lancet. 2008 Feb 16;371(9612):597-607.
  34. 34.  Clear chest on auscultation  Pupils with no wheeze  Lung sounds  Heart rate >80 beats/min  Pupils no longer pinpoint  Dry axillae  Systolic blood pressure >80 mmHg Indicators Pitfalls Critical Care 2004, 8:R391-R397
  35. 35.  With no improvement in 3-5 minutes: double dose the atropine until the goal is achieved  Continue doubling the dose each time that there is no response  From a review of 22 surviving patients with OP-poisoning and respiratory failure dose of atropine 1-75 mg(mean23.4 mg, 22.0sd) to clear the lungs, raise the pulse above 80bpm, and restore systolic blood pressure to more than 80 mmHg  Standard textbook therapy will take ◦ Up to 1380 mins to mean dose ◦ Up to 4440 mins to 75 mg dose  J Toxicol Clin Toxicol. 2004;42(6):865-75.  Crit Care. 2004 Dec;8(6):R391-7.
  36. 36.  Infusion of atropine  Rate per hour = 10-20% loading dose  Atropine intoxication: agitation, confusion, urinary retention, hyperthermia, bowel ileus and tachycardia  With intoxication: stop the atropine infusion and check every 30 minnutes  Once the atropine intoxication subsides restart the infusion at the rate 70-80% of the previous rate Lancet. 2008 Feb 16;371(9612):597-607.
  37. 37.  Oximes reactivate acetylcholinesterase inhibited by oganophosphorus  Despite the beneficial effects of pralidoxime, its effectiveness (and safety) has been much debated
  38. 38.  Meta-analysis of 7 studies of severe OP poisoning  382 patients  No significant risk or harm in terms of ◦ Overall mortality ◦ Need of respiratory support  Crit Care Med. 2006 Feb;34(2):502-10.
  39. 39. Crit Care Med. 2006 Feb;34(2):502-10.
  40. 40. Crit Care Med. 2006 Feb;34(2):502-10.
  41. 41.  A randomized controlled trial studied the effect of very-high-dose pralidoxime  Pralidoxime iodide (2 g loading dose, then 1 g either every hour or every 4 h for 48 h, then 1 g every 4 h until recovery)  200 patients with moderate organophosphorus poisoning  The high-dose regimen was associated with reduced case fatality (1% vs 8%; odds ratio [OR] 0·12, 95% CI 0·003–0·90),  Lancet. 2006 Dec 16;368(9553):2136-41.
  42. 42.  A prospective study on 802 patients self- poisoned with chlorpyrifos, dimethoate, or fenthion  Mortality: chlorpyrifos (8.0%), dimethoate (23.1%), fenthion (16.2%)  Endotracheal intubation: chlorpyrifos(15.0%), dimethoate (35.2%), fenthion (31.3%)  Patients poisoned by ◦ Diethyl OP pesticide (chlorpyrifos) responded well to pralidoxime ◦ Dimethyl OP (dimethoate, fenthion) responded poorly Lancet. 2005 Oct 22-28;366(9495):1452-9. Neth J Med. 2008 Apr;66(4):146-8.
  43. 43.  Dimethoate-poisoned patients ◦ Died sooner than other pesticides ◦ Often died from hypotensive shock  Fenthion poisoning initially caused few symptoms but many patients subsequently required intubation  Lancet. 2005 Oct 22-28;366(9495):1452-9.
  44. 44. Lancet. 2005 Oct 22-28;366(9495):1452-9.
  45. 45.  Acephate  Chlorpyriphos Dialifos  Dicrotophos  Diazinon  Dichlofenthion  Dimethoate  Dioxathion  Fenchlorphos  Fonofos  Fenitrothion  Isazophos  Malathion  Isoxathion  Methamidophos  Mephosfolan  Phorate  Methylparathion  Phosalone  Mevinphos  Phoxim  Monocrotophos  Quinalphos  Temephos  Triazophos  Thiometon  Trichlorfon Dimethyl- Diethyl-
  46. 46.  A double-blind randomised placebo-controlled trial of pralidoxime chloride (2 g loading dose over 20 min, followed by a constant infusion of 0.5 g/h for up to 7 d)  235 patients with organophosphorus insecticide self-poisoning  Pralidoxime reactivated RBC acetylcholinesterase significantly  Mortality was nonsignificantly higher in treatnment group: 30/121 (24.8%) vs placebo18/114 (15.8%)  PLoS Med. 2009 Jun 30;6(6):e1000104.
  47. 47. PLoS Med. 2009 Jun 30;6(6):e1000104.
  48. 48. PLoS Med. 2009 Jun 30;6(6):e1000104.
  49. 49.  Pralidoximes be given to all symptomatic patients who need atropine or manifesting neuromuscular manifestations  Pralidoxime chloride ◦ Loading dose of 30 mg/kg intravenously over 20 minutes, followed by an infusion of 8 mg/kg/h ◦ Adults: 2 g loading dose followed by 500 mg/h.  Continue until recovery (12 hours after stopping administration of atropine or once butyrylcholinesterase increase) Lancet. 2008 Feb 16;371(9612):597-607.
  50. 50.  In the cholinergic nervous system, diazepam appears to decrease the synaptic release of Ach  In CNS diazepam causes hyperpolarization of neurons making them significantly less susceptible to cholinergically induced depolarization ◦ The ultimate result is cessation of propagation of convulsions  BMJ. 2007 Mar 24;334(7594):629-34.
  51. 51.  Overall effects of benzodiazepine: reducing anxiety and restlessness, reducing muscle fasciculation and seizures, controlling agitation  Indications: patients poisoned with OP whenever convulsions, agitation or pronounced muscle fasciculation are present  Doses: ◦ Diazepam 5-10 mg (0.05-0.3 mg/kg/dose) ◦ Midazolam 5-10 mg (0.15-0.2 mg/kg/dose)  Lancet. 2008 Feb 16;371(9612):597-607.
  52. 52.  A bipyridium herbicide  Toxicokinetics ◦ Rapid absorption: peak plasma level within 1-2 hours ◦ Incomplete absorption: 10-30% ◦ Distribute to tissues: Lung, Kidney ◦ Elimination: 90% eliminated within 12 -24 hours via kidney (half-life 10-12 hours)
  53. 53.  Ingestion of paraquat leads to ◦ Generation of free oxygen radicals ◦ Lipid peroxidation ◦ Damaging cell membranes and leading to cell death.  Paraquat is actively taken up into type II pneumocytes and renal tubular cells.
  54. 54.  Mild poisoning: ◦ Local irritation: vomiting and diarhea ◦ Ingestion of less than 20 mg/kg of paraquat ion ◦ Full recovery without sequelae  Moderate to severe: ◦ Ingestion of 20-40 mg/kg of paraquat ion ◦ GI corrosion, acute tubular necrosis, hepatitis ◦ Delayed progressive pulmonary fibrosis ◦ Delayed mortality (1-4 weeks) from hypoxia ◦ Survivors may have gradual recovery of pulmonary functions over months to years
  55. 55.  Fulminant poisoning: ◦ Ingestion of more than 40 mg/kg of paraquat ion Usually die within 1-5 days ◦ GI ulceration ◦ Acute renal failure, myocardial damage, hepatic failure, pulmonary edema and hemorrhage ◦ Multiorgran failure, shock ◦ 100% mortality regardless of management
  56. 56.  Hart’s Nomogram  Plasma paraquat level drawn within 28 hours  Those with level 3 mg/L at anytime: 100% mortality  No fulminant poisoning:  2.0 mg/L at 4 hr  0.3 mg/L at 10 hr  0.1 mg/L at 24 hr Eddleston M, Wilks MF, Buckley NA. Qjm 2003;96(11):809-24. 61
  57. 57. Method Sensivitity Specificity Positive Negative predictive predictive value value Proudfoot/ 0.79 0.89 0.92 0.73 Scherrmann Hart (50% 0.77 0.92 0.94 0.71 survival line) Jones(p=0.5) 0.70 0.93 0.94 0.67
  58. 58.  In a study with 53 cases of paraquat poisoning  All patients with urinary paraquat concentrations less than 1 µg/ml(no color change-pale blue), within 24 h of ingestion, survived  Cases with results more than ++ (navy blue; >10 µg/ml) within 24 h following ingestion have a high probability of death  Hum Toxicol1987 Jan;6(1):91-3.
  59. 59.  A study using sodium dithionite test for plasma paraquat as a qualitative test in 233 paraquat poisoning patients  Blood samples were drawn within 12 hours  Detection limits: concentration ≥ 2 mg/L  Levels above 2 mg/L are associated with high mortality in many studies  Patients with a plasma paraquat level < 2.0 mg/L have the potential for recovery with vigorous treatment  Sensitivity 0.67  Specificity 1.0  Positive predictive value 1.0 ◦ Am J Med Sci2009 Nov;338(5):373-7.
  60. 60.  Urine should be tested serially for 24 h after ingestion  An early urinary semiquantitative testing may underestimate the amount of paraquat systemically absorbed  Crit Rev Toxicol. 2008;38(1):13-71.
  61. 61.  Although quantitative plasma paraquat concentrations have a greater predictive value, qualitative urine and plasma may contribute to a more rapid evaluation of prognosis with more availability ◦Am J Med Sci2009 Nov;338(5):373-7.
  62. 62.  Activated charcoal/ Fuller’s earth/ bentonite  Improve survival in animal studies  Equivocal efficacy in animal studies  Adsorbent therapy alone has never shown increase survival in human  Meredith TJ, Vale JA. Hum Toxicol 1987;6(1):49-55. 69
  63. 63.  Significant clearance and improved survival shown in canine models loaded with LD50 and LD100 dose.  No systematic study showing that hemodialysis or hemoperfusion is efficacious in human  Possible cause of failure:  Relatively small amount cleared  While renal function is still intact, external clearance is smaller than renal clearance  When renal failure develops, pulmonary uptake has already occurred.  Recommendation: perform charcoal hemoperfusion only if it can be started within 4 hours.  Med J Aust 1991;154(9):617-22. 70
  64. 64.  The most widely investigated and applied aspect of specific management is immunosuppressive therapy, especially the regimen consisitng of ◦ Cyclophosphamide ◦ Corticosteriods  Concepts: Reduction of pulmonary inflammation and fibrosis using antiinflammatory and immunosuppressive therapy
  65. 65.  Regimen: cyclophosphamide 5 mg/kg/day and dexamethasone 24 mg/day for 14 days  Total cases = 72  Mortality: treated 20/72(27.8)% vs historical control 42/61(68.9%)  Lancet. 1986 May 17;1(8490):1117-20.  Another study  Survival: treated 20/31(64.5%) vs historical control 9/14(64.3%)  Hum Exp Toxicol. 1992 Mar;11(2):129-34.
  66. 66.  A single-blinded randomized clinical trial in 142 paraquat-poisoned patients, pulse therapy reduced mortality in moderate to severe poisoning from 53/65(81.5%) to 38/56(67.9%)  Pulse therapy included 1. 15 g/kg/day of cyclophosphamide for 2 days 2. 1 g/day of methylprednisolone for 3 days  All patients also received dexamethasone 30mg/day for 14 days  Am J Respir Crit Care Med. 1999 Feb;159(2):357-60.
  67. 67.  N = 23 cases of paraquat poisoned patients with predictive mortality > 50% but < 90% by plasma level  Initial pulse therapy: cyclophosphamide (15 mg/kg/day, i.v., 2 days) and methylprednisolone (1 g/day i.v., 2 days) Followed by dexamethasone 5 mg, i.v., every 6 h until PaO2 > 80 mmHg  Randomized cases for repeated pulse therapy if PaO2 was < 60 mmHg: 3 days of methylprednisolone and 1 day of cyclophosphamide  Mortality rate: ◦ control 6/7 = 85.7% ◦ Study 5/16 = 31.3% (p=0.027)  Crit Care Med. 2006 Feb;34(2):368-73.
  68. 68.  A retrospective study in 54 cases  Significantly higher survival with suppression of leucocyte or neutrophil counts by at least 10% after the initiation of immunosuppressive ◦ Journal Of the Chinese Medical Association2009;72(9 supplement):S20-1.
  69. 69.  12 studies using immunosuppressive therapy in the management of paraquat poisoning ◦ Four non-randomized ◦ Six non-randomized comparing historical controls ◦ Two randomized controlled trials  The relative risk of immunosuppressive therapy in decreasing mortality with paraquat poisoning ◦ 0.55 (95 % CI 0.39- 0.77) for the non-randomized studies (comparing historical controls) ◦ 0.6 (95 % CI 0.27-1.34) for randomized controlled studies  Singapore Med J2007 Nov;48(11):1000-5.
  70. 70.  Systematic review  3 RCT  Total cases : 164 moderate to severe cases  Inclusion criteria: Urine navy blue or drak blue and/ or plasma level in the range of mortality 50-90%  Interventions: IV cyclophosphamide and dexamethasone  Main outcomes: mortality at the end of follow up (at least 30 days post ingestion)  Results: RR 0.72 (95% CI 0.59 to 0.89)  Cochrane Database Syst Rev. 2010 Jun 16;6:CD008084.
  71. 71. Cochrane Database Syst Rev. 2010 Jun 16;6:CD008084.
  72. 72. toxbuster@hotmail.com

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