Summon Chomchai, MD, MPH Department of Preventive and Social MedicineFaculty of Medicine Siriraj Hospital, Mahidol University
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
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
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
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
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
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
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
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
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.
Supportive and symptomatic care Naloxine may be considered in cases with respiratory depression J Med Toxicol. 2010 Apr 22.
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
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
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
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
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.
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.
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
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
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.
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.
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.
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
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.
Clinical diagnosis Cholinesterase level Wide normal range RBC cholinesterase Specific Hardly available Plasma cholinesterase More available Non-specific
Pupils Sweating Lung sounds: air entry, bronchospasm, secretion Heart rate Blood pressure Lancet. 2008 Feb 16;371(9612):597-607.
Antagonizing muscarininc effects Reactivating blocked cholinesterase Treatment of muscle hyperstimulation/ seizures Lancet. 2008 Feb 16;371(9612):597-607.
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.
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.
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 mmHgIndicators Pitfalls Critical Care 2004, 8:R391-R397
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.
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.
Oximes reactivate acetylcholinesterase inhibited by oganophosphorus Despite the beneficial effects of pralidoxime, its effectiveness (and safety) has been much debated
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.
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.
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.
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.
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.
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.
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.
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.
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)
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.
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
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
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
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.
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.
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.
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.
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
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
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
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.
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 included1. 15 g/kg/day of cyclophosphamide for 2 days2. 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.
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.
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.
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.
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.
Cochrane Database Syst Rev. 2010 Jun 16;6:CD008084.