Toxicology updates

80
Summon Chomchai, MD, MPH Department of Preventive and Social Medicine Faculty of Medicine Siriraj Hospital, Mahidol University

description

June 2010

Transcript of Toxicology updates

Page 1: Toxicology updates

Summon Chomchai, MD, MPH

Department of Preventive and Social Medicine

Faculty of Medicine Siriraj Hospital, Mahidol University

Page 2: Toxicology updates

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

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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

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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

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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

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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

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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

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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

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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

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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

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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.

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Supportive and symptomatic care

Naloxine may be considered in cases with respiratory depression

J Med Toxicol. 2010 Apr 22.

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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

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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

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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

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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

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J Am Pharm Assoc. 2009;49:e20–e27

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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.

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Clinical diagnosis

Urine test: false positive for PCP

J Emerg Med. 2000;18:379-381.

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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.

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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

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Abamectin is a potent antihelmintic, insecticide, and miticide

Derived from Strepto­myces avermitilis (species of Actinomyces)

Abamectin: a mixture of avermectins containing >80% avermectin B1a and <20% avermectin B1b

◦ Similar biological and toxicological properties

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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.

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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.

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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.

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Airway protection

Hypotension: intravenous fluid and vasopressor

Clin Toxicol (Phila). 2007;45(3):299-300.

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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

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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.

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Clinical diagnosis Cholinesterase level

Wide normal range RBC cholinesterase Specific

Hardly available

Plasma cholinesterase More available

Non-specific

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Pupils

Sweating

Lung sounds: air entry, bronchospasm, secretion

Heart rate

Blood pressure

Lancet. 2008 Feb 16;371(9612):597-607.

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Antagonizing muscarininc effects

Reactivating blocked cholinesterase

Treatment of muscle hyperstimulation/ seizures

Lancet. 2008 Feb 16;371(9612):597-607.

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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.

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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.

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Indicators Pitfalls

Clear chest on auscultation with no wheeze

Heart rate >80 beats/min

Pupils no longer pinpoint

Dry axillae

Systolic blood pressure >80 mmHg

Pupils Lung sounds

Critical Care 2004, 8:R391-R397

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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.

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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.

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Oximes reactivate acetylcholinesteraseinhibited by oganophosphorus

Despite the beneficial effects of pralidoxime, its effectiveness (and safety) has been much debated

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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.

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Crit Care Med. 2006 Feb;34(2):502-10.

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Crit Care Med. 2006 Feb;34(2):502-10.

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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 organophosphoruspoisoning

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.

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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

poorlyLancet. 2005 Oct 22-28;366(9495):1452-9.Neth J Med. 2008 Apr;66(4):146-8.

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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.

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Lancet. 2005 Oct 22-28;366(9495):1452-9.

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Dimethyl- Diethyl-

Acephate

Dicrotophos

Dimethoate

Fenchlorphos

Fenitrothion

Malathion

Methamidophos

Methylparathion

Mevinphos

Monocrotophos

Temephos

Thiometon

Trichlorfon

Chlorpyriphos Dialifos Diazinon Dichlofenthion Dioxathion

Fonofos Isazophos Isoxathion Mephosfolan Phorate Phosalone Phoxim Quinalphos Triazophos

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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 acetylcholinesterasesignificantly

Mortality was nonsignificantly higher in treatnmentgroup: 30/121 (24.8%) vs placebo18/114 (15.8%)

PLoS Med. 2009 Jun 30;6(6):e1000104.

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PLoS Med. 2009 Jun 30;6(6):e1000104.

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PLoS Med. 2009 Jun 30;6(6):e1000104.

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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.

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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.

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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.

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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)

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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.

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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

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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

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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

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Eddleston M, Wilks MF, Buckley NA. Qjm 2003;96(11):809-24.

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Method Sensivitity Specificity Positive predictive value

Negative

predictive value

Proudfoot/ Scherrmann

0.79 0.89 0.92 0.73

Hart (50% survival line)

0.77 0.92 0.94 0.71

Jones(p=0.5) 0.70 0.93 0.94 0.67

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In a study with 53 cases of paraquatpoisoning

All patients with urinary paraquatconcentrations 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.

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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.

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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.

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Although quantitative plasma paraquatconcentrations 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.

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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.

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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 clearedWhile renal function is still intact, external clearance is smaller than

renal clearanceWhen 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.

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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

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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.

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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

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.

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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.

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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.

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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.

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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.

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Cochrane Database Syst Rev. 2010 Jun 16;6:CD008084.

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