Site hosted by Angelfire.com: Build your free website today!

This copyrighted information is available online from:
emedicine: EMERGENCY MEDICINE  An on-line Medical Reference  


Toxicity, Organophosphate and Carbamate

Authored by Debra Slapper, M.D., Instructor, Department of Cardiology, University of Miami

Edited by Dana A. Stearns, M.D., Assistant Director, Undergraduate Education, Instructor, Department of Emergency Medicine, Massachusetts General Hospital; John T. VanDeVoort, Pharm.D., ABAT, Clinical Assistant Professor, Pharmacy Manager, Regions Hospital Pharmacy, University of Minnesota College of Pharmacy; Fred Harchelroad, M.D., Department of Emergency Medicine, Allegheny General Hospital; John Halamka, M.D., Executive Director, Center for Quality and Value, Instructor, Division of Emergency Medicine, Beth Israel Deaconess Medical Center; and Raymond J. Roberge, M.D., M.P.H., Vice-Chair, Clinical Associate Professor, Department of Emergency Medicine, Western Pennsylvania Hospital


Topic Last Updated:  12/29/1999 00:05:48

INTRODUCTION

Background: Over 25,000 brands of pesticides are readily available in the U.S. for a variety of home and agricultural uses. Most are either organophosphate or carbamate compounds and account for over 80% of the pesticide poisonings in the U.S.  Many of the toxic "nerve agents" used by the military are similar organophosphate compounds. Exposure to organophosphates and carbamates produces a characteristic, treatable syndrome in humans. Its recognition and timely intervention is of great importance to emergency physicians and their patients.

Pathophysiology: Organophosphates irreversibly bind to cholinesterase causing the phosphorylation and deactivation of acetylchoinesterase. The subsequent accumulation of acetylcholine at the neural synapse causes an initial overstimulation followed by eventual exhaustion and disruption of neural transmission in the central and peripheral nervous systems (CNS and PNS).

If the organophosphate/cholinesterse bond is not broken by pharmacologic intervention within 24 hours, large amounts of cholinesterase are destroyed causing long-term morbidity or death.

Carbamate poisoning exhibits a similar clinical picture to organophosphates. However, it temporarily binds cholinesterase for approximately six hours with no permanent damage. Carbamates have poor CNS penetration and cause minimal CNS symptoms.

The nicotinic effects from accumulation of acetylcholine at motor end-plate cause persistant depolarization of skeletal muscles, resulting in fasciculations, as well as muscle weakness, hypertension and tachycardia.

Muscarinic effects from potentiation of postganglionic parasympathetic activity of smooth muscles may cause smooth muscle contractions in all organs (e.g., lung, gastrointestinal [GI], eye, bladder and secretory glands), as well as reduction of sinus node and AV conduction, causing bradyarrhythmias or resultant ventricular dysrhythmias.

Central nervous system effects may cause excessive stimulation (possible seizure), then depression and coma.

Actual signs and symptoms depend on the balance between muscarinic and nicotinic receptors.

Frequency:  

In the U.S.: There are reported approximately 20,000 organophosphate exposures per year, although it is estimated that as few as 1% of field worker illness from pesticide exposure is reported. According to the 1998 annual report of the American Association of Poison Control Centers, there were 4332 exposures to carbamates, with one reported death, and 16,392 exposures to organophosphates, with 11 reported deaths in the United States.

Internationally: Exact numbers are not known but organophosphate poisoning occurs in virtually every country in the world. Third world countries have less legislation regarding safe agricultural use of pesticides and a much higher incidence of poisoning and among field workers and the public buying produce from these fields.

Mortality/Morbidity: Mild flu-like symptoms from minimal exposures frequently go unreported or untreated and may be considered a viral illness rather than recognized as poisoning.

     *Epidemics of flu among field workers have been found to be caused by
     
chronic, low-level exposure to organophosphates.

    *Common presenting symptoms include headache, diffuse muscle cramping,
      weakness, excessive secretions, nausea, vomiting and diarrhea
.
      The condition may progress to seizure, coma, paralysis, respiratory failure
      and death
.
      More often, one will see eventual resolution of the acute symptoms, though
      with residual neurologic symptoms if not treated acutely.

     *Organophosphate and carbamate exposures that are rapidly and adequately
      treated have a short course of illness with no residual symptoms.

     *Delayed or inadequate treatment of organophosphate poisoning can lead to
     
prolonged (months) or permanent neurotoxic symptoms.

    *Death is rare, from 0.04-1% in normal pesticide poisonings.
      Respiratory failure is the most common etiology.

     *Organophosphate compounds used as nerve gas for warfare are particularily
      potent. They more rapidly and more frequently cause death.

Race: There is no known racial differences in morbidity or mortality.

Sex: Poisoning is often related to agricultural workers, thus, males are more frequent victims. There is no sex difference in morbidity and mortality given the same exposure.

Age: Due to the high incidence of occupational exposure, significant poisoning is more common in males 15-45 years of age.

     A significant incidence of severe poisoning exists in young children as a smaller
dose is required to cause symptoms.

     Children have become ill after accidental ingestion in the home as well as playing in fields that have been sprayed recently.

CLINICAL

History:

  *Pesticides can be rapidly absorbed from lungs, skin, GI tract, and mucous membranes.

  *Symptoms typically appear within a few hours after exposure.

  *However, large doses can produce immediate symptoms.

  *Some of the highly lipid-soluble organophosphates may cause only mild initial
    symptoms and not produce cholinergic crisis for 24-96 hours.

    Occasionally, approximately 24 - 96 hours after appropriate treatment of
    acute organophosphate cholinergic toxicity, respiratory paresis, muscular
    weakness
(extraocular, nuchal, facial, palatal, and proximal limb muscles)
    and
depressed tendon reflexes occur, an entity termed the Intermediate Syndrome.

   *The patient often knows he or she was exposed and is able to tell you the
     exact compound.

  *When the exposure is not known by the patient, the emergency physician must
    rely on the physical assessment of classical cholinergic symptoms and high
    index of suspicion to try to identify a possible exposure.

Physical: Examination findings are dependent upon the specific poison which
can cause a predominance of muscarinic or nicotinic effects.

     Hypertension, tachycardia, muscle cramps and fasciculations may be seen
     when nicotinic effects predominate.

    Hypotension, bradycardia and excessive secretions occur if muscarinic
    receptors are dominant.

    Miosis, muscle fasciculations and increased secretions are the most
    consistently-reported symptoms.

    Altered mental status, pulmonary edema and cyanosis can be seen.

    Several mnemonics have been developed to describe symptoms
    of cholinergic excess.
    DUMBELS
refers to diarrhea, urination, miosis, bronchospasm,
    emesis, lacrimation and salivation
.

    One study showed 92% of victims had muscarinic symptoms,
    44% nicotinic, 40% CNS and 17% combined symptoms.

Causes:

   *Agricultural exposure is the most common cause of organophosphate
     poisoning and can affect any worker in the industry.

   *This might include field workers, truckers who transport pesticides
     or produce, crop dusters and manufacturers of pesticides.

   *Other occupational exposures include dog groomers who have suffered
     from overexposure to flea dip, pest control workers and various domestic
     and custodial workers who use these compounds.

    *Accidental exposure to the unsuspecting public near sprayed fields
      secondary to winds has been reported.

    *Accidental ingestion usually occurs by children or pets who find home pesticides.

    *There is a relatively high incidence of intentional ingestion as a means of suicide.

    *Mass public contamination from food has been reported in many countries
      but not in the U.S.

    *Military use of nerve gas can cause mass fatalities in warfare and accidental
      poisoning to military personnel handling these weapons.


DIFFERENTIALS

Abdominal Trauma, Blunt
Chemical Warfare Agents
Congestive Heart Failure and Pulmonary Edema
Gastroenteritis
[Plant Poisoning, Mushroom - Disulfuram-like Toxins]

Plant Poisoning, Mushroom - Gyromitra Toxin
Toxicity, Mushrooms
Toxicity, Phosgene

Other Problems to be Considered:

Several other poisons can mimic some symptoms of organophosphate poisoning,
including the muscarine-type mushrooms, paraquat, and inhalational agents
causing non-cardiogenic pulmonary edema. Delayed neuropathies as part
of either of two recognized syndromes (Intermediate Syndrome; Organophosphate-
Induced Delayed Neurotoxicity) should be considered in the differential with
other peripheral neuropathies.


WORKUP

Lab Studies:

The diagnosis of cholinergic excess is largely clinical. It requires recognition
of the syndrome in the appropriate clinical setting.

Supportive laboratory test (e.g., arterial blood gas [ABG], electrolytes and
serum glucose) should be ordered as indicated by the patients symptoms.

Markedly decreased red blood cell (RBC) cholinesterase levels are diagnostic
but usually not available in a timely fashion to guide treatment of the patient.
They should be ordered to facilitate correct diagnosis and long-term treatment,
should the patient have a complicated recovery.
RBC cholinesterase levels regenerate slowly (0.5% to 1% per day).
There is a wide distribution in the range of normal levels, and patients with a
"high normal" RBC cholinesterase level may be symptomatic with a level still
n the low normal range.

Ideally, the diagnosis is based on a decrease of 50% from baseline activity.
Unfortunately, only occupational workers frequently exposed to organophosphates
will have baseline levels.

Plasma cholinesterase levels are available on a more widespread basis
but are not considered the diagnostic test of choice.
It is a hepatic acute phase protein, and many other conditions (e.g.,cirrhosis,
neoplasia, morphine, cocaine, and pregnancy) will decrease its level.

Mild poisoning is defined as a decrease in the RBC cholinesterase activity
to 20% to 50% of baseline.
Moderate poisoning occurs when activity is 10% to 20% of baseline.
Severe poisoning is defined as a decrease in the RBC cholinesterase level
to less than 10% of the baseline activity.

In the case of a chronic exposure associated with peripheral neuropathy , or
increasing peripheral neuropathy following a significant exposure, a blood
speciman should be sent for neuron specific enolase.

Imaging Studies:

A chest x-ray is useful in evaluating pulmonary edema (rare).

Cranial CT scanning may be useful in evaluating the patient with altered mental status.

Other Tests:

An electrocardiogram (ECG) may be useful for evaluating the rare dysrhythmias
(e.g., atrial fibrillation, ventricular tachycardia and Torsades de points) or the
more common QT prolongation.

Procedures:

Rarely secretions become so profuse as to require intubation to protect the airway.
In such cases it will be difficult to ventilate the patient as well.

TREATMENT

Prehospital Care:

Paramount to the management of the organophosphate or carbamate-poisoned
patient is decontamination.
This should begin before or during the initial medical management.
Care is required to prevent secondary casualties, as the compounds are well
absorbed through the skin and lungs.
Appropriate barrier protection and ventilation must be maintained.

Supportive care, including airway control, oxygenation, ventilation and seizure
management
, is most important in managing the organophosphate or carbamate-
poisoned patient.
Placement of an IV line, use of a pulse oximeter and cardiac monitoring are indicated.

In identified, or strongly suspected, cases of cholinergic excess, anticholinergic
agents should be used to enhance supportive care.

Prehospital personnel are often key to the identification of the organophosphate
or carbamate-poisoned patient. The presence of agricultural spray equipment,
bottles of insecticides, odors (garlic-like) and other clues to the diagnosis are
often unavailable to other health care personnel. Failure to note these clues
and initiate prevention of secondary casualties may jeopardize the safety of
the patient and numerous other medical personnel.

Emergency Department Care:

Again, decontamination and prevention of secondary casualties must be a high
priority for the organophosphate or carbamate-poisoned patient.
Patients should be thoroughly decontaminated with clothing removal and a soap
and water (or hypochlorite) bath or shower before entering the ED.
If this is impossible, contaminated areas should be isolated and thoroughly
cleaned before used for other patients or by non-contaminated personnel.

Atropine, to control secretions and bronchospasm, may be more helpful than
intubation for the patient in respiratory distress
.

Anticholinergic agents should be used to antagonize signs and symptoms (e.g., bronchoconstriction, bronchorrhea and excessive secretions).
Inadequate use of atropine is a frequent cause of
treatment failure and morbidity. Anticholinergics do not reverse muscle paralysis and, thus, should be used with
pralidoxime (2PAM).

2PAM combats muscle weakness and paralysis. It is the definitive antidote
and reverses the phosphorylation of cholinersterase,
if used early
.

Arrhythmias may not respond to the usual medications and require pacing.
The patient should be monitored during administration of atropine and 2PAM
until the QT interval is normal.

Diazepam is the drug of choice for seizures, however, 2PAM can be administered concomitantly.

Gastric lavage and charcoal are indicated for acute ingestions.

IV fluids may be needed if the patient has had a prolonged course of vomiting, diarrhea and excessive secretions.


Consultations:

Consultation with the regional poison control center, or your local medical toxicologist (certified through the American Board of Medical Toxicology and/or the American Board
of Emergency Medicine) may provide additional information and patient care recommendations.

Prolonged critical care management is often required for the pulmonary complications in those patients requiring endotracheal intubation.

MEDICATION

Control of significant cholinergic excess is the key to management. Anticholinergic agents can be used to significantly reduce or eliminate the significant (gastrointestinal) and life-threatening (pulmonary and neuro-muscular) effects. Endpoints for therapy include elimination of bronchorrhea (atropine) and improved muscle strength (oximes). Reaching these endpoints may require more medication than is commonly prescribed.

Drug Category: Anticholinergics - Pharmacologic antagonism of excess anticholinesterase activity at muscarinic receptors.

Drug Name Atropine - The indications include GI or pulmonary distress
     in the setting of known or suspected organophosphate or carbamate poisoning.

     Continue therapy until control of bronchoconstriction and bronchorrhea occur.
     High doses may be required in the first 24 h of treatment. Treatment may be
     required for 48 h in severe cases. Doses required may be reduced by the
     concurrent use of oximes.

Adult Dose 1 mg IV (initial or diagnostic)
     2-4 mg IV q15min (therapeutic) until drying of pulmonary secretions
    There are reports of poisoning requiring 2 mg/kg/h IV drip for several
    week to control secretions.

Pediatric Dose 0.015 mg/kg (initial or diagnostic)
0.015 to 0.05 mg/kg q15min (therapeutic) until drying of pulmonary secretions

Contraindications Known atropine sensitivity or existing signs of atropinization

Pregnancy B - Usually safe but benefits must outweigh the risks.
Precautions Watch for atropinization (tachycardia, dilated pupils, dry red skin and dry mucous membranes).

Drug Category: Oximes - Reversal of inhibition of acetylcholinesterase
     and nicotinic effects, including muscle paralysis.

Drug Name Pralidoxime (2-PAM) - The indications include muscle weakness
     (especially respiratory muscle weakness) in the setting of known or
     suspected organophosphate poisoning. Pralidoxime is very rarely needed
     in carbamate poisoning. Increased muscle strength should begin in 30 min.


To be effective, they must be used early in the
course of poisoning
, before the organophosphate-
acetlycholinesterase bond has aged
.

Their use may help prevent intermediate and delayed neuro-muscular and neuropsychiatric organophosphate
syndromes and decrease the dose of atropine required.


Adult Dose 1-2 g IV over 15 min followed by 500 mg/h IV until improved
     muscle strength seen

Pediatric Dose 25 mg/kg IV given over 30 min, followed by 10-20 mg/kg/h IV
     until improved muscle strength seen

Contraindications Known pralidoxime sensitivity

Pregnancy C - Safety for use during pregnancy has not been established.
     Precautions Oximes are relatively non-toxic compounds.


Drug Category: Benzodiazepines - These are used for control of seizures.

Drug Name Diazepam (Valium)
Adult Dose 5-10 mg IV over 3-5 min

Pediatric Dose 30 days - 5 y: 0.2-0.5 mg IV (slowly) q2-5min
     until symptoms resolve or to a maximum dose of 5 mg
5 y or older: 1 mg IV (slowly) q2-5min until symptoms resolve
     or to a max dose of 10 mg

Contraindications  Known hypersensitivity and acute narrow angle glaucoma

Interactions Effects are potentiated by phenothiazines, narcotics, barbiturates,
     MAOIs and other antidepressants

Pregnancy D - Unsafe in pregnancy
     Precautions Monitor for respiratory depression with high or repeated doses.

Drug Category: GI Decontamination

Drug Name Activated Charcoal
 +/- Cathartics

Adult Dose 1 g/kg PO (first dose usually with cathartic, although
    not necessary if diarrhea, secondary to cholinergic stimulation,
    is present); up to 50-100 g  

    May repeat the dose q4h at 0.5 g/kg (alternate use of cathartic,
    monitor for active bowel sounds).

Pediatric Dose 1-2 g/kg PO (Under 2 y: omit cathartic); up to 15-30 g
    May repeat the dose q4h at 0.5 g/kg (alternate use of cathartic, if using
    and monitor for active bowel sounds.

Contraindications Unprotected airway with absent gag reflex

Interactions Will adsorb most recently ingested substances

Pregnancy A - Safe in pregnancy
Precautions   Monitor for presense of active bowel sounds before
     readministration to minimize the risk of a charcoal ileus.

FOLLOW-UP

Further Inpatient Care:

Most patients requiring therapy for organophosphate poisoning require hospital admission for continued monitoring and therapy. The patient should be observed for 24 hours after the last dose of atropine is given. There have been reports of delayed respiratory arrest following inadequate treatment.

Contact the poison control center, or your local medical toxicologist, for information on the anticipated duration of effect for the particular agent involved.

The use of opioids, phenothiazines and antihistamines should be avoided as they can potentiate effects of organophosphates. Similarily, succinylcholine has been reported to cause several hours of respiratory paralysis following one dose.

Further Outpatient Care:

Patients with non-life-threatening symptoms due to carbamate poisoning or with questionable exposure to organophosphates and no symptoms may be considered for discharge after adequate decontamination and observation for six hours.

Adequately treated patients require no medication when leaving the hospital and should be totally asymptomatic within one week.

Patients with residual neuropathies, neuropsychiatric symptoms, confusion, headaches and malaise may require neurology, medical toxicology, occupational medicine, or psychiatry follow up for extended periods.

Deterrence/Prevention:

Patients discharged after exposure to organophosphates or carbamates should
avoid
further exposure to such agents until they are
asymptomatic
and their acetycholinesterase activity level can be shown to
have returned to at least 75% of baseline, which may take several months.

Complications:

Persistent CNS effects
(i.e., irritability, fatigue, impaired memory, depression and psychosis) and
peripheral neuropathies
(i.e., weakness, paresthesia, ataxia and chronic pain)
have been reported
in survivors of significant organophosphate poisoning, as well as in patients with
multiple small exposures
over a long time period.
This can last for weeks, months or years
.

Prognosis:

In untreated, severely intoxicated patients, death usually occurs within 24 hours.
It may be much more rapid with nerve agents.

Most patients treated quickly and optimally fully recover
within 10 days
.

If treatment is delayed 24 hours or is inadequate, recovery may take months,
and
neurological complications may be permanent.

Patient Education:


Patients should be advised to destroy the clothes that they were wearing at the
time of exposure because of the risk of repeat contamination.

MISCELLANEOUS

Medical/Legal Pitfalls:

    *Failure to recognize the cholinergic symptoms, thereby delaying
     or missing treatment
.
     This will result in increased morbidity, and possible mortality.

   *Failure to adequately decontaminate the exposed patient resulting in
     secondary contamination of others.

   *Failure to consider the possibility of an Intermediate Syndrome
    or Organophosphate-Induced Delayed Neurotoxicity.

Special Concerns:

Pregnancy: Patients have been successfully treated after organophosphate poisoning in the second and third trimesters of pregnancy with atropine and palidoxime with delivery of healthy newborns.

TEST QUESTIONS

CME Question 1: A comatose patients arrives in your ED. You are told he was found unconscious in his back yard. He is in respiratory distress, has pinpoint pupils, is incontinent of urine and feces, appears to have vomited and has a large amount of secretions in his airway. What is the initial treatment?

A: Intubation
B: Atropine
C: Decontamination
D: CT brain
E: 2PAM

Your Choice:   (Answers provided on emedicine website, see below.)

CME Question 2: Which of the following chemicals does NOT permanently bind cholinesterase?

A: Malathion
B: Organophosphate
C: Parathion
D: Diazinon
E: Carbamate

Your Choice:  (Answers provided on emedicine website, please see below.)

Pearl Question 1: What is the most common cause of death from organophosphate
poisoning?   (Answers provided on emedicine website, please see below.)

Pearl Question 2: What is the definitive antidote for organophosphate poisoning?
(Answers provided on emedicine website, please see below.)

Pearl Question 3: Which drug is used to control the most uncomfortable symptoms
of organophosphate poisoning?  
(Answers provided on emedicine website, please see below.)

Pearl Question 4: For how long must a patient who has been treated for
organophosphate avoid exposure again to organophosphate?
(Answers provided on emedicine website, please see below.)

BIBLIOGRAPHY

Cable GG, Doherty S: Acute carbamate and organochlorine toxicity
causing convulsions in an agricultural pilot: a case report
. Aviat Space
Environ Med 1999 Jan; 70(1): 68-72 [Medline].

Carlock LL, Chen WL, Gordon EB: Regulating and assessing risks of cholinesterase-inhibiting pesticides: divergent approaches and interpretations.
J Toxicol Environ Health B Crit Rev 1999 Apr-Jun; PT - REVIEW, TUTORIAL(2): 105-60[Medline].

DeBeleecker J, Willems J, Van Den Neucker K, et al: Prolonged toxicity with intermediate syndrome after combined parathion and methyl parathion
poisoning
. j Toxicol Clin Toxicol 1992; 30: 333-345.

DeBleecker J, Van den Neucker K, Colarydn F: Intermediate syndrome in organophosphate poisoning. Crit Care Med 1993; 21: 1706-1711.

Ellenhorn MJ: Organophosphates. Ellenhorn’s Medical Toxicology
1997; 1614-1621.

Farrar HC: Continuous infusion of pralidoxime for treatment of
organophosphate poisoning in children.
Pediatrics 90; 116: 658.

Lotti M, Becker CE, Aminoff MJ: Organophosphate polyneuropathy:
pathogenesis and prevention.
Neurology 1984; 34: 658-662.

Morgan D: Recognition and management of pesticide poisonings.
US Government printing office 82;.

Tuovinen K, Kaliste-Korhonen E, Raushel FM: Success of pyridostigmine,
physostigmine, eptastigmine and phosphotriesterase treatments in acute
sarin intoxication.
Toxicology 1999 Jun 15; 134(2-3): 169-78 [Medline].

Whorton M: Persistence of symptoms after mild to moderate organophosphate
poisoning in 19 farm workers
. Journal of Toxicologic and Environmental
Health 83; 11: 347.

~~~~~~~*~~~~~~~~

The copyrighted text used on this page,
including the answers to the Test Questions,
may be accessed at:
       Source:  http://www.emedicine.com/EMERG/topic346.htm

We have reformatted, hyperlinked, and highlighted parts of this material
in order to present this reference information for educational purposes only
and provide emphasis on various portions of the text.  

This would not have been possible if we had
merely provided to link to the emedicine site.

  ~~~~~~~*~~~~~~~~

We ask for the gracious forbearance of the authors as
our intention is not to infringe in any way on this copyright,
but to educate an entire generation of  SBU students who,
without their consent or knowledge, have been unethically or illegally
exposed to potentially harmful organophosphate pesticides.

Please visit the emedicine website.  
The Table of Contents and Introduction:

emedicine: EMERGENCY MEDICINE
An on-line Medical Reference
 

  http://www.emedicine.com/emerg/index.shtml

  ~~~~~~~*~~~~~~~~

NOTE from the emedicine site:
Medicine is a constantly changing science and not all therapies are clearly established. New research changes drug and treatment therapies daily. The authors, editors, and publisher of this textbook have used their best efforts to provide information that is up-to-date and accurate and is generally accepted within medical standards at the time of publication. However, as medical science is constantly changing and human error is always possible, the authors, editors, and publisher or any other party involved with the publication of this text do not warrant the information in this text is accurate or complete, nor are they responsible for omissions or errors in the text or for the results of using this information. The reader should confirm the information in this text from other sources prior to use. In particular, all drug doses, indications, and contraindications should be confirmed in the package insert.

  ~~~~~~~*~~~~~~~~

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

 ~Top~

  ~Updates~       ~~Return to Welcome~~        ~How Can I Help?~

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~