Example of Detailed Protocol/Practice Standard for Physicians Diagnostic and Laboratory Evaluation

Definitive diagnosis must be made on the basis of a history of exposure and serial blood test of RBC cholinesterase. Until further information is available about urine PNP levels and its relationship to clinical effects, short- and long-term medical management needs serial RBC cholinesterase level, well-recognized as the "gold standard" in organophosphate exposure.

We recommend that subjects be tested under the following circumstances:

In situations where a high prevalence of OP poisoning is present or is strongly suspected (e.g., an illness outbreak or a group of applicators routinely handling OPs), or if subjects live in a home that has been identified as Level 1 (high environmental exposure), a single cholinesterase test within the laboratory normal range may not be sufficient to rule out poisoning, given the wide range of normal values in the population. In this situation, the diagnosis should be made by comparing a baseline value with serial follow-up tests, or by testing for regeneration of the native acetylcholinesterase enzyme following in vitro treatment of a blood sample with the cholinesterase antidote protopam. There is no clear evidence as to what level of cholinesterase inhibition is necessary to produce symptomatic illness, although claims have been made for various thresholds (e.g., 50% depression, or 80% depression) in the past on the basis of different case series. Variation in the degree of inhibition required to produce symptoms is related to the rate of inhibition.

Ongoing urinary PNP levels may be obtained in conjunction with the cholinesterase levels as a means of monitoring relatively acute additional methyl parathion exposure (i.e., on returning people to a contaminated home), methyl parathion metabolism, and its elimination from the body.

For chronic exposures to methyl parathion, it is likely that a high degree of inhibition would be required to produce symptoms and may be identified by a single test compared with laboratory reference ranges. The compound has some tendency to preferentially inhibit RBC ChE to a greater extent than the plasma ChE. Follow-up testing can be done when borderline normal results are obtained from the screening tests. Two to three weeks may be sufficient interval for follow-up testing for RBC cholinesterase, with monthly follow-up samples for 3 months. Weekly samples to discern a trend are an alternative.

Standardizing ChE Lab Data

Methods for monitoring ChE activity include Ph (Michel), BMC Reagent Set or BMC kit (Ellman-Boehringer), DuPont ACA, and Kodak-Ektachem. Results obtained by the different methods cannot be directly compared because of variations in reporting units and underlying test methodology. These variations cause problems when baseline samples are analyzed using one method at one lab and follow-up samples are analyzed at another (e.g., at time of illness). In clinical situations, the use of differing baseline and follow-up methods appears to be frequent. When records of OP-related illness reported to the California Pesticide Illness Surveillance Program (PISP) between 1982 to 1990 were reviewed, 123 (44.4%) of the 277 cases with multiple cholinesterase tests included samples analyzed by at least two different test methods and different population normal ranges. It is preferable that all labs analyzing ChE for MP evaluations use identical methodology.

Sample handling protocols--time to separate RBC/plasma and refrigerate samples--should also be standardized.

Treatment

Most of the exposed patients encountered so far in the recent targeted communities do not require hospitalization. For illnesses that do not require hospitalization (about 73% of definite-probable OP poisonings reported in California), decontamination of skin may be the principal treatment required. Return to activities that do not involve OP exposure is appropriate in the absence of significant impairment.

Antidotal treatment is usually reserved for hospitalized patients. Atropine reverses muscarinic symptoms (e.g., respiratory and gastrointestinal [GI] tract secretions, bradycardia) of OP poisoning for relatively short periods (pharmacologic half-life=70 minutes +30). One to two milligram (mg) intravenous (IV) doses may be used in place of the 0.5-1.0 mg doses used in treating symptomatic bradycardia associated with heart disease. Serious doses may be titrated to maintain clear breath sounds and a heart rate of 80-100 beats/minute. Protopam (2-PAM) breaks down the cholinesterase-OP complex when 1 gram (g) is given over 10-20 minutes intravenously (after taking diagnostic cholinesterase samples). It is effective against nicotinic, muscarinic, and central nervous system (CNS) poisoning symptoms.

In the most severely ill patients, oxygen, clearance of secretions, and artificial ventilation may be required in addition to antidotal therapy. For such patients, use of morphine, aminophylline, and phenotiazines are contraindicated because of the increased risk of cardiac arrhythmia. Atropine should not be given until adequate ventilation has reversed hypoxia. These intensive care measures are more typically required following deliberate or accidental ingestion of organophosphates than for occupational illness. Treatment is not expected to be an issue for most MP exposure cases.

Non-ChE effects.

In addition to ChE inhibition, many organophosphates are associated with irritation of the skin and upper respiratory tract. The agents producing odor and irritant effects associated with most OPs are thought to be low molecular weight mercaptans and sulfides. Monitoring studies of communities near application of OP cotton defoliant tributyl phosphorothioate (DEF) have demonstrated, for example, that the concentration of butyl mercaptan ranged from 0.29-9.93 parts per billion (ppb) (well above the odor thresholds for mercaptans), although concentrations of the active ingredient were orders of magnitude less (0-0.034 parts per trillion [ppt]). The odors associated with OPs often give rise to characteristic irritant symptoms, but they also provoke nonspecific systemic symptoms such as headache and nausea. Although most of the respiratory irritation is confined to the upper airways, occasional complaints of OP-associated wheezing and chest tightness are reported. These cases require careful evaluation, because bronchoconstriction sometimes results from systemic poisoning as well as airway irritation. Persistent reactive airways have occasionally been reported following exposure to OPs independent of cholinesterase inhibition. Pre-existing asthma is a risk factor for persistent symptoms. Sealants used in the remediation process should be evaluated for possible triggers of persistent reactive airways symptoms. If considering the possibility of reactive airways, you should refer such cases to those expert in such evaluations.

Delayed neuropathy and neurobehavioral effects of OPs

The most serious non-ChE-related effect of OPs is organophosphate induced delayed neurotoxicity (OPIDN), which becomes apparent 7-14 days after exposure. Historically, OPIDN has been principally associated with a handful of OP compounds that have a high propensity for inhibiting neuropathy target enzyme (NTE). These include compounds no longer registered, such as leptophos and EPN. Most OPs have the capacity to produce OPIDN following massive intoxication, but none of the currently used OPs preferentially inhibit NTE at doses that do not also cause ChE inhibition. It does not seem probable that chronic household exposures to methyl parathion are likely to produce this syndrome. Nevertheless, physicians evaluating patients should consider appropriate evaluation with nerve conduction tests, vibrometry, and electromyograms (EMGs) in patients with unexplained peripheral motor weakness or an unexplained, abnormal sensory examination of the extremities. Treatment of delayed neuropathy is supportive. Administration of atropine or pralidoxime initially or later does not influence the course of neuropathy. NB: The Risk Identification/Workgroup agrees with the Clinical Practice Workgroup that peripheral neuropathy caused by MP exposure in this setting is highly unlikely.

Occurrence of persistent neurobehavioral effects following recovery from OP poisoning is controversial. The study conducted by Savage demonstrated deficits in memory and abstraction

on test batteries, but normal neurological examinations. Rosenstock demonstrated several deficits with the WHO test battery and also subclinical decreases in vibrotactile sensitivity, but also reported normal clinical examinations. The test batteries conducted by Steenland showed deficits in two neurobehavioral tests (sustained visual attention and mood scales) and decreased vibrotactile sensitivity in the toe, but neurological examinations were again normal.

Clinical note: Neurobehavioral testing is a research tool not routinely conducted in individual clinical cases of organophosphate exposure or overt poisoning.

Background: classical high-dose acute poisoning

Organophosphates (OPs) poison the nervous system by inhibiting the breakdown of the transmitter acetylcholine by the enzyme acetylcholinesterase. This results in overstimulation of portions of the nervous system that contain acetylcholine: muscarinic--postganglionic fibers of the parasympathetic nervous system (control secretions of respiratory and GI tracts, heart rate, etc), sweat glands in the sympathetic nervous system, preganglionic fibers in the sympathetic nervous system, and skeletal muscle. The acronym MUDDLES is a helpful means of remembering the principal effects of cholinesterase inhibitors:

Mioses
Urination
Diarrhea
Diaphoresis
Lacrimation
Excitation (of CNS)
Salivation

Other effects of note include bradycardia (slowing of the heart rate). This effect may be quite severe in some instances and may be responsible for episodes of dizziness and syncope (fainting) associated with organophosphate poisoning. These same symptoms may be produced by inhibition of acetylcholinesterase in the central nervous system, so that it is frequently impossible to ascertain the physiologic cause of the symptoms in individual cases.

Outline of Suggested Medical Evaluation

Questionnaire

(must be standardized for all those undergoing evaluation)

A standardized questionnaire should have relatively easy capability of having data entered in a computerized database for future reference.

General health information

Need to discern pre-existing conditions that may mimic and therefore, be possible confounders in symptoms that would be seen in organophosphate overexposure.

• CNS (migraine, other headaches, depression, anxiety syndromes)
• Peripheral nervous system problems (from such conditions as diabetes, alcoholism, thyroid disorders, carpal tunnel syndrome, vitamin deficiencies)
• GI (irritable bowel, chronic diarrhea, malabsorption, inflammatory bowel)
• Respiratory (asthma, smoking, reactive airways)
• Psychological (chronic anxiety, depression)
• Occupational history
• Environmental history (home use of pesticides/gardening)

Exposure History

Anecdotal information about potential exposure

Dates of spraying

Times at residence; number of people in residence at time of spraying

Activities in residence likely to increase exposure of certain individuals (walking without shoes; crawling infants; homebound individuals)

Any acute symptoms

Symptoms Present

Relatively Specific Symptoms: hypersalivation, bradycardia in absence of cardiac disease, inappropriate sweating, muscle fasciculations, excessive urination (can be confused with urinary tract infection [UTI])

Nonspecific: headache, nausea, abdominal pain, diarrhea, trouble concentrating, blurred vision, metallic taste, wheezing, coughing

Irritant: odor, stinging eyes, nose/upper respiratory tract, skin paresthesia, skin rash

Physical exam: general physical status, orientation; blood pressure, heart rate, respiratory rate, temperature, pupillary exam; cranial nerves; pharynx

chest: wheezes, rales
abdomen: tenderness
extremities: reflexes; pinprick sensation; vibration

Additional Lab: Unnecessary for organophosphate exposure evaluation; however, to further evaluate other medical conditions, may do additional testing at the discretion of the physician: CBC, chem panel, UA: (PFTs/methacholine not indicated unless index of suspicion for RADs; see above)