abstract

Atropine aerosol spray (AAS) was used to treat three organophosphorus (OP)-intoxicated patients to determine if alternate routes of drug administration were as efficacious as intramuscular or intravenous routes when treating OP poisoning. Case I was a seriously intoxicated 20-year-old man classified as Namba IV (severe poisoning). Case II was a 25-year-old man classified as Namba II (mild poisoning), with bradyarrhythmia . Case III was a 23-year-old cyanotic, unconscious man with marked miosis and increased salivation, classified as Namba IV (severe poisoning). The recommended AAS dosing regimen used was 3 puffs every 10 to 15 minutes. Each puff contained 2 mg atropine sulphate, which is equivalent to 1.67 mg atropine free base. After AAS applications, salivation, diarrhea, and sweating diminished in all patients (where applicable). Additionally, in Case II, bradyarrhythmia converted to sinus rhythm. In conclusion, AAS dosage of nearly 30 to 35 mg/day (5 to 6 times/day) is an effective route to administer atropine sulphate for systemic use in patients who are poisoned by OP insecticides. Clinical findings suggest that significant systemic absorption occurs within 5 minutes of AAS application.

introduction

Organophosphate (OP) insecticides are toxic substances that frequently cause poisoning in humans. Worldwide, 3 million cases of acute, severe pesticide poisoning are reported each year, resulting in 220,000 deaths ( Rosenstock , 1991). In Turkey , more than 200 chemicals are registered as pesticides. Among these, OP insecticides are the more important and most widely used group in the country.

OP compounds bind to cholinesterase (ChE) and inactivate both true ChE in red blood cells and pseudocholinesterase in serum. This causes an accumulation of acetylcholine at synapses, leading to impaired neuromuscular transmission (Tafuri, 1987). In acute poisonings, manifestations generally occur only after more than 50% of ChE is inhibited; the severity of symptoms parallels the degree of ChE activity. Mild poisoning usually occurs when cholinesterase is 20% to 50% of normal; moderate poisoning occurs when ChE is 10% to 20% of normal, and severe poisoning occurs when ChE activity is less than 10% of normal (Aaron, 1990). The parasympathetic signs and symptoms of OP intoxication are mainly muscarinic, but nicotinic, motor, and central nervous system effects are also seen when the intoxication is severe. OP intoxication is graded as latent, mild, moderate, and severe by Namba Classifications (Namba, 1971) (table 1).

Treatment regimens of OP intoxication often include activated charcoal application, oxime and atropine sulphate administration, and benzodiazepine sedation. Atropine and oximes act synergistically to reverse the signs and symptoms of ChE inhibition. Atropine is an anticholinergic drug and has a highly specific blocking action on the muscarinic receptors. Oximes act to reverse the formation of the ChE–OP bond and release the ChE. Atropine has been administered by intravenous and intramuscular routes for many decades. Even oral or nasal inhalation routes are now possible with the development of atropine aerosol spray (AAS) (Schneider, 1997). We examined the possibility that AAS could be used either in addition to or instead of conventional intravenous administration. The advantage would be easier, less time–consuming administration of the atropine and less required training for assistants using this method.

materials and methods

We present three OP-intoxicated patients, with different grades of Namba Classification, who were treated with AAS (Aerochem, Bern , Switzerland ). When they were admitted to the emergency unit, their histories were taken, physical examinations were done, and information was collected regarding the name of the OP and the route of intoxication. They were transferred to intensive care and the following investigations were carried out on all patients: ECG,   arterial pressure, heart rate, central venous pressure, hourly urine output, amount of saliva, degree of sweating, number of diarrhea stools, blood and urine chemistry, blood gas analysis, plasma ChE activity, and chest x–ray. Samples of blood, urine, and nasogastric tube output were taken for the Toxic-Screen (Toxi-Lab, Inc., Irvine , CA 92718 ). Gastric lavage was performed and the slurry of activated charcoal was instilled by a nasogastric tube. After two 1-mg IV boluses of atropine, an atropine infusion was initiated at rates from 30 to 120 m /h over 24 hours, or the recommended AAS dosing regimen (3 puffs every 10 to 15 minutes) was used. Each puff contains 2 mg atropine sulphate equivalent to 1.67 mg atropine free base. Therefore, one application of AAS (i.e., 3 puffs) consists of 6 mg atropine sulphate. The benefits and potential risks of using AAS had been explained, and informed consent was obtained from conscious patients or from their first degree relatives when patients were comatose. Pralidoxime was also administered twice a day in 250-mg IV boluses over 20 minutes. Oxime therapy continued for one week. Intravenous diazepam was injected if convulsions occurred. Mechanical ventilation was applied whenever respiratory failure occurred.

Plasma ChE activity was determined on admission and every morning by the Pharmacology Department using Ellman's spectrophotometric method (normal range of plasma ChE is 40 to 80 U/mL) (Rappaport, 1959).

results

Case I

A 20-year-old male was admitted following ingestion of approximately 500 mL of OP insecticide (Paraoxon). On admission, he was found unconscious and was profusely salivating and sweating. His clinical findings were an absence of reflexes, miotic pupils, cyanosis, bronchorrhea, and respiratory failure. Auscultation of the lungs revealed coarse rales bilaterally. He was classified as Namba IV. When he arrived at the intensive care unit, intermittent mechanical ventilation (IMV) was begun immediately. For the first three days of treatment, two 1-mg atropine IV boluses were followed by infusion rates from 30 to 120 m g/h over 24 hours. His plasma ChE levels remained persistently low.   Furthermore, there was no decrease in the amount of salivation, sweating, and diarrhea. Therefore, we applied the AAS regimen 15 times on the fourth day and 7 times on the fifth day instead of using the IV route. After these applications, flushing occurred on his face, neck, and chest. AAS application was discontinued. The next day, diarrhea was seen twice; therefore, we decided to resume the AAS regimen for 8 times on the sixth day. In total, the AAS regimen was applied 35 times during five days. After the AAS applications, salivation markedly decreased from 2100 mL/day to 50 mL/day, sweating disappeared, and the number of stools became less. Atropine doses and clinical findings of Case I are shown in table 2.

During the treatment period, the patient developed the following symptoms of Adult Respiratory Distress Syndrome (ARDS) on the fourth day: hypoxemia, diffuse bilateral pulmonary infiltrates, and stiff lung. Positive end expiratory pressure (PEEP) was added to the ventilatory protocol. A chest tube (thoracostomy) was inserted after radiologic appearance of pneumothorax, which may have resulted from barotrauma, and PEEP ceased. Despite the treatment, clinical findings did not improve; he died on the eighth day.

Case II

A 25-year-old male was brought to the hospital after ingesting approximately 100 mL of Folimat 50 (omethoate) with the intention of committing suicide. On admission, he was conscious, salivating, and mildly sweating. He complained of nausea and vomiting, and had profound weakness in all his limbs. Bradyarrhythmia was seen on his ECG trace (heart rate: 50 beats/min). He was classified as Namba II. Whenever the heart rate decreased below 50 beats/min, one 2-mg IV atropine bolus was administered while we consulted the cardiology department regarding the bradyarrhythmia. They suggested that it was not related to cardiac pathology; therefore, we decided to use the AAS regimen. After the fifth application, the rhythm changed to sinus rhythm. On the second day of AAS application, salivation decreased dramatically. His clinical and laboratory findings recovered. Four days after arrival, he was transferred to the Psychiatric Clinic to continue therapy. The atropine doses and clinical findings of Case II are shown in table 3.

Case III

A 23-year-old male patient was cyanotic, unconscious, unresponsiveness to pain stimuli, and had increased salivation and sweating on admission. The clinical findings after physical examination were absence of deep tendon reflexes, miotic pupils, and respiratory failure. Although the patient's relatives said that he ingested 100 mL of carbamate analogue preparate, we considered that his clinical findings were more related to severe OP intoxication. The patient was transferred to an intensive care unit for supportive therapy and mechanical ventilation. Atropine in one 2-mg IV bolus was administered whenever the heart rate decreased below 50 beats/min. When the toxicity screening test revealed OP poisoning, he was classified as Namba IV. We decided to use the AAS therapy because of our experiences with its effectiveness in the treatment of Case I. The AAS regimen was given 12 times on the first day and salivation markedly decreased to minimal amounts. On the fourth day, the clinical signs of pneumonia developed but ventilatory support did not improve the condition. The ventilatory mode changed to inverse ratio ventilation (IRV) and the patient turned to the prone position; antibiotic therapy was begun. The patient gained good results after these changes and extubated on the tenth day. He was transferred to the ward on the following day. The AAS regimen was applied 33 times during seven days. The atropine doses and clinical findings of Case III are shown in table 4.

discussion

Atropine sulphate, a belladonna alkaloid with muscarinic receptor antagonist effects, can be used alone or in combination with various oximes as an antidote for anticholinesterase OP intoxication. Small doses of atropine can produce bradycardia, whereas higher doses produce tachycardia.   This drug inhibits salivation and secretion of the gastrointestinal tract and glands. Belladonna alkaloids also inhibit secretions of the nose, mouth, pharynx, and bronchi, and thus dry the mucous membranes of the respiratory tract. Atropine's bronchodilator effect is particularly effective against bronchoconstriction produced by parasympathomimetic drugs such as methacholine and anticholinesterase agents. Pupil dilatation is another effect of atropine (Melkkila, 1993).

Based on recent experiences in Iran and Iraq , OP nerve agents are still likely to be used in conflicts. For example, two OP nerve agents, tabun and sarin, were reported to be used by the Iraqi army against Iranian troops and innocent people. Hundreds of the exposed combatants and civilians died in the field. Even if medical support were near, it would have required large numbers of trained medical assistants to administer conventional drug therapy for those exposed. For military personnel who may be exposed to OP agents during chemical warfare, atropine sulfate alone or in combination with various oximes is fielded in an autoinjector to be administered as an antidote using repeated intramuscular injection. However, large amounts of atropine are often required, even in civilian exposures to OP pesticides. Atropine sulphate has been used successfully in large doses to counteract the muscarinic effects of OP poisoning (Balali Mood, 1998). We were interested in whether any alternate routes of drug administration were as efficacious as the intramuscular or intravenous routes.

Some drugs are applied to the mucous membranes of the conjunctiva, nasopharynx, oropharynx, vagina, colon, urethra, and urinary bladder primarily for their local effects. Occasionally, as in the application of antidiuretic hormones to the nasal mucosa, systemic absorption is the goal. Gaseous and volatile drugs may be inhaled and absorbed through the pulmonary epithelium and mucous membranes of the respiratory tract, allowing rapid access to the circulatory system. In addition, solutions of drugs can be atomized and the fine droplets in air (aerosols) can be inhaled. Advantages of an aerosol are the almost instantaneous absorption of the drug into the blood, the avoidance of hepatic first pass loss, and in the case of pulmonary disease, application of the drug at the desired site of action. For example, drugs can be given in this manner for the treatment of bronchial asthma (Brown, 1995).

It is possible that military or civilian personnel exposed to OP agents may be managed by aerosol treatments alone. Aerosol treatments are easier to manage, allow for less intrusive administration of drugs, and require less training for assistants. AAS as an alternate administration route and device was introduced in a mini-Chemical and Biological Medical Treatment Symposium in Hradec Kralove in 1997. For military and civil personnel, vials which have 100, 200, and 400 applications (equivalent to 600 mg, 1200 mg, and 2400 mg of atropine, respectively) are available (Schneider, 1997).

In this preliminary report, we wanted to determine whether or not nasal application of AAS could be useful in the treatment of OP poisoning. Atropine aerosol administration has been declared as an effective treatment in a number of reports. Pak et al. suggested that for adult patients with chronic airflow obstruction, 0.025 mg/kg delivered by a dosimeter approximates the optimally effective dose of inhaled atropine that can be given without unacceptable side effects (Pak, 1982). Georgitis suggested that 50 and 75 m g doses of atropine sulfate as a nasal spray improved the severity of rhinorrhea and postnasal drips for 2 to 3 hours (Georgitis, 1998). Baroody et al. showed that the anticholinergic activity of intranasal atropine lasts at least 2 hours with no significant difference in the duration of inhibitory action between the doses of 100, 200, and 400 m g of atropine in each nostril (Baroody, 1996). The literature contains only a few reports on serum atropine sulphate concentrations after aerosol administration (Kradjan, 1981; Kradjan, 1985; Harrison, 1986). Kradjan et al. gave a single aerosol dose of atropine sulphate (0.05 mg/kg) to 6 male subjects with chronic bronchitis. All subjects had a satisfactory bronchodilator response and detectable serum concentrations of atropine within 15 min. Although the degree of absorption was variable, the authors reported that significant systemic absorption occurred after atropine sulphate inhalation (Kradjan, 1981). In another study, Kradjan et al. measured serum levels of atropine sulphate after single inhaled doses (0.012 to 0.025 mg/kg), and again after 48 to 72 hours of inhalation every 4 to 6 hours, in 11 subjects with acute respiratory distress (Kradjan, 1985). Harrison et al. administered atropine sulphate 2, 4, and 6 mg by inhalation, and 1.67 mg of atropine free base (equivalent to 2.0 mg atropine sulphate) by intramuscular injection to 8 healthy, non-smoking subjects. They observed bronchodilating, anticholinergic, and other pharmacologic effects in all dose concentrations that were typical atropine-like effects. They suggested that the inhalation route is an efficient way to administer atropine sulphate for systemic use ( Harrison, 1986).

In the literature, there are two reported cases of victims of OP intoxication being treated with inhaled nebulized atropine sulphate or ipratropium, an atropine-like alkaloid (Shockley, 1989; Shemesh, 1988). Shockley reported that the patient who was suffering from OP intoxication seemed to improve markedly with the inhaled atropine as evidenced by an immediate decrease in his anxiety, work of breathing, sputum production, and hypoxemia as measured by a pulse oximeter (Shockley, 1989). Also, Cross and Skorodin reported that bronchodilation and a decrease in bronchial mucous production was seen immediately after atropine was inhaled. These authors suggest that this method of administration is highly protective against bronchospasm induced by cholinergic agents (Cross, 1994).

]

In this preliminary report, we demonstrated that AAS dosage of nearly 30 to 35 mg/day (5 to 6 times/day) is an effective route to administer atropine sulphate for systemic use in patients who are poisoned by OP insecticides. We could not measure serum atropine sulphate concentrations, but clinical findings suggest that significant systemic absorption occurs within 5 minutes of AAS application. In Case I, in particular, we observed a significant reduction in salivary secretions, especially salivation and sweating, after the fifth AAS application.   In Case II, we recorded a significant improvement in the severity of bradyarrhythmia after the fifth AAS application. Cholinesterase measurements also indicated that the amount of serum cholinesterase increased over time.

According to the case studies in this report, we believe that AAS offers the advantages of easy application. It is widely available, efficient against bronchoconstriction, and can decrease the symptoms of diarrhea and salivation. It has potential usefulness for military and civilian persons.

tables

references

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