Archives of Academic Emergency Medicine. 2019; 7 (1): e46 BR I E F RE P O RT Atropine Challenge Test in Screening the Organophospho- rus Poisoning Cases with Atypical Presentation; a Brief Re- port Shahin Shadnia1, Nasim Zamani1, Sara Nikpour2, Ali Saffaei3, Mohammad Reza Farnia4∗ 1. Department of Clinical Toxicology, Loghman Hakim Hospital, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 2. Forensic Medicine Department, Loghman Hospital, Shahid Beheshti University of Medical Sciences, Tehran. 3. Student Research Committee, Department of Clinical Pharmacy, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 4. Emergency Department, Imam Reza Hospital, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran. Received: June 2019; Accepted: July 2019; Published online: 19 August 2019 Abstract: Introduction: Atropine is not recommended in organophosphorus (OPs) poisoning cases without any obvi- ous clinical signs. This study aimed to evaluate the clinical utility of Atropine challenge test in screening OPs poisoning cases with atypical presentation. Methods: In this prospective cross sectional study, after primary supportive care, patients with atypical pretentions of OPs poisoning underwent Atropine challenge test (1 mg intravenously) and demographic parameters, clinical presentations, and serum level of cholinesterase enzyme were compared between cases with positive and negative test results. Results: 20 patients with the mean age of 47.60 ± 13.25 years were studied. The mean time since exposure and initial symptoms was 6.17 ± 2.99 hours. The most common clinical presentations were tachycardia (55%) and flushing (35%). The atropine challenge test was positive in 3 (15.00%) cases. The two groups were the same regarding gender distribution (p = 0.582), mean age (p = 0.957), clinical presentation (p > 0.05), and mean PR interval (p = 0.729). The level of cholinesterase was 220.00 ± 15.52 U/mL and 332.17 ± 143.99 U/mL in patients with positive and negative Atropine challenge test, respectively (p = 0.006). Conclusion: Patients with positive Atropine challenge test had a significantly lower level of serum cholinesterase and response to Atropine in their therapeutic management. Hence, Atropine challenge test could be considered as a useful clinical test in the setting of acute OPs poising. Keywords: Organophosphorus Compounds; Atropine; Organophosphate Poisoning; Acetylcholine; Toxicity Cite this article as: Shadnia Sh, Zamani N, Nikpour S, Saffaei A, Farnia M R. Atropine Challenge Test in Screening the Organophosphorus Poisoning Cases with Atypical Presentation; a Brief Report . Arch Acad Emerg Med. 2019; 7(1): e46. 1. Introduction Organophosphorus (OPs) insecticides are used for agricul- ture, vector control, and domestic usages. Despite the obvi- ous benefits of these agents, acute OPs poisoning is increas- ing worldwide (1, 2). Because of their ease of accessibility, OPs products are frequently used for self-poisoning inten- tions and it is an important public health issue in some devel- oping countries (3, 4). OPs products are the most important ∗Corresponding Author: Mohammad Reza Farnia; Emergency Depart- ment, Imam Reza Hospital, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran. Tel: 00988334276301, Email: mr.farnia@kums.ac.ir source of toxicity and death globally and they cause more than 200,000 deaths every year in some developing coun- tries (5, 6). Acute OPs poisoning can lead to acute choliner- gic syndrome, seizures, muscle weakness, loss of conscious- ness, and respiratory arrest. OPs through the inhibition of acetyl cholinesterase can stimulate both muscarinic, nico- tinic, and adrenergic receptors (7). These effects may lead to the accumulation of acetylcholine. Respiratory failure and cardiac arrest are the most usual causes of death in acute OPs poisoning patients (8). Patients with acute OPs poison- ing should undergo prompt evaluation and management of disorders in airway, breathing, and blood circulation. Fur- ther interventions are based on risk assessment and clini- cal observations during regular monitoring (9). Once clini- This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem Sh. Shadnia et al. 2 cal evaluations indicate the use of antidotes, they should be administered promptly. There are three most broadly used classes of antidotes, including muscarinic antagonists (for example: Atropine), oximes (for example: pralidoxime and obidoxime), and benzodiazepines (10). Atropine has no ef- fect on the neuromuscular junction and muscle weakness, therefore oximes are administered to reverse neuromuscu- lar blockage. Atropine is not recommended in patients with- out any obvious clinical signs (11). However, in cases where the physicians doubt the diagnosis or cases with atypical pre- sentation, Atropine challenge test is recommended (12). The aim of this study was to evaluate the clinical utility of At- ropine challenge test in screening the OPs poisoning cases with atypical presentation. 2. Methods 2.1. Study design and setting In this prospective cross sectional study, patients with OPs poisoning who were referred to the emergency department of Loghman Hakim Hospital, Tehran, Iran, between January 2017 and January 2018, were studied. This center is a na- tional referral center for poisoning and toxicity in Iran. This study was approved by the ethics committee of Shahid Be- heshti University of Medical Sciences (ethics code: 19663). 2.2. Participants Patients who were between 18 and 65 years old, were exposed to OPs intentionally or accidentally, and had atypical presen- tation of OPs poisoning (vague or alleviated signs of poison- ing and unknown sources of poison) were included. Patients who had received Atropine before presenting to ED or had hepatic or renal failure were excluded. 2.3. Data gathering Age, gender, clinical signs and symptoms (tachycardia, my- driasis, flushing, agitation and dyspnea), PR interval on electrocardiogram (ECG) (lead II and V1), time from expo- sure to presentation of initial symptoms, and level of serum cholinesterase were recorded for all patients. A toxicology fel- lowship was responsible for data gathering. 2.4. Atropine challenge test After primary supportive care including cardiac monitoring, airway management, supplementary oxygen therapy, and fluid and electrolytes management, Atropine challenge test was performed for all patients. First, basic heart rate of the patient was recorded. Then, Atropine at dose of 1 mg was in- travenously (median cubital vein) administered and patient heart rate was monitored. If the heart rate increased more than 20% of its baseline or more than 30 beats per second, the test was considered positive. Other anticholinergic symp- Table 1: Clinical presentations of patients with acute OPs poison- ing Parameter Frequency (%) Tachycardia 11 (55.0) Mydriasis 5 (25.0) Flushing 7 (35.0) Anxiety and Agitation 6 (30.0) Dyspnea 1 (5.0) toms such as tachycardia, mydriasis, flushing, agitation and dyspnea were recorded. All patients with positive atropine challenge test received atropine as treatment. 2.5. Statistical Analysis Data were imported into SPSS software version 23.0 (IBM, USA). Findings are presented as mean ± standard deviation or frequency (%). For all the tests (t-test, chi-square), the sig- nificance level was considered as 0.05 and results were re- ported as mean ± standard division (SD) or frequency (%). 3. Results 20 patients with the mean age of 47.60 ± 13.25 years were studied. The mean time since exposure and initial symp- toms was 6.17 ± 2.99 hours. The most common clinical pre- sentations were tachycardia (55%) and flushing (35%) (Table 1). On admission, PR interval was 77.95 ± 7.21 milliseconds and mean level of serum cholinesterase was 315.35 ± 138.47 U/mL. Atropine challenge test was positive in 3 (15.00%) cases. Patients with negative Atropine challenge test did not receive Atropine, except one patient. Table 2 compares the baseline characteristics of patients with positive and negative Atropine challenge test. The two groups were the same re- garding gender distribution (p = 0.582), mean age (p = 0.957), clinical presentation (p > 0.05), and mean PR interval (p = 0.729). The level of cholinesterase was 220.00 ± 15.52 U/mL and 332.17 ± 143.99 U/mL in patients with positive and neg- ative Atropine challenge test, respectively (p = 0.006). 4. Discussion Based on the findings of the present study, patients with pos- itive Atropine challenge test had a significantly lower level of serum cholinesterase and response to Atropine in their ther- apeutic management. Hence, Atropine challenge test could be considered as a useful clinical test in the setting of acute OPs poising. Patients with acute OPs poising must undergo prompt eval- uation and management (13). Clinical researches in Asia have shown how Atropine can prevent deaths in OPs patients (14). However, the practitioners are still unsure regarding which cases are most likely to benefit from the use of At- This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem 3 Archives of Academic Emergency Medicine. 2019; 7 (1): e46 Table 2: Comparing the baseline characteristics of patients with positive and negative Atropine challenge test Variables Atropine challenge test P Value Positive Negative Age (years) Mean ± SD 48.00 ± 12.12 47.53 ± 13.79 0.957 Gender Male 1 (5.0) 9 (45.0) 0.582 Female 2 (10.0) 8 (40.0) PR interval (millisecond) Mean ± SD 79.33 ± 4.16 77.71 ± 7.70 0.729 Tachycardia Yes 0 (0.0) 11 (55.0) 0.074 No 3 (15.0) 6 (30.0) Mydriasis Yes 0 (0.0) 5 (25.0) 0.399 No 3 (15.0) 12 (60.0) Flushing Yes 1 (5.0) 6 (30.0) 0.730 No 2 (10.0) 11 (55.0) Anxiety and Agitation Yes 0 (0.0) 6 (30.0) 0.319 No 3 (15.0) 11 (55.0) Dyspnea Yes 0 (0.0) 1 (5.0) 0.850 No 3 (15.0) 16 (80.0) Cholinesterase (U/mL) Mean ± SD 220.00 ± 15.52 332.17 ± 143.99 0.006 Data are presented as mean ± standard deviation (SD) or frequency (%). ropine (15). Since management of these patients should be done promptly, decision making regarding Atropine usage is an important issue. The results of the current study showed that Atropine chal- lenge test is a good predictor for necessity of Atropine usage. If the patient referred to emergency department with atypi- cal presentation of OPs poising, the Atropine challenge test can be performed. This way, the initial management strat- egy can be determined. This test was first introduced in case reports and based on our knowledge there is not any system- atic study in this regard. In one study, which was done by Cappato et al., the clinical applicability of Atropine challenge test was evaluated in discriminating organic from autonomic involvement of sinus automaticity (16). They found that at- ropine test is not very helpful in discriminating between an organic and an autonomic involvement of sinus automatic- ity in patients with sinus bradycardia. Another point about Atropine challenge test was discussed by Erdman et al. They previously noted that Atropine challenge test has never been empirically tested and may not be very sensitive or specific (17). It seems that patients with positive Atropine challenge test required Atropine in their therapeutic management and those with negative Atropine challenge test may not require Atropine. Hence, Atropine challenge test may be considered as Atropine requirement indicator, and it is recommended to evaluate every patient with atypical presentations of OPs poi- soning with Atropine challenge test. 5. Limitation The main limitation of current research was its small sample size, however this was due to low incidence of OPs poison- ing with atypical presentations. The advantage of current re- search was its novelty, which introduced Atropine challenge test as a crucial diagnostic test. 6. Conclusion Patients with positive Atropine challenge test had a signifi- cantly lower level of serum cholinesterase and response to Atropine in their therapeutic management. Hence, Atropine challenge test could be considered as a useful clinical test in the setting of acute OPs poising. 7. Appendix 7.1. Acknowledgements The authors wish to thank staff members who helped them perform this research. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem Sh. Shadnia et al. 4 7.2. Author contribution Shahin Shadnia, Nasim Zamani, and Mohammad Reza Farnia designed the study. Mohammad Reza Farnia and Sara Nikpour participated in acquisition of data. Ali Saffaei analyzed the data. Sara Nikpour participated in manage- ment of data. Shahin Shadnia, Nasim Zamani, Sara Nikpour, Mohammad Reza Farnia, and Ali Saffaei wrote the first draft and others revised the manuscript critically. All authors ap- proved of the final version of the manuscript to be published and are accountable for all aspects of the work. Authors ORCIDs Shahin Shadnia: 0000-0002-9401-0781 Nasim Zamani: 0000-0002-2091-0197 Sara Nikpour: 0000-0003-1986-3992 Ali Saffaei: 0000-0002-9563-924X Mohammad Reza Farnia: 0000-0002-4397-8661 7.3. Funding/Support This study was supported by Shahid Beheshti University of Medical Sciences. 7.4. Conflict of interest The authors declare that there is no conflict of interest. References 1. Soltaninejad K, Shadnia S. History of the use and epi- demiology of organophosphorus poisoning. Basic and Clinical Toxicology of Organophosphorus Compounds: Springer; 2014. p. 25-43. 2. Eddleston M, Buckley NA, Eyer P, Dawson AH. Manage- ment of acute organophosphorus pesticide poisoning. The Lancet. 2008;371(9612):597-607. 3. 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Downloaded from: http://journals.sbmu.ac.ir/aaem Introduction Methods Results Discussion Limitation Conclusion Appendix References