Emergency. 2018; 6 (1): e1 OR I G I N A L RE S E A RC H Predictive Factors of Mortality in Acute Amphetamine Type Stimulants Poisoning; a Review of 226 Cases Mitra Rahimi1, Somaieh Lookzadeh1, Roxana Sadeghi2, Kambiz Soltaninejad3, Shahin Shadnia1∗, Abdolkarim Pajoumand1, Hossein Hassanian-Moghaddam1, Nasim Zamani1, Masoud Latifi-Pour1 1. Toxicology Research Center, Excellence Center of Clinical Toxicology, Department of Clinical Toxicology, Loghman Hakim Hospital, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 2. Cardiology Department, Loghman Hakim Hospital, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 3. Department of Forensic Toxicology, Legal Medicine Research Center, Legal Medicine Organization, Tehran, Iran. Received: August 2017; Accepted: October 2017; Published online: 10 January 2018 Abstract: Introduction: Amphetamine type stimulants (ATS) such as amphetamine and methamphetamine (MA) are one of the most important causes of poisoning in the world. In this study we aimed to define the predictive factors of mortality in acute ATS poisoning patients. Methods: This is a retrospective cross-sectional study on all cases with acute ATS poisoning who were referred to a referral center for poisoning, Tehran, Iran, from April 2011 to March 2014. Using patients’ medical records, demographic data, route of exposure, type and amount of ATS, the cause of poisoning, clinical presentations, and electrocardiogram (ECG) and laboratory findings, as well as patient’s outcomes were collected and analyzed regarding the independent predictive factors of mortality. Results: 226 cases with the mean age of 32.9 ± 10.9 years were studied (77% male). MA was the most abused ATS (97.4%) and the most frequent route of exposure was oral (55.3%). The mortality rate was 5.4%. There was a significant association between agitation (p = 0.002), seizure (p = 0.001), loss of consciousness (p < 0.001), creatine phosphokinase level (p = 0.002), serum pH (p = 0.002), serum HCO3 (p = 0.02), and PCO2 (p = 0.01) with mortality. However, serum HCO3 [OR=1.27 (95% CI: 1.07-1.50); p value=0.005], PCO2 [OR=0.89 (95% CI: 0.84-0.96); p value=0.002], and loss of consciousness [OR=0.019 (95% CI: 0.003-0.106); p value=0.000] were the only independent predictive factors of mortality. Conclusion: PCO2 ≥ 51 mmHg, serum bicarbonate ≤ 22.6 mEq/L, and loss of consciousness on admission could be considered as prognostic factors of mortality in acute ATS poisoning cases presenting to emergency department. Keywords: Amphetamines; patient outcome; prognostic factors; poisoning; substance abuse © Copyright (2018) Shahid Beheshti University of Medical Sciences Cite this article as: Rahimi M, Lookzadeh S, Sadeghi R, Soltaninejad K, Shadnia Sh, A Pajoumand, Hassanian-Moghaddam H, Zamani N, Latifi-Pour M. Predictive Factors of Mortality in Acute Amphetamine Type Stimulants Poisoning; a Review of 226 Cases. Emergency. 2018; 6(1): e1. 1. Introduction A mphetamine type stimulants (ATS) refer to a class of substances whose main derivatives are amphetamine and methamphetamine (MA). Also, a range of other substances such as ephedrine, pseudoephedrine, methylphenidate, methcathinone, and 3,4- methylene- dioxymethamphetamine (MDMA) are included in this group ∗Corresponding Author: Shahin Shadnia; Department of Clinical Toxicology, Loghman Hakim Hospital Poison Center, Kamali Street, South Karegar Avenue, Tehran, Iran. Tel/Fax: +98-21-55424041, Cell Phone: +98-912-1947601 Email: shahin1380@yahoo.com (1, 2). The production and abuse of ATS have increased worldwide. However, the pattern of abuse of each type of ATS is differ- ent throughout the world based on social, cultural and ge- ographic parameters (1). For example, amphetamine abuse tends to be more common than MA in Europe, except in Czech Republic, Slovakia, Estonia, and Latvia. Amphetamine is used therapeutically and illicitly in the United Kingdom (3). MA, which is the second most popular illicit drug with an an- nual global prevalence estimated at 0.4% (3), is more domi- nant in the east, southeast Asia and Oceania (4). ATS abuse is a serious health, social and economic problem all over the world. Previous reports have determined the sig- This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: www.jemerg.com M. Rahimi et al. 2 nificant correlation between ATS abuse (mostly MA) via in- jection and risk of the transmission of blood-borne viruses (3). Dependency and addiction are other mental and clini- cal health problems among ATS abusers. Dependence and chronic usage are associated with MA psychosis and other re- lated psychosomatic and clinical adverse consequences (3). Another health problem in ATS abusers is acute poisoning, which is considered as a major problem in emergency set- tings (5, 6). The common features of ATS poisoning in- clude agitation, dilated pupils, tachycardia, hypertension, and tachypnea. Other clinical findings include tremor, dys- pnea, chest pain, hyperpyrexia and cardiac, hepatic and/or renal failure. Coma or seizures occur less frequently (7). Although there are reports about acute ATS poisoning (8-11), to the best of our knowledge there are limited data about prognostic factors of mortality in acute ATS poisoning cases (12, 13). Therefore, the aim of the present study was to define the predictive factors of mortality in acute ATS poisoning pa- tients. 2. Methods 2.1. Study design and setting This is a retrospective cross-sectional study. All cases of pure acute ATS poisoning, who were referred to the Toxicol- ogy Center of Loghman Hakim Hospital, Tehran, Iran, since April 2011 to March 2014, were studied. This educational hospital serves as a referral center for poisoning patients of Iranian capital, Tehran. The study was approved by Ethi- cal Committee of Shahid Beheshti University of Medical Sci- ences (Grant No.: M-384). The authors adhered to the prin- ciples of Helsinki declaration. The patients’ data were kept confidential. 2.2. Participants All cases of pure acute ATS poisoning who were admitted dur- ing the mentioned period were enrolled to the study using census sampling. The patients with co-ingestion or those discharged against medical advice were excluded. 2.3. Data gathering Using a self-made checklist, demographic data (sex, age), route of exposure, type and amount of ATS, the cause of poi- soning, history of addiction, clinical presentations, labora- tory findings, electrocardiography (ECG) finding, duration of hospitalization, and outcomes (mortality, disposition, and complications during admission) were collected by a trained physician for all participants according to the patients’ med- ical records. We used ICD10 classification for extracting pa- tients’ medical records from the hospital’s archive. Diagnosis of acute ATS poisoning was done based on the history given by the patients or their relatives, physical examination and diagram 1: Flow diagram of patient selection. ATS: Amphetamine Type Stimulants laboratory confirmation. 2.4. Statistical Analysis We used the social package for statistical analysis (SPSS) soft- ware version 16. The data were expressed as mean ± SD for continuous or discrete variables and as frequency and percentage for categorical variables. Chi-square test was used for statistical analysis of qualitative variables. The nor- mal distribution of quantitative variables was tested by Kol- mogorov – Smirnov test. The statistical comparison was done with Mann–Whitney U -test for nonparametric variables and independent student t-test for parametric variables. Logis- tic regression was used for evaluating the predictive factors of mortality. The best cut off points was determined by cal- culating the area under the receiver operating characteris- tics (ROC) curve. P values of 0.05 or less were considered to be statistically significant and data were presented with 95% confidence interval (CI). 3. Results 3.1. Baseline characteristics 1722 ATS intoxicated patients’ files were evaluated, out of which, 226 (13%) cases with acute ATS poisoning were in- cluded (Diagram 1). The mean age of the patients was 32.9 ± 10.9 (14 - 77) years (77% male). Baseline characteristics, clinical presentations, and laboratory results, as well as ECG findings are summarized in table 1 and 2. The most common type of ATS used was MA (97.4%) and the most frequent route of exposure was oral (55.3%). Abuse was the most common cause of poisoning (66.8%) and the mean ATS dose was 1.64 ± 1.59 grams. The mean time from expo- sure to admission was 5.9 ± 9.6 hours. History of addiction was positive in 123 (54%) cases with 5.3 ± 3.8 years mean du- ration of addiction. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: www.jemerg.com 3 Emergency. 2018; 6 (1): e1 Table 1: Comparing the baseline characteristics of acute amphetamine type stimulants (ATS) intoxicated patients who survived and those who died Parameter Total (n=226) Survived (n=214) Died (n=12) P value Sex Male 174 (77) 165 (77.1) 9 (75) 0.6 Female 52 (23) 49 (22.9) 3 (25) Type of ATS Methamphetamine 220 (97.4) 208 (97.2) 12 (100) MDMA 1 (0.4) 1 (0.5) 0 0.9 Methylphenidate 5 (2.2) 5 (2.3) 0 Route of exposure Oral 125 (55.3) 116 (54.2) 9 (75) Inhalation 93 (41.2) 90 (42) 3 (25) Injection 4 (1.8) 4 (1.9) 0 0.7 Oral and Inhalation 3 (1.3) 3 (1.4) 0 Oral and Injection 1 (0.4) 1 (0.5) 0 Cause of poisoning Abuse 151 (66.8) 146 (68.2) 5 (41.7) Suicide 54 (23.9) 47 (22) 7 (58.3) Accidental 2 (0.9) 2 (0.9) 0 0.7 Body packer 15 (6.6) 15 (7) 0 Body stuffer 4 (1.8) 4 (1.9) 0 ATS dose (gram) 1.64±1.59 (0.5-13) 1.7±1.6 (0.5-13) 1.1±0.3 (1-1.5) 0.8 Exposure to admission (hour) 5.9±9.6 (0.5-72) 6±9.8 (0.5-72) 4.4±3.1 (1-10) 0.9 Duration of addiction (year) 5.3±3.8 (1-20) 5.3±3.9 (1-20) 5.5±3.1 (3-10) 0.9 Age (year) 32.9±10.9 (14-77) 32.6±10.7 (14-77) 38.1±13.6 (19-55) 0.2 Data were presented as mean ± standard deviation (minimum-maximum) or frequency (%). MDMA: 3,4-Methylendeoxymethamphetamine. 3.2. Outcomes 19 (8.4%) cases were admitted to Medical Toxicology Inten- sive Care Unit (ICU) and others (207, 91.6% of cases) were admitted to general ward. In most of the cases (61.6%), the duration of hospitalization was ≤ 24 hours. Intubation was indicated in 24 (10.6%) cases. The mortality rate was 5.4% (12/226). 2 cases of acute respiratory distress syndrome (0.9%), 2 ventilator associated pneumonia (0.9%), 2 rhab- domyolysis (0.9%), and 1 case of deep vein thrombosis (0.4%) were the complications detected in 7 (3.1%) patients (All of them were male). 3.3. Predictive factors of mortality Table 1 and 2 compare the baseline characteristics, clinical presentations, laboratory results, and ECG findings of acute ATS poisoning among survived and non-survived cases. Based on univariate analysis, there were significant associa- tions between agitation (p = 0.002), seizure (p = 0.001), loss of consciousness on admission (p < 0.001), creatine phosphok- inase level (p = 0.002), serum pH (p = 0.002), serum HCO3 (p = 0.02), and PCO2 (p = 0.01) with mortality. However, the results of multivariate regression analy- sis showed serum HCO3 [OR=1.27 (95% CI: 1.07-1.50); p value=0.005], PCO2 [OR=0.89 (95% CI: 0.84-0.96); p value=0.002], and loss of consciousness on admission [OR=0.019 (95% CI: 0.003-0.106); p value=0.000] as the inde- pendent predictive factors of mortality in acute ATS poison- ing. Based on the area under the ROC curve (AUC) the best cut off points of PCO2 and serum HCO3 for prediction of mortality were ≥ 51 mmHg [AUC = 0.61 (95% CI: 0.401-0.822)] and ≤ 22.6 mEq/L [AUC = 0.704 (95% CI: 0.525-0.882)], respectively (figure 1). Screening performance characteristics of PCO2 ≥ 51 mmHg and HCO3 ≤ 22.6 mEq/L in prediction of acute ATS intoxi- cated mortality are summarized in table 3. 4. Discussion ATS are potent psychostimulants that are abused all over the world (4). ATS poisoning has recently emerged as a crucial health problem in clinical and forensic settings (8, 14, 15). Therefore, the emergency department staff should be aware of the clinical presentations, paraclinical findings and prog- nostic factors of acute ATS poisoning. In this study, the most common cause of poisoning was abuse and majority of cases, had oral exposure. In the previous study done in the same This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: www.jemerg.com M. Rahimi et al. 4 Table 2: Comparing the vital signs, clinical presentations, laboratory results, and electrocardiogram (ECG) findings among acute am- phetamine type stimulants (ATS) intoxicated patients who survived and those who died Parameter Total (n=226) Survived (n=214) Died (n=12) P value Vital signs SBP (mmHg) 125.5±23.6 (80-230) 126±22.7 (80-230) 115.8±36.3 (80-180) 0.1 DBP (mmHg) 78.5±13.9 (40-150) 78.9±13.7 (50-150) 70±16.5 (40-100) 0.054 Pulse rate (/minute) 99.2±19 (52-168) 99.2±18.5 (52-168) 99.8±27.1 (66-160) 0.6 Clinical presentations Agitation 172 (76.11) 168 (78.50) 4 (33.33) 0.002 Confusion 66 (29.20) 65 (30.37) 1 (8.33) 0.09 Judgment disorder 48 (21.24) 48 (22.43) 0 0.053 Seizure 16 (7.08) 11 (5.14) 5 (41.67) 0.001 LOC 16 (7.08) 9 (4.21) 7 (58.33) 0.000 Hallucination 14 (6.19) 13 (6.0) 1(8.3) 0.6 Diaphoresis 12 (5.31) 12 (5.31) 0 0.5 Flushing 7 (3.1) 7 (3.1) 0 0.7 Abdominal pain 5 (2.21) 5 (2.21) 0 0.8 Blurred vision 2 (0.88) 2 (0.88) 0 0.9 Laboratory findings Sodium (mEq/L) 140.1±5.0 (124-188) 140.1±5.0 (124-188) 140.1±5.1 (130-148) 1 Potassium (mEq/L) 4.1±0.5 (3-7.7) 4.1±0.5 (3.1-7.7) 4.2±0.9 (3-5.9) 0.5 CPK (U/L) 1067.9±2981.9 (28-30000) 813.2±1952.4 (28-17253) 7309.1±10263.3 (103-30000) 0.002 LDH (U/L) 909.1±841.3 (42-6033) 885.7±854.6 (42-6033) 1225±635.2 (563-2043) 0.1 Serum pH 7.36±0.09 (6.90-7.90) 7.36±0.09 (6.90-7.90) 7.27±0.15 (6.90-7.40) 0.002 PCO2 (mmHg) 43.9±9.8 (13-78) 43.6±9.2 (13-74) 51.2±16.5 (32-78) 0.01 Serum HCO3 (mEq/L) 24.3±4.9 (8.7-56) 24.5±4.9 (8.7-56) 21.2±4.5 (15.8-28.4) 0.02 ECG findings Normal sinus 104 (46) 97 (45.3) 7 (58.3) Sinus tachycardia 103 (45.6) 100 (46.7) 3 (25.0) Sinus bradycardia 8 (3.5) 7 (3.2) 1 (8.3) T inversion 10 (4.4) 9 (4.2) 1 (8.3) 0.3 QRS widening 7 (3.0) 6 (2.8) 1 (8.3) ST change 4 (1.7) 3 (1.4) 1 (8.3) Ventricular Dysrhythmia 3 (1.3) 2 (0.9) 1 (8.3) Hospitalization (hour) ≤24 139 (61.6) 132 (61.7) 7 (58.3) 0.07 >24 87 (38.4) 82 (38.3) 5 (41.7) Data were presented as mean ± standard deviation (minimum-maximum) or frequency (%). SBP: Systolic blood pressure, LOC: Loss of consciousness, DBP: Diastolic blood pressure, CPK: Creatine Phosphokinase, LDH: Lactate dehydrogenase; ECG: Electrocardiogram. Table 3: Screening performance Characteristics of PCO2 ≥ 51 mmHg and serum HCO3 ≤ 22.6 mEq/L in predicting the risk of mortality in acute amphetamine Type Stimulants (ATS) intoxicated patients Character PCO2 (95% CI) HCO3 (95% CI) Sensitivity 50.00 (22.28 – 77.71) 66.66 (35.43 – 88.72) Specificity 78.97 (72.77 – 84.10) 72.89 (66.33 – 78.62) Positive Predictive Value 11.76 (04.87 – 24.55) 12.12 (05.74 – 23.03) Negative Predictive Value 96.57 (92.34 – 98.59) 97.50 (93.31 – 99.19) Positive Likelihood Ratio 0.13 (0.06 – 0.28) 0.13 (0.07 – 0.26) Negative Likelihood Ratio 0.03 (0.01 – 0.07) 0.02 (0.01 – 0.06) hospital, although the main cause of poisoning was abuse, the common route of exposure was inhalation (12). In our study, most of the patients were young men, which is in con- cordance with the results of previous studies (6, 12, 13). Most of our patients had a positive history of addiction. This result is in line with previous studies (6, 12). MA was the most frequent type of ATS used by our pa- tients. The result is the same as previous studies in Iran (12, 16), however, the studies in European countries showed amphetamine and MDMA as the most frequent type of ATS This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: www.jemerg.com 5 Emergency. 2018; 6 (1): e1 Figure 1: Receiver operating characteristic (ROC) curve for PCO2 and serum HCO3 in predicting the risk of mortality in acute am- phetamine Type Stimulants (ATS) intoxicated patients. among intoxicated cases (10, 17). This difference could be due to demographic variables such as marital status and level of education (18). Previous studies introduced curiosity in trying different things and looking for pleasure as the most important reasons for MA abuse in Iran (18, 19). Other fac- tors are lower effectiveness of previous drugs, popularity and low price of new drugs, and emulation of others (18, 20, 21). Khodabandeh et al. reported MA abuse among methadone maintenance participants. The most common reasons were the good sensation, getting high, to enhance their sexual per- formance, and in some instances as self-medication for de- pression (22, 23). Agitation, confusion and judgment disor- der were the most common clinical manifestations. which are the same as the result of a previous study in Australia (6). In another study in Iran, loss of consciousness was the most common clinical finding, which could be due to co-ingestion with opioids and other drugs (12). Most of the patients had abnormal ECG, and sinus tachycar- dia was the major finding, which has been reported previ- ously (12, 24). The mortality rate was 5.4%, which was lower than previous studies (12, 13). This may be related to the delayed admission of the patients to the hospital in the previous studies (12). In our study, lower serum HCO3, higher PCO2 and low level of consciousness on admission were considered as predict- ing factors of mortality in ATS poisoning cases. In the pre- vious study performed in this center, age, history of suicide, route of poisoning and pulmonary manifestations on admis- sion were considered as predictive factors of patient’s out- come (12), which is not supported by the results of our study. According to our results, PCO2≥ 51 mmHg and serum HCO3 ≤ 22.6 mEq/L can predict the poisoned patients’ mortal- ity rate with specificity (78.97% and 72.89%, respectively) and sensitivity (50.00% and 66.66%, respectively). However, based on the AUC measures, serum HCO3 can better dis- criminate between those who die and those who survive. We did not find a study that had evaluated the relationship be- tween these laboratory findings and prediction of mortality. 5. Limitation We evaluated the patients’ records retrospectively, which could be considered as a limitation of our study. 6. Conclusion This study showed that high PCO2, low serum bicarbonate and loss of consciousness on admission, could be associated with higher rate of mortality of acute ATS intoxicated cases. 7. Appendix 7.1. Acknowledgements This article is the part of Dr. Somayeh Lookzadeh’s thesis, who was an Internal Medicine Resident at the time of the study. The authors wish to thank the nurses of Loghman Hakim Hospital Poisoning Center; especially Mrs. S. Bana- Jafari, the head nurse of MTICU, Mrs. M. Rezvani and Mrs. B. Barari the staff of MTICU. The authors would like to convey their full appreciation to Toxicology Research Center for their financial support. 7.2. Authors’ contribution All authors made a substantial contribution to analysis and writing of the paper draft and met the four criteria for author- ship recommended by the International Committee of Med- ical Journal Editors. 7.3. Funding/Support This study was supported by a grant from Toxicology Re- search Center, Shahid Beheshti University of Medical Sci- ences. Grant number: M-384. 7.4. Conflict of interest The authors declare that there is no conflict of interests re- garding the publication of this paper. References 1. World Health Organization. Amphetamine-type stim- ulants. Available 1 August 2017. [Available from: www.who.int/substance_abuse/facts/ATS/en/. 2. Kumar MS, Kumar S. Amphetamine type stimulants (ATS) use in India- An exploratory study. United Nations This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: www.jemerg.com M. 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Downloaded from: www.jemerg.com Introduction Methods Results Discussion Limitation Conclusion Appendix References