Archives of Academic Emergency Medicine. 2021; 9(1): e20 https://doi.org/10.22037/aaem.v9i1.1070 OR I G I N A L RE S E A RC H Effects of Intravenous Lipid Emulsion on Tramadol- Induced Seizure; a Randomized Clinical Trial Amir Mohammad Kazemifar1, Zohreh Yazdi1, Abbas Bedram1, Javad Mahmoudi2, Mojtaba Ziaee3∗ 1. Faculty of Medicine, Qazvin University of Medical Sciences, Qazvin, Iran. 2. Neuroscience Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. 3. Medicinal Plants Research Center, Maragheh University of Medical Sciences, Maragheh, Iran. Received: January 2021; Accepted: January 2021; Published online: 20 February 2021 Abstract: Introduction: There are numerous studies on the efficacy of intralipid emulsion (ILE) in various xenobiotic toxicities. This study aimed to evaluate the potential role of ILE as an antidote in tramadol-induced seizure. Methods: A single-blind clinical trial was undertaken to establish the efficacy and safety of ILE in patients with acute tramadol intoxication, who referred to Booali Hospital in Qazvin. Patients were randomly assigned to 2 groups. The Control group received standard care while the intervention group received intralipid emulsion (ILE) 20% in addition to the standard care. The occurrence of in-hospital seizure was compared between the groups. Results: 80 patients who abused tramadol and met the study criteria were randomly assigned to either the intervention (40 cases) or the control (40 cases) group. Seizure occurred in 44 (56%) patients before admis- sion to the emergency department. There were not any statistical differences between the groups regarding sex distribution (p=0.513) and mean age (p=0.19), presenting vital signs (p < 0.05), laboratory findings (p < 0.05), and mean abused dose of tramadol (p = 0.472) as well as occurrence of prehospital seizure (p = 0.7). In-hospital seizure occurred in 15 (18.75%) cases (all in the control group; p < 0.001). The mean duration of admission was 2.01 ± 1.13 days in the control group and 2.15 ± 1.04 days in the intervention group (p = 0.6). The number needed to treat for ILE to prevent tramadol-induced seizure was 2.7 (37.5% absolute risk reduction). Conclusion: The findings of this study supported ILE administration, as an adjunct to standard antidote protocols, in tramadol intoxication to prevent tramadol-induced seizures. Keywords: Tramadol; soybean oil, phospholipid emulsion; Poisoning; Seizure; Clinical trial Cite this article as: KazemifarA M, Yazdi Z, Bedram A, Mahmoudi J, Ziaee M. Effects of Intravenous Lipid Emulsion on Tramadol-Induced Seizure; a Randomized Clinical Trial. Arch Acad Emerg Med. 2021; 9(1): e20. 1. Introduction Tramadol is a synthetic analgesic drug that exerts opioid and non-opioid effects, acting predominantly on the central ner- vous system (CNS). It is prescribed to treat moderate to se- vere pain such as postoperative or chronic pain (1). Although it appears to be a safe and effective analgesic, there are ev- idence that have linked tramadol to illegal abuse and poi- soning and even anaphylactoid reactions (2). The prevalence of tramadol abuse and poisoning has risen significantly in the Middle East and many other countries (3). Major clin- ∗Corresponding Author: Mojtaba Ziaee; Medicinal Plants Research Center, Maragheh University of Medical Sciences, Maragheh, Iran. Tel: +98 41 33 37 22 52, Mobile: +98 914 313 1830, E-mail: ziaee.m@mrgums.ac.ir ; mjzi- aee@gmail.com, ORCID: https://orcid.org/0000-0002-9725-3033 ical findings of tramadol intoxication are seizures, apnea, hemodynamic changes (bradycardia or tachycardia and hy- potension), and coma (4). Tramadol-induced seizures are mostly not associated with dose and occur within the first 4-6 hours (5). Several studies have reported successful re- suscitation of these patients through the utilization of in- travenous lipid emulsion (ILE) as an antidote for the treat- ment of hemodynamic or neurological symptoms of poison- ing with lipophilic xenobiotics (6). Although several mecha- nisms have been postulated for the resuscitative properties of ILE, two theories are more interesting: Lipid sink (parti- tioning) and enhanced metabolism theories. The partition- ing theory suggests that ILE administration compartmental- izes the lipophilic drugs into the lipid phase and detaches them from the target tissues. Decreased drug concentra- tions in blood flow facilitate the elimination of the xenobi- otics from the affected organs through the generation of a 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 A M. Kazemifar et al. 2 concentration gradient (7). The enhanced metabolism theory argues that infusion of ILE elevates cardiac metabolism and has inotropic effects. Re- cent studies claimed that ILE administration increased left ventricular contractility. Both hypotheses were established based on pieces of evidence indicating that lipid therapy shows efficacy on a variety of xenobiotic groups with differ- ent receptor specificities. Thus, lipid therapy may counter- act particular poisons either through receptor-independent pathways or by a common downstream mechanism. Despite the existence of numerous studies on ILE efficacy and the satisfactory findings in various xenobiotics toxicities, limited clinical researches have studied ILE in patients who have overdosed on tramadol and experienced seizures (8). This study aimed to evaluate the potential role of ILE as an antidote in tramadol-induced seizure. 2. Methods 2.1. Study design and setting This randomized, single-blinded, clinical trial was con- ducted on 80 patients with acute tramadol poisoning who were referred to the emergency department (ED) of Booali Hospital, Qazvin, Iran, between August 2017 and Septem- ber 2018. The research procedure was approved by the Ethics Committee of Qazvin University of Medical Science (Code: IR.QUMS.REC.1395.267) and was registered at the Iranian Registry of Clinical Trials under registration number IRCT2017050120951N3. Written informed consent was re- ceived from all patients after a brief presentation, and before they participated in the study. The research was designed as a pilot and thus, had a relatively limited sample size. 2.2. Study population 80 consecutive cases, who were admitted to the ED during the study period, were studied. Patients were eligible for par- ticipation in the study if they met the following criteria: 1) Adults (16 years and above), 2) tramadol ingestion (based on patient’s history), 3) clinical presentations of tramadol over- dose and 4) referring to ED within 4 hours of tramadol intake. Patients were excluded from the study if they met the fol- lowing conditions: 1) multiple drug ingestion, 2) underlying heart disease, 3) hypersensitivity to the drug, 4) any previous history of seizure, and 5) abnormality in blood oxygen, elec- trolyte, and biochemical analysis. Multiple drug intakes were characterized based on history with or without confirmed urine or serum drug screening test. 2.3. Data gathering The baseline characteristics of the patients including sex, age, vital signs (pulse rate, respiratory rate, blood pres- sure, Glasgow coma scale, and oxygen saturation), history of seizure before admission to ED, dosage of abused drug, and lab tests were evaluated on admission of patients. The pa- tients were randomly assigned to control and intervention groups using a computer-generated randomization table and simple randomization method. All participants were blinded to the type of treatment received until the completion of the study. Blood samples were drawn for assessing blood sugar, blood urea nitrogen (BUN), creatinine (Cr), sodium (Na+), potassium (K+), liver function, hematological parame- ters. The diagnosis of seizures before admission to the emer- gency department was done based on an accurate medical history and reports taken from the witnesses who accompa- nied the patient and verified via scars of tongue biting. In- hospital events such as seizures were accurately monitored by the well-trained medical staff. An internal medicine spe- cialist was responsible for data gathering. 2.4. Intervention The patients in the intervention group received a single dose of 12 mL/kg of intralipid emulsion (ILE) 20% (30% as a bo- lus dose and the remaining infused over 3 hours) after sta- bilization along with routine treatment, while the control group only received the standard medical treatment includ- ing gut decontamination and adequate supportive care. The patients were monitored for vital parameters and seizures ev- ery 10 minutes. 2.5. Outcomes The main outcome of present study was the effect of ILE on occurrence and frequency of tramadol-induced seizure. 2.6. Statistical Analysis Data were tabulated using Microsoft Excel and analyzed us- ing SPSS software (v 21.0; SPSS Inc., Chicago, IL). Baseline data were presented using mean ± standard deviation or fre- quency (%). Continuous variables were analyzed using un- paired student’s t-test. P-values less than 0.05 were consid- ered significant. 3. Results 3.1. Baseline characteristics of participants 80 patients who abused tramadol and met the study criteria were randomly assigned to intervention (40 cases) or control (40 cases) groups. Figure 1 demonstrates the breakdown of all patients enrolled in the study. Seizure had occurred in 44 (56%) patients before admission to the emergency depart- ment. Table 1 compares the baseline characteristics of pa- tients between the groups. There were not any statistical dif- ferences between the groups regarding sex distribution (p = 0.513) and mean age (p = 0.19), presenting vital signs (p < 0.05), laboratory findings (p < 0.05), and mean abused dose 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. 2021; 9(1): e20 of tramadol (p = 0.472) as well as occurrence of prehospital seizure (p = 0. 7). 3.2. Outcomes Table 2 compares the studied outcomes between the two groups. In-hospital seizure occurred in 15 (18.75%) cases (all in control group; p < 0.001). All documented in-hospital seizures were tonic-colonic. The mean duration of admis- sion was 2.01 ± 1.13 days in the control group and 2.15 ± 1.04 days in the intervention group (p = 0.6). The number needed to treat for ILE to prevent tramadol-induced seizure was 2.7 (37.5% absolute risk reduction). It means that 2.7 pa- tients should be treated with ILE so that it can prevent one tramadol-induced seizure. 4. Discussion Current findings advocate ILE administration, as an adjunct to standard antidote protocols, in tramadol intoxication to prevent tramadol-induced seizures. ILE has been approved for parenteral nutrition and as a vehi- cle for lipophilic medicines by the Food and Drug Adminis- tration (FDA) since a long time ago. However, several stud- ies have reported the efficacy of using ILE as an antidote in poisoning with different drugs with no reported adverse effects. The first clinical study conducted by Rosenblatt in 2006 showed that ILE infusion attenuates CNS toxicity of lo- cal anesthetics, and increases consciousness score on Glas- gow coma scale (9). The use of opioids, including tramadol, and subsequent poi- soning have overwhelmingly increased in recent years (10). The most common symptoms of tramadol intoxication are a seizure, various cardiac dysrhythmias, and in some cases death. Seizure is the most important presentation of tra- madol overdose, and it has been reported in 54.4% of the pa- tients (11, 12). A recent experiment showed the efficacy of ILE administra- tion in managing tramadol poisoning (8). In the current re- search, ILE was able to attenuate tramadol-induced seizures, and was efficacious up to 100% with 12 mL/kg doses. The occurrence of seizures after tramadol consumption has been reported in many studies. Several studies noted the incidence of seizures after tramadol overdose, while some other studies claimed the dose-independent manner of this phenomenon (13). According to the results, 44 out of 80 pa- tients (56.2%) admitted to the emergency department had experienced a seizure before entering the emergency depart- ment. In the current study, 15 patients (37%) in the con- trol group experienced a seizure during the hospital admis- sion period. Talaei et al. described seizures in 46% of tra- madol abusers (13), while Jovanović-Čupićnoted reported that 54.4% of patients experienced seizure with the dose range of 250–2500 mg (14). In this study, the lowest dose resulting in seizure was 50 mg, which was in contrast with results by Marquardt et al. (15), Spiller (16), and Farzaneh et al. (17), who reported the low- est dose of tramadol leading to seizure as 200, 500, and 1000, respectively. In a case report by Beyaz et al. 75 mg of tra- madol caused a tonic-colonic seizure (18). Taghaddosinejad and colleagues (19) reported two cases of seizure at a dose of 100 mg and the results of our study is in accordance with these findings. This study was built upon the previous study by Vahabzadeh et al., which focused on the effect of intralipid infusion on seizure prevention in rabbits with acute tramadol intoxi- cation. They demonstrated the positive effect of ILE on seizure prevention, which is consistent with the findings of the present study (20). According to the results, ILE can be used as an effective an- tidote against seizure and possibly other adverse outcomes in patients with tramadol intoxication. Unfortunately, there is no high-quality controlled clinical study in this regard and we suggest performing large-scale controlled clinical trials to assess lipid emulsion therapy as a first-line therapy for in- dications such as tramadol poisoning. Lipid emulsions may have some adverse side effects. We suggest performing larger prospective studies along with patient follow-up in the future to elucidate the possible therapeutic effects and latent com- plications of ILE in tramadol-induced toxicities. 5. Limitations There were some limitations to our research. The study was done as a pilot with relatively limited participants. In this respect, another multicenter analysis must be done with a greater sample size. Considering the incomplete informa- tion about the history of using tramadol or other drugs in patients, the analysis, and comparison between the history tramadol use and seizure was not possible. 6. Conclusion The findings of this study supported ILE administration, as an adjunct to standard antidote protocols, in tramadol intoxication to prevent tramadol-induced seizures. How- ever, larger prospective studies along with patient follow- up should be performed in the future to elucidate the pos- sible therapeutic effects and latent complications of ILE in tramadol-induced toxicities. 7. Declarations 7.1. Acknowledgment The authors would like to express their gratitude to all oth- ers participating in this project through assisting data collec- 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 A M. Kazemifar et al. 4 tions, nurses, and emergency staff. 7.2. Author contributions The conception and design of the work by AK, MZ and ZY; Data acquisition by AB and AK; Analysis and interpretation of data by AK, JM, MZ and ZY; Drafting the work by MZ and AB; Revising it critically for important intellectual content by JM and MZ; All the authors approved the final version to be published; and agree to be accountable for all aspects of the work, ensuring that questions related to the accuracy or in- tegrity of any part of the work will be answered. 7.3. Funding/Support This study was supported by a grant received from Qazvin University of Medical Sciences. 7.4. Conflict of interest The authors declare that they have no competing interests. References 1. King S, Forbes K, Hanks G, Ferro C, Chambers E. A sys- tematic review of the use of opioid medication for those with moderate to severe cancer pain and renal impair- ment: a European Palliative Care Research Collaborative opioid guidelines project. Palliat Med. 2011;25(5):525-52. 2. 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Downloaded from: http://journals.sbmu.ac.ir/aaem 5 Archives of Academic Emergency Medicine. 2021; 9(1): e20 Table 1: Comparison of baseline characterises of patients between the groups Parameters Intervention (n = 40) Control (n = 40) P-value Sex Male 34 (85) 36 (90) 0.513 Female 6 (15) 4 (10) Age (year) Mean ± SD 25.1 ± 8.1 22.8 ± 5.7 0.190 Vital sign (on admission) Glasgow coma scale 13.65 ± 1.76 13.63 ± 1.87 0.951 Systolic blood pressure(mmHg) 118.5 ± 8.7 121.7 ± 1 0.177 Diastolic blood pressure(mmHg) 77.5 ± 9.6 77.3± 10.2 0.842 Heart rate (bpm) 85.7 ± 8 84.3 ± 7.5 0.463 Respiratory rate /minute) 15.2 ± 3 14.5 ± 4.2 0.547 SaO2 (%) 94.0±2.5 93.0±3.4 0.587 Laboratory findings Tramadol dose(mg) 229.8 ± 135.5 195 ± 156.5 0.472 Blood Sugar (mg/dL) 112 ± 44.6 109 ± 39.5 0.682 Serum sodium (mEq/L) 138.3 ± 3.1 137.8 ± 3.2 0.520 Serum potassium (mEq/L) 4.3 ± 0.36 4.2 ± 0.39 0.119 Creatinine (mq/dL ) 0.91 0.16 0.89 ± 0.15 0.791 pH 7.39 ± 0.37 7.39 ± 0.36 0.830 ALT (IU/L) 24.2±10.3 27±9.5 0.648 AST(IU/L) 34.92±9.31 35.07±13.1 0.195 BUN(mg/dL) 25.4 ± 7.3 26.1 ± 6.6 0.547 Hemoglobin (g/dL) 13.8± 1.5 13.6± 1.8 0.842 Pre-hospital seizure Yes 21 (52.5) 23 (57.5) 0.700 Data are presented as mean ± standard deviation (SD) or frequency (%). ALT: alanine aminotransferase; AST: aspartate aminotransferase; BUN: blood urea nitrogen. Table 2: Comparison of studied outcomes between the groups Outcome Intervention (n = 40) Control (n = 40) P-value In-hospital seizure Yes 0 (0.00) 15 (37.5) <0.001 No 40(100) 25(62.5) Duration of hospitalization (Days) 1 14 (35.0) 18 (45.0) 2 12 (30.0) 9 (22.5) 0.616 3 11 (27.5) 10 (25.0) 4 2(5.0) 1(2.5) 5 1(2.5) 2(5.0) Data are persecuted as number (%). 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 A M. Kazemifar et al. 6 Figure 1: Study enrollment and distribution of studied patients. 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 Introduction Methods Results Discussion Limitations Conclusion Declarations References