Archives of Academic Emergency Medicine. 2023; 11(1): e6 OR I G I N A L RE S E A RC H The Effect of Intravenous Metoclopramide on Gastric Emptying of Opium-dependent Patients based on Ultra- sonographic Criteria; a Case-control Study Faramarz Mosaffa1, Ali Arhami Dolatabadi2, Masoomeh Raoufi3, Faezeh Golpour4, Mahshid Ghasemi1, Mohammad Javad Yazdipoor2, Elham Memary5,6∗ 1. Anesthesiology Department, Akhtar Hospital, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 2. Emergency Department, Imam Hossein Hospital, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 3. Radiology Department, Imam Hossein Hospital, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 4. Men’s Health and Reproductive Health Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 5. Anesthesiology Research Center, Ayatollah Taleghani Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 6. Anesthesiology Department, Imam Hossein Hospital, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Received: October 2022; Accepted: December 2022; Published online: 1 January 2023 Abstract: Introduction: Induction of anesthesia for emergency procedures, without prior gastric preparation and incom- plete fasting, is associated with the risk of reflux of stomach contents and aspiration. This study aimed to eval- uate the effect of intravenous (IV ) metoclopramide administration on gastric emptying in opium users, candi- date for procedural sedation and analgesia (PSA). Methods: In the present case-control study, opium-dependent (case) and non-dependent (control) patients in need of PSA were administered with 10 mg IV metoclopramide after undergoing gastric ultrasonography for determination of its area and contents. Then, 30 minutes after the administration of metoclopramide, the area and contents of the stomach were measured again and compared with the measures obtained before the intervention. Results: 135 patients were evaluated in three groups of 45, including the case, control, and placebo groups. The three groups were similar regarding mean age (p = 0.068), sex (p = 0.067), weight (p = 0.596), height (p = 0.671), body mass index (BMI) (p = 0.877), duration of fasting (p = 0.596), and type of gastric contents (p = 0.124). Mean antral cross-sectional area (CSA) of the study participants in the case, control, and placebo groups before the administration of the drug was 8.49 ± 1.40, 8.31 ± 2.56, and 6.56 ± 1.72 cm2, respectively. Mean gastric area in the case (p < 0.001) and control (p < 0.001) groups had signifi- cantly decreased after the intervention. Mean antral gastric grade of gastric contents in the case (p < 0.001) and control (p < 0.001) groups had significantly decreased after the intervention. Conclusion: It seems that meto- clopramide administration in opium users in need of PSA leads to a significant decrease in mean gastric area and increases gastric emptying. Keywords: Deep Sedation; Emergency Treatment; Anesthesia; Respiratory Aspiration; Ultrasonography; Clinical Trial Cite this article as: Mosaffa F, Arhami Dolatabadi A, Raoufi M, Golpour F, Ghasemi M, Yazdipoor MJ, Memary E. The Effect of Intravenous Metoclopramide on Gastric Emptying of Opium-dependent Patients based on Ultrasonographic Criteria; a Case-control Study. Arch Acad Emerg Med. 2023; 11(1): e6. https://doi.org/10.22037/aaem.v11i1.1892. ∗Corresponding Author: Elham Memary; Anesthesiology Research Cen- ter, Ayatollah Taleghani Hospital, Velenjak, Shahid Arabi Street, Tehran, Iran. Email: drmemary@gmail.com, Tel: 00989122847642, ORCID: https://orcid.org/0000-0002-4845-9342. 1. Introduction Incomplete fasting at the time of anesthesia induction or ad- ministration of sedative-hypnotic drugs, which are associ- ated with loss of protective reflexes such as cough and swal- lowing, is associated with the risk of reflux of stomach con- tents and aspiration. Therefore, in contrast to candidate pa- tients for elective surgery, in emergency situations, when de- laying the intended procedure or surgery for increasing fast- This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: https://journals.sbmu.ac.ir/aaem/index.php/tem/index F. Mosaffa et al. 2 ing time is not possible, there is a higher risk of pulmonary aspiration (1-3). Considering that this event is a very serious and dangerous side effect of anesthesia induction and can be associated with substantial morbidity and mortality, taking proper measures for its prevention is essential (4, 5). Conditions such as pregnancy, drug abuse, diabetes, and renal failure, which are associated with decrease in gastric movement, as well as conditions leading to increase in in- traabdominal pressure, including obesity, ascites, and ab- dominal tumors are among known risk factors for aspiration during anesthesia induction. Gastric volume and acidity of its contents are among other factors that are known to in- crease the probability of aspiration and its severity and many interventions have been tested with the aim of affecting these variables (5). Various medications, like antacids, prokinetics, antiemetics, and anticholinergics or a combination of them have been used for decreasing the risk of aspiration before induction of anesthesia in emergency situations. Additionally, measures such as inserting nasogastric (NG) tube, and gastric empty- ing, placing the head in a downward 15- 20° angle and Sell- ick maneuver are among the non-drug interventions used in this regard (6). To evaluate the efficacy of these interventions various methods have been introduced. In recent years, ul- trasonography has been used for qualitative and quantitative evaluation of gastric contents as well as assessing the effect of different interventions, some of which were mentioned (7). The effect of prescribing metoclopramide on gastric motility based on ultrasonographic criteria has been evaluated in dif- ferent studies (7-11). However, its efficiency in patients with drug abuse has rarely been assessed. Meanwhile, consider- ing the effect of drugs on gastrointestinal tract movements, there is more concern regarding decrease in gastrointesti- nal tract movements and lowered response to prescription of prokinetic drugs, including metoclopramide, in these pa- tients (12-14). Considering the afore-mentioned points, the present study was designed and performed with the aim of evaluating the effect of IV metoclopramide on gastric emp- tying in patients with drug abuse, who were candidates for undergoing procedural sedation and analgesia (PSA). 2. Methods 2.1. Study design and settings The present case-control study was performed on opium- dependent (case) and non-dependent (control) patients in need of PSA in the emergency department of Imam Hossein Hospital, Tehran, Iran, between 2021 and 2022. After under- going gastric ultrasonography for determination of its area and contents, the patients were divided into 3 groups of case (opium-dependent patients who received 10 mg IV metoclo- pramide), control (non-opium-dependent patients who re- ceived 10 mg IV metoclopramide) and placebo (non-opium- dependent patients who received 2cc distilled water). Then, 30 minutes later, the area and quality of gastric contents were measured and compared with measures before the interven- tion. The proposal of this study was approved by the ethics committee of Shahid Beheshti University of Medical Sciences (IR.SBMU.MSP.REC.1399.154). In addition, the protocol of this study was registered on the Iranian registry of clinical tri- als under the code IRCT20210406050864N1. After providing explanations regarding the protocol of the study, informed written consent was obtained from the patients for participa- tion in the present study. No additional costs were inflicted on the patients or the health care system as a result of this study and the researchers adhered to the confidentiality of patients’ data and ethical principles in biomedical research based on the declaration of Helsinki. 2.2. Study population The study population consisted of patients with a history of daily drug abuse for more than 6 weeks, using any type of opioid (derivatives of poppies or opium), who were candi- dates for PSA and had eaten solid food less than 8 hours be- fore or drank liquids less than 2 hours before. Patients who were unable to assume the proper position for ultrasonog- raphy, those with body mass index (BMI) over 35, obstruc- tion in the gastrointestinal tract, diabetes, history of gastric surgery, hiatal hernia, those who had used medications that change gastrointestinal tract movements in the previous 72 hours, and those with history of allergic or extrapyramidal re- actions after receiving metoclopramide were excluded from the study. The control and placebo groups were selected from non-dependent individuals with a similar situation. 2.3. Intervention All of the patients included in the study were under full cardiopulmonary monitoring and their vital signs were recorded. Then the patients were divided into 3 groups of case, control, and placebo. All the patients underwent ultra- sonography by a radiologist in supine and right lateral posi- tions and their gastric area and its contents’ qualities were evaluated and registered. The control group included non-dependent individuals and the case group included dependent patients, all of whom re- ceived 10 mg (2cc) IV metoclopramide. The placebo group consisted of non-dependent patients who received 2cc dis- tilled water instead of metoclopramide. The onset of action of IV metoclopramide is 1-3 minutes and it reaches the peak of action in 15-20 minutes. Therefore, the second measure- ment was done 30 minutes after the prescription of the drug or placebo. The person prescribing the drug was aware of the groupings, but the patients and the radiologist in charge of performing the ultrasonography were blind to the groupings. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: https://journals.sbmu.ac.ir/aaem/index.php/tem/index 3 Archives of Academic Emergency Medicine. 2023; 11(1): e6 Table 1: Comparing the baseline characteristics of participants between the three study groups Variable Placebo (n = 45) Control (n = 45) Case (n = 45) P-value Age (year) Mean ± SD 50.8 ± 15.9 43.1 ± 18.0 49.3 ±15.8 0.068 Sex Male 25 (55.6) 16 (35.6) 26 (57.8) 0.067 Female 20 (44.4) 29 (64.4) 19 (42.2) Weight (Kg) Mean ± SD 69.5 ± 14.7 66.7 ± 9.3 67.2 ±14.5 0.596 Height (m) Mean ± SD 1.7 ± 0.05 1.6 ± 0.07 1.7 ± 0.04 0.671 BMI Mean ± SD 23.7 ± 3.9 24.3 ± 4.4 23.9 ± 3.8 0.877 Fasting time (hour) Mean ± SD 3.3 ± 1.4 3.6 ± 2.1 3.6 ± 1.4 0.596 Type of food consumed Liquid 32 (71.1) 39 (86.6) 36 (80.0) 0.124 Solid 13 (28.9) 6 (13.4) 9 (20.0) Data are presented as mean ± standard deviation (SD) or frequency (%). BMI: Body Mass Index. The control group included non- opium dependent individuals and the case group included opium dependent patients, all of whom received 10 mg (2cc) IV metoclopramide. The placebo group consisted of non- opium dependent patients who received 2cc distilled water instead of metoclopramide. Table 2: Comparing gastric ultrasonography findings in the three study groups before and after the intervention Group Before intervention After intervention p-value Antral cross-sectional area (cm2 ) Case 8.49 ± 4.34 4.34 ± 1.52 < 0.001 Control 8.31 ± 2.56 4.44 ± 1.37 < 0.001 Placebo 6.59 ± 1.72 6.34 ± 1.92 0.140 Antral gastric grade Case 1.56 ± 0.50 0.76 ± 0.68 < 0.001 Control 1.60 ± 0.49 0.87 ± 0.66 < 0.001 Placebo 1.42 ± 0.50 1.33 ± 0.94 0.486 Data are presented as mean ± standard deviation (SD). Figure 1: Measuring mean antral cross-sectional area (CSA) using ultrasonography in supine and right lateral positions. 2.4. Ultrasonographic evaluation Patients in all three groups underwent ultrasonography in supine and right lateral positions by a radiologist. Mean antral cross-sectional area (CSA) was measured and antral gastric grade (AGG) was also evaluated. - Mean antral cross-sectional area (CSA) This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: https://journals.sbmu.ac.ir/aaem/index.php/tem/index F. Mosaffa et al. 4 Figure 2: Evaluating antral gastric grade (AGG) using gastric ultrasonography findings. Table 3: Changes in antral gastric grade (AGG) of patients after the intervention based on group Variable Placebo (n = 45) Control (n = 45) Case (n = 45) P value 1 grade increase 11 (24.4) 2 (4.4) 1 (2.2) No change 22 (48.9) 15 (33.3) 14 (31.1) < 0.001 1 grade decrease 9 (20.0) 21 (46.6) 23 (51.1) 2 grades decrease 3 (6.7) 7 (15.6) 7 (15.6) Data are presented as frequency (%). The control group included non- opium dependent individuals and the case group included opium dependent patients, all of whom received 10 mg (2cc) IV metoclopramide. The placebo group consisted of non- opium dependent patients who received 2cc distilled water instead of metoclopramide. In all patients, CSA was determined by an experienced ra- diologist using sonosite2 device and rC60xi 2-5 MHz probe in supine and right lateral positions and in sagittal view of antrum, based on anatomical landmarks of the stomach. CSA and antral volume were calculated. Measurement of CSA was done using measures of vertical thickness in longitudi- nal d1 and posterior d2 planes in centimeters and from the serosa of one side to the serosa of the other side. For mea- suring the cross-section of the antrum, the following formula was used: [CSA = 3.14 (d1×d2) ×0.4]. Based on previous stud- ies, the cut-off for determining the volume of the stomach was considered to be > 1.5cc, and for determining the pres- ence of solid or liquid contents, it was considered to be 3.01 cm2 (figure 1). - Evaluating antral gastric grade (AGG) Qualitative evaluations of AGG for determining the presence or absence of solid and liquid contents were performed in 3 grades (0, 1, 2) as follows (figure 2): Grade 0: absence of contents; Grade 1: presence of evidence of contents only in right lateral position; and grade 2: presence of evidence of contents in both supine and right lateral positions. The mathematical model used for calculating the volume of con- tents and determining antral volume in this study was: VOL- UME=27+(14.6*RL CSA)-(1.28*age) 2.5. Statistical analysis Based on the study by Sayyadi et al. (8), the number of sam- ples in each group was determined to be 45 and sampling was continued until reaching the intended sample size in all 3 groups. To analyze the data, SPSS software version 26 was used and findings were reported as mean ± standard devia- tion or frequency (%). To evaluate the normality of data, Kol- mogorov–Smirnov test was applied. To compare the quanti- tative variables in the 2 groups, independent samples t-test or one-way analysis of variance, and for categorized vari- ables, chi square and Fisher’s exact test, and for normal quan- titative variables in each group (before and after interven- tion), dependent t-test or paired t-test was used. To compare the gradings of the patient’s stomach before and after the in- tervention, Mantel–Haenszel test was applied. In all tests, the significance level was considered to be less than 0.05. 3. Results 3.1. Baseline characteristics of the studied pa- tients In this study, 135 patients were studied in 3 groups of 45 in- cluding case, control, and placebo groups. The baseline char- acteristics of the patients has been compared between the 3 study groups in table 1. The 3 groups were similar regarding mean age (p = 0.068), sex (p = 0.067), weight (p = 0.596), height (p = 0.671), body mass index (BMI) (p = 0.877), duration of fasting (p = 0.596), and type of food consumed instead of type of gastric content (p = 0.124). The participants in the case group were opium- dependent, and would usually use it once a day, and most of them had a history of using opium for more than 7 years; their most common route of consumption was the oral route. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: https://journals.sbmu.ac.ir/aaem/index.php/tem/index 5 Archives of Academic Emergency Medicine. 2023; 11(1): e6 3.2. Ultrasonographic findings Mean CSA Mean CSA of the patients participating in the study in case, control, and placebo groups before the administration of the drug was 8.49 ± 1.40, 8.31 ± 2.56, and 6.56 ± 1.72 cm2, respec- tively. Table 2 compares the mean CSA before and after the administration of the drug in the 3 studied groups. In con- trast to the placebo group, mean CSA had significantly de- creased in the case (p < 0.001) and control (p < 0.001) groups after the intervention. Mean CSA of the patients after the ad- ministration of the drug in the case group was lower that the control group, and in the control group it was less than the placebo group (p < 0.001). Evaluating AGG Table 2 compares the mean qualitative score of gastric con- tents in the 3 studied groups before and after the interven- tion. In contrast to the placebo group, mean AGG had sig- nificantly decreased in the case (p < 0.001) and control (p < 0.001) groups after the intervention. Mean AGG of the pa- tients after the administration of the drug in the case group was lower that the control group, and in the control group it was less than the placebo group (p < 0.001). Table 3 compares AGGs of the 3 studied groups after the intervention. 4. Discussion Based on the results of the present study and considering the ultrasonographic findings, it seems that prescription of metoclopramide in opium users in need of PSA can signifi- cantly decrease mean CSA and increase gastric emptying. The effect of metoclopramide on acceleration of gastric emp- tying and decreasing gastric volume in patients in need of PSA, who have not had enough fasting time, has been con- firmed in previous studies using different measuring meth- ods, including use of ultrasonographic indices. Yet, the effec- tiveness of this intervention in opium users has been a matter of question. Most opiate agonists, including morphine, lead to less motil- ity in the gastrointestinal tract through stimulation of mu re- ceptors. Decrease in gastric motility, increase in tonicity of the sphincter, change in motility patterns, and peristaltism are commonly seen following use of opiates. In fact, these com- pounds lead to increase in contraction of gastric antrum and pylorus and the upper parts of the duodenum, as well as de- crease in tonicity in the relaxed state of the gastric muscles (12-14). On the other hand, metoclopramide is an antagonist of D2 receptor, which can inhibit the effects of the endoge- nous dopamine transmitter on the gastrointestinal tract. En- dogenous dopamine leads to decreased motility of the stom- ach and proximal small intestine by inhibiting the release of acetylcholine, and its effects are neutralized with the injec- tion of metoclopramide (15). In a study by Sayyadi et al., qualitative and quantitative ul- trasonographic evaluation of the stomach before surgery was done in candidate patients in need of emergency surgery, who received 10 mg metoclopramide. In that study, drug- dependent patients and those using opiates were excluded from the study. The results of that study showed that al- though AGG and CSA of the 2 groups were not significantly different after intervention, mean decrease in CSA in the metoclopramide group was higher than the control group, and the decrease observed in AGG after the intervention in the metoclopramide group was higher than the control group (8). Comparing the results of the present study with that study can lead to the hypothesis that metoclopramide has even higher effectiveness in opium users; as in the present study, those in the case group showed a significant decrease in CSA and AGG compared to control and placebo groups. In the systematic review by Priya Vijayvargiya et al. per- formed in 2019, there were 899 included articles, in 22 of which gastric emptying (GE) was studied, in 23 studies up- per gastrointestinal tract symptoms (UGI Sx), and in 14 stud- ies both GE and UGI Sx were evaluated. In 18 of the stud- ies the effects of D2 receptor antagonists, including meto- clopramide and domperidone, on both UGI Sx and GE were evaluated. In 6 studies, these medications were associated with 20 to 50% improvement in GE, in 4 studies no differ- ence was found in GE, in 13 studies there was 20 to 50% improvement in UGI Sx, and in 2 studies no difference was found in UGI Sx. Of course, in these studies the patients were mainly divided into 2 groups of patients with gastroparesis (GP) and functional dyspepsia (FD), both of which showed similar improvement in GE. The study also showed that there was a significant correlation between improvement in GE and changes related to UGI Sx. In that study, opioid users were not evaluated and analyzed, and thus, in the conclu- sion of the study, it was suggested to perform further studies in similar populations using optimal tests and more proper evaluations for GE and UGI Sx (16). It seems that considering the risk of aspiration of gastric contents in emergency proce- dures without gastric preparation, using medications such as metoclopramide, which accelerate GE, can help reduce the probability of this event. 5. Limitation The 3 studied groups were not homogenous regarding ul- trasonographic indices before the intervention. Additionally, considering the absence of aspiration in all of the groups fol- lowing induction of anesthesia, nothing can be said regard- ing the effect of this medication on the prevalence of aspira- tion. Also, there is the possibility of wrong and inaccurate self-declaration of opium users regarding the type of sub- This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: https://journals.sbmu.ac.ir/aaem/index.php/tem/index F. Mosaffa et al. 6 stance used and the last time using it and even the duration of fasting. Of course, we tried to minimize its probability by fully explaining the importance of receiving correct informa- tion. 6. Conclusion It seems that metoclopramide administration in opium users in need of sedation for emergency procedures leads to signif- icant decrease in ACS and increase in gastric emptying. 7. Declarations 7.1. Acknowledgments Not applicable. 7.2. Conflict of interest There is not to declare. 7.3. Funding and supports This study has been funded and supported by the Iran Uni- versity of Medical Sciences (IUMS); [Grant No: 1400-1-32- 20043.] 7.4. Authors’ contribution Study Design: AAD, SS; Data gathering: SJY, MR, EM; Analy- sis: SS; Interpretation of results: SS, AAD, SJY, MR; Drafting: SS, SJY; Critically revised: All authors. References 1. Kluger M, Short T. Aspiration during anaesthesia: a review of 133 cases from the Australian Anaes- thetic Incident Monitoring Study (AIMS). Anaesthesia. 1999;54(1):19-26. 2. Kluger MT, Culwick MD, Moore MR, Merry AF. Aspi- ration during anaesthesia in the first 4000 incidents reported to webAIRS. Anaesthesia and intensive care. 2019;47(5):442-51. 3. Cook T. Strategies for the prevention of airway complica- tions–a narrative review. Anaesthesia. 2018;73(1):93-111. 4. Hewson DW, Moppett I. Preoperative fasting and preven- tion of pulmonary aspiration in adults: research feast, quality improvement famine. British journal of anaesthe- sia. 2020;124(4):361-3. 5. Nason KS. Acute intraoperative pulmonary aspiration. Thoracic surgery clinics. 2015;25(3):301. 6. Robinson M, Davidson A. Aspiration under anaesthe- sia: risk assessment and decision-making. Continu- ing Education in Anaesthesia Critical Care & Pain. 2014;14(4):171-5. 7. Perlas A, Mitsakakis N, Liu L, Cino M, Haldipur N, Davis L, et al. Validation of a mathematical model for ultra- sound assessment of gastric volume by gastroscopic ex- amination. Anesthesia & Analgesia. 2013;116(2):357-63. 8. Sayyadi S, Raoufi M, Dolatabadi AA, Rostami M, Memary E. Ultrasonographic Assessment of Metoclopramide Ad- ministration Effectiveness in Accelerating Gastric Emp- tying Before Urgent Surgery in Patients with Insuffi- cient NPO Time. Anesthesiology and Pain Medicine. 2020;10(5). 9. Abdolrazaghnejad A, Banaie M, Safdari M. Ultrasonogra- phy in emergency department; a diagnostic tool for bet- ter examination and decision-making. Advanced journal of emergency medicine. 2018;2(1). 10. Nasr-Esfahani M, Behravan M, Esmailian M. The Cor- relation between Ultrasonographic Gastric Antral Area and Vomiting in Patients undergoing Procedural Seda- tion and Analgesia. Frontiers in Emergency Medicine. 2020;4(4):e83-e. 11. Bouvet L, Chassard D. Ultrasound assessment of gas- tric contents in emergency patients examined in the full supine position: an appropriate composite ultrasound grading scale can finally be proposed. Springer; 2020. p. 865-8. 12. Mahmoud Reza K, Masour Reza S, Farhad Z. < The> us- age of opioids and their adverse effects in gastrointestinal practice: a review. 2013. 13. Brock C, Olesen SS, Olesen AE, Frøkjaer JB, Andresen T, Drewes AM. Opioid-induced bowel dysfunction. Drugs. 2012;72(14):1847-65. 14. Farmer AD, Drewes AM, Chiarioni G, De Giorgio R, O’Brien T, Morlion B, et al. Pathophysiology and manage- ment of opioid-induced constipation: European expert consensus statement. United European gastroenterology journal. 2019;7(1):7-20. 15. Camilleri M, Atieh J. New developments in prokinetic therapy for gastric motility disorders. Frontiers in Phar- macology. 2021:2216. 16. Vijayvargiya P, Camilleri M, Chedid V, Mandawat A, Erwin PJ, Murad MH. Effects of promotility agents on gastric emptying and symptoms: a systematic review and meta- analysis. Gastroenterology. 2019;156(6):1650-60. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: https://journals.sbmu.ac.ir/aaem/index.php/tem/index Introduction Methods Results Discussion Limitation Conclusion Declarations References