DOI: 10.33962/roneuro-2020-087 Safety of metoclopramide in traumatic brain injury patients. A systematic review of literature Said Al Jaadi, Yahya Al Kindi, Tariq Al-Saadi Romanian Neurosurgery (2020) XXXIV (4): pp. 512-517 DOI: 10.33962/roneuro-2020-087 www.journals.lapub.co.uk/index.php/roneurosurgery Safety of metoclopramide in traumatic brain injury patients. A systematic review of literature Said Al Jaadi1, Yahya Al Kindi1, Tariq Al-Saadi1,2 1 College of Medicine and Health Sciences, Sultan Qaboos University, OMAN 2 Neurosurgeon. CANADA ABSTRACT Background: One in every three related-injury deaths in United State are linked directly to traumatic brain injury (TBI), for which it is considered as a leading cause of death. Traumatic brain injury took place due to severe head assault to a hard object, with headache and vomiting being amongst the most common presenting symptoms. Metoclopramide is an old antiemetic agent that has been used widely for nausea and vomiting in TBI patients. Aim: A systematic review of the literature to investigate the safety of metoclopramide in treating traumatic brain injury patients. Methods: A literature review was conducted in 6 databases, we determine the pertinence of a study to the inclusion criteria by assessing the title, keywords, and abstracts. Five studies were found to be relevant. Data were extracted using multiple variables that were formulated incongruent with the study aim and then further analyzed. Results: The collective sample size was 93 patients with an average of age 38.5 years. 51.6 % were male and 48.6% were females. Most patients received 10 mg metoclopramide IV with a percentage of 77.4%. While only 22.5% received 20 mg IV metoclopramide. Seventy-one patients received metoclopramide alone and 22 received combination therapy. Headache was the most common reported side effect (46.2 %), followed by anxiety and drowsiness with (39.7%) and (27.9 %); respectively. Fatigue reported in (24.7%), while dystonia was the least common and developed only in 5.3%. Conclusion: Metoclopramide is a common medication used to treat TBI patients in the emergency department. However, the review demonstrated that the central nervous system (CNS) side effect is excepted. Alternative options with lower CNS side effects may be better tried. BACKGROUND One in every three related-injury deaths in the US are linked directly to TBI, for which it is considered as a leading cause of death (1). As for paediatric cases the prevalence across countries varies from 47 and 280 per 100,000 children, more than 80% of which are minor head injuries with GCS of 14-15(2). Traumatic brain injury took place due to Keywords traumatic head injury, metoclopramide, safety, side effect, headache, vomiting Corresponding author: Tariq Al-Saadi Neurosurgeon. Canada tariq.dh.95@gmail.com Copyright and usage. This is an Open Access article, distributed under the terms of the Creative Commons Attribution Non–Commercial No Derivatives License (https://creativecommons .org/licenses/by-nc-nd/4.0/) which permits non- commercial re-use, distribution, and reproduction in any medium, provided the original work is unaltered and is properly cited. The written permission of the Romanian Society of Neurosurgery must be obtained for commercial re-use or in order to create a derivative work. ISSN online 2344-4959 © Romanian Society of Neurosurgery First published December 2020 by London Academic Publishing www.lapub.co.uk http://www.lapub.co.uk/ 513 Safety of metoclopramide in traumatic brain injury patients severe head assault to a hard object, which then can be classified into mild, moderate, and sever using GCS (3). Moreover, the main causes of TBI are road traffic accidents (RTA), falling, physical violence, exercise-related head injuries among others (1,3). Patients with TBI usually present to the emergency room (ER) with headache, nausea, and vomiting (4). Other common presentations are dizziness, blurred vision, loss of consciousness, amnesia, and disturbance in concentration (1,2,4). As for headache, 1 in every 4 patients reported persistent headache syndrome (4). TBI patients were treated with antiemetic agents for their symptoms. Metoclopramide (4-amino-5-chloro-2-methoxy-N- (2 dimethylamino methyl benzamide) is an old antiemetic agent that has been used widely for nausea and vomiting as well as other gastrointestinal disorders (2). It is an antidopaminergic agent, centrally and peripherally acting, in order to enhance upper gastrointestinal motility without affecting its secretion (3). Metoclopramide administration through PO takes about 1-2 hours for maximum plasma concentration while it takes only 15min on an IV root (2,3). It is metabolized by the hepatic Cytochrome P450 CYP2D6 enzyme (2). The drug has multiple side effects such as; dystonia, restlessness or anxiety, fatigue, drowsiness, confusion, insomnia, and flushing (2,3). Our main aim is to study the safety of metoclopramide in treating TBI cases by reviewing the literature. METHODOLOGY Literature search and formulating selection criteria This study is a literature review with the main aim being to study the safety of metoclopramide in treating TBI cases. We searched Pubmed, EBSCO, Proquest, ScienceDirect, Wiley Online, and Springer for pertinent studies. Moreover, we determined the pertinence of a study to the inclusion criteria by assessing the title, keywords, and abstracts. The keywords we used were; Traumatic Head Injury, Head Injury, Brain Injury, Subdural Injury, Epidural Injury, Metoclopramide, Safety of Metoclopramide, and Metoclopramide side effect. Furthermore, the inclusion criteria were; all English literature and articles about TBI that used metoclopramide and reported drug side effects while we excluded any articles that are non-completed, repeated, or did not meet any of the aforementioned criteria. Data Extraction Data were extracted using multiple variables that were formulated incongruent with the study aim. The variables are; article type and author’s name, number of patients, the average age, gender, the dose of metoclopramide, drug combination, drug side effects, mechanism of injury, GCS, and duration of follow up. All of which were gathered in a table and were set for analysis. Figure 1. PRISMA flow diagram show Methodology characteristic of included study Figure 1 represents flow chart depicting the study selection process. Of 21 relevant studies, one of them was found to be a repetition, 14 were not eligible and one was irrelevant to the research aim. 5 pertinent literature were studied thoroughly for data extraction. Data Analysis Data were collected in an EXCEL sheet, formula builder was used to calculating simple mathematic, including the total number of patients, the number of females and males, and the percentage of each, total number of side effects reported. SPSS has been used to calculate the mean of age and the days of follow up using a bar of weight cases. RESULT Our study included 5 articles, as shown in Table 1. Two studies were randomized controlled, one was 514 Said Al Jaadi, Yahya Al Kindi, Tariq Al-Saadi prospective, and two case reports. There were variations in the drug side effects reported in each study. Two studies used Diphenhydramine 25mg and Cisapride as a combination thereby, while the remained used metoclopramide alone. All the studies used 10 mg IV metoclopramide except one study used 20 mg IV. Headache was the most common reported side effect by 2 studies. There was some missing data especially on the mechanism of injury. Our sample size was 93 patients with an average of age 38.5 years. 51.6 % were male and 48.6% were female (Table 2). Most patients received 10 mg metoclopramide IV with a percentage of 77.4%. While only 22.5% received 20 mg IV metoclopramide. Seventy-one patients received metoclopramide alone and 22 received combination therapy. Headache was the most common reported side effect (46.2 %), followed by anxiety and drowsiness with (39.7%) and (27.9 %); respectively. Fatigue reported in (24.7%). While dystonia was the least common and developed only in 5.3%. DISCUSSION This is the first systemic review study of metoclopramide side effects on patients with TBI. There is a lack of clinical trial which study the side effect of metoclopramide in patients with TBI. Our study identified 93 patients who received metoclopramide after TBI. The average age of patients was 6.9 years (4-69). Male was relatively higher than female in our sample size as 51.6% of our sample size were male compared to 48.4% female. Comparing done to identify the incidence and management of moderate to a severe head injury which showed that male to female ratio is 2:1(5). This might be due to the type of our research as it is a systemic review and most of our data were collected from prospective and clinical trial research. A previous study on the identification of the efficacy of metoclopramide in TBI, showed that the leading causes of TBI were RTA, followed by fall (6). In comparison to our study fall and trip were the highest. In our review, 77.4% received 10 mg metoclopramide intravenously, and 22.5% received 20 mg intravenously. This dose was supported by the recommendation of the European Medicines Agency that the maximum daily dose of Metoclopramide is between 10 mg to 30 mg in order to decrease the risk of neurological and other adverse effect (7). Metoclopramide is a prokinetic agent that have been widely used in critically ill patient to improve gastric motility and the symptoms of head concussion, nausea, and vomiting (8). However, the concerns of metoclopramide’s safety have been raised (9). One of the studies included in our review showed that the effectiveness of metoclopramide and ondansetron was similar. However, because of the incidence of the complications in patients treated with metoclopramide were higher than ondansetron, they concluded with the suggestion to use ondansetron instead of metoclopramide inpatient with TBI (10). In TBI patient with an enteral feeding problem, the use of erythromycin instead of metoclopramide in some situation has been studied which show there is a significant decrease in high gastric aspirate volume with the use of erythromycin compared to metoclopramide (11). In the current systemic review, the most common symptom was the headache as it is presented in 45.2% of the sample size (10,12). In contrast to a survey study done by Hale.T which showed that among 32 participants in the study, 1-7% of participants complained of some central side effects ranging from dizziness and headache. We can see that patients with TBI are more susceptible to develop a headache and other neurological side effects, including extrapyramidal side effects, from metoclopramide compared to others (13). In our review, the incidence of anxiety and drowsiness were 37 patients (29.0%) and 26 patients (27.9%), respectively. Fatigue was only represented in 23 patients (24.7%)(10)(12). While another systemic review study done to study the use of metoclopramide in diabetic gastroparesis, showed that fatigue, drowsiness and lethargy were presented in 10% of patients (14). Dystonia was represented in 5 patients (5.3%). The incidence of dystonia in the previous systemic review was in an approximately 0.2–6% of patients who received metoclopramide (14). These side effects may explain by the ability of metoclopramide to cross the blood- brain barrier easily (15). The early signs of an increased ICP are headache, vomiting or nausea, ocular palsies, and altered level of consciousness. Side effects of metoclopramide overlap with raised ICP symptoms, since it is subtle it is difficult to recognize a rise in ICP unless you investigate it. In our literature review, a case report 515 Safety of metoclopramide in traumatic brain injury patients identifies an increased in ICP from baseline of 15 - 20mmHg to 36mmHg following a 10mg intravenous metoclopramide and the same dose in the following day reports another increases to 34 mmHg (16). Such side effects raise a question of the safety of the metoclopramide in patients with TBI. Inconsistent with our results that found an increased susceptibility for neurological side effects after metoclopramide administration in TBI patients. A controlled randomized clinical trial is recommended to exploit the relationship between raised ICP and metoclopramide. Limitations: The limitation of the study includes the lack of high evidence studies as there were only two randomized controlled trials and one prospective study. publication bias was not done because of the same reason. In addition, the lack of long term follows up was also noticed. In addition, in 75.2% of cases, the mechanism of injury was not mentioned. CONCLUSION Metoclopramide is a common medication used to treat TBI patients in the emergency department. However, the review demonstrated that the CNS side effects are excepted. Alternative options with lower CNS side effects may be better tried. Table 1. Summary of Metoclopramide and TBI studies Article type Author Year of publication No. of patie nts Age Gender Dose of metoclo pramide Combin ation Side effect Mechanism of injury GCS Duration of Follow up Controlled, randomize, double blind clinical trial Majid Zamani et al. 2015 60 36.1 M 33 10 mg, IV NA - Headache 30/60(30%) - Drowsiness 26/60(43.3%) - Fatigue 23/60(38.3%) - Anxiety 37/60(61.7%) - Dystonia 5/60 (8.3%) NA 14- 15 NA F 27 Prospective, randomize, controlled, double- blind Tarik Zafer Nursal 2007 10 43 M 8 10 mg, IV NA 5/10 develop complication * TBI not defined 11-6 5 days F 2 Prospective Benjamin W 2018 21 45 M 5 20 mg, IV Diphen hydra mine 25mg headache 12/19 (63%) - Trip/fall 9 - Impacted stationary object 4. - Projectile 4 - Assault 3 - RTA 1 NA 5 days F 16 Case report Simon Deehan 2002 1 22 M 1 10 mg, IV NA - Increase ICP - Raised MAP RTA 3 4 days Case report Thomas Altmayer, 1996 1 22 M 1 10mg, IV Cisapri de None RTA 9 69 days GCS: Glasco coma scale RTA: road traffic accident *Not defined but none of which were extrapyramidal symptoms 516 Said Al Jaadi, Yahya Al Kindi, Tariq Al-Saadi Table 2. Summary of Metoclopramide and TBI studies finings Number of patients 93 Average of age 38.5 Gender Male 48(51.6%) Female 45(48.4%) Treatment Metoclopramide only 71(76.3%) Metoclopramide and Diphenhydramine 21(22.5%) Metoclopramide and Cisapride 1(1.1%) Dose of metoclopramide 10 mg, IV 72(77.4%) 20 mg, IV 21(22.5%) Side effect Headache 42(45.2%) drowsiness 26(27.9%) Fatigue 23(24.7%) Anxiety 37(29.0%) Dystonia 5(5.3%) Increase ICP Increase MAP 1(1.1%) Mechanism of injury Not defined 70(75.2%) RTA 3(3.2%) Trip/fall 9(9.7%) Impacted stationary object, assault 7(7.5%) Projectile 4(4.3%) Undefined complication 5(5.3%) Average of the follow up 6.9(4-69) ABBREVIATION TBI: Traumatic brain injury ICP: Intracranial pressure CNS: Central nervous system GCS: Glasgow Coma Scale ER: Emergency Room RTA: Road Traffic Accident MAP: Mean Arterial Pressure REFERENCES 1. Report MW. Surveillance for Traumatic Brain Injury – Related Deaths — United States, 1997 – 2007. CDC. 2011;60(5):1997–2007. 2. Moezzi M, Delirrooyfard A, Motamed H, Mortazavi MK, Specialist EM. Antiemetic effects of metoclopramide with and without dexamethasone in children with minor head trauma: a single blind randomized clinical trial. 2018;188(December):7307–13. 3. Majid Zamani, Behnam Namdar, Reza Azizkhani, Omid Ahmadi MED. Comparing the Antiemetic Effects of Ondansetron and Metoclopramide in Patients with Minor Head Trauma. In 2015. p. 137–40. 4. Friedman BW, Babbush K, Irizarry E, Gallagher EJ, Health M. An exploratory study of IV metoclopramide + diphenhydramine for acute post-traumatic headache. 2019;36(2):285–9. 5. Maegele M, Lefering R, Sakowitz O, Kopp MA, Schwab JM, Steudel WI, et al. Inzidenz und Versorgung des mittelschweren bis schweren Schädel-Hirn-Traumas. Dtsch Arztebl Int. 2019 Mar 8;116(10):167–73. 6. Dickerson RN, Mitchell JN, Morgan LM, Maish GO, Croce MA, Minard G, et al. Disparate response to metoclopramide therapy for gastric feeding intolerance in trauma patients with and without traumatic brain injury. J Parenter Enter Nutr. 2009 Nov;33(6):646–55. 7. Medical Science News: Fda Requires Boxed Warning and Risk Mitigation Strategy for Metoclopramide- Containing Drugs [Internet]. [cited 2020 Apr 20]. Available from: https://elbiruniblogspotcom.blogspot .com/2009/02/fda-requires-boxed-warning-and- risk.html 8. Nursal TZ, Erdogan B, Noyan T, Cekinmez M, Atalay B, Bilgin N. The effect of metoclopramide on gastric emptying in traumatic brain injury. J Clin Neurosci. 2007 Apr;14(4):344–8. 517 Safety of metoclopramide in traumatic brain injury patients 9. van der Meer YG, Venhuizen WA, Heyland DK, van Zanten ARH. Should we stop prescribing metoclopramide as a prokinetic drug in critically ill patients? Crit Care. 2014 Sep 23;18(5). 10. Zamani M, Namdar B, Azizkhani R, Ahmadi O, Esmailian M. Comparing the Antiemetic Effects of Ondansetron and Metoclopramide in Patients with Minor Head Trauma. Emerg (Tehran, Iran) [Internet]. 2015 [cited 2020 Apr 20];3(4):137–40. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26495402 11. Makkar JK, Gauli B, Jain K, Jain D, Batra YK. Comparison of erythromycin versus metoclopramide for gastric feeding intolerance in patients with traumatic brain injury: A randomized double-blind study. Saudi J Anaesth. 2016 Jul 1;10(3):308–13. 12. Friedman BW, Babbush K, Irizarry E, White D, John Gallagher E. An exploratory study of IV metoclopramide + diphenhydramine for acute post-traumatic headache. Am J Emerg Med. 2018 Feb 1;36(2):285–9. 13. Hale TW, Kendall-Tackett K, Cong Z. Domperidone versus metoclopramide: Self-reported side effects in a large sample of breastfeeding mothers who used these medications to increase milk production. Clin Lact. 2018;9(1):10–7. 14. Shakhatreh M, Jehangir A, Malik Z, Parkman HP. Metoclopramide for the treatment of diabetic gastroparesis. Expert Rev Gastroenterol Hepatol. 2019 Aug 3;13(8):711–21. 15. Jolliet P, Nion S, Allain-Veyrac G, Tilloy-Fenart L, Vanuxeem D, Berezowski V, et al. Evidence of lowest brain penetration of an antiemetic drug, metopimazine, compared to domperidone, metoclopramide and chlorpromazine, using an in vitro model of the blood- brain barrier. Pharmacol Res. 2007 Jul;56(1):11–7. 16. Deehan S, Dobb GJ. Metoclopramide-induced raised intracranial pressure after head injury. J Neurosurg Anesthesiol. 2002;14(2):157–60.