Emergency. 2018; 6 (1): e21 OR I G I N A L RE S E A RC H The Effect of Low-Dose Ketamine in Treating Acute Asthma Attack; a Randomized Clinical Trial Mehrdad Esmailian1, Mahboubeh Koushkian Esfahani1∗, Farhad Heydari1 1. Emergency Medicine Research Center, Al-Zahra Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran. Received: March 2018; Accepted: April 2018; Published online: 10 April 2018 Abstract: Introduction: Efficient treatment of asthma can play an important role in controlling asthma attacks, rapid recovery and decrease of patient mortality. Therefore, in the present study the therapeutic effect of low-dose ketamine is evaluated in patients with acute asthma attack. Methods: In the present single-blind, randomized clinical trial with placebo control, the effect of low-dose intravenous ketamine in treating 18 to 85 year-old asth- matic patients who presented to the emergency department was evaluated. Peak expiratory flow rate (PEFR) and the patients’ response to treatment were measured before and 1 hour after treatment. Additionally, using SPSS 22.0, effectiveness of ketamine with 0.3, 0.4, and 0.5 mg/kg doses followed by infusion of the same dose during 30 minutes were compared with placebo. Results: 92 patients were enrolled (59.8% female, mean age 48.5 ± 13.9 years). 15 (16.3%) patients were treated with 0.3 mg/kg ketamine, 14 (15.2%) with 0.4 mg/kg, and 16 (17.4%) with 0.5 mg/kg doses. Mean PEFR was 336.2 ± 101.5 liters in the placebo group and 345.8 ± 84.7 liters in the ketamine group before intervention (p = 0.6), while after intervention, they were 352.1 ± 101.2 and 415.8 ± 76.2 liters, respectively (p = 0.001). Ketamine treatment with 0.4 and 0.5 mg/kg doses led to a higher increase in PEFR compared to 0.3mg/kg dose (df: 3, 88; F = 23.8; p < 0.001). Conclusion: It seems that administration of 0.4 - 0.5 mg/kg doses of intravenous ketamine followed by infusion of the same dose during 30 minutes can be effective for rapid recovery of PEFR in patients with mild to moderate asthma. Keywords: Ketamine; asthma; efficiency; peak expiratory flow rate; emergency service, hospital © Copyright (2018) Shahid Beheshti University of Medical Sciences Cite this article as: Esmailian M, Koushkian Esfahani M, Heydari F. The Effect of Low-Dose Ketamine in Treating Acute Asthma Attack; a Randomized Clinical Trial. Emergency. 2018; 6(1): e21. 1. Introduction A sthma is a diffused obstruction of airways that may present as shortness of breath, wheezing, and cough- ing. It is one of the most common chronic illnesses, which presently affects 300 million people all over the world and this number is predicted to rise to 100 million in 2025 (1). In Iran, the average prevalence of this disease in the un- der 18-year-old population is estimated to be 13.4% (2). Clin- ical symptoms of asthma are relieved spontaneously or us- ing drugs. Comprehensive research has been done on con- trol and treatment of asthma and standard treatments have been developed. Yet, a high percentage of patients do not re- spond well to the treatments and might experience severe at- tacks and dangerous complications such as hypoxia, respira- ∗Corresponding Author: Mahboubeh Koushkian Esfahani; Department of Emergency Medicine, Al-Zahra Hospital, Soffeh Blvd, Isfahan, Iran. Tel: 00989133266313 Email: Kushkian.m@gmail.com tory arrest, and mortality. A bunch of controlling or preven- tive drugs such as steroids, inhaled beta agonists and anti- cholinergics, and short-acting theophylline are suggested for management of the patients (3). Ketamine is a well-known drug with safe and predictable sedative, analgesic, and anti- emetic effects. The half-life of this drug is 2-4 hours and it is rapidly absorbed, crosses blood-brain barrier, and exerts its effect on central nervous system (CNS) (5). It is also a bronchodilator, and using a 1-2 mg/kg dose of it has been approved as an inductive agent in rapid sequence intubation (RSI) of asthma patients (4). It protects airways and respira- tory reflexes without any disturbances to the cardiovascular system. Therefore, it may be prescribed in emergency de- partments with limited monitoring devices. The important thing about this drug is that in doses lower than 1mg/kg it does not have sedative effects, while in higher doses it can cause side effects such as apnea and laryngospasm. These side effects can be severe in 1-2% of patients and are very dose-dependent and more probable in higher doses and in- 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. Esmailian et al. 2 travenous (IV ) prescription (6). Using 1-2 mg/kg IV doses fol- lowed by 2-3 mg/kg IV infusion has been able to delay the need for intubation in pediatric asthma attack (7). Intro- ducing new ways for controlling asthma attack with the aim of rapid recovery, decreasing cost, and discharging patients from emergency department seems necessary from thera- peutic and logistic viewpoints. Therefore, the present study aims to evaluate the effect of low-dose ketamine in treatment of patients with acute asthma attack. 2. Methods 2.1. Study design and setting The present study is a single blind, randomized clinical trial with placebo control that evaluates the effect of low-dose ke- tamine in treating asthmatic patients who presented to the emergency department of Al-Zahra teaching Hospital, Isfa- han, Iran, during January to August 2016. Informed written consent was obtained from all patients included in the study. In addition, the present study was approved by the Ethics Committee of Isfahan University of Medical Sciences. The researchers adhered to the principles of Helsinki Declaration and patient data confidentiality. This study has been regis- tered on Iranian Registry of Clinical Trials (IRCT) under the number IRCT2015102912072N9. 2.2. Participants Patients with mild to moderate asthma (table 1), aged be- tween 18 to 85 years old, without any prohibition for us- ing IV ketamine and history of allergic reaction, were in- cluded. If the patient’s clinical condition worsened during the study, or needed ventilator support for respiration or showed ketamine side effects, he/she would be excluded. Non-randomized, convenience sampling was done and pa- tients were randomly allocated to intervention (IV ketamine) and control (placebo) groups using block randomization. 2.3. Intervention: All patients underwent pulse oximetry and constant moni- toring of arterial oxygen saturation, as well as oxygen therapy if needed. Both groups received basic treatments of asthma attack with standard doses including inhaled beta agonists and anticholinergics, and IV corticosteroids. The interven- tion group received IV ketamine with 0.3, 0.4, or 0.5 mg/kg doses in addition to the standard treatment. Since ketamine is colorless and odorless and its appearance is like water, dis- tilled water was used as placebo for the control group. IV ketamine vials were 10 cc in volume with 50 mg/cc concen- tration (made by ROTEXMEDICA Company, Germany). At the time of use, drug was drawn in a syringe based on the patient’s weight and the volume was then set to 5 cc using distilled water. Its injection was done during 1-2 minutes in a peripheral vein. Subsequently, the same dose was in- fused during 30 minutes. Peak expiratory flow rate (PEFR) was measured and recorded before and 1 hour after treat- ment for all patients. The method for determining PEFR was as follows: first, the device was set at 0, then it was held in a horizontal state and the patient was asked to hold the de- vice’s pipe, which was washed and disinfected before, with their lips in a manner that air could only pass through the pipe. They were then asked to forcefully blow their expira- tory flow into the peak flow meter (SIBEL, Spain) after a deep inhalation. Finally, the indicator would show a number rep- resenting the peak expiratory flow. The peak expiratory flow for each patient was then compared to their expected natu- ral flow based on their sex, age, and height, and if it was lower than 70% of the normal rate, the case was considered as acute asthma attack. The peak flow meter number was read and re- ported by one person, for all patients. Response to treatment was determined based on PEFR an hour after treatment ini- tiation and was rated as good (PEFR > 70%), partial (40% < PEFR < 69%), and poor (PEFR < 40%) (table1). 2.4. Data gathering A senior emergency medicine resident was responsible for data gathering using a check list that consisted of demo- graphic data (sex, age), possible side effects of ketamine, and PEFR of patients before and 1 hour after intervention. 2.5. Statistical Analysis The sample size calculated for this study was 60 cases con- sidering Zα =1.96, Zβ = 0.84, S = 59, d = 30. Data were en- tered to SPSS 22.0. After making sure data distribution was normal using Kolmogorov–Smirnov test (p = 0.62), they were presented as mean and standard deviation for quantitative data and frequency and percentage for qualitative data. In- dependent t-test was used for comparison of PEFR between the ketamine and placebo groups. In addition, to evaluate the efficiency of various ketamine doses (0.3, 0.4, 0.5 mg/kg) one-way ANOVA was used. In all tests, p < 0.05 was consid- ered significant. 3. Results 92 patients were enrolled (59.8% female, mean age 48.5 ± 13.9 years). 47 (51.1%) of the patients were in the placebo group and 45 (48.9%) in the ketamine group. 15 (16.3%) pa- tients were treated with 0.3 mg/kg ketamine, 14 (15.2%) with 0.4 mg/kg, and 16 (17.4%) with 0.5 mg/kg doses. Age distri- bution between the studied groups was not significantly dif- ferent (p = 0.09) but sex distribution significantly differed (p = 0.01). Since patient’s sex is entered in the formula for cal- culation of PEFR, this difference in distribution is adjusted for the analyses. Mean PEFR was 336.2 ± 101.5 liters in the 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): e21 Table 1: Definitions and measurement PEFR * PEFR was measured using a peak flow meter and the normal rate varies a little based on sex, age, and height of the patient Asthma attack Acute attack: PEFR < 70% Mild to moderate attack: 40% < PEFR < 69% Severe attack: PEFR < 40% Response to treatment Good response: PEFR > 70% Partial response: 40% < PEFR < 69% Poor response: PEFR < 40% Apnea Oxygen saturation dropping to < 85% for at least 3 seconds or de- crease in respiratory rate to < 8 /minute *: Peak expiratory flow rate. Table 2: Comparing mean change in peak expiratory flow rate (PEFR) in different groups Group PEFR Change P* Before After Placebo 336.2 ± 101.5 352.1 ± 101.2 16.0 ± 30.5 Ref 0.3 mg/kg ketamine 325.3 ± 48.1 367.3 ± 56.9 42.0 ± 23.0 0.17 0.4 mg/kg ketamine 396.4 ± 89.4 443.6 ± 67.9 52.9 ± 45.0 0.02 0.5 mg/kg ketamine 320.6 ± 91.9 431.9 ± 80.2 111.3 ± 62.8 < 0.001 *, significance level has been reported based on comparison with the placebo group. Data were presented as mean ± standard deviation. placebo group and 345.8 ± 84.7 liters in the ketamine group before intervention (p = 0.6), while after intervention, they were 352.1 ± 101.2 and 415.8 ± 76.2 liters, respectively (p = 0.001). Treatment with low-dose ketamine has significantly increased PEFR compared to placebo (p < 0.0001). PEFR be- fore intervention was not significantly different between the placebo group and different ketamine dose groups (df: 3, 88; F = 2.2; p = 0.1). However, ketamine treatment with 0.4 mg/kg (p = 0.02) and 0.5 mg/kg (p < 0.001) doses led to a significant increase in PEFR compared to placebo. PEFR changes in the 0.3 mg/kg dose group did not differ from the placebo group (df: 3, 88; F = 23.8; p = 0.17) (table 2). Side effects of ketamine were not observed in any of the patients. 4. Discussion The findings of the present study reveal that treatment of asthma with low-dose ketamine increases PEFR. This rise is significant in 0.4 and 0.5 mg/kg doses. 0.5 mg/kg dose had higher efficiency compared to the 0.4 mg/kg dose. As we have mentioned before, asthma is one of the most common chronic illnesses all over the world. Based on the involvement of the area, symptoms vary between a wheez- ing sound to airway obstruction. Severe asthma can lead to respiratory deficiency and need for ventilator. Inhaled corti- costeroids are among the drugs suggested for asthma treat- ment in children and adults (8-11). To open the bronchial airways in asthmatic patients, ketamine may also be help- ful. The first effective use of this drug in relieving pediatric asthma has been reported about 30 years ago (12). In var- ious studies, ketamine has been suggested as an inductive agent for endotracheal intubation in asthma patients due to its benefits for bronchial airway stabilization. Its serial injec- tion will provide better results (4, 13-17). Ketamine increases respiratory rate and subsequently, oxygen pressure, and de- creases CO2 pressure, which leads to asthma symptom relief (18). Its most important probable side effects include halluci- nation, agitation, apnea, and laryngospasm (6). In a study by Huber et al., after ketamine prescription a two third increase in airway stability was reported (19). In a study to evaluate the effectiveness of ketamine in symptom relief and pediatric asthma indices, 1 mg/kg dose of ketamine on admission and 0.75 mg/kg dose during the first hour were intravenously ad- ministered and the patients’ vital signs, PEFR, and clinical asthma score were evaluated. The results showed that in all the afore-mentioned indices, after IV ketamine administra- tion, asthma symptoms were relieved (17). In a clinical trial by Howton et al. IV administration of low-dose ketamine with 0.2 mg/kg dose and repeated injection of 0.5 mg/kg dose 3 times per hour in patients over 18 years old, had a significant effect on respiratory rate, respiratory flow, and Berg’s score of asthmatic patients compared to the placebo group. While in a similar study with the same initial dose and twice a day in- jection with 0.5 mg/kg dose, asthmatic children’s condition did not significantly improve (20). The effect of low- dose ke- tamine in adults who were not ventilator-dependent showed 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. Esmailian et al. 4 that this drug is generally effective for relieving bronchial airway spasms and increasing blood oxygen saturation, al- though in some cases it will be accompanied by side effects such as hallucination, agitation and increase in pulmonary secretions (16). Some have reported ketamine to be the drug that makes asthmatic children independent of mechanical ventilators (7). Based on the findings of this study, it seems that administration of 0.4 and 0.5 mg/kg doses of ketamine can have beneficial effects in asthma symptom relief com- pared to the placebo group. 5. Limitation The present study had some limitations such as small num- ber of patients in each group of ketamine doses, which makes interpretation and generalization of the results difficult. Fur- ther study on the subject with a larger number of participants and more accurate methodology is suggested to make the findings more generalizable. 6. Conclusion It seems that administration of 0.4 - 0.5 mg/kg doses of IV ketamine followed by infusion of the same dose during 30 minutes can be effective for rapid recovery of PEFR in mild to moderate asthma patients. 7. Appendix 7.1. Acknowledgements None. 7.2. Author contribution All the authors meet the standard authorship criteria accord- ing to the recommendations of international committee of medical journal editors. 7.3. Funding/Support None. 7.4. Conflict of interest The authors declare that there is no conflict. References 1. Masoli M, Fabian D, Holt S, Beasley R. 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Southern medical journal. 1972;65(10):1176-80. 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): e21 20. Howton JC, Rose J, Duffy S, Zoltanski T, Levitt MA. Ran- domized, double-blind, placebo-controlled trial of intra- venous ketamine in acute asthma. Annals of emergency medicine. 1996;27(2):170-5. 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 Introduction Methods Results Discussion Limitation Conclusion Appendix References