- Email: [email protected]
Randomized, Double-Blind, Placebo-Controlled Trial of Intravenous Ketamine in Acute Asthma
GENERAL CLINICAL I N V E S T I G A T I O N / O R I G I N A L CONTRIBUTION
Randomized, Double-Blind, Placebo-Controlled Trial of Intravenous Ketamine in Acute Asthma From the Department of Emergency Medicine, Alameda County Medical Center, Highland Campus, Oakland, California.
Joseph C Howton, MD John Rose, MD Scott Daffy. MD Tom Zoltanski
Receivedfor publication November 28, 1994. Revision receivedAugust 16, 1995. Accepted for publication August 24, 1995.
M Andrew Levitt, DO
Presented at the Societyfor Academic Emergency Medicine Annual Meeting, Washington DC, May 1994. Copyright © by the American College of Emergency Physicians.
Study objective: To evaluate the efficacy of IV ketamine in the management of acute, severe asthma. Methods: This prospective, randomized, double-blind, placebocontrolled clinical trial at an urban teaching hospital emergency department involved 53 consecutive patients aged 18 to 65 with a clinical diagnosis of acute asthmatic exacerbation and a peak expiratory flow of less than 40% of the predicted value after three albuterol nebulizer treatments. All patients received oxygen, continuous nebulized albuterol, and methylprednisolone sodium succinate {Solu-Medrol). Patients then received either ketamine hydrochloride in a bolus of .2 mg/kg followed by IV infusion of .5 mg/kg per hour for 3 hours or a placebo bolus and infusion for 3 hours. Becauseof the occurrence of dysphoric reactions, the bolus dose was lowered to .1 mg/kg after the first 9 patients; the infusion dose was kept the same. Results: The first nine patients were eliminated from analysis. Repeated AN0VA testing on the remaining 44 patients determined significant improvements over time within each treatment group in peak flow (F=3.637, P=-.O04),Borg score (F=22.959, P=-.O001), respiratory rate (F=8.11, P=-.O001), and 1-secondforced expiratory volume (F=9.076, P=-.O001). However, no difference could be detected over time between treatment groups (power, 80%). Patients receiving ketamine gave the treatment a rating of 4.3 on a scale of 1 to 5, whereas those receiving placebo scored their treatment 3.7 (P=.0285).The hospital admission rate was not different between treatment groups (P=-.1088).
Conclusion: IV ketamine at a dose low enough to avoid dysphoric reactions demonstrated no increased bronchodilatory effect compared with standard therapy in treating exacerbations of asthma in the ED. Although there was a slight increase in satisfaction in the ketamine group, no clinical benefit in terms of hospital admission rate was noted. [Howton JC, RoseJ, Duffy S, Zoltanski T, Levitt MA: Randomized, double-b~ind,placebo-controlledtrial of intravenous
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ketamine in acute asthma. Ann EmergMedFebruary1996; 27:170-175.]
INTRODUCTION Despite advances in the understanding of asthma, morbidity and mortality continue to rise, 1 and treatment options for the patient with severe refractory asthma remain limited. Many authors have described the use of ketamine as an induction agent for intubation in severe asthma. There have been reports of rapid recovery after ketamine infusion for patients in status asthmaticus who were mechanically ventilated. 2-* Other reports have attributed the avoidance of intubation to ketamine after standard intensive modalities failed. 5 However, there has been no placebo-controlled, double-blind study of the role of ketamine in the management of acute asthma in the nonintubated patient. This study was designed to investigate whether ketamine in a dose low enough to avoid dysphoria could serve as a useful adjunct to conventional emergency department therapy for severe asthma. Accordingly, a clinical trial was performed to determine the safety and efficacy of ketamine plus standard therapy compared with standard therapy alone. The null hypothesis was that the addition of ketamine would not improve spirometric function or rate of hospitalization compared with placebo.
MATERIALS AND METHODS The study was designed as a randomized, doubleblind, placebo-controlled trial. It was conducted exclusively in the Emergency Department of Alameda County Medical Center, Highland Campus, an innercity county teaching hospital with an annual census of 70,000. Patients between 18 and 65 years of age who presented with a clinical diagnosis of exacerbation of asthma were considered for the study. Asthma was diagnosed according to the criteria of the American Thoracic Society's Committee on Diagnostic Standards for Nontuberculous Respiratory Disease. 6 Patients were excluded for history of chronic obstructive pulmonary disease, need for emergency intubation, hypertension, coronary artery disease, hyperthyroidism, pregnancy, psychiatric disorder, inability to perform bedside spirometry, or known allergy to ketamine. The study protocol was approved by the Institutional Review Board of the Alameda County Medical Center.
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On presentation, patients were given standard therapy for asthma exacerbation, which includes oxygen, bedside peak expiratory flow measurements, albuterol nebulizer treatments (0.5 mg in 2.5 mL saline solution) at a rate of one every 20 minutes, and methylprednisolone sodium succinate (Solu-Medrol) 125 mg intravenously. Patients with a peak expiratory flow of less than 40% of the predicted value after three nebulizer treatments were entered into the study. A study investigator, on call 24 hours per day, obtained informed written consent and initiated the study protocol. Before the protocol was begun, baseline measurements were obtained for blood pressure, pulse, respiratory rate, temperature, pulse oximetry, Borg visual analog assessment for subjective severity of dyspnea 7, mental status scoring, and spirometry (peak flow, 1-second forced expiratory volume [FEV1], and forced vital capacity [FVC]). Data measurements were then obtained at 15 minutes, 30 minutes, 1 hour, 2 hours, and 3 hours. Spirometry was performed with a Respirodyne Digital Spirometer; the best of three attempts was used in calculations. The patient was placed on a continuous albuterol nebulizer at 10 mr/hour. Vials of ketamine hydrochloride (10 mg/mL) or normal saline placebo were prepared by the pharmacy. Contents of each vial were assigned according to a randomization table. The dose used in the ketamine infusion was derived from case reports and from studies of ketamine use in nonintubated patients. 5,8 Patients received either an IV bolus of ketamine hydrochloride at .2 mg/kg over a 5-minute period, followed by an infusion of the same drug at .5 mg/kg per hour, or a placebo bolus and infusion. Of the first 9 patients, 6 received ketamine and 3 placebo; 3 of the 6 patients who received ketamine became dysphoric during the administration of the bolus. The bolus dose was lowered to. 1 mg/kg over 5 minutes for the remaining patients who received ketamine; the infusion dose was kept the same. Each patient was monitored by a study investigator for the entire duration of the study drug infusion. The study was terminated at 3 hours. No rigid criteria were used to determine the need for admission to the hospital. The decision for admission or discharge was made by the treating physician in the ED on the basis of the patient's overall clinical picture, including the home environment and the patient's ability to return if symptoms worsened. Patients and ED physicians were asked to complete a questionnaire regarding their impression of the treatment. A scale of 1 to 5 was used: a 5 indicated the opin-
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KETAMINE IN ASTHMA Flowton et al
ion that the regimen was "much better than standard therapy;" 3 indicated "same as standard therapy;" and 1 was "much worse than standard therapy." Patients were interviewed by telephone after 2 weeks to monitor for adverse outcomes, such as nightmares, and the need for subsequent admission. The subset of the sample population who received ketamine was compared with subjects who received placebo. Means and variances of interval level data were compared by Student's t test. Frequency calculations of nominal data were compared by Z2 testing with Yates' correction. Values obtained for the Borg score were analyzed with the Mann-Whitney U test. Continuous data that had multiple measures obtained over time were found to achieve a normal distribution in the study and were analyzed by repeated- measure ANOVA testing for betweengroup and within-group differences. FEV1 was the primary outcome variable used for sample size calculations. Variability was estimated at 23% on the basis of our institution's clinical experience @x=.05, 6=.2 to detect a 20% difference between groups). A post hoc power analysis was done. The power of this study was calculated to be 80% at an s-level of .05 to detect a 20% difference in efficacy. RESULTS
Fifty-three patients were entered into the study protocol. After the first 9 patients had been entered, it was noted by the investigators that there had been three episodes of dysphoric reactions. At this time, the code was broken for these first 9 patients, and it was found that all three
episodes occurred in patients receiving ketamine (accounting for 50% of the ketamine group). The bolus infusion dose was then lowered from .2 mg/kg to. 1 mg/kg. The bolus part of the protocol was changed because the reactions appeared to occur just after the bolus was infused. The second phase of this study, with the adjusted bolus dose, included 44 patients: 23 were randomly assigned to the ketamine group and 21 to the placebo group. Baseline characteristics of the study and control groups are listed in Table 1; the groups appeared to be similar with no statistically significant differences. Likewise, there was no statistically significant difference in competing interventions such as theophylline, ipratropium bromide (Atrovent), or magnesium. Repeatedmeasures ANOVA was applied to the continuous measurements over time of pulse, respiratory rate, systolic blood pressure, diastolic blood pressure, peak flow, FEV 1, and Borg score. There were statistically and clinically significant improvements over time within each treatment group in peak flow (F=3.637, P=.0001), Borg score (F=22.959, P=.0001), respiratory rate (F=8.11, P=.0001), and FEV 1 (F=9.076, P=.0001). However, no significant differences could be detected between treatment groups in any of the measured parameters over time. Table 2 illustrates the changes over time between groups and within groups in each of the measured clinical parameters. There was no statistically significant difference in the rate of adverse reactions between groups, although there was a tendency toward Table 2.
Clinical parameters.
Table 1.
*
Baseline characteristics. Variable Characteristic Age Weight (kg) Sex (M/F) Smoking history (pack-years) Previoushospitalization (%) Hours of symptoms Initial peak flow rate (L/minute) Initial FEV1 (L/second) Initial systolic blood pressure (mm Hg) Initial diastolic blood pressure (ram Hg) Initial heart rate Initial respiratory rate Initiat Borg score
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Ketamine (n=23)
Placebo (n-,21)
P
34.5!-9.7 76.9_+17.4 14/9 15.8_+17.8 65,2 85_+117 139_+53 .75_+.3 140_+24
33.4_+6.8 77.3_+21.7 17/7 11.2_+15.7 71.4 47_+46 124_+49 .62+.4 141_+19
.6788 .9644 .6897 .5884 .6586 ,1641 .3844 .2795 .9851
84_+15
86_+13
.6128
120_+21 28_+7 6.0+2.0
114_+16 30+10 6.3_+3.0
.3500 .4725 .7464
Ketamine
Placebo
Initial respiratory rate 28.4_+6.9 30.1+10.3 Final respiratory rate 23.7_+3.5 24.4_+6.1 Initial systolic blood pressure(mm Hg) 141.1_+24.1 141.0_+19.8 Final systolic blood pressure (mm Hg) 140.5-+16.9 131.9-+3.6 Initial diastolic pressure (mm Hg) 84.0_+16.0 86.6-+13.0 Final diastolic pressure (mm Hg) 81.9_+11.4 78.6-+13.0 Initial heart rate 120.5+_21.8 114.4_+16.0 Final heart rate 114.2_+16,5 113.~14,1 Initial Borg score 6.0_+2.0 6.3_+3.0 Final Borg score 2.6_+1.3 3.5-+1.7 Initial peak flow (L/minute) 139.0_+53.0(116-162)t 124.0_+49.0(182-146) Final peak flow (L/minute) 158.1_+47.9(137-179)163.1_+90.5(122-204) Initial FEV1 (L/second) .75_+.33(.61-.89) .62_+.39(.44-.80) Final FEV1 (L/second) .92_+.34(.77-1.07) 1.0_+.6(33-1.27) *All Pvalues are nonsignificant between groups. tValues in parenthesesare 95% confidence intervals.
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increased adverse reactions in the ketamine group compared with the placebo group (17.4% [95% CI, 4.9538.8] and 4.8% [95% CI, 12.0-23.8], respectively; P=. 1880). A difference was detected in patient assessment scores. The ketamine group rated the treatment regimen for their asthmatic episode more favorably than did the control group (4.3+_.6 versus 3.74-1.2, respectively; P=.0285). Physician rating of treatment success on a scale of 1 to 5 was 3.7+_.6 for the ketamine group and 3.4_+.7 for the placebo group (P=NS). Two patients from each group dropped out of the study and were not included in the analysis. Hospital admission rates were not statistically significant between groups (ketamine group 87% [95% CI, 66,4-97.2]; placebo group, 66.7% [95% CI, 43.0-85.4], P=. 1088). However, there was a tendency for the ketamine group to undergo hospital admission more frequently. DISCUSSION
Ketamine was structurally derived from phencyclidine in 1963 and introduced into general clinical practice in 1970. It has been used by anesthesiologists and other physicians as an induction agent before administration of general anesthetics. It has also been used as the primary anesthetic for short, painful procedures. The serendipitous finding that ketamine was a powerful bronchodilator was first reported by Betts and Parkin in 1971. 9 Since then, there have been numerous case reports of the value of ketamine in severe asthma. 2,5,8,1°15 The mechanism of ketamine's bronchodilating effect is considered to be a combination of drug-induced increase in circulating catecholamines, direct smooth muscle relaxation, and inhibition of vagal outflow. 16,17 In addition, ketamine increases bronchial secretions, which may help to prevent mucous plugging, although this effect has never been studied. A well-known side effect of ketamine is its propensity to cause vivid dreams and "out of body" experiences, which have been termed "emergence reactions." For standard anesthesia induction doses of i to 2 mg/kg intravenously, the incidence of emergence reactions has been reported to range from 0% to 50% in adults and from 0% to 16% in children. Although some patients have dreams they describe as pleasurable, others may have unpleasant, scary experiences. The negative experiences can be minimized by explaining to the patient what to expect and by using a lower dose and slower bolus. Benzodiazepines are also useful in preventing
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emergence reactions. We did not use benzodiazepines in this study because of the theoretic risk of inhibiting respiratory drive in asthmatic patients. Instead, we sought a dose of ketamine that would be low enough to avoid emergence phenomena while still demonstrating any potential benefits on pulmonary dynamics that ketamine may offer. The initial bolus dose used in this study was .2 mg/kg ketamine over 5 minutes. Three of the six patients receiving this dose complained of uncomfortable and scary sensations. After the initial bolus dose was lowered to. 1 mg/kg, followed as before by an infusion over 3 hours at .5 mg/kg, the ketamine was better tolerated. Adverse reactions were more common in the ketamine group than in the placebo group (19% versus 5%, P=. 1880); the most common adverse reactions were dysphoria and dizziness. Mthough this difference did not achieve statistical significance, it suggests that many patients may experience uncomfortable reactions with ketamine, even at very low doses. Nevertheless, when patients were asked, "Is the current treatment better than your usual therapy?" patients preferred the ketamine over placebo. There were no significant differences in pulmonary function tests between the ketamine and placebo groups. Three patients were intubated in the placebo group and only one in the ketamine group, but this difference did not achieve statistical significance. Conversely, the ketamine group had a higher rate of hospital admission, but this again did not achieve statistical significance. If ketamine had truly increased the rate of hospital admission, this would be a strong detriment to its value in the ED. Whether ketamine actually affects admission rate is a difficult question to answer, because the decision whether to admit patients in this study was not based on any rigid criteria. Patients were admitted on the basis of their response to therapy in the ED, their home situation and ability to return if symptoms worsened, and their history of prior severe asthma attacks. Another factor was the degree of aggressiveness of the consulting internal medicine resident in pursuit of outpatient management. The possibility of ]3-error exists, with not enough power to detect statistical significance in this subgroup analysis. The study found a small difference in how the patients rated their treatments. Although the difference was statistically significant, its clinical significance is questionable. There are several possible reasons why some
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patients may have preferred the ketamine therapy over placebo. At low doses, ketamine may have a mildly sedating effect, which may help to calm the anxious patient with asthma and make it seem subjectively as if they are breathing more easily without a true change in the severity of their illness. On the other hand, anxiolytics may reduce the severity of an asthma attack; it is known that anxiety can precipitate or worsen bronchospasm. 18 Another possibility is that low-dose ketamine may have clinical benefits for the asthmatic patient that may be perceived by the patient but not detected on spirometric testing. Because ketamine is widely recommended as an induction agent for intubation of the asthmatic patient in extremis, a trial of a low-dose ketamine bolus (. 1 to .2 mg/kg slow IV push) just before intubation may be worth considering. If the patient responds in a favorable manner, intubation may be avoided. If there is no rapid improvement, the patient can be intubated as would have been done anyway. Although the full induction dose of i to 2 mg/kg ketamine could then be given either before or immediately after intubation, clinical judgment should guide its timing. For the hypoxic, apneic patient, rapid sequence intubation would need to be performed without any delay. Further research is needed to clarify the role of ketamine in the management of severe asthma in the ED. Ketamine may have utility in the management of pediatric asthma, because children are much less prone to ketamineAnduced dysphoria than adults. Perhaps higher doses of ketamine could safely be given to children, which would be more likely to produce any beneficial bronchodilatory effects of the drug. There are some ways in which the study could have been improved. The sample size of 44 has a 20% chance of producing a type II error in detecting a 20% difference in treatment efficacy on the basis of peak flow improvement. A larger sample size would have reduced the risk of such an error. It is known that the S(+) optical isomer of ketamine causes a lower incidence of emergence reactions than the commercial, racemic mixture. 19 If the study were to be repeated using this isomer instead of racemic ketamine, it may be that a higher dose could be used to produce any potential salutary effects for asthma treatment while avoiding the major limitation of dysphoria. However, it is almost impossible to obtain isolates of the S(+) isomer at this time. A different approach would be to give benzodiazepines concomitant with the ketamine
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infusion; this combination could also permit use of a higher dose of ketamine. In this study, ketamine at a dose low enough to avoid dysphoric reactions demonstrated no measurable increase in bronchodilatory effect compared with standard therapy. There were an increased number of adverse reactions and admissions in the ketamine group, and a decreased number of intubations, but none of these differences achieved statistical significance. Some patients appeared to prefer ketamine over placebo as an adjunct to standard asthma therapy in the ED. However, on the basis of our findings, we do not recommend the routine use of low-dose ketamine as an adjunct for the management of asthma in the ED in adults. Further studies are needed to determine the feasibility of S(+) ketamine and the use of ketamine in the pediatric asthma population. REFERENCES 1. Spitzer WO, Suissa S, Ernst P, et al: The use of beta-agonists and the risk of death and near death from asthma. N EnglJ Med 1992;326:501-506. 2. Turnpenny PD, Nash SF: Ketamine in severe acute asthma (letter). Arch EmergMed 1991;8:291-292. 3. Park GR, Manara AR, Mendel L, et al: Ketamine infusion: Its use as a sedative, inotrope and bronchodilator in a critically ill patient. Anaesthesia1987;42980-983. 4. Sheref SE: Ketamine and bronchospasm(letter). Anaesthesia1985;40:701-702. 5. Strube PJ, Hallam PL: Ketamineby continuous infusion in status asthmaticus. Anaesthesia 1986;41:1017-1019. 6. Committee on Diagnostic Standards for Nontuberculous Respiratory Disease: Standards for the diagnosis and care of patients with chronicobstructivepulmonary disease (COPD) and asthma. Adoptedby the Board of Directors of the American ThoracicSociety, November 1980, Am RevRespirOis 1987;136:225-244. 7. Wilson RC, Jones PW: A comparison of the visual analogue scale and modified Borg scale for the measurementof dyspnea during exercise. Clio Sci 1989;76:277-282. 8. Sarma VJ: Use of ketamine in acute severe asthma. Acta AnaesthesiolScand 1992;36:106-107. 9. Betts EK, Parkin CE: Use of ketamine in an asthmatic child: A case report. Anesth Analg 1971;50:420-421. 10. Hemmingsen C, Nielsen PK, OdoricoJ: Ketamine in the treatment of bronchospasm during mechanical ventilation. Am J EmergMed 1994;12:417-420. 11. Boysen K, Strom J J, Eskildsen PC: Status asthmaticus treated with ketamine (in Danish).
UgeskrLaeger1987;149:2023-2024. 12. Gram-HansenP, Klausen NO: Ketamine in the treatment of severe therapy-resistant status asthmaticus (in Danish). UgeskrLaeger1988; 150:492-493. 13. Jorgensen BG: Ketamine as a broncholytic agent in status asthmaticus and as an anesthetic for patients with bronchial asthma (in Danish). UgeskrLaeger1992;154:2132-2135. 14. Kruger AD, Benad G: The treatment of status asthmaticus using ketamine: Experimental results and clinical experience (in German). Anaesthesio/Reanim1992;17:109-130. 15. L'Hommedieu CS, Arens J J: The use of ketamine for the emergencyintubation of patients with status asthmaticus. Ann EmergMed1987;16:568-571. 16. Hirshman CA, Downes H, FarboodA, et ah Ketamine block of bronchospasm in experimental canine asthma. Br J Anaesth 1979;51:713-718. 17. Huber FC, Gutierrez J, Corssen G: Ketamine: Its effect on airway resistance in man. South Med J 1972;65:1176-1180.
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18. PicadeC, MontserratJM, de PabloJ, et el: Predisposingfactorsto deathafterrecovery froma life-threateningasthmaticattack.JAsthma1989;26:231-236. 19. White PF,WayWL, TrevorAJ: Ketamine:Its pharmacologyandtherapeuticuses. Anesthesiology1982;56:119-136. The authors thank Ray Dawkins, MD; Shawn Bullock, MD; Boss Simkovur, PharmD; GaryYoung, MD; and Jim Fink, RRT,for their enthusiasm and support. Special thanks to the nurses in the ED at Highland General Hospital for their interest and help with the study. Reprint no. 47/1/69972 Address for reprints:
Joseph C Howton,MD EmergencyDepartment Lutheran Hospital 8300 West 38th Avenue Wheat Ridge,Colorado80033
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Randomized, Double-Blind, Placebo-Controlled Trial of Intravenous Ketamine in Acute Asthma From the Department of Emergency Medicine, Alameda County Medical Center, Highland Campus, Oakland, California.
Joseph C Howton, MD John Rose, MD Scott Daffy. MD Tom Zoltanski
Receivedfor publication November 28, 1994. Revision receivedAugust 16, 1995. Accepted for publication August 24, 1995.
M Andrew Levitt, DO
Presented at the Societyfor Academic Emergency Medicine Annual Meeting, Washington DC, May 1994. Copyright © by the American College of Emergency Physicians.
Study objective: To evaluate the efficacy of IV ketamine in the management of acute, severe asthma. Methods: This prospective, randomized, double-blind, placebocontrolled clinical trial at an urban teaching hospital emergency department involved 53 consecutive patients aged 18 to 65 with a clinical diagnosis of acute asthmatic exacerbation and a peak expiratory flow of less than 40% of the predicted value after three albuterol nebulizer treatments. All patients received oxygen, continuous nebulized albuterol, and methylprednisolone sodium succinate {Solu-Medrol). Patients then received either ketamine hydrochloride in a bolus of .2 mg/kg followed by IV infusion of .5 mg/kg per hour for 3 hours or a placebo bolus and infusion for 3 hours. Becauseof the occurrence of dysphoric reactions, the bolus dose was lowered to .1 mg/kg after the first 9 patients; the infusion dose was kept the same. Results: The first nine patients were eliminated from analysis. Repeated AN0VA testing on the remaining 44 patients determined significant improvements over time within each treatment group in peak flow (F=3.637, P=-.O04),Borg score (F=22.959, P=-.O001), respiratory rate (F=8.11, P=-.O001), and 1-secondforced expiratory volume (F=9.076, P=-.O001). However, no difference could be detected over time between treatment groups (power, 80%). Patients receiving ketamine gave the treatment a rating of 4.3 on a scale of 1 to 5, whereas those receiving placebo scored their treatment 3.7 (P=.0285).The hospital admission rate was not different between treatment groups (P=-.1088).
Conclusion: IV ketamine at a dose low enough to avoid dysphoric reactions demonstrated no increased bronchodilatory effect compared with standard therapy in treating exacerbations of asthma in the ED. Although there was a slight increase in satisfaction in the ketamine group, no clinical benefit in terms of hospital admission rate was noted. [Howton JC, RoseJ, Duffy S, Zoltanski T, Levitt MA: Randomized, double-b~ind,placebo-controlledtrial of intravenous
1 70
ANNALS OF EMERGENCYMEDICINE 27:2 FEBRUARY1996
KETAMINE IN ASTHMA Howton et al
I
l llll
ketamine in acute asthma. Ann EmergMedFebruary1996; 27:170-175.]
INTRODUCTION Despite advances in the understanding of asthma, morbidity and mortality continue to rise, 1 and treatment options for the patient with severe refractory asthma remain limited. Many authors have described the use of ketamine as an induction agent for intubation in severe asthma. There have been reports of rapid recovery after ketamine infusion for patients in status asthmaticus who were mechanically ventilated. 2-* Other reports have attributed the avoidance of intubation to ketamine after standard intensive modalities failed. 5 However, there has been no placebo-controlled, double-blind study of the role of ketamine in the management of acute asthma in the nonintubated patient. This study was designed to investigate whether ketamine in a dose low enough to avoid dysphoria could serve as a useful adjunct to conventional emergency department therapy for severe asthma. Accordingly, a clinical trial was performed to determine the safety and efficacy of ketamine plus standard therapy compared with standard therapy alone. The null hypothesis was that the addition of ketamine would not improve spirometric function or rate of hospitalization compared with placebo.
MATERIALS AND METHODS The study was designed as a randomized, doubleblind, placebo-controlled trial. It was conducted exclusively in the Emergency Department of Alameda County Medical Center, Highland Campus, an innercity county teaching hospital with an annual census of 70,000. Patients between 18 and 65 years of age who presented with a clinical diagnosis of exacerbation of asthma were considered for the study. Asthma was diagnosed according to the criteria of the American Thoracic Society's Committee on Diagnostic Standards for Nontuberculous Respiratory Disease. 6 Patients were excluded for history of chronic obstructive pulmonary disease, need for emergency intubation, hypertension, coronary artery disease, hyperthyroidism, pregnancy, psychiatric disorder, inability to perform bedside spirometry, or known allergy to ketamine. The study protocol was approved by the Institutional Review Board of the Alameda County Medical Center.
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On presentation, patients were given standard therapy for asthma exacerbation, which includes oxygen, bedside peak expiratory flow measurements, albuterol nebulizer treatments (0.5 mg in 2.5 mL saline solution) at a rate of one every 20 minutes, and methylprednisolone sodium succinate (Solu-Medrol) 125 mg intravenously. Patients with a peak expiratory flow of less than 40% of the predicted value after three nebulizer treatments were entered into the study. A study investigator, on call 24 hours per day, obtained informed written consent and initiated the study protocol. Before the protocol was begun, baseline measurements were obtained for blood pressure, pulse, respiratory rate, temperature, pulse oximetry, Borg visual analog assessment for subjective severity of dyspnea 7, mental status scoring, and spirometry (peak flow, 1-second forced expiratory volume [FEV1], and forced vital capacity [FVC]). Data measurements were then obtained at 15 minutes, 30 minutes, 1 hour, 2 hours, and 3 hours. Spirometry was performed with a Respirodyne Digital Spirometer; the best of three attempts was used in calculations. The patient was placed on a continuous albuterol nebulizer at 10 mr/hour. Vials of ketamine hydrochloride (10 mg/mL) or normal saline placebo were prepared by the pharmacy. Contents of each vial were assigned according to a randomization table. The dose used in the ketamine infusion was derived from case reports and from studies of ketamine use in nonintubated patients. 5,8 Patients received either an IV bolus of ketamine hydrochloride at .2 mg/kg over a 5-minute period, followed by an infusion of the same drug at .5 mg/kg per hour, or a placebo bolus and infusion. Of the first 9 patients, 6 received ketamine and 3 placebo; 3 of the 6 patients who received ketamine became dysphoric during the administration of the bolus. The bolus dose was lowered to. 1 mg/kg over 5 minutes for the remaining patients who received ketamine; the infusion dose was kept the same. Each patient was monitored by a study investigator for the entire duration of the study drug infusion. The study was terminated at 3 hours. No rigid criteria were used to determine the need for admission to the hospital. The decision for admission or discharge was made by the treating physician in the ED on the basis of the patient's overall clinical picture, including the home environment and the patient's ability to return if symptoms worsened. Patients and ED physicians were asked to complete a questionnaire regarding their impression of the treatment. A scale of 1 to 5 was used: a 5 indicated the opin-
'1 7'1
KETAMINE IN ASTHMA Flowton et al
ion that the regimen was "much better than standard therapy;" 3 indicated "same as standard therapy;" and 1 was "much worse than standard therapy." Patients were interviewed by telephone after 2 weeks to monitor for adverse outcomes, such as nightmares, and the need for subsequent admission. The subset of the sample population who received ketamine was compared with subjects who received placebo. Means and variances of interval level data were compared by Student's t test. Frequency calculations of nominal data were compared by Z2 testing with Yates' correction. Values obtained for the Borg score were analyzed with the Mann-Whitney U test. Continuous data that had multiple measures obtained over time were found to achieve a normal distribution in the study and were analyzed by repeated- measure ANOVA testing for betweengroup and within-group differences. FEV1 was the primary outcome variable used for sample size calculations. Variability was estimated at 23% on the basis of our institution's clinical experience @x=.05, 6=.2 to detect a 20% difference between groups). A post hoc power analysis was done. The power of this study was calculated to be 80% at an s-level of .05 to detect a 20% difference in efficacy. RESULTS
Fifty-three patients were entered into the study protocol. After the first 9 patients had been entered, it was noted by the investigators that there had been three episodes of dysphoric reactions. At this time, the code was broken for these first 9 patients, and it was found that all three
episodes occurred in patients receiving ketamine (accounting for 50% of the ketamine group). The bolus infusion dose was then lowered from .2 mg/kg to. 1 mg/kg. The bolus part of the protocol was changed because the reactions appeared to occur just after the bolus was infused. The second phase of this study, with the adjusted bolus dose, included 44 patients: 23 were randomly assigned to the ketamine group and 21 to the placebo group. Baseline characteristics of the study and control groups are listed in Table 1; the groups appeared to be similar with no statistically significant differences. Likewise, there was no statistically significant difference in competing interventions such as theophylline, ipratropium bromide (Atrovent), or magnesium. Repeatedmeasures ANOVA was applied to the continuous measurements over time of pulse, respiratory rate, systolic blood pressure, diastolic blood pressure, peak flow, FEV 1, and Borg score. There were statistically and clinically significant improvements over time within each treatment group in peak flow (F=3.637, P=.0001), Borg score (F=22.959, P=.0001), respiratory rate (F=8.11, P=.0001), and FEV 1 (F=9.076, P=.0001). However, no significant differences could be detected between treatment groups in any of the measured parameters over time. Table 2 illustrates the changes over time between groups and within groups in each of the measured clinical parameters. There was no statistically significant difference in the rate of adverse reactions between groups, although there was a tendency toward Table 2.
Clinical parameters.
Table 1.
*
Baseline characteristics. Variable Characteristic Age Weight (kg) Sex (M/F) Smoking history (pack-years) Previoushospitalization (%) Hours of symptoms Initial peak flow rate (L/minute) Initial FEV1 (L/second) Initial systolic blood pressure (mm Hg) Initial diastolic blood pressure (ram Hg) Initial heart rate Initial respiratory rate Initiat Borg score
1 72
Ketamine (n=23)
Placebo (n-,21)
P
34.5!-9.7 76.9_+17.4 14/9 15.8_+17.8 65,2 85_+117 139_+53 .75_+.3 140_+24
33.4_+6.8 77.3_+21.7 17/7 11.2_+15.7 71.4 47_+46 124_+49 .62+.4 141_+19
.6788 .9644 .6897 .5884 .6586 ,1641 .3844 .2795 .9851
84_+15
86_+13
.6128
120_+21 28_+7 6.0+2.0
114_+16 30+10 6.3_+3.0
.3500 .4725 .7464
Ketamine
Placebo
Initial respiratory rate 28.4_+6.9 30.1+10.3 Final respiratory rate 23.7_+3.5 24.4_+6.1 Initial systolic blood pressure(mm Hg) 141.1_+24.1 141.0_+19.8 Final systolic blood pressure (mm Hg) 140.5-+16.9 131.9-+3.6 Initial diastolic pressure (mm Hg) 84.0_+16.0 86.6-+13.0 Final diastolic pressure (mm Hg) 81.9_+11.4 78.6-+13.0 Initial heart rate 120.5+_21.8 114.4_+16.0 Final heart rate 114.2_+16,5 113.~14,1 Initial Borg score 6.0_+2.0 6.3_+3.0 Final Borg score 2.6_+1.3 3.5-+1.7 Initial peak flow (L/minute) 139.0_+53.0(116-162)t 124.0_+49.0(182-146) Final peak flow (L/minute) 158.1_+47.9(137-179)163.1_+90.5(122-204) Initial FEV1 (L/second) .75_+.33(.61-.89) .62_+.39(.44-.80) Final FEV1 (L/second) .92_+.34(.77-1.07) 1.0_+.6(33-1.27) *All Pvalues are nonsignificant between groups. tValues in parenthesesare 95% confidence intervals.
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increased adverse reactions in the ketamine group compared with the placebo group (17.4% [95% CI, 4.9538.8] and 4.8% [95% CI, 12.0-23.8], respectively; P=. 1880). A difference was detected in patient assessment scores. The ketamine group rated the treatment regimen for their asthmatic episode more favorably than did the control group (4.3+_.6 versus 3.74-1.2, respectively; P=.0285). Physician rating of treatment success on a scale of 1 to 5 was 3.7+_.6 for the ketamine group and 3.4_+.7 for the placebo group (P=NS). Two patients from each group dropped out of the study and were not included in the analysis. Hospital admission rates were not statistically significant between groups (ketamine group 87% [95% CI, 66,4-97.2]; placebo group, 66.7% [95% CI, 43.0-85.4], P=. 1088). However, there was a tendency for the ketamine group to undergo hospital admission more frequently. DISCUSSION
Ketamine was structurally derived from phencyclidine in 1963 and introduced into general clinical practice in 1970. It has been used by anesthesiologists and other physicians as an induction agent before administration of general anesthetics. It has also been used as the primary anesthetic for short, painful procedures. The serendipitous finding that ketamine was a powerful bronchodilator was first reported by Betts and Parkin in 1971. 9 Since then, there have been numerous case reports of the value of ketamine in severe asthma. 2,5,8,1°15 The mechanism of ketamine's bronchodilating effect is considered to be a combination of drug-induced increase in circulating catecholamines, direct smooth muscle relaxation, and inhibition of vagal outflow. 16,17 In addition, ketamine increases bronchial secretions, which may help to prevent mucous plugging, although this effect has never been studied. A well-known side effect of ketamine is its propensity to cause vivid dreams and "out of body" experiences, which have been termed "emergence reactions." For standard anesthesia induction doses of i to 2 mg/kg intravenously, the incidence of emergence reactions has been reported to range from 0% to 50% in adults and from 0% to 16% in children. Although some patients have dreams they describe as pleasurable, others may have unpleasant, scary experiences. The negative experiences can be minimized by explaining to the patient what to expect and by using a lower dose and slower bolus. Benzodiazepines are also useful in preventing
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emergence reactions. We did not use benzodiazepines in this study because of the theoretic risk of inhibiting respiratory drive in asthmatic patients. Instead, we sought a dose of ketamine that would be low enough to avoid emergence phenomena while still demonstrating any potential benefits on pulmonary dynamics that ketamine may offer. The initial bolus dose used in this study was .2 mg/kg ketamine over 5 minutes. Three of the six patients receiving this dose complained of uncomfortable and scary sensations. After the initial bolus dose was lowered to. 1 mg/kg, followed as before by an infusion over 3 hours at .5 mg/kg, the ketamine was better tolerated. Adverse reactions were more common in the ketamine group than in the placebo group (19% versus 5%, P=. 1880); the most common adverse reactions were dysphoria and dizziness. Mthough this difference did not achieve statistical significance, it suggests that many patients may experience uncomfortable reactions with ketamine, even at very low doses. Nevertheless, when patients were asked, "Is the current treatment better than your usual therapy?" patients preferred the ketamine over placebo. There were no significant differences in pulmonary function tests between the ketamine and placebo groups. Three patients were intubated in the placebo group and only one in the ketamine group, but this difference did not achieve statistical significance. Conversely, the ketamine group had a higher rate of hospital admission, but this again did not achieve statistical significance. If ketamine had truly increased the rate of hospital admission, this would be a strong detriment to its value in the ED. Whether ketamine actually affects admission rate is a difficult question to answer, because the decision whether to admit patients in this study was not based on any rigid criteria. Patients were admitted on the basis of their response to therapy in the ED, their home situation and ability to return if symptoms worsened, and their history of prior severe asthma attacks. Another factor was the degree of aggressiveness of the consulting internal medicine resident in pursuit of outpatient management. The possibility of ]3-error exists, with not enough power to detect statistical significance in this subgroup analysis. The study found a small difference in how the patients rated their treatments. Although the difference was statistically significant, its clinical significance is questionable. There are several possible reasons why some
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patients may have preferred the ketamine therapy over placebo. At low doses, ketamine may have a mildly sedating effect, which may help to calm the anxious patient with asthma and make it seem subjectively as if they are breathing more easily without a true change in the severity of their illness. On the other hand, anxiolytics may reduce the severity of an asthma attack; it is known that anxiety can precipitate or worsen bronchospasm. 18 Another possibility is that low-dose ketamine may have clinical benefits for the asthmatic patient that may be perceived by the patient but not detected on spirometric testing. Because ketamine is widely recommended as an induction agent for intubation of the asthmatic patient in extremis, a trial of a low-dose ketamine bolus (. 1 to .2 mg/kg slow IV push) just before intubation may be worth considering. If the patient responds in a favorable manner, intubation may be avoided. If there is no rapid improvement, the patient can be intubated as would have been done anyway. Although the full induction dose of i to 2 mg/kg ketamine could then be given either before or immediately after intubation, clinical judgment should guide its timing. For the hypoxic, apneic patient, rapid sequence intubation would need to be performed without any delay. Further research is needed to clarify the role of ketamine in the management of severe asthma in the ED. Ketamine may have utility in the management of pediatric asthma, because children are much less prone to ketamineAnduced dysphoria than adults. Perhaps higher doses of ketamine could safely be given to children, which would be more likely to produce any beneficial bronchodilatory effects of the drug. There are some ways in which the study could have been improved. The sample size of 44 has a 20% chance of producing a type II error in detecting a 20% difference in treatment efficacy on the basis of peak flow improvement. A larger sample size would have reduced the risk of such an error. It is known that the S(+) optical isomer of ketamine causes a lower incidence of emergence reactions than the commercial, racemic mixture. 19 If the study were to be repeated using this isomer instead of racemic ketamine, it may be that a higher dose could be used to produce any potential salutary effects for asthma treatment while avoiding the major limitation of dysphoria. However, it is almost impossible to obtain isolates of the S(+) isomer at this time. A different approach would be to give benzodiazepines concomitant with the ketamine
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infusion; this combination could also permit use of a higher dose of ketamine. In this study, ketamine at a dose low enough to avoid dysphoric reactions demonstrated no measurable increase in bronchodilatory effect compared with standard therapy. There were an increased number of adverse reactions and admissions in the ketamine group, and a decreased number of intubations, but none of these differences achieved statistical significance. Some patients appeared to prefer ketamine over placebo as an adjunct to standard asthma therapy in the ED. However, on the basis of our findings, we do not recommend the routine use of low-dose ketamine as an adjunct for the management of asthma in the ED in adults. Further studies are needed to determine the feasibility of S(+) ketamine and the use of ketamine in the pediatric asthma population. REFERENCES 1. Spitzer WO, Suissa S, Ernst P, et al: The use of beta-agonists and the risk of death and near death from asthma. N EnglJ Med 1992;326:501-506. 2. Turnpenny PD, Nash SF: Ketamine in severe acute asthma (letter). Arch EmergMed 1991;8:291-292. 3. Park GR, Manara AR, Mendel L, et al: Ketamine infusion: Its use as a sedative, inotrope and bronchodilator in a critically ill patient. Anaesthesia1987;42980-983. 4. Sheref SE: Ketamine and bronchospasm(letter). Anaesthesia1985;40:701-702. 5. Strube PJ, Hallam PL: Ketamineby continuous infusion in status asthmaticus. Anaesthesia 1986;41:1017-1019. 6. Committee on Diagnostic Standards for Nontuberculous Respiratory Disease: Standards for the diagnosis and care of patients with chronicobstructivepulmonary disease (COPD) and asthma. Adoptedby the Board of Directors of the American ThoracicSociety, November 1980, Am RevRespirOis 1987;136:225-244. 7. Wilson RC, Jones PW: A comparison of the visual analogue scale and modified Borg scale for the measurementof dyspnea during exercise. Clio Sci 1989;76:277-282. 8. Sarma VJ: Use of ketamine in acute severe asthma. Acta AnaesthesiolScand 1992;36:106-107. 9. Betts EK, Parkin CE: Use of ketamine in an asthmatic child: A case report. Anesth Analg 1971;50:420-421. 10. Hemmingsen C, Nielsen PK, OdoricoJ: Ketamine in the treatment of bronchospasm during mechanical ventilation. Am J EmergMed 1994;12:417-420. 11. Boysen K, Strom J J, Eskildsen PC: Status asthmaticus treated with ketamine (in Danish).
UgeskrLaeger1987;149:2023-2024. 12. Gram-HansenP, Klausen NO: Ketamine in the treatment of severe therapy-resistant status asthmaticus (in Danish). UgeskrLaeger1988; 150:492-493. 13. Jorgensen BG: Ketamine as a broncholytic agent in status asthmaticus and as an anesthetic for patients with bronchial asthma (in Danish). UgeskrLaeger1992;154:2132-2135. 14. Kruger AD, Benad G: The treatment of status asthmaticus using ketamine: Experimental results and clinical experience (in German). Anaesthesio/Reanim1992;17:109-130. 15. L'Hommedieu CS, Arens J J: The use of ketamine for the emergencyintubation of patients with status asthmaticus. Ann EmergMed1987;16:568-571. 16. Hirshman CA, Downes H, FarboodA, et ah Ketamine block of bronchospasm in experimental canine asthma. Br J Anaesth 1979;51:713-718. 17. Huber FC, Gutierrez J, Corssen G: Ketamine: Its effect on airway resistance in man. South Med J 1972;65:1176-1180.
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18. PicadeC, MontserratJM, de PabloJ, et el: Predisposingfactorsto deathafterrecovery froma life-threateningasthmaticattack.JAsthma1989;26:231-236. 19. White PF,WayWL, TrevorAJ: Ketamine:Its pharmacologyandtherapeuticuses. Anesthesiology1982;56:119-136. The authors thank Ray Dawkins, MD; Shawn Bullock, MD; Boss Simkovur, PharmD; GaryYoung, MD; and Jim Fink, RRT,for their enthusiasm and support. Special thanks to the nurses in the ED at Highland General Hospital for their interest and help with the study. Reprint no. 47/1/69972 Address for reprints:
Joseph C Howton,MD EmergencyDepartment Lutheran Hospital 8300 West 38th Avenue Wheat Ridge,Colorado80033
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