JOURNAL OF MAGNETIC RESONANCE IMAGING 28:866 – 872 (2008)
Original Research
Multicenter Trial: Comparison of Two Different Formulations and Application Systems of Low-Dose Nasal Midazolam for Routine Magnetic Resonance Imaging of Claustrophobic Patients Frank T.C. Tschirch, MD,1* Katja Suter, PhD,2 Johannes M. Froehlich, PhD,3 Ueli Studler, MD,4 Andreas Nidecker, MD,5 Boris Eckhardt, MD,6 Jan Beranek-Chiu, MD,6 Christian Surber, PhD,2 and Dominik Weishaupt, MD1 Purpose: To prospectively assess and compare two formulations and methods of administration of low-dose nasal midazolam for the treatment of claustrophobic patients undergoing magnetic resonance imaging (MRI) as part of a multicenter Phase III trial.
Conclusion: Nasally applied low-dose midazolam is a patient-friendly solution to facilitate MRI of claustrophobicpatients. The nasal spray of UDG is superior to that of MDG with a necessity of additional dosing. Key Words: midazolam; administration, nasal; phobic disorders; magnetic resonance imaging J. Magn. Reson. Imaging 2008;28:866 – 872. © 2008 Wiley-Liss, Inc.
Materials and Methods: In all, 108 consecutive adult claustrophobic patients were randomly assigned to one of two treatment groups (multidose group: MDG, unit-dose group: UDG). MDG encompassed 55 patients who received intranasally a 0.5% midazolam formulation into each nostril (total dose, 1.0 mg), whereas the 53 patients in UDG received a 1% midazolam formulation into only one nostril (total dose, 1.0 mg). This initial dose could be repeated once. Patient tolerance and anxiety were assessed using a questionnaire and a visual analog scale immediately before and after MRI. Image quality was evaluated using a fivepoint scale. Results: In all, 53/55 MR examinations (96%) with MDG and 52/53 (98%) with UDG were completed successfully. The dose of 1 mg had to be repeated significantly less often in UDG compared to MDG (4/53, 8% vs. 13/55, 24%; P ⫽ 0.003). The image quality of all MR examinations was rated good to excellent, and slightly better in UDG (P ⫽ 0.045).
1 Institute of Diagnostic Radiology, University Hospital Zu ¨ rich, Zu ¨ rich, Switzerland. 2 Hospital Pharmacy, University Basel, Basel, Switzerland. 3 Akroswiss AG, Zu ¨ rich, Switzerland. 4 Department of Radiology, Orthopedic University Hospital Balgrist, Zu ¨rich, Switzerland. 5 IMAMED Radiologie Nordwest, Basel, Switzerland. 6 Institute of Radiology, Kantonspital Winterthur, Winterthur, Switzerland. Contract grant sponsor: Akroswiss, Zu ¨ rich, Switzerland. *Address reprint requests to: F.T., Institute of Radiology, Hospital Zimmerberg, Asylstrasse 19, CH-8810 Horgen, Switzerland. E-mail:
[email protected] Received March 10, 2008; Accepted July 11, 2008. DOI 10.1002/jmri.21552 Published online in Wiley InterScience (www.interscience.wiley.com).
© 2008 Wiley-Liss, Inc.
MAGNETIC RESONANCE IMAGING (MRI) of claustrophobic patients still represents a challenge for the patients, the technicians, as well as the radiologists. According to the literature, up to 10% of all MR examinations cannot be completed or even started because of claustrophobia (1,2). In clinical practice, midazolam or other benzodiazepines are frequently used intravenously, orally, sublingually, or intrarectally for medical sedation and anxiolysis in order to enable MRI of claustrophobic patients. As an alternative, midazolam may also be administrated nasally. In contrast to the oral and rectal administration, nasal midazolam administration has no first-pass effect in the liver and does not interfere with bowel activity. Using a nasal spray absorption through the nasal mucosa is fast and nearly complete, resulting in conscious sedation (3). A limited number of studies (2,4,5) have shown the potential of nasally administrated midazolam for reduction of anxiety-related claustrophobia in patients undergoing MR imaging. However, all these studies were single-center studies with a limited number of patients. In addition, the formulation recently described by Tschirch et al (5) had some limitations, including the fact that the spray had to be administered with the patient in an upright position and the relatively high frequency of a temporary burning sensation after application of the nasal spray. The purpose of this study was to prospectively assess the potential of the nasal application of midazolam in a multicenter Phase III trial and to compare two formulations and application forms of a
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low-dose (1 mg) midazolam nasal spray in claustrophobic patients undergoing routine MRI. MATERIALS AND METHODS This prospective, randomized, parallel group, multicenter clinical Phase III study was approved by the local ethics committees of each participating center and by the national drug authority responsible for clinical studies. Written informed consent was given by all participating patients prior to inclusion. The study was conducted in compliance with the Declaration of Helsinki and the consolidated guideline of Good Clinical Practice approved by the International Conference on Harmonization. Two authors (K.S., C.S.) had received a grant from Akroswiss (Zurich, Switzerland) for the development of the anxiolytic nose spray. Author J.F. is the owner of Akroswiss (Zurich, Switzerland). Those authors who were not related to Akroswiss (F.T., U.S., A.N., B.E., J.B., D.W.) had full control of the data and information included in this study. The Hospital Pharmacy of the University of Basel provided the clinical trial units (K.S., C.S.). Authors K.S. and J.F. performed the clinical trial monitoring. All authors had control of the experimental design and information submitted for publication. Authors F.T., U.S., A.N., B.E., J.B., and D.W. were responsible for patient management, data acquisition, and on-site quality assessment in the various participating centers. Data analysis was performed by F.T. and K.S. Patients Patients were only included in the study if they fulfilled the following criteria: 1) referral for clinical MRI, 2) necessity to perform a sedation prior to MRI based on the request of the patient or the referring physician due to claustrophobia of the patient. Exclusion criteria were age ⬍18 years, general contraindications for MR imaging (ie, cardiac pacemakers, neurostimulators, ferromagnetic implants, etc), pregnancy or breast feeding, drug or ethanol abuse, general contraindications for the use of midazolam (ie, myasthenia gravis, known adverse or allergic reactions, etc), use of a benzodiazepine or similar sedative drug shortly prior to inclusion, participation in another study simultaneously, presence of otorhinolaryngeal diseases (eg, status postsurgery, rhinitis, nasal polyposis), other indicated methods of anxiolysis from the referring physician, MR study of the heart combined with a stress-test, and patients having previously been included in this study. For the purpose of the multicenter study design four centers with different patient populations were included: the Radiology Department of an academic hospital with an entire spectrum of MR examinations (center 1), the Radiology Department of an academic hospital specialized in orthopedic surgery (center 2), the Radiology Department of a nonacademic public teaching hospital (center 3), and a radiology private practice (center 4). In these four centers 110 consecutive adult patients were recruited (30 patients in center 1, 30 patients in center 2, 25 patients in center 3, and 25 patients in center 4). Two patients had to be excluded during trial monitoring
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and for further data evaluation (one patient received an initial dose of the unit dose midazolam nasal spray and by mistake a second dose of the multidose midazolam nasal spray; another patient withdrew his consent after nasal administration of 1 mg midazolam by the multidose nasal spray). Finally, a total of 108 consecutive adult patients (72 females, 36 males, mean age 51.1 years; total of 108 scheduled examinations) were eligible for the study. These patients were consecutively assigned to one of two treatment groups according to a previously defined randomization list. Administration of the drug was performed under control of the technicians to maintain the blinded character of the study versus the radiologists. The technicians explained exactly the usage of the chosen device to the patient. The dose was administered by the patient him/herself under supervision of the technician (Fig. 2A,B). Patients in the multidose group (MDG) received one pump corresponding to 0.1 mL of a multidose nasal spray containing a 0.5% midazolam solution into each nostril immediately prior to MR imaging in an upright position (total 1 mg midazolam). Patients in the unit-dose group (UDG) received 0.1 mL of a 1% midazolam solution (1 mg) by a single pump of a unit dose nasal spray into one nostril in the supine position on the MR table. If the dose of 1 mg was not sufficient in order to perform MRI the nasal administered dose could be increased up to 2 mg midazolam in both treatment groups. The decision whether a second nasal dose of midazolam had to be applied was made by the attending radiologist. Reasons to administer a second midazolam dose were persistent claustrophobic symptoms and motion artifacts possibly related to insufficient sedation. Nasal Midazolam Formulations and Spray Applications The multidose nasal spray device (E. Anwander, Oberwil, Switzerland) consisted of a 10-mL bottle with a microdoser nose-adapter screwed on top to allow a reproducible and standardized dosing of 0.1 mL (Fig. 1A). In order to exclude the administration of air it was important to use this type of device in an upright position of the patient after having checked the complete filling of the tubes and pump system by spraying five times into the air (Fig. 2A). The nasal midazolam formulation delivered by the multidose nasal spray was produced according to the NRF monograph (Neues Rezeptar Formularium, ABDA Bundesvereinigung Deutscher Apothekerverba ¨ nde, D-65760 Eschborn, GoviVerlag Pharmazeutischer, 2001). Patients of MDG received 1 mg midazolam by administration of 0.1 mL of a 0.5% midazolam solution (midazolam hydrochloride, Fa¨hrhaus Pharma, Hamburg, Germany) into each nostril. The multidose nasal spray delivered 0.1 mL per pump corresponding to 0.5 mg midazolam base. Benzalkonium chloride and sodium ethylenediaminetetraacetic acid served as preservatives. The unit dose nasal spray (Pfeiffer, Radolfzell, Germany) delivered a single pump of 0.1 mL corresponding to 1 mg midazolam base, independent of the actual position (Fig. 1B). Thus, administration of the unit dose nasal spray was possible in the supine (lying) position
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kee, WI; Achieva, Philips Medical Systems, Best, Netherlands; Avanto, Siemens, Erlangen, Germany; Espree, Siemens; Symphony, Siemens) according to the corresponding examination protocol (Table 1). All MR protocols were standardized and consisted of various sequences without and with contrast agent (intravenous and/or intraarticular). Coils as well as patient’s position were selected depending on the investigated body region. If necessary (particularly concerning abdominal and thoracic MR imaging) special examination techniques were used like respiratory triggering and breathholding techniques. Data Analysis Feasibility of the Study In both treatment groups the examination was classified as “feasible” or “not feasible.” The study was categorized as feasible if all planned MR sequences could be accomplished. If one or more MR sequences of the corresponding protocol could not be performed the study
Figure 1. Photograph of the nasal sprays used for the midazolam application. The device of the multidose nasal spray consisted of a 10-mL bottle with a microdoser nose-adapter screwed on top, allowing a reproducible and standardized dosing of 0.5 mg per pump (A). The unit dose nasal spray delivered a single pump of 0.1 mL corresponding to 1 mg midazolam base (B).
on the MR table (Fig. 2B). The unit dose nasal spray contained a preservative-free solution of 1% midazolam base (midazolam hydrochloride, Fa ¨ hrhaus Pharma, Hamburg, Germany) and 4% randomly methylated-cyclodextrin (Cavasol W7M Pharma, Wacker Munich, Germany). Both nasal spray formulations were composed of physiological osmolality (300 mOsmol/kg). The pHvalue was 3.0 –3.5 for 0.5% midazolam formulation (multidose nasal spray) and 3.5– 4.5 for 1% midazolam formulation (unit dose nasal spray). Both nasal sprays were prepared at a university hospital pharmacy (name blinded for review) according to the current guidelines of Good Manufacturing Practice (GMP). Monitoring of Patients During MR Imaging During MR imaging patients were in permanent contact with the technician performing the exam by means of headsets and a microphone. Additionally, the patient received an emergency ball to disrupt the examination if necessary. The antagonist flumazenil (Anexate, Roche Pharma, Switzerland) was available at any time. No additional monitoring (such as pulseoxymetry or similar) was performed. For safety reasons, all patients were alerted not to drive a vehicle or to operate machines 24 hours after application of midazolam. MRI All MRI was performed on one of five 1.5T scanners (Signa EchoSpeed EXCITE HD; GE Healthcare, Milwau-
Figure 2. Photograph shows how the nasal sprays were administered. In order to exclude the administration of air it was important to use the device of the multidose nasal spray with the patient in an upright position (A). The application of the unit dose nasal spray was independent of the patient’s position, thus allowing administration to the patient lying on the MR table (B).
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Table 1 Overview of the Performed MR Protocols MDG
MR protocol Head Neck Thorax Abdomen
Pelvis Spine
Extremity
Arthrography
MRA
Thoracic outlet Breast Liver Kidneys/adrenals Enteroclysis Anal fistula Defecography Prostate Bladder Total Cervical Lumbar Lumbar incl. sacroiliac joints Shoulder Upper arm Elbow Wrist Shoulder Wrist Hip Carotid Abdominal
Total/mean (⫾SD)
UDG
n
Mean scanning time (min)
n
Mean scanning time (min)
6 0 0 3 3 1 1 0 0 1 0 4 1 4 11 2 0 1 2 0 14 0 0 1 0 55
41 — — 35 37 55 20 — — 25 — 43 75 31 23 25 — 25 25 — 28 — — 20 — 33.9 (⫾14.9)
3 1 1 2 1 0 0 2 1 2 2 3 0 8 13 1 1 0 0 0 6 2 3 0 1 53
22 30 35 44 30 — — 30 30 50 43 37 — 31 25 60 20 — — — 22 32 37 — 30 33.2 (⫾10.3)
Scanning time was measured from the start of the first sequence until the end of the last sequence.
was rated as not feasible and the reason for the termination of the examination was noted. Anxiety, Sedation, and Adverse Effects The efficacy of midazolam in both treatment groups was assessed by the patients themselves as well as by the technician who performed the MR examination. Patient’s anxiety before the examination as well as the experienced fear during the investigation was evaluated by a visual analog scale (VAS) immediately before and 15 minutes after MR imaging. The VAS was presented as a line of defined length (commonly 100 mm) with anchors on either end. The patients were instructed to grade their fear sensation by placing a mark between the two anchors without being told the precise distance between them. The left anchor was defined as absence of fear, the right anchor was defined as maximal fear. The distance of one of the anchors and the patient’s mark was expressed in millimeters of the maximum of fear (100 mm). A reduction of the anxiety on the VAS below 50% was categorized as “not sufficient,” over 70% was categorized as “sufficient.” Values in between were described as “nonclassifiable.” In addition, all patients received a questionnaire that was filled out in the study center after MR imaging. Patients were asked if they had faced problems during the examination (eg, recurrent fear sensations), of what kind these problems had been, and if they had experienced any adverse effects by use of the midazolam spray (like nasal burning sensa-
tion, pain, etc). Additionally, the patients had to answer the question if they would repeat the examination. The technician who performed MR imaging was also asked to fill out a standardized questionnaire for each patient. This questionnaire contained a couple of questions concerning the patient’s cooperation and a subjective impression of the degree of anxiety or sedation of the patient during the exam. MR Image Quality Image quality among patients of MDG and UDG was rated by one of four radiologists (F.T., U.S., A.N., B.E. with 6, 7, 20, 8 years of experience in MR imaging). The reader was blinded concerning the application system and formulation of midazolam (multidose vs. unit dose nasal spray). MR image quality of each MR examination was assessed using the following 5-grade scale: grade 0, very poor image quality; grade 1, poor image quality; grade 2, satisfactory image quality; grade 3, good image quality, and grade 4, excellent image quality. Grade 0 or 1 was applied if the examination was of no or very little diagnostic usefulness because of extensive motion artifacts that were not caused by pulsation or normal peristalsis. Examinations classified as grade 2 were allowed to make the diagnosis but some motion artifacts were still present. Examinations graded as grade 3 and 4 included a good or excellent image quality with no or almost absent motion artifacts.
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tients receiving the multidose nasal spray described more often a slight intensity of the nasal burning sensation (MDG 22/55 patients (40%), UDG 13/53 patients (24.5%)), whereas patients of UDG stated more often a strong temporary burning sensation (MDG 0/55 patients (0%), UDG 4/53 patients (7.5%)). However, this was not statistically significant (P ⫽ 0.06/0.057). No other relevant adverse effects were noted in either treatment group. The antagonist flumazenil (Anexate, Roche Pharma, Switzerland) was not needed in any case. No patient required special monitoring or treatment after the examination. Anxiety and Degree of Sedation Figure 3. Diagram illustrates percentage of patients in both treatment groups with a feasible MR examination, sufficient anxiety reduction (⬎70% measured by VAS), and satisfactory to excellent MR image quality (grade 3 to 4).
Statistics Statistical analysis was performed with SPSS 12.0.1 for Windows (Chicago, IL). Statistical significance was accepted if P ⬍ 0.05. For MR image quality the chi-square test was used. The values of the VAS in both treatment groups were compared by means of the Mann–Whitney test. The need for a second dose of nasal midazolam during MR imaging and analysis of the questionnaire concerning the willingness to repeat the MR imaging was made by the Fischer exact test. RESULTS A total of 108 patients were scheduled for 108 MR examinations (Table 1). There was no statistically significant difference between either treatment group with regard to examined body regions and examination techniques (examinations with respiratory triggering: 2 (MDG) / 1 (UDG); examinations with breath-hold technique: 4 (MDG) / 2 (UDG)). There was also no statistically significant difference with regard to gender, age, and weight of the patients (female/male ratio in MDG 38/17, in UDG 34/19; mean age ⫾SD in MDG 50.9 years ⫾15.7, in UDG 50.7 years ⫾13.6; mean weight ⫾SD in MDG 71.9kg ⫾15.5, in UDG 77.2kg ⫾16.2).
The evaluation of the VAS for the reduction of the experienced anxiety resulted in no significant difference between the two treatment groups (P ⫽ 0.629). The percentage mean reduction of the experienced anxiety (⫾SD) in both treatment groups was 77.8% ⫾ 28.3. 40/55 patients (72.7%) of MDG and 39/53 patients (73.6%) of UDG showed a sufficient reduction of anxiety (ie, a decrease of the anxiety as assessed on the VAS over 70%) (Fig. 3). The reduction of anxiety was rated as not sufficient (ie, a decrease of the anxiety as assessed on the VAS below 50%) by 9/55 patients (16.4%) of MDG and 5/53 patients (9.4%) of UDG. The dose of 1 mg in MDG was not sufficient and had to be repeated (total dose of 2 mg) in 13/55 patients (23.6%), whereas in only 4/53 patients (7.5%) of UDG was a second dose required. This difference was statistically significant (P ⫽ 0.003). The relationship between anxiety reduction on the VAS and total dose in both treatment groups is shown in Fig. 4. Anxiety reduction was rated significantly more often as not sufficient by patients (7/17, 41.2%) receiving a second dose of midazolam compared to patients (7/91, 7.6%) receiving only one dose of midazolam (P ⫽ 0.03). Patients of both treatment groups receiving an intraarticular contrast application required significantly more often a second dose of midazolam compared to patients without intraarticular con-
Feasibility of the Study After application of the multidose nasal spray MR imaging had to be cancelled in 1/55 examinations (1.8%) due to patient reasons. MRI could not be started in another patient (1.8%) due to insufficient sedation of the patient, resulting in 2/55 nondiagnostic studies (3.6%). In 1/53 patients (1.9%) in UDG the MR examination could not be started due to severe claustrophobia (Fig. 3). Adverse Advents In all, 27/55 patients (49.1%) of MDG and 26/53 patients (49.1%) of UDG reported a temporary nasal burning sensation after application of the nasal spray. Pa-
Figure 4. Diagram showing the relationship between anxiety reduction on the VAS (over 70%: sufficient anxiety reduction, below 50%: insufficient anxiety reduction, values in between: nonclassifiable) and total dose (1 or 2 mg midazolam) in both treatment groups (MDG, UDG).
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trast application (7/25 (28%) vs. 10/83 (12%)). Apart from this there was no significant relationship with regard to the different MR scanner types, the MR protocol used, the examined body region, and the need of a second midazolam dose or the reduction of the experienced pain measured by the VAS (P ⫽ 0.067 to 0.613). According to the questionnaires that were filled out directly following MR imaging, 50/55 patients (90.9%) of MDG and 49/53 patients (92.5%) of UDG would repeat the examination. The technician’s impression about patient anxiety and cooperation during MR imaging did not differ significantly in either treatment group (P ⫽ 0.176). In 45/55 examinations (81.8%) of MDG the technicians described the patient as cooperative and calm during MRI; in UDG the technicians had this impression in 48/53 examinations (90.6%). No patient fell asleep during MRI. MR Image Quality Image quality of all MR examinations was rated as good to excellent (grade 3 to 4), and were considered diagnostic (Fig. 3). The MR image quality was rated as excellent in 44/52 MR examinations (84.6%) after application of the unit dose nasal spray compared to 36/53 feasible MR examinations (67.9%) after nasal application of the multidose spray. Statistical evaluation of image quality resulted in a significant difference in favor of UDG (P ⫽ 0.045). Image quality was rated significantly less often as excellent in feasible MR examinations (6/14, 42.9%) of patients receiving a second dose of midazolam compared to feasible MR examinations (74/91, 81.3%) of patients receiving only one dose of midazolam (P ⫽ 0.04). DISCUSSION A phobia is defined as an uncommon fear in which the reaction is out of proportion to the obvious danger of the situation (6). Claustrophobia is believed to be the most common phobia (7). Coping strategies of phobias are either avoidance or escape. In patients suffering from claustrophobia the panic attacks may occur in various situations such as staying in closed or small rooms as well as in large rooms where access to any exit seems impossible (7). It has been estimated that about $65,250,000 are lost annually in the US because of uncompleted MR examinations in claustrophobic patients (8). Midazolam is a frequently used agent for MRI in claustrophobic patients and permits conscious sedation if used at low dosages. Its pharmacological properties are excellent: fast onset of action, good controllability of effect, short duration of action of 20 – 40 minutes, short elimination half time of 1.5–3 hours, anxiolysis appearing at a low dosage, and usually no relevant adverse effects apart from a slight sedation (9). In contrast to the oral and intravenous (i.v.) administration route the experience with the nasal application of midazolam in patients for MRI is limited. Moss et al (4) reduced the necessity for i.v. sedation from 67% to 17% in claustrophobic MR patients using nasal mida-
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zolam drops (0.5–1 mg). Hollenhorst et al (2) showed in a double-blind placebo-controlled study that 4 mg of nasally applied midazolam lead to a significant reduction in MRI-related anxiety resulting in an improved MR image quality. In a recent study, Tschirch et al (5) demonstrated the effectiveness of low-dose (1 mg) nasal midazolam to overcome anxiety in claustrophobic patients. The current study differs from these studies. To our knowledge, for the first time the nasal application of midazolam in claustrophobic patients scheduled for MRI was investigated in a multicenter trial. Hence, a large number of claustrophobic patients (55 patients in MDG received the multidose nasal spray, 53 patients in UDG received the unit dose nasal spray) underwent a broad spectrum of MR imaging protocols in four different centers with different missions (two academic teaching and one nonacademic teaching hospitals, one private practice). The results of this multicenter trial were in accordance with the previous studies which reported the efficacy of nasally administrated midazolam for reduction of claustrophobic patients undergoing MRI. In the study of Hollenhorst et al (2) who investigated patients primarily undergoing MRI for neuroradiological indications no cancellation of MRI occurred in the midazolam group consisting of 27 patients. On the contrary, in the placebo group 4/27 (14.8%) patients panicked and terminated the MR procedure earlier. Tschirch et al (5) administrated midazolam nasally to 36 claustrophobic patients scheduled for body MR imaging and compared these patients to a group of 36 patients receiving 7.5 mg midazolam orally. In all, 35/36 MR examinations were completed successfully after nasal application of midazolam. However, 18/36 MR examinations had to be cancelled after oral application and the reduction of anxiety was insufficient in 12/18 remaining patients. Analysis of MR image quality showed a significantly better image quality in the patient group who received the midazolam nasally compared to the patient group who received the midazolam in an oral formulation. Moss et al (4) administrated nasal midazolam to 52 claustrophobic patients before MRI and reduced the necessity for i.v. sedation from 67% (without application of midazolam) to 17% (after nasal administration of midazolam). In the current trial, both midazolam formulations (the multidose as well as the unit dose nasal spray) demonstrated excellent results with regard to feasibility of MR imaging (MDG: 96.4%, UDG: 98.1%), MR image quality (good to excellent in all MR examinations), sufficient anxiety reduction measured by the VAS (MDG: 72.7%, UDG: 73.6%), and willingness to repeat MRI (MDG: 90.9%, UDG: 92.5%). It has to be emphasized that these results were obtained in different institutions and in the entire spectrum of current MR examination practice. In our multicenter trial one of the formulations of the used midazolam sprays (ie, the multidose nasal spray) was similar to that used in the recent study of Tschirch et al (5). Two possible limitations of this multidose spray are, first, that administration of the spray has to be performed with the patient in an upright position, and second, this formulation is associated with a relatively high frequency of a temporary burning sensation
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after application. Hence, we aimed to improve the practicability of the device by introducing a device that enables administration of the substance in a supine patient, and to develop a formula with fewer side effects. Hence, the multidose nasal spray was compared to the unit dose nasal spray that can be applied independently of the patient’s body position and which is administered only into one nostril. Additionally, the unit dose nasal spray contained a preservative-free preparation of 1% midazolam base and 4% randomly methylated--cyclodextrin (whereas benzalkonium chloride and sodium ethylenediaminetetraacetic acid served as preservatives for the multidose nasal spray). The pH value of the unit dose preparation was slightly elevated (3.5– 4.5) compared to the multidose nasal spray (3.0 – 3.5). However, there was no difference in the incidence of the temporary nasal burning sensation after application of the multidose (49.1%) and unit dose nasal spray (49.1%). Whereas the burning sensation of the multidose nasal spray probably results predominantly from the midazolam itself, preservatives, and the low pH value, an additional mechanical effect (strong single pump) and the double midazolam concentration may explain the unchanged burning sensation of the unit dose nasal spray. The MR quality of the patients receiving the unit dose nasal spray (UDG) was slightly superior compared to the image quality of the patients receiving the multidose nasal spray (MDG). The reason for this difference is difficult to explain. Since there was no statistical difference with regard to various factors including type of MR scanner, examined body region, imaging protocol, and various body measures, we hypothesize that either the double-concentrated form or increased pH value increase the transmucous uptake rate, which would also match the decreased readministration rate, or otherwise that an incorrect use of the multidose nasal spray (ie, application of the spray not in a fully upright position) may explain this difference. Another advantage of the tested unit dose nasal spray is the fact that it is a single-dose device, whereas the major portion of the multidose spray preparation is not used. As the breached multidose nasal sprays are not recognizable there is an additional risk for unhygienic multiple application to different patients. This risk is not present for the unit dose nasal spray, while in the case of repeated dosing a second unit dose nasal spray must be allocated. The two tested formulations and application forms seem to be safe and present a high patient acceptance. However, the unit dose nasal spray will be probably more widely accepted according to the above-mentioned advantages. We acknowledge the following limitations. In this multicenter trial we compared two formulations and
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application forms of nasal midazolam, but we included no control group receiving placebo. The reason for this is that Hollenhorst et al (2) already demonstrated the effectiveness of nasal midazolam for the reduction of MRI-related anxiety in a prospective double-blinded placebo-controlled randomized trial. Additionally, comparison with other simple administratable benzodiazepines such as sublingual lorazepam has not been addressed in the study. We only used a VAS to quantify the severity of claustrophobia before and after MRI, and no psychometric test was made such as the Spielberger State-Trait Anxiety Inventory (STAI). However, other investigators also worked successfully using only the VAS (5,10). On the other hand, Hollenhorst et al (2) found similar results using both STAI and VAS, whereas Dantendorfer et al (11) could not find a correlation between values of STAI and the presence of motion artifacts. Hence, it may be concluded that the VAS is probably sufficient to assess the grade of anxiety. In conclusion, in this multicenter trial the nasal application of low-dose midazolam before MR imaging was an effective and patient-friendly solution to overcome anxiety in claustrophobic patients. The tested unit dose nasal spray was superior to the multidose nasal spray in image quality and necessity of additional dosing. REFERENCES 1. Melendez JC, McCrank E. Anxiety-related reactions associated with magnetic resonance imaging examinations. JAMA 1993;270: 745–747. 2. Hollenhorst J, Munte S, Friedrich L, et al. Using intranasal midazolam spray to prevent claustrophobia induced by MR imaging. AJR Am J Roentgenol 2001;176:865– 868. 3. Knoester PD, Jonker DM, Van Der Hoeven RT, et al. Pharmacokinetics and pharmacodynamics of midazolam administered as a concentrated intranasal spray. A study in healthy volunteers. Br J Clin Pharmacol 2002;53:501–507. 4. Moss ML, Buongiorno PA, Clancy VA. Intranasal midazolam for claustrophobia in MRI. J Comput Assist Tomogr 1993;17:991–992. 5. Tschirch FT, Gopfert K, Frohlich JM, Brunner G, Weishaupt D. Low-dose intranasal versus oral midazolam for routine body MRI of claustrophobic patients. Eur Radiol 2007;17:1403–1410. 6. Kahn A. Getting acquainted with fears, phobias and other anxiety disorders. In: Kahn A, ed. Facing fears. New York: Checkmark Books; 2000; p 4. 7. Wiebe J. Is your patient claustrophobic? A study of claustrophobic patients in the MRI department. Can J Med Radiat Technol 2004; 35:25–32. 8. Murphy KJ, Brunberg JA. Adult claustrophobia, anxiety and sedation in MRI. Magn Reson Imaging 1997;15:51–54. 9. Schweizer E, Clary C, Dever AI, Mandos LA. The use of low-dose intranasal midazolam to treat panic disorder: a pilot study. J Clin Psychiatry 1992;53:19 –22. 10. Biro P, Weidmann G, Pietzsch S, Alon E, Brugger P. [The dosedependent effects of oral premedication with midazolam.] Anasthesiol Intensivmed Notfallmed Schmerzther 1997;32:672– 677. 11. Dantendorfer K, Amering M, Bankier A, et al. A study of the effects of patient anxiety, perceptions and equipment on motion artifacts in magnetic resonance imaging. Magn Reson Imaging 1997;15: 301–306.
