Treatment of agitation in terminally ill patients with intranasal midazolam versus subcutaneous midazolam: study protocol for a randomised controlled open-label monocentric trial (MinTU Study).

BACKGROUND: Intranasal (i.n.) drug application is a widely known and low-invasive route of administration that may be able to achieve rapid symptom control in terminally ill patients. According to the German S3 guideline "Palliative care for patients with incurable cancer", benzodiazepines, such as midazolam, are recommended for the treatment of terminal agitation. To the best of our knowledge there is no evidence for i.n. midazolam in terminally ill patients. We aim to assess the use of i.n. midazolam as an alternative to subcutaneous administration of the drug. METHODS: In this monocentric, randomised, controlled, open-label investigator initiated trial, n = 60 patients treated at the palliative care unit of a University Hospital will be treated with 5 mg midazolam i.n. versus 5 mg subcutaneous (s.c.) midazolam in the control arm when terminal agitation occurs (randomly assigned 1:1). The estimated recruitment period is 18 months. Treatment efficacy is defined as an improvement on the Richmond Agitation Sedation Scale (Palliative Version) (RASS-PAL) and a study specific numeric rating scale (NRS) before and after drug administration. Furthermore, plasma concentration determinations of midazolam will be conducted at t1 = 0 min, t2 = 5 min, and t3 = 20 min using liquid chromatography/mass spectrometry (LC-MS). The primary objective is to demonstrate non-inferiority of midazolam i.n. in comparison to midazolam s.c. for the treatment of agitation in terminally ill patients. DISCUSSION: Midazolam i.n. is expected to achieve at least equivalent reduction of terminal agitation compared to s.c. administration. In addition, plasma concentrations of midazolam i.n. are not expected to be lower than those of midazolam s.c. and the dynamics of the plasma concentration with an earlier increase could be beneficial. TRIAL REGISTRATION: German Clinical Trials Registry DRKS00026775, registered 07.07.2022, Eudra CT No.: 2021-004789-36.

Toxic Spongiform Leukoencephalopathy After Intravenous Heroin Abuse: Unusual But Important Differential Diagnosis of Acute Impairment of Consciousness.

Abuse of heroin vapour inhalation known as "chasing the dragon" is associated with toxic spongiform leukoencephalopathy. However, similar clinical and imaging findings may occur also after intravenous heroin abuse. We report on a 32-year-old male suffering from extensive toxic spongiform leukoencephalopathy after intravenous heroin abuse resulting in acute impairment of consciousness and a global state of confusion. MRI disclosed broad and nearly symmetrical diffusion restriction of the supratentorial white matter indicating cytotoxic oedema. In an emergency setting, differential diagnosis of acute impairment of consciousness and broad symmetrical white matter lesions in neuroimaging should also include toxic leukoencephalopathy due to intravenous heroin application.

Cardiovascular magnetic resonance phase contrast imaging.

Cardiovascular magnetic resonance (CMR) phase contrast imaging has undergone a wide range of changes with the development and availability of improved calibration procedures, visualization tools, and analysis methods. This article provides a comprehensive review of the current state-of-the-art in CMR phase contrast imaging methodology, clinical applications including summaries of past clinical performance, and emerging research and clinical applications that utilize today's latest technology.

Measurement accuracy of different active tracking sequences for interventional MRI.

PURPOSE: To compare the spatial accuracy of three typical active tracking sequences using a new, unique phantom design. MATERIALS AND METHODS: Three different tracking sequences (Single Echo, Dual Echo and Hadamard Multiplexed) were compared with each other in a phantom study with respect to their positional accuracy. A custom-built phantom was constructed to conduct the experiments with precise framework conditions which facilitated sufficient measurement accuracy. An electrophysiology catheter incorporating four micro-coils was used as an interventional device. Tracking profiles were acquired in all three spatial dimensions and validated against the distances that were measured by a Vernier caliper in combination with a three-dimensional reference scan. RESULTS: The Bland-Altman plots demonstrated that all three sequences show < 1.5 mm positional error. The measurement accuracy of Single Echo and Double Echo are prone to off-resonances, whereas Hadamard Encoding is immune to it. CONCLUSION: The developed phantom enabled the performance of objective measurements of the accuracy of different active tracking sequences. The proposed setup allows for objectively contrasting different methods for interventional procedures.

Image corruption detection in diffusion tensor imaging for post-processing and real-time monitoring.

Due to the high sensitivity of diffusion tensor imaging (DTI) to physiological motion, clinical DTI scans often suffer a significant amount of artifacts. Tensor-fitting-based, post-processing outlier rejection is often used to reduce the influence of motion artifacts. Although it is an effective approach, when there are multiple corrupted data, this method may no longer correctly identify and reject the corrupted data. In this paper, we introduce a new criterion called "corrected Inter-Slice Intensity Discontinuity" (cISID) to detect motion-induced artifacts. We compared the performance of algorithms using cISID and other existing methods with regard to artifact detection. The experimental results show that the integration of cISID into fitting-based methods significantly improves the retrospective detection performance at post-processing analysis. The performance of the cISID criterion, if used alone, was inferior to the fitting-based methods, but cISID could effectively identify severely corrupted images with a rapid calculation time. In the second part of this paper, an outlier rejection scheme was implemented on a scanner for real-time monitoring of image quality and reacquisition of the corrupted data. The real-time monitoring, based on cISID and followed by post-processing, fitting-based outlier rejection, could provide a robust environment for routine DTI studies.

Rapid freehand MR-guided percutaneous needle interventions: an image-based approach to improve workflow and feasibility.

PURPOSE: To develop and evaluate software-based methods for improving the workflow of magnetic resonance (MR)-guided percutaneous interventions. MATERIALS AND METHODS: A set of methods was developed that allows the user to: 1) plan an entire procedure, 2) directly apply this plan to skin entry site localization without further imaging, and 3) place a needle under real-time MR guidance with automatic alignment of three orthogonal slices along a planned trajectory with preference to the principal patient axes. To validate targeting accuracy and time, phantom experiments (96 targets) and in vivo paraspinal and kidney needle punctures in two pigs (55 targets) were performed. The influence of trajectory obliquity, level of experience, and organ motion on targeting accuracy and time was analyzed. RESULTS: Mean targeting error was 1.8 ± 0.9 mm (in vitro) and 2.9 ± 1.0 mm (in vivo) in all directions. No statistically significant differences in targeting accuracy between single- and double-oblique trajectories, novice and expert users, or paraspinal and kidney punctures were observed. The average time (in vivo) from trajectory planning to verification of accurate needle placement was 6 minutes. CONCLUSION: The developed methods allow for accurate needle placement along complex trajectories and are anticipated to reduce table time for MR-guided percutaneous needle interventions.

Agreement and reproducibility of apparent diffusion coefficient measurements of dual-b-value and multi-b-value diffusion-weighted magnetic resonance imaging at 1.5 Tesla in phantom and in soft tissues of the abdomen.

OBJECTIVE: To compare the coefficient of variation (CV) and long-term reproducibility of apparent diffusion coefficient (ADC) in a simple fluid-filled phantom and abdominal organs simultaneously. MATERIALS AND METHODS: Retrospective institutional review board-approved and Health Insurance Portability and Accountability Act-compliant study sequentially selected 100 patients who underwent clinically indicated abdominal magnetic resonance imaging. A subset of 58 patients had repeat scans within 2 to 5 months after the initial magnetic resonance imaging. Two diffusion-weighted imaging techniques (b-values 0-750 mm/s) were performed to compare the ADC values. Mean ADC values were calculated for 10 locations and the reference phantom. The CV and Bland-Altman plots were calculated for the phantom and soft tissues at each session and location. RESULTS: There were no significant differences in the mean ADC values between repeated acquisitions. However, ADC values were statistically higher using dual-b-value than multi-b-value diffusion-weighted imaging. The CV for the phantom was 8.6 versus 10.8 for dual-b-value and multi-b-value, respectively. The CVs for the soft tissues had a wider range compared with that of the phantom (liver, 12.6 vs 9.0; spleen, 11.7 vs 11.2; gallbladder, 11.0 vs 13.6; head of pancreas, 14.6 vs 14.7; body of pancreas, 13.4 vs 13.0; tail of pancreas, 14.8 vs 16.3; right kidney, 9.1 vs 9.6; left kidney, 9.3 vs 9.3; right paraspinal muscle, 7.9 vs 7.5; left paraspinal muscle, 7.3 vs 7.3, respectively). CONCLUSIONS: A change in ADC less than 11% falls into the range of measurement variability. Paraspinal muscle could potentially be used as an internal reference parameter.

Simultaneous myocardial strain and dark-blood perfusion imaging using a displacement-encoded MRI pulse sequence.

The purpose of this study is to develop and evaluate a displacement-encoded pulse sequence for simultaneous perfusion and strain imaging. Displacement-encoded images in two to three myocardial slices were repeatedly acquired using a single-shot pulse sequence for 3 to 4 min, which covers a bolus infusion of Gadolinium contrast. The magnitudes of the images were T(1) weighted and provided quantitative measures of perfusion, while the phase maps yielded strain measurements. In an acute coronary occlusion swine protocol (n = 9), segmental perfusion measurements were validated against microsphere reference standard with a linear regression (slope 0.986, R(2) = 0.765, Bland-Altman standard deviation = 0.15 mL/min/g). In a group of ST-elevation myocardial infarction patients (n = 11), the scan success rate was 76%. Short-term contrast washout rate and perfusion are highly correlated (R(2) = 0.72), and the pixelwise relationship between circumferential strain and perfusion was better described with a sigmoidal Hill curve than linear functions. This study demonstrates the feasibility of measuring strain and perfusion from a single set of images.

Comprehensive adenosine stress perfusion MRI defines the etiology of chest pain in the emergency room: Comparison with nuclear stress test.

PURPOSE: To compare standard of care nuclear SPECT imaging with cardiac magnetic resonance imaging (MRI) for emergency room (ER) patients with chest pain and intermediate probability for coronary artery disease. MATERIALS AND METHODS: Thirty-one patients with chest pain, negative electrocardiogram (ECG), and negative cardiac enzymes who underwent cardiac single photon emission tomography (SPECT) within 24 h of ER admission were enrolled. Patients underwent a comprehensive cardiac MRI exam including gated cine imaging, adenosine stress and rest perfusion imaging and delayed enhancement imaging. Patients were followed for 14 +/- 4.7 months. RESULTS: Of 27 patients, 8 (30%) showed subendocardial hypoperfusion on MRI that was not detected on SPECT. These patients had a higher rate of diabetes (P = 0.01) and hypertension (P = 0.01) and a lower global myocardial perfusion reserve (P = 0.01) compared with patients with a normal cardiac MRI (n = 10). Patients with subendocardial hypoperfusion had more risk factors for cardiovascular disease (mean 4.4) compared with patients with a normal MRI (mean 2.5; P = 0.005). During the follow-up period, patients with subendocardial hypoperfusion on stress MRI were more likely to return to the ER with chest pain compared with patients who had a normal cardiac MRI (P = 0.02). Four patients did not finish the MR exam due to claustrophobia. CONCLUSION: In patients with chest pain, diabetes and hypertension, cardiac stress perfusion MRI identified diffuse subendocardial hypoperfusion defects in the ER setting not seen on cardiac SPECT, which is suspected to reflect microvascular disease.

High spatial and temporal resolution cardiac cine MRI from retrospective reconstruction of data acquired in real time using motion correction and resorting.

Cine MRI is used for assessing cardiac function and flow and is typically based on a breath-held, segmented data acquisition. Breath holding is particularly difficult for patients with congestive heart failure or in pediatric cases. Real-time imaging may be used without breath holding or ECG triggering. However, despite the use of rapid imaging sequences and accelerated parallel imaging, real-time imaging typically has compromised spatial and temporal resolution compared with gated, segmented breath-held studies. A new method is proposed that produces a cardiac cine across the full cycle, with both high spatial and temporal resolution from a retrospective reconstruction of data acquired over multiple heartbeats during free breathing. The proposed method was compared with conventional cine images in 10 subjects. The resultant image quality for the proposed method (4.2 +/- 0.4) without breath holding or gating was comparable to the conventional cine (4.4 +/- 0.5) on a five-point scale (P = n.s.). Motion-corrected averaging of real-time acquired cardiac images provides a means of attaining high-quality cine images with many of the benefits of real-time imaging, such as free-breathing acquisition and tolerance to arrhythmias.

Axial black blood turbo spin echo imaging of the right ventricle.

Black blood turbo spin echo (TSE) imaging of the right ventricle (RV) free wall is highly sensitive to cardiac motion, frequently resulting in nondiagnostic images. Temporal and spatial parameters of a black blood TSE pulse sequence were evaluated for visualization of the RV free wall. Seventy-four patient studies were retrospectively evaluated for the effects of acquisition timing on image quality. Axial black blood TSE images were acquired on 10 healthy volunteers to assess the role of spatial misregistration on right ventricle visualization; increasing the double inversion recovery (DIR) slice thickness beyond 300% had no effect on image quality (P = 0.2). Thirty-five patient studies were prospectively evaluated with inversion times (TIs) corresponding to the mid-diastolic rest period and end-systole based on visual analysis of a four chamber cine. When TIs were chosen to be within the patients' RV rest period, mean image quality score was significantly improved (2.3 vs 1.86; P < 0.001) and the number of clinically diagnostic images increased from 32% to 46%. Black blood TSE imaging of the RV free wall is highly sensitive to cardiac motion. Image quality can be improved by choosing TIs concordant with the rest period of the patient's RV that may occur at mid-diastole or end-systole.

Motion-guided segmentation for cine DENSE MRI.

Defining myocardial contours is often the most time-consuming portion of dynamic cardiac MRI image analysis. Displacement encoding with stimulated echoes (DENSE) is a quantitative MRI technique that encodes tissue displacement into the phase of the complex MRI images. Cine DENSE provides a time series of these images, thus facilitating the non-invasive study of myocardial kinematics. Epicardial and endocardial contours need to be defined at each frame on cine DENSE images for the quantification of regional displacement and strain as a function of time. This work presents a reliable and effective two-dimensional semi-automated segmentation technique that uses the encoded motion to project a manually-defined region of interest through time. Contours can then easily be extracted for each cardiac phase. This method boasts several advantages, including, (1) parameters are based on practical physiological limits, (2) contours are calculated for the first few cardiac phases, where it is difficult to visually distinguish blood from myocardium, and (3) the method is independent of the shape of the tissue delineated and can be applied to short- or long-axis views, and on arbitrary regions of interest. Motion-guided contours were compared to manual contours for six conventional and six slice-followed mid-ventricular short-axis cine DENSE datasets. Using an area measure of segmentation error, the accuracy of the segmentation algorithm was shown to be similar to inter-observer variability. In addition, a radial segmentation error metric was introduced for short-axis data. The average radial epicardial segmentation error was 0.36+/-0.08 and 0.40+/-0.10 pixels for slice-followed and conventional cine DENSE, respectively, and the average radial endocardial segmentation error was 0.46+/-0.12 and 0.46+/-0.16 pixels for slice following and conventional cine DENSE, respectively. Motion-guided segmentation employs the displacement-encoded phase shifts intrinsic to DENSE MRI to accurately propagate a single set of pre-defined contours throughout the remaining cardiac phases.

Unsupervised inline analysis of cardiac perfusion MRI.

In this paper we first discuss the technical challenges preventing an automated analysis of cardiac perfusion MR images and subsequently present a fully unsupervised workflow to address the problems. The proposed solution consists of key-frame detection, consecutive motion compensation, surface coil inhomogeneity correction using proton density images and robust generation of pixel-wise perfusion parameter maps. The entire processing chain has been implemented on clinical MR systems to achieve unsupervised inline analysis of perfusion MRI. Validation results are reported for 260 perfusion time series, demonstrating feasibility of the approach.

Image-based coronary tracking and beat-to-beat motion compensation: feasibility for improving coronary MR angiography.

A method to reduce the effect of motion variability in MRI of the coronary arteries is proposed. It involves acquiring real-time low-resolution images in specific orthogonal orientations, extracting coronary motion from these images, and then using this motion information to guide high-resolution MR image acquisition on a beat-to-beat basis. The present study establishes the feasibility and efficacy of the proposed approach using human motion data in an offline implementation, prior to future online implementation on an MRI scanner. To track the coronary arteries in low-resolution real-time MR images in an accurate manner, a tracking approach is presented and validated. The tracking algorithm was run on real-time images acquired at 15-20 frames per second in four-chamber, short-axis, and coronal views in five volunteers. The systolic and diastolic periods in the cardiac cycles, computed from the extracted motion information, had significant variability during the short time periods typical of cardiac MRI. It is also demonstrated through simulation analysis using human tracked coronary motion data that accounting for this cardiac variability by adaptively changing the trigger delay for acquisition on a beat-to-beat basis improves overall motion compensation and hence MR image quality evaluated in terms of SNR and CNR values.

3D myocardial tissue tracking with slice followed cine DENSE MRI.

PURPOSE: To track three-dimensional (3D) myocardial tissue motion using slice followed cine displacement encoded imaging with stimulated echoes (DENSE). MATERIALS AND METHODS: Slice following (SF) has previously been developed for 2D myocardial tagging to compensate for the effect of through-plane motion on 2D tissue tracking. By incorporating SF into a cine DENSE sequence, and applying displacement encoding in three orthogonal directions, we demonstrate the ability to track discrete elements of a slice of myocardium in 3D as the heart moves through the cardiac cycle. The SF cine DENSE tracking algorithm was validated on a moving phantom, and the effects of through-plane motion on 2D cardiac strain were investigated in six healthy subjects. RESULTS: A through-plane tracking accuracy of 0.46 +/- 0.32 mm was measured for a typical range of myocardial motion using a rotating phantom. In vivo 3D measurements of cardiac motion were consistent with prior myocardial tagging results. Through-plane rotation in a mid-ventricularshort-axis view was shown to decrease the magnitude of the 2D end-systolic circumferential strain by 3.91 +/- 0.43% and increase the corresponding radial strain by 6.01 +/- 1.07%. CONCLUSION: Slice followed cine DENSE provides an accurate method for 3D tissue tracking.

Fully automatic, retrospective enhancement of real-time acquired cardiac cine MR images using image-based navigators and respiratory motion-corrected averaging.

Real-time imaging may be clinically important in patients with congestive heart failure, arrhythmias, or in pediatric cases. However, real-time imaging typically has compromised spatial and temporal resolution compared with gated, segmented studies. To combine the best features of both types of imaging, a new method is proposed that uses parallel imaging to improve temporal resolution of real-time acquired images at the expense of signal-to-noise ratio (SNR), but then produces an SNR-enhanced cine by means of respiratory motion-corrected averaging of images acquired in real-time over multiple heartbeats while free-breathing. The retrospective processing based on image-based navigators and nonrigid image registration is fully automated. The proposed method was compared with conventional cine images in 21 subjects. The resultant image quality for the proposed method (3.9+/-0.44) was comparable to the conventional cine (4.2+/-0.99) on a 5-point scale (P=not significant [n.s.]). The conventional method exhibited degraded image quality in cases of arrhythmias whereas the proposed method had uniformly good quality. Motion-corrected averaging of real-time acquired cardiac images provides a means of attaining high-quality cine images with many of the benefits of real-time imaging, such as free-breathing acquisition and tolerance to arrhythmias.

Stem cell therapy: MRI guidance and monitoring.

With the recent advances in magnetic resonance (MR) labeling of cellular therapeutics, it is natural that interventional MRI techniques for targeting would be developed. This review provides an overview of the current methods of stem cell labeling and the challenges that are created with respect to interventional MRI administration. In particular, stem cell therapies will require specialized, MR-compatible devices as well as integration of graphical user interfaces with pulse sequences designed for interactive, real-time delivery in many organs. Specific applications that are being developed will be reviewed as well as strategies for future translation to the clinical realm.

Modeling the human aorta for MR-driven real-time virtual endoscopy.

As interventional magnetic resonance imaging (iMRI) is getting closer to clinical practice, new means of visualization and navigation are required. We present an approach to create a virtual endoscopic view inside the human aorta in real-time. In our approach, defined cross-sectional slices are acquired and segmented in a highly optimized fashion. A geometric shape model is fit to the segmentation points and continuously updated during the intervention. The physician can then view and navigate inside the structure to plan the intervention and get immediate feedback about the procedure. As a component of this system, this work focuses on the segmentation of the cross-sectional images and the fitting of the shape model. We present a real-time 2D segmentation implementation for this application domain and a model fitting scheme for a generalized cylinder (GC) model. For the latter we employ a new scheme for choosing the local reference frame.

The interventional MR imaging suite: magnet designs and equipment requirements.

Soon after the introduction of MR imaging as an imaging tool, researchers began to investigate its capabilities to guide interventional minimally invasive procedures, such as biopsies. These early efforts have encouraged vendors and numerous research groups worldwide to identify clinical problems in the field of image-guided intervention, for which MR imaging is beneficial as an imaging modality, and to develop and refine soft-ware and hardware components to meet the specific requirements of interventional MR imaging. Over nearly 20 years, continuous advances in magnet and system design have accelerated the progress of MR-guided intervention.

Adjunctive role of cardiovascular magnetic resonance in the assessment of patients with inferior attenuation on myocardial perfusion SPECT.

PURPOSE: Inferior attenuation is a common problem in the interpretation of myocardial perfusion SPECT. We explored whether cardiovascular magnetic resonance (CMR) was a useful adjunct in differentiating between artifactual attenuation of the inferior wall and the presence of myocardial infarction and/or ischemia. METHODS: We used CMR to assess resting wall motion, myocardial perfusion, and the presence of infarction with late gadolinium enhancement in 30 patients with presumed inferior attenuation on ungated myocardial perfusion SPECT, but where uncertainty was present over interpretation of the inferior wall. Perfusion CMR was analyzed visually and quantitatively. RESULTS: In 23 patients (77%), CMR excluded infarction or ischemia in the inferior wall. The myocardial perfusion reserve index (MPR1) was the same in the inferior and remote myocardium (1.74 +/- 0.43 vs. 1.77 +/- 0.50, p = 0.61). Coronary angiography was performed in 11 of these patients, and was normal in all cases. In the remaining seven subjects (23%), significant abnormality was detected by CMR (infarction, 5; wall motion abnormality, 3; perfusion defect, 5). In these patients, the MPR1 was reduced in the inferior myocardium compared with remote (1.07 +/- 0.19 vs. 1.74 +/- 0.49, p = 0.04). Coronary angiography was performed in three of these patients, revealing significant coronary disease in the artery supplying the inferior territory in all patients. CONCLUSION: Approximately one-quarter of patients with inferior attenuation on ungated, nonattenuation corrected myocardial perfusion SPECT have abnormalities on CMR. CMR can readily distinguish between artifact, ischemia, and infarction in these cases and in some cases might obviate the need for diagnostic coronary angiography.