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Background
In individuals suffering from a rare disease the diagnostic process and the confirmation of a final diagnosis often extends over many years. Factors contributing to delayed diagnosis include health care professionals' limited knowledge of rare diseases and frequent (co-)occurrence of mental disorders that may complicate and delay the diagnostic process. The ZSE-DUO study aims to assess the benefits of a combination of a physician focusing on somatic aspects with a mental health expert working side by side as a tandem in the diagnostic process.
Study design
This multi-center, prospective controlled study has a two-phase cohort design.
Methods
Two cohorts of 682 patients each are sequentially recruited from 11 university-based German Centers for Rare Diseases (CRD): the standard care cohort (control, somatic expertise only) and the innovative care cohort (experimental, combined somatic and mental health expertise). Individuals aged 12 years and older presenting with symptoms and signs which are not explained by current diagnoses will be included. Data will be collected prior to the first visit to the CRD’s outpatient clinic (T0), at the first visit (T1) and 12 months thereafter (T2).
Outcomes
Primary outcome is the percentage of patients with one or more confirmed diagnoses covering the symptomatic spectrum presented. Sample size is calculated to detect a 10 percent increase from 30% in standard care to 40% in the innovative dual expert cohort. Secondary outcomes are (a) time to diagnosis/diagnoses explaining the symptomatology; (b) proportion of patients successfully referred from CRD to standard care; (c) costs of diagnosis including incremental cost effectiveness ratios; (d) predictive value of screening instruments administered at T0 to identify patients with mental disorders; (e) patients’ quality of life and evaluation of care; and f) physicians’ satisfaction with the innovative care approach.
Conclusions
This is the first multi-center study to investigate the effects of a mental health specialist working in tandem with a somatic expert physician in CRDs. If this innovative approach proves successful, it will be made available on a larger scale nationally and promoted internationally. In the best case, ZSE-DUO can significantly shorten the time to diagnosis for a suspected rare disease.
Aims
Treating patients with acute decompensated heart failure (ADHF) presenting with volume overload is a common task. However, optimal guidance of decongesting therapy and treatment targets are not well defined. The inferior vena cava (IVC) diameter and its collapsibility can be used to estimate right atrial pressure, which is a measure of right‐sided haemodynamic congestion. The CAVA‐ADHF‐DZHK10 trial is designed to test the hypothesis that ultrasound assessment of the IVC in addition to clinical assessment improves decongestion as compared with clinical assessment alone.
Methods and results
CAVA‐ADHF‐DZHK10 is a randomized, controlled, patient‐blinded, multicentre, parallel‐group trial randomly assigning 388 patients with ADHF to either decongesting therapy guided by ultrasound assessment of the IVC in addition to clinical assessment or clinical assessment alone. IVC ultrasound will be performed daily between baseline and hospital discharge in all patients. However, ultrasound results will only be reported to treating physicians in the intervention group. Treatment target is relief of congestion‐related signs and symptoms in both groups with the additional goal to reduce the IVC diameter ≤21 mm and increase IVC collapsibility >50% in the intervention group. The primary endpoint is change in N‐terminal pro‐brain natriuretic peptide from baseline to hospital discharge. Secondary endpoints evaluate feasibility, efficacy of decongestion on other scales, and the impact of the intervention on clinical endpoints.
Conclusions
CAVA‐ADHF‐DZHK10 will investigate whether IVC ultrasound supplementing clinical assessment improves decongestion in patients admitted for ADHF.
Background: Malignant hyperthermia (MH) is a rare pharmacogenetic disorder which is characterized by life-threatening metabolic crises during general anesthesia. Classical triggering substances are volatile anesthetics and succinylcholine (SCh). The molecular basis of MH is excessive release of Ca2+ in skeletal muscle principally by a mutated ryanodine receptor type 1 (RyR1). To identify factors explaining the variable phenotypic presentation and complex pathomechanism, we analyzed proven MH events in terms of clinical course, muscle contracture, genetic factors and pharmocological triggers.
Methods: In a multi-centre study including seven European MH units, patients with a history of a clinical MH episode confirmed by susceptible (MHS) or equivocal (MHE) in vitro contracture tests (IVCT) were investigated. A test result is considered to be MHE if the muscle specimens develop pathological contractures in response to only one of the two test substances, halothane or caffeine. Crises were evaluated using a clinical grading scale (CGS), results of IVCT and genetic screening. The effects of SCh and volatile anesthetics on Ca2+ release from sarcoplasmic reticulum (SR) were studied in vitro.
Results: A total of 200 patients met the inclusion criteria. Two MH crises (1%) were triggered by SCh (1 MHS, 1 MHE), 18% by volatile anesthetics and 81% by a combination of both. Patients were 70% male and 50% were younger than 12 years old. Overall, CGS was in accord with IVCT results. Crises triggered by enflurane had a significantly higher CGS compared to halothane, isoflurane and sevoflurane. Of the 200 patients, 103 carried RyR1 variants, of which 14 were novel. CGS varied depending on the location of the mutation within the RyR1 gene. In contrast to volatile anesthetics, SCh did not evoke Ca2+ release from isolated rat SR vesicles.
Conclusions: An MH event could depend on patient-related risk factors such as male gender, young age and causative RyR1 mutations as well as on the use of drugs lowering the threshold of myoplasmic Ca2+ release. SCh might act as an accelerant by promoting unspecific Ca2+ influx via the sarcolemma and indirect RyR1 activation. Most MH crises develop in response to the combined administration of SCh and volatile anesthetics.
Emery-Dreifuss muscular dystrophy (EDMD) is a hereditary neuromuscular disorder characterized by slowly progressive muscle weakness, early contractures, and dilated cardiomyopathy. We reported an uneventful general anaesthesia using total intravenous anaesthesia (TIVA) for cardiac transplantation in a 19-year-old woman suffering from EDMD. In vitro contracture test results of two pectoralis major muscle bundles of the patient suggest that exposition to triggering agents does not induce a pathological sarcoplasmic calcium release in the lamin A/C phenotype. However, due to the lack of evidence in the literature, we would recommend TIVA for patients with EDMD if general anaesthesia is required.
Malignant hyperthermia is a rare but life-threatening complication of general anesthesia in predisposed patients usually triggered by potent inhalation anesthetics and/or the depolarizing muscle relaxant succinylcholine. The authors present a case of delayed sevoflurane-induced malignant hyperthermia in a 21-year-old male patient that was sufficiently treated by discontinuation of trigger agent application and dantrolene infusion. After surviving an MH episode diagnostic procedures are indicated to increase patient safety. In the presented case, the use of a novel minimal-invasive metabolic test with intramuscular injection of halothane and caffeine successfully confirmed MH susceptibility and hence might be an alternative for invasive in vitro contracture testing in selected cases.
Background
While the impact of volatile anaesthetics to induce malignant hyperthermia (MH) is abundantly clear, the role of succinylcholine still remains controversial. To evaluate the influence of succinylcholine on porcine MH events, the authors investigated the hemodynamic and metabolic responses in MH susceptible (MHS) and non-susceptible (MHN) swine following either succinylcholine or halothane application alone or a combination of both substances.
Methods
With approval of the local animal care committee 27 MHS and 30 MHN pigs were anaesthetized and mechanically ventilated. Fiberoptic probes for continuous PCO2 measurement were inserted into the femoral vein and the triceps muscle. Group A received succinylcholine 4 mg/kg, group B incremental doses of halothane (0.5, 1.0 vol%) and group C succinylcholine and halothane simultaneously. Vital signs were recorded continuously.
Results
Prior to drug application measured values did not differ between MHS and MHN. While MHN pigs did not show relevant alterations, succinylcholine, halothane and the combination of both lead to significant hemodynamic and metabolic changes in MHS swine.
Conclusions
Hemodynamic and metabolic alterations following succinylcholine were similar to halothane in MHS pigs. The combination of both pharmacological agents potentiated the observed effects. According to these results succinylcholine acted as an independent and supportive factor during onset of an MH episode.
Background
Malignant hyperthermia (MH), a metabolic myopathy triggered by volatile anesthetics and depolarizing muscle relaxants, is a potentially lethal complication of general anesthesia in susceptible patients. The implementation of modern inhalation anesthetics that research indicates as less potent trigger substances and the recommended limitations of succinylcholine use, suggests there may be considerable decline of fulminant MH cases. In the presented study, the authors analyzed suspected MH episodes during general anesthesia of patients that were referred to the Wuerzburg MH unit between 2007 and 2011, assuming that MH is still a relevant anesthetic problem in our days.
Methods
With approval of the local ethics committee data of patients that underwent muscle biopsy and in vitro contracture test (IVCT) between 2007 and 2011 were analyzed. Only patients with a history of suspected MH crisis were included in the study. The incidents were evaluated retrospectively using anesthetic documentation and medical records.
Results
Between 2007 and 2011 a total of 124 patients were tested. 19 of them were referred because of suspected MH events; 7 patients were diagnosed MH-susceptible, 4 MH-equivocal and 8 MH-non-susceptible by IVCT. In a majority of cases masseter spasm after succinylcholine had been the primary symptom. Cardiac arrhythmias and hypercapnia frequently occurred early in the course of events. Interestingly, dantrolene treatment was initiated in a few cases only.
Conclusions
MH is still an important anesthetic complication. Every anesthetist must be aware of this life-threatening syndrome at any time. The rapid onset of adequate therapy is crucial to avoid major harm and possibly lethal outcome. Dantrolene must be readily available wherever MH triggering agents are used for anesthesia.
Objective: We investigated cerebral opioid receptor binding potential in patients with fibromyalgia syndrome (FMS) using positron-emission-tomography (PET) and correlated our results with patients’ systemic interleukin-4 (IL-4) gene expression.
Methods: In this pilot study, seven FMS patients (1 man, 6 women) agreed to participate in experimental PET scans. All patients underwent neurological examination, were investigated with questionnaires for pain, depression, and FMS symptoms. Additionally, blood for IL-4 gene expression analysis was withdrawn at two time points with a median latency of 1.3 years. Patients were investigated in a PET scanner using the opioid receptor ligand F-18-fluoro-ethyl-diprenorphine ([18F]FEDPN) and results were compared with laboratory normative values.
Results: Neurological examination was normal in all FMS patients. Reduced opioid receptor binding was found in mid cingulate cortex compared to healthy controls (p < 0.005). Interestingly, three patients with high systemic IL-4 gene expression had increased opioid receptor binding in the fronto-basal cortex compared to those with low IL-4 gene expression (p < 0.005).
Conclusion: Our data give further evidence for a reduction in cortical opioid receptor availability in FMS patients as another potential central nervous system contributor to pain in FMS.
Objective:
Halothane and caffeine are known to cause skeletal muscular contractions in vitro and have been proven to induce circumscribed metabolic reactions when injected into rat skeletal muscle. In this study 26 rats were investigated by either continuous application of calcium 160 mM or bolus injection of caffeine 160 mM or halothane 10% vol via a microdialysis probe in the tibialis anterior muscle. Tissue elasticity at the injection site was monitored by ultrasound strain elastography. Aim of this study was to detect (I) changes in local lactate concentrations and (II) whether these can be attributed to a muscular contraction detected by ultrasound elastography.
Results:
Localized metabolic reactions were verified by increasing intramuscular lactate concentrations following continuous application of calcium (0.6 [0.3;0.6] to 3.6 [3.0;4.3] mmol/l after 60 min) and bolus application of caffeine (0.2 [0.2;0.3] to 1.6 [0.9;1.9] mmol/l after 30 min) and halothane (0.3 [0.1;0.3] to 4.7 [4.3;6.3] mmol/l after 30 min). However, ultrasound elastography did not detect any differences in tissue elasticity compared to control animals. The authors identified potential limitations of the study conditions, which might be crucial to avoid for future investigations.
Background:
The calcium sensitizer levosimendan is increasingly used to improve hemodynamics in patients with acutely decompensated heart failure. By binding to cardiac troponin C the conformation of the calcium-troponin C complex is stabilized, which leads to acceleration of actin-myosin crossbrigde formation and increased force generating capacity of muscle fibers. Besides indications in cardiac failure, beneficial effects of levosimendan in skeletal muscle disorders are currently evaluated. The aim of this study was to investigate differential effects of levosimendan on skeletal muscle of pigs with and without susceptibility to malignant hyperthermia (MH) in order to identify possible risks of this emerging drug for patients with predisposition to MH.
Methods:
Muscle bundles of 17 pigs (9 MH susceptible (MHS); 8 MH non-susceptible (MHN)) were excised under general anesthesia and examined in the tissue bath with increasing concentrations of levosimendan (0.065; 0.125; 0.5; 1.0; 10 and 50 μg/ml). Baseline tension and twitch force were monitored continuously. Data are presented as median and interquartile range. Statistical evaluation was performed using D’Agostino & Pearson test for normal distribution and student’s t test and 2-way ANOVA for differences between the groups. P < 0.05 was considered significant.
Results:
There were no differences between the groups concerning length, weight, initial twitch force and pre-drug resting tension of the investigated muscle strips. After an initial decrease in both groups, twitch amplitude was significantly higher in MHN (− 3.0 [− 5.2–0.2] mN) compared to MHS (− 7.5 [− 10.8- -4.5] mN) (p = 0.0034) muscle at an applied levosimendan concentration of 50 μg/ml. A marked increase in resting tension was detected following levosimendan incubation with 50 μg/ml in MHS muscle bundles (3.3 [0.9–6.1] mN) compared to MHN (− 0.7 [− 1.3–0.0] mN) (p < 0.0001).
Conclusions:
This in vitro investigation revealed the development of significant contractures in muscle bundles of MHS pigs after incubation with levosimendan. However, the effect appeared only at supra-therapeutic concentrations and further research is needed to determine the impact of levosimendan on MHS individuals in vivo.