Werner Klingler

Complications of anaesthesia in neuromuscular disorders

The purpose of this review is to alert non-anaesthesiologists to the various complications from which patients with neuromuscular disorders and those susceptible to malignant hyperthermia can suffer during anaesthesia. The patients outcome correlates with the quality of consultation between anaesthesiologists, surgeons, neurologists and cardiologists. Special precautions must be taken, since many anaesthetics and muscle relaxants can aggravate the clinical features or trigger life-threatening reactions. Complications frequently occur in these patients, although anaesthetic procedures have become safer by the reduced administration of suxamethonium and the use of total intravenous anaesthesia, new volatile anaesthetics and non-depolarising relaxants. This review provides a synopsis of pre-operative anaesthetic considerations and adverse drug effects on skeletal, cardiac and smooth muscle tissue. It describes the pathogenetic aspects of typical complications and introduces anaesthetic procedures for the various neuromuscular disorders, including regional anaesthesia for patients in whom a restriction of respiratory and/or cardiac function is predicted.

What is 'fascia'? A review of different nomenclatures

There are many different definitions of fascia. Here the three most common nomenclatures are compared, including that of the Federative International Committee on Anatomical Terminology (1998), the definition included in the latest British edition of Grays Anatomy (2008) and the newer and more comprehensive terminology suggested at the last international Fascia Research Congress (2012). This review covers which tissues are included and excluded in each of these nomenclatures. The advantages and disadvantages of each terminology system are suggested and related to different fields of application, ranging from histology, tissue repair, to muscular force transmission and proprioception. Interdisciplinary communication involving professionals of different fields is also discussed.

Core Myopathies and Risk of Malignant Hyperthermia

In this article, we analyze myopathies with cores, for which an association to malignant hyperthermia (MH) has been suggested. We discuss the clinical features, the underlying genetic defects, subsequent effects on cellular calcium metabolism, and in vitro muscle responses to MH triggers. We describe in detail central core disease, multiminicore disease, and nemaline rod myopathy. We categorize the diseases according to the affected proteins and discuss the risk for MH, which is high or theoretically possible when the calcium-conducting proteins are affected.

A multicenter study of 4-chloro-m-cresol for diagnosing malignant hyperthermia susceptibility.

Standardization of the in vitro contracture test (IVCT) for malignant hyperthermia (MH) susceptibility has resulted in very rare false negative tests. However, false positive results stigmatizing the patient seem to be more frequent than false negative results and make supplementary tests desirable. This multicenter approach studied the usefulness of an IVCT with 4-chloro-m-cresol (4-CmC), a ryanodine receptor-specific agonist for a better definition of MH susceptibility. Diagnosis made by the standard IVCT was compared with the results of this 4-CmC test on muscle specimens of 202 individuals from 6 European MH centers. In the 4-CmC test, the results of the MH susceptible group differed significantly from both the MH normal and the MH equivocal group. 4-CmC revealed a qualitatively dose response-curve similar to caffeine. A correlation index of r = 0.79 for the concentration thresholds underlined the strong concordance of the caffeine and the 4-CmC effects. The optimal threshold concentration was determined to be 75 &mgr;M in the pooled data of all centers and is much lower than that of caffeine (2 mM), suggesting a more than 25-fold higher affinity of 4-CmC. The predictive value of 4-CmC is as high as that of caffeine and consequently higher than that of halothane. 4-CmC seems to be a suitable drug to refine diagnosis of MH susceptibility and could be used as an additional test substance. Implications Although in vitro contracture testing for malignant hyperthermia diagnosis is well standardized, with a relatively high sensitivity and specificity, false test results cannot be excluded and may be associated with serious disabilities for the concerned individuals. In this multicenter study, 4-chloro-m-cresol was evaluated as a new test substance for the in vitro contracture testing. Its use improves the accuracy of in vitro diagnosis of malignant hyperthermia susceptibility.

Strain hardening of fascia: Static stretching of dense fibrous connective tissues can induce a temporary stiffness increase accompanied by enhanced matrix hydration

This study examined a potential cellular basis for strain hardening of fascial tissues: an increase in stiffness induced by stretch and subsequent rest. Mice lumbodorsal fascia were isometrically stretched for 15 min followed by 30 min rest (n=16). An increase in stiffness was observed in the majority of samples, including the nonviable control samples. Investigations with porcine lumbar fascia explored hydration changes as an explanation (n=24). Subject to similar loading procedures, tissues showed decreases in fluid content immediately post-stretch and increases during rest phases. When allowed sufficient resting time, a super-compensation phenomenon was observed, characterised by matrix hydration higher than initial levels and increases in tissue stiffness. Therefore, fascial strain hardening does not seem to rely on cellular contraction, but rather on this super-compensation. Given a comparable occurrence of this behaviour in vivo, clinical application of routines for injury prevention merit exploration.

Clinical Relevance of Fascial Tissue and Dysfunctions

Fascia is composed of collagenous connective tissue surrounding and interpenetrating skeletal muscle, joints, organs, nerves, and vascular beds. Fascial tissue forms a whole-body, continuous three-dimensional viscoelastic matrix of structural support. The classical concept of its mere passive role in force transmission has recently been disproven. Fascial tissue contains contractile elements enabling a modulating role in force generation and also mechanosensory fine-tuning. This hypothesis is supported by in vitro studies demonstrating an autonomous contraction of human lumbar fascia and a pharmacological induction of temporary contraction in rat fascial tissue. The ability of spontaneous regulation of fascial stiffness over a time period ranging from minutes to hours contributes more actively to musculoskeletal dynamics. Imbalance of this regulatory mechanism results in increased or decreased myofascial tonus, or diminished neuromuscular coordination, which are key contributors to the pathomechanisms of several musculoskeletal pathologies and pain syndromes. Here, we summarize anatomical and biomechanical properties of fascial tissue with a special focus on fascial dysfunctions and resulting clinical manifestations. Finally, we discuss current and future potential treatment options that can influence clinical manifestations of pain syndromes associated with fascial tissues.

Letter to the Editor concerning “A hypothesis of chronic back pain: ligament subfailure injuries lead to muscle control dysfunction” (M. Panjabi)

In his article Panjabi gives a concise overview on the current knowledge and understanding of low back and neck pain [12]. He introduces the hypothesis that chronic back pain originates from subfailure injuries of three types of spinal ligamentous structures and their embedded mechanoreceptors: namely the spinal ligaments, the disc annulus and the facet capsules. These injured tissues then send out corrupted transducer signals to the neuromuscular control unit, and as a result corrupted muscle response patterns are generated leading to adverse consequences such as higher stresses, muscle fatigue, further injuries, and inflammation. While paying less attention to the central learning processes involved in chronic back pain [5, 6, 19], this model focuses mainly on the structural mechanisms of pain generation. We are appreciative about the value of the hypothesis within this structural field and are optimistic about its successful application to the understanding and treatment of many cases of back pain. While we agree with the basic hypothesis and its emphasis on the transducer (mechanosensory) function of ligamentous tissues, we suggest to refine the model in terms of an inclusion of the thoracolumbar fascia (TLF). We present evidence that the TLF is significantly involved in all three levels of the hypothesis concerning spinal ligamentous structures: the transducer function of these tissues, their structural spinal function, and their proneness for subfailure injuries.

Functional and genetic characterization of clinical malignant hyperthermia crises: a multi-centre study

BackgroundMalignant 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.MethodsIn 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.ResultsA 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.ConclusionsAn 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.

Bispectral index (BIS) and suppression ratio (SR) as an early predictor of unfavourable neurological outcome after cardiac arrest

INTRODUCTION Predicting the neurological outcome after cardiopulmonary resuscitation (CPR) is extremely difficult. We tested the hypothesis whether monitoring of bispectral index (BIS) and suppression ratio (SR) could serve as an early prognostic indicator of neurological outcomes after CPR. METHODS Cerebral monitoring (BIS, SR) was started as soon as possible after initiation of CPR and was continued for up to 72h. The functional neurological outcome was measured on day 3, day 7 and again one month after CPR via a clinical examination and assessment according to the cerebral performance category score (CPC). RESULTS In total 79 patients were included. Of these, 26 patients (32.9%) survived the observation period of one month; 7 of them (8.9%) showed an unfavourable neurological outcome. These 7 patients had significantly lower median BIS values (25 [21;37] vs. 61 [51;70]) and higher SR (56 [44;64] vs. 7 [1;22]) during the first 4h after the initiation of CPR. Using BIS<40 as threshold criteria, unfavourable neurological outcome was predicted with a specificity of 89.5% and a sensitivity of 85.7%. The odds ratio for predicting an unfavourable neurological outcome was 0.921 (95% CI 0.853-0.985). The likelihood to remain in a poor neurological condition decreased by 7.9% for each additional point of BIS, on average. CONCLUSION Our results suggest that BIS and SR are helpful tools in the evaluation of the neurological outcomes of resuscitated patients. Nevertheless, therapeutic decisions have to be confirmed through further examinations due to the far-ranging consequences of false positive results.

Functional Characterization of Ryanodine Receptor (RYR1) Sequence Variants Using a Metabolic Assay in Immortalized B-Lymphocytes

Mutations in the RYR1 gene are linked to malignant hyperthermia (MH), central core disease and multi‐minicore disease. We screened by DHPLC the RYR1 gene in 24 subjects for mutations, and characterized functional alterations caused by some RYR1 variants. Three novel sequence variants and twenty novel polymorphisms were identified. Immortalized lymphoblastoid cell lines from patients with RYR1 variants and from controls were stimulated with 4‐chloro‐m‐cresol (4‐CmC) and the rate of extracellular acidification was recorded. We demonstrate that the increased acidification rate of lymphoblastoid cells in response to 4‐CmC is mainly due to RYR1 activation. Cells expressing RYR1 variants in the N‐terminal and in the central region of the protein (p.Arg530His, p.Arg2163Pro, p.Asn2342Ser, p.Glu2371Gly and p.Arg2454His) displayed higher activity compared with controls; this could account for the MH‐susceptible phenotype. Cell lines harboring RYR1Cys4664Arg were significantly less activated by 4‐CmC. This result indicates that the p.Cys4664Arg variant causes a leaky channel and depletion of intracellular stores. The functional changes detected corroborate the variants analyzed as disease‐causing alterations and the acidification rate measurements as a means to monitor Ca2+‐induced metabolic changes in cells harboring mutant RYR1 channels.