Prof. med. Werner J. Z'Graggen, Inselspital Bern

Abstract (Lay summary see below)

In this project, recently developed muscle excitability tests sensitive to membrane potential will be combined with conventional methods to investigate the pathogenesis of critical illness myopathy (CIM). CIM is a frequent and serious complication of intensive care, which results in weakness that delays weaning from mechanical ventilation and increases mortality as well as morbidity. The current criteria allow diagnosis of CIM only at an advanced stage. The lack of a tool for early diagnosis of evolving CIM impedes the conduction of therapeutic trials and can have a negative impact on the patient’s treatment regime. Furthermore, the role of neuromuscular blocking agents, which are routinely used in clinical practice, as a causative factor for CIM is still unclear. Using muscle excitability tests, we could recently show that early muscle membrane depolarization/sodium channel inactivation precedes the development of structural changes in CIM in an animal model of sepsis and that this technique might be used for early detection of the disease. The aim of the present project is twofold:  

1. To prospectively evaluate the evolution and pathophysiologic characteristics of muscular abnormalities in patients during critical illness until the definite diagnosis of CIM according to the current criteria can be made. We hypothesize that structural damage is preceded by muscle membrane depolarization and that diagnosis of membrane depolarization is one of the first signs of evolving CIM. 

2. To compare abnormalities in excitability parameters of muscle fibers depending on the exposure to neuromuscular blocking agents in order to determine if treatment with neuromuscular blocking agents is an additional risk factor for CIM. 

The project is designed as a longitudinal prospective observational study. Patients with sepsis and/or systemic inflammatory response syndrome and patients under treatment with neuromuscular blocking agents will be evaluated repetitively using muscle excitability measurements until definite diagnosis of CIM is made. The current study proposal therefore provides the possibility of a tool for early detection of CIM before its clinical manifestations with the ultimate goal to improve treatment of affected patients. 

Lay summary

Das Projekt hat das Ziel mittels der Methode der Muskelfaserexzitabilitätsmessung die „critical illness“-Myopathie zu erforschen. Die „critical illness“-Myopathie kann bei Patienten, welche eine intensivmedizinische Behandlung benötigen auftreten. Als Folge können Patienten oft erst verzögert von der künstlichen Beatmung entwöhnt werden und benötigen eine längere Rehabilitation. Bei schwerer Ausprägung ist die Erholung inkomplett und die Mortalität erhöht. Bis heute ist die Ursache der Erkrankung nicht geklärt und es existiert keine Therapie. Die Methode der Muskelfaserexzitabilitätsmessung kann Störungen der elektrischen Eigenschaften der Muskelfasermembran aufzeigen.

Unsere Forschungsgruppe konnte bereits zeigen, dass solche als eines der ersten Zeichen der „critical illness“-Myopathie auftreten. Das Projekt will einerseits dazu beitragen, die Diagnosestellung zu erleichtern und andererseits die Ursache weiter erforschen. Insbesondere wird untersucht ob Medikamente aus der Gruppe der Muskelrelaxantien die Entstehung begünstigen.