Novel approach for Malignant Hyperthermia diagnosis

Abstract

In this thesis, a novel technique for malignant hyperthermia diagnosis is proposed and developed. Malignant hyperthermia is an inherited myopathy that features sustained skeletal muscle hypermetabolism caused by altered calcium homeostasis. It is a rare and potentially lethal syndrome. The well-established available diagnosis options are genetic testing, which is not entirely reliable, and in-vitro contracture testing of a surgically extracted fresh skeletal muscle sample, which is too complicated and costly. The thesis presents work towards inventing a new diagnosis technique through a device inspired by the well-established ABI micro-mechanocalorimeter that is used for measuring energetics of tiny cardiac trabeculae. This novel malignant hyperthermia diagnostic technique promises a very good sensitivity and significantly diminished discomfort to the patient. The goal is achieved in three steps: first a minimal invasive approach is established by using a needle biopsy based sampling method, and an extracted muscle sample is analysed for its viability prior to the testing procedure. The 1.6 mm diameter and 10 ± 2 mm skeletal muscle samples were extracted, intact, using micro-needle biopsy. The second goal was measurement, using an existing instrument, of the drastic increase in heat output rate from muscle when maximal contracture was initiated. The heat output rate for contracture was double that for normal contratile muscle. The final step was to develop a device capable of measuring the small heat output rate of very small muscle sample with high resolution. A calorimetry device was modelled, constructed and characterised. The device met the requirement of very good resolution, fast transient response and broad range require for the purpose. This innovative approach to malignant hyperthermia diagnosis also opens new research areas in measurement of muscle heat for genetic mutation diagnosis. The major outcomes of the thesis are:  The use of micro-needle biopsy utilization for the microcalorimeter instrument providing new approach for further investigation.  Utilization of skeletal muscle heat output measurement for the determining the presence of a genetic mutation syndrome.  Design and construction of the first flow-through muscle calorimeter for measurement of heat rate using biopsied skeletal muscle at room temperature, using robust thermoelectric modules as temperature sensors.