Joint Transnational Call 2022 (JTC2022)
SPMH: Metabolic test in vivo for malignant hyperthermia
Malignant hyperthermia (MH) is a potentially fatal hypermetabolic reaction to certain anesthetics, caused by an inherited dysregulation of calcium in skeletal myocytes. A minimally-invasive test with high sensitivity to diagnose MH susceptibility is still an unmet needed. Although genetic screening can detect MH predisposition, it is not sensitive enough to rule it out. Many suspected patients and their relatives require a surgical biopsy to evaluate in vitro muscle responses to MH trigger drugs by the so-called contracture tests, which are invasive, painful, and costly. We envisage developing a metabolic test to diagnose MH susceptibility by using in vivo intramuscular microinjections of caffeine and halothane, which would induce a localized hypermetabolic reaction in MH-susceptible patients only, producing unique molecular signals. To detect such potential MH biomarkers we will use solid phase microextraction (SPME), an innocuous sampling method consisting of an adsorbent phase mounted on modified acupuncture needles, which can be inserted intramuscularly adjacent to the injection site for extracting the drug reaction by-products. The extracted biomarkers can be desorbed for detection by analytical instruments or by a targeted biosensor. We have preliminarily identified potential biomarkers in muscle from MH patients ex vivo and in MH model mice. We have tested in vivo SPME sampling in human patients for other clinical applications.
Our target is to deliver a minimally invasive device with high sensitivity to diagnose MH susceptibility in vivo by detecting specific biomarkers. Aim 1 is to develop sampling and biosensing technologies tailored for detecting the molecular signatures of MH susceptibility from human muscle in vivo. Aim 2 is to identify and validate MH susceptibility biomarkers by comprehensive analytical approaches using MH animal models and human muscle ex vivo. Aim 3 (Primary Aim) is to carry out a multicenter prospective clinical trial to assess the diagnostic accuracy of a novel metabolic test for detecting MH susceptibility, using contracture testing as reference standard. Our main hypothesis is that the sensitivity of our novel test is at least 80% compared to that of the contracture tests to diagnose MH susceptibility. We require a sample of 228 patients to test our main hypothesis with 80% power. All patients scheduled for MH contracture testing will be eligible to simultaneously undergo the novel metabolic test during the biopsy.
We expect to deliver a high-accuracy minimally-invasive alternative test to diagnose MH-susceptibility, thus fulfilling an unmet need long sought by clinicians and patients alike, favoring testing acceptance by averting a painful muscle biopsy and its undesired consequences, and saving costs to patients and to the healthcare system.
Our target is to deliver a minimally invasive device with high sensitivity to diagnose MH susceptibility in vivo by detecting specific biomarkers. Aim 1 is to develop sampling and biosensing technologies tailored for detecting the molecular signatures of MH susceptibility from human muscle in vivo. Aim 2 is to identify and validate MH susceptibility biomarkers by comprehensive analytical approaches using MH animal models and human muscle ex vivo. Aim 3 (Primary Aim) is to carry out a multicenter prospective clinical trial to assess the diagnostic accuracy of a novel metabolic test for detecting MH susceptibility, using contracture testing as reference standard. Our main hypothesis is that the sensitivity of our novel test is at least 80% compared to that of the contracture tests to diagnose MH susceptibility. We require a sample of 228 patients to test our main hypothesis with 80% power. All patients scheduled for MH contracture testing will be eligible to simultaneously undergo the novel metabolic test during the biopsy.
We expect to deliver a high-accuracy minimally-invasive alternative test to diagnose MH-susceptibility, thus fulfilling an unmet need long sought by clinicians and patients alike, favoring testing acceptance by averting a painful muscle biopsy and its undesired consequences, and saving costs to patients and to the healthcare system.
- Ibarra Moreno, Carlos Alberto (Coordinator)
Malignant Hyperthermia Investigation Unit – TGHRI[CANADA]
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Díaz-Cambronero, OscarBiomedical Research Institute la Fe
[SPAIN]
- Ozkan, Sibel
Faculty of Pharmacy[TURKEY]
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Koellensperger, GundaFaculty of Chemistry
[AUSTRIA]
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Pawliszyn, JanuszDepartment of Chemistry
[CANADA]
- Barbas, Coral
Centre for Metabolomics and Bioanalysis (CEMBIO)
[SPAIN] - Bojko, Barbara
Faculty of Pharmacy, Collegium Medicum in Bydgoszcz
[POLAND] - Boyaci, Ezel
Department of Chemistry
[TURKEY]
