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Population at Risk of Malignant Hyperthermia: Ambispective Cohort.

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ClinicalTrials.gov Identifier: NCT04287556
Recruitment Status : Recruiting
First Posted : February 27, 2020
Last Update Posted : June 4, 2020
Sponsor:
Collaborator:
Universidad Autonoma de Madrid
Information provided by (Responsible Party):
Instituto de Investigación Hospital Universitario La Paz

Brief Summary:

Malignant hyperthermia (MH) is a pharmacogenetic disease that manifests itself as a hypermetabolic response of skeletal musculature, in genetically susceptible patients, with the inhalation of volatile halogenated anesthetics, depolarizing neuromuscular relaxants such and, rarely, physical stressors such as intense exercise and heat stroke.

HM diagnosis is based on the performance of two tests:

  • In vitro muscle contraction test (IVCT): it is the gold standard of the diagnosis of HM in Europe.
  • Pharmacogenetic study: about 50 genetic variants associated with HM have been described.

It also has been described that B lymphocytes of patients with MH have metabolic alterations.

The main objective is to evaluate the association of disorders that occur with hypermetabolic response of skeletal musculature and susceptibility to malignant hyperthermia (MH).


Condition or disease Intervention/treatment
Hyperthermia, Malignant Diagnostic Test: In vitro contracture test (IVCT) Diagnostic Test: In vitro test of hypermetabolism in B lymphocytes Diagnostic Test: Genetic test

Detailed Description:

Malignant hyperthermia (MH) is a pharmacogenetic disease that manifests itself as a hypermetabolic response of skeletal musculature, in genetically susceptible patients, with the inhalation of volatile halogenated anesthetics, depolarizing neuromuscular relaxants such and, rarely, physical stressors such as intense exercise and heat stroke.

Risk factors to present this disease are:

  • An adverse reaction to general anesthesia manifested as an unexplained increase in carbon, dioxide production, tachycardia, temperature rise, muscle. stiffness, rhabdomyolysis, disseminated intravascular coagulation or death, or both. During anesthesia or within 60 minutes of treatment discontinuation.
  • Family history of unexplained perioperative death.
  • Postoperative rhabdomyolysis after clinical exclusion of other myopathies.
  • Stress rhabdomyolysis, recurrent or persistent rhabdomyolysis increased serum creatine kinase concentration where no cause has been identified after neurological study (idiopathic hyperCKemia).
  • Heat stroke by effort that requires hospital admission, where known predisposing factors have been excluded.
  • Other myopaties Extreme physical activity, as well as environments with high temperatures favor the appearance of ischemia, anoxia and release of calcium from the sarcoplasmic reticulum, thus increasing the risk of developing MH.

There are also other infrequent diseases in which there is a ryanodine canalopathy by a mechanism similar to that seen in MH, but in cells of tissues other than skeletal striated muscle; as well as some drugs and other rare diseases that may be related to MH.

Despite the rarity of MH and given the severity of the disease clinic, it is mandatory to explore possible risks in patients with hypermetabolic response of skeletal musculature due to rare or trigger diseases (medications, drugs of abuse, exercise, extreme heat, others) whose MH risk is not defined.

Although the standard method for the diagnosis of MH is the in vitro test for halothane caffeine contraction (IVCT), it has been described that B lymphocytes of patients with MH have metabolic alterations. Alto, there are about 50 genetic variants associated with MH that have been described.

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Study Type : Observational
Estimated Enrollment : 90 participants
Observational Model: Cohort
Time Perspective: Other
Official Title: Population at Risk of Malignant Hyperthermia: Ambispective Cohort.
Actual Study Start Date : February 26, 2020
Estimated Primary Completion Date : February 28, 2025
Estimated Study Completion Date : February 28, 2025

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Fever

Group/Cohort Intervention/treatment
Population in risk of MH
Patient with hypermetabolic response of skeletal musculature by causes related with Malignant Hyperthermia in the literature.
Diagnostic Test: In vitro contracture test (IVCT)
In vitro study of muscle contraction after exposure to different substances (caffeine and halothane).

Diagnostic Test: In vitro test of hypermetabolism in B lymphocytes
In vitro study of the activation of lymphocytes B after being incubated with a cocktail of primary antibodies and measuring the acidification in response to the RyR1, 4-CmC agonist, using ryanodine as a positive control.

Diagnostic Test: Genetic test
Analysis of genes related to MH (CACNA1S and RYR1).




Primary Outcome Measures :
  1. Determination, by an in vitro study of muscular contraction, measuring the muscle tension, of the presence of Malignant Hyperthermia susceptibility in patients with a history of hypermetabolic response of skeletal musculature. [ Time Frame: 5 years ]
    Measured by the tension induced by the muscular contraction in response to the presence of caffeine and halothane.

  2. Determination, by genetic study, of the presence of susceptibility to Malignant Hyperthermia in patients with a history of hypermetabolic response of skeletal musculature. [ Time Frame: 5 years ]
    Identifying determined genes related with Malignant Hyperthermia risk.

  3. Study of the concordance of the genetic study and IVCT versus the hypermetabolic response of B lymphocyte, in patients with a history of hypermetabolic response of skeletal musculature. [ Time Frame: 5 years ]
    Extracellular acidification curve in B lymphocytes in response to the agonist RyR1 and 4-CmC.


Biospecimen Retention:   Samples With DNA
50 variants have been described that can be considered "diagnostic mutations" of RYR1 and CACNA1S, and other under study.


Information from the National Library of Medicine

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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Probability Sample
Study Population
Patient with hypermetabolic response of skeletal musculature by related causes in the literature with Malignant Hyperthermia.
Criteria

Inclusion Criteria:

  • Patients who have suffered at least one episode of rhabdomyolysis due to related causes in the literature with susceptibility to HM.
  • Patients who have been given information about the study and have agreed to sign the consent of the study. The muscle biopsy will be performed under usual clinical practice.

Exclusion Criteria:

  • Patients who have suffered episodes of rhabdomyolysis due to alternative causes: trauma, compression hypoxia during immobilization or loss of consciousness or infectious arterial occlusion (influenza A and B, coxackievirus, Epstein-Barr, HIV, legionella, Streptococcus pyogenes Staphilococcus aureus, clostridium), metabolic or electrolyte abnormalities (hypokalemia, hypophosphatemia, hypocalcemia, non-ketosic hyperosmolar conditions, diabetic ketoacidosis), others.
  • Children under 10 years or less than 30 kg are excluded for the in vitro test (muscle biopsy).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04287556


Contacts
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Contact: Elena Ramírez García +34 917277559 elena.ramirezg@uam.es

Locations
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Spain
Hospital Universitario La Paz Recruiting
Madrid, Spain, 28046
Contact: Elena Ramírez García    +34 917277559    elena.ramirezg@uam.es   
Sponsors and Collaborators
Instituto de Investigación Hospital Universitario La Paz
Universidad Autonoma de Madrid
Investigators
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Principal Investigator: Elena Ramírez García Clinical Pharmacology Department, La Paz University Hospital
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Responsible Party: Instituto de Investigación Hospital Universitario La Paz
ClinicalTrials.gov Identifier: NCT04287556    
Other Study ID Numbers: HUL-RHM-2019
First Posted: February 27, 2020    Key Record Dates
Last Update Posted: June 4, 2020
Last Verified: February 2020

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Fever
Malignant Hyperthermia
Body Temperature Changes
Intraoperative Complications
Pathologic Processes
Postoperative Complications