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Risk Factors for Malignant Hyperthermia Crises and Subsequent Complications to Inform Model Development for Population Newborn Screening 

Health Services and Implementation
  • Primary Categories:
    • Health services and Implementation
  • Secondary Categories:
    • Health services and Implementation
Introduction:
Malignant hyperthermia (MH) is a life-threatening hypermetabolic reaction to potent inhaled anesthetics and succinylcholine due to dysregulated calcium homeostasis in skeletal muscle. MH susceptibility is inherited in an autosomal dominant fashion with reduced penetrance and variable presentation. Genomic screening for pathogenic variants in RYR1 and CACNA1S can identify individuals with MH susceptibility and allow clinicians to use alternative medications to avoid crisis events. The American College of Medical Genetics and Genomics recommends screening for MH variants as a secondary finding during clinical genomic sequencing, and an increasing number of population-level research programs (e.g., All of Us) and clinical systems screen for MH variants as an optional service. However, the clinical impact of population genomic screening for MH is not well understood, including the consequences for identified patients and their relatives. Here, we summarize selective factors associated with risk for MH crisis and the likelihood of complications, including death, following an MH crisis.

 

Methods:
The Precision Medicine Policy and Treatment (PreEMPT) Model is developing a simulation model to estimate the benefits, harms, costs, and cost-effectiveness of newborn genomic screening for MH. As part of model development to estimate the benefits of avoiding a MH crisis, we reviewed key epidemiological papers about MH pathophysiology and MH crises. Here, we summarize factors associated with the likelihood of MH crises and, separately, factors associated with the likelihood of crisis complications that are conducive for simulation modeling.



 

Results:
The incidence of a MH crisis is between 1:10,000 among children and 1:100,000 to 1:160,000 among adults who are exposed to triggering agents. Risks are increased among patients with certain neuromuscular conditions or histories of exertional rhabdomyolysis as well as patients who are younger (median age 22.0 years (10.0, 41.0 years, range 116 days to 78.0 years) and male (74.8%).  Between 3% and 20% of patients experience MH crisis complications. Complications of MH crisis are change in consciousness level including coma, cardiac dysfunction, pulmonary edema, renal dysfunction, disseminated intravascular coagulation, and hepatic dysfunction.  The likelihood of a complication increased 1.61 times (95% CI, 1.16-2.25) for every 30-minute increase in time between the first sign of MH and the first dantrolene dose (the specific therapy for MH crisis) and 2.65 times (95% CI, 1.60-5.08) for every 2°C increase in maximum temperature. “Very likely” or “almost certain” MH mortality rates are 5% in pediatric patients and 9.5% in patients of all ages. Core temperature monitoring best distinguished patients who lived from those who died, with higher peak temperatures being associated with longer anesthetic exposures before first dantrolene dose.



 

Conclusion:
Findings highlight the importance of early identification of MH susceptibility and intervention to avoid known MH triggering anesthetics as well as the clinical and demographic factors associated with the incidence and severity of MH events. Our findings quantify the contributions of risk factors to the likelihood of MH crisis and complications. The results of this work will be incorporated into a simulation model to estimate the impact of newborn genomic screening for MH to guide policy development.



 

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