Multiacquisition T1-mapping MRI during tidal respiration for quantification of myocardial T1 in swine with heart failure.

OBJECTIVE: The purpose of this article is to evaluate a free-breathing pulse sequence to quantify myocardial T1 changes in a swine model of tachycardia-induced heart failure. MATERIALS AND METHODS: Yorkshire swine were implanted with pacemakers and were ventricularly paced at 200 beats/min to induce heart failure. Animals were scanned twice with a 1.5-T MRI scanner, once at baseline and once at heart failure. A T1-mapping sequence was performed during tidal respiration before and 5 minutes after the administration of a gadolinium-chelate contrast agent. T1-mapping values were compared between the baseline and heart failure scans. The percentage of fibrosis of heart failure myocardial tissue was compared with similar left ventricular tissue from control animals using trichrome blue histologic analysis. RESULTS: In the study cohort, differences were found between the baseline and heart failure T1-mapping values before the administration of contrast agent (960 ± 96 and 726 ± 94 ms, respectively; p = 0.02) and after contrast agent administration (546 ± 180 and 300 ± 171 ms, respectively; p = 0.005). The animals with heart failure also had a difference histologically in the percentage of myocardial collagen compared with tissue from healthy control animals (control, 5.4% ± 1.0%; heart failure, 9.4% ± 1.6%; p < 0.001). CONCLUSION: The proposed T1-mapping technique can quantify diffuse myocardial changes associated with heart failure without the use of a contrast agent and without breath-holding. These T1 changes appear to be associated with increases in the percentage of myocardial collagen that in this study were not detected by traditional myocardial delayed enhancement imaging. T1 mapping may be a useful technique for detecting early but clinically significant myocardial fibrosis.

Case report: Death in the emergency department: an unrecognized awake malignant hyperthermia-like reaction in a six-year-old.

A healthy 6-year-old boy developed lower extremity rigidity, trismus, and fever after playing in a splash pool. On arrival in the emergency department, he appeared to be seizing. An endotracheal tube was emergently placed using succinylcholine. Cardiac arrest followed. He could not be resuscitated. Postmortem genetic analysis found a novel RYR1 variant. Family testing revealed the same variant in his father who also had muscle contracture testing diagnostic for susceptibility to malignant hyperthermia and central core disease diagnosed histologically. Because there was no exposure to volatile anesthetics before the onset of symptoms, this is a case of "awake" malignant hyperthermia worsened by succinylcholine.

Genetic polymorphisms associated with exertional rhabdomyolysis.

Exertional rhabdomyolysis (ER) occurs in young, otherwise healthy, individuals principally during strenuous exercise, athletic, and military training. Although many risk factors have been offered, it is unclear why some individuals develop ER when participating in comparable levels of physical exertion under identical environmental conditions and others do not. This study investigated possible genetic polymorphisms that might help explain ER. DNA samples derived from a laboratory-based study of persons who had never experienced an episode of ER (controls) and clinical ER cases referred for testing over the past several years were analyzed for single nucleotide polymorphisms (SNPs) in candidate genes. These included angiotensin I converting enzyme (ACE), α-actinin-3 (ACTN3), creatine kinase muscle isoform (CKMM), heat shock protein A1B (HSPA1B), interleukin 6 (IL6), myosin light chain kinase (MYLK), adenosine monophosphate deaminase 1 (AMPD1), and sickle cell trait (HbS). Population included 134 controls and 47 ER cases. The majority of ER cases were men (n = 42/47, 89.4 %); the five women with ER were Caucasian. Eighteen African Americans (56.3 %) were ER cases. Three SNPs were associated with ER: CKMM Ncol, ACTN3 R577X, and MYLK C37885A. ER cases were 3.1 times more likely to have the GG genotype of CKMM (odds ratio/OR = 3.1, confidence interval/CI 1.33-7.10), 3.0 times for the XX genotype of ACTN3 SNP (OR = 2.97, CI 1.30-3.37), and 5.7 times for an A allele of MYLK (OR = 21.35, CI 2.60-12.30). All persons with HbS were also ER cases. Three distinct polymorphisms were associated with ER. Further work will be required to replicate these findings and determine the mechanism(s) whereby these variants might confer susceptibility.

The relationship between exertional heat illness, exertional rhabdomyolysis, and malignant hyperthermia.

Exertional heat illness, exertional rhabdomyolysis, and malignant hyperthermia (MH) are complex syndromes with similar pathophysiology. All three are hypermetabolic states that include high demand for adenosine triphosphate, accelerated oxidative, chemical, and mechanical stress of muscle, and uncontrolled increase in intracellular calcium. Although there are no controlled clinical studies to support a relationship, there is evidence to suggest an association between unexpected heat/exercise intolerance and MH susceptibility. There are multiple case reports and a small number of clinical studies that have used in vitro muscle contracture testing and/or genetic testing to make the association. However, such methodology is problematic in that these tests are validated for clinical MH in association with anesthesia, and not for exertional heat illness or exertional rhabdomyolysis. Nevertheless, these relationships may have implications for some MH-susceptible patients and their capacity to exercise, as well as for clinicians treating and anesthetizing patients with histories of unexplained exertional heat and exercise illnesses.

Trauma, systemic inflammatory response syndrome, dietary supplements, illicit steroid use and a questionable malignant hyperthermia reaction.

BACKGROUND: Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle calcium regulation associated primarily, but not exclusively, with mutations in the skeletal muscle ryanodine receptor. Associated environmental factors, however, may also be important for expression of the syndrome. METHODS AND RESULTS: A 24-yr-old trauma patient developed a fulminant MH crisis after a 3 minute exposure to sevoflurane. A thorough evaluation of underlying co-morbidities revealed a number of environmental factors that could have altered skeletal muscle calcium regulation, and may have potentially influenced the effects of volatile inhaled anesthetics. Since MH is a syndrome characterized by abnormal skeletal muscle calcium regulation, other factors that alter calcium homeostasis may exacerbate the impact of inhaled MH-triggering drugs. CONCLUSIONS: While a thorough history of MH episodes in a proband and family is emphasized as part of a complete preanesthetic evaluation, obtaining a history of other environmental entities that may alter calcium regulation may be equally important to knowing the family history.

Pathogenic and rare deleterious variants in multiple genes suggest oligogenic inheritance in recurrent exertional rhabdomyolysis.

Exertional rhabdomyolysis is a metabolic event characterized by the release of muscle content into the circulation due to exercise-driven breakdown of skeletal muscle. Recurrent exertional rhabdomyolysis has been associated with metabolic myopathies and mitochondrial disorders, a clinically and genetically heterogeneous group of predominantly autosomal recessive, monogenic conditions. Although genetics factors are well recognized in recurrent rhabdomyolysis, the underlying causes and mechanisms of exercise-driven muscle breakdown remain unknown in a substantial number of cases. We present clinical and genetic study results from seven adult male subjects with recurrent exertional rhabdomyolysis. In all subject, whole exome sequencing identified multiple heterozygous variants in genes associated with monogenic metabolic and/or mitochondrial disorders. These variants consisted of known pathogenic and/or new likely pathogenic variants in combination with other rare deleterious alleles. The presence of heterozygous pathogenic and rare deleterious variants in multiple genes suggests an oligogenic inheritance for exertional rhabdomyolysis etiology. Our data imply that exertional rhabdomyolysis can reflect cumulative effects or synergistic interactions of deleterious variants in multiple genes that are likely to compromise muscle metabolism under the stress of exercise.

Multifactorial Origin of Exertional Rhabdomyolysis, Recurrent Hematuria, and Episodic Pain in a Service Member with Sickle Cell Trait.

Individuals with Sickle Cell Trait (SCT), generally considered a benign carrier state of hemoglobin S (HbAS), are thought to be at risk for exertional rhabdomyolysis and hematuria, conditions that can also be caused by various other acquired and inherited factors. We report an SCT positive service member with an exertional rhabdomyolysis event, recurrent hematuria with transient proteinuria, and episodic burning pain in the lower extremities. Clinical and genetic studies revealed the multifactorial nature of his complex phenotype. The service member was taking prescription medications known to be associated with exertional rhabdomyolysis. He carried a pathogenic mutation, NPHS2 p.V260E, reported in nephropathy and a new variant p.R838Q in SCN11A, a gene involved in familial episodic pain syndrome. Results suggest that drug-to-drug interactions coupled with the stress of exercise, coinheritance of HbAS and NPHS2 p.V260E, and p. R838Q in SCN11A contributed to exertional rhabdomyolysis, recurrent hematuria with proteinuria, and episodic pain, respectively. This case underscores the importance of comprehensive clinical and genetic evaluations to identify underlying causes of health complications reported in SCT individuals.

Malignant Hyperthermia Susceptibility and Fitness for Duty.

INTRODUCTION: Malignant hyperthermia (MH) is an inherited hypermetabolic condition characterized by uncontrolled calcium release from the sarcoplasmic reticulum of skeletal muscle, usually from exposure to inhaled general anesthetics and/or the depolarizing neuromuscular blocking agent succinylcholine. Multiple case reports now reveal that crises may be precipitated by environmental factors such as exercise or high ambient temperatures. Common signs of an MH crisis include life-threatening hyperthermia, metabolic acidosis, muscle rigidity, and tachycardia. Treatment consists of stopping triggering agents, administering dantrolene, and actively cooling the patient. MH is a medically disqualifying condition for service in the U.S. Armed Forces. However, patients with MH-causative mutations may never have experienced an MH episode. If they previously have had an event concerning for MH, details are often sparse and a formal evaluation is absent. MATERIALS AND METHODS: We present 2 case reports with military service implications, one as a formal applicant to the service academies and the other as the father of an active duty Navy chief. Both patients experienced prior MH-like reactions to anesthesia but had not undergone testing with a caffeine-halothane contracture test (CHCT) or genetic analysis. Both patients underwent skeletal muscle biopsies of the left vastus lateralis with nontriggering anesthetics at Children's National Medical Center in Washington, DC, and MH diagnostic CHCT at the Uniformed Services University of the Health Sciences (USUHS) in Bethesda, Maryland. The CHCT was performed according to the North American MH Registry Protocol. With USUHS Institutional Review Board approval, ryanodine receptor type 1 gene (RYR1) and L-type calcium channel α-1 subunit gene (CACNA1S) sequencing was performed on the remaining muscle at USUHS. RESULTS: Each subject was CHCT positive, confirming a diagnosis of MH. One was found to have a known MH-causative gene mutation. The applicant to the service academy was therefore determined unfit for military service. The active duty son of the MH-positive patient underwent muscle biopsy and CHCT in order to continue his military career. CONCLUSION: A personal or familial history concerning for MH raises important questions on fitness for duty in the U.S. Armed Forces. Department of Defense regulation uniformly defines MH as a disqualifying condition; however, screening for a history of anesthetic complications during accession into the military is inconsistent. Medical standards across the services are also variable in the context of a familial history of MH. These case reports highlight the need for clinicians to seek expert consultation about how to proceed with MH-related issues. They also stress the importance of applying current understanding of heritable conditions to our fitness for duty determinations. Further investigation is also recommended to establish an MH-susceptible individual's propensity for exercise or heat-related injury outside the operating room. Department of Defense policy may thereafter be updated to reflect a quantitative assessment of MH's relative risk during inherently strenuous military operations.

Round Table on Malignant Hyperthermia in Physically Active Populations: Meeting Proceedings.

CONTEXT: Recent case reports on malignant hyperthermia (MH)-like syndrome in physically active populations indicate potential associations among MH, exertional heat stroke (EHS), and exertional rhabdomyolysis (ER). However, an expert consensus for clinicians working with these populations is lacking. OBJECTIVE: To provide current expert consensus on the (1) definition of MH; (2) history, etiology, and pathophysiology of MH; (3) epidemiology of MH; (4) association of MH with EHS and ER; (5) identification of an MH-like syndrome; (6) recommendations for acute management of an MH-like syndrome; (7) special considerations for physically active populations; and (8) future directions for research. SETTING: An interassociation task force was formed by experts in athletic training, exercise science, anesthesiology, and emergency medicine. The "Round Table on Malignant Hyperthermia in Physically Active Populations" was convened at the University of Connecticut, Storrs, September 17-18, 2015. CONCLUSIONS: Clinicians should consider an MH-like syndrome when a diagnosis of EHS or ER cannot be fully explained by clinical signs and symptoms presented by a patient or when recurrent episodes of EHS or ER (or both) are unexplained. Further research is required to elucidate the genetic and pathophysiological links among MH, EHS, and ER.

Anesthesia services aboard USNS COMFORT (T-AH-20) during Operation Iraqi Freedom.

USNS COMFORT (T-AH-20), the only U.S. hospital ship to be deployed in support of combat operations during Operation Iraqi Freedom, sailed from Baltimore, Maryland, on January 6, 2003, and returned on June 12, 2003. During the course of her deployment, 648 anesthetic procedures were performed. We describe the anesthesia services provided, lessons learned, and recommendations for future concepts of employment.

Improving awareness of nonanesthesia-related malignant hyperthermia presentations: a tale of two brothers.

A 30-year-old man developed unexplained rhabdomyolysis, persistently increased creatine kinase and severe debilitating muscle cramps. After a nondiagnostic neurologic evaluation, he was referred for a muscle biopsy, to include histology/histochemistry, a myoglobinuria panel, and a caffeine halothane contracture test. Only the caffeine halothane contracture test was positive, and a subsequent ryanodine receptor type 1 gene evaluation revealed a mutation functionally causative for malignant hyperthermia. His identical twin brother, who was suffering from similar complaints, was found to share the same mutation. They each require oral dantrolene therapy to control symptoms, despite difficulty in identifying health care providers familiar with treating this disorder.

Methadone-induced mortality in the treatment of chronic pain: role of QT prolongation.

Methadone is increasingly prescribed for chronic pain, yet the associated mortality appears to be rising disproportionately relative to other opioid analgesics. We review the available evidence on methadone-associated mortality, and explore potential pharmacokinetic and pharmacodynamic explanations for its greater apparent lethality. While methadone shares properties of central nervous system and respiratory depression with other opioids, methadone is unique as a potent blocker of the delayed rectifier potassium ion channel (IKr). This results in QT-prolongation and torsade de pointes (TdP) in susceptible individuals. In some individuals with low serum protein binding of methadone, the extent of blockade is roughly comparable to that of sotalol, a potent QT-prolonging drug. Predicting an individual's propensity for methadone-induced TdP is difficult at present given the inherent limitations of the QT interval as a risk-stratifier combined with the multifactorial nature of the arrhythmia. Consensus recommendations have recently been published to mitigate the risk of TdP until further studies better define the arrhythmia risk factors for methadone. Studies are needed to provide insights into the clinical covariates most likely to result in methadone-associated arrhythmia and to assess the feasibility of current risk mitigation strategies.